The Total Synthesis of the Enantiomer of Lasalocid A Citation Fitzsimmons, Brian Joseph (1984) The Total Synthesis of the Enantiomer of Lasalocid A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/w5gn-5650. https://resolver.caltech.edu/CaltechTHESIS:12072018-114316546 Abstract A convergent total synthesis of the enantiomer of the naturally occurring polyether antibiotic Lasalocid A (X-537A) and preliminary results of the biological testing of this compound are reported. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Grubbs, Robert H. Thesis Committee: Grubbs, Robert H. (chair) Ireland, Robert E. Goddard, William A., III Anson, Fred C. Defense Date: 27 June 1983 Funders: Funding Agency Grant Number Natural Sciences and Engineering Research Council of Canada (NSERC) UNSPECIFIED Record Number: CaltechTHESIS:12072018-114316546 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:12072018-114316546 DOI: 10.7907/w5gn-5650 Related URLs: URL URL Type Description https://doi.org/10.1021/ja00345a055 DOI Arcticle adapted for Appendix. Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 11296 Collection: CaltechTHESIS Deposited By: INVALID USER Deposited On: 07 Dec 2018 20:42 Last Modified: 31 Oct 2025 22:20 Thesis Files Preview PDF - Final Version See Usage Policy. 66MB Repository Staff Only: item control page

TIIB TOTAL S!lttBBSIS OP TBB ERA!ft'IOIIBR OP LASALOCID A Thesis by Brian Joseph Fitzsimmons In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1984 (Submitted June 27, 1983) ii To my wife, Mary Ann and my daughter, Victoria iii ACKBOWLBDGBIIBftS I wish to thank Professor Robert E. Ireland for his support, patience and scientific guidance. I am very grateful to Gwen Anastasi for her skillful typing of this manuscript. I also wish to thank NSERC (Canada) and the California Institute of Technology for financial support. iv ABSTRACT A convergent total synthesis of the enantiomer of the naturally occurring polyether antibiotic Lasalocid A (X-537A) and preliminary results of the biological testing of this compound are reported. v !'ABLE OP COlftBlft'S Page Chapter 1. Background 1 Chapter 2. The Total Synthesis of Polyether Antibiotics. The Synthesis of the Enantiomer of Lasalocid A (X-537A) 19 Discussion 21 Experimental Section 39 References and Notes 86 The Total Synthesis of Polyether Antibiotics. The Synthesis of Lasalocid A (X-537A). 93 Discussion 94 Appendix. Experimental Section 100 1 Chapter 1. BACKGROORD 2 BACKGROORD An ionophore was defined, by Pressmanl, 2 in 1964, as a t~e molecule that aids transport of ions through a lipophilic interface through prior complexation. Although the ion transported is most often that of an alkali or alkali earth metal, cases of iron(III), proton and biogenic amines have also been reported. The ionophores are a very broad class of molecules that encompass a wide diversity of structural types and biological properties. A common feature of all ionophores is the presence of heteroatoms. These heteroatoms, usually oxygen or nitrogen, are arranged in su~h a manner to allow their 3-dimensional inward orientation in the proper geometry to complex the ion, and the outward orientation of the ionophore's lipophilic substituent&. This property allows the ions to appear greasy to the lipophilic interace, and thus their passage is at least partially facilitated through the membrane. Westley has divided the naturally occurring ionophores into four classes based on their structure3: 1) peptide ionophores, 2) cyclodepsipeptides, 3) macrotetrolides, and 4) polyether antibiotics. Examples of these classes are shown on the following pages. The peptide ionophores, such as the gramicidins, 4 consist entirely of a linear or cyclic arrangement of amino acids. The cyclodepsipeptides, of which valinomycin 5 is the b~st known example, are composed of alternating amino and 3 PBHIDB IOIIOPBORBS )uu H < H~ 1111 H Val-GRAMICIDIN A 2 0 HN~ II N PheiOO Pro3 1 Vol 0 Pro2 ~ ,_ 0 H ~ ,_ 0 Alo 4 NH ~ 0 HN Pheg 60711 Pro 6.AO N .y 0 p(JQJO 0 0 PhiHN ~ Phe6 H ANTAMANIDE 4 CYCLODBPSIP~XDBS VALINOMYCIN IIACROrBftOLIDBS NONACTIN 5 POLYftiiBR AftiBimiCS MONOVALENT -- MONENSIN I ~,,o 711!\. HO MONOVALENT MONOGLYCOSIDE -- LENORMYCIN H DIVALENT LASALOCID A c DIVALENT PYRROLE ETHERS -- CALCIMYCIN OH 6 hydroxy acid units. The macrotetrolides, such as nonactin, are meso compounds consisting of an alternating sequence of (+) and <-> tetrahydrofuranyl hydroxy acids. The polyether antibiotics are diverse groups of compounds whose common feature is the presence of a linear chain of tetrahydrofuran and tetrahydropyran ring systems. These systems include a carboxylic acid function at one end and a hydroxyl at the other. The first representatives of this class, Nigericin and Lasalocid A (X-537A), were isolated in 1951.7 However, due to their considerable complexity, structural elucidation of this class of ionophores has only been feasible in the last fifteen years. The x-ray determined structures of monensina and Lasalocid A9 were not published until 1967 and 1970, respectively. Although a relatively new class, it has been growing rapidly in both· numbers (now over 57) and applications, and has been subdivided into the following categories on the basis of structure and the type of ions transported: 1) monovalent polyethers (i.e. monensin,a, nigericinlO and salinomycinll); 2) monovalent monoglycoside polyethers (i.e. lenormycin 12 and antibiotic A-204Al3); 3) divalent polyethers (i.e., the lasalocidsl4 and lysocellinl 5 >, and 4) divalent pyrrole ethers (i.e., calcimycin (A23187)16). Of these monensinl7,18, lasalocidl9,20, and A23187, 21 salinomycin and narasin, have been prepared by total synthesis. 7 Pressman22 has proposed an alternate classification that is based on the ionophore's mode of ion transport: 1) neutral ionophores, such as valinomycinJ 2) carboxylic iono- · phores like monensin and lasalocid AJ and 3) channel forming quasi-ionophores such as alamethecin, which simply cause holes in the membrane and thus facilitate the diffusion of ions. Of all the classes of ionophores, the polyethers have shown the greatest promise of utility. The only commercial application of their biological activity has been the marketing of monensin in 1971 and Lasalocid A (X-537A) in 19763 as coccidiostats and feed utilization enhancers. The polyether antibiotics also show cardiotonic properties23,24 which make them very interesting from a pharmacological standpoint. The effect of the polyether antibiotics on heart action has been studied extensively by Pressman etal.22,2S Pressman first demonstrated that lasalocid A stimulates isolated rabbit heart and then that a single dose C2mg/kg) of lasalocid A administrated intravenously to an intact sedated dog causes: 1) a two to three fold increase in contractility, i.e. an •inotropic• effect; 2) a doubling of cardiac output, 3) a small rise in aortic pressure and heart rate; 4) a drop in peripheral resistance, and 5) a large decrease in coronary resistance leading to as much as a tenfold increase in blood flow through the coronary arteries 8 of the left ventricle2 5 • Since oxygen consumption remains virtually constant, except for a small transient initial rise, the latter two effects translate into a large increase · in the pumping efficiency of the heart. The stimulation of the pumping characteristics of the heart without dramatic changes in pressure or rate may be useful during pathological cardiovascular conditions, such as those that occur in acute pump failure or shock. The latter use was confirmed with dogs that had been sent into shock by incision and ligation of their intestines.25 Increasing the efficiency of the heart may prove valuable under conditions of limited oxygen supply, such as occurs in coronary vessel disease (often accompanied by angina) or in selected regions of the heart following an infarction. These effects are in sharp contrast to those of the catecholamines (i.e. epinephrine) which although they increase cardiac work also increase oxygen consumption, which is undesirable under conditions with accompanying ischemia. This difference is interesting since lasalocid A has been shown to transport catecholamines26, and its vaseodilatory effects are inhibited by B-blockers. This inhibition indicates the participation of catecholamines. 27 However, since the other physiological properties of lasalocid A are not affected, the mechanism of its action must be multi-pronged. 9 The initial driving force for the testing of lasalocid A was its ability to complex and transport ca2+ and biogenic amines. It was this ability that formed the basis of the initial explanation of lasalocid A's physiological effects. This has proven to be, at best, an oversimplification since ionophores that cannot transport ca2+ or catecholamines were shown to be more effective at bringing about many of the same effects as lasalocid A. ionophore Also, the ca2+ specific A23187's .in llll.2 effects could sporadically reproduced in anesthetized dogs. only be Since the monovalent ionophores (i.e., monensin, X-204) are more ion specific and their various effects can be differentiated on the basis of dosage, the prevailing opinion is that they are more suitable candidates for pharmacological development.28 Although the mode of action of the polyether antibiotics is not clearly understood, it is believed that the monovalent ionophores cause an influx of Na+ into the cells activating either a passive release of ca2+ from sequestered pools in the cell or the influx of extracellular ca2+ via an exchange diffusion carrier, the so called •saker pump• .29 ,3 0 An increase in intracellular Ca 2 + is also postulated as the mode of action of the cardiac glycosides (i.e., digitalis) which are believed to increase intracellular Na+ by blocking the cells K+-Na+ pump.3l Since ca2+ specific ionophores can mimic physiological ca2+ mediated cell activation by increasing the permeability of 10 the cell's membrane to extracellular ca2+, and lasalocid A is able to transport both Na+ and ca2+, its mode of action may be a combination of the above pathways. Monensin, a highly selective monovalent ionophore, has been shown to cause the release of catecholamines from adrenal cells in the absence of extracellular ca2+ .29 This result indicates that an ionophore need not be able to transport catecholamines in order to cause their release. Monensin is believed to cause this release by freeing intracellular ca 2 +, by increasing intracellular Na+, which in turn stimulates the release of catecholamines. Again, this mechanism is possible for lasalocid A as well as the more direct pathway of increasing membrane permeability to catecholamines. Lasalocid A's ability to transport ca2+ also lead to studies · ·on its effect on numerous other ca2+ dependent processes. In addition to stimulating the release of catecholamines3 2 and its cardiotonic properties, lasalocid A bas been found to modify insulin release,33 inhibit ca2+ uptake by brain mitochondria in cats and in mice,34 and stimulate the release of acetyl choline.3 5 Recent reviews30,36-37 of the physiological properties of the various polyether antibiotics are available. The biological importance of the polyether antibiotics bas also led to numerous studies into the mechanism of their complexation and decomplexation of ions and their 11 .relationship with cell membranes. The conformations of complexed and •free• ionophores have been studied utilizing their c.o., N.M.R., I.R. and fluorescence spectra both in · solutions of various polarity and with membranes of varying phospholipid composition.38 These studies model. have led to the following proposed At physiological PB (7.4), the carboxyl function of the ionophores exists in its deprotonated state and is complexed to the polar face of the membrane via the ammonium functionali ties present on the membrane face. When a complexable cation om+ comes close enough, complexation begins by the formation of a solvated ion pair. The ionophore now wraps around the cation displacing the molecules of the cation's primary solvation sphere with its internally facing liganding functionalities. The complex thus formed is capable of passively diffusing across the lipophilic interior of the membrane where at the inside interface it can release the cation by the reverse of the complexation procedure. The ionophore is now held on the inside of the membrane and can combine with a different cation In+ and by the above sequence of events transport it to the outside interface and release it. The net result is an exchange of om+ and In+ across the membrane with maintenance of electrical neutrality. Therefore, the polyether antibiotics act as passive exchange carriers, possibly similar to the previously mentioned •saker pump•. Since an 12 . ionophore does not com-p lex and transport all cations equally, the exchange may not be on a one-for-one basis. An example of this is monensin which transports Na+ in and a mixture of x+ and a+ out. The ability to transport protons is very important physiologically. This transport is possible since the protonated ionophore is neutral and favors a conformation similar to that obtained when complexing a cation. This has been demonstrated by the X-ray determined structures of the free acids of monensin 40 and a derivative of lasalocid A.41 The above mechanism assumes that the ionophores interact only with the phospholipids of the membrane and not with the membrane imbedded proteins, which compose up to 70% of the membrane. The observed tissue selectivity of the ionophores is, therefore, ascribed to differences in their phospholipid composition. It should be noted that the cation complexing selectivity of the ionophores in bulk solvents is substantially different than the cation transport selectivity observed with membranes. This is thought to be due to two factors, first that the ionophore interacts with the membrane in such a way as to modify its selectivity; second, in order to transport cations, the ionophore must complex and release the cations. Therefore, a fine balance of complexation strength must be obtained in order to transport cations. Too weak a complexation would lead to the cation never forming a tight enough complex to 13 enter the membrane, while too strong a complexation would diminish the ionophore's ability to release the translocated cation. In light of this, the nature of the ionophores interaction with the membrane both in its •free• form and as a complex assumes an important role in understanding the effects of these compounds. Lasalocid A, as stated previously, has too wide an activity spectrum to be useful as a therapeutic agent. However, this non-specificity may make it useful as a probe into the importance of its various transporting abilities. One of the most interesting properties of lasalocid A is its ability not only to transport biogenic amines but also to distinguish between the enantiomers of those with asymmetric centers. Lasalocid has been shown to preferentially complex the natural (R) enantiomer.42 Lasalocid is sufficiently effective at enantiodiscrimination to warrant its being patented as a resolving agent43 and its marketing as such by Aldrich. It should, therefore, be possible to dissect out the ·various ion transporting abilities of lasalocid A and elucidate the nature of its interaction with cell membranes by the synthesis of modified versions of this ionophore. To this end, it was felt that the synthesis of the enantiomer of lasalocid A (enantio-X537A) to study the enantiodependence of its various physiological effects would be a logical first step. 14 If lasalocid A transports cations by simpl¥ forming a lipophilic complex which then diffuses across the membrane, the transport of metal cation and the effects due to this transport should be unchanged with enantio-X537A. However, if the transport involves interaction with membrane proteins or phospholipids, both of which contain asymmetric centers, some alteration of transport and physiological properties should occur. While the transport of biogenic amines that lack an asymmetric center (i.e., dopamine) should behave similar to that of metal cations, the transport of those with asymmetric centers should be affected to a noticeable extent. Since lasalocid A complexes preferentially with the natural R enantiomer of these amines, enantio-X537A should not complex these amines as well. Therefore, the effects elicited by the transport of these amines should be accentuated or reduced. A synthesis of enantio-X537A was designed and sufficient quantities of enantio-X537A prepared to allow for ~n y~~~2 and ~n y~~2 testing of its properties. The synthesis and the preliminary results of the tests are presented in the next section. 15 RBPBRBIICBS POR BACKGROURD SBCTIOR 1) Moore, c. and Pressman, B. c. ~ ~~ 1964, 2) ~, Biochem. Biophys. 562-567. Pressman, B. c., Harris, E. J.J Jagger, w. s. and Proc. Natl. Acad. Sci •• II.SA 1967, ll, Johnson, J. H. 1949-1956. 3) Westley, J. w. 4) Dubos, R. J. and Hotchkiss, R. D. AdL.. Appl. Kicrobiol. 1977, l,l, 177-223. .L. ~ K~ 1941, 1J., 629-640. 5) Brockman, H. and Schmidt-Kastner, G. Chem. ~ 1955, n, 57-61. 6) Keller-Schielen, ~ 7) ·w. and Gerlach, H. Fort. ~liLa. Naturst 1968, ~, 161-189. Nigericin: Harned, R. L.J Bidy, P. H.J Corum, c. J. and Jones, K. L. 6ntibiot. Chemotherapy, 1951, 1, 594-596. Lasalocid A: Berger, J.J Rachlin, A. I.J Scott, w. E.J Sternbach, L. H. and Goldberg, M. w. .L. Am.a. ~m..a. ~ 1951, 1.l, 5295-5298. 8) Agtrap, A.J Chamberlin, J. W.J Pinkerton, M.J Steinrauf, L. ibid. 1967, 9) ii, 5737-5739. Westley, J. W.J Evans, R. 8.1 Pruess, D. L. and Stempel, A. ~ Chem. Soc,. Chem, 10) ~~ 1970, 1467-1468. Steinrauf, L. K., Pinkerton, M. and Chamberlin, J. w. Biochem, Biophys, ~ ~~ 1968, ll, 29-31. 16 ·11) Kinashi, B.; Otaka, N. and Yonehara, B. Tetrahedron Lett. 1973, Ji, 4955-4958. 12) Blount, J. P.J Evans, R. B.; Liu, C.-M.; Hermann, T. and west 1 e y, J. w. Ala. t.lutm.... soc. , t.lutL t.2mm.u.n.... 19 7 5 , 853-855. 13) Jones, N. D.; Chaney, M. 0.; Chamberlin, J. W.; Hamill, R. L. and Chen, s. .I.. Am.. Chem. ~ 1973, i5. 3399-3400. 14} Johnson, s. M.; Herrin, J.; Lui, s. J. and Pahl, I. c. ibid 1970, !l, 4428-4435. 15) Otake, N.; Koenura, M.; Konashi, B.; Sato, s. and Saito, Y. Ala. t.lutL Soc •• t.lutL t.2mmlm....1975, 92-93. 16} Chaney, M. 0.; Demarco, P. Y.; Jones, N. D. and Occolowitz, J. c. .I.. Am.. Chem. ~ 1974, H,, 1932-1933. 17) Pukuyama, T.; Akasako, K.; Karenewsky, D. J.; Wang, C.-L.; Schmid, G. and Kishi, Y. 18) ibid 1979, JJU, 259-263. Collum, D. B.; McDonald. J. B. III; Still, W. C. ibid 1980, ~' 2117-2121. 19) Nakata, T.; Schmid, G.; Vranesic, B.; Okigawa, M.; Smith Palmer, T. and Kishi, Y. jbjd. 1978·, ll.Q., 2933-2935. 20) Ireland, R. E.; Thaisrivongs, s. and Wilcox, c. s. ibid 1980, ~' 1155-1157. 21) Evans, D. A.; Sacks, c. E.; K1eschick, w. A. and Taber, T. R. jbjd. 1979, JJU, 6789-6791. 17 22) Pressman, B. C. ~ ~ Biochem....1976, 23) Pressman, B. C. ~ Proc. 24) deGuzman, N. T. and Pressman, B. C. J..S., 501-530. 1973, .3..2., 1698-1705. Circulation 1974, fi, 1072-1077. 25) Pressman, B. c. and deGuzman, N. T. 1975, lf!, 26) ~ L. L. Acad. ~ 373-386. Johnson, R. G. and Scarpa, A. FEBS Lett. 1974, fl, 117-121. 27) Swartz, A.; Lewis, R. M.; Hanley, B. G.; Munson, R. G.; Dial, F. D. and Ray, M. v. Circulation B.e..L. 1974, ll, 102-111. t.h.e.m.... Abstr. 197 8, .8..8., P65986n pg. 23 6. 2 8) Westley, J. W. 29) Pressman, B. c. and Fahim, M. ~ ~ Pharmacol. 1982, l.2,, 465-490. 30) Van Breeman, C.; Aaronson, P. and Loutzenhizer, R. Pharmacol. 31) ~ 1978, ~, 167-208. Langer , G. A. ; Serena , S. D. ~' J..... II.Q.l Ce 11. Car d i o 1. 19 7 0 , 65-76. 32) · Ricci, A., Jr.; Sanders, K. M.; Portmore, J. and Van der Kloot, 33) Bellman, B. w. G. ~ Sciences 1975, ~, 177-184. Biochemica ~ Biophysica Akt4 1975, lii, 157-169. 34) Fairhurst, A. S.; Julien, R. M. and Whittaker, M. L. ~ 35) Sciences 1975, l2, 1433-1444. Kita, B. and Van der Kloot, w. G. 658-660. Nature 1974, 2..5..0., 18 36) Fahim, M. and Pressman, B. c. ~ Sciences 1981, 11, 1959-1966. 37) Pressman, B. C.; Painter, G. and Fahim, M. In: Inorganic Chemistry in Biology And Medicine, A. E. Martell, ed., ACS Symposium Series No. 14, American Chemical Society, Washington, D.C. 1980, pp. 3-22. 38) Painter, G. R. and Pressman, B. c. In: Topics in Current Chemistry, F. Vogtle, ed., Springer-Verlag, New York, N.Y. 1982, pp. 83-110. 39) Reed, P. W. ~ In: Polyether Antibiotics; Carboxylic Ionophores, Westley, J. w., ed., Vol.~, M. Dekker, New York, N.Y., in press. 40) Lutzl w. K.; Winkler, P. K. and Dunitz, J.D. Bely. ~ AktA 1971, ~' 1103-1108. 41) Bissell, E. c. and Paul, I. c. iL.. ~L. Soc •• Chem • .c.Qmlll.Wla. 1972, 967-968. 42) Westley,J. W.; Evans, R. H., Jr.; Blount, J. F. iL.. AL. ~m.Soc. 1977, 4 3) West 1 e y, J. W. ~' 6057-6061. ~L. Ab s t r. 19 7 9 , .i.Q., P151 7 8 4 t, p. 57 4. 19 Chapter 2. !'JIB !'O!'AL SYlft'BBSIS OP POLYftBBR Alft'IBIOTICS. mB S!R'tiiBSIS OP 'l'IIB BRA!lriOIIBR OP LASALOCm A (%-537A) 20 ~e ~otal ~e Synthesis of Polyether Antibiotics. 1 Synthesis of the Jnantio.er of Lasalocid A (Z-537A). Robert E. Ireland,* Lawrence Courtney2a and Brian J. Fitzsimmons2b Contribution ~ faS1 fLQm ~ Chemical Laboratories. California Institute ~ Technology. Pasadena. California 91125 Abstract: A convergent total synthesis of the enantiomer of Lasalocid A (X-537A) and the preliminary results of the biological testing of this compound are reported. 21 In a previous report3 from these laboratories, tbe total synthesis of the antibiotic ionopbore lasalocid A was presented. Tbe basic design of tbis synthesis was predicated on a desire to define a synthetic strategy that could be applied to the construction of other polyether antibiotics, both natural and non-natural. An example of the use of this strategy for the construction of a synthetic lasalocid analog--enantio-X537A--is reported bere. Lasalocid A is among the least ion selective of the polyether ionophores, for it complexes and transports the cations of all alkali/alkaline earth lanthanides, thallium and organic amines. metals, the The ability of lasalocid A to transport ca2+ and biogenic amines led to numerous studies of its physiological effects.4 Among many other effects lasalocid A was shown to be a powerful cardiotonic agent. 5 These effects were initially attributed to the transport of ca2+ and biogenic .aminesJ however, later evidence proved that hypothesis to be, at best, overly simplistic. The contrary evidence arose from studies involving polyether antibiotics which were able to transport neither ca 2 + nor biogenic amines (i.e., monensin and antibiotic X-204>. 5 These compounds were found to elicit many of the aame effects as lasalocid A. The physiological effects of the polyetber antibiotics are now believed to be priaarily due to ca 2+ and biogenic amine release induced by diaruption of the Ra+/tt+ gradient across the cell 22 The polyether antibiotics are thought t~ bring ·membrane.6,7 about this translocation of cations by acting as passive exchange diffusion carriers.& The potential importance of the physiological properties of the polyether antibiotics has generated considerable interest in the synthesis of their non-natural analogs. 9 Such analogs may be designed to exhibit specific properties or to provide information concerning the mechanism by which these antibiotics act. An analog that would test the dependence of the physiological activity of the polyether antibiotics on their chirality would be the enantiomer of the natural product. If the transport of cations across a membrane by lasalocid A is affected only by the gross physical properties (p, viscosity,~) of that membrane, enantio-X537A should exhibit properties identical to those of the natural ionophore. Since lasalocid A preferentially complexes the natural R enantiomer of asymmetric biogenic amines,lO enantio-X537A should not complex these amines as well. Therefore, the activity of enantio-X537A should reflect this diminished capacity for natural amine complexation and allow a determination of the contribution the transport of these amines makes to the overall effect of lasalocid A. Therefore, a synthesis of the enantiomer of lasalocid A (enantio X:~ZA> was devised and sufficient material 23 prepared to allow for comprehensive testing of the associated physiological properties. The critical feature of the current synthetic scheme was the development of syntheses for the enantiomers of key subunits used in the earlier synthesis] of the natural ionophore. While it was expected that much of the previously developed synthetic strategy,3 could be utilized, efforts were made to improve and modify the technology involved so as to provide an even more efficient overall process. A structural feature common to the polyether antibiotics is the aldol-type linkage, and this assemblage can be used antithetically to divide enantio-XS37A into the aldehyde 2 and the ketone 3 (Scheae I>. Technology used in the synthesis o~ lasalocid A3 that re-established this aldol-type linkage-was then available for the condensation of •enantio left-aldehyde• 2 and •enantio right-half ketone• 3. The pivotal point of this synthesis of •enantio righthalf ketone• 3 is the use of ester enolate Claisen rearrangements for the formation of the C(l4)-C(l5) and C(l8) -c (19) bonds. This convergent building block approach allows the use of preformed tetrahydrofuranoid and tetrahydropyranoid intermediates derived from readily available monosaccharides. 24 SCBBIIB I -_ ~ ~ + z J SCBEIIB II 5 fu ~ + ·ro,c:H· I ' (a) NBu 4NF, TBF, r.t. I ~I r 25 The synthesis of the •left-half aldehyde• 2 was envisaged as proceeding through the addition of an appropriate asymmetric aide chain to a non-aromatic precursor, and then the conversion of this adduct into the desired tetrasubstituted aromatic moiety. Ideally, this method would allow for the preparation of further analogs by simple variation of the precursors utilized. The route used to prepare left-half aldehyde in the synthesis of the natural ionophore3 suffered from several shortcomings, the most serious of which was its length. The length of the previous route made it less flexible than desired and would make a relatively large throughput of material difficult. These problems made this first route unattractive for the current work, and a new, more flexible and efficient synthesis for the enantio-left half aldehyde 2 was developed. Synthesis .Q.f E.nantjo-Left Half l,. .The genesis of the approach used to prepare aldehyde 2 was a report by Grimme and Papies that the cycloadduct 4 upon treatment with tetra n-butylammonium fluoride (TBAF) gave the aromatic ester 5 by facile alkoxide accelerated cycloreversion at room · temperaturell (Sche•e II). In order to make direct usage of ; this reaction, the synthesis of the aldehyde 2 would require a 3-alkyl propiolate. However, Grimme also reported that the Diels-Alder cycloaddition of the diene 6 and methyl 3butynoate could not be realized.12 26 The preparation of the aldehyde 2 by such a str~tegy would therefore require: 1) a dienophile that would undergo the desired Diels-Alder condensation and allow for the subsequent attachment of the alkyl side chain; and 2) a 2-methyl-1-silyloxy-1,3-cyclohexadiene derivative as the diene. Benzyl 3-bromopropiolate 7 appeared to be a suitable candidate for the dienophile. The methyl ester has been reported as a good dienophile13 and the bromo functionality would provide the necessary means to attach the alkyl chain. The ester 7 was prepared from the known 3-bromopropiolic acid,14 and used in a cycloaddition with 1,3-cyclohexadiene. The model bicycloadduct 12 formed was used to test the viability of the subsequent addition of the alkyl side c h a in • The p r e s en c e o f an a b so r p t i on band f o r the a ,a unsaturated ester at Amax=248 nm in the ultraviolet spectrum of this adduct 12 indicated that conjugate addition to this molecule should be possible, and indeed it was found that the ' bromo substituent was readily replaced when the bicycloadduct 12 was treated with homoalkylcuprate or copper catalysed Grignard reagents (Scheme III). Although the preparation of the desired diene initially appeared to be a simple matter, this did not prove to be the case in practice. Treatment of 2 methylcyclohex-2-en-1-one under a variety of conditionsl5,16,17,18 led to the 3methyl-2-oxy-1,3-cyclohexadiene and/or intractable tars. 27 Scbe.e I I I 7 . iffo.a.. !J 35-54i • 11 14 · 15:R=CH.. (12~ . 16:R=CH 1 17 :R ~H~H.CH{CHa}cHCH 1 li:R =t)-C:HzCHzPY:HCH 1 (97~ 2 (9ft) (a) 1,3 cyclohexadiene, PhH, reflux; (b) Me 2 CuLi, ether, 0°C; (c) CH 2 =CHCB (CH 3 ) CH 2 CH 2 MgBr /CuBr-DMS, ether, r. t.; (d) LiAlH 4 , ether, r.t.; 1e) NaiOA, Me0H/B 2 0, r.t.; (f) KB/TBSC1, TBF, r.t.; (g) 6:IO • 1:1.~, r.t.; (h) (.S.) CB2 = CHCH CCB3) CB2CB2 MgBr /Cu COAc) 2, ether, 0°C; ( i) 160°C, sealed tube; Cj> nBu 4 NF, THF, r.t.; Ck) 0 8 0 4 /NMO, TBF /H 2 0, r .t. 28 ·Only minor amounts (<St) of the desired dienic product could be detected. After the failure of other more direct schemes, a less direct approach was utilized (Scheme III>. · Hydride reduction of the Diels-Alder adduct of transpiperylene and methyl 2-acetozypropenoate 8, and then sodium metaperiodate cleavage of the resulting diol 9 afforded 2methyl-cyclohex-3-en-1-one 1019 in good yield. Addition of a solution of this 6,y enone 9 to a suspension of potassium hydride in a TBP solution of ~-butylchlorodimethylsilane at room temperature provided the desired diene 11 in excellent yield.20· When a mixture of this diene 11 and the dienophile 7 (1:1.3) was allowed to stand at room temperature under an argon atmosphere for 12 h, a moderate yield21 of the desired l-silyloxy-bicyclo[2.2.2loctadiene 14 was obtained as the only Diels-Alder cycloadduct detected. The ultraviolet spectrum of this cycloadduct 14 exhibited a complete lack of an absorption band due to the a,e unsaturated ester (Amax 248 nm>. This is possibly due to the buttressing effects of the bromine and silyloxy substituents on the carboxylate forcing it out of the plane of the adjacent double bond. While this apparent lack of conjugation cast some doubt on the outcome of the subsequent coppe~ catalysed addition reaction, bromine displacement still proved to be quite facile, for treatment of the cycloadduct 14 with lithiodimethylcuprate afforded the adduct 15 in excellent yield. 29 The bicyclo[2.2.2loctadiene 15 provided both a means for ascertaining the regiochemistry of the cycloaddition by la-NMR spectroscopy. Irradiation of the bridgehead proton led to Nuclear Overhauser Enhancements CN.O.B.'s) of approximately 25t and lOt of the signals due to the lone olefinic proton and the protons of the C - 3 methyl substituent, benzylic respectively. protons No N.O.E. of the was detected for the ester in this experiment. The bicycloadduct 15 also provided a model compound for testing the cycloreversion reaction. Treatment of a solu- tion of 15 in TBF with TBAF led to the deep burgundy color described by Grimme: 1 but no trace of the desired aromatic compound could be detected. In an effort to study the alkoxide assisted cycloreversion directly, the silyl ether of the adduct 15 was cleaved selectively with lithium tetrafluoroborate in acetonitrile and the alkoxide from res~lting alcohol formed with potassium hydride. This alkoxide also failed to generate a phenol by cycloreversion even after a period of several days at room temperature, indeed, the only discernable reaction was a slow decomposition of the starting material. Although the reported accelerated cycle- reversion could not be realized in this system, pyrolysis the adduct 15 at 160° for 20 h did afford benzyl 3,6dimethyl-2-silyloxybenzoate 16 in quantitative yield. The alkyl chain of enantio left half aldehyde 2 was derived from S-bromo-3S.-methyl-l-pentene.3 Copper(I)- 30 · catalysed addition of the Grignard reagent derived from this bromopentene to the cycloadduct 14 again proceeded smoothly and gave the alkylated product 17 in excellent yield. When this adduct 17 was pyrolysed in a sealed tube at 160° for ~2h, an excellent yield of the desired tetrasubstituted aromatic system 18 resulted. The ester 18 had physical and spectral properties (Rf, elemental analysis, ls-NMR, IR) that were entirely consistent with those of the enantiomeric material derived from natural lasalocid A, except that the optical rotation was equal in magnitude but opposite in sign. Cleavage of the silyl ether of the ester 18 with TBAP, and then osmium tetroxide oxidation of the olefin 19, afforded the diol 20. Treatment of this diol 20 with sodium metaperiodate provided the desired enantio left half aldehyde 2, which exhibited physical and spectral properties CRf, elemental analysis, ls-NMR, IR) that were in excellent agreement with those obtained for the aldehyde derived from the natural ionophore.3 As expected, the optical rotation was equal in magnitude but opposite in sign. From commercially available starting materials, this new scheme provided a 31' yield of left half aldehyde in 10 · steps versus a 71 yield in 14 steps for the scheme used · previously.3 This new scheme is also more convergent and provides for the incorporation of the alkyl side chain only 5 steps from the end versus 11 steps for the previous 31 · scheme.3. The above synthetic scheme should not only allow preparation of analogs of the aldehyde 2, but also other substituted benzoates by variation of either the diene component for the Diels-Alder condensation or the Grignard reagent used to introduce the side chain. ~n~hAaiA ~ ~nan~ Bish~ BA~~ ~. In order to take advantage of as much of the synthetic methodology and strategy developed for the synthesis of lasalocid Al as possible, the carbohydrate derivatives 27 and 39 (Scbeae IV) which are enantiomeric to intermediates in the synthesis of lasalocid A3 were set as initial targets. The lactone 27 is an L-carbohydrate derivative, · and as such is not generally readily available. However, the lactone 27 is a 2-~-methyl­ L-pentose derivative and a suitable precursor, L-arabinose, is both available and inexpensive. The sugar 39 is 6-deoxyD-gulose and is a known compound.22 The synthesis of the lactone 27 was carried out as shown in Scbeae IV. The glycoside 22 was prepared by a modification of the procedure of Fletcher,23 and the remaining hydroxyl group was oxidized with oxalyl chloride/DMSO in dichloromethane.24 Due to the anomeric . effect, the resultant ketone 23 should exist predominantly in the chair conformation with the benzyloxy substituent axial. Examination of molecular models of this conformer indicate that sterically controlled nucleophilic attack should occur from the a-face. However, addition of methyl 32 Scbe.ae IV · .. Lw,a &c.-\y,a "" • "" •• • (a) BnOH/AcCl; 50°; (b) 2,2-Dimethoxymethane/H+, acetone; (c) Swern; (d) MeMgBr, ether; (e) low hal ide MeLi, ether, -78°; (f) a 3 +o; (g) Br 2 /caco 3 , a 2 o; Ch> acetone/a+; CB 2 Cl 2 ; (i) (CH 3 o> 2 CH 2 /P 2 o 5 , (jf DIBAL-H, ether; (k) (Me 2 N> 3P/CC1 4 , TBF; then Li/NH 3 ; (1) nBuLi (1.0 eq) 1 nPrCOCll DA, THF/BMPA; TMSCl1 -OH; CB 2 N 2 ; (m) H 2 /SO% Pt-e, ethyl acetate; Cn> LiA1H 4 , ether1 fo) KH/BnBr, THF; Cp> Swern; then Ag 2 0/0H, li 2 01 (q) NaB/TsCimid), THF; (r) KH/CH 3 0CH 2 C1, ~HF1 (s) Li/NH 3 , THF; Ct) oxalyl ch1or ide/DMF rca t), benzene; <u> n-BuLi C1.0 eq), THF; <v> LDA, THF1 TMSCl; OBI CH 2 N 2 ; (w) t 3 P=CH 2 , THF1 (x) Raney Ni, ethyl acetate; (y) MCPliA, ca 2 c1 2 ; (zl LiMe 2 cu, pentane; (aa) EtMgBr, THF. . 33 magnesium bromide to the ketone 23 occurred exclusively from the S-face and gave the alcohol 24. However, addition of methyl lithium at -78° gave a 1:8 mixture of the alcohols 24 and 25, respectively.2 5 Molecular mechanics calculations were employed 2 6 in order to understand better this interesting reversal of face selectivity between the methyl magnesium bromide and the methyl lithium addition. MM2 calculations indicated that the chair conformer with the benzyloxy substituent axial was only 0.8 kcal/mole lower in energy than the alternate chair conformer with the benzyloxy substituent equatorial. Therefore, the face selectivity of the methylli thium addition may simply reflect the distr ibution of these two chair conformers. Still27 has suggested that the face selectivity of the addition of methylmagnesium bromide may be the result of the formation of an intermediate in which the carbonyl and glycosidic oxygen of a ketone such as 23 are complexed by magnesium. This complexation is then followed by nucleophilic attack of the organometallic reagent from the face opposite the complexing alkoxyl functionality. This is similar to the mechanism for the addition of Grignard reagents to simple a-alkoxy ketones also proposed by Still.28 Hydrolysis of the adduct 25 with aqueous acid removed the benzyl glycoside and acetonide and afforded L-ribose 24 in good yield.29 2-~-methyl­ Oxidation of the free sugar 26 with excess aqueous bromine and calcium carbonate (1.1 eq) 34 and then treatment of the resultant calcium salt with sulfuric acid in acetone gave the desired lactone 27. Lactone 27 exhibited physical and spectral properties Cm.p., Rt, 1B-NMR, IR, [a]D) consistent with its being enantiomeric with the corresponding intermediate utilized in the synthesis of lasalocid A.3 As stated previously, 6-deoxy-n-gulose 39 is a known compound. However, a new, although conceptually similar, route to the sugar 39 was developed CScbeae IV) in order to improve the overall efficiency of the process. Addition of a solution of the diol 3630 in TBF to a mixture of sodium hydride and tosylimidazolide31 in TBF afforded the epo~ide 37. Treatment of this epoxide 37 with excess lithium tetrahydridoaluminate in ether led cleanly to the 6-deoxy sugar 38. Hydrolysis. of this 6-deoxy sugar 38 removed the benzyl glycoside and the acetonide and afforded 6-deoxy-ngulose 34 in good yield. The methodology developed for the synthesis of the natural isomer was applied to the completion of the synthesis of enantio right half 3 with one notable exception as shown in SchemeiV. The enolization of the glycal butanoate utilized in the ester enolate Claisen rearrangement that converted the glycal 30 into the ester 31 was performed at -100° rather than at -78°. This led to an increased yield (67' vs. 54') of the Claisen products 3la and 3lb and to a more favorable ratio of diasteriomers (6:1 35 vs. 3:1>. This reaction could be performed routinely on a 15 mmole scale. The enantio right half ketone 3 that resulted from the indicated operations (Scbeae IV) exhibited physical and spectral properties (Rf, elemental analysis, ls-NMR, IR) consistent with material derived from Lasalocid A, except that the optical rotation ((alD • +23.6° (c•l.705, CBC1 3 >; lit for enantiomer3, [a] D24 • -19.6° (c•l.02, CBC1 3 >> is equal in magnitude, but opposite in sign. Synthesis ~ Enantio X-537A =Sodium Salt ~ Since the conditions employed for the aldol condensation in the synthesis of lasalocid A3 gave what were believed to be less than optimum results, this reaction was reinvestigated. These new experiments confirmed the previous results and also led to an improved procedure for the aldol condensation (Scbeae V). Reaction of the aldehyde 2 (2:1) in zinc enolate of 3 with the benzene at 0° gave a 64t yield of isolated aldol products C98t based on recovered 3). Chromatographic separation of the diasteriomers gave the four products in a ratio of 61:20:11:7, of which the major component represents a 39t yield of the desired diasteriomer 58a. The benzyl ester 58a and its diasteriomers were separately converted to their corresponding sodium salts as described in the synthesis of lasalocid A.3 An interesting difference between the ls-NMR chemical shifts of the 36 Scbe.e V a:b:c:d • 61:20:11:1. 8 aromatic B's R= Diasteriomer Bn a b c d 6.67; 6.65; 6.65; 6.60; 7.18 7.14 7.15 7.17 a b c d 6.43; 6.67; 6.69; 6.63; 6.95 7.22 7.23 7.21 a b c 6.40; 6.43; 6.43; 6.42; 6.92 6.98 6.96 6.98 B Na d (a) LDA (2.05 eq), ~B, 0° C; (b) znc1 2 (1.1 eq), ether 1 (c) a 2/10% Pd-C, ethanol; (d) Na 2co 3 , CH 2Cl 2 • 37 aromatic protons of the desired diasteriomer and the other diaster iomers CScheae V> has become apparent. The ls-NMR signals due to aromatic protons of the desired diasteriomer 58a shifted upfield by approximately 0.2 ppm on hydrogenolysis of the benzyl ester, while the signals due to the same protons of the other diasteriomers did not. The shift of the ls-NMR signals of the aromatic protons of the desired diasteriomer on formation of the acid may be due to a head to tail cyclic conformation with a hydrogen bond between the carboxylic acid and the tertiary hydroxyl group33. The lack of this shift on the formation of the acids of the other diasteriomers indicated that the added steric interactions along the backbone in these acids prevents the formation of the cyclic conformation. diasteriomers should not Although the other complex cations as well as enantio-X537A, they do form complexes with Na+ as indicated by the upfield shift of the ls-NMR signals due to their aromatic protons on formation of their sodium salts. This synthesis of enantio-X537A by virtue of its efficiency and convergency has led to the preparation of more than 1 gram of the salt 1, and this fulfilled the objective of preparing sufficient quantities of salt 1 for physiological testing of its properties. Preliminary results of the biological testing32 of enantio-X537A indicate that both the cardiotonic and the antimicrobialactivity of enantio-X537A are very similar to 38 those of the natural ionophore. These data indicate that the aforementioned effects are probably due to a passive disruption of inter/intracelular ion gradients. These results are entirely consistent with the model of ionophore mediated ion transport proposed by Painter and Pressman.a A detailed account of the biological testing of enantio-X537A will be reported elsewhere. 39 BXPBRIIIB!ft'AL SBC'l'IOR3 4 4-Acetozy-4-carbometbozy-3-aetbylcyclobezene (8).19 A degassed mixture of 5.0733 g (74.48 mmol), of trans-1,3pentadiene, 4.6974 g (32.59 mmol) of methyl-2-acetoxypro- penoate35 and 0.4 g of pyrogallol in a sealed evacuated, thick walled Pyre~ ampule was heated to 160° c. After 20 h, the reaction mixture was cooled to room temperature1 the ampule was then opened and the excess 1,3 pentadiene was removed under reduced pressure. Flash chromatography of the residue on 500 g of silica gel with lOt ethyl acetate in petroleum ether and then evaporative distillation of the chromatographed material at 110° C (0.5 mmBg) gave 6.71 g (97%) of the adduct 8: evaporative distillation 150° C (8 mmBg>1 1 H NMR (CDC1 3 > o 0.89 and 1.03 C2 doublets, 3B total, J=S Hz diasteriotopic CH3's), 2.05 (s, 3B, ca 3 , CO), 3.72 (s, 3B, ca 3 o>, 5.60 Cm, 2B, CH=CB.). 4-Bydrozy-4-bydrozyaetbyl-3-aetbylcyclobezene (9).19 To a stirred suspension of 4.0 g (105 mmol) of lithium tetrahydr idoaluminate in 100 mL of dry ether at 0° C under argon was added a solution of 6.71 g (31.6 mmol) of the ester 8 in 25 mL of dry ether over a period of 15 min. After 1 h, the reaction mixture was cautiously treated with 4.0 mL of water, 4.0 mL of a 15% aqueous NaOB and then 12 mL of water. The resulting suspension was stirred vigorously for 15 min, dried (Mgso 4 > and filtered. Removal of the 40 solvent under reduced pressure and flash chromatography of the residue on 200 9 of silica gel with 75' ethyl acetate in petroleum ether gave 3.947 _g (96') of the desired diol 9: evaporative distillation 110° C (5 mm B9) 1 IR <neat) 3380, 3010, 2975, 2962, 2935, 1450, 1095, 1045, 690 cm-1, 1a NMR (CDC1 3 > c5 0.93 and 1.05 (2 doublets, 3B-total, J•7 .5 Hz, diaster iotopic CB. 3 's), 3.43 (bs, 2B, CB. 20>, 6.63 (m, 2B, CB.=Cii). 2-aethylcyclobez-3-en-1-one (10).19 To a stirred solution of 3.947 g (30.32 mmol) of the diol 9 in 40 mL of methanol was slowly added a solution of 12 9 (56.1 mmol) of sodium metaperiodate in 40 mL of water. The resulting mixture was stirred at room temperature for 1 h then extracted with three 150mL portions of ether • The combined organic extracts were dried (Mgso 4 > and the solvent was removed under reduced pressure. Flash chromatography of the residue on 150 9 of silica gel with 10\ ether in petroleum ether and then evaporative distillation of the chromategraphed material at 100° C (25 mmHg) gave 2.469 gm (74') the desired enone 10: of evaporative distillation 100° C (20 mmBg); ls NMR (CDC1 3 ) c5 1.16 (d, 3B, J=7 .5 Bz, CB. 3 >, 2.47 (bs, 4H, =CCB. 2 CB. 2CO), 2.88 (m, lB, CllCB 3 >, 5.678 (ABX, 2B, Cll=CB.). 1-~-Butyldi.etby1silylozy-2-.etbyl-1,3-cyclobezadiene (11). To a stirred suspension of 1.74 g (43.5 mmol) of potassium hydride in a solution of 6.502 g (43.1 mmol) of 41 ~-butylchlorodimethylsilane in 25 mL of TBP under argon was added a solution of 1.582 g (14.36 mmol) of the enone 10 . in 25 mL dry TBP at a rate such that the temperature of the reaction mixture was maintained at less than 35° c. The resulting mixture was stirred at room temperature for 5 min, then diluted to 400 mL with ether and tne excess potassium hydride destroyed by the careful addition of 2 mL of water. The organic phase was washed with three 250 mL portions of water, dried (Mgso 4> and the solvent removed under reduced pressure. Plash chromatography of the residue on 100 g of silica gel with petroleum ether and then evaporative distillation of the chromatographed material at 100° C CO.S mmBg) gave 2.888 g (90%) of the desired diene 11: evaporative distillation 100°C (0.5 mmBg); la NMR (CDC1 3 ) 5 0.14 (s, 6B, <Cli 3 >2 si>, 0.95 (s, 9B, <Cli 3 >3 c> 1 1.63 Cbs, 3B, CB. 3 C=> 1 2.20 Cbs, 48, cu. 2ca 2 >1 5.01 (m, lB, =CB.C8 2 >1 5. 70 (d, l81 J=6 Hz, Cli=CH-CH 2 >. Benzyl 3-broaopropiolate (7). To a solution of 4.377 g (29.4 mmol) of 3-bromopropiolic acid in 20 mL of benzene was added 7 mL of benzyl alcohol and 20 mg of p-toluenesulfonic acid monohydrate. The flask was then fitted with a Dean- Stark trap and a condensor and the resulting mixture was heated under reflux. After 21 h, the reaction mixture was cooled to room temperature and diluted with 50 mL of ether. The organic phase was then washed with two 50 mL portions of saturated aqueous NaBC0 3 , dried (Mgso 4> and the solvent was 42 removed under reduced pressure. Chromatography of the residue on 400 g of silica gel with 5t ether in petroleum ether and then evaporative distillation of the chromategraphed material at 70° C (0.001 mmHg) gave of the desired ester 7: 5.145 g (73\) evaporative distillation 70° C CO.OQ1 mmHg); IR (neat) 3025, 2200, 1705, 1215, 1000, 740, 695 cm-1; 1a NMR (CDC1 3 > 0 5.17 Cs, 2H, Arca 2 o>, 7.38 Cs, 5H, AL>; Anal. Calcd. for c 10 a7 o2 Br: C 50.24; B 2.95; Br 33.42. Pound: C 50.15; B, 3.01; Br 33.51. 3-Broao-2-carbobenzylozybicyclo(2.2.2loctadiene(l2). A solution of 0.84 mL (0.84 mmol) of 1,3 cyclohexadiene and 0.85 g (0.42 mmol) of t;>enzyl 3-bromopropiolate 7 in 10 mL of dry benzene was heated to reflux under argon. After 5 days, the resulting solution was cooled to room temperature and the solvent w~s removed under reduced pressure. Column chromatography of the residue on 79 g of silica gel with 4% ethyl acetate in petroleum ether gave 913 mg (80%) of the desired adduct 12 as a white solid: evaporative distillation 70° C (0.005 mmBg) 1 IR (CBC1 3 ) 2950, 1700, 1590, 1265, 1245, 1220, 1070 cm- 1 ; UV cc 6 a 12 > max. 215 nm (19,500, Ar), Amax 248 nm ( E "'12,300, a,B unsaturated ester>; 1 s NMR (CDC1 > o 1.15-1.70 (m, 4H, ca ca >, 3.86 (m, lH, 3 2 2 CllCBr=), 4.30 (m, lB, CBC(C0 2 Bn) •), 5.20 (s, 2B, ArCll 2 0>_, 6.27 Cm, 2B, Cll=CH>, 7.35 Cbs, 5B, Arll>. C16B1502Br: C 60.21; B 4.74; Br 25.03. 4.64; Br 24.97. Anal. Calcd. for Pound: C 60.04; B 43 2-Carbobenzylozy-3-aethylbicyc1o[2.2.2Joctadiene (13a). To a stirred suspension of 24 mg (0.59 mmol) of cuprous bromide-dimethyl sulfide complex in 5 mL of dry ether at 0° C under argon was slowly added 0.29mL CO.S8mmol) of 2.0M methyllithium in ether. After 15 min, a solution of 119 mg (0.373 mmol) of the B-bromo ester 12 (0.373 mmol) in 5 mL of ether was added. and the resulting dark red solution was stirred at 0° C. After 25 min, the reaction mixture was quenched by the addition of 1 mL of water and then diluted to SO mL with ether. The organic phase was washed succes- sively with two 50 mL portions of saturated aqueous NH 4 C1 and one SO mL portion of brine, drie~ (Mgso 4 > and then the solvent was removed under reduced pressure. Column chromatography of the residue on 10 g of silica gel with S% ethyl acetate in petroleum ether gave 72.1 mg (76%) of the alkylated adduct 13a: evaporative distillation 60° C (O.OOS mmHg)1 IR (CHC1 3 > 2970, 1695, 1390, 1355, 1270, 1260, 107S cm- 1 1 1 a NMR CCDC1 3 > 6 1.33 Cbs1 4B, Cll 2 ca 2 >1 2.23 (s, 3HI ca 3 >1 3.4S Cm, lB, CBC(Me)=), 4.2 <m1 lB, CBCCC0 2 Bn>=>, 5.17 (s, 2B, ArCI1 2 0>, 6.30 (m, 2B, Cll=CJi), 7.37 (bs, SB, Arli); Anal. Calcd. for C17B1802: C 80.247 B 7.13. Found: C 80.12; B 7.01. 2-carbobenzy1ozy-3-(3-.ethy1-4-penteny1)bicyc1o[2.2.2J-octadiene (13b). To a stirred solution of 240 mg (0.746 mmol) of the a-bromo ester 12 in 8 mL of dry ether under argon was added a deep purple solution of the Grignard 44 ·reagent derived from 5-bromo-3-methyl-l-pentene 3 (1.2 mmol) and 24 mg (0.12 mmol) of cuprous bromide-dimethylsulfide complex (0.12 mmol) in 10 mL of ether. The resulting suspension was stirred at room temperature. After 1 h, the reaction mixture was quenched with 1 mL of water and then diluted to 50 mL with ether. The organic phase was washed successively with two 50 mL portions of saturated aqueous N8 4Cl and one 50 mL portion of brine, dried (Mgso 4> and then the solvent was removed under reduced pressure. Column chromatography of the residue on 10 g of silica gel with 5% ethyl acetate in petroleum ether afforded 99 mg (41%) of the desired adduct 13b and 98 mg (41%) of the starting material 12: For 13b: evaporative distillation 75° C (0.005 mmHg); IR CCHCl3) 2980, 1695, 1645, 1605, 1460, 1390, 1360, 1270, 1260 cm-1; la NMR CCDC1 3 > o 0.93 (d, 3H, J=6 Hz, ca 3 >, 1.32 Cbs, 48, ca 2 ca 2 >, 1.43 (m, 28, ca 2 ca 2 C8), 2.02-2.96 (m, 38, CB. 2CB.), 3.50 (m, 18, CB.C(R)=), 4.17 (m, 18, CBC(C0 2 Bn)=), 4.85 (m, 28, =CB. 2 >, 5.16 (s, 28, Arca 2 o>, 5.62 (m, 18, CHCB.=), 6.26 (m, 2H, CB.=Cll), 7.38 {bs, SH, Arli); Anal. Calcd. for C22B2602: C 81.95; H 8.13. Found: C 81.86; H 8.07. 3-Bro.a-l-~-butyldi.etbylsilylozy-2-carbobenzylozy- 6-metbyl-bicyclo[2.2.2loctadiene (14). To a stirred mixture of 310 mg of the diene 11 (1.38 mmol) and SO mg pyrogallol under argon was added 0.36 mL {506 mg, 2.12 mmol) of benzyl 3-bromopropiolate 7. The resulting mixture was stirred at 45 · room temperature for 12 h. Column chromatography of the reaction mixture on 80 gm of silica gel with 2t ether in petroleum ether provided 343 mg C54t) of the cycloadduct 14: IR CCHC1 3 > 2960, 1740, 1260, 1170, 950, 950, 840 cm-1; U.V. CC6H12> >..max 212 nm Ce-10,500, Ar) 1 1 H-NMR ~ 0.20 Cs, 3H, Cll3 Si), 0.23 Cs, 3H, Cll 3 Si), 0.92 Cs, 9H, (CH 3 ) 3 c>, 1. 7 8 (d, 3H, J•1.5 Hz, CB 3 C=), 3.46 Cdm, lH, J•7.2 Hz, CBCH=), 5.15 Cs, 2H, Arca 2 o>, 5.83 Cdm, lH, Ja7.2 Hz, CBa), 7.30 Cm, SB, Arll). Anal. Calcd. for C23H3103BrSi: 1 7. 2 4. Found : C 59.60; H 6.74; Br C 5 9. 7 5 ; H 6 • 7 0 ; Br 1 7 .15. The y i e 1 d of the above Diels-Alder cycloaddition varied from 35 to 54%. 1-~-Butyldi.ethylsilylozy-2-carbobenzylozy-3,6- dimethyl-bicyclol2.2.2loctadiene (15). By the procedure described for the preparation of the adduct 13a, 30 mg (0.065 mmol) of the 6-bromoester 14 in 2 mL of dry ether, 80 mg (0.39 mmol) of cuprous bromide-dimethyl sulfide complex, 0.19 mL (0.38 mmol) of 2.0 M methyllithium in ether afforded, after chromatography of the residue on 5 g of silica gel with 2% ether in petroleum ether, 21.1 mg (82%) of the dimethyl adduct 15: evaporative distillation 130° C (0.001 mm); IR (CBC1 3 > 2975, 2960, 2925, 1712, 1458, 1260, 1065, 1055, 835 cm-1; lH NMR (CDC1 3 ) ~ 0.17 (s, 3B, Cll3 Si), 0.20 (s, 3H, CB 3 Si), 0.95 Cs, 9B, CCH 3 >3 si), 1. 73 (s, 3B, Cll3C=C(C0 2 Bn)), 1.77 (d, 3H, Jal.S Hz, CB 3 C=CH), 3.08 (dm, lB, J•6.6 Hz, CBCH=), 5.14 Cbs, 2H, ArCB 2 0>, 5.77 (dm, lH, 46 J•6.6 Bz, CBCH•>, 7.30 Cbs, 58, ArK); Anal. Calcd. for C24H3403Si: C 72.32; B 8.60. Found: C 72.45; B 6.70; Br 17.15. l-~-Butyldi.ethylsilylozy-2-carbobenzylozy-6-.ethyl3~(3UV-aethyl-4-pentenyl)bicyclo[2.2.2Joctadiene (17). To 165 mg (0.81 mmol) of cupric acetate monohydrate in a stirred solution of 1.501 gm (3.24 mmol) of the B- bromoester 14 in 125 mL of dry ether at -35°C under argon was added dropwise 12.95 mL of a O.SM solution of 3(S)methyl-5-pentenyl magnesium bromide in ether. mixture was stirred at -35° The resulting to -25° C for 30 min, allowed to warm to room temperature for 30 min and then the reaction was quenched by the careful addition of 10 mL of saturated aqueous NH 4Cl. The organic phase was diluted to 250 mL with ether and washed with three 100 mL portions of saturated aqueous NH 4Cl, dried (Mgso 4 > and then the solvent was removed under reduced pressure. Flash chromatography of the residue on 200 g of silica gel with 2% ether in petroleum ether afforded 2.274 gm (90%) of the alkylated adduct 17. On a 50 mg scale the yield was 98%. IR (CBC1 3 > 2970, 17 40, 1645, 1610, 1465, 1260 cm-1; la NMR {CDC1 3 ) o 0.18 {s, 3B, CH 3 Si), 0.21 (s, 38, ca3 si), 0.84 {d, 3H, J•6.2 Hz, CH 3 CB), 0.90 {s, 9B, {CB 3 ) 3 c>, 1. 7 5 (d, 38, J•l.5 Hz, CH 3 C•), 1.22.3 {m, 98, 2Ca 2ca 2 and CHCB 3 >, 3.13 (dm, 18, J=6.3 Hz, =CCHC=), 4.8 Cm, 2B, CB=Cil 2 >, 5.07 (s, 2H, ArCil 20>, 5.47 (m, 47 lB, CB=CB 2 >, 5.74 (dd, lB, J•6.2 Bz, J 1 •1.5 Bz, CB•C(CB 3 >>, 7.27 (bs, 5B, ArB). Benzyl 2-tert-batyldiaetbylailylozy-3-aethyl-6-(3(a)- •ethyl-4-pentenyl)benzoate (18). In an evacuated sealed, thick ·walled PyreliJ ampule 2.624 g (5.622 mmol) of the degassed bicyclo[2.2.2loctadiene 17 was heated in a 160°C oil bath for 12 h, then allowed to cool to room temperature. Column chromatography of the residue on 200 g of silica gel with 2% ether in petroleum ether afforded 2.3816 gm (97%) of the desired tetrasubstituted aromatic 18: distillation 120° C (0.01 mmBg) 1 1=0.1 dm). evaporative [a l 0 23 -2.34° (neat, IR (CBC1 3 > 2965, 2940, 2870, 1720, 1482, 1418, 1275, 1138, 845 cm-1; la NMR (CDC1 3 ) 0.15 (s, (CB 3 >2 si>, 0.87 (d, 3B, J•6.9 Hz), 0.98 (s, 9B, 6B, (CB 3 >3 c>, 1.42 (m, 2H, Ar CBCB 2 >, 1.97 (m, lH, CB(CB 3 >C•), 2.17 (s, 38, ArCR3 >, 2.45 (m, 2B, ArCB 2 CH 2 >, 4.83 (m, 2B, CB=CB 2 >, 5.24 (s, 2H, Arca 2 o>, 5.57 (m, lB, CB=CH 2 >, 6.67 (d, lB, J = 8 .1 Hz , ArB> , 7 • 0 5 ( d , 1 B, J = 8 .1 Hz , ArB> , 7 • 3 5 ( m, 5 H, Arll). Anal. Calcd. for C27B3903Si: Found: C 74.06; H 8.57. C 73.95; B 8.73. Benzyl 2-hydrozy-3-aethyl-6-(3<a>aethyl-4-pentenyl)benzoate (19). To a stirred solution of 2.348 gm (5.35 mmol) of the silyl ether 18 in 25 mL THF under argon was added 2.5 gm (9.7 mmol) of tetra n-butylammonium fluoride and the resulting mixture was stirred at room temperature. The reaction mixture was diluted with 150 mL 48 of ether and the resultant organic phase was washed with two 100 mL portions of saturated aqueous NaNC0 3 , dried CMgso 4 > and the solvent was removed under reduced pressure. Plash chromatography of the residue on 120 g of silica gel with 5% ether in petroleum ether afforded 1.725 gm (99t) of the desired phenol 19: evaporative distillation 110° C (0.01 mmHg); IR (CHC1 3 > 3230, 2970, 1715, 1488, 1425, 1140 cm-1; ls NMR (CDC1 3 ) 6 0.84 Cd, 38, J=6.6 Hz, CB 3 CH), 1.41 Cm, 2H, 1.89 Cm, lH, CB(CH 3 >C•), 2.19 (s, 3H, ArCB 3 >, 2.75 (m, 2H, ArCH 2 CH 2 >, 4.83 (m, 2H, CH=CH 2 >, 5.33 (s, 2H, ArCH 2 CH 2 ~H), Arca 2o>, 5.53 (m, lH, CH=CB 2 >, 6.52 (d, lH, J•8.4 Hz, ArB), 7 • 0 0 ( d , 1 H , J • 8. 4 B z , A r H) , 7 • 3 4 ( b s , 5 H , A r ll) • Benzyl 2-hydroxy-3-aethyl-6-(4,5 dihydroxy-3<a>aethylpentyl)benzoate (20). To a stirred solution of 1.725 gm (5.32 mmol) of the olefin 19 in 1.4 mL TBP under. argon was consecutively added 920 mg (6.81 mmol) of 4-methyl morpholine 4-oxide, 2.5 mL water and 0.2 mL of 0.1 M osmium tetroxide in tert-butanol and the resulting mixture was sti~red at room temperature overnight. The reaction mixture was then quenched by stirring with 50 mL of 15% aqueous Na 2 s 2 o 4 for 30 min and diluted with 50 mL of water. The resulting mixture was extracted with three 100 mL portions of dichloromethane, the combined organic extracts were then dried (Mgso 4 > and the solvent was removed under reduced pressure. Flash chromatography of the residue on 120 g of silica gel with ethyl acetate afforded 1.857 gm 49 (98%) of the diasteriomeric diols 20 as a white solid: evaporative distillation 165-180° C (0.001 mmBg); IR(CHC1 3 > 3610, 1670, 1430, 1260, 1160 cm-1; la NMR (CDC1 3 > 6 0.78 (bd, 3H, J•6 Bz, CBCB 3 >, 2.20 (s, 3B, ArCH 3 >, 5.38 (s, 2H, C0 2 CB. 2 Ph), J•7. 5 Hz I 6.60 (d, ArB)' lB, J•7.5 Bz, ArB), 7.42 (bs I sa, C02CH2R.h) I ArOB). Anal. Calcd. for C21B2605: Found: C1 C1 7.17 (d, lH, 11.38 (bs' lH, 70.37; H1 7.31. 70.51; B, 7.30. Benzyl 2-bydrozy-3-aethyl-6-(l(a)-foraylbutyl)benzoate (2). To a stirred solution of 430.7 mg (1.20 mmol) of the above diols 18 in 18 mL of methanol was added 342 mg (1.60 mmol) of sodium metaperiodate in 7.0 mL of water. The reaction was stirred for 30 min at room temperature and then diluted with 50 mL of water and extracted with four 50 mL portions of dichlorometbane. combined and dried (Mgso 4 >. The organic extracts were Removal of the solvent under reduced pressure and flash chromatography of the residue on 30 g of silica gel with 5% ethyl acetate in petroleum ether gave 368.0 mg aldehyde 2: (94%) of the desired "enantio left-half" evaporative distillation 140° C (0.01 mmBg); [a] 0 23 +16.26° (k,l.l75 1 CHC1 3 ) 1 IR (CHC1 3 > 2990 1 2970 1 29351 2260(d)l 17151 16601 16201 14651 14201 13901 13001 1250, 1150 cm-1; 1a NMR (CDC1 3 ) o 0.92 (d, 3H, J=7 Hz, CH 3 >, 2.20 (s, 3B, ArCH 3 >, 2.81 (bt, 2H, J=7 Hz, ArCH 2 C>, 5.36 (s, 3H, C0 2 CH 2 >, 6.56, 7.14 (2d, 2H, J=7.5 Hz, 2 ArB), 9.37 (d, lH, J=l.5 Hz, CHO), 11.43 (s, lH, 08). 50 Anal. Calcd. for C20B2204: Pound: C, 73.60; B, 6. 79. c, 73.62; B, 6.78. Benzy1-6-~-arabinopryanoside (21).2 3 To a mixture 250 mL of benzyl alcohol and 10 mL of acetyl chloride at 0° C under argon was added 50 g (0.333 mol) of L-arabinose and the resulting mixture warmed to S0°C. After 24 h the reaction miY.ture was cooled to room temperature and poured slowly into 500 mL of ether with stirring. The product was allowed to crystallize at room temperature for 4 h, then the mixture was cooled to 0° C overnight, crystallization. to complete the Collection of the product by filtration gave 65.4 g (82') of the glycoside 21. Benzyl (22).23 3,4~(1-aethyleth1idene>-B-~-arabinopyranoside To a stirred suspension of 65.4 g (0.272 mol) of the glycoside (21) in 1.25 L of dry acetone was added 15 mg p-toluenesulfonic acid (0.08 mmol) and 62.5 mL (0.510 mol) of 2,2-dimethoxypropane and the resulting mixture was stirred at room temperature. After 36 h, the reaction mixture was neutralized with aqueous NH 40H and under reduced pressure. concentrated The residue was dissolved in 750 mL of dichloromethane and the resulting solution was washed with saturated aqueous NaBC0 3 (2x250 mL) dried (Mgso 4 > and the solvent was removed under reduced pressure. Evaporative distillation of the residue at 135° C (0.1 mmBg) gave 76.2 g (99.8') of the alcohol 22 as a clear syrup which slowly crystallized. 51 Benzyl 3,4~(1-aetbyletbylidene)-S-M-erythro-pent-2- alosyl-pyranoside (23). To a stirred solution of 13.5 mL (0.155 mol) of oxalyl chloride in 400 mL of dichloromethane · at -60°C under argon was added 27.1 mL {0.382 mol) of dimethylsulfoxide. After 30 min, a solution of 33.1 g {0.118 mol) of the alcohol 22 in 100 mL of dichloromethane was added to the reaction mixture. After 2 h, the reaction mixture mixture was treated with 81.0 mL {0.581 mol) of dry triethylamine, allowed to warm to room temperature and then 134 mL of water was added. After 15 min, the resulting mixture was poured into 650 mL saturated aqueous Naaco 3 , the organic phase was separated, and the aqueous phase was extracted with 300 mL of dichloromethane. The combined organic phases were dried CMgso 4 > and the solvent was removed under reduced pressure. Flash chromatography of the residue on a 10x26 em column of silica gel with 20% ethyl acetate in petroleum ether and then evaporative distillation of the chromatographed material at 100° C (0.05 mmHg) afforded 30.6 gm (93%) of the ketone 23: evaporative distillation 100° C {0.005 mmHg) 1 [a 1 0 25 +191.2 (k0.94, CHC1 3 > 1 IR CCHC1 3 ) 2980, 1755, 1260, 1080 cm-11 la NMR (CDC1 3 > 5 1.32 Cs, 3H, CH 3 >, 1.43 (s, 3B, CH 3 ), 3.9-4.5 Cm, 4B, B-3, -4, -5's), 4.72 (d, 2H, J•7.5 Hz, Ph-CH 2 >, 4.87 Cs, lB, B-1), 7.4 (s, lB, Ph). 64.731 B, 6.52. Found: Anal. Calcd. for c, 64.681 B, 6.59. c 15 a 18 o 5 : c, 52 Benzyl-3,4~(1-.ethylethylidene)2~-.ethyl-B-~ arabinopyranoside (24). A solution of 5.100 9 (18.46 mmol) of the ketone 23 in 90 mL of dry ether was added slowly to a · stirred solution of methyl magnesium iodide (110.76 mmol) in 210 mL of dry ether at 0° under argon, and the resulting solution was allowed to warm to room temperature. After 1 h the reaction was quenched by the careful addition of 200 mL saturated aqueous NH 4 Cl, the ether phase was separated, dried (Mgso 4 > and the solvent was removed under reduced pressure. Column chromatography of the residue on 200 g of silica gel with 20t ethyl acetate in petroleum ether gave 4.190 gm (83t) of the adduct 24 : evaporative distillation 100°C (0.005 mmBg) 1 [a] 0 25 +129.1 (k,l.2, CBC1 3 >; IR (CBC1 3 > 3350, 2960, 1610, 1270, 1060 cm-lJ la NMR CCDC1 3 ) 6 1.26 Cs, 6B, 2CH3), 1.41 (s, 3B, CB3), 3.1 (bs, lB, OH), 3.3-4.3 (m, 48, B-3, 4, S's), 4.55 (s, lB, B-1), 4.69 (AB, 2B, PhCB 2 >, 7.3 cs, sa, Ph>. Anal. Calcd. for c 16 a 20 o 5 : c, 65.29; B, 7.53. Found: C, 65.23; H, 7.37. Benzyl-3,4~Cl-.ethylethylidene)2~-methyl-S-~-ribo and arabinopyranosides (25) and (24). To a stirred solution of 12.806 g (46.0 mmol) of the ketone 23 in 300 mL of dry ether at -78°C under argon was added 23.4 mL (46.0 mmol) of 1.97 M methyllithium in ether was stirred at -78° c. and the resulting solution After 30 min, 5.4 mL (9.4 mmol ethanol) of lOt ethanol in ether was added. After 15 min, 9.4 mL (18.4 mmol) of 1.97 M methyllithium was added, and 53 the resulting mixture was allowed to warm to room temperature. After 1 hr, the reaction mixture was quenched by the careful addition of 100 mL of saturated aqueous NB 4Cl. · The organic phase was separated, dried CMgS0 4 >, and the solvent was removed under reduced pressure. Medium pressure liquid chromatography of the residue on a Lobar C column with 10% ethyl acetate in petroleum ether afforded 10.472 g (80%) of the adduct 25 and 1.131 g (9%) of the adduct 24: evaporative distillation l00°C (0.005 mmBg); [aJ 0 23 +186.5° (k,1.0, CBCl3); IR (CBC13) b 3350, 2980, 160 5, 12 80, 1070 cm- 1 ; 1 H NMR (CDC1 3 > o 1.23 (s, 38, CH 3 ), 1.37 (s, 38, CH 3 >, 1.59 (s, 3H, CB 3 >, 2.55 (s, 18, OB.), 4.0 (d, 2B, For 25: J•3.0 Hz, B-S's), 4.1 (d, lB, J•l1.5 Hz, H-3), 4.2 (dt, lB, J 1 •3.0 Hz, J 2 all.S Bz, B-4), 4.62 (s, 1H, H-1), 4.63 (AB, 28, Ph-CB.2 >, 7.32 (m, 58, Ph). Anal. Calcd. for C16H2005: c, 65.29; H, 7.53. Pound: 2-~-Kethyl-L-ribose C, 65.49; H, 7.71. (26). To a stirred solution of 39.0 g (133.4 mmol) of the glycoside 25 in 50 mL of methanol was added 1 L of 4% aqueous a2so 4 over a period of 1 h and the resulting mixture was heated under reflux at atmospheric pressure. After 22 h, the reaction mixture was neutralized with concentrated aqueous NH 40B and the solvent was removed under reduced pressure. The residue was taken up in 1 L of methanol, filtered and then the solvent was removed under reduced pressure. Flash chromatography of the 54 residue on 800 g of silica with 30% methanol in dichloromethane afforded 17.05 9 (78') of the free sugar 26. 2,3~(1-.ethylethylidene)-2~-~thyl-L-ribono-1,4- lactone (27). To a stirred solution of 6.388 g (38.91 mmol) of the 1acto1 26 in 220 mL of deionized water was added 3.45 mL (66.92 mmol) of bromine and 4.47 g (44.66 mmol) of calcium carbonate, and the resulting mixture was stirred at room temperature. After 30 min the excess bromine was removed by aeration and the water was removed under reduced pressure. The residue was dried under vacuum (0.005 mmHg) for 12 h, slurried in 300 mL of dry acetone with 10 g anhydrous Na 2so 4 , sufficient concentrated sulfuric acid was then added to adjust the pH to approximately 0.5 (moist test strip). The resulting mixture was stirred at room temper- ature for lh, neutralized with concentrated aqueous NB 4oa, filtered washing with two 100 mL portions of dichloromethane, and then the solvent was removed under reduced pressure. Column chromatography of the residue on 500 g of silica gel with 30% ethyl acetate in petroleum ether gave 6.450 g (82%) of the lactone 27. scale was 90%. The yield on a 2 mmol Recrystalization from ether/hexane afforded an analytical sample: MP 62-62.5° C (lit. for the antipode 62°-63°c36; [a1n22 +39.15° (~1.51, CBC1 3 > lit for the antipode -38.4 36; IR (CBC1 3 ) b 3450, 3000, 2950, 1780, 1180, 1225, 1025 cm-1; ls NMR (CDC1 3 ) 6 1.42 (s, 68, (CH 3 >2 c>, 1.63 (s, 38, CH 3 C>_, 3.33 (bs, lB, Oll), 3.87 (m, 55 28, 8-5's), 4.52 Cs+m, 28, s•8-3, m•8-4). Cg8 14 o 5 : C, 53.46, 8, 6.98. Found: Anal. Calcd. for C, 53.55; 8, 6.84. 2,3~(1-.etbyletbylidenel-S~.etbozy.etbyl-2~­ •etbyl-~ribono-1,4-lactone To a stirred (28). solution of 22.296 g of · the lactone 27 (0.110 mol) in 250 mL of chloroform at 0°C was added 59 mL(0.667 mol) of dimethoxymethane and 49 g of P2o 5 :Celite (1:1), and the resulting mixture was stirred at room temperature. After 1 h, the reaction mixture was poured into iced aqueous saturated Naaco 3 with stirring and the resultant mixture was filtered. The organic phase was separated, and the aqueous phase was extracted with two 150 mL portions of chloroform. The combined organic phases were dried (Mgso 4 > and then the solvent was removed under reduced pressure. Evaporative distillation of the residue at 100 °c (0.005 mmHg) gave 26.896 g (99%) of the methoxymethyl ether 28: evaporative distillation 90-l00°C, (0.005 mm8g); 1780, 1380, 1220, 1160, 1105, 1060, 1020 cm-1; la NMR (CDC1 3 > o 1.42 (s, 68, C (CH 3 >2 >, 1.62 (s, 38, CH 3 >, 3.33 (s, 3H, OCH 3 ), 3.74 (d, 28, J=3 Hz, CCB 2o>. Anal. Calcd. for c 11 HHH 18 o 6 : C, 53.65; 8, 7.37. Found: C, 53.71; 8, 7.42.· 2,3~(1-.etbyletbylidene)-S~.etbozy.etbyl-2~­ •etbyl-a-ribose (29). (0.109 mol) of the To a stirred solution of 26.859 g lactone 28 in 500 mL of dry ether at -78°C under argon was added 153 mL (0.153 mol) of 1 M diisobutylaluminum hydride in hexane (0.153 mol) over a period of 56 30 min, and the resulting mixture was stirred at -78°C. After 1 h, 36 mL of dry methanol was cautiously added, the reaction mixture was allowed to warm to room temperature, · and then 650 mL of 0.5 M aqueous potassium sodium tartrate was added with stirring. When two distinct phases could be noticed Capprox. 2 h), the organic phase was separated and the aqueous phase was extracted with two 500 mL portions of dichloromethane. The combined organic phases were dried (Mgso 4 >, and the solvent was removed under reduced pressure. Evaporative distillation of the residue at 110°C (0.005 mmBg) yielded 27.072 g (99.7t) of the desired lactol 29: evaporative distillation 90-l00°C (0.005 mmHg); [a 10 22 -18.36° (k4.48, CHCl3); IR (CHC13) 3600, 3450, 1460, 1380, 1210, 1160, 1105, 1060, 1030 cm-1; la NMR (CDC1 3 > (minor anomer, major anomer) 3.31, 3.34 Cs, 3H, oca 3 >, 3.59, 3.63 (d, 2B, J•2 Hz, cca 2o>, 4.58, 4.64 (s, 2H, oca 2o>, 5.00, 5.17 (d, lB, J=ll Hz, Hl). Anal. Calcd. for C11H2006: C, 53.22; B, 8.12. Found: c, 53.36; a, 8.12. 1,4-Anhydro-2-deozy-2-methy1-5~aethozymethyl-L­ erythro-pent-1-enitol (30). To a stirred solution of 6.559 g (26.42 mmol) of the lactol 29 in 80 mL of dry TBF at -78°C was sequentially added 3.15 mL (29.9 mmol) of carbon tetrachloride and 5.2 mL (28.6 mmol) of tr isdimethylaminophosphine, and the resulting mixture was stirred at -78°C. After 30 min the reaction mixture became opaque and was allowed to warm to room temperature with stirring until it 57 became clear. The resulting solution was canulated into a stirred solution of 53 em Capproz. 0.3 mol) of lithium wire in 400 mL dry ammonia at -78°C rinsing with two 10 mL · portions of dry TBF, cooling was then discontinued (ammonia reflux). After 2h, 18.8 gm of dry ammonium chloride was cautiously added, the resulting colorous mixture was diluted with 200 mL ether, and the ammonia was allowed to evaporate. The resulting suspension was filtered, washing with four 50 mL portions of ether, and the solvent was removed under reduced pressure. Flash chromatography of the residue on 200 gm of silica with ether and then evaporative distillation of the chromatographed material at 80°C (0.005 mmBg) gave 9.053 9 of a 4:1 mixture (18-NMR) of the desired glycal 30 (79') and ~he deschloro compound 60 (20,). Chromato- graphy of this mixture on silica gel with 20' ethyl acetate in petroleum ether provided pure samples for analysis: 30 - evaporative distillation 60-70°C (0.005 mmBg); For [ a1 23 0 -190.7° (k2.0, CBCl3); IR CCBCl3) 3590, 3450, 1675, 1460, 1380,, 1210, 1150, 1100, 1020 cm-1; lH NMR (CDC1 3 ) ~ 1.69 c B3) ' 3. 3 7 ( s 3 B' oc B3) ' 3. 56 ( d 2 B' J=6 Hz, cca 2 o>, 5.08 (s, 28, oca 2 o>, 6.22 Cbs, lB, B.C=C). (d I 3 B' J = 2 Bz I I I Anal. Calcd. for c 8 u14 o 4 : C, 55.16; B, 8.10. Found: C, 54.89; B, 8.00. For 60 - evaporative distillation 40°C (0.005 mmHg); [a] 0 21 -26.58 (c2.25, CBC1 3 >; IR (CBC1 3 > 1460, 1385, 1220, 1160, 1040 cm-1; 1a NMR (CDC1 3 ) o 1.38 (s, 38, c B3 ) I 1. 50 ( s I 6 BI c (c B3 ) 2) ' 3 • 3 3 ( s ' 3 B oc B3) ' 3 • 6 0 (d I I 58 2H, J=6 Hz, CCH 2o>, 3.62 (d, 1H, J•9 Hz, Hla), 3. 79 (d, 1H, J•9 Hz, Hlb) I 4.17 (dt, 1H, J-3 Hz, 6Hz, B4), 4.27 (d, 1H, 2H, OCB 2 0>. Anal. Ca1cd. c, 56.88; H, 8.68. Pound: C, 56.71; B, 8.58. B3), J•3 Hz, C11 8 2o 0 5= 4.59 (s, for lletbyl 2W-and 2QU-5(S)-IIethozYJ1etbylenozyaethyll-3(Rl-aethyl-2(R)-tetrahydrofuryl)botanoate (3la) and (3lb). To a stirred solution of 2.931 g (15.1 mmol) of the glycal 30 as a 4:1 mixture with the byproduct 60 in 49 mL of dry THF and 11.3 mL of dry HMPA at -78° C under argon was added 6.69 mL (15.1 mmol) of 2.26 M n-butyllithium in hexane, and then after 5 min, 1. 7 mL of n-butanoyl ch1or ide (16.4 mmol) was added. After 10 min the reaction mixture was canulated dropwise into a stirred solution of 22.3 mmo1 of LDA in 53.5 mL of dry TBF and 15.4 mL of dry HMPA at -100° C rinsing with two 5 mL portions of dry THF. After 10 min, the reaction mixture was treated with 7.5 mL of the supernatant centrifugate from a 3:1 mixture of ch1orotrimethylsilane and triethylamine (44.3 mmol of TMSCl). After 2 h at room temperature, the reaction mixture was treated with 100 mL 1 N of aqueous NaOH and the resulting mixture was stirred for 15 min. The aqueous phase was then saturated with NaCl and acidified ( PH2) with concentrated sulfuric acid. The organic phase was separated and the aqueous phase was extracted with three 100 mL portions of ether. The combined organic phases were dried (Mgso 4 > and the solvent was removed under reduced pressure. Ester- 59 ification of the residue with ethereal diazomethane and then flash chromatography of the resultant esters on 200 g of silica gel with 25t ethyl acetate in petroleum ether afforded 2.621 gm (67t) of a 6:1 (1B-NMR) mixture of the diasteriomeric esters. The yield of the above ester enolate Claisen reaction varied from 54 to 67\ using 1 to 20 mmol of the glycal 30. The above mixture was dissolved in 125 mL of ethyl acetate, 500 mg of 5\ Pt/C was added and the resulting mixture was stirred under an atmosphere of hydrogen. After 12 h, the catalyst was removed by filtration and the solvent was removed under reduced pressure. Medium pressure liquid chromatography of the residue on a Lobar C column with 20% ethyl acetate in petroleum ether, gave 1.9713 g (75\) of the desired 2S. ester 3la and 297 mg (11%) of the 2R ester 3lb: For 3la- evaporative distillation 80-90°C (0.005 mmHg); [a 1 D2 5 - 8. 0 4 ° (k2. 6 4 , C8 C1 3 ) ; I R ( C8 C1 3 ) 1 7 3 0 , 14 6 0 , 12 7 5 , 1220, 1160, 1105, 1040 em -1; lH NMR (CDC1 3 ) t5 0.88 (t, 3H, J=6 Hz, OCH 3 >, ca3 ca 2 >, 0.99 (d, 3B, J=6 Hz, CH 3 >, 3.36 (s, 38, 3.51 (d, 28, J=S 8z, CCB 2 o>, 3.68 (s, 38, co 2 ca 3 >, 4.62 Cs, 28, oca 2 o>. B, 9.29. Found: Anal. Calcd. for c, 59.84; B, 9.16. c13 8 24 o5 : c, 59.98; For 3lb - evaporative distillation 80-90°C (0.005 mmBg); [a] 0 25 -15.07° Ck2.48, C8Cl 3 ); IR (C8Cl 3 > 1730, 1460, 1390, 1110, 1040 cm-1; la NMR (CDC1 3 ) t5 0.90 (t, 38, J=6 Hz, CB. 3 C8 2 ), 1.06 (d, 38, J=6 Hz, . ~B 3 C8CC), 3.36 (s, 38, OCB 3 >, 3.52 (d, 28, J~S Hz, CCH 2 0>, 60 3.69 (s, 3B, co 2 ca 3 >, 4.61 (s, 2B, oca 2 o>. c 13 a 24 o5 : c, 59.98; s, 9.29. Pound: Anal. Calcd. for c, 60.06; a, 9.26. 2 (JU -5 (JU- (llethozymethylenozpaethyl) -3 (IJ -.ethyl-2 (&)tetrahydrofuryl)-butan-1-ol (32). By the procedure described for the preparation of the alcohol 8, 5.8337 g (22.41 mmol) of the 2S methyl ester 3la in 110 mL of dry ether with 850 mg (21.7 mmol) of lithium tetrahydridoaluminate afforded, after column chromatography on 300 g silica gel with 30% ethyl acetate in petroleum ether, 4.9391 g (9S%) of the alcohol 32: evaporative distillation -24.7° (k0.45, CBC1 3 >; IR CCHC1 3 > 3650, 3SOO, 1460, 1230, 11SO, 110S, 1030 cm-1; la 60-70° C (O.OOS mmBg); NMR (CDC1 3 > (a 10 24 (t, 3B, J=6 Hz, C1i 3 CB 2 >, 1.01 d, 3B, 2.67 (dd, lB, J=5 Bz, 6 Bz, CllCB 3 >, 3.33 (s, o 0.93 J=6 Bz, CB 3 >, 3H, ocs 3 >, 3.47 Cd, 2B, J=5 Hz, cca 2 o>, 4.60 Anal. Calcd. for cl2H240 4: <s, 2B, oc~ 2 o>. c I 6 2 .o 4; B, 10.41. Pound: cI 62.12; B, 10.42. Benzyl 2 (ll) -S(JU-(IIethozyaethylenozyaethyl)-3 (BJmetbyl-2 au -(tetrahydrofurfyl) butyl ether (33). To a sus- pension of 1.02 gm (24.5 mmol) of potassium hydride in SO mL of dry THF and 4.1 mL (34.S mmol) of benzyl bromide under argon was added a solution of 4.937 g of the alcohol 32 (21.3 mmol) in SO mL dry THF was added over a period of 30 min. The resulting mixture was stirred at room temper- ature for 1 h, then 75 mL of saturated aqueous Naaco 3 was cautiously added with stirring. After 1 h, the mixture was 61 diluted with 600 mL of ether, the organic phase was separated, washed with two 200 mL portions of saturated aqueous Nasco 3 , dried (Mgso 4 >, and then the solvent was removed under reduced pressure. Column chromatography of the residue on 4~0 g of silica gel with 1St ethyl acetate in petroleum ether afforded 6.7732 9 (99\) of the benzyl ether 33: evaporative distillation 100-110° C (0.005 mmBg); £a1 0 24 -17.8° (~1.00, CBC1 3 >; IR (CBC1 3 > 1460, 1380, 1120, 1040 cm-ll 1 H NMR CCDC1 3 > c5 0.92 (t, 38, J=6 Hz, ca3 ca 2 >, 1.02 (d, 38, J•6 Hz, CB 3 ), 3.33 Cs, 38, OCB 3 >, 3.47 Cd, 48, J=S Hz, CCB 2 o>, 4.43 (s, 28, c 6 a 5 ca2 >, 4.60 (s, 28, OCB 2 0>, 7.28 Cbs, 58, C6Bs>· Anal. Calcd. for C19H3004: C, 70.77; B, 9.38. Found: C,70.74; B~.34. Benzyl 2 (ll) -5 (ll)- (Bydrozy.etbyl)-3 (BJ-aetbyl-2Wtetrahydrofuryl)-butyl ether (3,). To a solution of 21.70 9 (67.3 mmol) of the methoxymethylether 33 in 520 mL of THF was added 150 mL of aqueous 10% BCl and the resulting mixture warmed to 50° C. After 12 h, the reaction mixture was cooled to room temperature, neutralized by the careful addition of saturated aqueous NaHC0 3 and extracted with three 500 mL portions of ether. The combined extracts were dried CMgso 4 > and the solvent was removed under reduced pressure. Flash chromatography of the residue on 500 9 of silic~ gel with SOt ethyl acetate in petroleum ether afforded 18.74 g (100%} of the alcohol 3': evaporative d isti lla tion 100-110°C (0.005 mmHg}; [a] 0 21 - 51.8 (~2.57, 62 CHCl3); IR CCHCl3) 3600, 3450, 1460, 1380, 1220, 1100, 1080, 1040 cm-lJ la NMR CCDC1 3 ) ~ 0.93 Ct, 38, J•6 Hz, CH3CB2), 1.02 (d, 3H, J=6 Hz, CB 3 ), 3.47 (d, 2B, J•6 Hz, CCB 2 0>, 4.48 Cs, 28, C6BsCH2>, 7.33 Cbs, SB, C6Bs>· C17H2603: C, 73.35; B, 9.41. Found: Anal. Calcd. for C, 73.38; B, 9.37. Benzyl 2C&)-SCB)-carbometbozy-3QU-aetbyl-2QUtetrabydro-furyl)-butyl ether C35a). By the procedure described for the preparation of the ketone 23, 16.25 g of the alcohol 34 (58.37 mmol> was treated with 9.9 mL (139.7 mmol) of DMSO activated with 6.6 mL of oxalyl chloride (75.9 mmol) then 24.6 mL of triethylamine (excess> in 220 mL of dichloromethane. The resultant aldehyde was dissolved in 440 mL of absolute . ethanol and a solution of .28.7 g (1676 mmol) of silver nitrate in 44.0 mL of water was added. To the resulting mixture 364 mL of 0.93 M potassium hydroxide was added over ' 30 min and the resulting mixture was stirred at room temperature for 5 min then filtered. The filtrate was concentrated under reduced pressure to approximately 400 mL, washed with two 300 mL portions of ether, acidified CPH 2) and extracted with five 300 mL portions of dichloromethane. The combined dichloro- methane extracts were dried (Mgso 4 > and the solvent was removed under reduced pressure to give .16.26 gm (95%) of the acid 35. A portion of this material was treated with diazo- methane in ether and chromatography of the resulting methyl ester 3Sa on silica gel with lOt .ethyl acetate in petroleum 63 ether afforded an analytical sample: evaporative distillation 100-110° C (0.005 mmBg) 1 [ al 0 20 -1.28° (~1.08, CBC1 3 >; IR (CBC1 3 > 1740, 1460, 1370, 1220, 1100, 1040 cm-1; 1 . B NMR (CDC1 3 > o 0.93 (t, 38, J•6 Bz, CB3 ca 2 >1 1.01 (d, 38, J•6 Bz, cs 3 >, 3.49 (d, 28, J•6 8z, ccs 2 o>, 3. 70 (s, 38, co 2ca 3 >, 3.80 (dd, 18, J•S 8z, 8 8z, OC8CC), 4.38 (t, 18, J•7 Hz,, caco 2 ca 3 >, 4.47 <s, 28, c 6 8 5 ca 2 >, 7.32 Cbs, sa, C6BS). Anal. Calcd. for C19B2604: Found: C, 70.75; B, 8.54. Benzyl C, 70.56; B, 8.55. 5,6-anbydro-2,3~(1-aetbylethylidenel-p-~ galofurranoside (37). To a stirred suspension of 8.9 9 (370.9 mmol) of sodium hydride in 300 mL of dry TBF at 0° C was cautiously added a solution of 51.2 gm (165.0 mmol) of the gulonoside diol 36 in 300 mL of dry TBF and the resulting mixture was stirred at 0° c. After 15 min a solution of 41.0 g (1.84 mmole) of p-toluenesulfonylimidazolide25 in 400 mL of dry TBF was added over 1 h and the resulting mixture was stirred at 0°C. After 45 min the excess sodium hydride was destroyed by the careful addition of 50 mL of water and the reaction mixture was diluted with 4 L of ether. The organic phase was washed with two 1.5 L portions of water, dried (Mqso 4 > and then the solvent was removed under reduced pressure. Crystallization of the residue from dichloromethane/petroleum ether afforded 34.0 gm of the desired epoxide 37 and flash chromatography of the mother liqueurs on 500 g of silica gel with 20% ethyl 64 - acetate in petroleum ether gave a further 8.1 g of the epoxide 37. (87\): ~he total yield of the MP 87.5-88.0° C1 epoxide 37 vas 42.1 9 (a]D22 -86.95° (~2.28, C8Cl 3 )1 IR (CHC13) 2995, 2930, 1448, 1380, 1370, 1102, 1075, 1015, 850, 69S cm- 1 1 1 8 NMR CCDC1 3 > c5 1.31 and 1.50 Cs, 68, CC8 3 >2 c>, 2.65 Cdd, 18, J 6 a, 6 b•4.5 8z, J 5 , 6 a•3.0 8z, 8-6a), 2.90 Cdd, 18, J 5 , 6 b J 6 a, 6 b•4.5 8z, 8-6b), 3.30 Cddd, 18, J 5 , 68 •3.0 Bz, J 5 , 6 b•4.5 Bz, J 4 , 5 •6.6 8z, B-5>, 3.58 Cdd, 18, J 4 , 5 -6.6 Bz, J 3 , 4 •3.5 Bz, 8-4), . 4.60 (AB quartet, 2B, PhCB 2 0>, 4.72 (m, 28, B-2 and B-3), 5.16 Cbs, lB, B-1), 7.31 (bs, 5B, PhB). Anal. Calcd. for C16B2005: C, 65.741 B, 6.90. Found: C, 65.75; B, 6.86. Benzyl 6-deozy-2,3~(1-•etbyletbylidene)~-~ulo­ furanoside (38). By the procedure described for the prepar- ation of the alcohol 32, 14.370 9 (49.16 mmol) of the epoxide 37, 2.5 gm (65.9 mmol) of lithium tetrahydro- aluminate and 200 mL of dry ether afforded, after crystallization from dichloromethane/pentane and flash chromatography of the mother liqueurs on silica gel with 20% ethyl acetate in petroleum ether, 11.487g of the desired alcohol 38 (79%). The yield on a 5 mmol scale was 91\: MP 111-112.5° C1 [aJ 0 2 2 -99.83 (kl.6, CBC1 3 >; IR(CBC1 3 > 3600 (sharp), 3520 (broad), 2995, 2940, 1455, 1385, 1375, 1105, 1075, 1015, 855, 695 cm-1, la NMR (CDC1 3 ) c5 1.26 (d, 3H, J 5 , 6 -6.2 8z, B-6's>, 1.27 and 1.44 Cs, 68, CC8 3 >2 >c>, 2.7 Cbs, 18, OB), 3.76 (dd, lB, J 4 •6.2 Bz, J 3 , 4 •2 Bz, B-4), 4.13 65 (dt, 18, J 5 , 6 J 4 , 5 •6.2 8z, 8-5>, 4.57 CAB quartet, 28, PhCH 20>, 4.65 (bs, 28, 8-2 and 8-3), 5.10 Cs, lB, 8-1), 7.30 ( s, 58, P hH) • An a 1. Ca 1 c d. for Cl& 8 2 2 0 5 : 7.53. c, 65.24; B, 7.49. Pound: 6-deoxy-R_-gulose (39). C, 6 5. 2 9 1 8 , . A solution of 11.473 gm (39.0 mmol) of the glycoside 38 in 300 mL of 4:1 acetic acid/water was heated under reflux under argon. After 12h the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Passage of the residue through a 10x20 em pad of silica gel, eluting with ethyl acetate, afforded 5.224 gm (86%) of the free sugar 39. Benzyl-6-deozy~and~~-gulopyranoside C40a,b). To a stirred solution of 9.316 g (56. 7 mmol) of 6-deoxy-)l-gulose 39 in 100 mL of benzyl alcohol was added 2.5 mL of acetyl chloride and the resulting mixture w'a rmed to 50° C. After one day, the reaction mixture was diluted with 100 mL of chloroform and then neutralized with 100 g of barium carbonate. The resulting suspension was filtered and the solid residue was washed with three 100 mL portions of chloroform. The combined filtrates were concentrated at S0°C ( 0.01 mmBg). Plash chromatography of the residue on 1000 g of silica gel with ethyl acetate gave 11.231 g (78%) of the benzyl glycosides (a: scl:2) 40 .,b: 134.5°-135.5° C (ethyl acetate-hexane) 1 Ci~.0.863, CBCl3); a -glycoside: mp I a 1 0 21 +117 .8° IR CC8Cl3) 3600, .3450, 1220, 1175, 1080, 66 1040, 1000 cm- 1 ; 1 a NMR (CDC1 3 > ~ 1.23 Cd, 3B, J=6 Hz, ca 3 >, 4.54 (d, lB, J•l2 Bz, c 6 a 5 CBH), 4.73 (d, lB, J•l2 Bz, c6 a5 CHH), 4.93 (bs, lB, Bl), 7.38 Cbs, SB, c6 a5 >. Calcd. for C13H1805: B~ 7.14. B -glycoside: C, 61.41; B, 7.14. Pound: Anal. · C, 61.79; evaporative distillation 130-140°C (0.005 mmBg); [()(] 0 25 -117.8 3600, 3450, 1220, 1175,, 1080, 1060, 1000 cm-1; la NMR (CDC1 3 > o 1.27 (d, 3H, J•6 Hz, CB 3 ), 4.53 (d, 1H, J•l1 Hz, c6 a5 CHH), 4.62 (d, 1H, J•8 Bz, Hl), 4.89 (d, 18, J=ll Hz, C6 H5 CliB) , 7 •3 4 ( b s , 5 H, C.-. 6 B5 ) • An a 1. Ca 1 c d. for C13 H18 0 5 : c, 61.41; H, 7.14. Found: c, 61.31; a, 7.22. Benzyl-6-deozy-2,3-Q-(1-~~etbyletbylidene)-a and B- Q-galopyranosidea (41 a•b>. To a stirred solution of 11.231 g (44.17 mmol) of the benzyl glycosides 40 a•b in 500 mL of dry acetone was added 70 mg (0.37 mmol) of Rtoluenesulfonic acid monohydrate and 9.5 mL (76. 7 mmol) of 2,2-dimethoxypropane. After 12 h, the reaction mixture was neutralized with concentrated aqueous NH 40H. The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. Flash chromatography of the residue on 500 g of silica gel with 25% ethyl acetate-petroleum ether gave 12.74 g (98%) of the corresponding ketals. glycoside: mp 79-80°C (hexane>; [a] D21 +62.1 a- (k,0.965, CHCl3) 1 IR CCBCl3) 3970, 3460, 1380, 1240, 1160, 1100, 1030 cm-1; la NMR (CDC1 3 > o 1.19 (d, 3B, J=6 Hz, ca 3 >, 1.36, 1.50 (s, 68, C(CB 3 >2 >, 4.56 (d, lB, J•12 Hz, c 6 a5 CHH), 4.71 67 (d, lB, J•l2 Hz, c 6 s 5 CHB), 4.87 Cbs, 1B, Bl), 7.33 (bs, SB, CBs>. Anal. Calcd. for C16B2205: Pound: C, 65.36; B, 7.46. C, 65.29; B, 7.53. 6 -glycoside: distillation 100-110°C, 0.005 mmBg; evaporative [~l 0 21 -106.2 (~1.206, CBCl3) 1 IR (CBC13) 3560, 3350, 1390, 1230, 1180, 1120, 1060 cm-1; 1s NMR CCDC1 3 ) 1.30 (d, 3B, J•6 Hz, CB 3 ), 1.31, 1.40 (s, 6B, C CCB 3 >2 >, 4. 73 (d, 1B, J=4 Hz, B1), 4.58 (d, 1B, J•12 Hz, c 6 s 5 CBH), 4.84 Cd, 1B, J=l2 Hz, c 6 s 5 CHB), 7.33 Cbs, 5B, 7.53. c6 a5 >. Pound: Anal. Calcd. for c16 a 22 o 5 : c, 65.29; B, C, 65.21; H, 7.50. Benzy1-6-deozy-2,3~(1-methylethylidenel-4~ •ethozyaethyl-aanda-n-galopyranoside 42 a and b. To a suspension of 5.15 gm (128.5 mmol) of potassium hydride in 160 mL of dry TBF at 0° C was cautiously added a solution of 29.41 g (99.9 mmol) the alcohols 41 a and b in 80 mL dry THF_ and the resulting mixture was stirred at 0° c. After 15 min, 15.1 mL (200 mmol) of chloromethylmethy1 ether was added and the resulting mixture was stirred at room temperature. After 12 h, the excess potassium hydride was quenched by the cautious addition of 10 mL of water and the mixture was diluted with 750 mL of ether. The organic phase was washed with two 300 mL portions of water and one 300 mL portion of brine, dried CMg~o 4 > and the solvent was removed under reduced pressure. Flash chromatography of the residue on 350 g of silica gel with 25% ethyl acetate in petroleum ether afforded 28.37 gm of the methoxymethyl ethers 42 a and 68 b (84,): a -glycoside: evaporative distillation 120-130° C tal 0 21 +41.0° (0.005 mmBg); (~0.80, CBC1 3 >1 IR (CBC1 3 > 1380, 1240, 1150, 1100, 1020 cm-1; 1s NMR (CDC1 3 ) 6 1.20 (d, 38, J•6 Bz, CB 3 >, 1.36, 1.51 (s, 6B, C(CB 3 >2 >, 3.40 (s, 38, OCB 3 ), 4.57 (bs, lB, 81), 7.34 (bs, 5B, c 6 s 5 >. Anal. Calcd. for C19B2606: C, 63.89; B, 7.74. 7.64. S -glycoside: Pound: C, 63.90; B, evaporative distillation 100-110° C [ al 0 21 ·• -148° (~0.904, CBC1 3 ); IR (CBC1 3 ) 1390, 1230, 1155, 1040 cm-1; la NMR (CDC1 3 ) 3.40 (s, 3B, (0.005 mmBg); OCH 3 >, 4.57 (d, 1B, J•12 Hz, B1), 7.30 (bs, 58, Anal. Calcd. for C19B2606: C, 63.89; B, 7.74. c 6 a 5 >. Found: C, 63.82; B, 7.75. - 6-Deozy-2,3~(1-.etbyletbylidene)-4~.etbozy.ethy1-~ gulose (43). To a stirred solution of 21 em (128 mmol} of lithium wire in 200 mL of anhydrous ammonia at -78° C under argon was added a solution of 14.68 g (43.38 mmol) of the mixture of benzyl glycosides 42a and b in 40 mL of dry THF. Cooling was then discontinued (ammonia reflux) and after 1 h,· 8.0 g (150 mmol) of anhydrous ammonium chloride was cautiously added to the reaction mixture. The resulting mixture was then diluted with 300 mL of ether and the ammonia was allowed to evaporate. The resulting suspension was filtered, and the solid was then washed by trituration with four .100 mL portions of ether. Removal of the solvent from the combined filtrates gave 10.2 g (95') of the crystalline lactol 43: mp 139° C (ethyl acetate-hexane): 69 [aJ 0 22 -62.5° (~1.201, CBC1 3 ) 1 IR (CHC1 3 ) 3600, 3460, 1390, 1230, 1160, 1100, 1040 cm-11 18 NMR (CDC1 3 ) ~ 1.27 (d, 38, J•6 Hz, CH 3 >, 1.33, 1.47 (s, 6H, C(CH 3 >2 >, 3.40 (s, 38, OCB 3 ), 3.57 (d, 18, J•6 Hz, 08), 3.63 (dd, lH, J•3 8z, 3 Hz, H4), 4.00 (dq, lH, J•3 Hz, 6 Hz, H3), 4.63 (d, 18, J=6 Hz, OCBaO>, 4.77 (d, lH, J•6 Hz, OCBHO), 4.87 (dd, 18, J•6 Hz, 6 Hz, Hl). Found: Anal. Calcd. for C11H2006: C, 53.22; H, 8.12. C, 53.351 B, 8.06. 1,5-Anhydro-2,6-dideozy-4~.ethozy.ethyl-~xylo-bez-l­ enitol (44). By the procedure described for the preparation of the glycal 30, 4.4 mL (45.6 8.74 g (35.2 mmol) of the lactol 43, mmol) of carbon tetrachloride, 6.8 mL (37.4 mmol) of trisdimethylaminophosphine in 140 mL of dry TBF with 71 em (432 mmol) of lithium wire in 600 mL of anhydrous ammonia and 25 g (468 mmol) of anhydrous ammonium chloride afforded, after passage through 100 g of silica gel with 50% ethyl acetate-petroleum ether and evaporative distillation at 60° C (0.1 mmBg), glycal 44: [ a1 0 22 +199.8° 5. 73 mg (93%) (k0.65, CHC1 3 >; IR of the (CHC1 3 > 3620,, 3450, 1640, 1240, 1150, 1090, 1030, 940 cm-1; la NMR (CDC l3 ) o 1. 3 6 ( d , 3 H, J • 6 Hz , CH3) , 3 • 4 0 ( s , 3 H, OC B3 ) , 3.56 Cm, 1B, H4), 4.10 Cm, 28, 83 and 85), 4.66 Cd, 18, J•6 Bz, OCHRO), 4.73 (d, 18, J•6 Hz, OCaBO), 4.89 (m, lB, H2), 6.50 (d, 1H, J=6 Hz, B1). c, 55.16; B, 8.10. Found: Anal. Calcd. for C, 55.19; H, 8.23. c 8 s1404: 70 Benzyl 2 (&)-I 5 (S) aDd 5 (ll) -carbomethozy-3 (I) -aethyl-5(5,6-dihydro-5(BJ-.etbozymethylenozy-6(BJ-methyl-2(S)pyraDyl)-2(ll)-tetrabydrofaryll-batyl ether (45a,b). By the procedure described for the preparation of the methyl esters 3la,b, 660 mg (3.48 mmol) of the glycal 44, with 1.62 mL (3.48 mmol) of 2.17 M solution of n-butyllithium in hexane and 3.98 mmol of the acid chloride of the acid 35 in 9 mL of dry TBF, added to 7.0 mmol of LDA in 9 mL of dry TBF, followed by 21.0 mmol of trimethylchlorosilane afforded, after treatment with ethereal diazomethane and chromatography on 200 g of silica gel with 20t ethyl acetate in petroleum ether, 226 mg · of the methyl ester 45a and 817 mg of the methyl ester 45b, or a 22:78 ratio of a 65t combined yield. Methyl ester 45a: evaporative distillation 150-160° C (0.005 mmBg) 1 (a] 0 22 -149.2 (kl.256, CBC1 3 > 1 IR (CBC1 3 > 1740, 1460, 1215, 1160, 1100, 1040 cm-11 lH NMR (CDC1 3 ) ~ 0.92 (t, 3B, J=6 Hz, ~B 3 cs 2 >, 0.97 (d, 3B, J•6 Hz, CB. 3 CHCC), 1.18 (d, 3H, J=6 Hz, CB. 3 CBOC), 3.34 Cs, 3H, OCH 3 >, 3.73 (s, 38, co 2 ca 3 >, 4.47 Cbs, 2H, c 6 a 5 CB. 2 >, 4.62 (d, lB, J=7 Hz, OCHB.O), 4.71 (d, lB, Jc7 Hz, OCB.HO), 5.67-6.17 (m, 2H, BkCB>, 7.33 Cbs, 5B, c 6 H5 >. C, 67.51; H, 8.28. 45b: Found: C, 67.64, B, 8.26. Methyl ester evaporative distillation 150-160° C (0.005 mmBg); Ia 10 2 2 -1 7 7 .1 ° .(k. 0 •5 5 2 , CHC1 3 ) 1 I R ( CBC1 3 ) 1 7 5 0 , 1730 , 1460, 1385, 1155, ·1100, 1040 cm-11 ls NMR (CDC1 3 > ~ 0.90 (t, 3H, J~6 Hz, CB.3CH2), 0.97 (d, 3H, Ja6 Hz, CB.3CBCC), 1.16 (d, 71 ca3 CBOC), 2.50 Cq, 1B, J=6 Hz, CB 3 CllCC), 3·. 34 Cs, 3B, OCB 3 ), 3.68 (s, 38, co 2 ca 3 >, 4.43 (s, 2B, c 6 s 5 ca 2 >, 3B, J=6 Hz, 4.57 (d, 1B, J•6 Bz, OCBJiO), 4.70 (d, 1B, J•6 Bz, OCllBO), · 5.31 Cbs, 2B, B.C•Cll), 7.32 (bs, SB, c 6 s 5 >. C26B3907: C, 67.511 B, 8.28. Pound: Anal. Calcd. for C, 67.481 B, 8.41. The yield of the above ester enolate Claisen varied from 59 to 69t on a 0.5 to 5.0 mmole scale. Benzyl 2(ll)-[5(8)-carbometbozy-3(1J-aetbyl-5-(5(8).etbozymetbylenozy-6(~-.etbyl-2(JO-tetrabydropyranyl)-2(ll)­ tetrabydrofuryll butyl Btber (46a). By the procedure described for preparation of 3la,b, 203 mg (0.44 mmol) of the methyl ester 45a in 5 mL of ethyl acetate with 20mg of St platinum on carbon catalyst afforded, after chromatography on 20 9 of silica gel with 1St ethyl acetatecyclohexane, 181 mg (89t) of the 46a: evaporative distillation 150-160° C (0.005 mmBg); [aJ 0 22 -5.1° 1110, saturated methyl ester (k1.118, CBC1 3 ); IR (CHC1 3 ) 1730, 1460, 1380, 1040 cm-1; 1s NMR (CDC1 3 ) cS 0.93 (t, 3H, J=6 Hz, CB. 3 ca 2 >, 0.95 (d, 3B, J=6 Bz, Cll3 CBCC), 1.17 (d, 3B, J=6 Hz, Cll 3 CBOC), 3.33 Cs, 3B, oca 3 >, 3.70 Cs, 38, co 2 ca 3 >, 4.47 c 6 a 5 ca 2 >, 4.59 Cbs, 2B, oca 2 o>, 7.33 Cbs, sa, c 6 a 5 >. Anal. Calcd. for c 26 a 40 o7 : c, 67.221 a, 8.68. Pound: c, 67.471 B, 8.75. Cbs, 2B, 72 Benzyl 2QU-[S(B)-carboaetbozy-3(B)-aetbyl-5-(5(.&)aethozy.etbylenozy-6(B)-aetbyl-2(4)-tetrabydropyranyl)-2(BJtetrabydrofuryllbutyl Btber (46b). By the above procedure, 8.347 g (18.0 mmol) of the methyl ester 45b in 165 mL of ethyl acetate with 220 mg of St platinum on carbon catalyst afforded, after flash chromatography on 400 g of silica gel with 20% ethyl acetatecyclohexane), 7.51 g (90') of the saturated methyl ester 46b: evaporative distillation 150- 1600 C (0.005 mmHg); [a] D -34.0° (k,0.662, CHC1 3 >; IR (CHC1 3 ) 1750, 1730, 1460, 1390, 1110, 1040 cm-1; 1a NMR (CDC1 3 ) o 0.90 (t, 3B, J•6 Hz, ca 3 ca 2 >, 0.94 (d, 3B, J•6 Hz, Cll 3 CHCC), 1.12 (d, 3B, J•6 Hz, Cll 3 CHOC), 2.39 (q, 1B, J=6 Hz, CH 3 CilCC), 3.32 (s, 3B, OCB 3 >, 3.67 (s, 3B, co 2 ca 3 >, 4.47 (bs, 2B, c 6 a 5 Cll 2 >, 4.60 (bs, 2B, OCB 2 0>, 7.33 (bs, SB, C6H5). Anal. Ca1cd. for C26H4007: Found: C, 67.40; H, 8.88. C, 67.22; H, 8.68. Benzyl 2(B)[5(B)-Porayl-3(B)-aetbyl-5-(5(B)-aetbozy.ethylenozy-6R-.etbyl-2(&)-tetrabydropyranyll-2C&>tetrahydrofurylbutyl Btber (47). By the procedure described for the preparation of the lactol 29, 8.801 gm (20.25 mmol) of ester 46b, 29.1 mL (29.1 mmol) of 1 M Diisobutylaluminum hydride, 110 mL of dry ether, 3.0 mL of methanol and 200 mL 0.5 M potassium sodium tartrate afforded, after chromatography on 400 gm of silica gel with 20% ethyl acetate petroleum ether, 7.312 9 (89%) of the aldehyde 47: evaporative distillation 150-160° C 73 (0.005 mmBg) 1 [a]D -51.8° (~0.541, CBC1 3 ) 1 IR (CBC1 3 > 1735, 1460, 1380, 1110, 1040 cm-1; lH NMR (CDC1 3 ) ~ 0.90 (t, 3H, J-=6 Hz, CB.3 CB2), 0.94 (d, 3B, J•6 Hz, CB.3 CBCC), 1.12 (d, 3B, J•6 Hz, CB. 3 CBOC), 2.33 (q, 1H, J•6 Hz, CB 3 CB.CC), 3.30 (s, 3B, OCH 3 ), 4.46 Cbs, 2B, C6 H5 ca 2 >, 4.57 Cbs, 2H, OCH 2 0>, 7.30 (bs, SB, c 6 s 5 >, 9.67 Cs, 1H, CBO). Anal. Calcd. for C25H3906: C, 69.10; B, 8.81. Found: C, 68.85; B, 8.75. Benzyl 2(BJ-lS<a>-Vinyl-3(&)-aetbyl-5-(5(BJ-aetbozy.etbylenozy-6R-.etbyl-2(a)-tetrahydropyranyl)-2(JO-tetrabydrofuryll-botyl Bther (48). To a stirred suspension of 14.86 gm (41.43 mmo1) of methy1tr iphenyphosphonium bromide in 150 mL of dry TBP at -78° C under argon was added 14.9 mL (39.18 . mmol) of a 2.63 M solution of n-buty11ithium in hexane. Cooling was then discontinued and the reaction mixture was stirred at room temperature for one hour, then cooled to -7 8° c. A solution of 7.285 g (16. 76 mmol) of the aldehyde 47 in 50 mL of dry THF was added, and the cooling was discontinued. After 10 h, the reaction mixture was treated with 20 mL of saturated aqueous Naaco 3 , diluted with 600 mL of ether, washed with 200 mL of saturated aqueous NaBco 3 , 200 mL of saturated aqueous NaCl, and then dried (Mgso 4 >. Removal of the solvents at reduced pressure and flash chromatography of the residue on 500 9 of silica gel with St ethyl acetate in petroleum ether afforded 6.71 g (92t) of the adduct 48: evaporative dis~illation 140-150° C 74 co.oo s mmBg> 1 lal D -50.9° (~1.065, C8C1 3 >1 IR CC8Cl 3 > 146 o, 1380, 1100, 1030 cm-1; 18 NMR (CDC1 3 ) <5 0.91 (t, 38, J•6 8z, ca3 c8 2 >, 0.94 Cd, 38, J•6 8z, CB.3 C8CC), 1.20 Cd, 38, J•6 8z, CB. 3 CBOC), 3.32 (s, 38, OCB 3 >, 4.47 Cbs, 28, C6 8 5 CB. 2 >, 4.59 Cbs, 28, OC8 2 0>, 5.02. (dd, 18, J•3 8z, 10 8z, BC•CHB(c)), 5.20 (dd, 18, J•3 Bz, 18 Hz, HC•CBB.(t)), 5.87 (dd, 18, J=lO 8z, 18Hz, HC•CB2), 7.32 Cbs, 58, C6Hs>· Anal. Calcd. for c 26 a 40 o5 : c, 72.19; B, 9.32. Found: c, 72.04; B, 9.32. Benzyl 2W-IS(B)-Btbyl-3(lU-aethyl-5-(5(&).etbozy.etbylenozy-6ClU-aetbyl-2(a)-tetrabydropyranyl)-2(B)tetrabydrofuryllbutyl Bther (49). To a solution of 6.71 gm (15.4 mmol) of the olefin 48 in 200 mL of ethyl acetat~ was added approximately 20 mL of W-2 Raney Nickel catalyst and the resulting atmosphere. suspension stirred under a hydrogen After 12 h, the catalyst was removed by filtration and then the solvent was removed under reduced pressure. Flash chromatography of the residue on 300 g of silica gel with 8\ ethyl acetate in petroleum ether afforded 6.509 g (97%) of the saturated material 49: distillation 140-150° C (0.005 mm8g); (k,1.011, CHCl3) 1 IR 1040 cm-1 1 CCHCl3) 1460, 1380, evaporative (a1 0 21 -27.8° 1210, 1110, 18 NMR (CDC1 3 ) 6 1.17 (d, 3H, J•6 Hz, CH 3 CHOC), 3.33 Cs, 38, OCh 3 >, 4.44 Cbs, 28, OCH20), 7.33 Cbs, SB, C685). 71.85; 8, 9.74. Pound: c 6 8 5 ca 2 >, 4.57 Cbs, 28, Anal. Calcd. for C2684205: c, 71.89; B, 9.64. C, 75 Benzyl 2(B)-(5(&)-Btbyl-3(&)-aetbyl-5-(5(BJ-bydrozy6()0-.etbyl-2(JU-tetrabydropyranyl)-2(1J-tetrabydrofuryllbutyl Btber (50). By the procedure described for the preparation of the alcohol 34, 6.509 g (14.98 mmol) of the methoxymethyl ether 49 in 80 mL of TBF and 20 mL of lOt aqueous BCl afforded, after flash chromatography on 200 g of silica gel with 25\ ethyl acetate in petroleum ether, 5.8S mg (100\) of the alcohol 50: evaporative distillation 14 0-lS 0 ° C ( 0. 0 0 S mmBg )_J [ a 1 D -2 6 •3 <k 0. 6 81 , CBC1 3 ) ; (CBC1 3 ) 36SO, 3480, 1470, 1400, 1120, 1080 cm-11 IR la NMR (CDC1 3 )60.83, 0.92 (2t, 68, J•6 Bz, 2Ca3 ca 2 >, 0.97 (d, 3B, J=6 Bz, CH3CBCC), 1.17 (d, 38, J•6 Bz, CB3CBOC), 4.46 (s, 28, Phca 2 o>, C24B3904: 7.32 (bs, SH, Ph-a>. C, 73.81; B, 9.81. Found: Anal. Calcd. for C, 74.02; B, 10.03. Benzyl 2 (&)- ( 5 (IJ -Btbyl-3 (&) -aetbyl-5- (6 (IJ-aetbyl-5ozo-2(4)-tetrabydro-pyranyl)-2(1J-tetrabydrofuryll-butyl Btber (51). To a stirred solution of 1.7 mL (19.5S mmol) of oxalyl chloride in SO mL of dry dichloromethane at -60° C under argon was added 3.12 mL (44.0 mmol) of dimethylsulfoxide. After 10 min, a solution of 5.85 g (14.98 mmol) of the alcohol 50 in SO mL of dry dichloromethane was added to the reaction mixture. After 15 min, the reaction mixture was treated with 12.5 mL (89.7 mmol) of dry triethylamine, allowed to warm to room temperature and then diluted with 3SO mL of ether. water, This mixture was washed with 200 mL of 200 mL of saturated aqueous Naaco 3 , 200 mL of 76 saturated aqueous NaCl, and then dried CMgso 4 >. Removal of the solvents at reduced pressure, and flash chromatography of the residue (10' ethyl acetate in petroleum ether), afforded 5.753 g distillation (99') of the ketone 51: 120-130° CCO.OOS mmHg); evaporative [a]D21 +61.1° (k0.570, CBC1 3 ); IR (CBC1 3 > 1720, 1460, 1380, 1110 cm-1; 1 B NMR (CDC1 > 6 1.27 Cd, 3B,, J•6 Bz, Cll CBOC), 4.30 (q, 3 3 1B, J=6 Hz, caco>, 4.44 <s, 2B, c 6 a 5 ca 2 >, C6Bs>· Anal. Calcd. for C24B3604: Found: c, 74.26; B, 9.47. 7.33 Cbs, sa, C, 74.19; B, 9.34. Benzyl 2 (Jl)- [ 5 (&) -Btby1-3 (Jl) -aetby1-5- (6 W-aetbyl-Smethylene-2(a)-tetrahydropyranyl)-2(Jl)-tetrahydrofuryl1butyl Btber (52). By the procedure described for the preparation of the adduct 48 2.850 g (7.33 mmol) of the ketone 51 in 53 mL of dry TBF with 18.33 mmol of methylene- triphenylphosphorane afforded, after flash chromatography on 150 g of silica gel with 4% ethyl acetate in petroleum ether 2.764 g (97%) of the corresponding olefin 52: evaporative distillation 120-130° C (0.005 mmBg); [a1 0 2 4 -8.2° IR 1460, (kl.203, CBCl3); (CHC13) 1080 cm-1; ~B NMR (CDC1 3 ) o 0.83, 0.93 1380, 1120, (2t, 6H, J=6 Hz, ca 3 cH 2 >, 0.97 (d, 3B, J=6 Hz, ca 3 cacc>, 1.30 (d, 3B, J=6 Hz, C1i 3 CHOC), 4.43 (q, lH, J=6 Hz, CHC=C), 4.47 (s, c 6 a5 ca2 >, 4.67 (bs, 2B, C=CB 2 ), 7.31 Cbs, SB, C6 H5 ). Calcd. for C25H3903: H, 10.00. C, 77.68; B, 9.91. Found: 2H, Anal. C, 77.81; 77 Benzyl 2 (&)- [ 5 (JU -Btbyl-3 (Jl) -aethyl-5-(3 W-1,5-diozo4(ll)-.etbyl-spiro-[2.5]-6(!0-octyl)-2(ll)-tetrabydrofuryllbutyl Btber (53). 'l'o a stirred solution of 2.612 g (6. 76 mmol) of the olefin 52 in 70 mL of dry dichloromethane at 0° C under argon was added 2.3 g (27.4 mmol) of solid NaHC0 3 and 2.3 g perbenzoic acid. (10.6-11.9 mmol> of 80-901 m-chloro- Cooling was then discontinued, and the reaction mixture was stirred at room temperature for 3 h. After treatment of this mixture with 30 mL of 10% aqueous Na 2 so 3 , the resulting mixture was diluted with 300 mL of ether, washed with two 100 mL portions of saturated aqueous NaHC0 3 , 100 mL of saturated aqueous NaCl, and then dried CMgso 4>. Removal of the solvents and chromatography of the residue ·on 300 g of silica gel with lOt ethyl acetate in petroleum ether afforded 1.950 g of the epoxide 53 and 568 mg of the epimeric epoxide (ratio of 3.4:1 of 93t combined yield). Epoxide 53: evaporative distillation 13014 0 C ( 0. 0 0 5 mmHg) 1 [ a ] D2 4 +4 • 8 ° (k_l. 0 2 5 , CBC1 3 ) 1 I R (CHC1 3 ) 1460, 1380, 1120, 1080 cm-lJ lH NMR (CDC1 3 ) o 0.86, ° 0.93 (2t, 6H, J=6 Hz, ca 3 ca 2 >, 0.97 (d, 3H, J=6 Hz, C1i 3 CHCC), 1.27 (d, 3H, J•6 Hz, C1i 3 CHOC), 2.52 (d, lH, J•4 Hz, CCHliO), 2.59 (d, lH, J•4 Hz, CCB.HO), 4.47 Cs, 2B, C6 B5 CB. 2 ) , 7 • 3 3 ( b s, 5 H, , C6 H5 ) • An a 1. Ca 1 c d. for C2 5 H3 80 4 : C, 74.59; H, 9.51. Found: c, 74.70; H, 9.60. Epi-epoxide 53: evaporative distillation 130-140° C (0.005 mmHg); IR (CHC1 3 ) 1460, 1380, 1120, 1080 cm-11 lH NMR (CDC1 3 ) a 0.86, 78 ca 3 cs 2 >, 0.97 (d, 3B, J•6 Bz, ca3 CBCC), 1.24 Cd, 3H, J•6 Bz, ca3 CBOC), 2.58 Cd, 1H, J•5 0.93 (2t, 6B, J•6 Bz, Hz, CCBJIO), 2.71 (d, lB, J•5 Hz, CCllHO), 4.47 (s, 2H, c 6 H5 ca2 >, 7.31 Cbs, 5H, c 6 H5 >. Benzyl 2(JU (5(1l)-Bthyl-3W-•ethyl-5-(5(S)-ethyl-5bydrozy-6(1l)-.ethyl-2(~-tetrahydropyranyl)-2(~-tetrahydro­ furyll-butyl ether (54). To a stirred suspension of 5.1 g (24.9 mmol) of cupric bromide-dimethyl sulfide complex in 36 mL of dry pentane at 0° C was slowly added 32 mL (49.2 mmol) of 1.54 M low halide methyl lithium in ether and the resulting white suspension was stirred at 0° c. After 30 min· a solution of 1.901 g (4.72 mmol) of the epoxide 53 in 12 mL of dry pentane was added slowly. After 2 h, the reaction mixture was treated with 40 mL of saturated aqueous NB 4 Cl and diluted with 200 mL of ether. The organic phase was separated and washed with two 200 mL portions of saturated aqueous NB 4 Cl and one 200 mL portion of brine, then dried (Mgso 4 > and then the solvent was removed under reduced pressure. Plash chromatography of the residue on 150 g of silica gel with 1St ethyl acetate in petroleum ether afforded 1.975 g (99.9%) of the alcohol 54: ative distillation 180-190° C (0.005 mmBg) 1 evapor- lal D24 -21.3° (k1• 3 2 0 , CBCl3 ) 1 I R (CBCl3 ) o 3 5 8 0 , 14 6 0 , 13 8 0 1 112 0 1 11 0 0 1 1050, 960 cm-1; 1a NMR (CDC1 3 ) ca 3 CBCC), 1.18 (d, 3B, J•6 Bz, 0.96 (d, 3H, J•6 Hz, ca 3 CBOC), 3.76 (q, lB, 79 J=6 Hz, CB 3 CHOC), 4.47 (s, 2B, Phca2o>, 7.33 (bs, SB, PhH). Anal. Calcd. for C26B4204: C, 74.60; B, 10.11. Found: C, 74.707 B, 10.18. 2(1J-15(1J-Btbyl-3(&)-.etbyl-5-(5(4)-ethyl-5-hydrozy6(JU-.ethyl-2(~-tetrahydropyranyl)-2(BJ-tetrahydroforyll­ batan-1-ol (55). To a stirred solution of 3.5 em (21 mmol) of lithium wire in 80 mL of anhydrous liquid -78° C under argon was added a ammonia at solution of 1.975 g (4. 72 mmol) of the monoben.z yl ether 54 in 20 mL of dry TBF. Cooling was then discontinued (ammonia reflux> and after 1 h, 1.75 g (33 mmol) of anhydrous ammonium chloride was cautiously added to the reaction mixture. The resulting mixture was then diluted with 100 mL of ether and the ammonia was allowed to evaporate. The resulting suspension was filtered and the solid was washed by trituration with four SO mL portions of ether. Removal of the solvent at reduced pressure from the combined filtrates and then chromatography of the residue on 120 g of silica gel with 40% ethyl acetate in petroleum ether afforded 1.507 g (97%) of the diol 55: mp 74-75° C (hexane); [a1 0 21 -14.5° (k,l.l6, CBCl3); IR (CBC13) 3600, 3500, 1460, 1380, 1100, 1050, 950 cm-1; 1a NMR (CDC1 3 ) 6 0.96 (d, 3H, J•6 Hz, ca 3 CBCC), 1.22 (d, 3B, J=6 Bz, CH 3 CBOC), 3.73 (q, lH1 J=6 Bz, CB 3 CHOC). An a 1. Ca 1 c d. for C19 B3 6 0 4 : 69.55; B, 10.97. C, 6 9. 4 7 1 B, 11. 0 5. Pound : C, 80 2CJ0-15C&)-Bthyl-3(&)-.ethyl-5-(5(A)-ethyl-5-bydrozy6CI)-.ethyl-2(JD-tetrabydropyranyl)-2(1J-tetrabydrofuryllbatanal (56). By the procedure described for preparation of the ketone 23, treatment of 1.5070 9 (4.588 mmol) of the aicohol 55 with 0.81 mL (6.0 mmol) of DMSO, 0.45 mL (5.05 mmol) of oxalyl chloride, 1.6 mL of dry triethyl amine in 20 mL of dry dichloromethane afforded, after flash chromatography on 120 9 of silica gel with 1St ethyl acetate in petroleum ether 1.499 9 ClOOt) of the aldehyde 56: evaporative distillation 130-140° C (0.005 mmH9); [a] 0 21 +2.4° (0.971, CHCl3>1 IR CCHCl3) 3600, 3450, 2750(d), 1720, 1460, 1390, 1230, 1130, 1100, 1060, 960 cm-1; la NMR (CDC1 3 > 0.97 (d, 3H, J•6 Hz, CH 3 CBCC), 1.18 (d, 3H, J•6 Hz, CH 3 CHOC), 9.64 (d, lH, J•3 Bz, CHO). <5 4CIJI5(B)-Btbyl-3C&>-.etbyl-5-C5Ca)-ethyl-5-bydrozy6(BJ-.ethyl-2CJD-tetrabydropyranyl)-2(&)-tetrahydrofuryllbezan-3-ol (57). To a stirred solution of 1.499 9 (4.589 mmol) of the aldehyde 56 in 35 mL of dry TBF at -78° C under argon was added 8 mL (16 mmol) of a 2.0 M solution of ethylmagnesium bromide in TBF. solution wa~ The resulting stirred at room temperature for 12 h, cautiously treated with 10 mL of saturated aqueous NB 4Cl and then diluted with 200 mL of ether. The organic phase was separated and wa.shed with 200 mL of saturated aqueous NB 4Cl and 100 mL of saturated aqueous NaCl, then dried (Mgso 4 >. Removal of the solvent at reduced pressure and then flash 81 chromatography of the residue on 230 g of silica gel with a gradient of 30 to SO\ ethyl acetate in petroleum ether afforded 98.4 mg (6\) of the alcohols 55 of the diastereoisomeric mixture of and 1.502 g (92\) alcohols 57: evapor- ative distillation 120-130° C CO.OOS mmHg)J IR (CBC1 3> 3600, 3500, 1460, 1380, 1130, 1100, 1060, 960 cm-1, 1H NMR (CDC1 3 ) 1.20 Cd, 3H, J•6 Hz, Cll 3 CHOC). 4 CJ.)-[5 <&> -Bthyl-3 C&> -.ethyl-5- (5 Cal-ethyl-5-hydrozy6C&>-.ethyl-2(S)-tetrahydropyranyl)-2C&>-tetrahydrofaryllhezan-3-one (3). By the procedure described for the preparation of ketone 23, treatment 1.502 g of the alcohol 56 (4.213 mmol) with 0.81 mL of DMSO (6.0 mmol), 0.45 mL oxalyl chloride (5.05 mmol), 2.5 mL of triethylamine in 20 mL of dry dichloromethane afforded, after flash chromatography on 120 g of silica gel with 15\ ethyl acetate in petroleum ether, 1.286 g (87\) of the enantio-right half ketone 3: evaporative distillation 200°C (0.001 mmHg) 1 [ a] D2 5 + 2 3 • 6 ° (~1. 7 0 5 , CBC1 3 ) 1 I R (CBC1 3 ) 3 6 0 0 , 1 7 1 0 , 14 6 0 , 1385, 1135, 1100, 1060, 960 cm-1; 1a NMR (CDC1 3 ) o 1.20 (d, 38, J=6 Hz, CB 3 CBOC), 3.74 (q, 1H, J=6 Hz, CB 3 CHOC). Calcd. for C21B3904: C, 71.151 H, 10.80. Pound: Anal. C, 71.20; H, 10.81. Bnantio-Benzyl Lasalocid A (58a). To a solution of 1.799 mmol of LDA in 2 mL of dry benzene at 0° C a solution of 303.6 mg (0.856 mmol) of the ketone 3 in 3 mL of dry benzene was added over 10 min and the resulting solution 82 stirred at 0° c. After 10 min, 1.43 mL (0.88 mmol) of 0.66 Jl zinc chloride in ether37 was added to the reaction mixture. After 20 min a solution of 142.8 mg (0.438 mmol) of aldehyde 2 in · 2 mL of dry benzene was added rapidly and the resulting mixture was stirred at 0° c. After 4 min, the reaction mixture was poured into SO mL of vigorously stirred saturated aqueous NH 4 Cl, and the resulting mixture was extracted with two SO mL portions of ether.The combined organic extracts were dried (MgS0 4> and then the solvent was removed under reduced pressure. Plash chromatography of the residue on a 2.7x24 em column of silica gel with 300 mL of lOt, SOO mL of 1St, SOO mL of 20t and SOO mL of 30t ethyl acetate ·in petroleum ether and then high pressure liquid chromatography of the mixed fractions with 1St ethyl acetate in hexane afforded 116.1 mg (39t) of the d -e sired diasteriomer Sla, 38.2 mg Cl3t) of the aldol product Sib , 22.0 mg C7t) of the aldol product Sic and 13.7 mg C4.6t) of the aldol product Sid or a 64t combined yield in a ratio of 61:20:11:7: Compound Sla exhibited la NMR and IR spectra that were in agreement to those obtained from Benzyl Lasalocid A.9 Aldol 2 Sib CErythro-Cram): [a] 0 22 +20.60° Ck1.19, CBC1 3 )J IR CCBC1 3 > 34SOvb, 2980, 29SO, 289S, 168Sb, 160S, 1460, 138S, 12SO, 1150, 9SS cm-lJ lB-NMR CCDC1 3 ) Cs, 38, ArCB 3 >, S.41 (s, 2H, PhCB2 -o>, 6.6S (d, lB, J•7.S Hz, ArB), 7.18 (d, lH, J•7.5 Hz, ArE), 7.40 Cm, SB, 6 2.20 Phll). 83 Aldol 3 Sic (Three-Anti Cram): CBCl3) 1 IR (CHC13) 3400b, 2970, 2940, 2885, 1700, 1655, 1460, 1385, 1250, 1148, 955 cm-1, 1H NMR (CDC1 3 ) 2.25 Cs, . 3B, ArCH 3 >, 5.40 Cs, 2B, PhCH 2 0>, 6.65 Cd, 18, J•7.5 Hz, ArH), 7.15 Cd, 1B, J•7 .5 Bz, ArB), 7.38 Cm, 5B, PhH). Aldol 4 Sid (Erythro-Anti Cram): (a 1 0 22 +8.81 ° (~1.84, CHC1 3 >1 IR CCHC1 3 > 3500vb, 2970, 2940, 2880, 1695, 1655, 1455, 1382, 1265, 1145, 955, 700 cm-lJ lH NMR CCDC1 3) o 2.20 Cs, 3H, ArCH 3 >, 5.40 (m(AB), 2H, PhCH 2 0>, 6.60 Cd, lB, J•7.0 Hz, ArH), 7.17 Cd, lB, J•7.0 Hz, ArH), 7.40 Cbs, SB, Phil). Bnantio Lasalocid A-aodiua salt (1). A solution of 774 mg (1.147 mmol) of the ester 58 in 12 mL of absolute ethanol containing 70 mg of 5% palladium on carbon was stirred under an atmosphere of hydrogen for 12 h. The catalyst was then removed by filtration and then the solvent was removed under reduced pressure. Plash chromatography on a 3.0x24 em column of silica gel eluting successively with 200 mL of each 20t, 30t, 40t and SOt ethyl acetate in petroleum ether afforded 641.2 mg (96%) of the corresponding acid: (aJ 0 22 +40.1° (~0.565, CHC1 3 >1 IR CCHC1 3 ) 3300 vb, 2940, 2880, 2860, 1705, 1655, 1460, 1385, 1100 cm-1, la NMR CCDC1 3 > o 2.16 Cbs, 3B, ArCll3 >, 2.85 Cm, 2H, CllCOCll), 3.34.4 (complex multiplet&, 4H, CllOC's), 6.43 Cd, lB, J•6.5 Hz, Ar>, 6.95 Cd, lB, J•6.5 Bz, Ara>. To a solution of 616.6 mg (1.04 mmol) of the above acid 84 in 15 mL of dichlorometbane was added 0.7 g (8.3 mmol) of anhydrous sodium carbonate and the resulting mixture was stirred at · room temperature under argon. After 10 h, the mixture was diluted with 35 mL of benzene and filtered. Removal of the solvent under reduced pressure gave 663.1 mg (99. 7') of enantio Lasalocid A-sodium salt: mp 169-172° C (benzene/cyclohexane, 1:20); (al 0 22 +84.0° (~0.96, CBC1 3 >; ( 10 22 +31.4° (~0.89, MeOB) 1 IR (CBC1 3 ); 3530 b, 2980, 1710, 1600, 1460, 1385, 1170 b, 1105, 1050 cm-1; la NMR (CDC1 3 ) ~ 2.18 (s, 3B, Arca3 >, 6.40 (d, lB, J•6.6 Bz, ArB.), 6.92 (d, lB, J•6.6 Hz, ArB.), 14.3 Cbs, lB, ArOB.). The IR and lH-NMR spectra were in excellent agreement with those obtained from natural lasalocid A-sodium salt. Anal. c 34 a 53 o8 Na: c, 66.77; c, 66.64; a, 8.72. Found: Bnantio-epilasalocid A-sodiua salts. Calcd. for a, 8.61. The undesired diasteriomers from the above aldol were transformed into their respective acids then sodium salts by the above procedure for the preparation of 1. follows: Their physical data Aldol 2 acid (Erythro-Cram): [a] D22 +13.27° CBCl3) 3460b, 2970, 2940, 2880, 1700, 1655, 1458, 1415, 1382, 1230b, 1160, 1100, 1040, 950 cm-1; 1 H NMR (~1.605, (CDC1 3 > o 2.28 (m, 3B, ArCB 3 >, 6.67 (d, · lB, J-8.0 Bz, ArJl), 7.22 (d, lB, J•8.0 Hz, ArB). Aldol 3 acid (Threo-Anti Cram): [ a]D22 +13.10° (~1.43, CBCl3); IR (CBC13) 3440b, 2970, 2940, 2880, 1695, 1655, 1460, 1415, 1385, 1230vb, 1165, 1095, 1045b, 965b cm- 1 ; 85 1a NMR (CDC1 3 > o 2.23 ( s, 3H, Arca3 >, 6.69 (d, 1H, J•8.0 Bz, ArH), 7.23 (d, 1B, J•8 Bz, ArH). Aldol 4 acid CErythro-Anti Cram): [a 10 22 +81.67° (~1.10, C1:ICl3) J IR CCBCl3) 3520b, 2970, 2940, 2880, 1698, 1652, 1460, 1410, 1380, 1230vb, 1155, 960 cm-1, la NMR (CDC1 3 ) ~ 2.23 {s, 3B, Arca3 >, 6.63 (d, 1B, J•8.0 Bz, ArB), 7.21 (d, lH, J•8.0 Bz, ArR). Aldol 2-sodium salt {Erythro-Cram): [a] 0 22 -35.52° (~0.855, CHCl3); IR CCBCl3) 3300b, 2960, 2920, 2870, 1695, 1588, la NMR (CDC1 3 ) 6.47 (d, lB, J=6.5 Hz, ArH), 6.98 (d, 1452, 1378, 1100, 1025, 960, 940, 905 cm-1J o 2.20 {s, 3B, Arca3 >, 1H, J=6.5 Hz, ArR). Aldol 3-sodium salt {Threo-Anti Cram): {k2.025, CHCl3); IR (CHC13) 3300b, 2960, 2920, 2870, 1685, 1590, 1455, 1380, 1100, 960, 945, 905 cm-lJ o 2.18 Cbs, 3B, ArCR3 >, 1H-NMR (CDC1 3 ) 6.43 (bd, lB, J=6.5 Hz, ArR), 6.96 (d, lH, J~6.5 Bz, ArR). Aldol 4-sodium salt {Erythro-Anti Cram): [a1 0 22 -36.18° {kl.345, CHC1 3 )J IR {CBC1 3 > 3250vb, 2960, 2920, 2870, 1690, 1595, 1455, 1378, 1310, 1095, 945, 905 cm-1; la NMR o 2.20 Cbs, 3B, Arca3 >, {d, lB, J•7.0 Bz, ArR). (CDC1 3 ) 6.42 {d, lB, J=7.0 . Bz, ArR), 6.98 86 llBPBRBBCBS 1. The authors express their grateful appreciation for the support of this program by a grant from NIB Grant No. BL-23167. Acknowledgement is also made for use of the Southern California Regional NMR Facility (National Science Foundation Grant No. CBE-79-16324). It is a particular pleasure to acknowledge the support of the Hoffmann-La Roche Foundation through a grant and to the late Willy Leimgruber, Director of Chemical Research, for his moral support and supplies of Lasalocid A. 2a. Postdoctoral Fellow of the National Institute of General Medical Sciences (GM 08522). 2b. NSERC (Canada) Predoctoral Student.s hip (1979-1982). 3. Ireland, R. E.; Anderson, R. C.; Badoud, R.; Fitzsimmons, B. J., McGarvey, G. J., Thaisrivongs, s. and Wi 1 cox, C. S. ~ Am... th.e.Dl.a. ~ 19 8 3, l..Q.S., 1988-2006. 4. Pressman,B. C.and Fahim, M. ~ ~ Pbarmacol. 1982, ll, 465-490. 5. Pressman, B. C. and deGuzman, N. T. ~ 1975, .2..U,, 6. Van Breemen, ~ LL. Acad. 373-386. c., Aaronson, P. and Loutzenhizer, R. Pharmacol. ~ 1979, ~' 167-208. 1. Pressman, B. c., Painter, G. and Fahim, M. in: Inorganic Chemistry in Biology And Medicine, 87 Martell, A. B., ed., ACS Symposium Series No. 140, American Chemical Society, Washington, D.C., 1980, pp. 3-22. 8. Painter, G. R. and Pressman, B. c. in •Topics in Current Chemistry•, P. Vogtle, ed., Springer-Verlag, New York, N.Y. , 1982, JJU, pp. 83-110. 9. Westley, J. w., Oliveto, E. P., Berger, J.J Evans, R. B., Jr., Glass, R.J Stempel, A.J Toome, v. and Williams, T. 10. Westley, J. ~ ~ Chem. 1973, 16, 397-403. w., Evans, R. B., Jr., and Blount, J. P. J..&. Am... kh.am.... Soc. 1977, ll, 6057-6061. 11. Papies, 0. and Grimme, w. Tetrapedron Lett. 1980, 2799-2802. w. 12. Grimme, Personal Communication 1980. 13. Chamberlain, P. and Rooney, A. B. Tetrahedron Lett. 1979, 383-386. 14. Straus, F. 1 Kollek, L. and Beyn, w. kh.all.L Ber ichte 1930, Al, 1868-1885. J..&. Q..t..;,.. kh.am... 19 7 4 , J.i, 3 913-3 918. 15. Brown, C. A. 16. Bouse, B. o. and Thompson, B. w. .2.6,, 17. ~ kh.alll.&. 1961, 3729-3734. Bouse, B. o., Czuba, L. J.J Gall, M. and Olmstead, B. P. ~ o..t.g._ Chem. 1969, ll, 2324-2336. 18. The use of LDA, LBMDS, Ph 3C-Li+ under thermodynamic conditions (<1.0 eq. base). 19. Teck, A. B. and Siong, B. K. kh.am... Abstr. 1979, J..Q., 88 203355a, p. 558. 20. Cooling of the reaction mixture or addition of the trapping reagent after enolization led to substantially lower yields of the diene 10. Diene 10 vas stable at 0° under argon for several weeks, however, exposure to air led to slow aromatization. 21. The yield of the cycloaddition could not be improved by the addition of radical inhibitors or insoluble bases, while addition of soluble nitrogen containing bases led to immediate decomposition of the dienophile. 22. Lerner, L. M. 23. Pletcher, B. G., Jr. in •Methods Carbohydr. Chem.•, Carbohydr. ~ 1975, ~' 116-120. R. L. Whistler and M. L. Wolfram, ed., Academic Press, New York, N.Y., 1963, ~, pp. 386-389. Tetrahedron 1978, l!, 1651-1660. 24. Omura, K. and Swern, D. 25. If methyllithium-lithium bromide complex was used, rather than low halide methyllithium, the selectivity of addition drops to 3:1 (a:B attack). 26. Kindly performed by w. c. Still, Columbia University. 27. Still, w. c. 28. Still, w. c. and McDonald, J. B., III. Personal Communication 1982. Tetrahedron Lett. 1980, 1031-1034. 29. The glycoside oxygen of 25 vas initially protected as the benzyl glycoside with the intention of removing it at this point by hydrogenolysis or lithium/ammonia reduction. Unfortunately, hydrogenolysis could not be 89 accomplished under any conditions attempted and although lithium/ammonia removed the benzyl group, the product proved difficult to isolate i"n good yield. 30. Ireland, R.· E. and Vevert, J. P. iL.. QI.sJ.... Chem. 1980, ,iS., 4259-4260. 31. Hicks, D. R. and Fraser-Reid, B. Synthesis 1974, 203. 32. Kindly performed by Dr. M. Spedding, Centre de Recherche, Merrell International, Strasbourg, Prance, and Dr. J. w. Westley, Research Division, Hoffmann-La Roche, Inc., Nutley, N.J. 33. Phillies, G. D. J. and Stanley, B. E. iL.. ~ Chem. ~ 1976, !a, 3892-3897. 34. Boiling points are uncorrected. Melting points were determined using a Hoover capillary melting point apparatus and are uncorrected. Infrared CIR) spectra were determined on a Perkin-Elmer 2378 or infrared spectrometers. Proton nuclear magnetic resonance <lB-NMR) spectra were recorded on Varian EM-390 or Bruker WM-500 spectrometers. Chemical shifts are reported as values in parts per million relative to tetramethylsilane Co 0.00) as an internal standard. Optical rotations were measured in 1 dm cells of 1 mL capacity using a Perkin-Elmer Model 141 or a JASCO Model DIP-181 polarimeter. Chloroform, when used as a solvent for optical rotation determinations, vas filtered through neutral alumina immediately prior to 90a use. Analytical vapor phase chromatographic (VPC) analyses were performed on a Hewlett-Packard 5750 gas chromatograph, equipped with a flame ionization detector, using helium carrier gas at a flow rate of 2 mL/min, preparative VPC on a Varian 930, equipped with a thermal conductivity detector, at a flow rate of 60 mL/min. The indicated liquid phase was absorbed on 60-80 mesh Chromosorb W AM DMCS. Analytical thin layer chromatography (TLC) was conducted on 2.5 x 10 em precoated TLC plates, silica gel 60 F-254, layer thickness 0.25 mm, manufactured by E. Merck and Co., Darmstadt, Germany. Preparative TLC was conducted on 20 x 20 em glass plates coated in this laboratory with a 0.6 mm thickness of silica gel G •for TLC ace. to Stahl• (5-2Sp) manufactured by E. Merck and Co., Darmstadt, Germany. Silica gel columns for chromatography utilized E. Merck •silica Gel 60•, 70-230 mesh ~TM, flash chromatography used 230-400 mesh ASTM. Alumina ~efers to the Brockmann Activity I-Neutral material manufactured by M. Woelm. Analytical high pressure liquid chromatographic (BPLC) analyses were performed on a Perkin-Elmer Series 2 BPLC equipped with a Perkin-Elmer analytical silica column and a variable wavelength ultraviolet absorption detector using the indicated solven · ·t 1.9 mL/min. - ~rmed Preparative BPLC wasp~ a flow rate of on the above system except that a Perkin-Elmer preparative silica column and a flow rate of 23 aL/min were used. •ory• solvents were distilled shortly before use from an appropriate drying agent. Ether and tetra- hydrofuran CTBF) were distilled under dry argon from sodium metal in the presence of benzophenone. B- Pentane was distilled from sodium metal under argon. Benzene and toluene were distilled from calcium hydride. Dichloromethane was distilled from phosphorus pentozide. Methanol was distilled from magnesium methozide. Bexamethyl-phosphoramide CBMPA) was distilled at -1.0 mmBg from pulverized calcium hydride. Triethylamine and diisopropylamine were distilled under argon from sodium-benzophenone immediately prior to use. Pyridine and hexamethyldisilazane were all distilled before use from calcium hydride. Ammonia was distilled from the tank and then from a blue lithium solution. Other reag,nts were purified as follows: oxalyl chloride was distilled under argon, n-butanoyl chloride vas heated at reflux for 3 hours with phosphorus pentachloride, then distilled, and the distillate was treated with quinoline and redistilled; methyl iodide was distilled from phosphorus pentozide immediate before use, trisdimethylaminophosphine (TDAP) was distilled under argon before use; chloromethyl methyl 91 ether was dried for several hours over anhydrous calcium chloride, decanted and stirred briefly with anhydrous potassium carbonate, and then distilled under argon from anhydrous calcium chloride. Ammonium . chloride was dried at 75° C under vacuum (1 mmBg) over phosphorus pentoxide for at least 12 hours. All other reactants and solvents were •Reagent Grade• unless describ~d otherwiRe. •Ether• refers to anhydrous diethyl ether which is supplied by Mallinckrodt and Baker. •petroleum ether• refers to the Analyzed Reagent grade hydrocarbon fraction, bp 35600 C, which is supplied by J. T. Baker Co., Phillipsburg, NJ, and was not further purified. Reactions were run under an argon atmosphere arranged with a mercury bubbler so that the system could be alternately evacuated and filled with argon and left under a positive pressure. Syringes and reaction flasks were dried at least 12 hours in an oven (at 120° to 140° C) and cooled in a desiccator over anhydrous CaS04 prior to use. Elemental combustion analyses were performed by Spang Microanalytical Laboratory, Eagle Harbor, MI. 35. Wolinsky, J.; Novak, R. and Vasileff, R. ala.~ th.e.m.... 1964, ~, 3596-3598. 36. Whistler, R. L. and BeMiller, J. N., Jlethods Carbohydr. Chem. ~' 1963, 484-485. 92 37. Bouse, B. 0.; Crumrine, D. s., Teranishi, A. Y. and Olmstead, B. D. ~ ~ Chem. ~ 1973, ~' 3310-3324. 93 APPENDIX The Total Synthesis of Polyether Antibiotics. The Synthesis of Lasalocid A (X-537A) 94 The Total Synthesis of Ionophore Antibiotics. A Convergent Synthesis of Lasalocid A (X537 A) 1 ..... E.fnUII.• . . . . c. ~2 . . . . . . . . . . . . ., . . . . J.l'k"' Ga.. J. MeGaney,1 Slmt n.ilrtt011p.1 Ull Cnia S. Wilen c:.trllndiDII No. 6704 ,,., tlw Clwrrlieal l.lllloNlorta. Clll/ontill lllllitut• of T«lutoloo. ,,..,.. Clli/onUII. 91J2j. ll«ftt»d Sqtmtlln 22. 1912 ~ The callltniCtion ol both the lift-tide aklellycle lllld the riabt... biGDCl awailable (ram tbl ,..,.. aJdal NICtian with tualocid A (X537A) il delcribed. For eacb ayathelia chiraJ sWtiDa materiala an ued. For the &Jdchydc l. (R)(-)<iuu.ilmc il the IGW'tiC of the loDe uymmctric CCDtCr ud the aromatic rill& ia prepared by a ~Alder r.ctiaa betweeD the pyrone 22 and Hdibcnzylamino)· I·P"It'YftC· for the ketone l . c:arbobydrate pi"'CW''Irr..W u the 10tarC1C of the fUI'IJIOid &ad pyranoid aubuniu. TIMie aubuDita an thea joiJMid tbroup the uc oC the liter CDOAate C1ai1eD rannacmcnt. Dctaila for the aJdol c:ondcnlatiOD betweaa the aldehyde 1 aDd the ziDc enolatC the Utofte 3 U'C pracnt8d, &Dd tbe formatioa tbe uuaral ioaophorc from tbia ~ complcta the Jliably tacaliJIItblaia. or caweraeat Tbc recCDtly characterized' polyether ionopbore aatibiotic:l' repnscnt a broad new c:1asa of bioqjc:ally potcnt c:anpou.nda that bave rapidly round cammc:rc:iaJ value • .......;cticwlta' and uabatic (I> n. aahan a..- tMir .,...,._. ~ r• .a.....,., o1 Lllil ......., by 1 P'IJII (ram NIH. Grut HL·l3167. Gra...nl acbcnr.........t i1 a11o made for - ol tal ScN&Mn Califcnil a.p.al NMil Facility (Natiaul sa- Foudatioa Grut CHE·'7t-1632'). It il a pilll\icUr ......,. 10 acbcnrladp tal apport ol Ho«_..Ldoc:lle FoudaU. dlraqll I P'IJil ud tae laLI 'lr'ilJy ~. ov-a. o/ o..ica1 ba.rch, ror lbl moral appan ud a,U. oii...MIIocid A. (2) NRC (Cuada) Patuloc&aral Fdlow, 19'71-lf79; NSEaC (C...· • )-NATO~ Fdlow. 1~1910. (l) Fa.dl Nat.iaDal SU. • Ia a.... ~ P ' :nl ,....,., 1979-1910. (') NSEilC (C&Mda) ........_,.1St........ l~lfl2. (5) Paa&dociGral Fallow ol .a. Nau..J USPHS, 19'71-1979. (6) UpjaMCo. ~ ....,_, 19'71-ltiO. ,_ttna.tlalailloiWil wart.-.: ~ S. ft.J). n.i1. CalifGnia a.iatt.c oiT.-...,, I flO. (7) Laalac::id A: . . . . . . . . . . . J.; a..lia. A. 1.; Saou. W . E.: Slaiablda. L H.; Ga6dllw&, M. W. J. Aa 0... Soc. lf51,1J, 5295-5291. ~W.UC, , J. 'lr'.; EYUI. a. H.. Jr~ " - . D. L.; ~ A. 0.... c-u-.. Jf'71. 1.t67-l'61. W.., S. M.; Jt.rria. J.; U.. S. J.; hal. 1. c. J. Alit. a-.. Soc. •,.. f1 • ..~)5 . (I) w-., C.; , . _ . . I . ....._-..~. . .. c - . .... IJ. 562. (f) 1iti1rcMc. M.; f*N' ' G. IWI. U. 1974. JJ. 1441. * c.- ......... a. or apnu 10 ia animal medicine. ID addition. tbe demonstration of tbc:ir powerful c::ardiotonic Ktivity 11 and appuent tilluc ldectMty 11 iD mammalian systems bolds promise for tbcir usc in buman pbannac:oloay. Ia liabt of thcac rauJu. it iJ not surprisina tbat tbe synthesis of t.bac molecules bas attracted tbc concern of IIUIDCr'OUI racarch IJ"CCUPP. and IC¥a'al reprscnutiYCs or this c1ua have yielded to tacal synthais. 12 One such effort raultina in the t.oW tyDtbcaia of luUocid A (X537A) (I) ia dacribed bercin.u (10) W.U.,, J. 'lr'. ~ . .. ll.t. a-. lt'75. ;o. 2oM. llua. A. P. V.S. hint~ 39J7 I H . (II) , . _ . . I . C. -n. lo6l ol M•..._ ia Maabatic Raplatian•; MUlmaa. M. A.. Hulaa. ll. \\'.,e..; Academic Praa: Ntw York. 1972; p 1'9. l..e¥y, J. V.; Coka, J. A.; I-'. Ci. N.,..n (l.GMCM) 19'73,141. .t61 . Gillal1a. P. C~ M - . ll.; Lft;a. Ill. M.; Sdlwaru. A. F«<. !"roc•• F«<. A"'· Soc. Eq. ltDI. 19'7,, JJ, 397. MlliT'Iy, J. J.; llellll. P. W.; Fay, F. S.l"roc. 11•1. .MM. Sft. U.S.A. lf'7S. 11, " "· .Oumu. N. T.; ,__.,I. C.; "-ter, k..; PUaar, P. ClUa. Ita. lf'7l.11, •n. 5awuu. A.; L&wU. R. M.; Huky, H. G.; M-.ll. G.; Dial. F. D.; llay, M. Y. On.lt.a. Jf'74. J4. 102. (ll)(a)~ e....D . A.;s.cb.C. E.;~'Ir' . A.; Tallar, T. a. J. Alit. a-. S«. Jm. /01, 671H791. c::m.:o. P. A.; 'lr'illiaml. E.; a•. T...U.. H.; Gilmaa. S. J. ()or. a.... 4J, 3537-3539. (b) l..aaJacid A: Nabta. T.; Sduaid. G.; Vr&DIIic, I .; Okipwa, M.; Smitii·Pa.hncr. T.; ~. Y. J . a . a.... S.. Jm.Joo, 2933-2935. (c) M011e111in: FU.· ,..._ T.; AbaUa. K.; ~. D. S.; 'lr'ua, C.·L J.; Sdlmid. Ci.; KiiiM. Y . /~. tm, 101,259-263. Still. 'lr'. C.; McDoMid. J.; CGMIIa. D. /IU. ....101.2117-llll. . 000l-7163/ll/1505-1911S01.50/0 0 1913 Amcricu Chemical Society 95 J. AM. CMa Soc., Jlol. 10$, No. 1, J98J TIIMI Syr~~IMIU ofltiiiOplltw AMIIIilllla n. ._.-.. r. tllil.,adlllil ... pndicat8d • •...,. ...... •IJIIliMI&ic . ...., tlaat caUl •..-.n) applild t.o . . . _ L Dlpld&U. 1811 Allloi-T,e J I! I 1989 of 1Miiodd A (X.S37A'/' GCiila ol....-aaa--- oldal..,.,.... ...... ... . . • ..u u t.o ,..tially illlpartut -an~ ........ 0.. tD &MIIniC:bnJ caaaplaity ud cMmical.-itiftty ol &M OCICIIIIriaa,.,.,....,..,...... • ..uy it_, .ay ........ .ma-t tala! .,..... tlaat • wider ...... olllicll li:aUy .. r.-tift anctan1 ftriutl will - - . aftilabll • _,... .....-m- r• ....tuatica nu. tala! IJIItMiil ot lllalocid A (X.537A) dla ,..._II DGI aa.ly u iiDpanaat objcm. ill ... fiabt. t.t a1lo 1 ......,.blc ~ ia wlaida t.o .,..._.. tM JIIIUIDtial .....,.Uty ot tM ~ ayatMUc ...... A llriJdaa llniCIIIriJ r..aare fli aat fli tbl pafytQir k rt • II till cbaia ol18bllitutld tarahydraiwu ud UIU'I.bydropyru rillp. Oae ol tJac limplelt IDIIIlber ol tbil paup illuUocid " (X537A) wlaida GDetaiDI ODC t.uahyclro(~ .ud ~ 18Ua· ·~ riq ia .-quace. It wu tJ.c obJCift ol tlail wart tD...., • IDitbadolocY t.o ......te tbe polyethlr ........ ia a buiJdiDc blact IDUDII' by joiniaa iadmdually perf'GnDid • · rallydro(wu ud/« tetrahydropyru riap. Not Gilly illllda • - · • pat apprcacll pouatiaUy JoPtic:aUY efllcicDt. bat it allo Gft'en the opponuaity (or I flaibll caaabiaatiaa fJI theG~ypD.....,. buildiDa blocb witllp8ibll widlllniCIUralwuiaa.. Allother llniCtUral f•tve tbat ilpnvallat ia ...... palywdllr ~-- ud a.11o oeatral t.o lualocicl A (X537A) il the al4lal·type liab... Ia the utitJaetjc-. tJac ClO.ll ._.. ol luaJoc:id A (X537 A) ~ the idlaJ paiDt at wllidl t.o dmde &MJDD61cU. ~ cb oLIIY piDid thraqb a ~ ia wbicb tbil panicuJar aldol-type IWap c:u be ~blilbed from oc.dcn.... fli the lctt4de aJdebY* 2 ud the .......... 3 ...... apply clinctly t.o o&hcr IDIIDben ol tbil clua. n.. ob;.cu.. aad buic CIDIIC:.PII t.beD Conn the buia ot a ...... ayatMtic prGirUl clirectld toward pol~ ~ t1ae tint adaie¥emat ia wbieb il the t.olalsyathclia oC lua.locid A (X537 A). Tbe ~ cft'an may be dividld iDto *- c1i1tiDct ......-. fira., dlp'adalive wart willa the aabU'IJ producl illdf'• lid quietly t.o the natizatDt tbat the aldol-type caadenlatian .... iadeed • 'Viable approaeb rr. the CIOIIItnaCtioD ol luaJocid " (X537A), ud llftl'&1 key ttnact~an~ Cor caaapariloa were alto prepared fran the f'i&bt-lide Ulaac 3. s.caad, I syno.ia of the dairalleft-side aldehyde 2 (rom the rcadily anilablc terpeDOid p1'1Q111Gr (R)-(-)-Qtronellcne I ud aaaaramatic 18bltraU. wu .. a aped. Third. a ltrateaJ ror the COII\'Crllftl Jylltbail o( the npt-side t&toae lwu realized tbroup tM application of the ..a.er aolatc Clailcu rcanaoaemcnt to appropriate tetrabydrofvaDoid &Dd tetrabydropyranoid iD&enDidialll dcriwld (rom readily available IDCIIIOIIccbaridel. L Aw. Tne I d...- tl 1.-IM:W A (X531A) (1). Tbe iDitial dqradation ol lualocid A (X537A) (I) (Scbcme I) tbroup the rcvenc aldol-type IWCtion followed prmou!y reported 1• CDDditiou. Alter (ormatiaa of tbe benzyl 8lter o( tbe ionopbore. pyrolyaia led t.o the aldehyde 2 &Del the ua.e 3 ill aood yidd. Tbia ......... aJdol-typc ~ prorided ~y pure o( botJa putDII'I ill CIODU'Ut to I pnwiaul npart.IS wbieb iadicated tbat the npt-tide Utone ) WU epim16 W'ized at Cl4. Ia the .,_at mv.tiptioa. Ollly 1liqlc dia· . . _ . wu obllrwd iD the 1lC NMR lpiCU'Wil ol canpauad 3. For this purJDe tbe pyrolytic ~ il alwioualy •perior to tM buic CODditiollwbicb alto will df'ect the dlawap bat llada tD inrim ol the alddlydc 2 ud ~- ol the kiiGDI .,...dee_, 1&111,.. n l. A!t'.amcb expu iawatatiaa with • ....wry ol oaaditiaaa, it . . f...t tllat tM ......anactiGD ollualocid A (X537A) (I) u ill ...... a. (IJ) ,_..........,,.._.~Wia..t,._ E.;~ 101, lJSs-1157 . ....._ ll. £.; 1.: Wi1e1a. C. S. I . AM. 0... S«. 1-. · ~.O.J~~R. C.;WL;P'• . I.J.;n.iao ........ s. /l!iil. .... 101. 61'7Hll0. (14) W.a.,, J. W.; e.... L H.. Jr.;....._ T.; ...... A. I. or,. 0...1971 II, MJI-MJJ. (IS) W.U.,, J. W.; ....... L 0.: .... H. J. I . ....... lt'tl. Jl, 219-213. (16) ~A . . . . . . . .....,. .,._il_. ................ ,_ ~ ~~~. - ~-::..~ ..O- ~c~. r-J!;_~ ~~·-< ~l'o-T1-o../"'c "t'Dt' ~~ 4 1110.... ~ c~ t"t 1 / ~C"s "'1 n r-\. _ _ - ! - ._.1-o~~ . c~ • , 'tHs IIIO~~~ Hs .... ()H ..... -•. •c HO ! HO •• c~ ·. tH, ' ·c" , • (a) Nault oflullocid A CX537A), lair, dioxane; (b) 230 •c; •c; •c, (0.01 mmH,); (c) LDA, nhcr, -71 ZaCl,, 0 RCHO, 0 S llliD: (d) H,. Pd/C. EtOH: (t) ltNCMe,Si) 1 , THF; (Me,Si)(l; CO 0,, CH 1 0H-cH 1 C,: NaiH. ; CH,N,, Et,O; (J) LiAlH •• Et,O; (b) II· lu.NF, THF; (i) ICH, THF, hlr: 0) ltH, C5s, CH,l. THF; ll•t; (t) 0 1 , CH,OH<H,O,; NaiH •. t.azyt . . aUI .. ..,.....,...... tbraqb the aldakype .aian bctwea 2 equiv of the aldehyde 2 ud oae of the ziDc aolatc 1' fli the UlaDcl. n. ilaln-'c cwtpCIIitiun ol the praducu obWned ia 6~ yield bued oa tbl t&toae l UMd (95" bued oa anreCIIMII"'d u.anc 3) wu S4:32: 10:4. No CXIDditianl were found tbat would duplicate tbe pre¥iouiy r.porud 1a renlu ia wbieb aldehyde 2 ot lipi('IC&Dtly lower optical purity wu Uled. Cbromatop'lpby o( lhil isomeric m.ixture r.ulted iD the ilolation of tile desired bcozyl tiler iD ilomeric:ally pure form iDa 34~ yield. ud bydrocenotysia tbea Cr* the oatural product iuc.lf. Wbile lhilaldol-typc condCDMtion efrec:u tbe desired reconltitutioa of the ioaopborc ud thereby uaura the succaa of any lyatbclic ICbaDe tbat caD pnerl\e the two panncn. the e{f"teiency ot the proc:aa illcu tbao ideal, and Cunbcr modifacations are in order. HoweYCr, tbe currcat resulu are sufficient to wanant a abift of attc:ntioa to I)'Dtbael of tbe aldehyde 2 and tbc ketone 3. Ia lhil coanection, i.Dtcrmediatc comp&rilon aampla were ..u-ed for the st.enocbanically more daDandina syntbais eX tbe ..._3. ParticuJariy ..efuJ would be a oaturally derived system ot stap ill tbe syathelillbortly aCtcr tbe Wlioa ol the tetrahydrofuru &Dd tetrahydropyraa riap. Tbc dqraclation o( the ketoae 3 outlined in Scbcmc I wu apiored . From the previoua aldol-type ~ apa iuwuu. it wu known tMt kiactic CDOlizatiOD of the ketone 3 ICDCrated tbc leu IUbaituted caola\e. 1llil .... trapped with trimctbyichJaralilanc &Dd tlaeD the nsultiq ailyl eaol ether wu azoaized. Esterification ol the acid fanned led to the tater •· wb.ieb wu aublequently CIDIIvertld to the benzyl ether 5. SiDc:c tbc pAaJlDed I)'Dtbetie ...... lel't tbe iDtrodw:tioa or the teniary alcobol i.D the tctrallydrapyraa riq utillut. it would be advantapoua t.o ~ tbiiiUbltitution iD tbe curreDt clqndation. Uafortunately. this ClOilld Ollly be accampliabed iD poor yield, liDce dehydration of tJUa teniary aJc:obol iDvariably led t.o predomiutc formation of tt. eadocyelic o1crm. ODJy the dacribed uatbatc pyi'CHyais (anaed small bat worbblc UDOUDl o( tM aaqdie olcC'm 6. ••••native a (17) 0ri1iMJ ~ ~ t t - • a1. ("-.H. 0.: en.;., D. 5.: TII'UiiMii. A. Y.; a-..d. H. D. I . .-. 0... S«. lt'71 fS, lll~JJ~) . 96 1990 J. Aa 0... S«.. Yol. IOJ. No. 1. INJ /rwlall " aJ. .._D.S,...oftllll~ ..._ aL Alltna• S,.IM* of lroaao. . . . . ., ...... J\ ,._~ .clzC ~'-..OAc OAc • 0 , I 10 ~ t J) ~OTr OH • .,~I ' ll,f II • tel: •II~ .. .,.~ II t.l!'-su• • (a) MCPIA. CH,Cl,; {b) H 1 IO•• Et,O; c.H,Ma.Br, Et,O; (c) PCC. CH,Cl,; (d) HCO,C,H,. NaOCH,; (t) NaiO., equ.oua CH,OH; (0 UAlH •• Et 1 0; (J) MaC. Et 1 N, CH,~; ~r. acttoae; (h) LDA, THF, -71 •c; Me,SiC; (I) Aalf •• Me, SO; (j) IN H,· CrO., acetoM; (k) 9-IBN, THF; H1 0 1 , OH"; 0) AcCl. Et,N; (m) 0 1 ; 1 N H,CtO•• acnoae; (D) Pb(OAc>•• 01(0Ac) 1 , c.H.-pyr.: (o) NaOCH,. CH,OH. Ozanolysia. reductic.. ud tbaa darcaat.,.rapby ol the misture o1 thllc olef"maled to the ilolatiaa o1 tbc a1cobol 1. ne pbysical ud spectral COIIIWits of this alcobol prowed to be iDvaluable iD the dcfulitiaa of t.be ~ wtoamc ol the eaauiq synthetic effort. 0. S,..... tldlt OhiiAft·SWI ~- 2. For the syathelia o( tbc aldebyde 2. u aJ'III'GKh ... dDal tbat •tailed tbe COillti'UCtion of the aromatic riD& 1J1taD from aliphatic pncunors. The more apparent a~cb tbat relied oa ';he IUbltitutioa of a preformed aromauc rmaiiCIDed fraupt wwth clifriCU.Ity by Yirtue ol the tetruubltiau.ed pattem. ne m. (ocua (or this ICbane il tbc pncratiaa ola suitable li6M-bain ail tbat cu lei'\'C u a la&.cat aldehyde ud carrie~ the laDe uymmetric caner o( the syacm. While iDitial ~ apioratioa of this syatbclil WU dane in I ~ madd ...... tbilrwpart il caafiDed to a dilc:ullioa of the ~ts witJa .....u..ncauy pure cxa- pauada. The c:biraJ uit cbmca u IWtiq -..w for thil wort wu tbc~(R)-(-~I(ScMmlll). lylaitable IDOdifteatioa ol tbc r.d.ioa .......... it ........ to CIDIIftrt .ttlwr o&crlllK arm of tiUa .....,._ to the required bromoethyl a,..U.. firR by per.ad alidabca r.Utld l'llidue t11 wa1. ill pre{ereatial attack at the triaubltitutld olcf'm aDd thcDc:e Ill· timatc coaveniaD 10 the biowopeataDc 14 ~(or the syntbelis ol the a.idcbyde 2 from uturaUy oaa&r1"iq luaJcx:id A (X537A) (1). Ia thia wort two procedv. were cWveloped for die dlavqe olthe J*D~ II; cme ._. tbraqb t1ae acid 12 to t1ae Ucobol 15 ud the otMr proriclel the same . . , . 15 dinc:t.ly. Tbe braaide 14 obWMd from tbe latter approada wu tba reaUdized 10 the acid 12 for campa.riloa parpa~~~. 1D 1Kb CUI. wileD tbc -.Dtiamcric purity ol tbc acid 12 wu dalcbd by ualylil ol ita 1H NMR ipKUWil with a cbiral IIWt .....t. 11 . ., . . . . .u.. cauJd .. cletectld (>95~). nu.. ..,_.ti¥c (II) Tril().(....,._._,.,..,...,........ J' .....,._ -10). rH.H!s ~ ~-:J Br 10 Br w: tile.._,__ 1,. • (a) (C H1 ),CO. p,ridine; {b) S.C(illlid),,acnone: (c:) Nt<Ra), acnon•: (~I) LiNe,Oa. ether; <•> s~ Pd/C. .u.&aol. H,o·; <O MaC. Et 1 N, CH,~; Ulr, THF; (&) U, NH 1 0), THF; (It) LWH •• Et,O. 1u u altenatift _ . to cblct this point aad u well to pnMde.,. to tbc ~ aldebyde 2. iaitial ~ o1 (R)-(-)-citroMlleDe I wu iiMitipt.ed u a IDIUI to modify the lea IUbltituted olef'mic ann (Scbane II). Alter coa..UO.. ol the ltydroboratioa product to tbe acid 9 by OIODization with u alidativl warklqa. Kacbi dlcarbalylatift alidatian 19 COil¥Wted the carbolyl·bcaria& ann to the Yiayl pwp. aad ultimately the .utiomeric bromide 13 became available. n. optical rocatiaft of tbia bromide wu equal iD mqnitude. but oppalitc iD sip. to that ol the brGmidc 14. Tbia l'llu.lt dearly dcmanltratld tbat no panial racaaizatiaft bad occ:umd durin& . . ~c:tian ~llCDCII ud wu a •tiafyiaa c:lauical support for the optical punty ol tbc two CD&Dtiamen. Tbua. from the same cbiraJ IWtina material. bolll CUDtiomen ol the allpbatic lidc cbaiD ol the aldeb)'de l are r.dily available. Ia coatrut to material oblam.t dleabcre1atbrauab attempted I'IIOiution ol riCICIIUc acid 12. tbc bi&b caantiamcric: purity ol the bramidc 14 iD thia aw.tiptiaft wu conf'umed ~ly (rcn aDOthcr lynthc:ais o( the bromide 13 from D-( + )-ribonic: aad. ..,..~aaoac (16), u 1bowD iD Scbcmc III. A liqle ilamcr l'llllltld (rom addition o( lithium dimethyl c:upratc to the Wll&turated lac:toac 11. The acid lO, wbicb is cnantiomeric: to the acid 12. wu obtaiDed via a reductiYe (rapnca&ation o( the bromide demative of the lac:toae 19. The specific rocation o( the bramidc 13 Ma&red from this lyBthetic route was iD aclllJalt qncmcDt with that demed from (R)-(-)-citroaellnc. For the coaatnaction ol the aromatic: rina. the Diels-Aider ,.c:tion betweca a carbometboxy-a-pyroac aad u ac:etylenic ,..at wu c:balcn. Such u aromatic riD& syntbclilwu reponed earlier by ~ry~oa» (oq I) for the pareat a-pyroac. and the •bNEt2 t • "'c tHs COzCHs -~~· EtzN:C . I (1) ~ CHs l&it11tiaa pattcrD ol the nsultina aromatic riq wu altr'letMiy limiJar to tbat or the clelired aldehyde 2. For the cue at baad, il ... tint ......, to CGDitnld u Cl-pyrGnC that bore tbc alkyl lidc cbaiD pnpared abowe ud then to aplore the pmlibility that (19) ..... J. D.; 1oc11i. J. ~. T.......... IM. 14. Uts-%126. (20) ..,_, T. A.o 0.... D. W. J. OrJ. a-.. am. 41,ltlG-29lt. 97 J. bL CMa S«.. Yol. 10$, No. 1, 198J TOUJI Syrultau ofltlllllplttln ~ . . . . IV. CoutrucUDa of 1M OUnl AIIIIIIJdl ~ ~'"• ~! limiluty..,. ia pd yield with t.ba ct.Md ~ ~ II It /COzCHJ CHs :;;;o-1 ... ~·~ ~ COrCHJ ~ ~ CHs HQ~ .. CH, CHs u la·~' LASALOCIO & ( X!l31& I SODIUM SALT ---!.:..:..u ... HO:tr+> ? I ... CHO CHs I t•l:-•u• • (a) BrW.CH,CH,CH<CH,)CH-cH, Crom 14, THF ; (b) MnO,, CH 1 C 1 • (c) Bn,NC.CCH,. C,H, : (d) 0.0,, NNO, aqueo.aa CH,COCH,; (e) H,. Pd/C, EtOH: (f) 1-.AmONO, HBF •• EtOH; H,O. A; (I) (CH,)1 C(OCH,)1 , H•, CH,COCH,; (h) KH, CH,OCH 1 CH10CH1C1; (i) n<,H~SLi. HNPA: BnBr: (j) H,cr; (It) NatO., aqueous CH,OH; 0) BnBr. dioxane; (m) 130 •c (0.01 mm~t~). u CBYJCIHUbltituted ratber thu nitJ'OICIHUbltituted acetytenic IYI'CID could be ued in tbc Dicls-AJder reac:boa. A IOiutioa 10 tbc former problem wu readily found, but an atcuive leUCh far oayaa..ubstituted dicnopbil• prowed frviU... lu a r.Wt. a syntbais of the aldehyde 2 wu built arouad tbc utilization ol u ynaminc in tbc Dicla-Aldcr rac:tiaa witb tbc substituted •PYfODe (Scheme IV). A noteworthy facet of this syatbaia wu tbc initial trauf'or· mation of tbc a-pyrone ll to iu subltituted derivati¥c 22. It wu proposed that the preferred mode of orpnomctallic coajuptc addition to tbc Cit-pyrone 21 would be 1,4-addition rather tbaD 1.6-addition by virtue of tbc deac:Uvation o1 the 6-palition by tbc ether o1y1en. Rcaromatization of tbc reaultina 1.4 adduct wu then to be accomplished by dehydroaenation. ID model cxperi· mcau. aa addition ol t.bc ..pyrone ll to lithium dimethyl c:uprate -05~Zl lte R•Et ar cupric acetate/ctbylmaan-i1111l bramidc IDhatiaa. tbc reac:tiaa milture turned purple, and alter YUYinl reaction times &Del &emperaturea. workup led to 110 delired adduct. Oa tbc pranile t.bat tbCic I'IIUlu were t.bc c::on~~qucnca ol initial declron tranlfcr from an incipient cupntc to tbc aromatic ar-pyrone. tbc addition ol ethylmaanesium bromide iuelf in tbc abscDcc of copper salt wu investipted. It wu p-atifyiq to fiad that the yield of the 1,4 adduct lla under tbcse CDDditiona wu ~- This reault udcncor• tbc diffcreacc in cbaractcr bet..a tbclc two or· paomcWlic reaaau. dehydrotenation o( the 1.~ adduct 21a &lao pnMd 10 be aa iaitia.l oblladc. ScwaaJ IWidanS ,....u.IUdlu ll&lfur. DDQ. and chJoranil. were ineffective. ud ac:&ivated mupnac dicWdc, while cffec:tive, wu capric:ioua. Ia tbia modcllerica. dehydropaation wu IDGit clficicatly (65«1 yield) etrec:aed by aicbl peroxide which pvc tbc model aubltihated Cit-pyrone 21,. Wbca tbclc aperienca wen applied 10 tbe preparation of tbe clllind Cl-pyraDC 22 in wbicb both tbc nmmic ud apcica1Jy KIM biwuopcalCDII 14 were ...S. tJac cx.jupted 1,4-additian wu ne 1991 ..... n.aicUI paalidcdeb~- ~ ......... ... ..,.. iDdTectuaJ. It ... .,.._...s t.bat tbe llickel ,.acat CIDIDpicul with tbc termiDaJ .r'lD of tbe clill)'d,..._pyraae aad il then iaactMt.ld. A&r furtber apa'imatation. apin with a wide ..nety oiNipata. it wu foud t.bat Gilly activated (Attnburrow1 1) maqaaae clioa.idc pvc a ,.....bie yield of tbe delind • . , . . 21. Tbu. iJI both .,.. tbia Cl-pyi'GDC wu rauliady avai&abie ill madlnte yield an a .... _ . ud allllltian wu U&rDid 10 tbc Dicli-AJder ,.c:tioa. The rwaJta reported llrlier by ~ry~oaa aqaated t.bat tbe Dicit-Alder ooadcaaatW. between a 3-carbomcthoxy-o-pyronc ud a betc:ralubltituted ICIItyieDc wouJd lead 10 u aromatic riq with tbc dlaind rqiocbemiltry far tbc synthesis o( tbc aklchydc 2. Since in tbc pr11ent aituatioa a pbcaol derivative is desired rather thaa tbc aaili.ne aystcm obtaiaod in tbc earlier work. 210 oonaidcrablc ctrort wu apcaded to condcuc tbc substituted J.c:arbomethoay·ca•pyroMSIO l·methoxy· I ·propyac. l, I -dieth· cay·l·propcac.. tm·butylclimethylailyl tetcacaccul o( methyl propioaate,lZ ud t•n·butylctimctbylailyl keuleaminal of N .N· dimethylpropionamide.u ID ao cue wu uy (~ + 2) adduct or aramatic l)'ltCin daected iD a CIDIIlpia riiCliaa product. Ia order 10 &CICOmpiisb tbc desired cydaaddition ruction. tbc reaction betwtllll tbe ar-pyraae 21' &Del N.N-dicthyl·l·amino-l·propyne wu iaveltiptcd aad found to produce the apectod aromatic syst.cm ill hiP (IK) yield aatbermic:ally wbcn t.bc ~u were miud in bcazcne at roam tclllperature. Happily, substitution of lither tbc racemic or optically active substituted ..pyrone 22 and N.N-dibcnzyl·l·~l·propyne did not alter U..C nsults. and iD each cue the aniliDe derivati¥c 13 wu obtained in biah yield. Tbe cboicc of the N.N-dibcazyl·l·amiao-1-propyne wu predicated by t.bc DICIIIity 10 replace tbc nitroten by Olytal tbrou&b diazotization o( the aailine dcrivativc obtainable after hydroacnolysis o( tbc initial aromatic product 13. This proceu ~u ctriCiauly accomplished u abow1l in Scheme IV. &Del tbc maJOr skeletal and fuactional synthetic problema pracated by tbc al· dchyde 2 were solved. further cc.mctic wort to acbanp the methyl far a bcazyl cater and 10 ummask the aldehyde function led to tbe desired aldehyde l. The aeeeuity 10 eacbanp the methyl for the benzyl•ter wu dictated by the observation that t.bc mctbylllla' wu biahlY raiawlt to hydrolysis. and puticularly after aldol·type c:ondensation with the riaht-side ketone J. tbc methyl ester could aot be t'IIIICMid without scvere dqradation of the systclll. The identity o( tbe chiral synthetic aldehyde l wu established by oamparison ol iu physical and spec:uaJ data with thole oblcMd oa sample of the aldehyde l derived from D&turallaaalocid A (XS37A) (1). A reliable {2~ from cr·pyrone ll and 8~ from (R)-(-)-citronellenc (I)) synthesis of the chiral aldehyde l was thus available» and construction of the pc:Myctbcr ketone J wu pursued. ~of die Polyedler JtiPt-SWt let- 3. The buic concept for the synthesis of the ri&ht·sidc ketone 3 is presented in Scheme V. Tbe bean of this hiahly converaent &pp'QICb il the union ol t.bc furanoid acid 25 to the pyranoid aJ)'C&l 26 throuah application oC tbc cater enolate Claiscn rearranae· mcnt.24 Such aa approach allows for tbc stcreochcmical c:aurol m. (21) AU.IIwrow, J.; ea-.. A. F. 1.: 0apa~U. J. H.; Ewa-.lt. M.: Hcma. I . A.: J--., A. I . A.: Walker, T. J. 0..... Soc. 1M2. 1094-1111. Fa\iadi. A . J. s,.,lwns 19'76. 65-ICM. (ll) PNpand by LDA CDOtizatica ud W. _..,. tl'afltUI ol IMtltyl prapioaatc or N.N-dimetllylprGpioaalllicle. (lll All iaitiaUy .-cttUq r.,.,.. o1 Will wart ... • IKt o1 c:one~ bit...., \M a,cicaJ racau.....,.,.. ror OIIIIUIICIII iMcnnldiatea ud \M aldcllyde Z ia tiaia wart ud tJaat ol ~ Uld c.wartcrs.•• Since 1M a,tical purity ol \M ICid IZ wu ..ntaed by \M - ol clliral aWt rwqenu i1 1H NMR a,.n-t&. badl ~ oi\M bu ; 13 and I~ wer& ,.,.,... Uld tbe opticaJ racatica ol badl 8yfttMUc ud uuarally deri...S aldciiY* 2 ......tical • a,cicaJ putty o( • lya&anl reponed llcrc il ........ 1.0 1111 08 I (um lluia. TM for tblle ,...,..,y ,.........,....... .,._ .... ~an. 10 . . . . . ., . . . . . . . . .u- ... - paniaJiy .....UCmaa.ial. (l~) b*Dd, 1.. E.: ........ 1.. H.; Willard, A. L J. MI. 0... Soc. .,.,..... 2161-2171. 98 1992 J. Am. Clwm. S«.. Yol. JOj, No.1, 191J .--.v. ltwlluttJ 61 Ill. Cl4" ia subait 25. 0. tile odllr llud. tJw ~ Qirality at CU" by the daoicl ol (vuaid PJca1. while IJDlbltic ~ wu ClftaiJI by Yimle ol tJw aftilability ol bacJl 1M 14R ud 14S caalipratiaal 16 C... the appropriate ...... tM CGmiCt CDDditioal oouJd DOt ... defiMd IUltiJ tJal ,.,. clia· lla'eoalen 1 ud s.-g were pnpand aacl cam.-red witla • · flria1 ~ fram dep'adatioa ol t.be aaan.l praducl illclf'. On tM ~ that the a.reocbaDicaJ NIU.It of the aolizatian o1 tile butyrate o1 thc Jlyc:all 21 aacl 21 is thei&IDC u that for .,aiclltln lltablilbld cartilr,a. the la&er canpariloa rewealld that the pn{ared tr&Diitioa lUte far this Clailen ,.rrupment ... -t-liltc. the 145' c:alfipntioa 16 iD •buDit 25 ..W be cleriYed fram tJal (Z')-bcae &Cllta1 ria IDOlilaU. iD 23~ HMPA iD THF. CDnltniCtioa of the acid 25 wu r~nt appraacbed tbroup the af)Q1 rf" (ram wllidl the acid 2t wu pi'CIIUed (Scheme VI) u a mizture of C14 ilomm 16 (LOA/THF: 73'1; ntio'1 11:19 aac1 LDA/HMPA-THF: ~; ntio'Z 21 :79) u ct.cribld tar· lilr.• n. problem wu DOW t.be iDuoductioa olthe C161MtbyJ .,.,.•• aacl for this apkntioa the man canveaiendy amiable LDA(IHF ilomaic miman 2t wu Ulld. 11aia ICid mimare wu CIIIIIYCfted 10 t.be CMJrieagd epoaidelll iD 90'1 oweraU yiekl Qroqh the iDtcnDidiate iodolaClODI 31. R•ctioa of this ..., lpOiidc miman witla litlaium dimltbyl aapnte iD ctber /ptlfJtaM ISih.td iD the iDtroducliaa ola ~ IDilbyl poup. and after cbromatopapbic MpUatioD. tJM alcoboll4, aJona with 1241 of ita C14 cpimer." wu obtaiMd. lll:mcMJ of tbe llydraayl poup aad liJyl ether dlayqe lid to the ilama'ic:aDy pure primary akxJbol 33. In ordlr to UCIIIUia theloc:atal ~ the DeWiy inuaduc.d rina methylaroup. this alcohol wu c:lOIIvened to the UDUtunted al· deb,.SC31 1b1 1H NMR spec:tnam ~this a.ldeb,.SC .....u.d that the ~ d.ae 10 the Olefmic b)'drapn wu a triplet. Me· tllylaU. aa the delired Cl6 palition 16 lbouJd 1M rile 10 aa usatanted aJdebyde iD wbicb this olcrmic hydropa is c.Jy a doablct. pauibitity of this lipa1 beiDa a pair ol daubleu. due 10 the pauible farmaU. ol o1crm ilamln dariDa bue eliJD. iutioa. wu naW out by aamiaatian ~ t.be lpiCinllllat clifJ'crent fic.ld stnqths. Tbia r.Wt ~bowed that cupratc c:leayqe bad occurred at the 1&DCI.Iirtd Cl7 palitioa. 16 SiDc:c the mcthylatioa bad taka place at the more biaclered C17 palitioa 16 witla lithium ctimcthyl cuprate, it wu bypott.i~ that the delvqc eataillld prior canplaation mthe arpnametallic napnt with the adjac:cnt a.tboaymcthylcac blockina poup. To avoid this cf'f'eet. the o-cpolide mixture 31 wu treated with lithiated 1,3-dithiuc.D o.ullurization ol tbc ..u.JtiDa praducu tben prcMded a DeW methylated aJcoboJ 37 ia moderate yidd. Ia order to Yerify that this DCW alcohol wu iacleed the result of cpox.idc c:lcavaac at the Cl6 palition!' it wu convened 10 the IIDIAturated aldehyde 35, uaina the same sequence u described abowe. In this inlta.nc:c. t.be ~ due to the olcf'lDic: b)'droten ill the 1H NMR spectnun wu the apected doublet. With tbc UIUJ'UCC that the stnacture of the ruran rina wu now correct, tbc iDtcnnediatc primary alcoboll6 wu canvcrted 10 the uticipated furuoid subuDit u ita methyl •tcr lta. CMrall yield of this CIOIIItnaction wu diaappointina aad prompted u apkntion iDIO an alternate approach throup a braached-cbain carbobydratc precursor. For this pui'OIC, •cr·-~ afucaucdwinic acid. "(•lactone (41),,. wu tbe ideal subltratc. Available OD larp scale by the treatment of invert supr with aqueous caJcium bydrcWdc,,. this brancbed~baiD supr fit tbe pnriouly delc:ria.i tecbDoioaY (Scheme VII). Systanatic application ol tbc preYioua ~uenc:r' led iD pd yield to t.be minure ~ aaatunted CIICrS 43 iD wbidl citbcr tbc R or S epimcr at C 14 16 cauJd be made 10 pndomiaatc. It wu IOIDCWbat IUrprisina. but P'8tif)'ina. to dilcover that catalytic llydrotcaation of C J6,17 double band" iD Iller'S 43 pve a nadily tcpanble minare ol two 111en that _.. Olfly epimeric at tbc ..rticr C 14 pat- wu....,... I I • 6:··0MOM 0 I R • ''CHs ,PH \-{~ (._)r- CH 20MOM • CHsCHzCHzCOzH 0 H ol the formation of the Clllltra.l carttc.-arbaa boDd ill u IIIINMOI«tJtv naction alter tbe two partnen bave bleD joined iD u liracnt ilrl~ ...Uatian ~ n. known pDI8ltia1 for ltei"'ICbemic:al cantrol duriDa the C1ailcn ~t25 il aupnaued iD tbc titer enolate VWiion tbrauab tbc ~bility that either the wytllf'O or,,.,., product is acauiblc fram the I&IDC pncursora.l' by cboice o( IDOlization conditiaaa. . Carbobydratc pncunon were llpCICially suitable for the oaallniCtion of the cbira1 furaaoid 25 and pyruoid 26 subuDita. ID u earlier report, tbc prepantion• of various Jlycala aaclsu~ 11quent IDOdelatudi•lt f'or e11er cnolatc Clailcn reanupmeat _.. prwengd. For this syntbllia. the pynnoid subunit 26 could be -=ured with minor modification of the aistina sequenc:c.zuo It remained to prepare t.be furuoid subunit 25 in ordlr to apkn the remaillina features of tbia symhctic ICbcmc. . n. basic stratqy for the c::anstnactioa ol this subunit entailed the application of tbc •ter enolate Claisn narrupmeat tecb· DOioay to the butynte of either Jlyc:al 2'7 or 21. Ia the former cue, it would tbcn be .....ary to iDuoducc tbc C16 mctbyl IJ'OUp, 16 while ia the latter situatioa. syathetic IUCCIII dcpeads c. the stmaeleetive bydroacaation of a C 16,17 double bond. 16 An additional stereocbcmical point wu W1C11rtain at t.be ou~~et. While it wu tnownU that nolization of u •ter produces preclamiDatcly citbcr ilamcric enolate and bela t.be lilyl krtcnecetal by suitable solvent modification, the cbanctcr (boet-~kc vs. chair-like) of the trauition sate for the subMqucat Clailca rearnnacment of a cyclic allylic .w wu DOt udentood at tbc timc.l 1 Tbcreforc, it wu DOl ~ble to pndict iD advaDce which eaolatc pomevy would lead 10 the clllind S CIOBfipratioa at n.. n.nrorc. n. n. n. •tura* (l2) . . . . . . . . . . . . _ . , . . • • : e ,.• •, . u -.11117 GLPC (~ SE·lO, 120 •c. '/• ia. x 61'l). w.a,t (ll) v........ A.; a.a...r,. A. J. ~· a... lf'N. 4/, )122-)125. ()I) Wllildlr. L L; J. N. ll••· O..IIU.1. ~. .Miilllr. c.w,-. 99 Tottal Sy11111Gu of IDIIDpltift AllliiHOiiu J. AM. CIM,._ Soc., Yol. JOJ. No. 7. 198J 1993 .._. VL Sra.._ of EpDeric F-ill s.batt l,. . __ "'t• A HsC(t'o~ ~ ~o~ ~~ • OIIC)M • .. .. • (a) Kl,l,. aqueous NaHCO,; (b) AIH,, ntF: (c) Na,CO,, CH,OH; (d) TISC. imidazole, DMF; (e) LiMe, Cu. tther-t*ltane: <O NaH, CS,, CH,I, THF; (I) ,..Ju1 SnH, toluene, 4: (h) ~t-Bu.NF. THF; (i) PC'C, N.OAc, CH,O,; (j) Ko-t-lu. THF: (k) C.H,S,U. niF. 0> Ni(Ra), EtOH; (m) KH.C.H,CH,Br, THF; (n) lK HCJ. nlf; (o) Pt, O,,aq...,•NaHC0 1 ;01,N1 • ..._. VBL Sratbllil of U. GlyCII 26• . . _ VIL Synthaia of Furuoid Subuait 25.. .. .. 0 ··' ·--·-· tiC"- . .... '" .. ..... ...,.... .. •.·c,.., .•,... Q><o c~~OUOM . OM "'1'~· HO-..... r ,,OH HOJ.J. • ••• c 62"- n. . OMOM •• enoJ.oJ.·cH, ... ., .. C... HsCOzC~"~OMOM Ho"" •• ...•....• ... . . . • l' (r"t.•a•M _.... ,.,,.. , • (a) CH,COCH,, H,SO,; (b) KH, CICH,OCH,, THF; (c), DIBAL. ether. -78 •c. (d) P(NMe,),. CC1,, THF. 0 •c; U. NH,(l), then NH,Ct; (e) ,..c,H,COO; LOA, THF (HMPA); Me,· SiO: OH" . (0 CH,N,. ether ; (I) H,. I~ Pt/C, EtOAc; (h) UAlH,. ether : (i) KH. C,H,CH,Br. THF; (j) lK HO. THF. (k) Pt. 0,, aqueous NaHCO,. ilian. 16 Hydropnatian bad t&Ua piMe ill alliPJy . . -=iective manner and in the dclired a . . . Hydride reduction oi tbc 14$ .ur 16 led to tbe previously fanned (Scbane VI) aJcobof 36, wbiJc reduction of the 14R catcr 1' pvc tbc alcohol~. Both alcohols were readily transformed to the CllCTI Js. and lta. Wbile the bail for the stcreoeclec:tivity of the catalytic bydroaenatioa of the eaten 43 ia DOt obvioua.. the ouu:ame patty inc:reued the eff"ICicncy of the synthetic route for tMic furaDOid aubuniu. Tbc CDIIIU1ICtian ~ tbe aJcaball61Wted with 6-dealy-L-suDc (45)JO u shown iD Scbcme VIII. The bydroxylaroupa were dill'ereatiatod u benzyl Jlycalide. 0-ilapropylidenc. and mctb· oaymethyl ether iD compound 46. Removal of the benzyl ctbcr tbea led to tbc llcla 47 wbicb wu CDMNd to &be clllind tl)'C&l J6 by the prcvioualy delcribed pi'OC*ture.2t Tbc buildina btocb (ac:idl 25 ud lt &Dd tbc aJ)QI ~ of tbc filbt-lidc ketaDc 3 were now iD bud. 1Gptbcr with the -=-ary a.:lula&oc for thlir uiaa.21 It na the iDtclltioa to ..-.ac aU • (a) BnOH, AcCl. (b) (CH,),C(OCH,) 1 • H•, acetone; (c) KH . CICH,OCH,, THF; (d) U. NH,O>. THF; (e) P<NMe 1 ) 1 , CO,, THF; 0 •c; U, NH,(l), then NH,Cl. (our pouiblc diutcreoilomen 1 and 56-5I from the connection ol the pyranoid subunit 26 to both cpimcrs of the furaaoid acids 25 and lt and to c:orrclate the resultant atereoisomcrs with the utural dqradation product 7. lu dacribed previou.s.ly, 29 it wu not pouible to alter dramatically the stereochemical outcome of the enolization of a· lteteralubltituted eaten, and bcnce the more convenient THF canditionl were Ulld in tbelc eiUir enc:Utc C1ailcn ~u (Scbcmc IX). ID this manner, the acid l5 resulted in the formation of the readily separable iaomcric eaten • and 49, wbilc the Cl• epimer lt16 afforded the ilomcric: catm 50 and 51. Altboup the yields of eYCD tbe major diastcreailomcn 49 and 51 were madill. tbii c:rucialstep lent c:ndability t.o tbe COIMI'JCftt synthetic ICbeme. Sublequcnt trauformatioa of tbac eaten iDdividually to the projected alcobols 1 and ~ proceeded in acellalt yields. With aU four o( the diutereoilomen in band, it wu now .,a.iblc. tbrclqb oamparilon to tbc natural delradation product 7, &o define completely their stereocbemiatry. Tbe syntbetic . .eoiiomer tbat ... identical witb tbe dep'adation produc:t 1 il that dcmed from the major Clailcn ilomer 49 from tbe faruoid acid 25 wbic:b iuc1f wu tbc major Clailal ilcmer wbcn it i -~~.: I ::1~ ~ -4 i o n li · It j · a.~ i c: l " . II" ! .i . . ll. 4. E i · .,. .. Fn :z: f n I;; e !,;;. ,. 0 & ~I e ..n X. ! .. J" > ~~ % g.J ~~- .. I s .. ):r % 0 G' ·~..z:: ~~!" • 0 8 ;:Pn !1: £--'.: . • ~· . I._ _ ~ :1 % N... x .} . • j. an ., ) • n···· " .1 1 . • 5! ~ ~ ~ .... r: ~~ , J 6s · -:o-f:.. j !:' .... · :. ·· :1: o = ""an T ..% % '. rt •'' , :1 ;s w a a ll: tlr •• ~ ) • % !)-' 1.~. z .• -• !-- i nt f' i ~ i~~, !~ ":.71 • I; % '' rt'' • J z B. it. 1: _.. ·:r w ·~~~JJJ . · 51 j. .,.x -. . a• • I " .· # ~ ~ a "" ... z •.... ,. ~ l • O¥ ~ -~I I ~. . . ~ ~~·· ~ ....... ~ ,= z % 0 l n .1 a • rt'' 5~~ :1 -• -• g · ....•n ....% ~ • • i . ~·t·--· ~~ b~ n ';.~. ~:~ ·! ) ~ -• • • -•• II "... ·..•~ --=-- · ~-· P~;;.~~ n ... : ~~ n ... ;! ~ e ) 1 i z )1 AJ "" b ~ I ~~~ :l .I; jz % 0 A ·g~ ~~ .. n !~ ;-~L ~ ~ ~ iJ ~ -: ~ ~ n f • ~!!!E f i. .} g·~ n.~ & , , ~ II: i ~~~ s >~ .. & ...... i i 1 ~ '< 1 1 G J: i g 1 '1' .. C'l il 11 :: • ·•· II : c: t ~"r' ~ 15 ftl!s~1.fi!ft~i~&!J I g 'fl!ijt I~~ UHUIUUlHfiUfUU~!~!~r~-~~ IJUU fai11 11 ~~~ i-~~,.1 ~, lt t ~ i' i· t g:~1 . J. I :I . .1 1 I·[ i i .., l .,. . i 18&-! I i 1 J li['f'f 1JI!'!Ill f~ss I 1~ ~hfg;!f ;J1iblttf[IJI'fl !t:,IH!if!h!1 1! Ituti!ett ~~ •Jrlnfi! l!J:(;~ 11t1i H~!! h Ill! ~~ifl l ,~z::JI· r~!g~. Is I ~~~ ( ·l!J~Iiif 'i~ l:il t~u hHi~r ~-~hlti 1= r. ill~~ t11~1:l~t'Jrfla f!1!f. t!ie.!!if i ~iii! r1~lj!U!~:idJ;i~ I~~~ ibJ~f~i~ dlh Jfri fefl(s~~~~~~:~l,l~ 'ahh iP il:. d ·EllS~_ fll ~ ~u. 1 1 a_ll ~~J!l~ltil~·~~~~~~!: -~,. JI'!B '-s dfltl 1:1: Ulffh ~! · j,H ~ 111if Uif. ttU i~-', ~!~I iU ~~~~~i~ Hifil Ut ~~ ~~~·1! • Jl 1 • is 1 l 1i JI lJ "1· 1 · ~ f~ii"l" J •"ii'" -~~{' J.' • • · ~~ !u .~~.f~~lrlf ·.niJ],~~ 1 1 · [i !_ r( 1·Hdlh:!UU~iHIUi!i iH:~1l!i,tf!fUt~ ~~~~ ~i~' ~fr ~-~l~}a.~t· ~~~ t~tr' JII£JI§I p~~~~iUl'idl,~ J.t~l f[fftft[li{fl ! ~~-- s(l s~; 1 (I-! 1if t ·1· :ci·] ~ri~i~:c ( (·1-fJII 1- ~z~i ~ s;~;ir ·tirlls·J O 1·• ij- ~111 ti; ~~~j ltlfi.la.a ;~fl fJ~.- E! 11~ ~! a... 1:!~fJI~ a= . i .• I II' ~ !-' l5 I~jif~~~~ · afJr;;l~- ~ ~ =-I tI!a. j'I. I (I. i ,.;.,.I II r p.. r:. 15 . •.c. j ::Cq. ... J~ .a· >~ ~J;! z o a,1J - .i •.t IIc.11 i"Ull. il ~~- )~ l .. f~ •. _. . Utta.i~ i ~~~ ~a-al·;; ~~ i 1 '(~ -~ 1 •nr~J" a. ~~t .i! dI~l ~Hi ~~ I ~li' ~i ~·-a fR.la- . w ~~;.8 ~~ · l'i~ I f~g ( :i!e7 i' a. it· It'!!. :. i I ; =" r Q I S:ft: l"f•a. ~ li'! &(.I=I :rIsII '!!.i' .P!t;;5! • .. ~ IrJsraC. g ,. •t!Jl II' ~;f; ·15 • ... 101 J. bL OlaL S«.. Yol. lOS, No. 1, JNJ TOUJJ Syt~~ltaU ofiOifDPiun Alllibtolla .,..,.)-2($~,._ (l). . . . . . . . . clillillaila .t 2.77 1 (3.7 8111101) til bluyllualacid A at 0.01 aaHa ,._. ow........,.._ (X....,.. at 21~220 •C) IP'I a dau Gil.-.. . . DuO cllrolllaaopapW oa 100 1 olliliclllll wiG lOS ayl.-a.. ill ,.,.._ .... tofi" 0.91 (7~) til-.~ (2) ud 1.11 (14) ., . . . . . . . (3). ~ 2: (a) 21D -IS.4• (e 1.00. CHCI1); IR (CH01) 111S. IMO. 1620, 1465, 1420, 1390, 1300, llSO. I ISO .a·•: 1H NMR (CDCI,) f 0.92 (d. 3 H. I • 7 Hz. CH 1). 2.20 (a, 3 H. ArCH,). 2.11 (be. 2 H. I • 7Hz. ArCH,c), S.l6 (a, 3 H. CO,C:Hs). 6.56, 7.14 (2d,l H. I • 7.5 HI. 2 ArH), 9.37 (d. 1 H. I • 1.5 HI. CHO), 11.43 (a, I H. OH). MIL Calod lor CJfuO.: C. 73.60; H. 6.79. fGad: C. 73.56: H. 6.70. X...l: [•J"D -19.6• (e 1.02. CH01); IR (CH0 1) 3600, 1710. 1460. IllS, IUS, 1100, 1060. t60 .a·•: 1H NMit (CD0 1) J 1.20 (d. l H. J • 6Hz. CH,CHOC).l.74 (q. I H. I • 6Hz. CIICH,oc): 11(: NMit (CDCI,) J 6.10. 7.01, 7.73, 12.15, 13.14. 16.37. 20.79, 20.". 21.33.29.01, 30.15. 36.64. 36.14• .0.41. 51.11. 70.57. 72.65. 76.55.14,01, IS.SI. 213.21. AMI. Calcld for CttH.O.: C. 71.15; H. 10.10. Fo.8d: C. 7l.l4; H. 10.71 . ~~A. To allimd IOhdiaa ol0.3 _...til LDA ill O.S a1. o( dry .U. II -71 •c uder U arp aunoaptacn WU added dropwile a o/35.5 all (0. 1 IIUDOI) ol tile npt-IW! U... J ia 0. 7 mL til dry . -. Alter S min, tM paJc yellow eolutioe wu .uo..d • wann After 10 IIIia. 430 .,J. (0.3 IIUIIOI) ola 0.7 M lllhatiaD t11 wydrclulziDc claiclr* ia . . _ ... adMd dropwilc aad tbl ,_.... ..._ e • lllimaN ... llimd ror 20 Ilia 11 o•c. A ICihnion o/65.3 . . (O.liiiiiiCX) ol tJM lett·laalr aldah,. 2 ia 0.4 mL til wu tMII Mded raptdly llroup a CIUUlula. A~ wlaitc pncipi&atc wu iaunldia&cly formed. n. awultiq wu ltimld for 5 IDia at -cud tJaen q~ by tJM addition ola IDia1n olanan..S ..-a NH.CI ud tdw. T'llc aqueGUI ptwe wu ..,.,a..S ud tM1t auaaad 3 timla witb . . .. and tJM Clllllbined etberal pbaMI..,. wublld willa atua..S aqueous NaCI ud csn.d (M,S04 ). llemo¥al ol tile....._. uder reduc.d .,._..,. ud bitb-pr.aurcliquid cbnaatopaplly ol tile Nlicluc oa lilic:a ad w1tb a ~t aradint or s-1 K ceyl . . . . . iD parolcum ether al~ed the ...,ation ol four aldol praducu iD a cam..._. yield of 62. 4~ (95~ bued oa .......,..,... U.... l) ud a ratio til 54:32:10:4. ,.,. .UW ~: 23.0 ma (33.ft); 1ft O.ll (~ atJtyluauta ill ...,._, at!ter); 1H NMR (CDCI1) Jl.lf (a, 3 H. A.r CH,). 5.31 (a, 2 H. COzCH 1). 6.60. 7.11 (2d.2 H. I • I Hz.2 A.rH). 11.31 (a, I H. ArOH); ideetical witJI au&Matic bluyl lueJoc:id A. S.C.. .UW ~ Jl.5 . .; • 1 0.16 (MIM ..ucat); 'H NMR (CDCI,) •2.19 (a.3 H. AICH 1). 5.39 (a,2 H. CO,CHs). 6.6l. 1.13 (ld. 2 H. J • I Hz. 2 A.rH). ll .lJ (a, 1 H. OH). nH AWal ~ 4.3 aaa; R1 0.10 (M~Melllcnt): 1H NMR (CDCI1) '2.21 (a. 3 H. ArCH,), S..O (a, 2 H. CO,CHs). 6.62. 7.13 (ld.l H. J • I Hz. 2 ArH). ll.ll (a, 1 H. OH). F..- .UW ..,.._.: 1.7 me; R1 0.06 (amt ..._t). When oaly 1.1 ..uiv ol Ude!lyde lwu _.1M tJM ractiaa 1ime ... 4 miD at 0 tM y1cld ol tJM aWoi praducllwu 46.3~ ud tbl ratio 53:11: 11:6. .._._.. A (I). To a ltimd . .tioa oll90 . . (0.43 mmol) ol benzyllualoc:id A ia S ml. olallloNae ...._. wu added 30 . . o( IK ..Uadium oe carbon. The I'IIU.Itina aaiAtlli'C wu ltimld at room temperature under bydroccn atmolpbcre for 3 b. n. ca&alyst wu tba remo¥ed by rtltratioa and wuMd wid! tJar. 5-IDL portiaaa ol ~ mabaoc. n. COIIlbiMd r~~trata ~ra~~..­ mtioa too •c. a._ maan o •c. ....-urc. .,... ..., The abcM f'lliduc f t l clilloMd ia 5 a1. til c!jc+l T I Mw ud J00 ma ol eolicl NazCO, wu added. n. .-Jtiat aaiAturc wu ltimld at I'Oillll t.lllqllnhll"& for 10 bud ~ filwtd. c.a.r.tiall ol tile fillrale ader raduc.i ..-n p¥el60 . . (lOft) oltM llldium ah ollaa· Jocid A. n. ..-uaJ ~til tlail a.paad .... -..aJ willl tlaala til .._ autbentic IOdium aJt ol lueJoc:id A. 4(. H5(S)-Eayi-3(S~S.(5(.)4Jt-5-(H ... ,....,..._.J.el. -.mctJiyldiliJ&zide 0 ..,,. ,~~~e (S )-..071·1(. )·cetrU7*-"1UYil·l(S )·......,tlnlllrJIJ-l-(trt- To altimd ~ o/11 .2211111101 ol ......... iD 20 mL ol dry THF at -71 •c ....- .,._ wu Mded a ICMutioa oll.ll5 1 (3.74 IIUIIOI) ol tile - - . 3 iD 3 aaL oldry THF. Al1M I 0 mill tJM nKlioe lllimarc wu tra..S wid! 2.1 mL ( ll.l _... ol Mc,5iCI) ol tJM ..,.,_...., c.crifqatc '"-a IDiDift ol4.l a1. ol trimaJlylcJaloraliWic ud 1.4 aaL ol dry trill.bylamiae. Cooliaa wu tMit aa.tia...S ud U. .-ltiq IDiatun wu ltirred at 1'00111 t8lllpll'ablr& lor 90 IIIia. clilutad witlllOO mL olecJMr. w..a.d wid! twO 10-IDL ....,._olwa• ud 40 mL ol....,.... ~ NaCl. aad t1a1D ..., (Na,S04 ). Ramaftl ol tile......_. udcr ~ ..-n ud .,.panU.. cliRillatioa oldie....-. atforded 1.761 (94~) oltMiilyl .,.....a.. dill:illaliaa t90 -c <O.OS -ata>: I•JAD +ur .---= 199S (e l.JO. CliO,); Ia (CHQ,) 1610. 1~. 12SS, 1010. ..5 .a·'; 1H NNR (CDCl1) f US (a, 9 H. (CH,),siOC-). 0.210 (a, 9 H. (01,),5iOCC1). 0.11 <'&. 9 H. I • 7 Hz. CH,CHs). 0.'2 (d. 3 H. I • 7 H&. CH,cHCC). l.lS (d.3 H. I • 7 HI. CH,CHOC). I .SO (d.3 H. I • 7 Hz. CH,at-). 3.13 (q. 1 H. I • 1 HI. CH,c.HOC). 4.5'7 (q, 1 H. I • 7 Hz. CH,cH-). AMI. Calad r. c:,H,.0.5i 1: C. 65.00: H. 10.91. f'oad: C. 64.93; H. 10.15. ....,. Z<•HS<S)~l(S)__..,..s-(5(.,.,.._5-(al *'... ..,)4(s). ...,._l<•,_....,..,..,.,_J<S>·.....,••'•,_.. (4). A......_ o/0.96 1 (1 .92..._.) ol 1M a._.lilyl18011 Clhcr ia1S aL til dry_.... ud 4 aL tlldrf 4id.l aaanlaa• at -n•c wu tra..S willa- ulil it wu faially bhle. n. NKtioa aaiAturc wu&Ma u...S wid! two 1.l·l (31.7 . - ) paniCIIII olllldium baroo .,... CAatiaa ... ~ diJs-rieeed . . tlal...utifta ........-,n ... llirNd at , _ .....,....... lor 2 • ud tlaiD ODDCatta&ad under Nllhlald ,_,.. n. Nliclue wu &ab8 •P ia SO aL ol aturated aquou NH4 CI ud .._ acidified (pH • 2) witJl IK . . - . HCJ. The .._.._. ,._. wu atnaed witJl fo.r 40-IDL ,anioM ol dic:laloro_ . _ ud tM COIIlbiMd orpaic auacu ..,. dried (Na,SO.) and ~-lllldlr,....... T...... ol tJM l'llidue witJI ~- iD .....,, aad tMit c:laromaaopaplly o1 1M raaultina • .., • SO 1 ol ailica ... widi1K ~ cdllr p¥e 599 . . (7241) o1 t11e --.~ . . . 4: ........u.. clil&illatioa 1-.145 •c (O.OOI .... .,_... -'fa); [•J D 1.3• (t 1.01, CHCJ,) J 0.020 (a, 9 H. (CH,),Si). 0.13 ("- 9 H. I • 7 HI. CH,cHs). 0.90 (d. 3 H. I • 6Hz. CH,CHCC). I.IS (d. 3 H. I • 7 Hz. CH,CHOC), 3.67 (a, 3 H. CO,CH,), 3.13 (q. 1 H. I• 7Hz. CH,CJIOC). Aaa.l. Calad lor CJ1.,0,5i: C. 64.44; H • 10.35. Foud: C. 64.40: H. 10.26. 2(S).(5(S)-~3(S).....,..S.(5(.~S.(H ,, . . .:,)+ (S.....,._2(.) ....., • .,uwfi}-2(S~I4. To al&imd . . . . . . . eolut.iOD ol 6001111 (1.41D11l01) ol tJM mctbyl•tcr 4 iD 4 mL oldry et.llcr 1Uid.r 1J1011 wu added 160 ma (16.1 aunol of •ydride) olliamum IIU'Uydridoahuaiaatc. Al-.r l Ia tM ~ IIlia· 111ft wu cautiauty u...S witJI 0.16 mL til water. 0.16 all. ol 1St, .._. . . . NaOH. ud tlaiD 0.41 mL olwat.er. atirnad for O.S Ia and tlacn IDtand. Jt--.J ol tile .._t udlrl'llduaad ......,,. atrarded SS7 ma (JIK) til tM ..... ; 1i•• primary aloolaol: ...porati¥e distillatioa UO•ISS •c (0.001 JaiiiHI); [ca)ZZD +7.13• (t 1.06. CHCJ,); IR (CHCJ 1) 3520, 1460, 1255. 1100. 10SO, 140 .a·•: 'H NMit (CDCI,) '0.13 (a, 9 H. (CH,),Si). 0.1'7 (bt.. 9 H. I • 7 Hz. CH,CH 2). 0.93 (d. 3 H. J • 6Hz. CH,CHCC), 1.17 (d.3 H. I • 7 Hz.·CH,CHOC). 3.10 (q, I H. J • 7 Hz. CH,CHOC). AMI. Calcld for CaaH.O.si: C. 6S.9S; H. 11.07. Foud: C. 66.00; H. 11.06. 2(S)-{5(S .....,._%(. ol )·~71·3(5 )•....Jl-5-(5(. , .....,,_,_.,. .sy·6(S)· )·....,..,..,.)· 2(S)-~..,_,.,_.141. To a ltimld eoluticla 2641111 (0.66auaol) ol tJM abcM aJc:obol ill I mL of dry THF wu aclded a IOiutioa o/430 1111 (1.64 auaol) oliCU'I·•buty· lammoaium iD 3.2 aL ol dry THF. Alter 4 k. tJM ractioa muare wu dilu..S witJI 70 mL ol llMr, Well wuMd witJI two 30-IDL ,..,._ olauara&ad aq..-. NaHCO, ud 30 mL olatuatcd aq'*'ll NaCL ud tlaaa dried (MpO.). a...owaJ oldie IOMau ud c:hnDI· topaplay ol tile Nlicluc oa 10 1 olliJica pi witJI 3St, etllyl acetate in qdaOaanc atrarded 196 1D1 (9241) ol tJM ~ diol: cap 74-7S •c (bcune); (•JliiD +14.1• (t 1.16, CHCI,); IR (CHCI,) l600,3SOO. 1460. 1310, 1100. 10SO, 9SO em·•; 1H NMR (CDCI 1) a 0.96 (d. l H. J • 6 Hz. CH,CHCC). 1.22 (d. 3 H. J • 6 Hz. CH,CHOC). A.Dal. Calcld for C 1tff 160 4 : C. 69.47 ; H. 11.05. Found: C. 69.37; H. 10.96. nuoridc llu,l l(S)-{5(S)·£ail-3(S)......,._5-(5(.)4yl-5-.,*ny+ (S,.....,..2(. )·IICI'Ui..,.,_,I)·2(SHa&rM,*-'wyl,_,. £aer (5). To a atined 1U1J1CD1ion of 22-. (0.6 aunol) of powaium bydridc ill2 mL ol dry THF at 0 •c uder araoa wu added a IOiution of 164 . . (O.S IIUDOI) ol tile abcM dieM iD I mL ol dry THF and tlaal 0.09 ml (0.75 IIIIDOI) ol bazyl braaaide. n.I"'IIWLiq ..Uture wultimd (or 21l at roam ....-.turc. trat.ed witJI S mL olatuated aqMeDU~ NaH· co,. ud tba diJu..S witJI 60 mL ol . . .. nc orpa.ic ..... wu ~~parated aad wuMd witb two ~IDL ponioal ol atua..S aqueous NaHCO, ud 20 mL olatua..S aqu.ua NaCI ud dacn dried (Mpo OJ. Alt. I'CIDCM1 ol tJM . . _ . at ~'~dueled pnaw-c. c:llromaqrapby til die ..-.... oa 20 1 ol liJica pi witJI 3S~ etller-pctroieum etJ1cr ,...,.... 172 . . (I~) ol tile IDOilObauylahcr 5: .,.porati¥1 ctiatil· latiaa 110-190 •c (0.005 mmH.c); [ca) 22 0 +21.1• (t 1.40, CHCI,); IR (CHC1 1) 3510. 1460, lliO, 1120. 1100. lOSO. 960 em-•: 1H NMR (CDCI,) '0.96 (d. 3 H. J • 6Hz. CH1CHCC), 1.1 I (d. 3 H. J • 6 Hz. CH,CHOC), 3.76 (q, I H. J • 6 Hz. CHCH,OC). 4.47 (a, 2 H. c.Jj,cH,). 7.33 (b a, 5 H. c..Hs>· MIL Calad lor c.HGO.: C. 74.60: H. 10.11. Foud: 74.SO; H. 10.01. a.u,1 2(S)-{5(S)·EdiJI-l(S)·.-,I-5-(5(S)·.,._•J-6<S)· _.,..2(.)·....,~)·2(S)........,.*-f.,.._,l £dllr (1) • To altimld ICMulioe o/60 1111 (0.30 IIUDOI) ol pot&lliumlaydridc iD 0.5 ... ttlcky THF ..... arp wu adMd aiGbdiaa otiS 1111 (0..210 BUDOI) c. 102 l~llut/J , 1996 J . .41ft. 0..... S«.• Yol. /OJ. No.1. INJ flldll alciDMl 5 ill 0.5 aL ti*J THF. ,. . . . ., O.G6 .&. (1.0 ....) tl cartloa dila1fiM. Att. 5 ~ .......... ..,... ........ . . 0.015 811. (0.4 818101) fii.Uyl iodide ... alllr u ~ JO .... Ullllimn ... clilu&.t widl410 811. ., .................. s-.1. partia. oiwaw ud IS aL oi•tan&.t .....- N.O. ... U.. drild (M,SOJ. R---.1 tldii.._.IM a ,.aa. oil . . . • .....a.. pa c:Uoma&opaplly (Ciobuaa: S£·30. 0.25 ill. x 6 ft. 220 •;.a. JIGft lOO •c> • a~...._ J& . . ., . . . . . aiati&N (ao:ado. 1:$) 6. AIOhtU.fii\M~.... ...-..ill20al.flldry .......... 2al. fll dry dialot ~ m• """ at -11 •c wu .,._, n. ... util it wu laiady .... n. ~ milbn ... ~ tra&llll ............. (2.6 ..al) ponioM ollodiUIIl ......, . .. Cooliaa ....... clilaaatiRid ud u. ....Utia1 ..., . . _ wu llimd at,_......,.. . ror tO • ud lMa a.catra\ed ..., ~ ,_.,... n. ......... au. . , ia 30 llll. ol atura\ed . . . . - NH.CJ. n. tq..., pllue wu ..,.,..&ad aDd tJMII atnaed witJa ....,_ IS.IIIl. ~ oiallllr. n. -bi.nld ethlraJ ..... ""' ...... witb 15 mL NaCI ud thea dried (Na$0.). a.a.a.aJ oi me ..._, ud * - · 1apaplly ol me !Widuc oa 10 1 oililica pi witb 15' edlyt .-......,.. troMum...., prcMded 3.5 ... (4.5') fll lite....,. 7: diatillatioa •••50 •c (0.005 111111H1); (•J~'o +15.1• (e0.96. CHO,): IR (CHCI 1) 36.50. 3410. 1470. 1400. 1120. 1010 c:aa·•: 1H NMR (CDCl1) I 0.13. 0.92 (lt. 6 H. J • 6Hz. CH1CHJ). 0.97 (d. 3 H. J • 6Hz. CH1CHCC). 1.17 (d. 3 H. J • 6 Hz. CH,cHOC). 4.~ (1. 2 H. c.H.CHv. 1.32 (~a. 5 H. c.Hs>· MaL Calod ror c.H.O.: c. n.ll; H. 9.11. Foud: C. 73.76; H. 9.79. a. s,..... ti ... Ltft.§We AIM7* 1. a..-IJt ~(It). To altirrad IOiution oi435 lll1. oi 0.5 M 9-IIN ia THF (0.2175 mol) at 0 wu added 30.01 (0.217 mol) oi (R)-(-~.,.. 45 u. n. ....Utiq IOiatioa wu allowtd 10..,.. 10 after 2 b. 130 mL oi a-..•sc ......,. ud 43.5 mL fll 6 N ...-a NaOH . . . added. n. ....Utia1 miauare ... CIIDOW 10 o •c ud 14 llll.tii-HAidiWG~~~W30mia. n&...utinalniDire . . ...ou.t lor 1 • aDd then .....,.... 10 o •c. ud me ~q_.. ,..._ •tura&.t witll 200 1 oi KzC(),. n. orpaic ...... wu ..,.,.._, ud tileD dried (Na$0.). llaDcMJ oi..._t uder reduced ,.._.,... II" a Nlidu wb:b .... clillilJatioll (IIG-115 •c (15 auaHa)) II" 24.1 I fila .a&t~~t~ fll c:ittaedlol ud 1.$-q:looe~adiol. abcM mi&uare wu diaaoMd ia 600 llll. fll dry~ ud tile ....Utiaa IOiutioa CIOOW 10 o•c. To dUII&imd IOIIItioa wu added 25.9 mL oilriedaylaaUM ud 13.1 811. fll.-yl ~. AJt. l b. 400 mL fllutura..t~q. . . . NaHCO, wu added. lad me orpaic p11uc ..,ara&ad ud tlleft dried (Ma$0.). a.a.a.aJ oi..,.... uder .......... .,.._,.. and f1ub c:bralnat.op'aplty oi . . . . . witb 10. edlyl aGitate ia paro&.um ltMr P" a Nlidue wlaicll .... ..aporatm diltiUatioa <1~ •c (15 IIIIDHa> >.... 23.6 1 oi citroelllyt - . ... 11 tram ciU'CIMilcae): 1H NNR (CDCI 1) I 0.91 (d. 3 H. J • 5.5 Hz. CH1CH); 1.62 lad 1.61 (21. 3 H (2X). -c(CH,)J). 2.03 (1. 3 H. CH,COt). 4.10 (t.2 H. J • 6Hz. CH,PM). 5.10 (aa. 1 H • .a<H). '"AcllenJ~·)·_.,. lin-* MM (f). flllO.O I (.SO anol) ol citroMUyl ICIIC&tc (II) ia _ , mL f11 ~- wu CIOOMd 10 -71 •c aDd a auam o i - ia oaypa babbled ia aatiJ me IOiutioiii"CCD&iaed btuc for 10 miD. ne IDiutioa ... tMa pnpd witll • IU'C'aJ'n ol aiuopn 10 l"eeftCCW ac. aDd tile ....... f'IIDIIMd . . . , reduced pnuurc. ne f'lliduJ _ _ . ... dilloMd ia 1.50 mL fll acctoDC and tile re~~~ltin1 IOiutioft CIOOW too -c. A lolatioe oil N H 1CrO. ia acaonc wu u.ca added Uowly util me IOI1It.ioa ..-u.t browD. n. ~ miat~~t~wu tltea ,.,.t illaoiOO mL oiwaw ud tile ....Utiq miauare atraaed witb SOO.. 300-. ud 200-IDL ,..U.. fll ~. n&oamlliMdcqui:,...__...._(M.SOJud CIOIICIIluaa.d ..., redUC*l ..-n. !Yaporatm diltillatioe oi • Niduc (160 •c (0.5 11UDH1)) pw 7.41 (TK) «WI title acid. n. Jidd •• S.anoiiCillc ... " ': .......tm diaillatioa 1so-160 •c (0.5 aunH1); [•Juo +2.61• (c 3.52. CHCI,); IR (. .t) 3200, 17410, 1710. 1310. 11.50 em·•: 1H NMR (CDCI 1) I 0.93 (a. 3 H. J • 5 Hz. CH1CH). l.l-1.9 (aa. 5 H. CHrCHCH2). 2.01 (1. 3 H. CH,CO). 2.37 (t (dd). 2 H. J • 7 Hz. CH1CO,H). 4.10 (t (dd). 2 H. J • 6 Hz. CH,PAc). A.ul. Cakld for c,H..O.: C. 57.43; H. 1.57. Faud: C. 57.45; H. 1.62. l(S)-~ • 5 ;I ~ To a....._ t/13.002 1 (15.94 ..a) oi me acid 9 ill 105 1DL til..._ ud 0.47 1DL fll pyridial-.. added 710 811 (3.56IIUDOI) fll Clllfric --..sc '7*a18 ud 12.14 1 (21.96 ...... ) ol-.. I8U'UCIIUI8. ~ miatan ... rtl1aud b 16 b. lad 6.01 (13..53 mmol) oillad..,...... . . diaD .... ud ~. Alw 6 . . . r.c:tiaa . . . . . . . . . . . . to . . . .....,.uare ud tJMII,..,.., i1110 I~ IDL oiwaw. n. wu t11a ..,.,...._ ......_ witll ..,_ 150-m ,.,._ fllwaw. aa· tnclad wi~ two 100-IDL .....,._ oiatva&.t . . . - NaHCO,. ud ........ (M,so.) . ........, til.._ at.. ,. ic ,._,.. 4'- -c. • ... ..,. « ....... ...-- ....-u.. •c ,_...,..,an; n. <,., A....-. n. ...n.w.. 0f1111ic,..... GJ. ..... a JO.aa Vilr'IU ooluiDII P" a ...... wllicllwu tn.ioaaUy diltiiJed (JOG-105 •c (1511UDHJ)) 10 pe 1.511 1 (6~) flldlll(S)...,.....,.....yl.-atc: [•) 0 +19.,. (e 1.11. CHO,); Ul ( - t ) 2990. 1742. 1310, 1245, 1010.920 --•: 1H NNa (CDCI,) • 1.00 (d. J H. J • 6.5 Hz. CH,CH). Ul (d t. 2 H. J • J' • 5.5 Hz. HCHCHrCH,P). 2.00 (a. 3 H. CH,CO). 1.25 1 H. ~HCH(CH,)CHJ). 4.07 (t. 2 H. J • 6 Hz. CHzCH,P). 4.95 (a. 2 H. CH~JI.>. 5. 70 (aa. I H. HCCH-cfl.~. Mal. Calal for CeH,A: C. 67.57; H. 9.92. Faud: C. 67.63; H. 9.19. n. llicarboaal8 aauacu _.. acidiliad 10 pH 2 ud aatr'ICUII W. <• (...). two 100-ml.. ,...u... fll~ n. ........... aatracU ...... dried <MaSO.l ud CIOIICIIltra..t ..., red1ac* ..-.... a..porati" 6tillatioa flit~~~,..... uoo •c <0.005 ..ttan .... "' .. <26'> fldllacid 9. J(S)-~..... 14. To allimd ........ oi4.69 1 (33 -.of) fll tile abcM ICIItlte ia 21 mL oi-MDOI wu adcW 30 . . oiiGdi~~tn - - - . ud tile ,..UtiJia IOhatioa l&imd at room l.llllplraUft. Alw I b. lite r.c:tiae lllist11t1 wu pound ia10 150 mL oi U. ud the .-Jtiq lllist~~t~ wuMd witJa two SO.IDL ...,._ ol waw ud t.1aa *illd (N,SO.). RancwaJ fll.,...t by dillillatioe at a~ ,.._,. daroqb a JO.aa va,r.a .... pw a ....,. •b:b ..,.. . .pont"- distillatioa (10 •c (15 BIIDH1)) .... 3.261 <tK> o1 u. wtwpundiitc ~: [•J•o +l9.W (e I 54. CH01); IR <-t) 3350. 1655. 1060. 1005,920 c:m-t; 1H NMR (CDCI,) • 1.01 (d. 3 H. J • 4.5 Hz. CH,). 1.53 (dt. 2 H. J • J' • 4.5 Hz. HCCH,cHJ). 1.21 (m. 1 H. -<:H-<H(CH,)CHJ). 4.97 (-. 2 H. CH-cHJI.>. 5.70 (aa. I H. CH-CH.H.>. 5-.._.l(S,__..,..I.,._ (13). To altimd . . . . . oi4.~ I (44.97 aunol) fll tM . . . . . . . . . ia 100 mL til cliclaJoroalelMDC at added Ullll. (49.1tmnal) ol-laai'WUifoayl cbloridc and 0 6.91 811. (49.6 IIUDOI) fll tn.tllylamiM Wllt~C~ttially. lad till twaJtina aiatvc IUrNd at 0 lor U .ua. n. NICliaa miauare wu tileD ,..,.S iaiO 100 mL oi•t11n-.d .....- NaHCO, aad tiM ....Utiq .awre 10 .u.. n. orpaic J*ua wu .,.,.ted. dried <NaSO.>. lad*" W~Catra..t..., ..... . - ,_...,.. nc rwiduc wu ._..... ia 130 aL fill dry THF ud 5.17 1 (67.6 IIIIIIGi) ol wydrou liuu... llrolnida wu added. rwultiq miat~~t~ wu ,. ftuud lor 4 • ud tJMII ooolad 10 room -..,.anare. It iJito 300 mL fll palWII. lad WI arpaic plluc ....._. witll two 100-tnL ...,._ fll•tura&.t NaHCO, ud fM 100-ml.. ~fill water lad tJMII *illd (Ma$0.). 5oMBt wu,.....,.,.. by cliiUUaU. tllroup a JO.c:m CIOiuma at aiiiiCIIpMric pnwure. a..,.... cliiWiatioa oi t11e rwiduc (70 •c (10 mmHJH .... 6.21 1 <"'> fll* bromide ll: (•J•D +32.7• (e 2.74. CH,OH)~ Dl (-t) 1655. 1470. 1435.1270. 1015, 915 em·•; 1H NMR (CDCI,) • 1.01 (d. 3 H. J • 5 H&. CH 1). 1.10 (cit. 2 H. J • J' • 5 Hz. CHrCHtBr). 2.35 (m. I H. J • 5 HL -<:HCH· (CH,)CH 1). 3.36 (t. 1 H. J • 5 Hz. CH 1CH18r). S.Gl (aa. 2 H. HCCHJ111). 5.64 (m. I H. HCCH-CH.H.>. I.I·~Z..(l(•) udi;l •u ;1,.._, Toulinwdmiallre t/111.99 • (110 aunol) ol ~ acid ud 15.19 • (110 IIUDOI) or lodiwn bicaraatc iD 4~ mL oi CHaCI, at 0 •c wu added. ill oac poniCIII. 12.5 1 (9CU IIUDOI) ol (RH-~. n. NaCtion aiztwc wu ltined for 1.5 • at o •c ud wu u.ca qlleftCbed by the additioa tll150 IDL oil O.~q.... Na.p:J,. n. rwuh.iq mixture wu ltirred ror 15 miD aad tJaCD 25 1 ol NaHCO, ill 50 mL ol water wu added. ne orpnic layer ... ..,.,.. . aDd tileD wuMd with two 200-mL portio~~~ olwatcr ud t.laa dried (MaSO.). nc .._, wu ,_.ed UDder reduced ,...aure to live a rwiduc wb:b was CYaJIOn• tMiy diltiUed <150 •c (251111DHJ)) 10,;.. 11.2 1 <~> otlhc Clliruel: •H NNR (CDCI 1) • 1.00 (cl. 3 H. J • 6 HL CHCH1). 1.25 (a. 3 H. CH 1), 1.30 (a. 3 H. CH 1). U7 (Ill. 4 H. CHCHrCH1CHO). 2.15 (Ill. 1 H. HrC-<:HCH). 1.10 (Ill. I H. CHrCHO). 4.93 (m. 2 H. H,CCH). 5.70 (Ill. I H. HrC-<:HCH). Aaal. Cakld for C._H,.O: C. 7'7.17: H. 11.76. Found: C. 77.11; H. I 1.65. I ..OS. I·~• )~s-a..- (II). To altirrad IOiutioa ol U .O1 (97 .14 aunol) ot tile abowc cpoaidel in 450 mL oi ether at o •c wu added. i1l ponioalower 1.5 ._ 26.6 a (116.7 aunol) olpa,..,.....ic acicl. Tllc ~ ~Diann WU t.laa allowed 10 WU"'DIO room LCiftpcf• atwe. Alter 5 b. 13 I oi NaHCO, wu added lad t.M miawre WU llirrld for 2 •· n. ~ llialWC wu U. dried (MaS().) uc1 •c...,. •c stirrad......, ror n. wu,...,.. v.,_. ftl18nd. Tile ltblral eanatioa ClbcaiMd abcM . . ooolad 10 0 -c. ad lOO IDL fll a 2.0 N IOiutioa oi pllcayllllapwiwn brcaide ia ttbcr was alowly addld. n& r.cUoa llliaul . . llimd at 0 for I • ud U... at ,..._ -...uare ~t. It wu tMII q...-.s by tJac c:arefal additioa o1 ~ mL fll •mra&ad ~q_.. NH.Cl IDiatioa. faUoftcl by 300 lllL ol waw ud C11GU111 3 N ~q-- HO 10 dilloM all tile ,...:ipitated lalla. n. ...... layer ... ..,.,.ted ud ............... ~y wid! I 200-m1.. panioa flllldl oi t11e rollowiq': atua..t ~q.- NH.CI ...--, ...... . . . - NaHCO, . .tioa. ....... ...-- Na0. -c 1Q3 Tot.J SYfllltaU of/_,... ,..illiotkr n....-.. ,...... ..., ........ ,.._,. .. lift J. Alfl. Clwlfl. Soc•• l-tN. IUJ. i\11. ,, n1~.J (JqSOJ ... ta. ............... u aily .......... To allirnd IOhaU. oi ... a._. aily ,..... i1450 & fll CHA . . . addld2.61oiiGIIIiuaao~~ataud741ola1:1(•/•).-..fl Celitc ... , . . . . dllluaca:k...... aa room ...,_.uan I• 5 ~.....,.... ialol.2 L of*'.._, ud .... ma.rad ...... CeUta. a.-..1 o( . . . . . . . . . . ,....._. , . _ . . udflaM.__...,oi&M,...._•IOOiflllilila ... wiD1. . . . . . . . . . . . . . . 2.21(6~)ttl ... ,...,. . . . . ll: ........ 61UUaU. tO •c (I ..H1): [•) 21D +10.1• (t 1.76, CHCa); Ia (CH· Ca) 1690, 1610. 1590, 1..0. 920 •-t: 1H NMR (CDCI,) ll.OS (.. J H. I • 7.5 Hz. CHCH1), 1.73 (-. 2 H. CHCH.CHa), 2.16 (-. l H. Hp.cHCJI), 2.90 (1. 2 H. I • 7.5 Hz. COCHaCJia). 4.92 (a. 2 H. Hp.cH). 5.67 (-. I H. H,c-cJICH), 7.4 (-. .J H. Alii). 7.t2 (a. 2 H. Alii). AMI. Calad f• Ce,H..O: C.I2.N; H. 1.57. '--1: C. 13.01: H. 1.45. J(a)-~ • I 1-41 (IS) (~ A). A ...._ of 1.0 I (42.5 lllmGf) fll dll lraalll ud 1.5 1 (157 a.Dal) ttlllllliul...._. i1250 lllL ttl dry .Uyl rwmace wu l&imd at room ._,....,.,.. ...lliPt ud &Ma acidU..t 10 pH 4 wi~ ..UC acid. n. ~ ..._. wu dil•a.d witll I L ttl ather ud tJia atnatd wiw two G-lllL ,..,-.ttl a 5~ -.. . . . NaOH IOhatica n. _..._. a q - a· cncu _.. acidil'..t 10 pH 2 wiD 6 N ....... HO ud ~ ~ wiiJatwo 400-mL pllftica ttl ..... n. . . . . . ta. ,._... .... ....... ,.._.,.. 10 aM .. oily ......... 'neabowe,....._wu-....ia 175aLol ....... ad175aL olpH ~ bd• ud tMil ~.51 (115 _ . ) fllllllilaD _ . , _ . ... WI ...... n. ..aa. ID&&tvtwullimd at,_ . . . . . . . . r. 7 . , . ud lMa aVICUd witla tJarw 1CJO.IIlL pllftica ttl dicllJ I t lee• ...,UC auacu . . . oombiaed ud tJia ......., with *- loo..L ,...UO. ttl!" aca- NaOH autica. n. _..._. aca-anc~~ _.. ecidir..t 10 pH l witJa 6 N aq...,.. HCI ud U. atnaed witJa ..,_ ICJO.aaL portiaal ttl daJ = at1111..U.. n- ftal orpeic auacu wen dn.d (M,SO,). ud thea tk IOMat wu,....,.,.. ..... ,....._.. ,.._,. 10 alford a ,...... OGDtaiailla dllind ICid ... --acid. n. aaiatun o( ICiiM wu dilloMd ia «JJ lllL ttl dry . . _ ud 2 1 (52.7 ...al) ttllidailllll tard~le ... &deW. n.--- - . .... llirred at I'OOID r. 2~ ~ ud lila 2 aL o( waw. 2 aL or 15~ ....... NaOH. ud 6 aL olwaw _.. addld ....-...,. Alw lleiq llirred ..,.._., far 20 alia. ... ~ 8iaturt wu drild (M,SO,) ud &Mil Cite IOMDt wu ,....,.,.. by at• ~ cliltillation tJuooup a Vipeu aoiulllll. n. f'llidue wu &Mil fractioeaUy diltilled (60 •c (.JO mmHaH cop. 2.1011 <~K) ttltJ. .-.,. 15: (•) 21D -21.92• (t 2.5. CHCI,): Ill (. .t) 3350. 1655. 1060. 1005. 920 em·•: 1H NMR (CDCI 1) I 1.01 (d.3 H. I• 4.5 Hz. CHCH1), 1.53 (elL. 2 H. I • 4.5 Hz. ~.5 Hz. CHCHzCH~. 2.ll (-. I H. CIICH 1). 4.9'7 2 H. 5.70 1 H. H.C-cll). A.uJ. Calad I• c.H 1P: C. 71.95; H. 12.01. Foud: C. 71.13: H. 12.00. J(a)o~ •1 1-41 (15} ~a). To allimd ...._ttl 90.51 aunol ol LDA ia 300 lftl. ol dry THF at -71•C wu &deW 1~.20 1 (75.4liiUDOI) o( the ketone II ia oiO lllL ttl dry THF. n. NKta. mt"re wu ltirnd at -71 •c I• o.s ~ ud thea 19.2 aaL oiW. c.trilqace oblaiDed from .JO m1. o( ll'iiDedlyiliJyl ~ ud 10 aaL fll dry triethylamine were added. Al1. WI mi&tun wu l&imd at .._. ~ture for 2 k. 1M reactiaB lllliUare WM dilldld witla 1 L fll,..... ud tJia wuMd witb two 500-lllL ,..,-. o( water ud 500 lllL fll atu.ra&ed aq_.. NaCl. n. arpllic Ia,. WM cbild (K~ Na~.). ud u.a the . . . . . . . ,...... . . . . ,......... ,._.,.to lift a ODiorteu raidue. n. abowe . - . . wu clilaciMd ia lOO aL fll CHA ud CIDIIIId to 0 •c. To tJUs IOA•tioe wu addld 14.31 (12.96 IDIDOI) ol ll'foQJwopa lteuaic acid ud 12.6 1 ( 150.14 . . - ) ttl NaHCO,. n. ~ llliaUift wultimd for 1 b ac 0 ud m. far 3 ~at.._...,....._ At tJaia tiJne. 1 .~ 1 (1.2IIUDOI) o( ....cUu::opa' IIDic acid wu addld. n. ..-c:tiaD mi&t•re wu llimd at r-. I• ...._ 311 ud tMII ct..acbed a, 1M aclditioe o( 100 lllL oil• .,.._ Na,SO, ud 100 lftl. ola auara&ed NaHCO, ...- . n. ....- Ia,. wu ..,arated. wuW with two 1~11lL panioaa fllwater. ud dla drild (M,SO,). a-...1 ttl.._ udlr,......... , _ , . pt~e a ....... n.,.... ............. n. * ....,.,.uan <-. s.c-an. <-. •c ._,..tan raiduc. n. a-.l'llihe wu clilaaMd ia 350 a oi.W .._ ud 22.4 1 (ti.OS . . .) ttl~ acid ........ n. ~ lllimnllirnd at o •c f• 1 111 ud .._ at ..-. ._,..tan I• 3 ~ n. ..._. IOhatioa wu W. ...W witlt two lOO-IIIl. ,..,-.ttl a • • lallld NaHCO, ..... ud D»ml.fll..-.tlld . . . . - Naa_. ta. .._(M,SO.). o-c.udta.5.71(150.1 ..... ) ollitiUaa .......~. . . . .,.,...., ..... ..at.iaaaaiatan wualirndat 0 •c f•11aud wu ~ u.a.d ~ ...a..ty wiQ 5.7 aL o~ ..... 5.7 aL fla I S . . . . - NaOH-. n.abowe.....,...._,......, .. n. .. .,.~ n.--. .. ..,... ..,_., ,. . . . . ... 11 aL o~ ..... 15 . . ad ta. . . . (MaSOJ. n. ..._WI,._...~ I' 1' tc 6aillaU. *-PaIS.. V.,.. _,_, Ull 1M .......... ,..._ W11 ...,..u..ty 4tillillld (.. tol20-<: (21..tia)) to lift 5,.. I ~)oltlllaJoMoi(IS). J.._.J(.~I.,-(14). Toallirnd ....licaol21.15 1 (211 a.Dal) flltJ. ud 45.51-.L fii*Y ~ ia 520 -·-".,C ..._..It ...... aL o1 dry CH,ct2 at f1' . . added ....... 11.S611lL (240 IIUDOI) fll a ·~·s..u. n. ...-.llliaurc ....... llirred c:lllaridl, . 15 ..... 0 -c ....... ,..,... iato 500 aL ol ..... n. ...- ..,.... .. ....,.... ud . . GU'8CUd witlt ~. . 250--.1. panioaa ol diclala IteM. n. ....-I~ wen drMd ....n. .-. ......_ (JqSOJ ... ~............... ,_.,.to aiw u oily,... wu ....... ia .00 aL ttl dry THF ud tMII 36.06 1 (300 tllliDOI) flllidliaa ......_ WM addld. 'n&I'IKiiae ~Dimarc at r'lllus r. 4 ~ ud tMI ,.,..,.. iato 500 lllL ttl ..w . TU .... attaaad witlt ..... 250-lllL panioaa ttl - - . . . . . . . tbn ..-...s ud ........ wit.1a 250 lllL ttl•tana.d ......,.. NaCl. nc ...... layer . . . . <MaSO.>.... tllle tM ....... ,...,.. by a~ clistillaU. tlaraqb a 25<m Vicnu oaluu. n. raiduc ... u. diltiW (6119 -c (60 111111H1)) 10 ,m 25.72 I (7~) fllQI ...... . _ _ 14: (•) 21D -JJ.7• (c 2.76. CH,oH): IR (..a) 1655, 14'70. 1435. 1270. 101.5. 925 em·•: 1H NMR (CDCl,) I 1.01 (d. l H. I • 5 Hz. CHCH,). 1.10 (dl. l H. I • 5 Hz. 5 Hz. CHzCH,ar). 2.35 (-. 1 H. I • 5 Hz. CHCH 1). 3.36 (t. l H. I • 5 Hz. CH,.), 5.02 (-. 2 H. H.C-Citl. 5_.. (-. 1 H. H.C-cH) . J(a)-~ • 5 I Adll (12). To a ....tion o( 164 1111 (0.14 - ' l olliMr ~te ill 0.1 aL ttl M.,SO wu added 123 . . (0.10 oiW. . . _ . ••. , . ....aac. . . .,. ... stirred at roc. I• 2' ~ ud lila 10 •L fll dry m.tltylamine wu ....,_ TU wullirnllf• 1 ~ ud WID clilua.d witlt 20 lllL o( ctber . n...atwe ... tliLawd ud r&ltnce ... ....a.s with tJnc 10-lllL panioaa ttlftCir ud 10 aaL ttl•tun&ed aq-- N1Cl. .. ._Uid adtr........, ..-.. -'> ._...tan ....._<Aide * , . arpaic ..,... . . . . <MaSO.> ................ brouabt wp to .JO aL a, tM lddiU. ttl dry ltMr. To Qia .u.r.J IOhatiaa at o•c wu &deW 261 . . (6.t . - ) ollidliul tavab,.Sridoalumiute. n. ~ - - - .. llimd at 0 1.5 ~ ud u.a 261 ttl waw. 261 .&. o( a 15~ .,.._ NaOH . .- . ud 713 .&. fllwacer ... addld Mty. llimll ,...._,. 20 lllliD ud m.. dn.d <M.SOJ. SoMat . . ,...,.... a, a• r' "dil&iJ. lltioa t1lroqJI 1 Vipwa oalula 10 lift u oily raidue. a-. ................ ia 10 lllL ttl---. ud tbln ..... " - ~ wu &deW to aM till IOhaU. a browa tiqe wlbdlpa-• tillad for k11111r tlu IS IIIia. Tlte . . . . lnimn wu tbln u.llldwith ~ aquou NaOH to pH 14 ud &Mil dilua.d witlt 20 lll1. olwatcr. nc aquou lay.r ........... with tllnc 10-llll. ponioal ol dicllJoro. _ . . . ud tt. acidil'aad witlt 6 N....,.. HC 10 pH l. Tlte . . . a.,_ wu auactad wit.b *'- 10-llll poniaal o( ciic:blcnlnctbaDC. aDd WID tk Gtrac:ll . . . oombiDad ud dried (M,S0 4). n. IOiveat wu ....,.,.. a, a~ diltillatioa tbroqb 1 Vipw& oahama aDd taen 1M raiduc wu tvapentiYely diltiUid (10-100 •c (l7aunHa)) to aive 30 1D1 (31,) oltk acid 11: (cr)»D -13.9'7• (c 2.90. CHC1,); IR (CH· Cl 1) 3200. 1710, 1~10, 1300, 9.JO em·•: 1H NMR (COCI 1) 4 1.12 (d. 3 H,l • 7 Hz. CHCH1). 2.37 (ABXM. l H. CHz(:~H). 2.6 (m. I H. CHCH 1), 5.02 (m. 2 H. Hz<:-CH), 5.10 (m. I H. H 2C~H). ADal. Calcd for c.H 1A : C. 63 . 1~: H. 1.13. Foud: C. 63.21 : H. US. S.O-(Ta. . .JL:6JI)·~l......._, To al&ilftd IOI"tioa of 1.15 1 (55 IDIDOI) ol o-riboaic Kid. -,.aaa..c ia 400 lllL ttl dry pyridine . . added 11.6 I (66.7 tllliDOI) ttl c:blaroc.riJIIaayiiM&baM. n. ~ IOhaU. wu......, 1t 70 I• 16 b. n. c:DaW ~ lllimlre wu ~a.d wit.ll600 aL ttl diclalaftlt" '"• wuMd with W. .JOO.mL , . . , - . o( IK ....... HC1ud two ICJO.Iftl. panioal ol•UU'I&ed .,.._, NaHCO,. ud tJaa drMd (M,SO,). RCIIIOW'I! o( the IOiwftu ... dlrcaal.op'lpby ol the Niduc - 300 I ttllilict pi witlt 5(JII c&Jlyl .-ate ia ,..,....... ecMr atr«ddld 11 1 (14~) o( WI uipblftylmctbyl 8tltcr: IR (CHC1 1) 3$90. .J020. 1790. 1490. 1450, 1125, 1095 em·•: 1H NMR (CD,COCDa) I 3.40 (ABX (ddd).2 H./41 • 1-.r • 3 Hz). ~.l7 (d. I H. I • 5 Hz. H-3), ~.47 (dd. 1 H. I • I' • l Hz. H-4). ~.77 (d. I H. I • 5 Hz. H-2), 7.33 (-. 15 H. Plt 1) . •c ,. ne--. .. .a. r. n. •c u-o-('nfea....,t)-s-o-<.,._,....,.,.~• ...a.ce- (1'7). To a tbmd IOAutila ol41 (10 IIIIDOI) ttl tJ. ab!M dD ill .SOO all. oldry MIIIGM wu &deW 2.7~ 1 (15.4 alDOl) ttl N.N'·tbarboeYidi· .-u. ilaidazale. n. ,_.tiD& wu ._.., to rtllu ror l.S 11. nc Clllllltd NKtioe lllizhare WM ~ted udlr ,...._ ..-re 10 ba.lf t111 .;p.u ..._ ud ~,..,.... iato 500 lllL ttl ..... nc ~ .ut.n WU aU'aCI.Id witlt . . 200-aL ,...UC. ttl ctidalorolnetAaM. arpllic ......... ...., witlt twO ~llll. ~ o( amra&ed aq._. NaH~ ud two ~aiL para.. ol . .a.r and din . . . . (M6$Q.). 1.-.lfll..._ud._......,ttltMIWiidUC n.--- 104 1991 J. Alii. 0..... S«.• Yol. 10$, No.1, JHJ • 2001 ttllilica Ill witJ1 M Gyl - . . 8,.,... .._.,.... ).$ I (7K) ttl CIOIDpaud 17: . , llt-190 I•J11a ~.,. (" 1.1. •c. CHO,); IR (CHCI,) 1120. UOS. 1-. UIS, lito. 1010 _ NMR (CDO,) ll.l (d. I H. I • U Hz. H·2). l.IS (.._ 1 H. 11 • U Hz. J2 • 2 HI. H·l), •.1 (a. I H. H-t), S.J (UX. 2 H. H·S'a), 7.3 (.. 15 H. Pll 1). AM!. Calal (or C.H.O,S: C. 6tAl; H. •.66; S. 7•• 1. Faud: 69.41; H. •. 71; 7 .•) . c. .. , 1H s. • S)·H,...,·J.<• ....., .......,,., 0 I .... ~a..- (11). A..,..._ ttllJ I oC W-4 aa..,-.. ia 125 aL ~~-­ 2 'dia JOO aL oC aaralaydro(1arao ud 1.011 (7.1 filM c-.rt •• 11wu ....a. n. YiJorouiy ltimd minve . . ._._. 10 rw11u ror 2• ll. n. CIIIOWIIIinllra wu tM8 tut.nd ud me IDlid ....._ ........ widt two 5().m1. panioal ttl ~UI'U. 1'k CIIIDIIiDid ftltraW . . . ..atralad uader NdiiOid ,_,.. 10 lift atalid ......_wilD wu c:ryaaJ1i..s !ram Allyl..-......-.. 10 lift 1.1 1 (73') ttl CIOIDpiiUd II: mp ISJ-153 •C; (cr)zso -50.2• (" 1.0, CHC11): Ill (CHO,) 1510, 1465, 1110, 1105 em·•: 1H NMR (CDCl1) ll.l (d. 2 H. I • 5 HI. H·S'a), 4.55 (ID. I H. H-4), 4.9$ (ID. 1 H. H·J), 6.1 (dd. I H. 11 • f HI. J 2 • 2.5 Hz. H·2). 7.3 (m. IS H. Pll1). AMI. Calal for CaJI.O,: C. 10.11: H. S.66. F•nd: C,I0.69; H. S.69. .S)-Hy....,·J(S)~S.( .......t . . . .aJ). . . . . . AdiiJA. ' - ( I t ) . To altirrad .......... oC 4.97 1 (2l.S . - ) ol~ bramicle-diJDetyl autrldc CIOIIlpia ia 150 1111. oC .._ at 0 udlr UJG11 wu aiowly added 21.15 lll1. (<10.2 . - ) fla I.U M lalaa oC .-byllithium ill Mer. Afu:r Ulllia. a IGbltiaa oC l.lt 1 (3.35 . - ) ol Ule bu&eDOtide II ill 30 mL oC . . _ wu added. Ate. 1 k. 1M ,.ctioD lllisuare wu wuiMd with W. 100.1111. ,..ua. oC NH.Ct/ NH.OH pH I buffer aDd two 100.1111. .,..U.. oC waa.. n. arpllic layer wu dried (MaS04 ) and c:oac:.atralad udlr ,...._. ........... Cianaatop'lpily oC the~-- on 7S 1 ollilica tt1 with~ Allyl ecaa~ ill J*roMwn ether afforded 0.94 1 (76') oC tJaa laaGM It: (cr) 110 +2.2.3• (t 2.1. CH0 1); IR (CH0 1) 1950. 17'70. 1500, 1450. 1160. 1100 em·•; 1H NMR (CDCI 1) I O.H (d, 3 H. J • 6Hz. CH 1),2.1 (dd. 1 H. J 1 • 6 Hz. 12 • 17 Hz. H·2). 2.35 (ID. 1 H. H·3), 2.75 (dd. 1 H. J 1 • 5Hz. 12 • 17Hz. H·la), 4.1 (a. 1 H. H·S), 7.3 (a. 15 H. Pll1) . Aa1. CaJad for C 11H,,,: C,I0.6l; H. U9. Fault C.I0.73: H. 6.39. .S).J-0.,*-Y·J<S)·..-,.,.._. AcM ~A-U... To a llirnd IOiutioa ol 0.941 (2.5 llllnOf) ttl tk tripkllyiiiiUyi.U. It ia 50 mi. oC ctbaaof wu added lO IDI ol ' ' pallacli11111 • c:art. ud 2 . . oC Cll*lllltral.t aalf'uric acicl. r.altiq . . . , - . . . ....,.. 11 room tanpcrauare uder a bydroplt at!DCIIpMn !or2•11.. ud tM8 0.5 1 of lolid NaHCO, wu adc*l. IDWan wu flhenld ud 1M raJuatc CI08Caltrated uDder r-.duCied ..-.-e. Ciana&IOp'lpby filM ~uc c-. lO 1 ol silica pi with ~ ctllyl -.ate ia parolauD . all'orded 0.25 1 (7611) of 1M ~ aJcobol: .,_poradw dilt.iJ. l&tioo 90 •c (0.01 aunH1): (a)uo +II.,. (t' 0.3, CHO,): IR (CH0 1) l600, 2950. 1790, 1470, 1170, 1110. 1030 em·•; 1H NMR (CDCl,) I 1.05 (d. 3 H. J • 6Hz. CH,), 2.~3 .0 (a. 3 H. H·l'a. H·3),l.3! (b a. I H . OH). 3.75 (m. 2 H. H·S'a), 4.15 (a. 1 H. H-t). Aal. Calal ror c,.H 1,01: C. 55.37; H. 7.75. Foud: C. 55.50; H. 7.72. 5-.._...S)_.,. ..,.J(S}.-Jis _.., AcM IA-U... ly die procedure dacribed for tbe prcparatiae ol tJac bromide 1._ 52S IDI (4.03 aunol) ol tJac abcM ~ iD l!llll. ttl~ with 1..!6 1111. (20. aunol) ol lllctlla..wfonyl daJoride ud 2. 791111. (20 IIIIDOi) ol trictlaylamiDc pYC tJac ~paediq a.yia&e. nil illla'mldia~ iD 2S lll1. ol tetrabydrofuran with 51 oC litbi11111 bnaidl P" 615ma (1811) ol tM cleaired bromide after .,.ponu.. diaiilatioa at 105 •c (0.025 IIUDH1 ): 1H NMR (CDCI 1) I 1.2 (d. 3 H. J • 6Hz. CH,), 2.1-l.O (ID. 3 H. H·2'a. H-3). 3.05 (m. 2 H. H·S'a). 4.3 (a. 1 H. H-t). l(S).MGJI• 1 I Adlt(ll). Toa ...... fl0.11(l.allllol) ollit.hium ill .eo lllL of liquid ....a at -71 •c wu ...._.a - . ol 27S . . (1.4 IDJDOI) oldie a - . ...... ia 10 1111. o( dry ...... 'ydroluru. ~ 2 II.. ac. dry NH.O wu added ud IIIUDOIIia . . , . . 10 . . . . . . tc. cliluYd with 100 lllL o( ..... ud die ~ aqueau pUle wu aciciUIId ud m. atrachd witJl .._ 20-llll. pan.ica oC ctbe:r. n. aambiaad arpaic .,..._ ..,. dried (M,S04 ) allid ~MD CCIIICI:Dtralad udlr hpontift clilt.illatioll of tJac .-icbac at 90 •c (0.01 IDIDH&) pw 140 1111 (16') oC Ule acid 21: (cr)~tD +IJ.SS• (t 3.3. CHO,); ut (CH01) 3200, 1710, 1410. 1300, 930 em·•; 1H NMR (CDCI,) I 1.12 (d. 3 H. I • 7 Hz. CH1), 2.37 (AIX m. 2 H. HCCH.Ji,CO,H), 2.6 (a. 1 H. -cHCH· (CH,)CH 1), 5.02 (m. 2 H. CH-cH.Jit;), 5.10 (m. 1 H. CHCHCH.Ht;). Au.l. Calal r. c.H~: c. 6l.l4; H. 1.13. Faud: c. 63.21; H. 1.15. ......... 10rwl1u~L TMIDlid._... . . n• ._.1) -c n. n. n. ........ red.- ,_,... J.Cart lk&j-t-(J(.,.....,..~l.· . ,• • 211~ J4a To 33 a1. ol 0.10 M THF . ..._ (26.4 allllol) ttl die on.-nt ,..... derMd rram me..._. 1• wu added 3.699 1 (24 ...a) oC . , . _ 21 illiO 1111. ol dry 1HFoliO miD. nc ,_.., a,.... ................... llirndl« 1S-.a~o•CutQia . . . . . iMo 250 IILti ... 10S a.a- HO wiU . . . . . . . . . n. 11,.. . . . a.a- ..,_ wu atriUII .U. U.. 1CJO.IDL pot• *- ttl dic:Wm plot• n. CIOIDIUIIl arpaic 11,.. _.. dried ..,.,.._. ud me (NISO.>. Uld U. 1M...,_ wu,.........., ,....._. ,._,... n. ...-.. ... ...,..a..~y diaaiW 01~120 •c o ..a,n 10 IIford 4.956 1 (I") ttltk pUI ,.00. adlt1lcu: lit. (-t) 1775, 17•s. 1660. 1215 -·•; 'H NMR (CDCl,) I 0.91 (d. 3 H. J • 4 Hz. CHCH1). 2.11 (a. 1 H. CIICH,). 2.,. (m. 1 H. CIICH-cHO), 3.44 (d. 1 H• I • 5 Hz. CM::O,CH,). 3.74 (.. 3 H. oo,cJ#1). 4.95 (2 b a. 2 H. CH-cHs). 5.21 (del. 1 H. I • J, • Hz. CH-CHO), U0-5.15 (m. 1 H. CH-CH,). 6.49 (dd. 1 H. I • I , 4 Hz. CH-cNO). Au.!. Ca1a1 ,. c,,H,.O.: c. 65.53; H. 7.61. foud: c. 65..!6: H. 7.60. J.Cat 1 J-+(J(.~s.,..,t)-211..,....~ (Z2). To a IDhla oC S.OO I (21 ...a) ttl tM a.... cli.ydlop)rOIW ill I L oC ~ wu lllldalll 100 1 II acdftlad MaO,. n. r.ction lllimare ... .und ~a& roam . . . .bill for 3 ... nc aUtv.rl wu raJt.a'ell tJaroqb a p.cl oC Cali~ wtaida wu t.Ma tlaorauabJy wuhed wiU ,,_.. didLiar0111 MM. 'nallltra~ wu dried (MaS0.) ud the .alwat ........... ..-re 10 2.979 ttl the ..PYJ'OIW Z2: .,.ponu.. diiWlat.ion 105-JJo (0.5 -.H,): (cr) 210 +3.)• (t 1.00. CHO,); Ill (llllat) 1730. 1640. 1555. 1250 1 em·•; H NWR (CDCI,) I 1.00 (d. 3 H, J • • Hz. CHCH,), 3.16 (a. 3 H. co,cH,). •.16 (\ .. 1 H. CH-CHH). 5.G3 (\a. 1 H. CH-<:HH), 5_.. (ddd. 1 H. J • S, 6. 12 Hz. CH,-cH). 6.11 (d. 1 H. J • 3.5 Hz. CH-CHO), 7.42 (d. 1 H. J • 3.5 Hz. CH-cHO). Aul. Cakld for C 1,H 1.04: C. 66.09; H. 6.13. Foa&t C. 66..2!; H. 6.74. I·<Da 7' .._,.,.,..,_ Toa IOIIniaB oC 17.01111. (11.3 aunal) II ,......., dil&i1W N.}1-dibazyla.miae ia 7S 1111. ttl 1tMr wu added 21 .0 1 ( 176.51 . - ) olf~y diltilltd prapuayl bramicM. ,.ction .amn Wllltimd at roam taDp~r~tve ror 15111ia. ._._.at 40 •c for 12 L ud tJaaa CIIIOW 10 roG1D . . . . . . .twe ud tnalad witb 11.5 1 of kOH ill 50 lll1. olwatar. Ala. tal rw.hiq lllisturc wu Yiaoroufy llirrad atil all oltk . . . Md dilloMd. tbe layws .... ...,.ted and 1M aqueaa pUle ... avacud with 100 mL o1 fthcr. ne ct~aaal _......a-t with 100 IDL flaaaru.d aqueoua NaO and tJaea ..... (k,CO,). a.-.J ~·--t and f1uh caromatop'lpey c-. 100 I ol lilica llf wiU 1K .U.yiiCIN~ iD ~ ..._ ctller oC tha naiclu P" 13.01 (63') ttl the crysW1iDC prapyae: _, 42-43.5 Ill (CH0 1) 3300. 1600. 1410, 1450. 1330, 1120 em·•: 1H NMR (CDC1 ) f 2.12 (t.. 1 H. c-cH). 3.2.3 (d. 2 H. c-cCH ), 1 1 3.67 (&. 4 H..2XNCH,ft). 7.30 (ID. 10 H. 2XN.I"~) . Allal. Cakld for C.,H.,N: C.l6.77: H. 7.21; N. 5.95. Faud: C.l6.74: H. 7.26: N, 5.15. 1-(0. 71 .._,.,..,..,... To a IOiatioa ttl S.O 1 (21..2! aunal) oC tJac allowe propyne ill 3 lllL oC dry M.,SO wu added a IOI..UC. oil 00 1111 (0.91 IDIDOI) oC ...-um terr·bu-* in 0.7S lllL ol dry M.,SO. TM r.ctioa lllistllft wu stirred at roam tanperatare for I • and tJacD IOMot ... raDO¥Id by .,.ponu.e clistillatioa ..... r-.duCied , . . .,.. (0.01 mmH1> with tJac OINt temperature beiDa iDc:Nuad rapcuy to 100 n. raid.ae wu tbea rapcuy .,.pontiwly diiUlled (I 30-190 •c (0.0 1 IDIDHI)) lO pc the deaired yu..miDc. nil yumiM couJd be lt.Ond ill a f~ forap 10 2 . . - . if~ from IDOiauarc but wu a!ways .,_pontively f'lldiatilled illuMdiateJy before ac: 1H NMR (CDCI 1) I 1.10 (&. 3 H. CH,). 3.9S (&. 4 H.2XNCH,ft). 7.21 (ID. 10 H. lXN.I"~) . J.(O.WZyl at ).3 aada;~(J(.) u&;l II I tl~ AcW. ,.._,. t:.r (13). To a IOiutiae ~ 503.3 lftl (2. 13 IDIDCM) of tJac .. pyraDC 12 ill 5 1111. ol dry bcuae .... added 1.4 IDI (l.l4 aunol) or 1M fraAJy d.iltilled yumiDc ill 2 IDL of dry bcuale. reaction lllizalre .,. t.ted at rcnu for 1 II ud tJacn c:oa6ld to roam ~t&&re ud ....... iiiiO 15 1111. olwatcr. Tile raWWll llliat&&re WU atraaed wiU two 25-1111. parUc.a ol dicblarcllnctll. ud tJac arpllic frac:tioal _..dried (MaSQ4 ) . R.aDCMl of tJac IOMnu laDder reduced .,_ure ud Clftma c:llraaaqraplly ~ tJac ,..._ c-. 30 1 ollilica ld with 2.5.. ...,. ill ~ abcr aiJorded S42.lma (6011) of tJac aromatic .u:r 23: waporatift dillillatioa 165-l?S •c (0.005 mmHa): (cr) 12 0 +4.1• (t 1.11. CHC1 1); 11. ( - l ) 1715. 1275, IllS, 750,695 em·•; 1H NMR (CDC1 1) 11.00 (d. 3 H. J • 4Hz. CHCH1) , 1.93 (&.3 H. luCH,). 3.71 (&. 3 H. Cf).!:.N1), 4.10 (&. 4 H. 2XNCH,Pb), S.OO (ID. l H. CH-<:Ht), 5.70 (ddd.. I H. J • S. 6, 12 Hz. CH-CH 1), 6.94 (dd. 2 H. J • 5 Hz. 5Hz. AIH), 7.l3 (&. 10 H. 2XNCH,1'~) . Au.!. Cak:d for c,H,NO,: C. 11.46; H. 7.71; N. 3.21. Fouad: C. 11.41; H. 7.65; N. 3.27. 2-(DII yl d )-3---I+(J(.~O ..... .,, .. ...,..,.._. Adll ,.._,. U... To a IDNUoll oC 4.2.33 1 (9.92 IDIDOI) fltlac aramatic *liD 2l ud 1.6761 (12.41111Daf) ol4-tnldaytmarp8cltinl ..._. ia 4.41 a1. olwater aDd l.lO Jn1. ttiiCIMOM wu added 1.9 1111. (0.019 ...al) ola IOiatioo ol 0.01 M CIIIDium I.IUOiide ia un-butyl ~- TM ...aa. IDi.uarc Wllltirnd for2• II al roam ....,_..aarc llld tlala q...-.. by me addiU. ttl a ~huT} ol SO IDI ol Na~. ud 2 1 oC Flariai1 ia 1 lll1. II water. AltM baiq ltirnd for S IDia. the .an.. wuru...t tJaraqla a p.cl ol c.ti~ witJl ~ wulaiJia oC tJy,...,.....,., --- a<""'> rc •c n. . . ,. . . . . . . rr.cuc. •c; * •c. ss n. 105 J. AM. 0... S«., Yol. 10$, No.1, INJ Toul S~lwN ofiii#IOpiiiJiw AlllllliMiD fUw ... n. ...._filM ftbrata . . . . . . . . . •... ._,.,at. . . ..,..lsom. fill" ..... HOud\M ....._ . . . wuallolnd to..-at wiQ . . . . . "'*~fl---.udtodil .-.......-.r.l581ia. n. ................... . . liJO.IIlL paftionl fl&h' .... ud ................ ...... ........ (MJ50J. n. ...,_ .. ,._... ...,......_. ,._. ...... a . . . . . . . . . . ,.... ~--l*d. 100 I flU. ... .u m uyl-.ata ill,..,.._..., to alford 4.JIO 1 (tl~) flu .....,............ fi&M ..... 6&illaU. 1•1" •c <0.005 ..He>: Ja 1ns. 1210. 1230. 1145, 1065, 710 --•: 1H NMR (CDCl,) I 0.14, 1.00 (2d. 3 H. I • 4 Hz. CHCH,), l.lO. US (211. 6 H. C(CH,h), UO (a.l H. AICH,}, J.17 (a. J H. CO,CH,). 4.0f (a. 4 H. 2JCNCH,.), 6.tl (& 2 H. AI/I), 7.tt (a. 10 H.llCNCH,.). AaU. Calal r. Calf,.NO.; C. 16.61; H. 7...; N, 2.19. Foud: C. 76.12: H. 7.13: N. 2.74. ...-tic_,.. ........... <-&) i-~l ....JI+{l(.) .....,. u-o~ Adll. ~ .:... A IDiaulre ol 5.1S6 1 (1 0.3 IIUIIGi) olllll a - . dibaazylamiao c:aDp-adl ud 516 llll fiiK palladium • c:arboa ia 103 mL olablohate tttw.al wu alaat.. uder a SO pli a• p' • ol r.,.srapa • a Parr •yc~,.._ r. 10 1a. n. r.ctiaa ..m... wu ..... fihcNd and llll rahrata ... clihlled wiQ 300 mL flwew. nil .muan wu atracUd wid! ttu. l»mL ,.W. ol dalv m "'" w..U ""tJIIa cxabinld ud drild (M,SOJ. ~ olllll.._. udlr NdUCid ~ p¥1 al'llideat Olllllailliq die.....,.,._ ud die ftc:iuJ diola. nil lllistan OC*id bt ill die ..... ..-t ~ • .,.,.ted by llaU . . _ _ ..., • 1001 flliliaa ... widl etllyl acetate to p.. SII llll oldie •mi.....tioh ud 2.419 1 ol . . . . . . . (93~ CIIII"NN::ed toW yield): ...,....u..dillillatiaa 135-1«) ec (0.001 aunH&); IR <-t) 1490. 3390, 1690, 1615, 160, 105 --•: 1H NMR (CDCI ) I 0.90. 1.02 (ld. 3 H. I • 4Hz. CHCH ), l.lO, l.J$ 1 1 (la. 6 H. C(CH,)J), 2.02 (a. 3 H. AICH1), 3.12 (a. 3 H. co,cH 1), 4.90 (b a. 2 H. NH 1), 6.47 (dd, I H. I • S.S Hz. S.S H&. AIH), 6.91 (d. I H. I • S.S Hz. ArH). AM!. Cakd f« C 1,H17NO.: C. 61 .26; H. 1.47: N, 4.36. Found: C, 67.12: H. 1.37; N, 4.27. .. .....-tJ, .... ).~(3(.)-....,1-U ..,.=,.... ,.,..,.MM.~ r.... To allirred IOAuU. oll.319& (7.45 IIUIIGi) ol tJac abcM . . - . ud 7.45 mL ol 41-SCJII t.etrall~ acid ia 74.5 mL ol ablol•ta ~&.~~ana~ at o•c wu added. ia a dropwile ...... l,j() mL (11..2 BIIDOI) olilaalllyl nitrite. ud o. ....,_ colclr'- a.U. wullirred r. lO IIlia at o•c. At tllil time die . .aa. llliaun wu _.,....., . . . , reduc.d ,.._,.. alld thai lk oaecntra&e wu clillolwoad ill 115 mL ol .... n. ....ruaa auu. ... u........, at ao •c UliiiS IIIia,.. die ~u. olpstwohaU. u ....Utorld by a.,.....,, n. ~ IDWW'I wu tJiaa atractlld witJl tine IOO.mL parQa. ol ~ -.bane aad tJae COIDbiald altaCII _.. U. drild (M,SO.). a.-..1 ol tJilc IGMet uader reduced ~ II"' a reliduc wbidl atrordld 1.719 1 (IS~) ol tJac pbaok after ool1111111 Wolllatopaplly • 100 1 oiiWca Jill wn~~ etbyl-.t.c: dilrillatiaa 16s-110 ec (O.OI BDHa>: IR <-t) 3500. 1665, 1420, 12,, 11SS, ICMO em·•; 1H NMR (CDC11) I 0.97 (ld. 3 H. J • 4 Hz. CHCH1), 2.19 (a. 3 H. ArCH,), 3.93 (a. 3 H. CO,CH 1), 6.62. 7.16 (ld. l H. I • S.S H&. S.S Hz. ArH), II~ (111. 1 H. NOH). Allal. Cakd f« C.,Hu(),: C. 63.11: H. 7.15. foud; C. 63.12: H. 7.90. 3-~(3(.) . . .,. &S-O ..... .,. 5 , •....,. M1aJ1 U. (~). A lllistun ol2 aL oi2.2~J1II'OPUIC, 2 mL ol acetone. 179.7 llll (0.636 IIUDOI) old~~ abiM diok. ud a catalytic UIIOUill ol potof....WJ~h-ic acid ... llirNd at I'OGID r. IS IIlia. n. ~ lllisture wu U. taba., ill .a mL oi.U., aad t.lllia wu wulled with two 20-mL ,..U... ola •taraled NaHCO, -. lata. ud lO mL or •uaraled aq-- NaCJ ud U. dNd (M,SO.). ~ ol 1M IDMat uder NdiiGid ,._.. P"' 201.5 . . (9K) ol 1M . . . . .u, ,.,. . . . . - ~: dil&illaa 95-105 •c (0.003 aamHa>: lit 1660. 1155. 11SO, 1075, 110. 110 .-•: 1H NMR (CDC11) 10.17, 1.03 (ld. 3 H. I • 6 H&. CHCH1). I.J3.1.3' (21., 6 H. C(CH 1)J),l.ll (a. 3 H. AICH1), l.tS (a.3 H. co,cH 1), 6.63 (dd, I H. J • 2.2. 7.5 Hz. AzH). 7.11 (d. I H. J • 7.5 H&. ArH), II.JJ (a. I H. NOH). AMI. CaJat f« C,,H_o,: C. 67.06; H. I.U. foud; C. 67.17; K. 7.93. ...,...u.. 7 <-tl MM. ...,..t11n ...,..u.. 2-(I·M..._,..._.,_.,I)·,__..,t+(l(.) .....,. u-o.I Jl)ldcylcAdiLMI6yiU.. Toallimd.....-. fl 2.11 ...... ol poiUiiiUil ~ ill 5 mL ol dry THF at 0 •c wu lddld 93.0 . . (O.lii!IIIDGt) fl die , . _ . 24 ia 1 aL oi*Y THF. nt . . . . - llliawrawuacirnd r. 20 • at o•c ud die O.J3 aL (2.11 IIIDOI) ol ,__.yeQG&,.Uyl clalorida wu added. n. ~ .Uuarc wullirnd at 0 •c f« I II ud die at I'OGID . . . . .tan f« O.S II. n. r.ctiaa lllianan wu Cllf'IIUly q..a.d a., lk Mdi&iaa ol P:CfJ" ..... a few dra,a olwew ud IMa dilllled witJtlO aL ol.._ wl*:ll . . u.. ....... witJl two IO.al .,.UC. olwew ud 10 mL ol•tara... ...................... ,._,. ..... ~ Naet n. ~Ill,_ . . . - (MISOJ ud U. ...._. ~ 1999 1iaiiJ ,.,. ....yt~~~~~~: ...,.... 4iiiWIU. us-us •c co.oo1 -.ita): J:a (CHCI,) 11JO,J150.12l0. lCMO•-t: 1H NMR (CD0 1) I 0.11, 1.01 (2d. 3 H. CHCH,), l.Jl. l.JI (21. 6 H. C(CH1h),l.27 (a. J H. AICI/1), J.AO (a. J H. CHpc:Hs). J.t2 (a. J H. CO.CH 1). 5.01 (a. 2 H. OCH,O), 6.t0 (dd. I H.l•l. 7.J H&. Alii), 7.11 (d. I H./ • 7.J lb. AIH). ~ ea.- lar c.H,.O,: C. ...17: H.I.JS. , _ _ c. ...52: H. 1.32. u-o.- J.CI·Med.ay,..aJ_..JI}-3 =*;1-6-tl(•) &d:JI ,...,. ' 1 Jl}tllcJic AcW. a-,t .....,, To allimd ...... ol o.s2 aL cs.16 ..a~> fll•pa 1 •Will s a1. oldry ,...... ac o ec . . ..._. l..lS mL (2.11IIIDOI) ola ......._ oll.l M llilltyllidiiul ill ....... n.llliavl ... llirM at for IS • ud u.. ...... ...... ..., ......... ,.._... n. ........... dilloMd ia 4 aL fll dry HMPA ud diia wu 0 To diia lllllhllioa 111.4llll (O.lll IIUIIGi) ol die abcM udyl ...,. ia 2 aL ol dry HMPA wu . . . . . . . . . ~ ...... wullimd at 0 •c r. 10- ... &ala at .-a l« 45 .U. At~ timl. 0.69 mL (5.7611111101) ol a.u,t llraalidc ........ udllll ~ .Wun wullimd at room .........,. r. 2 11 ud u.. 11.-cMd ., die additiaa ol4 aL o11 K . . . - . HO ud .a aL olu.r. n. .ua..J Ia,_ wu U.. C108111C· .u..ly ....-. witJl tJar. ~IDL ...,._ oiiK . . . . - HCl.lO mL fla _,..... aq-- NaHCO,. aad 20 aL olaatamld . . . - NaCI. n. orpaic .... wu die drild a-..1 oii.M IOtYeat .... f'llluc:lld ,_..pwa,.._diat ... ._...,......., c.IO 1 oiiWca pi witJl ~ .Uyl .-ate ia ,..,.... u.r to ai¥1 119.0 . . (15~> t1 die-.,.-..: ... diltillau. 110-195 •c (0.001 maMa): Ja (-t) 1131, 1150. II«). 1040, 740 --•: 1H NMR (CDO,) 10.75. 0.90 (2d, 3 H. CHCH1), l.J2. 1.35 (la. 6 H. C(CH 1)t), 2.%7 (a. 3 H. AtCH,), 3.33 (a, 3 H. OCH,), 4.97 (a. 2 H. OCH/)), 5.33 (a.1 H. OCH,ft), 6.17 (dd, I H,/• 3.7, 7.J Hz. ArH), 7.13 (d. I H. I • 7.5 Hz.u/1), 7.31 (aS H. OCH,.). AaU. Cakd f« C.H,.O,: C. 69.11: H. 7.17. F__.: C, 69.17; H. 7.94. J.~l(·) . . .,1 u .,••,,..,.,..,. AdiL _ , . Iller. A llliatva ol0.75 aL oll" a q - HCl. 3 mL ol THF. and 19.5 . . (0.114 . - ) oi&J.a abcM bluyt....,. wul&irred at room r. 4 111 ud u. ...... at so •c r. 1 11. n. ..aion .w.r. ... dihiYd widi lO aL oi~Qyl-.ta wbic:lt ....... wuiMd widli *- IJ-IDL ...,._ ol•nn... .,..._ NaCI ud dried (M,S. o.). ~oidia-......_,..._,,.._.,. p¥1 .,...uaau..ty &J.a dlairad ...,...u.. dil&illaU. 165-IIS •c (0.003 .-HI); lit (CHCI1) 3610. 1670, 14JO. ll60, 1160 em·•; 1H NMR (CDCI1) I 0.71 (b d. J H. I • 6 H&. CHCH1), UO (a. J H. AICH1). S.JI (a.l H. CD,CH,.). UO (d. I H. I • 7.5 HI. AIH), 7.17 (d. I H. I • 7.5 Hz. AzH), 7.42 (b a. S H. CO,CH,.), 11.33 (b a. I H. NOH). Mal. Cakd l« Ca.H.O,: C. 70.37; H. 7.31. Foud: C. o•c _.....to •c. ....,..Uift <NaSO.>· ,....u.. ...,_.t.,. dill,._, .......: '70.21; H. 7..27. 3-~(3(• )-fw&J . . .JI>-Ic7lc Adll. - , 1 r... (2). To a auU. fl 66.0 llll (0.114 IIUDOI) oldie abcM diola ill 4 mL ol _.._ wu lddld 47..2811 (0..221 BIIDOI) oiiOdiwn -.pariodaa.c ill I.S mL flwetlr. n. ..ca. llliatllft wultined l• 2 Ia at I'OGID ._....,.,. ud tlla dihaled witJl IS mL olweter ud atracted wtt.. two I 5-IDL paniolll ol clidaloraaletJw. Tbc orpaic C1tr1C11 were caDbillled aad dried (M&SO.). ...,... ol tJilc IOMIIt ...., Nduc.d prwure ud darcaatopapey ol reliduc • 10 1 litica pi witJl SIJI uyl.-ate ia ,.,..._ ltMr 41.0 ma <~> oii.M dlaind ...,.,_....,. aldelayde 2. dla or P"' ... . . .,.I I ( ~lllly~2<• )- .,..,.,._,.fair . . ·2(S)-(3(. ),4(S)...,·5(S)· (31). To ' &fUiidi)lwea)UiidiJI)-l(•) . . ., • a ~tined llltutioft o/1.17 1 (S.07 IIUDOI) oldie acida lt an ~ lllL or o.s M . . . - NaHCO, wulddld alS mL aq....,. IOAaU. or 1.4& (~.6 IIIDOI) ol powlium iadide ud 3.15 I (lS..l IIUDOi) ol iodiDe. Tbc .-Jtialllli.u..- ... llirNd at I'OGID lallparat.n ia lM dark r. 12 h. tMil a..led widl 100 mL oiiK aq....a Na,SO,. ud t.laell atncUd witll *- 60-IDL ,.W. ol ~... n. c:aDbiDid orpnic ..... "".,..._ wit!l40 llll. ol•turat.ld aqueous NaHCO, and thaa Mid (M,SOJ. a.mc...1 ordla-... 111111Mr die ... ==·=-..a.. ....._,_.,..II"' To a llimd ... fl 101 llll (2.15 .....,i) ol litJbul tatra~te ia 4 mL fl dry THF at uder wuldded 0.01 llll. ol _,.. Rlt11ric acid. AIU:t I h. a a•lioa ol 746 llll (2.09 _ . , ol 0. abcM i=hlan-= l l ill 3 mL ol dry THF wu added 10 1M~ llliaun. o•c araoa Att.t u additiouJ -.,, 0. lllistl&ft wu waled _ ........Ivy widli O.OIIIll. olwatcr, D.OI aL fll S~ . . . . - NaOH. and 0.24 mL olwe•. AIW uotJaer IS IDia, die....,...._ wu tlltand ud ... filtrate .................................... To allimd autiaa ol tllil ,..._ ia 10 mL ol _ . . _ wu added 443 llll (4.11 mmol) ol Na~,. Att.r 24 h. &M IDizban wu...., waled uder nd.- s--re ud &ala taba •P ia 20 mL ol•uaraled . . . - . NaHCO, ud 60 mL ol &hlaram:u ... •. n. «paic ,..._ . . U. ....... wit!t20 aL ol•aara• a q - NaO ud U. drild 106 2000 J. AM. CJnL Soc•• Yol. JOJ, No. 1,JNJ /r.lillt4 ft Ill. (K.CO, ... Na~J ........ tltlll .............. .._.. .... till cndl...., ...... Toallimd .-ua. fll~ ......_ a• al.tl., DMF . . . . . . . U7 . . (6.3....al) fll ......... •72 . . (l.J . . . ., fll ~ . . .~ AIWII6 ~ tiii...U. . . _ . ....... wt6 .., aL tlldllr, ...... willa 210 aL fll ............. NaHCO,ud a1. fll_.... .....-N.C. ... .-.._. <KtCO. ... Na,SOJ. a-..1 flltlll .,.._ ud *-IGpai*J fll to 1 tl lllica ... wiUIK-,.~ . . . . 6ll.l . . (tft) f!ltile tlpD&J lilyl...,. Jl • a - - . . fll die• w ...,..... 6ailla.._ 9~105 ec (0.005 ..tq); II. (CHC,) l.aS, 1.,5, IM 11.0. 11210. 10.0, M» --•; 1H NMJl (CDC,) I 0.12 (a. 6 H. (CH,),si), 0.17 (a. t H. (CH,),c), l.JO (a. l H. OCH,), l.SJ (d. 2 H. I • S Hz. CCHp), •.51 (a. 2 H. OCHp). AMI. CU. ,_ C 1,H,.0,5i: C. 51.92; H. '·"· f'aud: C. 51.91; H. t.ll. ,.,.-~2<•>·2(5)-(J( • ....,._,.S(S~ _,...,._s,~S).....,..2(•)-....., Edllr <3' _. l:f'-,.). To allimd .......-.fill .I 1 (9.•s -.al) fll...iadide ill lO aaL o1 dry •patanc at o •c ..., .,.. ,.. 10 a1. fila I .I M IOhatica tl-.iyllidUUIIl iD ..... Att. 15 .... I ....... fii6J1 auDDI) tltlll ...... Jl . . . . . fl .................. to 1M...-. • ..,.. AJt.r 3 ~ tba mimln ........ widiiO aL f11 ....,.... . . . - NH.C. dillll8d witll60 aaL tlltlllr, ...... widlcwo 2ID-a1. ,.,._ fll•t81'1c.d eq..- NH.C ud 20 aaL fll•..,.a.d ...-N.O.ud*- . . (M,SO,). a....atltlll.._...._ ........ , _ , . . . . . . . . . . . . . ., tltile . . . . - 50. flllilica ... widt25. ayiiCIICa&e q~"'+-•• afforded 3,. . . (SK) tltlll ai_ . . , . ... IOmt(la)fiiiMaJaallal . .K AlaDIIaiU: 4il&illatiollllo-120 •c (0.005 aamHa); (a) 220 -H.oe (~ O.tl. CHC,); Ill (CHC1) 3360. 1410. 1•10. 1260. lo.ta. a.oa~~'"'; 1H NMI. (CDCl1) I 0.01 (a. 6 H. (CH 1),5il. 0.90 (a. 9 H. (CH,),C). 0 ... (d. 3 H. I • I II&. CHCH,). 3.30 (a.3 H. OCH 1). •.s'7 (1.2 H. OCHp). Mil. Calal lor C,,H,.O,si: C. 59.63; H. 10.56. Foud: C. St.6S; H. 10.62. AI. . . ._,.: .aJIIII'IU.. diiUIIaU. ICJo-1210 ec (O.OOS anHJ); (aJ31o +II.,. (t l.CJ2. CHCI 1); II. (CHCI 1) 34l0. 1460. 1260. ICMO, M» Clll-r; 1H NMI. (CDC1 ) I 0.10 (a. 6 H. (CH ),5i). O.t3 (a. t H. (CH ),C), 1 1 1 3.33 (a. 3 H. OCH,), •.62 (a. 2 H. OCHp). Mal. CaJal I« C..H.O,Si: C, 59.63; H. 10.56. Foud: C. 59.64: H. 10.50. II: ,a)-4 ~J(·)·(=-st kl tt'r ~· ~,-,,_~,....., .... , ..... tr1 U.. To a llimd ....,..._ fll 26.5 ma (1.1 ....a) tllodiul . , . _ ia I .al. fll dry THF at 0 •c .... .,._ wu ldMd a . .tioll fll 3M 1111 (0.92IIUIIOI) tltlll a.laMoi,. ift I .aL flldry THF. AJt.r I ._ 0.21 aaL <•.7 IIUIIOI) fll carboft clilull'* wu addld. ud atw u ldllit-.1 ...,, 0.12 m1. (1.93 ....,., tl-.tayt iadick .......... ne -..,. ... llimd far 3 'ud ta. cliaa.d willa 10 aaL fl.._. It . . tllal wuMd witlt two »mL ponioal fll•unc.d eq..-a NaHCO,. 210 aaL o/11t81'1c.d .....- NaCl. ud tllla dried (M.,SO.) . ..._... filM -...uP" •25 1111 (IOK) filM wa I dina ua\Mu: ......... clil&illatian uo-:40 •c (0.005 IBIIlH&): (a) 210 -3.s• (t l.SO. CHCI,): Ill (CHCI,) lao, 1230. 1070, 1050. 150 em·•; 1H NMR (CDC1 1) I 0.03 (a, 6 H. (CH 1),5i), 0.17 (a. 9 H, (CH1),C), 1.05 (d. 3 H. J • 7 Hz. CHCH,). 2.53 (a. 3 H. SCH 1), 3.35 (a. 3 H. OCH,), •.63 (1. 2 H. OCHp), 5.67 (d. I H. I • • Hz. $.zCOCH). AMI. CaJal far c:.a..o,si: C. 53.o6; H. 1.91; S. 14.16. faud: C. 53.27: H. 1.91; S. 1• •11. _,..., ......., .., .. 2(.)-(S(S)-( 1 , ...., ......, ...., ..... <•l~2(S)·...,..s••JI~ ldllr. To allirnd IOI.U. fll •25 ma (0.92 amol) ol till et.M IUQa"' • t aL flldry ...._ at l'llflu ...., arp wu ..w.t O.l aL (l.t• -..1) fll tri • llatyltill .,.,.... AJt.r 2. ~.,.... .w.re ... . . . . .,_..... ud '*'-aUip'lplaJ tltlll,......- JO. tlailica p1 wiO 5• ayt q ~lahn•• afforded 255 . . (IK) oldie • _,..yt -...r. cliltillatian '75-15 •c (0.005 IIUD.Ha>; (a]•D -IJ.9t• (t 1.055, CHCI 1); Ill (CHCI,) tao, 1260. ltOO, ICMO, l.tO --•: 1H NMil (CDCl 1) I 0.03 (a. 6 H. (CH 1),5i). 0.19 (a. 9 H, (CH 1),C). 0.95 (d. 3 H. I • '7 Hz. CHCH,), 3.33 (a. 3 H. OCH 1), 3.52 (d. 2 H. I • 6 II&. CCHP). 3.63 (d. 2 H. I • s II&. SiOCHs), 4.60 (1. 2 H. OCH~) . AMI. CaJal f• Ctt11,.0.5i: C. 62.31; H. 11.05. Faad: C. 62.l6: H. J 1.05. JC•)-(S(S)-(I'I ....as=-slma; ....sl)-oi(•~2(S......_ .,..,_,.,.._.1-41 (lJ). To a llirNd ...._ fll W.S 1111 (0.645 oltlle a.... lilyl . . . ia 3.2 aL ol dry THF wu ldded a a tile....._ • _. •.,.,.,..,.. .. cu ....-a.. _,...,.....,..,a.2(.)-(5(S)-( a,_.., ....,.... -a.• .... ,. .-.w ....-u.c -'> .....U.f114JO . . (I .M..al)tl~n.rideill J.2 aL ol dry THF. AJt.r • ~tile~ .m.n wu dihta.d wit1a .,., aL fl . . .. ...... wid two JO.al. ~ fll•auu.t . . NaHCO, ..tlO a tl....,...S ...--N.C. ud dlla .... (WISO.>. ..._.. tltlll .._.. ud . . _......., tltlle ....._ • 10 I olaitica pi widl 35. ayt-... q h. I " afforded 123 . . caa) t1 • ...., u : .......... 60-'10 ec (O.OOS -..u. ..a,); (e)•o -21.P (e U05, CliO,); IR (CHQ,) , . _ IC'70. 11.0. Ill G. 1050 •'"'; 1H NMa (CDC,) I O.M (d. 3 H. I• 7 HI. CHCH,), J.ll (a. J H. OCH 1), J.SJ (d. 2 H. I • 6 HI. CCHpc). •.a (a. 2 H. OCHp). AMI. CaW,_ Caaii,.O.: C. 62.01; H. IOAI. Faad: C. 62.16; H. ao..a. J(S)-(S(S)-(M 11: , ...., ...., .... · ,~,_....,..2(S,__. .,.....,.,.__, To allimd . . . _ fll '71 . . (0.336 __.) fll till ....,Dilll.7al.flldrydictd a•mhe• ... addediJ . . (0.134 ....) fll . ., . _ .............. I•S . . (0.6'73.-) olp,ri. . . . c:Maaoclta-t& AJt. 2 ~tile~ .atww,.. diluled widt a aL flldry . . . . . . ~ llirnd far 15 . . . tile IW&Iwlt ......... ... flhll'lld ud tile IOiid ......... ~ trit81'1lioe witla . . 20-all. ,..,u.a fllltlllr . ....,.. oltlle ........ ud dmlmiiGp'apby oldac , . . . • '7 1 tlliiMa pi widl25• Myi&Cita.. qcta••n• alfardld 6'7 . . (IS.) tltile wa 1 rtiq aAdeltJ*: .aJIIII'Itm diltillalioe 60-70 (0.005 ..HI); (e) 11o +W• (t 1.11, CHCI,): Ill (CHCI,) 2'750. 1'725. 1•15, 1260. J2lD. lo.tO. t20 --•: 1H NMR (CDCI,) '0.91 (t. 3 H. I• 6Hz. CH,CHs). 1.00 (d. 3 H. I• 1Hz. CHCH,). Ul (a. l H. OCH,), 3.53 (d. 2 H. I • 6 II&. CCHpc), •.07 (dd. 1 H. J • 6, 12Hz. OCHCC), 4.33 (dd. I H. I • 7, 1• Hz. OCHCC), 4.60 (a. 2 H. OCHp), 9.'72 (d. J H. I • • HI. CHO). AuJ. CaJal for C 12Hu0.: C. 62.51: H. t .6J. f'aud: C. 62.56; H. 9.66. ~S....,...,-7-(a II: .,,..,..2_. (32). To a lbrNd IDI•U. fll 50 ma (0.217 8UDOI) ol U. abowe IIII*J* ia • ·• •L ol dry THF na added 5 ma fll powaium ,.,.,••• at '10 ec for 20 ... ....,... 10 oooA 10 ,_ .......,., ... u- dilll&ld .nu JO a1. fll tthlr. 1'1111etMnal ,.._ wu wuMd with rwo lo..L ,.UC. ol•aarat.t .,....., NaHCO, ud 10 a1. tlaablnllld .,.._. NaCl. ud tMa dried (M.,SO,). a-..J tl.._ta ud *-&GFapltJ ol 1M r.iduc oa alilica pi TLC piau ~ 35. uyl . - ... q ta>ve• P" 25 1D1 ol U. ,_ lbUatioa prod.a 32: diltiltatioll 10-90 •c (0.005 -Ha): IR (CHC 1) 3600, 3450. 1610, 1460. 1160. 1120. lo.tO cas·•; 1H NMR (CDC1 ) I 0.93 (t. 3 H. I • 6 Hz. CH,CH ). 0.96 (d, 3 H, 1 2 J • '7 Hz. CHCHs). 3.33 (a. 3 H. OCH 1), 4'.61 (a. 2 H. OCHp). 6.•2 (t. 1 H. I • I Hz. c-cH), t .40 (a. I H. CHO). Aul. CaJal for CulfzP,: C. 62.51: H. 9.63. Foud: C, 62.1•: H. 9.'71. ,.,....,," ',. ., .. 2(.)- _. -2(SHl(S)-(1~2-)'1).4 (S)·.,. .&J·5(• )·(..... To • llimd IONtioll tl1.46 1 (12.2 ....&) o/1.3 ditUM ill 12 aaL tl dry THF at -20 wu added. drapwila. •.1 aaL (12 aamol) fila 2.5 M IOI•tioa fll •IMtyllit.laiam ia ...... IJw 90 JDia. I IDhatioll o/140 1D1 (2.42 - - ) fll lM epo _ . . J6 ia ••S aL fll dry THF wu llowly added iftto tile r.ctioe .Ucwc. wlliQ wu t11a bpl at 5 for 2 deys. n. aaianarc wu dillll.ld widt 60 aaL tlltMr. wuMd with two 25-aal. partica olwaw. 25 aaL fll•nanled aqiiiOUI NaHCO,, ud 25 aaL tl•turaled aq....,. N.O. ud tllla dri.t (M,SO.). llaDIMJ flldac IOMata udcr awduced ..._.. ud dlrama&ap'aplty of tile Nlidul CID 50 I fllliJica ~~~ ~ 25.. ayt.-aa.=q ' hn•• atrardld 5091111 (45•> of u. di....... of • lR-ilamer ud 110 11\1 ( 1~) ol u. dithioacalal oldac lS-ilolncr. lR·boaler: ...JIIII'I&m cliltillatiCID 160-170 •c (0.005 IDIDHa): I•Juo +11.«»- (t 0.255, CHCl,); IR (CHCl,) 3600, MSO, sao. 14'70, 1260. lo.tO• ..a em·•; 1H NMR (CDCI,) I 0.09 (a. 6 H. (CH,),Si). 0.92 (a. 9 H. (CH 1) 1C), 3.33 (a. 3 H. OCH 1), 4.63 (a. 2 H. OCH 10). AuJ. Cakll far C11 Hcz(),s,si: C. S..04: H. 9.07; S, 13.7• . Faud: C. S..26: H. 9.ol: S. 13.71. lS-IIamlr: wapal"ltift diltillatian 160-1'70 •c (O.OOS (a) 210 +22,t• (c 1.095. CHCI 1); IR (CHCI,) MSO. 1410, 1470. 1260. 1010, 140 a~~· 1 ; 1H NMR (CDCI,) • 0.13 (a. 6 H. (CH 1),Si). 0.93 (a. 9 H. (CH 1),C), 3.33 (a. 3 H. OCH,). 4.60 (a. 2 H. OCH~) . AMJ. CaJal for C21 Hc0,5,5i: C.,...,.; H. 9.07: S. 13.7• . Faud: C. 53.16; H. 1.92; s. 13.,.. •c .,...,,...._,,_5(.) ..... n...,...... ........ .,.....&m ...,.,_,. '*'· aJ'_..,...._,_..,.I)·2(·)·..._.,... •c ..._ .,._ •c -a.>: <...., ....,..._..,.....,,,.2<• >·<•<S)-''*"'·5<• H......,.. ...., ...., ....,l)·l(S,.....,...l(Sl-..Ut••tl~ Edllr (3'7). A ealutioa o/640 ma (1.37 8IIDOI) ofdac lR-ditll.icacaal i.a 20 anL o1 .....,. ... added to o1 w~ Raacy BicUf (fnab.Jy iDAdc" tram 210 a t1 Ni alloy) ia 50 aaL tlldauolat 90 •c ud aimd far s b. ne a.,. aaaJyst wu tllal .....,..... by fUualioe ud wuMd with tltr. lO-mL ,.,._ tlUuol. R.emotal ol u. .,..., (ram ... cambiaed raltratll .... Nlbtcid ,.._... ud datamaUip'lpby fll tM r.idaac CID 30 I ol lilica ... with JOII ayl.-.se q ' ' •• alfardld •21 IDI (IS..) fll 1M~ wapaud 1'7: .aporatift cliltiUaU. 11CH20 •c (O.OOS ..Ha); (a]U0 +9.4• (t J.CM, CHCI,): IR (CHCI,) 3350. tao. 1260. ICMO.I40 Clll" 1; 1H Nt.Ol (CDCls) • O.o7 (a. 6 H. (CH,),5i). 0.90 (a. 9 H. (CH,),C). 1.10 (d. l H. J • 7 Hz. CHCH1), 3.31 (a. 3 H. OCH,). •.67 (a.2 H. OCHp). Mil. Calad for C.,H,.O,si: C. 59.63; (J1) W_.: Adtila. H.;"*- A. A. J. A& 0... Sc. 1tM. a. 1471: ...,, "· J039-JCMI. 107 Toc.J Syrultau of/OifOPiuln AlrlibiDiia H. Jo.J6. Faud: C. 5t.1t: H. JO.S7. 2(.)-(5(.)-( 1 ,..., ...., ....,.,.,. ~)-(--/'' 1' .. ra.. ly &k proaedU'I .-rla.d lor die pnpanU. fll&k . - ... 41ldle •••. . . , . ......ll . . (1.16 ..al) flldle . . . . , ....... (1.74 . . . . ) fiiiDIIiaaa ~ ia 9 aL 4ll 4r)' THF. 0:35 aL (5.12 ....) fll c:arllol clilal(. . . . . 0.11 aL (2.19 . . . ., ., . . , . ialliM alrardld. aiW . _ . . . . . . , • 401 flllilica Ill wiQ u,t _. .... q k+-•• .,. .. (f5.)flldlewu ; OOJ...a....: ~ . . . diuWiau. •••40 co.005 ..t~a>: l•l~ c~ u2. CHC1,); Ia (CHC1 1) 1475. 1465. 1220. 1060. 140 ca-l; IJl NWa (CDC1 1) • O.CM (a. 6 H. (CH 1),Si). 0.90 (a. 9 H. (CH,),C). 2.53 (a. J H. SCH 1). l.ll (a.3 H. OCH 1). 4.63 (a. 2 H. OCH,O). 5.67 (dd. 1 H. . . . . . . ., , ? ,...,,.2(S).........,.,..,. , . . ,. . s• •c +u• I • • Hz. • Hz. SzCOCH). Aaa1. Calad lor c.H.O,Si: C. SJ.06; H. l.fl; S. 14.61. Foud: C. Sl.OO; H. l .lf; S. ll.ft. _, •..,......,~, .. 2(aHS(S)-( II: , _ . , ..... (S)..-,..l(S)......,• .,_,I)_,. Edllr. ly die ......... . . ICI"ia.d ror tbe prwpuatiaa o1 rilyl . . . oldie 4R__.,..--. •70 . . (I.CM aunol) ollblabcM uadaau ia 10.4 aL fll dry t.ol- witlt 0.•1 lllL ( 1.55 mlllol) ol tri-11-l•atyltia llydridc all'ardld. aiW *-· tlllpaplty • 30 1 ol rilica acJ witit 5~ «Jlyl . - .... q :I all •• 353 ,_.,1)-J. * . . (91'1) ollbl cuu s 'ina rilyl-...r. .,....a.. dilrillaa 10-10 -c (0.005 .mt1>: l•J 13D +to.•• <~ t.u. CHCJ,); Dl (CHCJ,) 1470, 1460. 1260. 1100. ICMO. 140 em·•; 'H NMit. (CDC1 1) • O.Gl (a. 6 H. (CH 1),5i). 0.11 (a. 9 H. (CH 1),C). 3.33 (a.3 H. OCH1). 4.63 (a.l H. OCH,O). AMI. Calad for C..H.O.st C. 62.31; H. J1.05. r.-1: C. 62...; H. 11.07. J(R)-(5(S)-(,..._a, ....tlwnt_.JI)-l(S.....,._2CS,_.... .,..,.,.).....,14 (36). ly &M.......,. .-rla.d for die pnpa· ruion of tbe aJcolaol J.J. )40 ... ( 1.01 DIIDOi) oldie abclw rilyl . . . ia 5 1D1. ol dry THF witit 530 1D1 (2 . . - ) olaan_,..buy....._. lhlaridc all'orded. after cllromatop'lplay • 20 1 ol rilica Ill witlt 35~ ..,....a.. ldayl...ata q cl +--•• 2361111 (I~) flltlll aloaeall6: dil&ilJaU. •10 •c (0.005 aaHa); l•J=D +5.•• (t uw. CHCJ,); Dl (CHCI 1) 3490, 1..0, 1110, ICMO em-t: 1H NMit. (CDCI 1) . 0.96 (&. J H. I• 6 Hz. CH,CH 2), 1.05 (d. 3 H. I • 6 Hz. CH,CHCC). 3.34 (a. 3 H. OCH 1), •• 62 (a. 2 H, OCH,O). AMI. CaW lar C 1aH..0.: C. 61.0.; H. 10.•1. Foaad: C. 62.12; H. 10.32. 2(S)-(5(S)-(Medle.,_.llw&f_.JI)·J<S.....,..2(S....... .,..,_,.,......_ ly the proDid.,. for &M prepuatiaa ol till ol tbe 4R-IDClhyl--. UO . . (0." BIIDGII) ol 1k aloDeal 36 in 3 lllL of dry diciLioramctltaDc, II 1D1 (0.22IIIIDOI) ol aallydrau IDdiiUil .-au, aad 240 1D1 (1 .11 8111101) ol ~ dllarodaramate afforded. alter chnleatocraplly • 10 a ollilic:a Ill witlt 25' edlyl .-ate-eye~oMuae. 90 ma (7~) ol tile wu ; 1iaa alddtydc: ...para&M dil&ili&U. •c (o.oos ..aHa>: (•J 22D +tt.5•1 (t ul5. CHC1 1); lit. (CHCI,) 1720, 1410, 1110, ICMO. 920 em·•; H NMR (CDCI 1) • 0.93 (t. 3 H. J • 6 Hz. CH,CH,>. 1.05 (d. 3 H. I • 6 Hz. CHCH),3.l6 (s.3 H. OCH 1), 3.52 (d., 2 H. I • 5 Hz. CCHpc), 3.?0 (del., I H. J • • Hz. I Hz. <>-CCCH) ••.62 (s. 2 H. OCH,O), 9.77 (d., I H. I • 6 H&. CHO). AuJ. Caklt lor C 1aHJP.: C. 62.51; H. 9.63. Foud: C. 62.67; H. 9.61. .-nw Udell,. •10 ~~s>-~·1·< *,. , ,,...,.....,~s> _.,..,..~ . . . (35). ly the pracldun .-rla.d ror. preparatiaa ol etiminatiaft prod-.ct 32. 62 .... (0.27 - - ) fll a...,.. alddtJ* ia 2.5 aL ol dry THF aad I 1D1 ol .....-am ,.,••. _ . all'orded. after prq~arativc ailica pi TLC witlt 35~ .Uyl . - ... C) =I :II 1 111&. 25 1111 *~-product lS: ...,...a..~ 10-90 •c (O.oo5 amHa); lit. (CHCI,) 3500, 1610, 1460, 1150, 1040 em·•; 1H NMit. (CDCI 1) • 1.00 (t. 3 H,/ • 7 Hz. CH,cH,>. 1.12 (d. 3 H. J • 6Hz. CHCH,), 3.40 (s. 3 H. OCH 1). •.67 (s. 2 H. OCH,O). 6.27 (d., I H. I • 10 Hz. C-<:H), 9.36 (s. I H. CHO). AMI. Calad lor C 1afi:().: C. 62.51; H. 9.63. Foud: C. 62.65; H. 9.53. * ., _ , . J(R )·(5<SHM•*'•t••slwwt ....JI)·l(S~~ (S)-tllrMJ6wfwyl)t.ryt Edllr. ly till pracldve .-cnw lor die ol tbl llazyl . . . s. 97.9 . . (0.42 1811101) oldie~ 31. 20 ma (0.5 IIIIDOI) ol pawliam llydridc. aad 0.075 lllL (0.6 IIIIDOl) fll bluyl braaUde in • aL ol dry THF all'ardld. after ~play • to 1 otlilica,.. wiQ t5~ ayl ~ 122.1 . . (91~) ol till w u ; 'in! bazyl .w. diiCillaU. 1oo-uo •c (0.005 ..tla); (•J 'D (t 0.97, CHCI,); lit. (CHCl,) 1450. 1310. 1 1 U65. lllO. 1100. 1030 em" ; H NMit. (CDC11) • 0.90 (t. 3 H. I • 6 H&. CH,CH,>. 1.01 (d., 3 H. I • 6 Hz. CH,CHCC), l.JJ (a. 3 H. OCH 1). 4 .• 3 (s. 2 H. c.Jf,J;H,), •.61 (s. 2 H. OCHp). 7.30 (b a. 5 H. c.Jf,). MIL Calad lor C..H,.O.: C. 70.77; H. 9.31. Faad: C. 10.61; H. 9.15. -,e 2(•)-(5(S)-(II;•w;&1116ti)-J(S.....,._2(S) • • • • • (ll). To allirnll......_ oll2.1 IDI (0.26 -.al) ol ·~--a..,.il•aLoiTHF . . IIddld 1 al.flll" . . . . . He. -....at50-ca&6 ........ ....-rau. +f.,. .,.,...tiYC ...,.,._,.lair n..--..-... .. .. ............... w- ....... 50al.tl .... n..,... . . . . . . . . . . . . . 210 aL ., ..... 210 aL., ....... ...-. NaHCO,. ud 210 aL fila._.... . . . - NaO ud W. .... (Ma- IO.). AIW......&flldle..._at ...... , _ . . , . _ _ . . . . . , 4ll die,....._ • 10 I ollilica Ill wiU 35, tllyl ._.... C) I ' I " aft'ardld 10 . . (9K) flltlll alaiM!ll: ......... dilliUa&ial 100..110 ec (0.005 ..tit); l•l"• +26.,. (~ l.GOS.1 CHC1,): Ill (CHO,) MOO. )160. 1460. UIS. 13'70. 1100. lOlO --•; H NNit. (CDC11) • 0.,. (l. J H. I • 6 Hz. CH,CHa). IJM (4. 3 H. I • 6 Hz. CH,CHCC)••.49 (a.l H. c.Jf,clla). 7.l6 (b a. 5 H. c.Jf1). AM!. CaW for C,,H.o,: C. 73.35; H. 9.41. F~: C. 13.42; H. 9.40. a-,t 2<•HS<SKa.._*'*f•l(S).....,..2(S) ......., • • ..,.,._,. Edllr (Jh). To allirnd 5 aL ...-a aoi•U. ol Adam"a .W,.a (rr.iy ......,.. from lGO ma ol 14~ pU&illum Cllidl) wu ..._. lO 1D1 (0.36 BIIDGII) fll aolid NaHCO, ud tM8 a lolutioll ol 70 . . (0.25 .....) oldie~ l l ia I aL o l - - .. Att. aa.piiU eddi&Ma. .., . . . . bii.....S dlraiiP &JMallliatllra at 50 •c l• • 1a. n. &aWyl& . . . . . ,....,.... tr.l till CDaild ~...,..by IUtralioft ud 1Ublequeetly wuW witit two 20-llll. ....,-a ol 0.2 M aq.-. Na,HPO.. a.lliDIIIl fil&ftlll . . . ......, wida lO iDL ol..., aad \MD acidif'..S to pH -2. wu atnclld witJllOW" 210-aaL ~ ol . . . . ud till ................. GU'ICII . . . . . . . . . W'it!llO lllL ol•naraud a q - NaCl ud tM8 dried (Mpo,). Re...U oldie . . _ , at ......._.. ,._a ,... 61.1 . . (,.~) ol&M n. -· $ n. .._.......... ti .. acid ...... A partiae oldlil....., . . tnWd ~die " " ia ttMr aad W. dltoma...,...y oldie ...UU., IDitbyl . . Jh a lilica ... with 1" etbyl acaate=q cl II •• prvriMd &M uaJytical ample: .,.~ •c IUM diatillatiaa 100..110 (0.005 .aMI); IR (C.HCl,) 1740, 1..0• 1315, ll70. 1100 em"1; 1H NMR (CDC11) '0.93 (t. 3 H. I • 6 H&. CH,cHt). I .GO (d., 3 H. I • 6Hz. CH,CHCC). 3.70 (s. 3 H. C~H,). •.43 (a. 2 H. c.H,CHJl, 7.31 <s. 5 H. c.Hs>· A8a1. Calal ror c,e~~.o.: C. 70."; H. 1.55. Foud: C. 70.51; H. 1.45. ~,..,._2.J-0·(1..., ..., , )-~ AcW. 't-'--. To allimd ........- ol67.0 . . (O.•t 11101) ol ~tl~AC~G~&CICUriaic acid. ~ ia 115 iDL ol *Y - - at , _ tempentun wu ..... 1.15 lllL fll96~ -.1f1lric acid. AI-. 30 ... till r.cUoD ...... <•> wuadjuaudsopH-IwiQaq-...-.. n..._..tiqllliatare n. ... fU&Ind ud till ftltnta _ . . . .. . ..., nd..S pNIUrt. oil wu dilloMd ia 100 iDL olaMr uclwul..t wiQ 500 mL ol wac.. n. .._..... Ia,.- wu tJ.a auac:..d witlt dane IOO.IIll. .....,... fll.u.r. orpaic ................ W'itJl 300 aL olaturat8d .._..... NaCI ucl that dried (M,SO,). lt.aDCMI ol ..,.._ ..... ,..... .,.....,.. .... nua c:bnaatopapby ol Qe Nliduc - 100 • ol ailica acJ witlt .,...... ia peuoAeul etblr afforded 77.9 1 (,.,., oltbe wu p=dina UW.mp ~~ •c (Ut.• mp 6111.5 •c). ~,...,.. ~.(1....,...,.._)-5-0·( 1 .,...., ...~ AdL 'r·'--t (41 ), To a aimld IUipal&ioD ofl.l 1 (32.• IIUDOI) of potallil&lllhydride ia 90 iDL ol dry THF at 0 UDder arp wu ldiW a aolutioll ol 5.03 1 (2•.16 BIIDGII) ol tbe l.HCIItOilide of ~~~UCIOI­ ec:daarinic acid. T·lactoec ia 20 ID1. ol dry THF. ud that 3 llll. (39.5 amol) ol ~yl mcthyledaer wu ..W. The r.ultifta mixtun wultimd at , _ ~nare for I ll. tnated wiQ lO llll. ol•uarated &q'**~ NaHCO,, aad tllla cliluted witlt 400 IDl. ol edlcr. The orpnic p8ue wu ..-rated ucl that wubld wit!l two 200-mL portiona of aturated aq..oua NaHCO,. lGO ID1. olaaturated aqueous NaCl. and dlca dn.d (Mpo,). Altc raDO¥al ofiOiYCrtta UDder nduced prwaure, daromatotni*Y ol the Niduc 011 200 1 ol ailic:a pi w1t!l 5K ether in piU'CMum edaer prvriMd 5.701 (93") of tile IMlhoaymethyl ether 41: ...pami\oe clillillaDc. 9CHOO •c (0.005 IDIDHI); [a) 22 D -22.4• (c 1.32. CHCI 1); IR (CHCI,) 1710. 1310. 1220. 1160, 1105, 1060. 1020 em·•: 1H NMit. (CDCI ) ' 1.42 (a. 6 H. C(CH )t), 1.62 (5. 3 H. CH ), 3.33 1 1 1 (a.l H. OCH 1), 3.74 (d., 2 H,l• 3Hz. CCH~). 4.47 (&,I H. H3), •-" (b a.l H. OCH,O). Aal. Calallor C 11 H 1,0,: C. 53.65~ H. 7.37. Foud: C. 53.67; H. 7.25. .-....a n. ....... •c ~uo-u _.., ...,se >-S.O·< 1 . ,. . . ,n.~ To a llirnd IOiuU. ol 5.70 1 (23.1 aunol) o{ tbc lactoDC 41 ill I00 mL ol dry .u.r IUider u p at -71 •c wu Mded, d,..ilc ower 30 min, 35 iDL ola 1 M ealuDc. ol cliilobutylaJuminiUil hydride iD llauc. Altc I ll. tile ~ ~Dimarc wu ca•tioully u.ted witit 2 ID1. ol maUnol. auo..d so wum so,_ ~nare.. ud tbcn clilut8d wit!l 500 ID1. ol .U.. 'nilealutiaa wu wubld witlt tJane 7~1Dl. paniaal olauarated .....- 10di1Uil pawlium tanarau eaiutiaft aad 70 ID1. ol aaturated ...-a NaCl aad tllla dried (Mpo,). Altc I"'IIICMJ of tile IOIYent ............ ..-n. darolaatopaplly ol tbe u.iduc 011 200 • ol rilica ... wiQ 75~ . . . . ,..,...._ . . . all'orded 5.76. (I~) ol the (31) l1GiL L M.; OrUiliM. G. 0 . Dolcl. AUII. NM SSSilJtO. 9J. JOI. s...lla. J. C.. llair, N . 0.; K - . D. J. J. MI. 0.... S«. lf5'7• 1f.......,.. 108 lreUuWfltU. 2002 J. MI. eMIL S«.. Yol. /0$, No. 1, INJ ' . . . . . . . . . . . . . f l . - . : ...,..U..dildllldaa to-loo •c (O.oos ..tta>; I•J», +17.r <~ 1.11. CHC,); a (CHO,) MOO. 3450. 1460. UID. 1210. 1160. llOS, 1MO. 1030 _ .., 1H NNa (CDCI,) I ( . . _ . _ , ajar._, J.ll, J~ (lo 3 H. OCH,), WI J.Jt, J.6J (d. 2 H. I • 2 Hz. CCH,O), Ul. ._.. (lo 2 H. OCH,O). S.OO. 5.17 (d. l H. I • II Hz. H·l). AM&. CaW ltr CuH.O.: C. Sl.ll; H.Ut ,_..: C. SJ.G6; H. I.OS. -...~,.._,.,._.,..s-o-< • ,.....,n 1 . ,. . . . . 14111111 (G). To allimd - - fi6.S2 1 (26.26 -..!) tldll .-.. t.c1a1 ud u aL (32 aaol) fl.,._ tend'' ida ill 100 aL fl., THF at •71 •c ...._ 11J011 wu ..._. S.l aL (21 -.1) flll'il(4i- ...,...._)J' r·;· ,..., ....... ,........,. .. ....,.. towuat.oO-cudwutM8.....,Yiaa..,...u,.d...U..toa llirnd - - fl 52 at (317 ...... ) tllidliut '"" ia 400 .... fl ..., . . . ...... . _ . •• -71 -c ........... m. dilclaWa_, (aauaoaia Nf'lua). ud ata.r 2 ~ 11.7 1 (350 __,) fl _.,..._ aaunoaham clalori* wu on~ lddld 10 die ..aioB .uu.r.. n. r.a1tiaa CIDiort.l mWU'I ... dated wjg . , aaL fl . . . . . . lM IIIIIDODia ... .uo..dt.o .,....... ......- wu ud dieD -U'IIioe t1 tile ftluatc ...._ ,..... ...-n atronW a cnde IDianlft fl tile pycal G. tile ..,.. •ydraluru rlduaioD ud HMPA. Alw rallid ,_.., t1 &M cnde pradua *-lb 50 1 fllilica ... wiW 75~..., ia , . trolcua . . . . CIOIICeiiU'Itiall fl tM tlut.t .......... , _ , . ... dla dillillatiall (Kqdrollr, 110 •c (0.01 IIIIIIHI)] fl dat ...-.. II"" 4.6N 1 t1 a mtve ol t1at lf)aJ G ud dill ~ AM1J1i1 ol tlail llliatU'I b7 1H NMR ~,...,.... a ralio fl4:1 for ll,cal t.o ~ Oramatopapby fla ..U ,.UO. ol Wia.aiiiN •lilica ... wida 75~ ~ .._ prGridld pve prad.a for ualylia: .......u.. dillillatioe •70 •c (0.005 maMa>; I•J»1 +l06.t• c 1.11. c:.oaa. ... n. ,_.. .... raJ...., ..,...uct... CHCI,); IR (CHCI,) 3590, 3450. 1675. 1460, 1310. 1210. 1150. 1100. 1020 em·•; 1H NMR (CDCI,) • 1.69 (d. 3 H. I • 2Hz. CH 1), 3.37 (lo 3 H. OC:H 1). 3.56 (d. 2 H. I • 6 Hz. CCH,O), 5.GI (lo 2 H. OCH,O), 6.22 (b a. I H. HC~). ~ CaW for c.H 1.0.: C. 55.16; H.UO. Feud: C, 55.11; H, 1.03. M1e71 2(a)- _. l(SH2.5 AJ6•S(S)-(• It ,,_.,.......,... * ....,..,.,.....,._JtaH'wyt)......._ (O). A. ,,.. Qr.l a ., Dip eiee a. niF. To allimd aotulioa o/4.6 1 (19.1 ..al ol • ll,cal G) o1 tJat 4:1 aiatve olta. ud • ~ill "aaL ol dry THF It -71 -c ...., .,... .......... aaL (19.1 -.ol) tla 2.41 M aot•lioa ol••tyWtlaiua ud dla ata.r 5 miD. 2.1 aaL (20.2 anoO ol..-tyryt clalorilk wu lddld. Alw 10 .W. at 0 tM rMC&ica IDiatllft ... tabe., ia ...... n.w lyriqa ... edded drapwill to a llirnd IOhalioa oC 24.1 IIUDOI ol LDA ia 57 aaL ol *Y THF a& -71•C llldlr arp. ANIIO miD. tM ~--. . . u.ted wi~ 6.4 a1. (37.1 auDOI ol Mc,SiCI) oldlll .,........, Clllttril...t.t lrmn a 3: I aaiaarc ol cn.n.dayldaioroailaae ud triedaylamia AJt. 2 bat room ...........~~...... &M naaaa lllimn wu ~ wida 100 aL oil N a.t- NaOH ud llimd for 15 alia. 1'111 .......... . . ..-rated ucl aU'ICUid wida *- 50-aal. ~oil N a.tNaOH. aDd lJieD tlM CIOIIltued a.t- tu. ........ ...a.d witJa 50 1DL oi.U., acidified (pH -2) ud atnaed witJa 1081 100-aal. ~ o1 eUler. nc comu.t . . . . - auac:ta . . . ...a.t wida 50 a1. oC l&tunc.d aq..._ NaCI aDd tJ. dNd (M,SO.). ltciDoral ol .._ eot¥aat lUSdcr reduced .,.._.... all'onW 1 mis11U't ol tile ~ ..X acids wbic:h . . . ..nr..t wiQ ...,.., die . . . . Qrcaa. ......., ol u.c ,.Wtiq metllyf .... - 300 • ollilica pf witJa ~ tdlcr ia petrOleum «bbr alfonW 3.071 (..,..) ol.._ _.,. tiUrl 0 . 1H NMR ualysia ......... a ralio ol 9:1 lor .._two diu:w ic .U.yl•. .: .....-c.M diltillalioa .70 -c (0.G05 -.Hi); IR 1 (CHCI,) 17)0, 1460. 1440. I ISO. 1110. IC.O. IOlO aa·•; H NMR (CDCls) • 3.33 (a, 3 H. OC:H,), 3.49 (d. 2 H. I• 4 Hz. CCHp), 3.60, 3.61 (a, 3 H. CO,CH 1). 4.60 (a, 2 H. OCH,O), 5.50 (b a. I H. c-cH). Aa1. Calat for C 1,H2Pt= c. 60.45; H. 1.51. Fc.all: C. 60.47; H. 1.49. a. ,,_ 1111 QpC8I C ., Dip efee a. HMPA-niF. ly dill --,.....,.. u ct.crit.d ill pan A a-.. 17.17 ...... ol U.C al,cal G wida I0.51DL (24.15 ..al) o/2.3 M ......_ ol•...tyllitlaiiUD ia ......._ 2.6 aaL (25 IIUDOI) ol..-tyryt d'lcwidl ia 70 aaL ol dry THF. ud 10 aaL ol dry HMPA. added to 2J.5IIIIDOI ol LDA ia 66 aaL olcky THF ud 16 aaL ol dry HMPA. fauo..d b7 59 IIIIDOI fl uWIUayJ. ~ atronW..,.., .,... . dall dia.. ic . . . wjg . . -1 d'• ....... c:laromatopaplly oldat ~ ....,. .... • 200 I ollilica pf wiW lQII.U. ia ,.,..._ . - . 2.4 1 (52'1') ol lila -....;c .-yt .... 0 . 1H NMR ra&io oli:J . . tM two diut I ic ..oyJ ..... 2(SHS(S)-(MIIIII:as_., ...., ....,a)-)(S). .....,..2($) _ . . • ...,,.,._...., To allimd ......._ ol2.4 1 (9.3 ..at) oldlll dius ic .Uyl . . . G (fraa HMPA/THF rr . . . .) ia, a1. oldyt .............. 140 . . fllft ,... . . . ---- n. .............. llirl'llll& , _ ............... ..,_.a iD-..... •c. _.,.,_...a Mlefll<•>- _. n.....,. ............ _, • .,.... ......... far, .. lltratiaa ............. tlni25--.L ....-.fl..,. ...... ... .... fldll ..... rr- dall _..... tlllrata ... . _ _ , . , . , fl .... ~- 200 I fllilica ... widl 25~..,. ....... q d alrordlllll U 1 (66~) oi\M , . . - , . . . , _. 0.53 1 (21~) fll tile ~ 1S _.,. . . . 1S....,. . . . ~ 6&illalioa 10-90 -c (0.005 - " I ) ; (•J•o +16..J- (c- 1.01, CHO,); Ut (CHCI,) 17JO. 1460. J390. 1110. ICMO _ ... , 1H NNI. (CDCt,) I 0.90 (t. 3 H. I • 6Hz. CH,CHa), IM (d. J H. I • 6 Hz. OI,CIICC), 3.36 (a, 3 H. OCH 1), 3.52 (d.2 H. I • S Hz. CCH,O). lM (a, l H. CO,CH,), .UI (a.2 H. OCH,O). AM&. CaJCid for C 1,H,,,: C. 59.91; H. 9.29. feud: C. 59.92; H. 9.31. 2a Nayt .ur: ...,_.._ diltillalioa 10-90 -c (0.005 ..tit); 1•)•1 +5.4• (c 1.16, CHCI1): IR (CHCI,) 17JO. 1..0. 1275, 1220, 1160. I lOS, ICMO aa·•: 1H NMI. (CDCI 1) I 0.11 (t. 3 H. I • 6 Hz. CH,cHa), 0.99 (d. 3 H. I • 6 Hz. CH,), 3.36 (a, 3 H. OCH 1), 3.51 (d. 2 H. I • 5 Hz. CCH,O), 3.61 (a, 3 H. C()zCH 1), 4.62 (a, 2 H. OCH,O). Aa1. Calat ror C1,H,.O,: C. 59.91; H. 9.29. '--d: C. 59.93: H. 9.12. t " 2(a)-(S(S)-{Mid.:f.-lllwai_.Jl)-J(S,._..,..2(S,...._ .,..,.,.,._., ... (36). ly dall prGCIIdan cleaaibld lor dat Jft1111• ralioa ol lila wa ; rtm1 .-..... ol _,........ 4. 530 . . (2.0 ..al) tldii1S adlyl- • ..,.. iiiiO aL ol dry U. wida 10 Gil ollil.laiua tl&rdyclridoalaliaat.t (1.4 ..... ol ~ydrida) atronW. att.r daroma· ......, 011401 olliliaa ... witJa ... tUyt .-at.t ill q I ' a• 440 . . (95~) flu alcloMI. dill 1H NMI. .,.ana olwlla wu idalical widatllatol .......... 2(S)-(S(S)-(Mclkaf_.illwiJ_.JI)-J(S.......,._2(S.....,._ .,..,.,.). . . . . . . (oM). l y . praoadve dllaibld ror lila pnparalioa ol dall WI z liq ...... ol..,..ad 4, 1.67 I (6.4 ..al) ol dall 211 ~ ........ ia 32 aL ol dry .a. wjg 24o . . ol ~~t~Y. . WU'IJaydridoaluliaat.t (25.6 . . - ollaydricle) alfonW. alwr d'raeatopa..y• 1001 ollilica pf wig~ aJiyf ICIIUt.l in cycb ........ 1.45 1 ("') ol dat ..... oM: ..aparaU.. clilliUatiall • 70 (0.005 maHJ); (•) 110 +%7.4• (c J.26S. CHO,); IR (CHC1 1) 3650. •c 3500. 1..0. lllO. I 150. I 105, ICMO aa" 1; 1H NMR (CDCI1) • 0.93 (t. 3 H. I • 6Hz. CH1CHa). 1.01 (d. 3 H. I • 6Hz. CH,), 2.67 (dd. I H. I • 5. 6 Hz. CHCH 1), 3.33 (a, J H. OCH,), 3.47 (d. 2 H. J • S Hz. CCH,O), 4.60 (a. 2 H. OCHp). ~ CaW r. CaaH,.O.: C. 62.CM; H. 10.41. Fa.d: 62.01; H. 10.32. - , t 2(S)-(5(S)-(Mctk:JaaGI'-.,_...,.,_J(S,_....,..J. (S) ....., ..... ly tM prDCIIdun dllcribld ror lila Jftlllll&lioa ol dat bluyl.._ S. J .45 1 (6.22 ...a) oi\M .._... oM wiW 3001111 (7.41 18111101) ot.....-;ua hydride ud 1.2 aaL (9.6 aaoi) ol bluyl bramidt ia lO aa1. ol dry THF atrordld. after ._..,.pity • 100 aotlilica ... witJa u~«~~y~..w. ia q 1 ' . . . 2.01 <~> ol lila QW I p d~ ba.lyl aMr: ..aparatM clilliUalioa 1•11 0 •c (0.005 iiiiiiHI): (•) 0 +II.,. (c- 1.71. CH01); IR (CH0 1) 1460. 1310, 1120. ICMO cm"1; 1H NMR (CDCI 1) I 0.92 (t. 3 H. I • 6 fU. CH1CHa), 1.02 (d. 3 H. I • 6 Hz. CH 1), 3.33 (a. 3 H. OC:H,), 3.47 (d. • H. J • 5Hz. CCH,O). 4.43 (a. 2 H. c.H,CH1), 4.60 (a, 2 H. OC:H,O). 7.21 (b a. 5 H. c.H 1) . AMI. Ca1at far C.,H.O.: C. 70.77: H. 9.31. Faud: C, 70.51; H. 9.22. lauyi2(S)-(5(S)-{HJ6Uay_.yl)·l(S,._.,..2(S)-.....;6• ..,.,._,. Edllr. By the prai*IUR dacribld for U.C ~tian ol U.C a.laolaolll. 2.01 (6.2IIUDOI) oC data-. metboay ..U.yi.U. ill 41 a1. ol THF aad J21DL oiiCJII aquoua HCialfont.d. after c:laroma· top'lpby 011 JOO a ollilica pi wida 35'1 aJiyl acaatc in cydobaaDC. 1.7 • (99"1) ol u.c ~ aJcoDol: C'laporlti¥1 clillillation 1•110 •c (0.005 illlllHI): (•) 11 0 +49.3• (c l.tn, CHC11) : IR (CHCl,) J600. 3450, 1460. 1310. 1220, 1100. 1010, JCMO em·•; 1H NMR (CDCJ,) I 0.93 (t. 3 H. I • 6 Ha. CH,CHt), 1.02 (d. 3 H. I • 6 Hz. CH,). 3.47 (d. 2 H. J • 6 fU. CCH,O). 4.41 (a, 2 H. c:.H,CHt), 7.3~ (b a. 5 H. c.H1). A.&. Calat (or C1,H.O,: C. 73.35; H. 9.41. Faad: C. 73.46; H. 9.36. _ , . 2(S)-(5(S)-Ca1 I • 1)'-J(S).......J(S......,... c. ,.)..,.l:dllr. ..,....,. ...... (ls.). ly the ..,..tun dllcribld rar lila pnparatiaa ol dall .....,. .... lea. 1.7 • (6.12 aanol) ol tM ......... ia 60 lll1. fl .... witJa 643 ... (7.7 anoi) oliOticl NaHCO, ud I...Wy ......,.S Adam's catalyll (from 21 ollft platiaum Cllidl) atrorded 1.63 1 (91'1) ot• acid 25. A~ ol tllila.Wia.l wu tratM wiQ dia lee• • ..., ... d'raeatopaplly ol lila~ metlliyl . . . - ~ ... witJa I011 ldayf .-.t.t ia q I ' a• prGrided tJae U&lytica1111npc oC zs.: ..aporac.M diltillaaioa ••110 (O.oo5 -"1>: (•)•o +t .4• (c 1.11, CHCI1); IR (CHCI1) 1740, 1460. 1370, 1 1 lllO. 1100. 1040 cm" ; H NMR (CDCI1) I 0.93 (t. l H. J • 6 Hz. CH1CHt), 1.01 (d. 3 H. I • 6 Hz. CH 1), 3.49 (d. 2 H. J • 6 Hz. CCH,O). 3.70 (a, 3 H. co,cH,), 3.10 (dd. I H. J • 5, I fU. OCHCC), 4.31 (t. I H. I • 7Hz. CHCO,cH,). 4.47 (a. 2 H. c.H,cHv. 7.32 (b .._ _.Y, .... a. 5 H. c.Hs>· AMI. CaJCid I• cae~~.o.: c. 70.J4: H. 1.52. •c c. 7o.56; H. 1.55. '--l: 109 Toul S,_IIGU of I~ Alatlliocln J. AM. CMa S«.• Yol. IOJ, No. 1, 198J 2003 -,t 6 ...., ....... ...._......... To a and . . . . . tl U 1(9.14 __., fl .....)'-1...... (411) i1111-'- fl...,. . . . . . . . ..... 0.35 -'. tl.-,1 clllaride. A/WI 2 da71- die . . . - - - . . . ...... wiQ .eo aL fll c*laral- ud .._ ...,.._. wtda 10 1 fll ..,._ cart.aM&&. ne ~ ..,...._ wu Rklrlll ... • lllid ......., ....w .... dlrwl$el. ,..u.. f!llcMiral-. JUtna. . . . -..11111 ., 50 ec (O.OI ....,, ... • , . . . . . . . . . . . . . . . . . . . . . . tllilica . . ~Gyl ........... l ... ~) fl • ...,. .., . . . (.:1 • 1!2). ~ . , IM-S-135.5 (Gyf .-.u ' 'M); (•J•o •Ill. I• (t I.IH. CliO,); Ja (CHCI1) .MOO, 3500. 1220, 1105, 1CJIO. UNO, 1000 cm·1; 1H NNJ. (CDC11) I 1.ll (d. l H. J • 6 II&. CH,). 4.,. (d. I H. J • 12 II&. CJisCH/1), 4.1] (d. 1 H. J. 12 lb. c.H,cHH). 4.9) (b .. 1 H. H-1). 7.31 (b a. 5 H. c.Hs>· AMI. CaJal r. C 1,H 1.0,: C. 61.41; H. 7.14. '-d: C. 6J.ll; H. 7.11. 1-QI}CIIIIidc: ewapan&M clillillalia. IJ0-1.0 ec (0.005 lalftHa); [•)•• +117.,. (t'0.515.1 CHCI,); Ja (CH01) MOO. M"l. 1220. 1115. 1010. 1060. 1000 em·•; H NNR (CDCJ 1) I 1.%7 (d. 3 H. J • 611&. CH 1), 4.53 (d. 1 H. J • II II&. c.HsCHM. 4.62 (d. I H. J • lib. H·l), 4.19 (d. 1 H. J • 1111&. c.HsCHH), 1.M (b a. 5 H. c.H,). AMI. CaJal ror C 1,H..O,: C. 61.41; H. 7.14. ro..d: C. 61..39; H. 7.11. _ , , ' Jwat·U.0-(Iuudi;II6JEI ,... ... .,.._........ Toa llirnd f!lll.la (7.01 IIIIDOf) f!lldle allcMIIIuyt ~~~ill 10 a1. f!llclry . . . . . . . ..._. 70 . . (O.l7..a) fl ,..wu-w.-c . . . . .ydn..... 1.1 aaL (1.9 . . ., fll.l~,.... AIWI1lla. tM re.c:a. ......... -tralizlld witlllluiam .......... n. ru..r.~ ud iklatid ........ w.. ...w wiQ tJanc »aaL ~fl-. n. CIIDbillld Rltraa. _.. n.--.. •c .-u. ,...w.a....,...... ... ~tlld ....,rid.............................. - 100 I f!lllilica ... wida 2.511 lldtyl.-.& .... to pw. I.M 1 (9314) oftJauon ; dina awa. ..OI)'CIIIide: . , 79-10 •c O•· 23 . .); (•1 D 12.1 •c (t' 0.955, CHCI,); IR (CHCI,) 3910. )460, 1310. 12.0. 1160. 1100. 1030 c:m" 1; 1H NNJ. (CDC1 1) I 1.19 (d.l H. J • 6 lb. CH 1). 1.36. 1.50 (a. 6 H. C(CH 1),), 4.56 (d. 1 H. J • 12 II&. c.H,cHH). 4.71 (d. 1 H. J • 1211&. c.HsCHH). 4.11 (Ita. 1 H. HI), 1.3l (b a. 5 H. c.Hs>· AMI. Calod r01 C 1.Jfu(),: C. 65~ H. 7.Sl. 6S.l6; H. 1.51. ~ ewapaniM dillillatimi1CJ0-110 Faad: ec (O.OOS .aHa); [•)11D +105.5• (t'O.S5,1 CHO,); IJ. (CHO,) 3560, 3350. 1390,1130,1110, 1120. 1060cm·•; H NNR (CDC1 1) 11.30 (d. l H. J • 611&. CH,), 1.31, 1..0 (a. 6 H. C(CH,),), 4.1) (d. 1 H. J • 4Hz. H·l), 4.51 (d. 1 H. J • 1211&. c.HsCHM. 4.14 (d. 1 H. J • 12 lb. c.HsCHH). 7.33 (b a. 5 H. c.Hs>· AMI. CaJalf• C..Ha:P,: C. 65.29: H. 7.53. Foud: C, 65.31; H. 7.41. _ , , 6 Ju :rUO·Uuudit ...l., ).+()-(& 'A ,...,.,.,._. ... -1-L...-. (46). ly die praGidun clllc:ribed for die pnparatioa f!ll I .... c. &M lllltbolymcdlyl ct.blr 41. I.M 1 (6.6 aiiDIII) f!llallliuww f!lldle a - . . . . . _ 0.341 (1.5 aiiDIII) ol ....... ..,._ aad I aaL (13.2.-) fl ctalclroaMtbyl ...._..yl . . _ ill l2 aL ol dry THF all'orded, ata.r ._tap"aJJity 011 1001 f!lllilica Ill will 2ft lldtyl.-a.....,...._ . - . 1.91 1 (1611) oldie IDI&bo&ymetbyl -.lam 46. ..OIJCIOiide: ....ponu.c ctiatdlation •••30 •c (0.005 llllllHI): [crJ 11' ..,.u• (t' 0.75. CHC1 1) ; nt (CH0 1) 1310, 1240. 1150, 1100. 1020 em·: 1H NMR (CDCI,) 11.20 (d, 3 H. J • 611&. CH,), 1.36. 1.51 (a. 6 H. C(CH 1h), 3.40 (a. 3 H, OCH 1), 4.$7 (b a. 1 H. H-1 ), 7.34 (b a. 5 H. c.H,). AMI. CaJat r01 c,,H.o.: c. 61.19: H. 1.1•. Faad: c. 64.03: H. 7.75. 1-QI~: IWapOI"'tm clillillatiaa 1CJ0-110 •C (Q.OOS GIIDH&); (•) 11D +147 .1• (c 0.565, CHCI 1); JJt (CH01) 1390, 1230. 1155, 10.0 c:m·•; 1H NMR (CDC1 ) I 3.40 (a.l H. OCH,), 4.51 (d. 1 H. J • 12Hz. H-1 ), 1 1.30 (b a. 5 H. CJ1 1) . AMI. Calal for CJI.O.: C. 63.19; H. 7.74. Faud: C. 63.13; H. 7.57. 6-0.:,.U.0-(1 ..,...,, ).+()-( 1 , .... (.-7). To allimd aution fill em (ll.l...t) f!lllitJUIUII wire ill 50 aL f!ll ....,...,_ UI'UIIOIIia at -71 UJOII ......... a IOhaU. oil. 91 1 (5.64 .......,.) oldie IDishlft f!ll'-zyt pyallidla 46 ill 10 mL fii*Y THF. Coolilllwu U. 1' .._. (IIIIIIIIDa J'lllu.&), ud att.r I Ia, 1.1 1 (20.6 DUDOI) ol aaJiydrou I ' um ddaridll . . cutiouly ..w.d 101M~ n. ..-Jtiq aainaft wu *- clilatad wit.b 50 aaL fi...W ud • . - i a ... .uo..d to twaponte.. .-Jtina ......- ... filt.lnd. ... 1M IOtid ... tllllll ....-:1 .., tritvatioa wit.b fu.r 20-aal. ~ ol.._. ll.-..J f!IIIM .._, ,_die ...-... flltrwiii\I'C 1.21 (1614) f!IIIM cr,...lli8et.aG~ ~= . , 139 <.U.yl.-........... ); l•JDo +61.,. t-215. CHO,); m (CH0 1) J600, lot60, 1390, 1130, 1160. 1100, ICMO •·•; 1H NMR (CDCl,) I 1.%7 (d.l H. J • 611&. CH 1). l.ll, 1.47 (a. 6 H. C(CH 1),), J..eo (a. l H. OCH 1), 3.57 (d. I H. J • 6 Hz. OH), 3.63 (dd, I H. J • l Hz. lib. H~). 4.00 (dq, I H. J • l lb. 6 Hz. H-5), 4.03 (dd, I H. J • 6 lb. 6 II&. H·2)••.ll (dd, I H. J • l II&. 6 lb. H·)), 4.63 (d. I H. J • 6 lb. OCHHO), 4.17 (d. 1 H. J • 611&. OCHHO), 4.17 (dd, I H. J • 6 lb. 6 Hz. H·l ). AMI. Calod for CuH.O.: C. 53..22: H. l.ll. Had: c. 5).12; H.l-21. ,.)-L_.. 2 •c ..... ...w..... •c n. <" J.S.~J.' M:IQ+0·(• *•Juudi;t)·L·..,.-IIIa·l-06), 1y 1M ,...,...,.. 4111crilllll f• 1M pnpara&ila f!IIIM llycal C. 4l7A . . (1.76 ..m) ti&M ...... #f, G.22 aL (2.21..ul) flcart. snn" -.o.M.a.(l.l1.-l)tltril(~).....,....ill 1-'. f!lldry THF tria l.S • (21.l...a) fllidli- wire ill JO mL fill ...,.._ . - i a ud U 1 (26.2 ..ul) fl...,.._ hm ........ all'ardld, att.r ...... tJ1raP 5 I flllilica fll witJI Sft .U.yl .-ara ,.. • • .._ ud clillillatiaa [Kat**, 60 ec (0.1 -.Jfa)J, 210 ma (90'1) f!IIIM p,.1 ~ [•J 11o -206.4• (t' 0.59. CHO,); IJ. 1 (CHC11) 3620, M50.1640.1340. 1150. 1090, 10JO. MJem-t: 1H NMR (CDCI1) I l.J6 (d.l H. J • 6 lb. CH,). l ..O (a.l H. OCH,). 3.56 (Ill. I H. H...). 4.10 (-. 2 H. H-3 ud H·5), •.66 (d. 1 H. J • 6 Hz. OCHNO). •.73 (d. I H. J • 6 lb. OCHHO), 4.19 (m, 1 H. H·l), 6.50 (d. 1 H. J • 611&. H·1). AMI. CaJal ror CtH 1.0.: C. 55.16; H,I.IO. Faad: c. 55..%7; H. 1.20. a-,1 J<•HS<•)- _. 5(S).(Mtew*=t·3(S).....,._5-(5.64.,..5(S)-(_.a;w..,...._,)-6(S,_....,._l(.).,_,.).JCS)· . . ., • .,.,.,.,. E.llllr (51 ... 51). ly tJaa part A prooldl&re de· ..... (Oldie,.,.,..... f!ll tM IDit.layl . . . . G. %72 . . ( 1.56 .......,., filM aJycal i6 wiUI 0.71 aL (1.63 mmol) f!lll.l N IOfutioll fii•IMI· tyllitbi. . ill ....._ ud 1.61 ...a oiiM acid~ fill tJaa acid 39 ia 6 aaL f!llclry THF, ..._.to 3.•5 _.fill LDA ill 71Dl. ol dry THF, ,..,.... .., 5.1..-f!ll~-.atrordld.att.ru.tmatt wiG ..,_. die tit~• ud ~~apaplay • 30 1 ollilica pi .umuyt.-... q · n ·• 12S.7maf!lllk..ayt . . . ud 213.4 . . fill die .Uyl . . 51. 01 a 30:70 ratio fill a 5711 combiaed JieW. ~~ ... • ..,...u.. diltillau. u~160 •c (0.005 ..tla); [•) D +135.,. (c UIS, CHO,); IR (CHC1 1) 17.0, 1460, 1390, 1160, 1100. ICMO -·•; 1H NNJ. (CDCl,) I 0.93 (t. l H. J • 6 II&. CH,CH 1), 0.91 (d.l H. J • 611&. CH,CHCC), 1.20 (d. l H. J • 611&. CH,CHOC),l.l7 (a.l H. OCH,), 1.73 (a. l H. ~H 1 ). 4.44 (ba.l H. c.HsCH1), •.60 (d.1 H.J •111&. OCHHO), 4.71 (d. 1 H. J • 7 Hz. OCHHO). 5.631. U (m, 2 H. HC-<:H), 7.ll (b a. 5 H. c.Hs>· AMI. Calad ror c.H,.O,: 67.51; H. l.ll. Faud: 67.70; H.l.ll. Nayt-.. 51: .,.pontift diltillati011150sl60 (O.OOS .aHa): [•J 11D +159.5• (t 0.145, CHCI,): JJ. (CHCI1) 1745, 1730, 1460, 1310, 1140. 1090. ICMO cm· 1; 1H NNR (CDC1 1) I 0.17 (t. l H. J • 611&. CH1CH,), O.M (d.l H. J • 6Hz. CH,CHCC). 1.13 (d. 3 H. J • 6 lb. CHs(:HOC).l.ll (a. 3 H. OCH,).l.64 (a.l H. COtCH,), 4.41 (b a. 2 H. C,.H,cH,). 4.51 (d. I H. J • 611&. OCHHO). 4.70 (d. 1 H. J • 6 II&. OCHHO). 6.00 (Ill. l H. HC~). 7.30 (b a. 5 H. c.Hs). AMI. Calad for c.H,.O,: C. 61.51; H.UI. Faud: C. 67.61; 11. 1.35. c. c. •c a-,1 lCSHS(•)- _. S(S)-CF ' •t·J<S~5-(5.64.,..5(S)-(.-.at ....ilwnt)~S)....,._2(•)·,....,.)-2(S)­ .......,..,..,.~ E.llllr (. . . . 49). ly tM put A proolduR deICribed r01ik pnpuatioll f!II&M a.t~ay~ ..... 4l.ll1ma (l.ll aunoi) f!ll die aJycal 26 witJl I aaL (2.3 mmol) oll.l N IOfatioe fill •IMityllitbiiUII ill ....._ ud 2.45 8UDOI fill die acid cblGride fill tJae acid 25 in 5 aaL fill dry THF, added to 4.6 .......,. ol LDA ia 5 mL ol dry THF• r~ .., 9.5 mmo~ o1 tna.t.~a~ atrorded. alter u.unent witJl ctJMr.J ~ ud du'omatop"aplly 011 50 1 ollil.ic:a 111 witJa ~ etllyl.-.w q cl t unc. 171 1n1 ol the methyl eater • and 504 me ol 1M metllyt._ e. or a 26:74 ratio ola '"combined yield. Metllyl ..ur • : .,.pontiw ctiltillation 150sl60 •c (0.005 mmHal: (•) 23 0 +141 .6• (t 1.22. CHO,); IR (CH0 1) 1740, 1460. 1215. 1160, 1100, I()eO cm-l; 1H NMR (CDC1 1) I 0.92 (t.l H. J • 6Hz. C1f,CH 1), 0.97 (d. 3 H. J • 6 lb. CH,CHCC), 1.11 (d. l H. J • 6 Hz. CH,CHOC).l.l4 (a.l H. OCH,). 3.73 (a, l H. CO,CH,). • .47 (b a. 2 H. c.HsCH,), 4.62 (d. 1 H. J • 111&. OCHHO), 4.71 (d. 1 H. J • 111&. OCHHO), 5.671.17 (Ill. l H. HC-<:H). 7.ll (b a. 5 H. c.H 5) . Aal. Calod f01 CJt,.O,: C, 67.51: H. l.ll. Folaad: C. 67.70; H. 1.39. Metllyl~~ter e: .,.ponaw ctiaWlation 150sl60 •c (0.005 mmH1l: (•J 23o +171.1• (t' 1.30. CH01) : IR (CHCI 1) 1750. 1730. 1460, IllS, 1155, 1100. 10.0 em·•; 1H NMR (CDC1 1) I 0.90 (t. l H. J • 6 Hz. CH,CH,), 0.97 (d. 3 H. J • 611&. CH1CHCC), 1.16 (d. l H. J • 6Hz. CHsCHOC),l.SO (q. 1 H. J • 6 Hz. CH,CHCC), 3.34 (a. l H. OCH 1), 3.61 (a. l H. CO,CH,), 4.43 (a. 2 H. c.HsCHl,). 4.57 (d. I H. J • 6 Hz. OCHHO), 4.70 (d. 1 H. J • 611&. OCHHO). 5.31 (b a. 2 H. HC-<:H) • 7.32 (b a. 5 H, c.H,). AM!. Calod f• c.,H,.O,: C. 67.51; H. l.ll. Nud: C, 67 .43; H. 1.21. - , t J<•HS<•Kn 1: t·l<S~So(S(S)-(....._,. ....lllw&J)-6(5)-~2(·) ....., • .,,a..,t)-2(S) .....J*• To allirnd IOf•tion oll40 ma (0.30 aanoi) ol tile .UyiiiW 5 aaL f!ll uyl .....te ......... 0.1 ID1. f!IIJ.ancy ..,.,_,.lair. "ill .....aarc..., . ,..._ ••ne, . . . catalyst . . , . . . .." NKtiCIII miature wultimd at roc.n J • , r. 3 11. n. c:ataJyst wu IMft ,._... .., Rltratiaa ud ...... witJI w. 5-aL ,..... o( etllyl - .• . ne CIOIDbiDed fUt.ra. . " " a.a~Dtra_. ...., ,....._. ,... --. ud ~y f!lldle ....ati111 ,..._ • 101 f!lllilica pi 110 l004 J. Aa Oal. S«.. Vol. IOJ, No. 1, IHJ lrelall n Ill. . . . 15~ . , . ..... ia ............... 120 . . (1,.) fldll •tantld .-yt~~~r. ...,anU.. 6KillaU. 1»-160 -<: (O.GD5 ..,)-6($~2(·)---, • . ,••, ... 2($~ ~1): [e)•D +3.4• (t 0.13. CHC1,): Ill (010,) 1'730, .... (52). J, 1M,......,. dllcrilllll ...._ Ut . . (0.30 __,) fll 1-. UIO. 1100. ICMO ma-t; 1H NMil (CDCI,) I 0.93 (t, 3 H. I• 6 HI. CB,ata). 0 ... (d. 3 H. I • 6 Hz. CH,cHCC), 1.20 (d. J H. I • 6 HI. CH,cHOC), 3.31 (a. 3 H. OCH 1). 3.69 (a. 3 H. CC¥:11,). 4.4J <'a. 3 H. CJI,cHs). 4.51 (~a. 2 H. OCH,O), 7.30 (It a. 5 H. CJis). MIL Calad f• C..MA: C. 67.22; H. 1.61. ra..d: C. 67.46: H. 1.67. _,.. J<aHS<SKakcalkzt J(S~s-(5(.1)-(......,_ _.,._.,~S)-~2(a)-. . . ...,...,.).J(S) ...., . , ..,...,. £1111r, ly tM ~ clllc:rilllld ....... )eO . . (0.74 ~) fll .a~tyl . . , 51 ia a1. flluJI . . . . . witll G.l fllaa., 8icbl cawytt ~, all'ardld. aA. ._...,..., • 30 1 fll 1i1ica pi witla ~ cdlyl .-a~a ill ,.,....... ldllr, lOO . . (IK) fll ..... ,.,.,.... .a~tyl~~&er. ...,....,"'- diltillau. 1»-160 (0.005 s o. .t. •c -.Ha): (a) 21D +19.3• (e 0.56. CH01); Ill (CHC11) 1745, 1730. 1460, UU. 1210, 1140. 1105, 1030 c:m·•: 1H NMJl (CDC1 1) I 0.93 (L 3 H. J • 6 Hz. CH,CH 1). 0.97 (d. 3 H. J • 6 Hz. CH,CHCC), 1.12 (d., 3 H. J • 6 Hz. CH,CHOC). 3.30 (a. 3 H. OCH 1), 3.63 (a. 3 H. co,cH 1), 4.40 <'a. 2 H. CJI,CH,), 4.57 (b a. 2 H. OCH,O), 7.lO (a. J H. CJf,). Aal. C'alat , . c.H.O,: 67.ll; H. 1.61. '--1: 67.23: H. 1.69. ....,. 2(S)-(5(a).C.kaadM:K)·J(S,_....,..~(5(S)-(...._,. _.,.lany)-6(S)---I-2(a)-..._,....,..,.).2(S) ....., • • ._,.,_,. Edllr. ly tM aamc bydfOIIUUaa,.,.....,., 161 me (0.36 amol) filM ..U.yl ...., • ia ' lft1. fllldllr . . . . . witll 0.1 . . fll ltancy llicbl caWylt ........., all'ardld. .,__ ._.....,..,- 20 1 flllilica pi witla I ' ' ctlayl acau.aa q I t •• 150 1D1 (1,_.) fll tM •hinted met~ayl ....,: ...,....tiw cliltillaU. 1»-160 (0.005 ~); (a),.D +3.$• (e 1.255, CHC1 1); Ill (CHC1 1) 1730. 1460, 1310, 1110. ICMO c:~n·•; 1H NMil (CDCI1) '0.93 (1. 3 H. J • 6Hz. CH,cHs), 0.95 (d. 3 H. J • 6 Hz. CH1CHCC), 1.17 (d. 3 H. J • 6 Hz. CH1CHOC). 3.33 (a. 3 H. OCH,), 3.70 (a. 3 H. ~ 1 ), 4.47 (It a. 2 H. c.H,CH2), 4.59 (It a. 2 H. OCHtC}). 7.33 (It a. J H. CJf,). Aaal. CaJad f• C.H.O,: C. 67 .ll; H. 1.61. Foud: C. 67.02: H. 1.69. 2(S)-(5(S).cart I .... ,.J(S,.....,..~(5(S)-(.....,. _..y~an,>-6<S>·..Gyl-1(a) ...,..,....,,.,,,.1(S) ...,..,• • ,_.,...-,1 Edllr. ly tiM abowc procedure, 494 me (1.07 anal) flltlll ..U.yl ~ ., ia I lllL ol ethyl ...... witlt 0.3 aL fll lla.., .... ca&aJya ....,...._, aii'CII"CW. af._ 40 1 flllilica pi willa • etltyl acaate-cyeloMu-. 420 IDI (15') ol tlae auana.d .-llyl-.cr. ..aparaU..cliiUUatiaaU0-160 •c (0.005 .-Jia); [a} 11D +33.o- (e 1.03. CHC1 1); Ill (CHCJ1) 1750, 1730. 1460. U90, 1110, ICMO c:m· 1; 1H NMil (CDCI 1) '0.90 (L 3 H. J • 6 Hz. CH1CHs), 0.94 (d. 3 H. J • 6Hz. CH1CHCC). 1.12 (d. 3 H. J • 6Hz. CH1CHOC). 2.39 (q, I H. J • 6 Hz. CH,CHCC), 3.32 (a. 3 H. OCH 1), 3.67 (a. 3 H. C<¥:H 1), 4.•7 (b a. 2 H. c.H,CH1), 4.60 (It a. 2 H. OCH,O), 7.33 (It a. 5 H. c.H1) . Aaal. CaJad for CJI.P,: C, 67 .22; H. 1.61. Foud: C. 67.31 ; H. 1.72. -,e 1(a)-{5(a)-F..,._J(S~5-(5(S)-( 1 a;uudlslway)-6(S,___I-2(•) ....., • .,,..,a)-1(S)·.....t*•YI,_,. f.llllr (54). To a Gin"ed laiutian flllOO 1D1 (O.llaiiDOi) fll the atllmed mcdlyl •tcr from tM • • 5I in 211ll. ol dry .W uder arp at-11 •c wu added dropwilc CMr 1oIIIia o.7 lllL o1 a 1 M 1aaue laiutioD fll diiaobuty&aJumiaum laydride. All« I L tM r..a.a. IDiauare wu cautioualy u.a.d with 0.1 a1. fll..o..ao&. .uo..d to wvm to ,.... lallpcrature. ud then dilua.d with30 Ill!. fllltMr. nil lai•U. wu wM.bld with *- l~llll. panaa. fllalllna.d aq-.lllltiluD &anuaiC ud 10 Ill!. olauaraa.d.queoua NaC1 ud dlea (M,S04 ). Allar ....a! ol 1M lliMDt ...., rldUCIId .,._,.., fll tiM l'lllidliC .- 10 1 fllllilica pi willa ~ dyl ..we ia peua6auD .._ P" 90 me <96') o1 alddaY* 54: ... cliltillaU. 150-160 •c (0.005 asmH1): (a),.D +6.2• (t 1.015, CHC11); Ill (CHC1 1) 173$, 1 1460, 1315. 1110. ICMO em·•; H NMR (CDC1 1) I 0.93 (L 3 H. J • 6 Hz. CH,CH 1). 0.94 (d. 3 H. J • 6 Hz. CH,CHCC), 1.17 (d. 3 H. J • 6Hz. CH,CHOC). 3.33 (a. 3 H. OCH 1), ...... (Ita. 2 H. C,.H,cHs), UO (It a. l H. OCHz()). 7.33 (It a. J H. CJf,), 9 ..57 (a. I H. CHO). AMI. CaJad for CJI,.O.: C. 69.10; H. 1.11. Faud: C. 6t.06; H. 1.71. _,.1(.H5(S)-F..,._l(S......,._~(5(S)-(z 1: s=-slw_,)~S,__..,..2(.)-..Ut*Wf7'•si)-2(S) ....., • .,.,.,_,. ..._(55). ly &M procedure dlac:riltld abcM. 206., (0.4-t DIIDOI) fll tM .......... ~- f'raallllltllyl . . . 51 ia 4 aL fllcky . . wida 1.4 Ill!. fll 1 M IOhaU. fll cliilotMatylaJ..U.... llydride ia ....._ af. larded..,__ dlrama...,..y • 20 1 flllilica Ill wiiJa ~ ay~.-... • ,.,..m U.. 190 me (9K) ol &M aJdMydl 55: .w~&tiaa 150-160 (0.005 -'Ia); [aJ,.D +JO.,. (t 0.95. CHC11); Ill (CH01) I 0.92 (L 3 H. J • 6 Hz. CH,cH,), 3.32 (a. 3 H. OCH 1), 4.41 (It a. 2 H. CJI,CHs). 4.59 (It a. 2 H. OCHtC)), 7.30 <'a. 5 H. c.H,), 9.67 (a. 1 H. CHO). ~. Calal t. c.H.O.: C. 69.10; H. 1.11. Foud: 69.11; H. l .tt. c. c. •c -,I c:lnma......., • ** .._..,.,..y * •c c. ,....u.. ...,...u.. ._,. 2CSH5(a)-F_,..l(S......,._J.(5(S)-(r 1 .,...., ... .......... ...,._,....__..,._ • • , . . fii.,.U.widt O.t a fill M .,... flldiilaiMatytatuaina ~ iii ...._ al· . . . . . . . . . _ _ ...y •lO 1 flllilica fll ilq I ' •• 120 . . (9~)flltM_...,.SI: .....,.u.eclilaiiJia 1.160-<: (o.oo5 .-Ha); (e) 21D +II.,_ (e 1.55, 010,): II. (CH01) 1730, 1460, 1390, 1100. ICMO c.·•: 1H NMil (CDCI1) I 0.93 (t. 3 H. I • 6 lb. CH,CH 2), 0.93 (d., 3 H. I • 6Hz. CH,cHCC), 1.17 (d. 3 H. J • 6 Hz. CH,CHOC), 3.33 (a. J H. OCH,), 4.47 (~ a. 2 H. c.H1CHs), 4.60 (It a. 2 H. OCH,O), 7.33 (It a. S H. CJI1), t.60 (a. I H. CHO). ~- Calalf• c.H.O.: C. 69.10; H. 1.11. Faud: C. 69.GI; H. 1.73. - , . 2CSH5(S)-F_,..l(S.,._.,..~(5(S)-(adM:af . . .Siw_,~s).....,._1(a)-~)·2(S) ...,.., • .,.,,.._,1 ldllr (SJ). ly tM procedare dacriltld aliaiN. 407 IDI (0.11 aunoi) ol .......... IDUyt- " - ~--., iD 5 aL olcky-- witla 2.7 .t. fll I W lai•U. f11 diilotlutylaJu.mialllll laydrida ia lilaaM af. fatdld. afw .........,...., ._ 30 I ol ai1ica fll wida ~ ltltyiUNte Ia q I ' •• 363 1111 (95~) oi&M Udellyde SJ: ..apantiw cliaWiatian 150-160 •c (0.005 IIIIBH&); [•J 11D +50.1• (e 1.00. CH01): lit. (CHCI,) 1735, 1460, 1310. 1110. ICMO c.·•: 1H NMil (CDCl 1 ) I 0.90 (t. 3 H. J • 6Hz. CH,CH 1), 0.94 (d. 3 H. J • 6 Hz. CH,CHCC), 1.12 (d, 3 H. J • 6 Hz. CH1CHOC), 2.33 (q, I H. J • 6 Hz. CH,CHCC), 3.30 (1. 3 H. OCH,), U6 (b a. 2 H. c.tl,cHJ), 4.57 (It a. 2 H. OCHz()). 7.JO (It a. S H. C,.H,), 9.67 (a. I H. CHO). AMI. Calal f• CJI,.O.: C, 69.10; H. 1.11. Foud: C. 69.06; H. 1.10. a-yt 2(aH5(S)-vt.,i-J(S,_....,I-~(5(S)-( ll , . . ., .... _,~S,......,I-2(a) ......,• .,,_,1)·2($) .....,.wfayl...,_ ldllr. To a llined laiatiaa ol 161 me (0.45 aunol) ol mcthyhri· pllatytJ t i•m ..._.. ia 1 aL fllcky THf at -71 uder arp wu added 0.115 Ill!. (0.•3 . . . .) fila 2.3 M laiutica ol •lllnyllithium iii-... Coaliq wu dlea ......... ud &M r.ctiaa llllature wu llirnd at,.... I.IIDplnaart for 1 Ia ud ta.a ·CIIIOied to -71 •c. A laiutioa oliO 1D1 (0.11 . . - ) fll 1M aldellyde 54 ia I aL ol dry THF wu added ud the r.ctiaa -...,. .uow-1 to..,. to roam .....,_.. atn, aiW 10 b. 1M~ milan,.. u.tld witll I Ill!. fll•uaraa.d ....-. NaHCO,. dihaa.d wit1140 aL olldllr• ...-.t witla 20 Ill!. fll lllllrUid ..__. NaHCO, ud 20 aL fllaUII'UIIII ........ NaCl. ud t111tt dried (M,S04 ). a.a-aJ fll the IOhau at,......_ ......,. ud ._topaphy fll • l"'liduu • 10 a flllilica fll with ft uyt.-... ia ~ .ucr atrcwded "" 1D1 (WI) fll &M adduct: ..aparatift cliatillatioe 140-150 •c (0.005 IIUDHI); (a)•D -2.1• (t UM, CHCJ,); Ill (CHCI 1) 1•10, 1390, 1110, ICMO em·•: 1H NMil (CDC1 1) I 0.92 (L l H. J • 6 Hz. CH1CH 1), 0.93 (d. 3 H. J • 6 Hz. CH,CHCC), 1.13 (d. 3 H. J • 6Hz. CH,CHOC), 3.31 (a. 3 H. OCH,), 4.4-t (b s. 2 H. c.H,CH1). 4.51 (It a. 2 H. OCHtC)), 4.96 (dd, I H. J • 3. 11 Hz. HC-<:HH(c)), 5.19 (cld. I H. J • 3, II Hz. CH-<:HH(t)), 5.17 (dd, J • II, II Hz. HC-<:H 2), 7.31 (It a. 5 H. c.Hs>· Aaal. CaJcd for C.H.O,: C, 72.19; H. 9.32. fouad: C, 72.11: H. 9.20. wida-..,. .-... s· •c a.u,1 J<•H5(•>-~J<S)~t-(5(Sl·<adln,....,._. _,.)-6(S,.....,..2(.)·~1)·1(S)·......,..,.,t,_,l f.llllr, By tiM ptOC*iure delcribed abcwc, 110 IDS (0.41 aunol) of tbc aAdebydc 55 iD 4 lllL ol dry THF with 0.15 ~ ol IDithylcnctri· peaylpbalpOoraac atrorded. after daromalCIIJ'Iphy .- lO 1 ollilica pi ~It, ctllylaoaate ia ~ether. 160 ma (IK) of tJac adduc:t: ...,...tiYC distillation 140-150 •c (0.005 aunH1): (aJ•D +42.1• (e 0.96, CHC1 1) ; Ill (CHC1 1) 1460, 1310. 1100, 1030 em·•: 1H NMR (CDC1 1) I 0.93 (L 3 H. J • 6 Hz. CH1CH,). 0.97 (d. 3 H. J • 6 Hz. CH,cHCC), 1.20 (d. 3 H. J • 6Hz. CH,CHOC), 3.33 (a. 3 H. OCH 1). 4.4-t (It a. l H. c.H,CHz), 4.59 (b a. 2 H. OCHz()), 5.00 (dd. I H. J • 3, II Hz. HC~(c)). 5.13 (cld. 1 H. J • 3, 11 Hz. HC-<:HH(t)). U7 (dd. I H. J • 11, 11 Hz. HC-<:Hs). 7.30 (b s. 5 H. C:.H,). Al&al. CaJcd for C.,H.O,: C. 72.19; H. 9.32. Found: C, 72.01 ; H. 9.20. - , t 1(S)-(5(S)·vt.,i-l(S)-....,...~(S(S)-(_.a,...,._. _,~S)---1-l(a )-t~«ruy*...Yn811l·1(S)~,_,I ldllr. ly the procedure delc:ribed abowc. 109.5ma (0.25 auDOI) oi the aldMydc 52 iD 2 aL fll dry THF willa 0.57 aunoi oiiDCttlylcactri· ,._,.~ atrCII"CW. after cllraalatopaphy oa I 0 1 ollilica p.l wit1l ~ethyl . - ... ia qcia' ••· 90 ma (13') fll &M adduct: ...,....tiw diltillaU. 140-150 •c (0.005 mmH1): (aJuD +2.1• (c 0.905, CHC1 1); Ill (CHC11) 1460, 1310, 1205. 1110, ICMO c:m·•: 1H NNil (CDC1 1) I 0.93 (t. 3 H. J • 6 Hz. CH1CH 1). 0.93 (d, 3 H. J • 6Hz. CH,CHCC), 1.1• (d. 3 H. J • 6Hz. CH1CHOC), 3.33 (a. 3 H. OCH 1). 4.4-t (It a. 2 H. c.H,CHs), 4.61 (~a. 2 H. OCHz()), 4.93 (dd. I H. J • 3, II Hz. HC-<:HH(c)), 5.13 (dd. I ... J • 3. II Hz. Hc:-cHH(t)), 5.90 (dd. 1 H. J • 11, 11 Hz. HC-<:H 2), 7.33 (It a. 5 H. c.H,). AMI. Calalf• C.H.01: C. 72.19; H. 9.32. Fond: C. 72.10; H. 9.29. 111 1. b1. 0... S«.• Vol. lOS, No. 1, IHJ 200S ToM/ S~'-11 of/IMIIfllton ~ _,.. 2(SH5(a)·Villri-J(S,._..,..S.(S(S).( , .,.....,... -r)-'CS)_...,..2(.,._..,.n,.n.,,)-2(S,.._.., • .,.,.,_,. r.a.. lytlle .......... dllcriblda..._lS3.4 . . (0.11_.)fldll aldiiiY* 53 ill 5 aL fll dry THF _ . 1.'72 _.. fll ~ all'..._ after~. . . . a.lO 1 flliliGa ... witJa "ellayl aCIIIaU ia q:'a' · • 310 . . (II~) fll U. 81111111:1: ...panu.. dil&iUatioa 140-JSO •c (O.oo5 -.lfc); l•J~ +SJ.•• (t 0.97, CHC1 1); JJ. (CHC1) I~ 1310. 1100. IOJO c. ; 1H NNa (CDC11) I 0.91 (L. 3 H. J • 6 Hz. CH,CHa). O.N (d. 3 H. J • 6 Hz. CH,CHCC). J.lD (d. 3 H. J • 6 HI. CH,CHOC). 3.32 (a. 3 H. OCH,). 4 .41 (b a. l H. C,JI,CHa). 4.59 (b a. 1 H. OCHs()), 5.G2 (dd. I H. J • J. 10 HI. Ho-c.HH(c)). 5.lD (cld. I H. J • 3. II HI. Hc-at.R(t)), 5.17 (cld. I H. J • 10, II Hz. HO-CHa), 7.32 (b a. 5 H. c:.Hs). Mal Caicld for CaJI.C),: C. 72.19; H. 9.32. foud: C. '72.26; H. US. _,.. 2<•HS<•)·ra,t-3(S,._..,..S.(5(SH_.,a;audi;lwo ,._,.pbcllpllar&M _,)-'CS)·..-,~2(.)_.....,~)·2(S)·.._.,•.,.,~ a.. By the procedure Mcribld for the b.,clraputiae ol-. • 55 . . (0.13 IIUIIGI) ol 1M 8ddua aldeltyde S. iD l aL olldlyl.-... witJa 0.05 lll1. ol llaMy ai:UI caul)'lt . . , . . . . , all'..._ after *-UIIfapily 011 10 1 ollilica pi with" edayi acecate ia pltJ'CIIIum . - . 49.5 1111 (9011) olthe abU'al8d CCIIIIJIGI&IId: ..apaniM diltillatiae 1«)-UO •c (0.0051111ftHa): (•) 21D +14.CJ'I (t0.97, CHC,); IR (CHC1) 1460. 1310, 1100. 1035 em·•; 1H NMR (Cl)(:J 1) I l.lD (d. 3 H. J • 6 Hz. CH,CHOC). 3.33 (a. 3 H. OCH 1), 4-'2 <' a.1 H. c.JitCifa), 4.61 <'a. l H. OCHz()). 7.33 (b a. 5 H. c:.Hs)· AMI. Caicld (or c.HaO,: C, 71.15; H. 9.74. faud: C, 71.11; H. 9.74. ma llayt 2<•H5(S)-~3(S,....._S.(5(S).(•Ika;audi;lwo ftl)-'CS)....,..l(.,.._...,~)·l(S)-....,..,_,.,._,. ldllr. By the pi"Cadwe cMic:ribld for 1M llydropaatiae o1 . . . • 141 . . (0.33 mmal) ol 1M lldduel framaidltlyde 55 ill 3 mi. ol ayt ...... witJa 0.1 111L ollt.aaey llicbl ca&alyst ll&lpCDiiaa, all'orcled. after c:tu. __..piy on 15 1 ollilica pi with" cbyi _ ... ill ......... .._, 130 1111 (92') of tJM anaral.lld caaqiOUd: ..apant.M diaillatioll 140-150 •c (0.005 aunHa): (a) 21D +14.3• (C' 0.955, CHCI 1): IR (CH· 0 1) 1460. IllS. 1105, 10.0 em- 1; 1H NMR (CDC1 1) I 1.20 (d. 3 H. J • 6Hz. CH,CHOC), 3.33 (a.3 H. OCH 1), 4.43 <'a. 2 H. C,JI,CH2), 4.60 (b a. l H. OCHz()). 7.30 (b a. 5 H. CJ1 1). Aul. Caicld for C.H.JO,: C. 71.15; H. 9.74. Foud: C. 71.11; H. 9.11. llayt l(SHS<• )-l:aJ~l(S)_...,..5-(5(S)-(_.,a;•di;tw­ _,)-6(S)_..-,I-l(•)·...,..,..,..._,l)·l(S)·......,..,.,.,_,. ra.. By the prcDdurc cMic:ribld for the llydrapaation ol.- e. 77.4 . . (0.11 IDiftDi) ol 1M ldduct !ram aldeltydc 52 ill3 mi. olldlyl.-.1e wi\h 0.1 mL ol Raney lli:Ui ca&alys& ....,...._, all'orcled, alter ctar. . .CGifapby oa I0 1 ollilica pi with " etJtyl acecate ia eydo'w•• 65 1111 <14') ol tba atwal.lld Clllllpouad: ~Wapanti¥e diatillatioa 140-150 •c (0.005 IDIDHa); (a)uD +l7.CJ'I (c 1.565, CHCI 1); Ill (CH· Cl1) 1460, 1310. 1210, 1110. 10.0 em-•; 1H NMR (CDC1 1) I 1.17 (d. 3 H. J • 6 Hz. CH,CHOC), 3.33 (a. 3 H. OCH,), 4 ...- (b a. 1 H. c,)i,CHJ). 4..57 (b a.l H. OCHP). 7.33 <' .. 5 H. c:.H,). Aal. Calad for c_a.p,: C. 71.1.5; H. 9.74. Foud: C, 71.61; H. 9.51. t.zyl l(S)-i5(S)·ra,l· l(S)~~(5(S)o(•diea;MdiJiw­ ny)-6(S)_..-,I-l(. )·...,.,..,...,l)·l(S)-........,..,_,.,._,. U.. By tbc prcx:.dwe dllcribld for 1M h~tioa ol...., • 300 1111 (0.69 aunol) ol the adduct m.n aldellyde 53 ill 5 mi. ol.cllyt . . . . . with 0.1 mL ol Raney ai:kcl cawya ....,..._, all'orded. after :II» . .lCIIJ'Ipby oa 25 1 ollilica pi witJa ' ' cdtyll&lltat.c ill cyclobaaac, 270 1111 (tot,) or tJM uuaral8d Clllllpaud: ...panaw. diatillatioa 140-150 •c (0.005 IIIIDH&); (a)•D +li.J• (c 1.03, CHC1); IJt (CHC 1) 1460, 1390, 1100. ICMO cm-1; 1H NMR (CDC1 1) I 0.12. 0.90 (lL. 6 H. J • 6 Hz. CH1CHa), O.N (d. 3 H. J • 6 Hz. CH,CHCC), 1.11 (d. 3 H. J • 6 Hz. CH,CHOC), 3.32 (a. 3 H. OCH 1), 4.46 (b a. 1 H. c,)i,cHa). 4-'9 (It a.l H. OCHp), 7.lO (b a. 5 H. c:.H 1) . AaL Calad for CaJf.,05: C, 71.1.5: H. 9.74. Foud: C. 71.11: H. 9.59. a.EYI 2(. )-(5(• )·!Gyi-)(S)...ayi-5-(5(S)·.,*-*Y-6<S)~l(•) .......... ;*CfJ'WJI)-l(S~ Edilr (5'7). By the procildwe clelcribld for 1M ,...,.,.. ol 1M ak:ollolll. 40 1111 (0.09 aunol) ol 1M mcthoi)'IDQyl.u.r from alddaydc S. ia 3 mi. ol THF ud 0.75 mi. o/10115 aq-- HC aft'anW. att. .,......_., oa 7 1 ollili:a pi wi\h 15~ ellayl -.&e iD ,.,.... ellaer. 35 1111 <'"l o1 u. aJco~ao~ ..apantn. cliltiUa&ioll 140-t.so (o.oo5 ~a); (•) 21 D + 1 (c 0.93, CHO,); IJt (CHC1,) 3620. l4.50, 1460. 1310. 1100. 1070 c:.-1; 1H NMR (CDC11) I 1.14 (d. 3 H. J • 6Hz. . CH,CHOC). 4.44 (a.1 H. c,)itCifa). 7.31 (b a. 5 H. CJ11). Aal. Caicld for c.H,.O.: C. 73.11; H. 9.11. foud: C. 73.79; H. 9.70. n: u• •c .._,. 2(. )-(5(S)-~)(S).....,._~(5(S)..,._,-6(S)· ...,._l(.)......,..,.,..)-2(S,_....., • .,.,~,IIdllr (.). 1J 1M pi'OQIII1arc dll:ribld for till ......,.... ol 1M alciDMill. 120 . . (0.21 -.1) ol u. . . .,....,, . . . ,.,........,.55 ill 4 .aL fl THF ud I .aL ti10S . . . . - HO all'ardld. after._........, a. 101 ollilica ... widl ~ dyl - . u ia ......... .U., lOS . . ~l flltM ..... •: ...pana.. diltillatioa •••.so ec <o.oo.s -.Jia); (•)210 +9.,. (1'0.96. CHC,); Ill (CHC1) »10. l4SO. 1~ 1310. I lOS. 1070 -·•: 1H NMil (CDO,) I O.M (d. 3 H. J • 6 Hz. CH,CHCC). 1.17 (d. l H. J • 6 Hz. CH,cHOC). 4.41 (a. 2 H. CJftCif,). 7.32 <' .. ' H. Aal. Calad ,_ c.H.O.: 13.11: H. 9.11. foud: C. 73.91; H. 9.73. c. c:.as>. ._,. 2(S)-{5(• )·'*fi-J(S)·_.,I-5-(5(S)·.,.._,-6<S)· ...,._l(.).....,.J•ifJIWft)·l(S~ Edilr (16). ly 1M praDIIbarc cMic:rit.d for 1M pnparatioa ol 1M akiDMI ll. 54.1 . . (0.13 ...,&) fll tM --ymldlylellaer (ram . . . ., . 52 ill4 mi. fiTHf ud I .aL tllK ~~~- HCI all'ardld. al&er ._lOif'lpily - 10 I ollilica ... with ~ llllyl ..... 'C) 45 1111 (9~) flu. a~aD~ao~M: ...,..u.. diatillaliall 140-I.SO •c (o.oo.s ~~~~nH1>: (•J»D +19.1• (c 1.0. CH01); IJt (CHC,) l650. )450, 1460, 1310. 1100, I t ... 1070 --•: 1H NMR (CDC11) I 1.17 (d. 3 H. J • 6Hz. CH1CHOC). 4.41 (a. l H. c:.H,CH1). 7.33 (b a. 5 H. c.JI,). Aul. Cak:d for c,.H,.O.: C. 73.11: H. 9.11. foud: C. 73.71: H. 9.72. a.zyt 2(S)-(5(S )·Edlyi·J(S )·..-,1-5-(S(S ).,,. .sy-6(S )...,_l(.)·.....,..,..._,t).J(S)-.......,....,., Edler (1). ly 1M ~ cMic:ribld for \he preparation ol 1M aJcDbat ll. 265 1111 (0.62 ....,.) o1 1M metboaymctJlyl cUMir from alddly.k 53 ill I mL of 1Hf ud l aL oliO!. aq-- HCI all'orcled. alter :llromatop'lpily oa 20 1 ollilica pi witJa 2.5~ .cllyl .-.u ia llller, 240 llll u~> ott~ae a~aoDa~ ' · ne ..-ua• :Mract.cril&ic:l or \his •teriaJ . . . -.ucal wi\h tt.a ol tM aiDDMI dlrMd !ram ol luaJo:id A. ..,..Ill ..,_tioa llayl l(S)i5(S)o._..3(S,._.,..S.(6(S,._..~S....2(•)· ....,., • .,,,.,l).J(S~ Edllr (59). To altU'Ted . . .ti011 ol 0.06 IIIL ol ou!yl ='Iorick (0.69 mmal) ia 2 lllL ol dry ~ ac10 •c uder arp ... lddld 0.11 lft1. (1 ..55 11111101) ol clilnedlyl all'oaide. Alter 10 min. a o/240 1111 (0.61 mmol) fll tlae ~ 1 ia 1.5 mi. ol dry di:lllorolnetlla• wu added to tile r.ctioa llliaaan. Alter I 5 .u.a. tJM ,.c:tioa llliatun wu u.ted with 0.44 mi. (3.16 aunol) ol dry lrietllyla~Diat. allowed to warm to room c.Dperat111'1, aad thea clil•l8d wi\h 40 mi. ol ctber. nilllliaturc wu wuMd wi\h 15 mi. olwaw. 1.5 mi. olahlr'&t.lld ......- NaHCO,. ud IS mL olatanl8d . . . - NaCI. ud tbat dried (Mpo.). Rancwal til 1M IOMau at Nduced .......,.. ud dlromatop'lpily ol the Niduc 011 20 1 ollilica pi with I Of. llllyl .-ate ill CJdolta,ue alf'orded 125 . . (94-.) oltbl UtoDe tt: ..apanu.e cliltillat.ion 1•130 •c (0.00.5 _..tioa IDIIlHa): [•J•D -5.9• (c 0.95, CHCI 1): IR (CHC1 1) 1720, 1460. 1310, 1110 em-•: 1H NMR (CDC1 1) I 1.l1 (d. 3 H. J • 6 Hz. CH,CHOC), 4.30 (q, 1 H. J • 6Hz. CHCO), 4 ...- (a.l H. c.H,CHa), 7.33 (b a. 5 H. CJis). Aul. Caicld for C,.Ha.O•: C. 74.19; H. 9.34. Foud: C. 74.02; H. 9.35. - , . . 2(S)-i5(S).ra,t-3(S)_...,..5-(6(S,._.,..5 _..,...,_ By tbc proCIIdurc "-aibld for the preparation ol 1M lddu:t ol aldellyde S..ll4.5 1111 (0.55 aunol) ol the ketOM 5t ill 4 mL ol dry THF wi\h I .31 aunol ol medl~yl......... aft'ardecl. alter c:llroawtop'lpby 01120 I ollilic:a phrit114' llbylac:Nte iD C) I "M 200 1111 (94-.,) ol the CIII1Wpanclilll a01Mlhy6eec oidia: ..apancm diltillation 1~ 130 •c 2(·)~1)-l(S.......,...,_,.,_,. Edllr. t (0.005 mmHa): (a))ID +7 .~ (c 1.~. CHC1 1); IR (CHCJ,) 1460. 1310, 1120, 1010 em-•: 1H NMR (CDCI 1) I 0.13, 0.93 (1t. 6 H. J • 6 Hz. CH1CH 1). 0.97 (d. 3 H. J • 6Hz. CH,CHCC), 1.30 (d. 3 H. J • 6Hz. CH1CHOC), 4.43 (q, I H. J • 6 Hz. CHC-<:). 4.47 (a. 2 H • c,)i,cHt), 4.67 (b a. l H. c-cHt), 7.3 I (b a. 5 H. c.Hi). AMI. Calcd for C 13H 110 1: C. 77.61: H, 9.91. Foud: C, 77.64: H. 10.03. .._,. l(S)-{5(S)·E"YI·l(S)·.-Gyl-5-(3(• H.5-41ea.-.(S)· Mdi; ....•P-st6(• ~)-2(S.......,...,_,..,_,.. Edllr (61). To allirnd aulioa of 1911111 (0.49 aunol) ol the abcM olefin ill 5 mL of ~ added 160 1111 <1.9 aunoi) fiiOlicl NaHC01 ud 160 1111 (0.74-0.13 mmol) or~~ ~acid . CoaUq wu dw:D di~~Dttin'*- and 1M~ lllisuarc WMitirftd at raalll Wll\plrature (or 3 ~ Alter U.UDCnt or tllil rnillturc with l mL oiiK aq..au Na,SO,. the r.ultiD& llliaturc wu diluted witJa 60 lll1. ol .ocr. wuMd with two »mL portions ol uturated ....,_ NaHCO, ud liO mi. ol aaual.lld aq-- NaCJ. and thin dried (Mpo.). RIIDOftl ol 1M IOMIIta ud dlroma&alfapby or tile residue • 20 1 ollilica pi with 10115 edlyi~C~et&te ia petroleum ct.ber afforded J41 . . ol 1M cpoaide 61 ud 40 1111 ol tM cpiiDeric: ..,oxide (ratio of 3.5:1 ol "~ Clllllbiaed yield). Epaide . . ..apantiw distillation IJCH40 •c (0.005 mmHa); (a]•o -4.4• (c 1.03, CHC1 1): IR (CHCJ1) 1•. 1310, 1120. 1010 :m-1; 1H NMil (CDCI 1 ) I 0.16, 0.93 (2t. 6 H. J • 6Hz. CH,CH 1). 0.97 (d. 3 H. J • 6Hz. CH,CHCC). 1.27 (d. 3 H. J • 6 Hz. CH,CHOC), 2.51 (d. I H. J • 4 Hz. CCHHO). 1..59 (d, I H. J • 4Hz. CCHHO), 4.47 (a. 2 H. C.H,CHa). 7.33 (b a. S H. CJfs>· .u.J. Calad for Czslt.O.: C. 74..59; H. 9.5 I. Foud: C. 74..50: H. 9.46. Epi .side . . .,.pantn. diiUllation 13CH40 •c (0.005 ..He): (a]•o +7.1• (c 1.01. CHC1 1); ~ (CHCI 1) 1•. 1310, 1120, *" ., o•c.....,.,.. ... 112 J. Alft. Oat. S«. ltll, JOj, 2006-2009 2006 'CLI6. O.fl (21. 6 H. J • 6 Ha. CB,afJ). 0.97 (d. l H. J • 6 HI. CB,c:HCC). l~ (d. 3 H. J • 6 IlL 1_, c:.-t: 1H NNR (c:nc::J.) CH,cHOC), ~ (d. l H. J • 5 HI. CCHBO). 2.71 (d. I H. J • S HI. ...., fll . . . . . . . . . 3 aL flldry flrt' " " ~ 10 . . (0.12 . . ., ol...,._ IIIIi.......... Ill . . (0.62 . . . ., f/1 rJiidii:Yea ~ aft'ordld..,.. . _. . ...,- 10. ol CCHHO), • .• '7 (1, 2 H. c.H,cHJ). 7.JI <'I, 5 H. c.Ht). Mil. Calld r. CJI.O.: C. 7•.St: H. t .SI. Fault: C. 7•.Jt: H. t.J6. - , 1 2C5H5(5)-~3(5......,._5-(J<•)·•••,u •s•=t+ (5~~(·)-......,...,.).2(5~ U . (5). ly tJM pracllllan dllcribed ror u. ,.,.,.... fll u. .-... .M. llO . . (0.30 auaol) f/1 ............ i8 lal.. flldry..,...... . . . llO . . (U6 .-ai) f/1 aapplr(l) Ill ., u •hJI ........... ad 1.4 aL (3.01 . - ) fll2.2 M ~ ia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 . . (M)fliU......,. 61: ..,_.a..~ 1•1.0 ec (O.OOS -'18); (•JA. -2.5• (e 1.1, CHO,); Ill (CHO,) 3600. )450. 2150. 1120. 1-. lJtO, 1230. IIJ0.-1100. 1CNO. HO c:."1: 1H NMR (CDCI,) ' O.f7 (d. l H. J • 6 IlL CR,CHCC). l.ll (d. l H. J • 6 HI. CH,c:HOC), t ... (d. I H. J • J IlL CHO). MIA. CaW r. c..H..O.: C. 69.~ H. 10.50. .....: c. 69.17; H. 10.... c~na~acopap~ay • to a flllilica,.. ..._. _.. u~..,.-... • ,.,..... - . . 120 . . (90S) f/IU. alooalol5. n. ...... ..... ....... flltlail•tcria1 . . . idiMicalwim .... fllta. . . . . . . . . . lroat . . , . .... flllualocid A. ....,..2(.). . . .J64JI&)l).2(S~l..&. Toa llimd ......_ f/162 . . (0.1t -..1) fll U. UdMyde 61 i8 4 aL ol dry THF at -11 ec ..._.,... wu ..._. 0.12 a1. (0.51 . . .) olu o.a W ...._ ollt.b)'laa..-aua ..._. i8 THF. n. ,_,tiq toiaa&.ioa ........ u o•c cr.&lld wit.ll s a1. fllatwa&8d aq. . . NH.O, ud U.. dihl&8d wiG 25 a1. o1-.. n. orpaic plaua wu ....,.. . . . . . . witJt 10 a1. fll....,.&lld aq_. NH.CJ ud 10 mL fllatwa&8d . . . - NaQ,ud t.ble dried(~.). AltM ,..,.I ol &Ill.._.. at red.- ,_re a.S ._copat*y ol 1M Nidaac 011 10. ollilica ... wit.b .5K-- .............. .u.. tMn . . oblailllld tO., (IK) ola di111 · ..;c mixtv1 olllw w• ; dma ate. .-: .,.panU.. diltillaU. 120-llO •c (0.005 aunHa); IR (CHCI 1) l600,l500, 1460. UIO. 1130. 1100, 1060, HO c:m·•: 1H NMR (CDCI 1) ' l.lO (cl. l H. J • 6 Hz. CH,cHOC). .._......_.a. 2(5).(5(5)·1:..,.1·3(5)·....,..5-(J(.)....,._,..,._,_..S).-,a-2(. )-.....,64Ji..,t)-2(5)........,..,_,.,1-tl. To a llirrad toiiiU. ol 0..5 CiD (l auaol) olli~·· wire ia 10 aL fllaallydrou liqaaicl.....aia at -'71 wu liCidld a_..... ol54 . . (0.13 ....-) ol tJ. IDIIIIDIIIilzyt ..... S ia I aL flldry THF. c.1i11t wu lJaa clilcaetinld (IIIUDIIeia rellu) ud at. 1 ~ 2.50 . . (4.'7 mmol) ol aabydrou ammaeiiUil ~ wu canu..iy ..w.t to U. MClioB mixtnre. n. ~ mixtan wu tJiee cliha&8d witJa lO aL f/1 - - ud llw aaamaaia ... a1Joond to ~ta. n. -.Jt;q -.maiae wu rdt8nd aad t1w IOtid wu ....._. ., U"iaraciaa willa rour JO.ml. paniaal ol cdler. llcmaftJ f/1 U. ...._t at rediiCIIII ..-n fraal llw caaabilllld r.Jua• ud tJiee c:laromacopat*y fllllw Nlid1lll • 10 1 ollilica pi wit.b ~ ttbyiiOIIIta ia ........ .._ atrordad 42 . . (91~)oltMCGII i , .•• diol. TM.,.::uaJ~oltJail •tcriaf . . . idaticaJ wit.b .... fllllill diol clarMd ,.,. ........... ol LuaJocid A. 2(. ).(5(5)·1-1-3(5)·....,._5-(5(. )-edtJI-5-.,._,-6(5)· ~2(•)......,..,.._,1)-2(S~;Awfwtl,...._. (61). ly U.........,. deacribed (or U. oaidaU. f/10. ~ ll. M . . (0~ •c...,.,.... 4(S HS(S)-~)(S)......,._S.(S(• ,....,._,_.,._,_..S )· r. lO-. ~· ).(5(5)-~l(S,_....,I-5-(5(• )....,._,_.,. . .,-6(5 )· ,..,.u. o. ....,. , •. ....,._%(.) ......J64Ji&JI)·2(S~~ (3). ay dllc:ribed r. u. o1 JS . . (O.IO...ol)fliU..-..-..ia I al.oldty~ne wit.b 50 ma (0.%3 aamol) ol Pfridiai.. ~tc af'forcW. after *-topaJ*y Oil 10. f/1 ailica ... wit.b 3.5~ ..... ia pllrokum ct.ber. l U ma (9K) ol till--. 3. n. .,.:traJ ud pily8cal daca oblaiMd OlldUUIGN . . . ..._.wit.bta.aolU.----aM&iMdfram U.,.... &Idol flllualoc:id A (X5l7A). o. .......,. 113 PROPOSI~IORS 114 ABSTRACTS OP PROPOSI~IORS Proposition ~ The design of a new class of suicide enzyme substrates for -lactamases and penicillin sensitive enzymes and general methods for their preparation are proposed. ~L2~2Ai~i2n ~ A systematic study of the effects of electron withdrawing substituents on the rate of the alkoxide accelerated cycloreversion of 1-hydroxy-bicyclo[2.2.21 octadienes and the comparison of these effects with those predicted by a Hucke! Molecular Orbital based model are proposed. Proposition ~ The use of an asymmetric ene reaction to provide access to optically pure tetrahydrothiophenes and the conversion of these compounds into optically pure cyclobutene and cyclobutane derivatives are proposed. Proposition ~ Syntheses of the antibiotic Amipurimycin and its C-6' epimer are proposed. Proposition ~ A suicide substrate for S-Adenosylmethionine decarboxylase is proposed. 115 PROPOSI'!IOR 1. The design of a new class of suicide enzyme substrates . for 6-lactamases and pencillin sensitive enzymes CPSE's>Ctranspeptidases and D,D-carboxypeptidases) and general schemes for their preparation are proposed. RCO 1 Pencillin 1 2 and cephalosporin 2 antibiotics and analogs thereof are medicinally very important. This is due to their ability to inactivate enzymes responsible for cell wall synthesis by irreversibly acylating a specific serine residue in the active sitel (Figure 1>. Unfortunately, many bacteria have acquired a gene which causes the production of an enzyme similar in composition and activity to the PSE's, in which the acylation is now reversible. termed 8-lactamases, These enzymes, hydrolyse the 8-lactam and therefore protect the PSE's from S-lactam antibiotics. of bacteria to become resistant to This ability pencillin and cephalosporins has led to a large amount of work aimed at producing 8-lactamase resistant 8-lactam antibiotics. 116 PIGOllB 1. H More recently, a different approach has come to the fore, spurred on by the isolation of clavalate acid 32. Although a poor antibiotic, clavalate inhibits B-lactamase s (Table 1) 4 and therefore may be used in synergy with conventional B-lactam antibiotics3 (Table 2> 4 • Pencillin sulfone CP-45,8995 4 closely duplicates the action of clavalanate in both inactivating B-lactamases6 and its synergy with other B-lactam antibiotics.' The mechanism of the action of these e-lactamase inhibitors has been studied by KnowlesB who has proposed the following suicide substrate mechanism (Scheme I). 117 '!'able 1. {3 -Lactamase Inhibitory Activity of Sodiua Clavulanate. 1 5o Source of -lactamase Staphylococcus aureus (Russell) ~ ~ ~ ~ JT410 <chromosomally mediated) JT4 CRfactor mediated) Proteus mirabilis C889 Enterobacter cloacae P99 Klebsiella aerogenes NCTC418 Pseudomonas aeryginosa (Sabbath type) Pseudomonas aeryginosa Dalgleish '!'able 2. Substrate g/ml> Benzylpenicillin Cephaloridine Benzylpenicillin Benzylpenicillin Cephaloridine Benzylpenicillin Cephaloridine Benzylpenicillin 0.06 56.00 0.08 .().03 10.00 0.03 160.00 0.10 Effect of sodium clavulanate upon the RICs of ampicillin against producing organis... ~-lactamase MICs ( g/ml) Organisr.t Staphylococcys ayreys (Russell) Staphylococcys aureus (Russell) ~ ~ NCTCl0418 ~~Bll Klebsiella aerogenes A Klebsiella aerogenes sp62 Enterobacter cloacae Serratia marcescens Sodium Clavulanate 15 62 31 62 31 31 62 125 Ar.lpicillin g sodium clavulanate + 1 Ampicillin 500 250 1.8 125 125 125 250 >500 <0.4 7.5 <0.4 <0.4 <0.4 <0.4 62 62 118 SCBEIIB I p X ___.. · . GO Deacylation X (Turnover> nJ J:r • HO,C . "~~· ~ ~ 1 ~;) IRAC'fiVA'.l'BD BRIYIIB ' - " - " :ENZYME SCBBIIB II • Deacylation (Turnover) 119 A second class of 8-lactamase inhibitors are the carbopenams9,10, which are reversible inhibitors. The proposed mechanismlO for these compounds action is shown in Scheme II. A third, totally synthetic class of S-lactamase inhibitors are pencillin analogs where the 6 amino group has been replaced by a good leaving group (i.e.: •bromo•), thus activating C-6 as an alkylating center. Of these three classes of inhibitors, the suicide substrate approach is the most attractive, since it allows for the inactivation of a specific type of enzyme, based on its mode of action. This irreversibility of the inhibition allows the inhibitor to be used less often and often in lower doses. The ideal suicide substrate would not only inactivate 6-lactamases, but also be a good antibiotic. Although the relationship of structure to activity for S-lactam antibiotics and S-lactamase inhibitors hasbeen extensively studied,12 the picture is far from clear. A summary of characteristic structural features of S -lac tam antibiotics and 8-lactamase substrates 5 is given below: Rl n=0,1 1) A S-lactam fused to another ring. This forces the nitrogen from its preferred planar conformation, thus destabilizing the S-lactam are bond. Exceptions to this 120 the nocardicinic acids 613 and monosulfactoms 71 4 ; H RN'r-1 . H~ 7 2) 503 Non-planarity of the 6-lactam ring; If R1 = R'-NH, it must be on the B -face of the lactam as drawn and R' should be an acyl group; 3) 4) 5) R2 must be H or oca 3 ; In cephalosporin& the presence of a good leaving group on the substituent at C3 generally increases its antibacterial activity and its ability to act as a substrate for B-lactamases. This is thought to be due to the further destabilization of the lactam bound due to the electronegativity of the substituent; 6) Extension of the conjugation of the double bond in cephalosporin& should destabilize the lactam bond and thus may increase the activity of the compoundlS; 7) The carboxylate as the free acid. on C-3 of the pencillin must exist In the cephalosporin& it may be lactonized to the C3 hydroxymethyl, if present. Given this data, compounds of the general formulae 8 and 9 appear to be good candidates as 6-lactam antibiotics and/or 6 -lactamase inhibitors. 121 =N-Ts 9 x·=s,o,CHz Both compounds 8 and 9 possess the necessary carboxylate and should not have a planar lactam nitrogen or lactam ring. In the simplest variants X•S and R= acyl N the structure of 9 would be very similar to that of the natural cephalosporin&. Therefore, its binding to the active site should be similar. Compound 9 possess a good leaving group at C-3 that also extends the conjugation of the arB unsaturated ester; therefore, the lactam bond should be doubly activated. This activation should also apply with compound 8 as well. Both 8 and 9 should function as suicide enzyme substrates in a similar manner, as outlined below in Scheme III. SCBEIIE Ill Ts • • 122 The opening of the S-lactam ring would render 8 or 9 susceptible to the irreversible loss of nitrogen and the generation of the C-2/C-3 car bene or the loss of Rso 2 - and the generation of the C-2/C-3 diazo compound. Either of these moieties would then alkylate the enzyme on the active site. This would inhibit the enzyme irreversibly, thus removing it from the active pool. The viability of this approach is indicated in studies with carbapenem 12lO wh~ch is a potent S -lactamase inactivator and by studies on enzymes which have pyridoxal phosphate as a co-factor. Studies on 12 have shown that the product of its enzymatic hydrolysis is 13 with no trace of the double bond isomer 14 being found. This study also determined that the proton at C-2 could be completely exchanged for deuterium by incubation of 13 at neutral PH in o2o. These results indicate that the resonance form of 10 or 11 with the negative charge on the substuent bearing carbon should contribute strongly to the overall character of the molecule, and that the proton at this center in the neutral form is very acidic. An example of increased acidity due to a -N= function is found in the action of pyridoxal phosphate in conjunction with transamines (Scheme IV). 123 SCBBIIB IV • J{;NH 2 As with all compounds with physiological properties, the optimal type of R and X groups would have to be determined by testing. Therefore, the preparation of 8 and 9 will be discussed in general terms. There are many methods to prepare pencillin and cephalosporin analogs. These involve either the incorporation of R into a starting material or the introduction of R at a late stage in the synthesis via the enolate of the B-lactam. For the purposes of this proposal, the latter method of introducing the desired R group would be preferred. This would allow the preparation of compounds with various R groups from an intermediate late in the synthetic scheme. 124 Preparations of compounds of type 15 are reported in the literature for a wide variety of R' and X•O, cs 216,17,18,19,20 by numerous routes. S or These compounds could then be converted into the desired azo derivative by three simple steps (Scheme V). SCBBIIB V a • HNH-Ts 15 Addition of tosyl hydrazine to 1516 followed by elimination of ·oR would give the desired C-3 hydrazine. Air oxidation of the compound followed by deprotection of the acid would then afford the desired azo compounds. 125 Since very little is known concerning the preparation of 2 heterosubstituted penem, the schemes proposed for their preparation do not possess direct precedent in the literature. Again here, it would be best for the purpose of generating numerous structural analogues for testing to introduce R late in the synthesis. For X=O, the desired azo compound could be prepared from S-lactam 16 1 6 (Scheme VI). Treatment of 16 with chlorine in carbon tetrachloride would give the corresponding chloride, which then could be displaced by the carboxylate salt of the half ester of malonic acid to give the ester 17. The ester 17 could then be converted to the 18 by treatment with ao 2 cc 6 a 4 so 2 N3 , then Rh(0Ac> 2 • 19 Compound 18 could then be converted to the desired azo compound 19 as outlined previously. For X=S, treatment of the chloride from the disulfide 16 with the thioamide 20 would afford the ester 21. Compound 21 could then be converted to the desired azo compound 23 by treatment with ao 2 cc 6 a 4 so 2 N3 then Rh(OAc> 2 .1 9 followed by isomerization, oxidation and removal of the ester protecting group. For compounds where X=CH 2 intermediate 24 used in the synthesis of thienamycinl9 could be converted to the desired azo compound by addition of TSNHNH 2 , analogous to the addition of HS-R in the thienamycin synthesis, followed by air oxidation and deprotection of the acid. 126 SCBBIIB IV 16 N-lj R 127 In conclusion, the proposed strategy of suicide enzyme substrate design should provide a wide variety of penicillin and cephalosporin analogs that would be potential inactivators of PSE's and/or a-lactamases. These compounds would also be potential probes into the nature of the active site of these enzymes. This could be accomplished by observing which amino acids of the protein are alkylated by these compounds. 128 PROPOSI!'IOB 2. A systematic study of the effects of electron withdrawing substituent& on the rate of the alkoxide accelerated cycloreversion of 1-hydroxybicyclo£2.2.21 octadienes and the comparison of these effects with those predicted by a Buckel Molecular Orbital (HMO) based model are proposed. A study of the mode of the cycloreversion is also proposed. The effect of substituents on the rates of pericyclic reactions is of considerable theoreticall,2,3 and synthetic interest4,5,6,7. To account for the effects of substituent& on the rate of pericyclic reactions, Carpenter2 has proposed a comprehensive theoretical model. Carpenter's model compares the effect of a substituent on the total 1r energy of the ground state CGS) of the reactant(s) with the effect it exerts on the total 1r energy of the transition state (TS) of the reaction. This model predicts that a substituent which increases the total 1r more than it increases the energy of the transition state 1r energy of the reactant(s) will increase the rate of the reaction. This model uses the tabulated HMO 1r energies8,9 of analogous compounds to calculate the state. 1. 1r energy of the reactants and of the trans! tion Samples of the equivalences used are shown in Table 129 !~able Compound/TS 1. Energy CS> Equivalent x•Polarizing allyl radical 2.838 x•Conjugating butadiene 4.472 UN SUBSTITUTED ethene 2.000 x•Polarizing benzyl radical 8.720 x•Conjugating styrene 10.425 UN SUBSTITUTED benzene 8.000 Application of this model to the singularly substituted retro-Diels-Alder reaction yields the results shown in Table 2.2 Since ~ is the effect of a substituent on the reactant(s) minus its effect on the transition state, a negative value for ~ indicates that the substituent should increase the rate of the reaction. Therefore, this model 130 !'able 2. 2 1··~~ .. [ l.S)JJ 1 2 ____.... .. II ~t TS ENERGY ( S> SUBSTITUENT Position Type 1 or 2 3 R TS Polarizing 2.000 8.720 -0.721 Conjugating 4.00 10.425 -0.425 Polarizing 2.838 8.720 +0.108 Conjugating 4.472 10.425 +0.047 2.000 8.000 0. 000 . Unsubstituted predicts that a substituent at position 1 or 2 will increase the rate of the retro-Diels-Alder reaction; while a substituent at position 3 will decrease the reaction rate. The above predictions are supported by the examples shown in Figure 1. Figure 1. Polar substituent at position 3. kx=OLi < kx=B 131 Polar substituent at position 2. • ~OzCH1 ~oaat. Polar substituent at position 1. + Although the alkoxide assisted cycloreversion of example 2 above is potentially synthetically useful, the presence of the two ester groups make determination of the effect of the alkoxide alone impossible. Therefore, in order to better understand the effects of an ester substituent on the above cycloreversion reaction, the preparation of the bicyclo[2.2.21 octadienes shown in Figure 2, and a study of the ratio of their alkoxide assisted cycloreversions are proposed. 132 ·Figure 2. M 1 2 5 ' A comparison of the observed effect of the carbomethoxy functionality at the various positions and the effect predicted by an extension of Carpenter's model is also proposed. Application of the extended model to the above systems yields the results presented in Table 3. Since the carbomethoxyl moiety can act both as an electron accepting and as a conjugating substituent, its effect should lie between the effect predicted for the two types of substituents for a given position. 133 :6 4 Type Accepting Conjugating Position R :6 4 TS 2 3 4 5 6 UNSUBSTITUTED 2.828 2.828 2.000 2.000 2.000 2.000 9.954 9.431 9.925 9.431 9.954 8.721 -0.405 +0.118 -1.204 2 3 4 5 6 UNSUBSTITUTED 4.472 4.472 4.000 4.000 4.000 2.000 11.204 11.142 11.190 11.142 11.204 8.721 0.000 +0.051 -0.469 -0.421 -0.483 0.000 -o. 110 -1.233 0.000 The extended model, therefore, predicts that a carbomethoxy substituent in any position other than position 3 will increase the rate of the cycloreversion. model, Based on this the order of increasing rates for the esters 1 through 6 should be 3<1<2<5<4<6. The results presented in Table 3 are based on the assumption that the cycloreversion is concerted. However, if the reaction is not concerted, then different transition states must be considered. model to the Application of the extended non-concerted cycloreversion of the bicyclo[2.2.21octadiene 6 gives the results presented in Table 4. 134 !~able &-Or R 4. ·0 • ' ... TS, •6+1(x ~ TS~ ENERGY <a> X R TS 1 ~1 Int. TS 2 ~2 Accepting 2.000 6.472 -1.644 6.472 9.518 +0.537 Conjugating 4.000 7.464 -0.636 7.300 10.628 +0.255 Unsubstituted 2.000 4.828 0.000 4.472 8.055 0.000 Therefore, the model predicts that the rate of the cleavage of the first bond (R -> Int.) of the ester 6 will be increased by the carbomethoxy substituent, while the rate of cleavage of the second bond will be decreased. If the cycloreversion is not concerted and the cleavage of the second bond is rate determining, then the rate of the cyclereversion should be reduced by the presence of a carbomethoxy substituent at position 6. However, if the cycloreversion is concerted or if the cleavage of the first bond in the stepwise pathway is rate determining, then the reaction rate should be increased by the presence of a carbomethoxy substituent at position 6. 135 In order to test the concertedness of the cycloreversion further, the preparation and cycloreversion of the bicyclo r 2.2.2 l octadiene 7 is proposed. If the cycloreversion is not concerted, then either Ts 1 or the intermediate anion lat. should eliminate Tso- thereby short circuiting the reaction pathway as shown in Scheme I. 7 SCBBIIB I Proposed synthetic schemes for the preparation of the desired bicyclo£2.2.21 octadienes 1 through 7 are presented in Scheme II. Treatment of the 1,4 cyclohexadienel2 8 with lithium fluoroborate 1 3 would give the corresponding a, y enone. This enone could then be enolized, and the enolate trapped with ~-butylchlorodimethylsilane (TBSC1)14 would give diene 9. Diels-Alder addition of the diene 9 to an acetylene 136 SCBBIIB II I ' 11 ;\;:'• ' iD 7 lt=TBS (a) LiBP 4 , CB3 CNJ (b) KB/'l'BSCl J (c) •ac ca• aee Sche•e I I I J (d) B-e c-c02ReJ (e) RaOMe/MeOBJ (f) LiAlB41 (g) Swern, then Ag 20J (b) CB 2N2 J (i) Rai0 4 , MeOB/B 20J (j) cs 3c 6s4so 2Cl. 137 equivalent, and then the generation of the second olefin would give the desired parent compound 1. Three possible acetylene equivalents are shown in Scheme III. SCBBIIB III (a) trans ClBC•CBCl1 (b) ••-anthracene, Cc) Ra/ws 3 1 Cd> Jig, Ce) •aleic anhydride, Cf) .r~o, Cg> PbCOAc> 41 Cb> CB2•CCCl)COCl1 (i) RaN 3 r Cj) 8.3 C1J (It) LDA/CIIe 2 NJ 2 PCO)Cll (lf Ha/CB 3CB 2HB 2 r (~ 2 ~a~BHB r rn) ~uLi. Cycloaddition of 1,2 dicbloroethene to the dienelS would give the corresponding adduct. Treatment of this adduct with sodium anthracenelS, sodium in ammonia or magnesium, and then lithium fluoroborate would give the desired diene. Addition of maleic anhydride to the cyclohexadiene and hydrolysis of the resulting anhydride would give the corresponding bicyclo[2.2.21octene dicarboxylic acid. Treatment of the diacid with lead tetraacetatel6 give desired would the bicyclo[2.2.21octadiene. Addition of 2-chloropropenoyl chloride to the cyclohexadiene and conversion of the adduct into the corresponding ketonel7 would give the bicyclo [ 2.2.21 octenone. This ketone could then be converted to the desired olefin by 138 way of the corresponding tosylhydrazonel8 or by way of the phospho-diamidate derivative of the its enolate.19 Treatment of the diene 9 with methyl propiolate and cleavage of the TBS ether of the cycloadduct with lithium fluoroborate would give the desired alcohol 2. Treatment of the 1,4 cyclohexadiene 1020 with mild base would isomerize the unsubstituted double bond into conjugation giving the 1,3 dien~ 11. Cycloaddition of this diene with an acetylene equivalent, as described for the preparation of the parent compound 1, would give the bicycloadduct 3. Conversely, reduction of the ester 10 with lithium tetrahydridoaluminate and then treatment of the resultant alcohol as described for the conversion of the 1,4 diene 8 to the 1,3 diene 9 would give the diene 12. Treatment of this diene with an acetylene equivalent, as described above, would give the 4 substituted bicyclooctadiene 13. Removal of the TBS protecting groups, oxidation of the primary hydroxyl group, and esterification of the result acid with diozomethane would give the desired ester 5. Hydrolysis of the silyl enol ether of the 1,4 diene 421 would give the corresponding ketone. Enolization of this ketone and trapping of the enolate with TBSCl would give the 1,3 diene 15. Treatment of this diene with an acetylene equivalent, as described above, would give the desired cycloadduct 4. 139 Treatment of the anhydride 622 with LAB and sodium metaperiodate cleavage of the resulting triol would give the a,y enone 17. Enolization of the enone 16 and trapping of the enolate with TBSCl would give the 1,3 diene 18. Treatment of the diene with an acetylene equivalent and then removal of the protecting groups would provide the diol 19. Oxidation of the primary alcohol of the adduct 19 and then esterification with diazomethane would give the desired ester 6, while selective tosylation of the primary alcohol would yield the sulfonate 7. The corresponding alkoxides of these alcohols c9uld be generated by treatment with nBuLi, sodium or potassium hydride, and the cycloreversion rates of the alkoxides of alcohols 1 through 6 could then be determined by the observation of the time dependent appearance of the ultraviolet absorption band of the aromatic ester products. In the case of the tosylate 7, analysis of the products of the reaction would also be necessary to determine if any elimination had occurred. In summary, the preparation of the bicycle [ 2.2.21- octadienes 1 through 7 and the study of their anion assisted cycloreversion will provide useful information about this interesting and potentially valuable rea~tion. 140 RBPBRBRCBS POR PROPOSI~IOB 2. 1) Sauer, J.; Sustmann, R. Angew. Chem. l..DL.IJL. Bngl. 1980, li, 779-807. 2) Carpenter, B. K. Tetrahedron 1978, ~' 1877-1884. 3) RajanBabu, T. V.J Eaton, D. P. and Pukunaga, T. J..... Q.I.s... ~L. 1983, J.S., 652-657. 4) Evans, D. A.; Nelson, J. v. ,lU, 5) J..... AL. Chem, ~ 1980, 774-782. Thies, R. w. and Seitz, E. P. J..... Q.I.s... Chem.. 1978, J..l, 1050-1057. 6) Ireland, R. E.; Mueller, R. B. and Willard, A. K. ~ ~ 7) Cbem. ~ 1976, 1!, 2868-2877. Cohen, T.; Bhupathy, M. and Matz, J. R. Ibid, 1983, lJlS., 520-525. 8) Coulson, c. A. and Streitwieser, A., Jr. g.f v -Electron Calculations A Dictionary 1965, Pergamon Press, New York , NY. 9) Heilbronner, E. and Straub, P. A. Buckel Molecular Orbitals 1966, Springer-Verlag, New York, NY. 10) Miller, R. D. and Dolce, D. L. Tetrahedron Lett, 1977, 3329-3332. 11) Papies, 0. and Grimme, w. Tetrahedron Lett, 1980, 2799-2802. 12) Donaldson, R. E. and Fuchs, P. L. Jl,, 2034-2040. ~ ~ Chem. 1977, 141 13) Metcalf, B. w., Burkhart, J. P. and Jund, K. Tetrahedron Lett. 1980, 35-36. 14) Fitzsimmons, B. J. Ph.D. Thesis 1983, California Institute of Technology. 5) Gilbert, A.; BinSamdusin, M. Wilson, s. 16) ~ Chem. Soc •• w., Taylor, G. N.; and Perkin~ Cimarusti, c. M. and Wolinsky, J. 1980, 1225-1229. ~ ~ Chem. ~ 1968, ~' 113-120. 17) Corey, E. J.; Ravindranathan, R. and Terashima, s. ~ ~ 18) Chem. ~ 1971, 1l, 4326-4327. deMeijere, A. and Meyer, L.-o. Tetrahedron Lett., 1974, 2051-2054. 19) Ireland, R. E.; Muchmore, D. c. and Bengartner, o. ~ ~ 20) Chem. ~ 1972, i!, 5098-5100. Birch, A. J. and Slobbe, J. Aust. ~ Chem. 1977, ~' 1045-1049. 21) Chao, B. s. I. and Berchtold, G. A. ~ ~ Chem. ~ 1981, ~, 898-902. 2 2) I r e 1 and , R. E. and Thompson , W. J. 3041-3052. J.a. .Q.1:.s... ~m.... 19 7 9 , 142 PROPOSI~IOR 3. The use of an asymmetric ene reaction to provide access to optically pure tetrahydrothiophenes and the conversion of these compounds into optically pure cyclobutene and cyclobutane derivatives is proposed. Asymmetric induction in carbon-carbon bond formation has received substantial interest in recent years. The most common method of achieving asymmetric induction is the incorporation of a chiral auxillary into one of the reaction substrates. This method has been successfully applied to aldol condensations,l,2 enolate alkylations3 and acylations,4 Diels-Alder cycloadditions,S,6 the reaction, and conjugate additions.9 ene7,8 However, this method cannot be extended directly to 2+2 cycle-additions due to the nature of the transition state of the reaction. Therefore, the preparation of opti~ally pure cyclobutenes and cyclobutanes requires the development of an alternate strategy. An alternate method for the preparation of four-membered rings is the contraction of a five membered ring by the extrusion of one of its members. A suitable candidate for such a process would be available through the thio analog of the asymmetric ene reaction reported by Oppolzer•s group,7 as shown in Scheme I. The tetrahydro- thiophene 2 produced from the above ene reaction would be well suited for the preparation of optically pure cyclobutenes and cyclobutanes since both enantiomers would be 143 SCBBIIB I 1b:cis R= 1a minor major 1b major minor SCIIBIIB II a • c Rr-r===L3 lU:' (a) N-chlorosuccinimide; (b) MCPBA; (c) KOt-Bu, 0° C. SCBBIIB III 53 o/o 144 available by variation of the enoate portion of the 1,6 diene utilized in the ene reaction. In addition, there are numerous methods available for the contraction of rings by the extrusion of sulfur. For the purpose of this proposal, the Ramberg-Backlumb rearrangementlO _ (Scheme II) would be the method of choice since it has been successfully used to prepare cyclobutenes in good yieldll (Scheme III) and does not involve the use of harsh reagents or reaction conditions. The cyclobutene thus prepared could be converted to the corresponding cyclobutane by hydrogenation of the highly strained endocyclic olefin. Conversely, the highly reactive olefin could be utilized for further functionalization of the ring (i.e.: cycloaddition, epoxidation, or bydroboration). A proposed example of the use of this method is shown in Scheme II. Fragenol 3 is a terpene isolated from the roots of Artemisia fragrans Willd. The structure was assigned solely on the basis of la-NMR data. Treatment of the <z> 4 bromo-3-methyl-2-butenoate 413 with the anion of 3 methyl-2-buten-1-thiol 6 would give the 1,6 diene required for the preparation of one enatiomer of Fragenol 3. Likewise, the (E) butenoate 5 would provide the 1,6 diene that would lead to the other enantiomer. Treat- ment of the butenoates 7 or 8 with Et 2A1Cl as described by Oppolzer 7 should then lead to the enantiomeric tetrahydrothiophenes 9 and 10. Reduction of the ester and then 145 SCBBIIB IV ~CH3 '1 ~%t\Ct\OH (a) Et 2 A1Cl; (b) LiAlH 4 ; (c) BzCl; (d) N-chlorosuccinimide; (e) Nai0 4 1 (f) KO~-Bu; (g) H2/Pd-PbS0 4 ; (h) NaOMe. 146 protection of the resulting alcohols would give the enantiomeric benzoates 11 and 12. Treatment of the esters 11 and 12 successively with N-chloro-succinimide, sodium metaperiodate and potassium ~-butoxide would effect the Ramberg-Backlumb rearrangement giving the enantiomeric cyclobutenes 13 and 14. Selective hydrogenation of the highly strained endocyclic olefin would then provide both enantiomers of Fragenol 3. In summary, the asymmetric induction of the ene reaction could be utilized to provide access to optically pure cyclobutene and cyclobutane derivatives. 147 RBPBRBHCBS POR PROPOSI~IOR 3. 1) Evans, D. A. and Taber, T. R. Tetrahedron Lett. 1980, .21,, 4675-4678. 2) Evans, D. A., Takas, J. M.; McGee, L. R., Ennis, M. D., Mathre, D. J. and Bartroli, J. Pure and Agplied Chem. 1981, ~' 1181-1201. 3) Evans, D. A.; Ennis, M. D.; Mathre, D. J. ~~ 4) Chem. Soc. 1982, ~' 1737-1739. Ennis, M. D. Ph.D. Thesis 1983, California Institute of Technology. 5) Oppolzer, W.; Kurth, M.;; Reichlin, D.; Chapais, C.; Mohnhaupt, M.; Moffat, P. Belv. Chim. Acta 1981, i!, 2802-2807. 6) Corey, E. J. and Ensley, H. E. ~m. Chem. Soc. 1975, ll, 6908-6909. 7) Oppolzer, w. and Robbiani, C. Belv. Chim. Acta 1980, ll, 2010-2014. 8) Oppolzer, W.; Robbiani, C. and Buttig, K. Bely. Chim. Acta 1980, fi, 2015-2018. 9) Oppolzer, W.; Lober, B. J. Bely. Chim. Acta 1981, i!, 2808-2811. 10) Paquette, L. A. in: ~ ~' Mechanisms of Molecular Migrations. Tbyagarian, B. s., editor, 1968, Interscience, New York, NY, pp. 121-156. 148 11) Paquette, L. J. 12) Am· Chem. Soc. 1971, il, 4516-4522. Bohlmann, P.; Zdero, c. and Paass, o. ~, 13) A., Philips, J. c. and Wingard, R. E., Jr. Chem. Ber. 1973, 2904-2909. Ahmad, I.J Gedye, R. N. and Nechuatal, A. ~, 1968, 185-187. J. Chem. Soc. 149 PROPOSI~IOR 4. A total synthesis of the nucleoside antibiotic Amipurimycin methyl ester 1 and its C-6' epimer is proposed. Amipurimycin is an antibiotic isolated from S~LA~~~m~kAA n~~~g~~nA~n~A by Harada and Kishi. 1 Amipurimycin was shown to be active against various agricultural blasts in yitro and in vivo at low dosages2 and therefore is potentially valuable as an agricultural antibiotic. The structure for amipurimycin shown above was determined by Goto and coworkers3 on the basis of chemical and spectral data. However, the relative stereochemistry of C-6' and the absolute stereochemistry of the antibiotic was not determined. Therefore, a total synthesis of both C-6' diasteriomers of one enantiomer of amipyrimyciin methyl ester would erase any ambiguity about the structure of amipurimycin. Amipurimycin methyl ester 1 can be divided, in an antithetic sense, into three parts as shown in Scheme I: 150 SCBBIIB I 4 151 1) ki.a.-2-aminocyclopentanecarboxylic acid 21 2) the novel branched carbohydrate moiety 3J and 3) 9B.-2-aminopurine 4. Examination of the carbohydrate moiety 3 reveals it to be a L-pentose, C-1'-C-3', C-8' and C-9 1 , branched at C-3'. Since both the R,a and the a,a diasteriomers of the amino alcohol side chain are required, an intermediate that would lead to both would be advantageous. This strategy bas been employed in this proposed synthesis. The proposed syntheses of amipurimycin methyl ester and its C-6' epimer are shown in Scheme II. Protection of the primary alcohol of the L-arabinose derivative s4 as its tert-butyldimethylsilyl (TBS) ether and oxidation of the remaining hydroxyl group would provide the ketone 6, required for the attachment of the amino alcohol chain. Addition of the enolate of acetaldehyde or an equivalent to the ketone 6 from the less hindered S-face and acetylation of the resulting alcohol would give the aldehyde 7 required for the generation of both C-6' epimers. · Aldol condensation of the boron enolate of the glycine derivative aS utilizing the conditions developed by Evan's group6 would provide the .e.u.th~-amino alcohol 9. Protection of the resulting alcohol 9 as its TBS ether, removal of the chiral auxiliary and then removal of both TBS groups would afford the diol 10. Treatment of the diol 10 with ethanedithiol and protection of the resulting vicinal hydroxyl groups as their acetonide derivative would provide 152 SCBBilB I I NOx= -olll R= (/) (a) TBSCl; (b) Swern [ o]; (c) LiCH 2 CHO; (d) AcCl/Et 3 N; {e) CH 2 =CB-CH 2 Li; {f) 0 3 ; {g) R'BCB{NOx_1COXc (8); (b) TBSCl; (i) B n 0 L i ; ( j1 n- B u' N F ; ( k ) B Sf H 2 C B 2 S BIB P 3. • E t 2 0 ; ( 1 ) 2 , 2 Dimethoxypropane a+; (m) Bg +; {n} 82/Pa; \o) RCl; (p) CH2N2; (q) a3P=CBCBO; (r) NaBH41 (s) Ru0 4 ; (t) (+)ai~sopropyltartrate/Ti (Oi.Pr) 4/.t.BuOOB; (u) NB40H; rv) RCl; (w) C~2N21 . (x) TiC14/2-t-butoxycarbonylamino-9-chloromercur~c pur~ne. 153 the thioacetal 11. Hydrolysis of the thioacetal 11 and acetylation of the resulting pyranose would give the pyranoside 12. Hydrogenolysis of the benzyl ester and nitrogen protection group, N-acylation of the resulting amino acid with the acid chloride of N-tALt-butoxycarbonyl ~-2-aminocyclopentanecarboxylic acidl2 and esterification with diazomethane would afford the pyranoside 13. Treatment of the aldehyde 7 with formylmethylene triphenylphosphorane7 and reduction of the resulting aldehyde would provide the allylic alcohol 14. Epoxidation of the alcohol 14 using the conditions described by Sharpless et ala and oxidation of the resulting epoxy alcohol9 would give the epoxy acid 15. Treatment of the epoxy acid 15 with ammonium hydroxide should open the epoxide a to the acid,lO N-acylation of the resulting amino acid and esterification with diazomethane would give the threo-amino ester 16. Removal of the TBS protecting group, opening of the furanoside 16 with ethanedithiol and borontrifluoride etherate and protection of the resulting vicinal diol as its acetonide derivative would afford the thioacetal 17. Hydrolysis of the thioacetal and acetylation of the resulting pyranose would provide the pyranoside 18. This pyranoside would be epimeric at C-6' to .the pyranose 13. Treatment of pyranoside 13 or 18 with titanium tetrachloride and the chloromercuric salt of N-tertbutoxy- 154 carbonyl-2-aminopurinell and then removal of the protecting groups would afford amipurimycin or its C-6' epimer. In summary, the syntheses described above would provide the information necessary for the determination of the relative and absolute stereochemistry of amipurimycin. 155 llBPBRBRCBS POR PROPOSI'l'IOR 4. 1) Harada, s. and Kishi, T. J, Antibiotics 1977, ~' 11-20. 2) Iwasa, T., Kishi, T., Matsuura, K. and Wakae, o. J, Antibiotics 1977, 34, 1-10. 3) Goto, T.~ Toya, Y.; Ohgi, T. and Kondo, T. Tetrahedron Lett, 1982, 1271-1274. 4) Abde1 Rahman, M. M. A. Chem. Abstr. 1979, !1, 211693v, p. 714. 5) Sheehan, J. c. and Guziec, P. s., Jr. ~ ~ Chem, 1973, l!, 3034-3040. 6) Evans, D. A.; Takas, J. M.J McGee, L. R.r Ennis, M. D.; Mathre, D. J. and Bartro1i, J. ~And ARRlied Chem, 1981, ~, 1181-1201. 7) Zamboni, R. and Rokash, J. Tetrahedron Lett, 1982{ 4751-4754. 8) Sharpless, K. B.; Behrens, c. B.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, s. M.; Walker, P. J. and Woodward, s. s. ~ 9) And ARplied Chem, 1983, li, 589-604. Carlsen, P. B. J.; Katsuki, T.; Martin, v. Sharpless, K. B. ~ ~ Chem, -1981, ~, 3936-3938. Chem, 1966, 11, 1407-1410. 10) Harada, K. 11) Srivastava, v. K. and Lerner, L. M. ~ ~ 1979, ll, 24-28. s. and il.&. K.e.4.. t..h.Am... 156 12) Nativ, E. and Rona, P. ~ ~ Chem. 1972, ~, SS-57. 157 PROPOSI!IIOR 5. The design and synthesis of a suicide enzyme substrate for s-adenosylmethionine decarboxylase is proposed. s-adenosylmethionine decarboxylase (SAM-DC) converts its namesake 1 into s-adenosyl-S-methylhomocysteamine 2, a propyl amine transfer compound utilized in the biosynthesis of spermidine 4 and spermine 5 (Scheme I). Spermidine 4 and spermine 5 have been implicated in cellular division and growth;l therefore, a potent inhibitor of their biosynthesis might be useful in controlling physiological disorders involving excessive cell proliferation. Inhibitors of ornithine decarboxylase COrn-DC) have been shown to retard the growth of a mouse sarcoma2 lending credence to this proposal. SCBEIIE I ~· u. T- " .. --~~~Ha ~ - H I ..-u. Competitive inhibitors of Orn-DC lead to an accumulation of the enzyme and thus a burst of putrescine 3 when the inhibitor is cleared from the organism. Therefore, irreversible suicide enzyme substrates for Orn-DC were 158 synthesized and tested for their ability to lower putrescine 3, spermidine 4 and spermine 5 concentrations.3,4 One of these a-difluoromethylornithine 6 proved to be effective in blocking the testosterone induced increase of putrescine 3 and spermidine 4 and slows the accumulation of spermine 5 in castrated rats. 5 a -difluoromethylorni thine also prolonged the survival time of mice innoculated with leukemia cells6 and slows tumor growth in mice7 combined with minimal toxicity. The proposed mechanism of action of 6 is shown in Scheme 11.8 Unfortunately, Orn-DC is synthesized rapidly; therefore, adequate .levels of any Orn-DC inhibitor must be constantly maintained in order to keep putrescine 3 synthesis to a minimum. Also, organisms can maintain or restore the spermine 5 pool, even when putrescine 3 concentrations are low. Therefore, in order to suppress the biosynthesis of spermidine 4 and spermine 5 effectively, the inhibition of another enzyme in the synthetic pathway must be inhibited, individually or in conjunction with an Orn-DC inhibitor. The ideal enzyme to inhibit would seem to be SAM-DC since the S-adenosyl-S-methylhomocysteamine 2 it produces is used at two points in the biosynthesis of spermine. This would greatly accentuate the effect of any reduction in the activity of SAM-DC. 159 6 SCBBIIB II R= '&- (a) Binding to pyridoxal phosphate, (b) elimination, (c) Micheal addition of enzyme nucleophile. SCBBIIB III + + Ad~~H..._AdS~ tH, - ,. ' CH3 ~~ 160 The proposed mechanism of SAM-DC's action is shown in Scheme III. It is important to note one major difference between the mechanisms for SAM-DC and most decarboxylase& and transaminases . (ex. Orn-DC, Scheme II). While .Orn-DC utilizes pyridoxal phosphate, SAM-DC uses)evolutionally more primative,covalently bound pyruvate as an electron sink.9 The use of this less effective electron sink not only raises the energy of the decarboxylation but also severely reduces the attractiveness of the traditional approach to suicide enzyme substrates. This approach (Scheme II) uses an enzyme mediated elimination to generate a Micheal acceptor which utilizes cofactor as its electron sink. The u~e of 3-chloro SAM 7, as a suicide enzyme substrate for SAM-DC, and methods for its preparation are proposed. The preparation of both epimers at the chlorine bearing carbon and their use separately will be necessary, since the conformational rigidity imposed by the enzyme active site may lead to different results with each diasteriomer. The proposed mechanism of action of 7 is shown in Scheme IV. Decarboxylation would be accompanied by loss of an electro negative group as for Orn-DC inhibitor adifluoromethyl ornithine; however, with 7, both a Micheal acceptor and more importantly a vinyl sulfonium moiety 8 which can act as a powerful alkylating agent would be generated. In order to fully appreciate the potential of 8 161 SCBBIIB IV ~0; Ad CHs I 7 • Hz a • • b,c R=C02t-Bu (a) CB 3SC1J (b) s 3+oJ (c) CP 3co 2B. SCBBIIB IV iOiBu ~COzt·Bu 9 H (a) IClJ (b) 2 1 ,3'-Q-(1-methylethylidene)-5'thiomethyladenosineJ (c) s 3 +o, (d) cr 3co 2s 162 as an alkylating agent, one only needs to consider its no bond resonance form Sa. Compound 7 should be available optically pure by several methods starting with protected L-vinyl glycine.lO Two possible schemes (V and VI) are shown below. Addition of methylsulfenylchloride to t-Butyl t-BOCvinylglycine 9 would give the terminal sulfide 10. Treatment of the sulfide 10 with 2',3'-Q-(methylethylidene)s•-trifluorosulfonate adenosine 11 followed by deprotection of the product wo~ld afford the desired SAM derivative 7.12,13 Addition of ICl to 9 would yield the terminal iodide 12. Treatment of the iodide 12 with 2',3'-0-(l-methyl- ethylidene)-5'-thiomethyladenosinel4 followed by deprotection would also yield the desired SAM-derivative. In summary, compound 7 should be a suicide enzyme substrate for SAM-DC by virtue of an enzyme mediated generation of an allyl sulfonium moiety. 163 RBPBRBRCBS POR PROPOSI~IOR 5. 1) Janne, J.; Poso, B. and Raina, A. M. l&.ta 2) Biochim. Biophys. 1978, JlJ., 241-293. Jung, M. J .; Kack-Weser, J. and Sj oerdsma, A. in Enzym~ Inhibitors Aa Drugs, Sandler, M. editor, The MacMillan Press Ltd., New York, NY, 1980, pp. 95-114. 3) Metcalf, B. W.; Bey, P.; Danzin, C.; Jung, M. J.; Casara, P. and Vevert, J. P. ~ ~ Chem. ~ 1978, .l.D..O., 2551-2553. 4) Bey, P.; Metcalf, B.; Jung, M. J.; Kozard, J.; Koch-Weser, J. 5) Pharmacochem. Libr. 1982, ~' 89-106. Danzin, C.; Jung, M. J.; Claverie, N.; Grove, J.; Sjoerdsma, A.; and Koch-Weser, J. Biochem. ~ 1979, .1.8.0., 507-513. 6) Prakash, N. J.; Schechter, P. J.; Grove, J. and Koch-Weser, J. 7) ~Cancer ~ 1978, la, 3059-3062. Seiler, N.; Danzin, C.; Prakash, N. J. and Koch-Weser, J. in Enzyme Actiyated Irreversible Inhibitors, ed. N. Seiler, M. J. Jung, and J. Koch-Weser, Elssevier, New York, NY, 1978, pp. 55-71. 8) Bey, P. ibid. 1978, pp. 27-41. 9) Walsh, C. Enzymatic Reaction Mechanism, w. B. Freeman and Company, San Francisco, CA, 1979, p. 859-861. 10) Afzali-Ardakani, A. and Rapoport, B. 1980, ~, 4817-4820. ~ ~ Chern. 164 11) Giese, B.J Mazumdar, P. Chem. ~ 1981, ll!, 2859-2865. 2) Samejima, K.J Nakazawa, Y.J Matsunaga, I. Chem. Pharm. Bull. 1978, 2(, 1480-1485. 13) Hildesheim, J.J Bildesheim, R.J and Lederer, E. Biochimie 1972, ~' 431-437. 14) Metcalf, B. W.; and Jung, M. 187293 w, p. 699. Chem. Abstracts 1979, !il,,