Silicon-Directed Carbon-Carbon Bond Forming Reactions Citation Widdowson, Katherine (1992) Silicon-Directed Carbon-Carbon Bond Forming Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z89M-4K49. https://resolver.caltech.edu/CaltechTHESIS:09282011-115011728 Abstract It is shown that O-silyl ketene N,O-acetals react with aldehydes, without catalysis, to form aldol-type products with high diastereoselectivity. For example, the prolinolderived O-silyl ketene N,O-acetal 7 reacts with benzaldehyde to form the anti aldol product 9 with > 98% diastereoselectivity. Mechanistic studies are presented which support a scheme involving formation of trigonal bipyrarnid (tbp) G, pseudorotation to form tbp T boat , and rate-determining C-C bond formation to produce 9. [Formula. See abstract in scanned thesis for details] It is shown that aldehydes react with pyridine, benzeneselenol, dichlorodimethylsilane, and an allylic alcohol to form O-allyloxy dimethylsilyl hemiselenoacetals in high yield. These derivatives undergo efficient free radical-mediated cyclization upon treatment with BU 3 SnH, as exemplified by the transformation of 7→8. Together these steps provide an efficient method for carbon-carbon bond formation between the carbonyl carbon of an aldehyde and the terminus of an allylic alcohol. [Formula. See abstract in scanned thesis for details] 2,3-Epoxy alcohols are transformed to C2-inverted cyclic carbonates upon treatment with cesium carbonate under an atmosphere of carbon dioxide (e.g., 5→6).The reaction is completely stereospecific, within experimental error, and forms only 5-membered ring cyclic carbonates. [Formula. See abstract in scanned thesis for details] 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): Myers, Andrew G. Thesis Committee: Unknown, Unknown Defense Date: 2 March 1992 Record Number: CaltechTHESIS:09282011-115011728 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:09282011-115011728 DOI: 10.7907/Z89M-4K49 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 6693 Collection: CaltechTHESIS Deposited By: INVALID USER Deposited On: 28 Sep 2011 22:35 Last Modified: 16 Mar 2020 18:21 Thesis Files PDF - Final Version See Usage Policy. 4MB Repository Staff Only: item control page

Silicon-Directed Carbon-Carbon Bond Forming Reactions Thesis by Katherine Widdowson In Partial FulfIllment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1992 (defended March 2, 1992) 11 Acknowledgements I would like to thank my advisor Andy Myers for his enthusiasm, support, and advice throughout my graduate career. He added considerably to my knowledge of organic chemistry both in theory and in practice. I would also like to acknowledge Mr. Giles for introducing me to chemistry and Tom Dunne for guiding me during my undergraduate research. I would like to thank my family for their financial support. Without them none of this would have been possible. I am indebted to all the members of the Myers' group past and present for providing a pleasant and stimulating environment in which to work. Pete Dragovich, Nat Finney, Mark Fraley, Dan Christen, Elaine Kuo, Susan Kephart, Vijaya Subramanian, Tommy Chen, and David Gin deserve special thanks for proofreading large portions of this manuscript. Finally I would like to thank my friends: Elaine Kuo Kathleen Kramer Tommy Chen Leslie Jimenez Dan Shennan SonBinhN guYen Nat Fin_ -<lley Greg Kiefer et al. for everything else. ill Abstract It is shown that O-silyl ketene N,O-acetals react with aldehydes, without catalysis, to fonn aldol-type products with high diastereoselectivity. For example, the prolinolderived O-silyl ketene N,O-acetal 7 reacts with benzaldehyde to form the anti aldol product 9 with >98% diastereoselectivity. Mechanistic studies are presented which support a scheme involving formation of trigonal bipyrarnid (tbp) G, pseudorotation to form tbp Tboat, and rate-determining C-C bond formation to produce 9. 9 G Tboat IV It is shown that aldehydes react with pyridine, benzeneselenol, dichlorodimethylsilane, and an allylic alcohol to form O-allyloxy dimethylsilyl hemiselenoacetals in high yield. These derivatives undergo efficient free radical-mediated cyclization upon treatment with BU3SnH; as exemplified by the transformation of 7~8. Together these steps provide an efficient method for carbon-carbon bond formation between the carbonyl carbon of an aldehyde and the terminus of an allylic alcohol. H3 C, ._,CH 3 Si H3 C, ._,CH 3 Si 0/ ' 0 Ph~"'IH l SePh ~ Ph~ 7 8 2,3-Epoxy alcohols are transformed to C2-inverted cyclic carbonates upon treatment with cesium carbonate under an atmosphere of carbon dioxide (e.g., 5~6). The reaction is completely stereospecific, within experimental error, and forms only 5membered ring cyclic carbonates. OH Ph~O HO-( 5 6 o v Table of Contents Chapter I. Aldol Reactions of O-Silyl Ketene N,O-Acetals Page Discussion 2 Experimental Section 31 Synthesis of Amides 34 Synthesis of O-Silyl Ketene N,O-Acetals 36 Synthesis of Aldol Products 44 Desilylation of Aldol Products 64 Synthesis of Mosher Esters 74 NMR Experiments 78 Determination of Deuterium Isotope Effect 88 References 90 Chapter II. Radical Cyclizations of O-Allyloxy Dimethylsilyl Hemiselenoacetals Discussion 98 Experimental Section 107 Synthesis of Hemiselenolacetals 109 Radical Cyclization with Tributyltin Hydride 115 Group Transfer Radical Cyclizations 120 References 127 Chapter III. Synthesis of Hydroxy Carbonates from Epoxy Alcohols under Basic Conditions Discussion 131 VI Experimental Section 139 Synthesis of Starting Materials 141 Hydrolysis of Hydroxy Carbonates 155 Synthesis of Mosher Esters 161 References 169 Appendices I-III. Spectral Catalogs Chapter I 171 Chapter II 202 Chapter ill 214 Chapter Indices Chapter I 230 Chapter II 232 Chapter ill 233 Vll Index of Tables and Figures Chapter I Table I 4 Table II 7 Figure 1 9 Table ill 12 Table IV 13 Figure 2 19 Table V 20 Chapter II Table I 103 Chapter ill Table I l35 viii List of Abbreviations! A angstrom Ac acetyl AIBN 2,2'-azobisisobutyronitrile ASTM American Society for Testing Materials atm atmospheres [a] optical rotation Bu butyl c concentration (g/IOO mL) cal calories CI Chemical Ionization em centimeters CSA camphorsulfonic acid CC degrees Celsius DMAP (4-dimethylamino)pyridine DMF N,N-dimethylformamide DMS dimethyl sulfide DMSO dimethyl sulfoxide E entgegen (together) ee enantiomeric excess EI Electron Impact Ionization equiv equivalents Et ethyl ether diethyl ether eu entropy units E dielectric constant IX FAB Fast Atom Bombardment Ionization FT fourier transfonn g grams GC gas chromatography h hours H enthalpy HMPA hexameth yl phosphoramide HPLC high pressure liquid chromatography HRMS high resolution mass spectroscopy hu light Hz hertz i iso IR infrared irr irradiation J coupling constant k rate constant Keq equilibrium constant KHMDS potassium hexamethyldisilazane LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazane m meters m meta M Molar (moles/L) M+ molecular ion m-CPBA meta-chloroperoxybenzioc acid Me methyl x mg milligrams NlHz megahertz min minutes mL milliliters mm millimeters rnM millimolar mmol millimoles mol moles mp melting point MS mass spectrometry MTAP a-methoxy-a-( trifluorometh yI)pheny lacetic acid (Mosher acid) MTAPCl a-methoxy-a-(trifluoromethyl)phenylacetyl chloride ilL microliters Ilm micrometers n normal (unbranched) nm nanometers NMR nuclear magnetic resonance nOe nuclear Overhauser effect p para pet. ether petroleum ether (bp: 30-60 0c) Ph phenyl ppm parts per million Pr propyl pyr pyridine Xl (R) rectus (clockwise priority) Rf retention factor (5) sinister (counterclockwise priority) t tertiary TBDMS tertbutyldimethylsilyl ten tertiary tbp trigonal bipyramid THF tetrahydrofuran TLe thin-layer chromatography TMS trimethylsilyl tol toluene Torr rnillime~ers of mercury UV ultraviolet W watts w/w weight percent \jI pseudorotation Z zusammen (together) > greater than < less than approximately (±) racemic 1Abbreviations used in the compilation of spectral data are defined in the beginning of each experimental section. 1 CHAPTER I Aldol Reactions of O·Silyl Ketene N,O·Acetals 2 The aldol reaction is one of the oldest carbon-carbon bond fonning reactions in organic chemistry.! In the last 10 years it has developed into one of the most powerful ways of generating acyclic stereocenters. 2 Because two sp3 centers are generated in the aldol condensation, a maximum of four stereoisomers can be fonned. Two different issues of stereocontrol need to be addressed: control of relative sense of 1t facial attack (anti vs. syn) and control of absolute sense of 1t facial attack (antil vs. anti2 and synl vs. o - Y -o M = Li, e, Zr, Ti, etc. o OM OM AA syn OM ~ anti The reactivity of O-silyl enol derivatives of amides (O-silyl ketene N,O-acetals) toward aldehydes was explored with the goal of developing new aldol methodology and improving stereocontrol in the process. We chose to investigate these compounds since amide enolates are generally more nucleophilic than their ketone or ester counterparts. Also, these enolates can be formed with high Z stereoselectivity.3 One of our goals was to develop a silicon-directed aldol reaction of O-sHyl ketene N,O-acetals. Extrapolation of recent mechanistic proposals for group transfer polymerization reactions, involving a hexavalent transition state with the carbonyl oxygen bound directly to the silicon, suggested that such a strategy might be feasible. 4 ,S 3 A survey of the literature revealed that only a few O-silyl ketene N,O-acetals had been synthesized, primarily by condensation of a lithium amide enolate with chlorotrimeth ylsilane. 6 In this procedure, O-sHyl ketene N, O-acetal formation is often accompanied by significant amounts of C-silylated product. Rathke demonstrated that the amount of C-silylated product is strongly affected by sterics, increasing when the carbon ex to the carbonyl is less hindered. 6b For example, the lithium enolate of N,Ndimethylacetamide reacts with chlorotrimethylsilane to produce both C - and O-silylated products (13:1, respectively), while the lithium enolate of N,N-dimethylpropionamide affords a 1:9 ratio of C- and O-sHylated products. 6b OSi(CH 3b 0 CH3 ...... N I ~ CH 3 1) LOA • CH3 ...... 2) TMSCI N~ 0 + ~Si(CH3b I I CH 3 CH3 ....... N CH 3 CH 3 13 0 CH3 ....... N~CH3 1) LOA I 2) TMSCI CH 3 0 OSi(CH 3b r- CH3 ....... N~CH3 + I CH' .... 7~CH, CH 3 CH 3 Si(CH 3h 9 We found that hydrosilylation of acrylamides is a convenient way to produce 0sHyl ketene N,O-acetals on a large scale, with little competitive C-silylation. 7 A number of catalysts were screened for this reaction. Wilkinson's catalyst (Rh(PPh3)3CI) worked best for less reactive silanes such as triethylsilane and triethoxysilane while Pd(CH3CNhCh worked better for the more reactive chlorodimethylsilane. These hydrosilylations produced the O-silyl ketene N,O-acetal fairly cleanly; a small amount (510%) of siloxane (R3SiOSiR3) was also formed as a by-product. 4 o CH3"N~ OSiR 3 Rh( PPh 3hCI ( 0.1-0.2 I molO/~ CH 3 " N ~CH3 + I R 3 SiH CH 3 CH 3 Table I N,O-acetal R Time {h2 Tem2{oq 1 Et 10 50 2 OEt 3 65 Solvent %Puri~b %Yield a C6H6 65 90 79 93 aRepresents total distilled yield including impurity. bMajor impurity is siloxane; represents %purity by weight, as determined by 1H NMR. O-Silyl ketene N,O-acetals 1 and 2 reacted without catalysis with benzaldehyde at -30°C to 0 °C.8 PhCHO • -30°C 1 3 80% anti:syn 1.8:1 4 2 5 53% anti:syn 6.2:1 6 This type of reactivity is not completely unprecedented; Creger reported that an O-silyl enol derivative of an ester (O-silyl ketene acetals) reacted with benzaldehyde at 150°C to afford the aldol adduct in 68% yield (relative stereochemistry not reported).9 PhCHO, 18 h, 150°C 68% 5 Aldol reactions of O-silyl ketene N,O-acetals are dramatically accelerated as compared to reactions of the corresponding O-silyl ketene acetals. O-Silyl ketene N,Oacetal 1 was observed to react with benzaldehyde at -78°C, although reactions conducted at higher temperatures (-30°C) afforded higher yields of aldol products. The reaction of 1 with benzaldehyde was slightly anti selective (1.8:1). When the ligands on silicon were changed from ethyl to ethoxy the reaction rate decreased while the anti selectivity increased (6.2: 1). Anti selectivity is unusual for Z enolates.2 The syn selectivity observed with most Z enolates is often explained by invoking a chair transition state. 10 The chair transition state leading to the syn product contains fewer unfavorable 1,3diaxial interactions than the chair transition state leading to the anti product. Consistent with this analysis, E enolates are generally anti selective, though E enolates are often less diastereoselective than Z enolates.2 Thus the d~velopment of anti selective aldol reactions remains a challenging problem. ~ X)H H ~ ," .' r-- .' (1 .0// ' L o • RR' o • OH X~R' R To address the stereochemical issue of differentiation between the two possible anti aldol products, chiral O-silyl ketene N,O-acetals were examined. We chose to prepare cyclic O-silyl ketene N,O-acetals from prolinol (e.g., 7) for several reasons: (1) 6 the chiral auxiliary prolinol is readily available in both enantiomeric forms, (2) the derived secondary amide should selectively enolize in the Z fonn,3 and (3) the fonnation of a bicyclic system should impart more rigidity to the O-silyl ketene N,O-acetal and hopefully increase diastereoselectivity. 1) LOA, THF, -78°C • 778% Initial attempts to synthesize the desired O-silyl ketene N,O-acetal 7 from the corresponding acrylamide, in analogy to the experiments described previously, were abandoned due to the instability of the acrylamide. A second route involving condensation of the dianion (prepared from prolinol propionamide and 2 equiv of LDA at -78°C) with dichlorodimethylsilane was investigated. In the optimized procedure, dichlorodimethlysilane was added to a solution of dianion at room temperature. Concentration and distillation afforded O-silyl ketene N,O-acetal 7 as a water-sensitive liquid in 78% yield. Irradiation of protons NCH2 led to an nOe enhancement of the vinylic proton of 7 supporting the assignment of Z stereochemistry for the double bond. The enolization was highly selective; none of the E isomer could be detected by BC or IHNMR. 7 Table II. Synthesis of O-Silyl ketene N,O-acetal 7 Me2SiCl2 Base Ratio of % Yield c Addition Temperature (oq 7:8 -78 LDA 1:0 49 0 LOA 1:0 58 23 LOA 1:0 78 oa LOA 8.4:1.0 66 -78 b LOA 8.4:1.0 23 LHMOS 23 KHMOS 1:l e 1:l e aInverse addition (lithium enolate to Me2SiCI2). bRatio determined from integration of crude NMR. cOistilled yield. The yield of 7 was strongly dependent upon the temperature at which the dichlorodimethylsilane was added. The major by-products in this reaction appeared to be polymeric; formed when the dichlorodimethylsilane reacted with two different molecules of lithium enolate. The amount of polymer decreased as the temperature of dichlorodimethylsilane addition increased - correspondingly higher yields of O-silyl ketene N,O-acetal 7 were obtained (Table II). Inverse addition (lithium enolate to dichlorodimethylsilane) also decreased the amount of polymer, but a new impurity was formed. Removal of this impurity, tentatively assigned as 8, was especially problematic 8 since it co-distilled with the desired product. A two-step synthesis in which one of the silicon-oxygen bonds was preformed (by addition of dichlorodimethylsilane (10 equiv) and triethylamine to the prolinol propionamide prior to enolization) also produced 7, but the reaction was not as clean. The alternative bases lithium hexamethyldisilazane and potassium hexamethyldisilazane failed to enolize the amide completely as determined by 1H NMR of crude reaction mixtures. Reaction of O-silyl ketene N,O-acetal 7 with benzaldehyde at room temperature produced adducts 9 and 10 in a 39:1 ratio. 8 23 °e, 24 h • 977% 102% Anti aldol product 9 crystallized directly from the reaction mixture in 77% yield. The anti stereochemical assignment of 9 was suggested by the observation of a 9.7 Hz coupling constant between protons H2 and H3. X-ray crystallography confirmed the assignment and further established the product as the (2S,3R)-anti stereoisomer (Figure 1).11 This product results from attack of the aldehyde on the more hindered concave face of the enolate, supporting the idea that the aldehyde is directed to that face by prior coordination, perhaps in a cyclic transition state. The reaction takes place readily in noncoordinating solvents (CH2Ch, hexanes, benzene) but is slow in coordinating solvents (THF, DMF), an observation supporting coordination of the aldehyde to the silicon. 9 0 T- I , # &0- M '(6 J: ! (.) I ~- 0 CJ) I M ---0 o M t- ~ 0 .Q t- 10 Interestingly, the reaction is quite rapid in acetonitrile, which is often considered a coordinating solvent. However; acetonitrile coordination usually contains a large 7t backbonding component and silicon is a poor 7t acceptor. The rate of the reaction in hexanes (E = 2) is similar to that in acetonitrile (E = 37) a fact which disfavors mechanisms that involve highly polar transition states (e.g., an open transition state). The formation of monomeric 9-membered ring siloxanes is also suggestive of a pericyclic transition state. These products (9 and 10) appear to be unstable with respect to polymerization and can not be formed directly from the diols and difunctional silicon compounds «CH3hSiCI2, (CH3hSi(N(CH3n)), even under high dilution conditions. A small amount (2%) of syn aldol adduct 10 was also isolated from the reaction mixture. The syn stereochemical assignment is suggested by the small coupling constant (3.9 Hz) between protons H2 and H3. X-ray crystallography11 establishes the product as the (2S, 3S)-syn stereoisomer, resulting from attack on the same 7t face of the enol ate, but the opposite 7t face of the aldehyde. No products resulting from attack on the convex face of the enolate were observed. Crystal structures 9 and 10 provide insight into the mechanism of the reaction. In each structure, the amide carbonyl lies over one face of the silicon-centered tetrahedron; with the carbonyl oxygen in van der Waals contact with the silicon. The portion of the molecule derived from the enolate reflects the original Z orientation. It is easy to visualize the hypothetical transition states Tboat and T chair within structures 9 and 10 by reversing the bond formation of the aldol reaction. More accurately, the transition states are viewed to lie somewhere between Tboat and 9, and T chair and 10; however, for simplicity they will be referred to as Tboat and T chair. The important features of these hypothetical transition states are: (1) the silicon is trigonal bipyramidal, (2) the enol oxygen is apically bonded to the silicon through a p-type orbital, and (3) the aldehyde is 11 'equatorially bonded to the silicon through the carbonyl lone pair which is trans to the phenyl ring. This transition state is supported by crystal structures of silyl enol ethers in which Si-O-C=C dihedral angles range from 60 to 120 degrees. 12 The Si-O-C angle for the enol oxygen in the hypothetical transition states Tboat and T chair, is smaller than the typical Si-O-C angle in these crystal structures (110°-150°) because the enol oxygen in these transition states is bonded to the silicon through a p-type orbital instead of a sp3 hybridized orbital. 12.13 An appealing feature of this hypothesis is that bonding of the enol oxygen to the silicon through a p-type orbital allows for continuous overlap during C-C bond formation and Si-O bond cleavage. The unusual anti selectivity of this reaction is believed to result from a boat-like transition state (as represented in Tboat) and stands in contrast to chair-like transition states invoked for other metalloenolate reactions. The minor stereoisomer is believed to be produced by a chair transition state. Two possible reasons for this preference are suggested. First, the boat transition state provides better overlap between the 1t systems of the aldehyde and the O-silyl ketene N,O-acetal. Second, the boat transition state lacks the unfavorable sterle interaction between the interior hydrogen on the CH20 and the aldehyde proton which is present in the chair transition state. The latter is probably not solely responsible for the anti selectivity observed since the achiral O-silyl ketene N,Oacetals 1 and 2 are also anti selective. Aldol reactions of O-silyl ketene N,O-acetal 7 with aliphatic aldehydes are found to proceed with even greater diastereoselectivity than with benzaldehyde (Table III). The stereochemistry of the aliphatic aldol adducts is assumed to be analogous to the stereochemistry observed with the benzaldehyde adduct, an assertion supported by the similarity in coupling constants between protons H2 and H3 exhibited by these products (123 = 9.7,9.7, and 9.3 Hz for R = Ph, i-Pr, and Et, respectively). 12 Table lIT. Diastereoselective Addition Reactions of 7 with Aldehydes RCHO Diastereoselectivitya C2S)-anti b % (2S)-anti %(2S)-syn %(2R)-anti,syn yield (%)C mp (OC) Ph- 97.2 2.5 0.3 77 50-51 77-79 i-Pr0.8 68 98.5 0.7 33-35 Et1.0 58 1.3 97.7 aBased on capillary GC and highfield NMR analysis of crude reaction mixtures. Numbers for (2S)-diastereomers are minimum values. bMaximum combined yield of (2R)-diastereomers as estimated by capillary GC. CIsolated yield of pure (2S)-anti diastereomer. The Si-O bonds of the 9-membered ring siloxanes are relatively stable to hydrolytic cleavage, and the siloxanes can be isolated by crystallization or by silica gel chromatography.14 Further investigation reveals that the yields of aldol products can be improved by employing higher reaction temperatures, with little decrease in diastereoselectivity. Reaction of benzaldehyde with O-silyl ketene N,O-acetal 7 at 60°C gave pure 9 in 88% isolated yield. Interestingly, crotonaldehyde reacted with 7 in a predominantly Michael fashion to produce a 7:1 ratio of two diastereomeric ll-membered ring O-silyl enol ethers (stereochemistry not known). + 7 73% (7:1) 5% It is worthwhile to compare the diastereoselectivity of aldol reactions of 7 with the existing methods for anti aldol bond construction (Table N).15 "'y':: b CH, TiCl4 13 94.4 93.5 97.4 C2HSCHO 76.4 93.7 94.9 99.6 13 12 (CH3hCHCHO CH, CH, 0 .\ 14 CH, CH, 92 14 TiCl4 CH:s 0- BOMS )='r CH3I\.-CH:s I so, OT60M5 w ...... 99.2 98.9 99.5 15 TiCl4 15 CH3~'~~ ~ CH'rq:N~CH' jp'~ N(CH'l' OTMS Diastereoselectivity (%) 12 CH3 95.1 CF, Y 97.2 11 CH. C6HsCHO "> '. )-PfI /B'N o.s'N-\ 11 7 o-S\,. 7 Aldehyde Lewis acid Ketene N,O-acetal ~,/ SH:s CH . o?,b L f8uO\ o;yyCF, E"cs~ci. Table Iv 1Sa-e 14 These methods often require lengthy syntheses (11 and 12), expensive starting materials (14 and 15) or Lewis acid co-reagents (13, 14 and 15). Interestingly, O-silyl ketene N,Oacetal 15 is the only other substrate which has a Z configuration. It has been proposed that the aldol reaction of 15 proceeds by an open transition state, rather than the boat transition state believed to operate in our system. 15e As previously mentioned, the solvent effects and product structures in the reaction of O-silyl ketene N,O-acetal 7 with benzaldehyde suggested an associative mechanism in which the aldehyde binds to silicon prior to aldol condensation (equation 1).16 7 + PhCHO {7· PhCHO} 9 (1 ) ? Because of the unique features of this reaction, we decided to study it in more detail. Kinetic analysis of the reaction of 7 with benzaldehyde over a 6O-degree range showed that it was second-order overall, and fIrst-order in each reagent.1 7 ,18 The following activation parameters were obtained from the Eyring plot: ~H* = 12.0 ± 0.5 kcaVmol and ~S* = -41 ± 2 eu. Both the reaction order and the large negative entropy of activation are consistent with the associative mechanism proposed in equation 1. Eyring Plot Reaction of 7 with Benzaldehyde -5.8 -6 -6.2 f .:0: ..., '-' ! -6.4 -6.6 -6.8 -7 -7.2 -7.4 2.8 2.9 3 3.1 3.2 Iff x 10· 3 (lIOK) 3.3 3.4 3.5 15 Reaction of 7 with a 1: 1 mixture of C6HSCHO:C6HsCDO (10.5 equiv) afforded the anti aldol adduct 9 disproportionately enriched in deuterium (50% yield). The calculated secondary isotope effect (kH/kD = 0.76) is close to the theoretical maximum (-0.71),19 suggesting the existence of a later transition state, involving carbon~arbon bond formation instead of aldehyde coordination. The direction of the deuterium isotope effect (kHlkD < 1) supports the proposed mechanism wherein the hybridization of the carbon bonded to HID undergoes an increase in p-character. 20 Kinetic analysis of the reaction with a series of para-substituted benzaldehydes showed that electron-withdrawing groups greatly accelerate the reaction (Hammett p = 3.5 ± 0.2).21 Hammett Plot ·2 Reaction of 7 with para-substituted benz aldehydes .~ ·3 .6 MeO ·7~---'r---.---~~~~---.----.---~ ·0.4 ·0.2 o 0.2 0.4 0.6 0.8 1 (j para This result also supports a later transition state, involving carbon~arbon bond formation. By contrast, rate-determining aldehyde coordination would be anticipated to exhibit a negative p value. 22 At high a values the Hammett plot becomes nonlinear, indicating a change in mechanism. This is interpreted as a shift towards an earlier transition state involving aldehyde complexation. The positive p value is likely attributable to a 16 destabilization of the ground state by electron-withdrawing groups, rather than a stabilization of the transition state. 23 The hypothetical transition state Tboat contains equatorially-bound aldehyde. Direct formation of Tboat requires attack on the edge of the silicon-centered tetrahedron. 24 1. ' .. -~ 'lin .. B" ;;Y--:JH3) _t.··D~1~H3 H3 Tboat X Alternatively, formation of Tboat may arise by facial attack of benzaldehyde, forming trigonal bipyramid X. One or more pseudorotations (",n) then may transform this intermediate with apically-bound benzaldehyde into Tboat. 25 This theory is more consistent with the consensus of mechanistic and theoretical studies concerning pentavalent silicon since it allows for apical attack of the aldehyde. 24 ,25 .. : :a /!. :: ~1 • A' ,., :., B3-"'~E!s ,,~ 4 • .. ~~ First proposed in 1960, Berry pseudorotation is the most commonly invoked mechanism for interconversion of two isomeric trigonal bipyramids. 27 ,28 The process is 17 believed to go through an intermediate square-pyramid which is accessed by simultaneous opening of the B4ABS angle and closing of the BIAB2 angle. For a trigonal bipyramid with five different ligands there are twenty unique isomers. Each trigonal bipyramid can be converted into three other isomers by pseudorotation around one of its three equatoria1ligands. These isomers and the pseudorotations interconverting them can be represented by the Desargues-Levi graph shown below. 29 34 . .. . .. ,.-_. ' 35 "" - ' ·· · ......;;·.. ' I I I I :13 .. ,,, - ...... .. "' .. ",... .. . ' ' '. '. '. 23·~-------------- ... ......... -: - .24 '. ' 45 1. ~:--'13 I 14 : .. ..\. .......... "." ,#"" 35 45 34 Deargues-Levi graph projected on a plane. Vertices represent isomeric tbps and the lines represent pseudocotations interconverting those structures. Each isomer is designated by the indices of its apical ligands. Thus 14, has ligands 1 and 4 apical and 1 4" is its mirror image.26b 18 Analysis of all possible tbp isomers of {7 ·PhCHO} is simplified by the presence of two identical ligands. This reduces the number of possible stereoisomers from 20 to 10. The graphical representation of these isomers can be represented by the trigonal prism shown below. The dots on the graph represent the tbp isomers and the lines represent pseudorotations interconverting those isomers. 25b The center point of the prism represents the structure where the two identical ligands are axial. The other points in the central plane represent structures where the two identical ligands are equatorial. The graph can be further simplified for the 7-membered ring O-silyl ketene N,Oacetal 7. The isomer which requires the 7-membered ring to span the axial positions can be eliminated from further consideration (this structure is extremely strained) thus reducing the number of plausible structures to nine (Figure 2). Study of this figure shows that isomer T lies one pseudorotation from isomers G and A, each with apically-bound benzaldehyde. The other two tbps with apically-bound benzaldehyde (E and C) require at least two pseudorotations to form T. 19 Yj ''''tt H3 - ~...J T (1~~ t
_---phCHO---__. T ~~ F CH 3 ~ _HH' "I::~ ~~ H E __----OCH2-----.-----enol----~ A A CH3 E ,H3)=<~.~"q", CH3 ~---PhCHO----~ CH.·~-~ H~- H. B o c c Figure 2. A graph of all tbp O-sUyl N,O-acetal '-benzaldehyde complexes and pseudorotational paths interconverting these isomers (the isomer where the 7-membered ligand spans axial positions is omitted). 20 Attempts to observe any reaction intermediates, by 13C or 1H NMR were unsuccessful. Solutions of benzaldehyde (1.6 M) and 7 (1.3 M) in Q,DSCD3 showed no evidence of complex formation between -80°C and 23°C. Thus, if an equilibrium between PhCHO and (PhCHO·7} exists, it lies far to the left (Keq ::;; 0.03). A number of other complexing agents were also examined with O-sHyl ketene N,O-acetals 7 and 16 (Table V, vide infra). ~H3 CH 3 ~.I , I "'bAr"' 7 Reagents (cone., M) :pH 3 H3 Table V H 16 Upper limit for N,O-acetal Lewis base solvent Comments Estimated detection limit for complex formation (%) 7 (1.3) PhCHO (1.6) toluene no complexation 3a 0.03 7 (1.3) HMPA (1.5) toluene Sa 0.07 7 (0.13) DMF (d7) (12) DMF 20b 0.02 7 (0.07) THF (dS) (11) THF 20b 0.02 7 (0.66) TASF(0.71) THF decompositionc 7 (0.66) KOt-Bu (1.3) THF potassium enolate 16 (1.1) HMPA (1.6) toluene no complexation Sa 0.12 16 (Ll) DMF(4.1) toluene 3a 0.03 16 (0.86) TASF (0.76) THF decompositionc 16 (0.46) KOt-Bu (0.76) THF potassium enolate Deuterated Keq aDetermined from 13C chemical shifts of Lewis base. bDetermined from 1H chemical shifts of O-silyl ketene N,O-acetal. 'No enolic peaks other than starting material observed. 21 Only potassium tert-butoxide reacted cleanly with either O-silyl ketene N,O-acetal. The reaction product formed from 16 and KOt-Bu displayed a peak at 8 7 in the 29Si NMR spectrum, suggesting formation of the potassium enolate rather than a pentavalent silicon complex.3 0 • 16 It is interesting to note that pathways which involve odd numbers of pseudorotations invert the configuration of the central atom. In the case of 7 and 16 reversible complexation of benzaldehyde interceded by an odd number of pseudorotational steps will serve to exchange the diastereotopic methyl groups. We never observed coalescence of the methyl groups under any conditions and thus conclude that a hypothetical reaction path such as G~T ~F ~G is slow on the NMR time scale. Although direct experimental evidence for a tbp precursor does not exist, some indirect information is available from a parallel study, in which Dr. Paivi Kukkola synthesized the O-silyl ketene N,O-acetaI17 derived from (lR,2S)-ephedrine.3 1 Dr. Kukkola found that 17 did not react with benzaldehyde, even under forcing conditions (110°C, slow addition of 17). 22 o + d'" No Reaction The analogous transition state (T e)31 for substrate 17 appears quite reasonable and offers no explanation for the lack of reactivity of 17 (see page 23), However, consideration of the tbp precursors of 17 suggest a rationale for the observed reactivity difference between 7 and 17. Derivation of the pseudorotational pathway is easier when the process is analyzed in reverse. Of the three tbps accessible from T e by a single pseudorotation only G e31 explains the experimental results observed. Examination of G e reveals a severe steric interaction between the methyl group on the 7 -membered ring and the apical aldehyde. Since G e contains apically-bound benzaldehyde it can be immediately decomposed to 7 and benzaldehyde without further pseudorotation. In contrast, the structures A e 31 and F e 31 do not appear to be sterically encumbered. A pathway involving Fe is unlikely because this pathway requires pseudorotation around benzaldehyde which is the most apicophilic ligand. At present, it is unclear which features disfavor Ae. It may be the case that attaek of benzaldehyde on 17 to form Ae is disfavored for sterie reasons. 23 T. CH 3 CH W,C~CH3 '-. 3 H ~ OI' •. ..• '\O 'l'OCHPh I'CH 3 :- °oH '1 ~ 'l'RCHO :. Inspection of the tbp G e suggests that a viable intennediate might be produced by epimerization of the axial methyl group on the enolate ligand. To test this theory the (lS,2S)-pseudoephedrine-derived O-silyl ketene N,O-acetaI16 was synthesized.3 2 24 60°C, 64 h 1870% + 16 20 19 O-Silyl ketene N,O-acetalI6 reacted with benzaldehyde at 60°C to fonn the (2S,3R)-anti aldol product 18 in 70% yield. Analysis of the 1H NMR spectrum of the crude reaction mixture showed three isomers (18, 19, and 20) were present in a 9.2:1.0:1.7 ratio, respectively. isomer. 33 X-ray analysis establishes the major product 18 as the (2S,3R)-anti The similarities between this structure and the prolinol-derived crystal structure 9, support but do not prove a common reaction mechanism. Crystal Structure of 18 Crystal Structure of 9 25 The relative stereochemistry of the C2 and C3 centers in siloxanes 19 and 20 was tentatively assigned by converting the siloxanes to their respective diols 22 and 23 and examining the coupling constant between protons H2 and H3 (123 = 8.3 and 5.6 Hz for diols 22 and 23, respectively). O ... X I 3 CH CH3 ,." CH O-Si 3 N:tol" 0 '0 I - CH 3 CH 3 ~ 18 19 MaOH These coupling constants suggested a syn stereochemical assignment for 20 and an anti stereochemical assignment for 19 (the protons HI' and H3 were assigned by spectroscopic analysis of the products isolated from reaction of 16 with C6HSCDO).2 For the purposes of comparison, the major product 18 was also desilylated; the resulting diol 26 had a proton coupling constant (123) of 7.7 Hz, consistent with the anti stereochemical assignment determined from the X-ray crystal structure. The absolute stereochemistry of C2 and C3 of the syn stereoisomer 20 was tentatively assigned by examining the 1H NMR spectrum of this compound. Proton HI' was much more de shielded in isomer 20 (0 5.99) than in either isomer 18 (0 4.39) or 19 (15 4.54). H118,19,2O H1' 20 H1'18 H1'19 Midfield region of 1H NMR for crude reaction mixture from reaction of 16 with benzaldehyde Models of the (I'S,2'S,2R,3R)-syn stereoisomer predict that the HI' proton will be about 2A away from the carbonyl oxygen which could lead to significant deshielding. There is no obvious reason why proton HI' should be shifted so far downfield in the (l'S,2'S,2S,3S)-syn stereoisomer. (1' S,2'S,2R,3R)-syn stereoisomer 20 (1'S,2'S,2S,3S)-syn stereoisomer 27 An examination of the four hypothetical transition states gives a possible explanation for the selectivity observed. attack on attack on Si face of enolats Si face of enolate Anti-18 Syn not observed attack on attack on Re face of enolate Re face of enol ate Anti-19 Syn-20 Attack appears to occur predominantly from the Si face of the enolate, via a boat-like transition state.3 4 This transition state is probably favored for considerations of overlap. The syn product resulting from attack on the Si face of the enolate is not observed because in the corresponding chair-like transition state there appears to be a unfavorable sterlc interaction between the aldehydic proton and the HI' proton on the enolate. The 1t overlap also seems poor in this transition state. Attack from the Re face of the enolate also occurs to a limited extent and may be disfavored by poorer overlap. It is interesting to note that attack at the Re face favors syn aldol formation. 28 The hypothetical transition states resulting from attack at the Re face of the enolate have the p-orbitals of the equatorial OCHPhR ligands parallel to the equatorial plane while in the other transition states this orbital is perpendicular. Calculations on pentavalent phosphorous indicate that the former orientation is favored thermodynamically for 1t donors,35 although the larger radius of silicon should diminish the importance of this effect. 36 In any case, these effects are apparently outweighed by the better 1t overlap obtained by attack on the Si face of the enolate from a boat transition state. Models suggest that it is difficult for the nitrogen lone pair to conjugate fully with the enol double bond when attack occurs at the Re face of the prolinol-derived O-silyl ketene N,O-acetal 7. This may be responsible for the almost perfect facial selectivity of 7. attack on Re face of enolatB not obselV8d Although crystal structures of O-sHyl ketene N,O-acetals I2 and lithium amide enolates 37 show that the nitrogens are at least partially pyramidalized and hence not fully conjugated with the enol double bond, it is reasonable to assume that conjugation might be a necessary condition for these (late) aldol transition states, since planar amides are produced. I I In summary, we have discovered that O-silyl ketene N,O-acetals undergo aldol condensation without catalysis. The chiral O-silyl ketene N,O-acetal 7 reacts with 29 aldehydes at room temperature to produce a single anti diastereomer, with> 98% diastereoselectivity. The unusual selectivity observed for this Z enolate is rationalized by invoking the boat transition state Tboat. Since Tboat contains apically-bound aldehyde, it is probably not formed directly by attack of the aldehyde on the O-silyl ketene N,O-acetal 7. Instead the silicon-centered tetrahedron suffers facial attack forming G. This trigonal bipyrarnid then undergoes pseudorotation about the OCH2 ligand to form the transition state Tboat. ... ? G ?d?' ~H'> Ll..,"'::-\I~H3 6H3 9 Tboat Although other mechanisms are not ruled out, this is the simplest mechanism which explains the differences in reactivity observed with the ephedrine- and pseudoephedrinederived O-silyl ketene N,O-acetals. Kinetic analysis of the reaction is consistent with the 30 associative mechanism shown and suggests that carbon-<:arbon bond formation is involved in the rate-detennining step. 31 Experimental Section Melting points were recorded with a Blichi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded with a Beckman 4240 Infrared spectrometer or a Perkin Elmer 1600 FTIR spectrometer. Data are represented as follows: frequency of absorption (cm- 1 ), and intensity of absorption (s=strong, m=medium, w=weak, br=broad). The IH NMR spectra were recorded on a JEOL JNMGX400 (400 MHz) NMR spectrometer; peaks are reported in ppm (8 scale), using the residual solvent peak as reference (CHCI3:7.26, C6DsH:7.15). Data are represented as follows: chemical shift, multiplicity (s=singlet. d=doublet. t=triplet, q=quartet, qn=quintet, m=multiplet, br=broad), integration, coupling constants in Hertz, and assignment. The 13C NMR were obtained on a JEOL FX-90Q (22.5 MHz) or a JEOL JNM-GX400 (100 MHz) NMR spectrometer and are reported in ppm (8 scale) using the solvent as reference. The 29Si NMR were obtained on a JEOL FX-90Q (17.87 MHz) or a JEOL JNM-GX400 (79.43 MHz) NMR spectrometer and are reported in ppm (8 scale) using tetrarnethylsilane (0 ppm) as reference. Combustion analyses were performed by Mr. Fenton Harvey (California Institute of Technology). Crystal structures were obtained by Dr. Bill Schaefer, Dr. Richard Marsh, and Mr. Lawrence Henling (California Institute of Technology). Mass spectra and high resolution mass spectra were obtained from the UC Riverside Mass Spectrometry Facility. Analytical gas-liquid chromatography (GC) was carried out on a Hewlett Packard 5890 gas chromatograph equipped with a splitless mode capillary injection system and a flame ionization detector, using a 25 m x 0.2 mm x 0.5 Jlm HP-5 flexible, fused silica capillary column coated with 5% Phenyl Methyl Silicone or a 25 m x 0.25 mm Alltech Chirasil-Val III chiral fused silica capillary column. Data are reported as follows: column type, oven temperature, and retention time. 32 Liquid chromatography was performed using a forced flow (flashchromatograpy)38 with the indicated solvent using JT Baker Silica Gel (40 Ilm) or Merck Silica Gel 60 (230-400 mesh ASTM). Analytical thin-layer chromatography was performed using Merck pre-coated silica gel 60 F-254 plates (0.25 mm, glass-backed, fluorescent at 254 nm). Tetrahydrofuran and diethyl ether were distilled from sodium-benzophenone ketyl. N,N-Dimethylformamide, acetonitrile, methylene chloride, hexanes, pyridine, triethylamine, diisopropylamine, and HMPA were distilled at reduced pressure from calcium hydride. Benzene and toluene were distilled from sodium. Toluene (d9), C6D6, and 1,1-diphenylethylene were dried over activated 3-A molecular sieves. N,N- Dimethylformamide (d7), and CD2CI2, were vacuum transferred from CaH2 and stored in the glove box. Tetrahydrofuran (d8) was vacuum tran'sferred from sodium-benzophenone ketyl and was stored in a nitrogen-filled glovebox. All nonaqueous reactions were performed in flame-dried glassware under argon, unless otherwise noted. Deoxygenation of solutions was accomplished by evacuating and flushing the solutions with argon five times, unless otherwise specified. Organic solutions were concentrated on a Biichi rotatory evaporator at 10-20 Torr, unless otherwise specified. Solvents used in the workup and purification of compounds were HPLC-reagent grade and were used without further purification. Benzaldehyde and dimethyl acrylamide were distilled from CaH2 under reduced pressure. Propionaldehyde, isobutryaldehyde, and crotonaldehyde were distilled from CaCl2 immediately prior to use. Triethylsilane, triethoxysilane and oxalyl chloride were distilled prior to use. Dichlorodimethylsilane was distilled from magnesium. Potassium tert-butoxide was sublimed under vacuum (0.1 Torr) and stored in a nitrogen-filled 33 glovebox. The molarity of n-BuLi was determined by titration against diphenylacetic acid.3 9 All other reagents were used as received. 34 • THF, 0.5 h, 23°C 92% Synthesis of (1 'S.2'S)-Pseudoephedrine Propionamide Propionic anhydride (21.3 mL, 166 romol, 1.1 equiv) was added over 10 min to a solution of (lS,2S)-(+)-pseudoephedrine (25.0 g, 152 romol, 1.0 equiv) in THF (250 mL). The solution was stirred for 30 min, then was partitioned between ethyl acetate (250 roL) and saturated aqueous sodium bicarbonate solution (200 mL). The organic layer was separated and the aqueous layer was washed with two 200-mL portions of ethyl acetate. The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Recrystallization of the solid product (70% ether-CH2Ch), afforded two batches of (l'S,2'S)-pseudoephedrine propionamide (30.57 g, 92%, mp: 114.5-115.0 °C) as a white, crystalline solid. Cl'S.2'S)-Pseudoephedrine Propionamide Crotameric mixture) 7.00-7.38 (m, 5H, aroro), 4.88 (s, IH, OH), 4.52 (t, IH,1=6.0, HI'), 4.19 (s, IH, OH), 4.12 (t, IH, 1=8.0, HI'), 3.68 (ro, IH, H2'), 3.07 (ro, IH, H2'), 2.78 (s, 3H, NCH3), 2.44 (m, 2H, H2), 2.08 (s, 3H, NCH3), 1.73 (m, 2H, H2), 1.21 (t, 3H, 1=7.5, H3), 1.01 (t, 3H, 1=7.5, H3), 0.95 (d, 3H, 1=8.0, H3'), 0.55 (d, 3H, 1=8.0, H3'). 35 FTIR (neat film), em-I: 3378 (m), 2966 (m), 1614 (s), 1449 (m), 1402 (m), 1402 (w), 1296 (w), 1120 (w), 1049 (m), 1020 (w), 767 (w), 703 (m). MS (CI:NH3): 222 (MH+), 204 (MH+-H20). HRMS (CI:NH3): Calculated for C13H20N02Si (MH+): 222.1494 Found: 222.1488 TLC (ether): Pseudoephedrine propionamide 0.51 (UV) Pseudoephedrine 0.05 (UV) 36 o CH 3 'NN Rh(PPh 3 hCI ( 0.1 mol%) • I OSiEt3 C""7-\-C"' CH 3 CH 3 H 159% Q-Silyl Ketene N.O-Acetal 1 Triethylsilane (10.0 mL, 62.6 mmol, 1.0 equiv) was added rapidly to a solution of Rh(PPh3hCI (0.058 g, 0.062 mmol, 0.0010 equiv) in N,N-dimethylacrylamide (6.45 mL, 62.5 mmol, 1.0 equiv). The reaction mixture was warmed to 50°C and was held at that temperature 10.5 h (the solution darkened within 30 min). The mixture was distilled at reduced pressure (70-77 °C, 2 Torr) to·afford 1 (7.89 g, 65%, 90% pure by weight). O-Silyl Ketene N,O-AcetaI1 3.72 (q, 1H, 1=10.0, olefinic), 2.31 (s, 6H, NCH3), 1.75 (d, 3H, 1=10.0, CH3), 1.03 (t, 9H, 1=12.0, SiCH2CH3), 0.71 (q, 6H, 1=12.0, SiCH2CH3)· FTIR (neat film), em-I: 2954 (s), 1665 (s), 1458 (m), 1413 (m), 1381 (m), 1332 (s),1239 (m), 1165 (s), 1083 (m), 1044 (s), 1007 (m), 860 (m), 730 (m). MS (CI:NH3): 37 o CH 3 ...... N N I CH 3 OSi(OEtb Rh(PPh 3 bCI (0.2 mol%) • C6 H6 , (EtObSiH, 65 ac, 2 h ~ ... CH CH 3 ...... N, " CH 3 "I 3 H 273% (24:1 Z:E) Q-SHyl Ketene N.o-Aceta12 Triethoxysilane (30.0 mL, 16 mmol, 1.0 equiv) was added to a solution of Rh(PPh3hCI (0.250 g, 0.27 mmol, 0.0020 equiv) and N,N-dimethylacrylamide (17.6 mL, 171 mmol, 1.0 equiv) in benzene (20 mL). The reaction mixture was heated at 65°C for 2 h. The reaction mixture was cloudy after 1 h and completely black after 2 h. Analysis of an aliquot of the reaction mixture by 1H NMR indicated that the reaction was complete. Benzene was removed under vacuum (0.10 Torr), and the residue was fractionally distilled (45-50 °C, 0.07 Torr) producing 2 (24:1 Z:E-mixture, 34.0 g, 79%, 7% impurity by weight) as a light yellow, moisture-sensitive liquid. Q-Silyl Ketene N.O-Aceta12 3.92 (q, 6H, 1=7.2, SiOCH2CH3), 5.19 (q, IH, 1=7.5, olefinic), 2.42 (s, 6H, NCH3), 2.49 (d, 3H, 1=7.2, CH3), 1.18 (t, 9H, 1=7.5, SiOCH2CH3). FTIR (neat film), em-I: 2976 (m), 1671 (m), 1479 (w), 1457 (w), 1396 (w), 1336 (m), 1168 (m), 1086 (s), 969 (m), 884 (m), 792 (m), 739 (m). MS (EI): 262 (MH+), 206 (MH+-CH3CHCO). 38 HRMS (EI): Calculated for CllH24N04Si (MH+): 262.1474 Found: 262.1478 39 OH b H"" 0 II 1) LOA, THF, -78°C N~CH3 _ _ _ _ _ _ _ _ .. 2) (CH3)2SiCI2, 23°C 778% (l'S)-Q-Silyl Ketene N'o-Acetal 7 n-Butyllithium (135 mL, 63.7 mmol, 2.57 M in hexanes, 2.2 equiv) was added over 10 min to a deoxygenated solution of diisopropylamine (19.8 mL, 141 mmol, 2.3 equiv) in THF (200 mL) at -78°C. The flask was placed in an icebath for 10 min, then was recooled to -78°C. A solution of (1'S)-prolinol propionamide 39 (9.208 g, 58.6 mmol, 1.0 equiv) in THF (20 mL) was then added by cannula to the LDA solution. The transfer was quantitated by rinsing the flask with two 10-mL portions of THF. The reaction mixture was stirred at -78°C for 1 h, at 0 °C for 1 h, and then was diluted with THF (500 mL) at 0 °C. The reaction mixture was warmed to 23°C and (CH3hSiCi2 (4 mL, 33.0 mmol, 1.13 equiv) was added rapidly over 5 min. After the reaction mixture was stirred for 30 min, all the volatile components were removed under vacuum (0.1 Torr). The residue was taken up in toluene (15 mL), and a fine precipitate formed. The precipitate was allowed to settle and the supernatent was decanted by cannula from the solid. The transfer was quantitated with two lO-mL portions of toluene. The combined toluene washes were concentrated under vacuum (0.1 Torr). The product was carefully distilled (KUgelrohr, 100°C, 0.04 Torr) affording pure (1'S)-7 (9.70 g, 78%) as a nonviscous, clear liquid. 40 (l 'S)-O-Silyl Ketene N.O-Acetal 7 3.71 (q, 1H, J=6.5, H2), 3.52 (dd, 1H, J=1.5, 9.4, H5'), 3.41 (m, lH, HI'), 3.35 (dd, IH, J=9.4, 10.5, H5'), 2.86 (m, 1H, H4'), 2.81 (m, 1H, H4'), 1.91 (d, 3H, J=6.5, H3), 1.31 (m, 3H, H2', H3'), 0.87 (m, 1H, H3'), 0.31 (s, 3H, SiCH3), 0.29 (s, 3H, SiCH3) 150.9, 74.9, 70.9, 62.0 , 50.4, 28.0, 24.6, 10.7, -1.8, -3.3. 29Si NMR (18 MHz, C4DSO): -8 FTm (neat film), em- 1 : 2916 (m), 1667 (s), 1339 (s), 1296 (s), 1260 (s), 1184 (s), 1118 (s), 1060 (s), 861 (s), 798 (s). MS (FAB): 436 (MH++3(CH3hSiO), 362 (MH++2(CH3hSiO), 288 (MH++(CH3hSiO), 214 (MH+). HRMS (FAB): Calculated for ClOH20N02Si (MH+): 214.1263 Found: 214.1260 41 ELEMENTAL ANALYSIS: Calculated for ClOH19N02Si : C, 56.30; H, 8.98; N,6.S7. Found: C, 56.36; H, 8.61; N, 6.20. 42 1) LOA, THF, -78°C • (1 '5,2'S'l-O-Silyl Ketene N.O-Acetal 16 n-Butyllithium (20,0 mL, 2,50 M in hexanes, 50 mmol, 2,2 equiv) was added over 5 min to a deoxygenated solution of diisopropylamine (7,0 mL, 51 mmol, 2,2 equiv) in THF (300 mL) at -78°C, After 5 min at -78 °C, the solution was placed in an icebath for 10 min, The reaction mixture was recooled to -78°C and a solution of (1'5,2'5)pseudoephedrine propionamide (5,01 g, 22,7 mmol , 1.0 equiv) in THF (50 mL) was added by cannula over 30 min. Two 5-mL portions of THF were used to quantitate the transfer. The solution was stirred at -78°C for 3.5 h more and then was gradually warmed to room temperature over 30 min. After 30 min at 23°C, dichlorodimethylsilane (3.01 mL, 24.8 mmol, 1.09 equiv) was added over 5 min and the reaction mixture was stirred for an additional 2.5 h at 23°C, The reaction mixture was concentrated to -10 mL under vacuum (0.1 Torr). The residue was taken up in hexanes (10 mL) and a fine white solid precipitated. The supernatent was decanted off using a cannula and the transfer was quantitated with two 5-mL portions of hexanes, The combined hexanes extracts were concentrated under vacuum (0.1 Torr), The residue was purified by distillation (KUgelrohr, 100°C, 0.005 Torr) into a flask cooled with liquid N2 affording (1 '5,2'5)-16 (5.01 g, 80.0%) as a moisture-sensitive oil. 43 Cl 'S,2'S)-O-Silyl Ketene N.O-Acetal 16 7,04-7.28 (m, 5H, arom), 4.53 (d, IH,1=8.8, HI'), 3.82 (q, IH, 1=6.1, H2), 3.10 (dq, 1H, 1=8.8, 6.6, H2'), 2.32 (s, 3H, NCH3), 1.88 (d, 3H, 1=5.7, H3), 0.63 (d, 3H, 1=6.6, H3'), 0040 (s, 3H, SiCH3), 0.26 (s, 3H, SiCH3). 29Si NMR (18 MHz, C4DSO): -3 FTIR (neat film), em-I: 2964 (m), 1675 (s), 1451 (m), 1376 (m), 1317 (m), 1253 (m), 1221 (m), 1136 (m), 1077 (m), 1034 (m), 906 (m), 863 (m), 794 (m), 703 (m). ELEMENTAL ANALYSIS: Calculated for C15H23N02Si: C, 64.9; H, 8.36; N,5.04. Found: C, 64.9; H, 8.28; N, 5.37. 44 o -30 oe, 7 h 1 • 3 80% anti:syn (1.8:1) 4 Reaction of O-Silyl Ketene N.O-Acetal! with Benzaldehyde O-Silyl ketene N,O-acetal 1 (0.46 mL, 0.396 g, 1.84 mmol, 1.69 mmol corrected for impurity, 1.01 equiv) was added dropwise to a solution of benzaldehyde (0.171 mL, 1.68 mmol, 1.00 equiv) in CH2Ch (1 mL) at -78°C. The reaction was stirred 1 h at -78 °C and then wanned to -30°C. After 7 h at -30°C the reaction appeared complete, so the reaction mixture was warmed to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography (20% ethyl acetate-hexanes) afforded a mixture of 3 and 4 (0.4336 g combined, 80%, 1.75:1 anti:syn ratio), as colorless oil. A portion of the reaction mixture was further purified by thin-layer preparative chromatography (50% ethyl acetate-hexanes) to separately afford pure (±)-3 and (±)-4. Racemic Anti Aldol Adduct 3 6.95-7.50 (m, 5H, arom), 5.02 (d, IH,1=1O.0, H3), 2.92 (dq, IH, 1=7.5, 10.0, H2), 2.42 (s, 3H, NCH3), 1.92 (s, 3H, NCH3), 1.50 (d, 3H, 1=7.5, CH3), 0.91 (t, 6H, 1=12.2, SiCH2CH3), 0.57 (q, 9H, 1=12.2, SiCH2CH3). FTm (neat film), em-I: 2944 (m), 2872 (m), 1643 (s), 1490 (s), 1455 (m), 1408 (m), 1237 (w), 1079 (m), 1061 (m), 1002 (w), 820 (m), 738 (m), 697 (m). 45 MS (CI:NH3): 322(MH+), 292 (MH+-C2H6), 190 (MH+(CH 3CH2»SiOH). HRMS (CI:NH3): Calculated for ClsH32N02Si (MH+): 322.2202 Found: 322.2200 Racemic Syn Aldol Adduct 4 7.30-7.00 (m, 5H, arom), 4.97 (d, IH, 1=9.4, H3), 2.94 (dq, IH, 1=9.4,6.7, H2), 2.80 (s, 3H, NCH3), 2.58 (s, 3H, NCH3), 0.91 (t, 6H,1=7.9, SiCH2CH3), 0.83 (d, 3H, 1=6.7, CH3), 0.57 (m, 9H, SiCH2CH3). FTIR (neat film), em-I: 3389 (m), 2931 (m), 1619 (s), 1490 (m), 1449 (m), 1414 (m), 1396 (m), 1337 (w), 1302 (w), 1249 (m), 1149 (m), 1032 (m), 761 (m), 697 (m). 322(MH+), 292 (MH+-C2H6), 190 (MH+CH3CH2»SiOH). HRMS (CI:NH3): Calculated for C18H32N02Si (MH+): 322.2202 Found: 322.2206 46 TLC (50% EtOAc-hexanes): Anti aldol adduct 3 0.62 (UV) Syn aldol adduct 4 0.66 (UV) Benzaldehyde 0.75 (UV) 47 2 57% 646% Reaction of O-Silyl Ketene N.O-Acetal 2 with Benzaldehyde Benzaldehyde (0.82 mL, 8.0 rnmol, 1.3 equiv) was added dropwise to a solution of O-silyl ketene N,O-acetal 2 (2.02 mL, 1.83 g, 7.01 rnmol, 6.58 mmol corrected for impurity, 1.0 equiv) in CH2C12 (3 mL) at 0 °C. After 1 h the reaction mixture was warmed to 23°C and stirred for 5 h at that temperature. The reaction mixture was concentrated in vacuo and the residue was treated with a solution of KF·2H20 (3.13 g, 53.9 rnmol) in methanol (25 mL) for 1 hat 23°C. The reaction mixture was neutralized with solid ammonium chloride (5 g) and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solid was removed by filtration through a pad of silica gel (2 cm x 2 cm). The filtrate was concentrated in vacuo, and purified by flash chromatography (50% ethyl acetate-hexanes) affording separately (±)-5 (0.620 g, 46%, mp: 87.5-88.5 °C) and (±)-6 (0.100 g, 7%, mp: 110-111 °C) as white, crystalline solids. Racemic Anti Aldol Product 5 7.00-7.36 (m, 5H, arom), 5.15 (d, lH,1=7.0, OH), 4.80 (dd, 1H, 1=5.3, 7.0, H3), 3.98 (dq, 1H, 1=7.0, 7.0, H2), 2.41 (s, 3H, NCH3), 1.96 (s, 3H, NCH3), 1.10 (d, 3H,1=7.0, CH3). 48 FTIR (neat film), em-I: 3378 (m), 2928 (m), 1621 (s), 1493 (m), 1452 (m), 1411 (m), 1396 (m), 1258 (w), 1150 (m), 1109 (w), 1043 (m), 1017 (w), 895 (w), 757 (w), 701 (m). MS (CI:NH3): HRMS (CI:NH3): Calculated for C12HlSN02 (MH+): 208.1338 Found: 208.1340 Racemic Syn Aldol Product 6 7.5-7.08 (m, 5H, arom), 5.66 (d, 1H,1=1.2, H3), 5.19 (s, IH, OH), 2.51 (s, 3H, NCH3), 2,49 (dq, IH, 1=1.2, 7.0, H2), 2.00 (s, 3H, NCH3), 0.94 (d, 3H, 1=7.0, CH3). FTIR (neat film), em-I: 3388 (m), 2928 (m), 1621 (s), 1493 (m), 1447 (m), 1411 (m), 1396 (m), 1334 (w), 1304 (w), 1252 (w), 1196 (m), 1150 (w), 1104 (w), 1027 (m), 767 (m), 700 (s). MS (CI:NH3): HRMS (CI:NH3): Calculated for C12HlSN02 (MH+): 208.1338 Found: 208.1327 49 TLC (50% EtOAc-hexanes): Anti aldol product 5 0.19 (UV) Syn aldol product 6 0.32 (UV) Benzaldehyde 0.75 (UV) 50 CH 3 , ._,CH 3 C?H3 CH 3 ..... / O-Si,o b H,.,. N )y '- PhCHO, hexanes, CH 3 .. 23 oC, 10 h + H ,\3N°i;lPh 3' 4' 7 CH 3 102% (1 'S,2S,3R)-Anti Aldol Product 2 A solution of (l'S)-O-silyl ketene N,O-acetal 7 (0.5028 g, 2.36 nunol, 1.0 equiv) in hexanes (0.1 mL) was treated with benzaldehyde (0.25 mL, 2.4 nunol, 1.0 equiv) for 10 h at 23 °C, at which point the product had precipitated from solution. Cold hexanes (2 mL, -20 °C) was added to quantitatively precipitate the product. The crystals were collected by vacuum filtration and washed twice with two I-mL portions of cold hexanes (-20°C). Pure (I'S,2S,3R)-9 (0.5827 g, 1.82 nunol, 77%, mp: 139-142 °C) was collected as a white, crystalline solid. Synthesis of Aldol Adduct 9 under Conditions used in Kinetics Experiments A solution of (1 'S)-O-silyl ketene N,O-acetal 7 (0.300 mL, 320 mg, 1.50 mmoI, 1.0 equiv), and benzaldehyde (0.170 mL, 1.67 nunoI, 1.11 equiv) in benzene (4 mL) was subjected to three pump-freeze-thaw degas cycles. The reaction mixture was heated at 60 °C for 6 days, and then was concentrated in vacuo. Purification of the residue by flash chromatography (50% ether-petroleum ether) afforded pure (1 'S,2S,3R)-9 (0.4205 g, 88%, mp: 141-142 °C) as a white, crystalline solid. The (1'S,2S,3S)-diastereomer (10, 0.005 g, 1%, mp: 117-120 °C) was isolated in a separate fraction, 51 (1 'S.2S,3R)-Anti Aldol Product 9 7,05-7.40 (m, 5H, arom), 4,99 (dd, IH, J=3,2, 10,8, H5'), 4,80 (d, IH, J=9,7, H3), 3,98 (dt, IH, J=2,9, 6,7, HI'), 3,57 (dt, IH, J=2,9, 9.4, H4'), 3.31 (d, 1H, J=11.1, H5'), 3,00 (dt, 1H, J=2.9, 8.8, H4'), 2.83 (dq, 1H, J=9.7, 6.6, H2), 1.79 (m, 1H), 1.57 (m, 2H), 1.30 (m, 1H), 1.10 (d, 3H, J=6,6, CH3), 0.33 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3), 174,143,128,128,127,81,62,59,49,47,29, 25, 13, -1, -6, FTm (neat film), em- 1: 2964 (w), 2872 (w), 1631 (s), 1431 (m), 1251 (m), 1200 (w), 1108 (m), 1067 (m), 1051 (m), 990 (w), 908 (w), 872 (m), 846 (m), 795 (m), 697 (m). MS (EI): HRMS (EI): Calculated for C17H25N03Si (M+): 319.1604 Found: 319.1598 52 (l'S,2S,3S)-Syn Aldol Adduct 10 7.05-7.35 (m, 5H, arom), 5.47 (d, IH,1=3.8, H3), 4.88 (dd, IH, 1=2.7, 10.9, H5'), 4.02 (dt, IH, 1=3.0,8.7, HI'), 3.23 (dt, IH, 1=7.5,3.2, H4'), 3.22 (d, IH, 1=10.7, H5'), 3.05 (t, IH, 1=7.5, H4'), 2.79 (dq, IH, 1=4.0,6.7, H2), 1.73 (m, IH), 1.50 (m, 2H), 1.27 (m, IH), 1.08 (d, 3H, 1=6.6, CH3), 0.29 (s, 3H, SiCH3), -0.05 (s, 3H, SiCH3), FTm (neat film), em- l : 2995 (m), 2873 (m), 1632 (s), 1432 (s), 1254 (s), 1197 (s), 1092 (s), 1021 (s), 985 (m), 882 (m), 795 (m), 692 (m). MS (FAB): HRMS (FAB): Calculated for C17H2~03Si (MH+): 320.1682 Found: 320.1682 TLC (40% EtOAe-hexanes): Anti aldol product 9 0.26 (UV) Syn aldol product 10 0.19 (UV) Benzaldehyde 0.55 (UV) 53 GC (Ph-Me Silicone, 200°C): Anti aldol product 9 36.65 min Syn aldol product 10 46.81 min 54 CH2CI2, ':'PrCHO, • 23 oC, 26 h (1 'S.2S,3S)-Anti Aldol Product 24. A solution of (l'S)-O-silyl ketene N,O-aceta17 (0.510 g, 2.39 mmol, 1 equiv) in CH2C12 (0.2 mL) was treated with isobutryaldehyde (0.228 mL, 0.181 g, 2.5 mmol, 1.05 equiv) for 26 h at 23°C, at which point the product had precipitated from solution. The reaction mixture was purified by flash chromatography (20% ethyl acetate-hexanes) affording (1 'S,2S,3S)-24 (0.4893 g, 72%, mp: 99-100 °C) as a white, crystalline solid. (l'S,2S,3s)-Anti Aldol Product 24. 4.94 (dd, 1H, J=2.9, 10.9, H5'), 3.95 (dt, 1H, J=2.9, 7.3, HI'), 3.70 (dd, 1H, 1=2.1, 9.7, H3), 3.41 (dt, IH, J=6.5, 9.6, H4'), 3.29 (d, IH, 1=11.1, H5'), 2.97 (dt, 1H, 1=9.7,3.2, H4'), 2.72 (dq, 1H, J=9.7, 6.4, H2), 1.87 (m, IH), 1.68 (m, 1H), 1.54 (m, 2H), 1.21 (m, IH, H4), 1.06 (d, 3H, J=6.4, H6), 0.96 (d, 3H, J=4.4, H5), 0.93 (d, 3H, J=4.4, H5), 0.26 (s, 3H, SiCH3), 0.18 (s, 3H, SiCH3). 55 173.8,82.0,61.9,58.9,48.8,42.1,29.3,28.6, 24.8,20.8,13.9,12.7, -1.2, -6.1. FTIR (neat film), em-I: 2942 (w), 2877 (w), 1620 (s), 1433 (m), 1246 (m), 1125 (w), 1105 (w), 1044 (m), 984 (w), 867 (w), 847 (w), 827 (w), 787 (m). HRMS (CI:NH3): Calculated for C14H28N03Si (MH+): 286.1838 Found: 286.1843 TLC (40% EtOAc-hexanes): Anti aldol product 24 0.284 GC (Ph-Me Silicone, 170°C): Anti aldol product 24 27.98 min 56 (l'S,2S,3S2-Anti Aldol Product 2S A solution of (l'S)-O-silyl ketene N,O-acetal 7 (0.379 g, 2.36 mmol, 1.0 equiv) in CH2Ch (0.1 mL) was treated with propionaldehyde (0.132 mL, 0.106 g, 1.02 equiv) for 16 h at 0 °C, at which point the product had precipitated from solution. The reaction mixture was purified by flash chromatography (25% ethyl acetate-hexanes) affording (l'S,2S,3S)-25 (0.2729 g, 58%, mp: 46-47 °C) as a white, crystalline solid. A separate fraction afforded (l'S,2S,3R)-26 (0.0028 g, 1%) as a colorless oil. (l'S.2S,3S)-Anti Aldol Product 25 4.95 (dd, IH, 1=3.6, 9.3, H5'), 3.94 (dt, 1H, 1=3.6,7.6, HI'), 3.66 (dt, IH, 1=2.2,9.3, H3), 3.43 (dt, 1H, 1=5.7,9.8, H4'), 3.30 (d, IH, 1=9.3, H5'), 2.97 (dt, IH, 1=3.1,9.7, H4'), 2.53 (dq, 1H, 1=7.1,9.3, H2), 1.77 (m, IH), 1.53 (m, 3H), 1.23 (m, IH), 1.07 (d, 3H, 1=7.0, H6), 0.88 (t, 3H, 1=7.2, H5), 0.27 (s, 3H, SiCH3), 0.21 (s, 3H, SiCH3). 57 173,7, 79.7, 62.2, 58.9, 48.9, 45.2, 28.6, 28.1, 24.6, 13.3, 10.4 , -1.0, -6.0. FTm (neat film), em-I: 2954 (m), 2872 (m), 1631 (s), 1431 (m), 1256 (m), 1123 (m), 1067 (m), 1016 (w), 846 (m), 795 (m). MS (EI): HRMS (EI): Calculated for C13H25N03Si (M+): 271.1617 Found: 271.1617 (1 'S.2S,3R)-Syn Aldol Adduct 26 4.89 (dd, 1H, 1=2,7, 10.9, H5'), 4.02 (dt, 1H, 1=3,0,8.7, H3), 3.92 (dt, 1H, 1=2,7,9.8, HI'), 3,17 (d, 1H,1=1O.7, H5'), 3.05 (m, 1H, H4'), 3.05 (t, 1H, 1=7.5, H4'), 2.45 (dq, 1H, 1=3.0,6.7, H2), 1.68 (m, 1H), 1.15-1.55 (m, 5H), 1.08 (d, 3H, 1=6.6, H6), 0.76 (t, 3H, 1=7.2, H5), 0.22 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3). FTIR (neat film), em- 1: 2954 (m), 2872 (m), 1631 (s), 1431 (m), 1256 (m), 1123 (m), 1067 (m), 1016 (w), 846 (m), 795 (m). 58 MS (EI): 271 (M+), 256 (M+-CH3), 213 (M+-CH3CH2CHO). HRMS (EI): Calculated for C13H25N03Si (M+): 271.1617 Found: 271.1612 TLC (ether): GC (Ph-Me Silicone, 170°C): Anti aldol product 25 0.27 Syn aldol product 26 0.19 Anti aldol product 25 26.70 min Syn aldol product 26 36.03 min 59 60 ·C, 64 h 1870% + 16 O CH3 CH ' ..' I "" 'X" l' 0 2 CH 3 'J 3 O-S' N 1.....0 2 1 3 CH 3 CH 3 I 4 19 7% 20 (1 '5.2'5.2S.3R)-Anti Aldol Product 18 Benzaldehyde (0.095 mL, 0.93 mmol, 1.1. equiv) and CH2Ch (0.2 mL) were added sequentially to (1 '5,2'S)-O-silyl ketene N,O-acetal 16 (0.2310 g, 0.83 mmol, 1.0 equiv) at 23°C. The solution was subjected to three pump-freeze-thaw degas cycles and heated at 60°C for 64 h, at which point the product had crystallized from solution. Analysis of the crude reaction mixture by 1H NMR revealed three diastereomeric products 18, 19, and 20 (77.1, 8.4, and 14.4% respectively). Purification of the reaction mixture by flash chromatography afforded (1'5,2'5,25,3R)-18 (0.222 g, 70%) as a white solid (mp: 156-158 °C) and a mixture of (1'5,2'5,2R,35)-19 and (1'5,2'5,2R,3R)-20 ( 2:3 ratio, 21.2 mg, 7%) as a colorless oil. (1 '5.2'5.25.3R)-Anri Aldol Product 18 7.02-7.36 (m, lOH, arom), 5.7 (dq, 1H, 1=10.0, 7.4, H2'), 4.89 (d, 1H, 1=9.7, H3), 4.40 (d, tH, 60 1=10.1, HI'), 3.22 (dq, 1H, 1=9.7,8.6, H2), 2.88 (5, 3H, NCH3), 1.08 (d, 3H, 1=7.4, H3'), 0.62 (d, 3H, 1=8.7, H4), 0.09 (5, 3H, SiCH3), 0.01 (5, 3H, SiCH3)· FTIR (neat film), em-I: 2966 (m), 1643 (5), 1484 (rn), 1449 (rn), 1402 (rn), 1367 (w), 1284 (rn), 1255 (5), 1202 (w), 1132 (m), 1079 (5), 1049 (5), 1020 (m), 932 (m), 879 (5), 867 (s), 797 (m), 697 (5), 550 (m). 384 (MH+), 306 (MH+-Q)H6), 278 (MH+Q)H 5CHO). HRMS (CI:CH4): Calculated for C22H30N03Si (MH+): 384.1995 Found: 384.1981 (1 'S,2'S,2S,3R)-Anti Aldol Product 18 Deuterated at C3 7.02-7.36 (rn, 10H, arorn), 5.7 (dq, 1H,1=10.1, 7.4, H2'), 4.40 (d, 1H,1=1O.1, HI'), 3.22 (q, 1H, 1=8.6, H2), 2.88 (5, 3H), 1.08 (d, 3H, 1=7.4, H3'), 0.62 (d, 3H, 1=8,7, H4), 0.09 (5, 3H, SiCH3), 0.01 (5, 3H, SiCH3). 61 FTIR (neat film), em- 1: 2966 (m), 1643 (s), 1484 (m), 1449 (m), 1402 (m), 1367 (w), 1284 (m), 1255 (s), 1202 (w), 1132 (m), 1079 (s), 1049 (s), 1020 (m), 932 (m), 879 (s), 867 (s), 797 (m), 697 (s), 550 (m). MS (CI:NH3): 385 (MH+), 278 (MH+-Ct;HsCDO). HRMS (CI:NH3): Calculated for C22H29DN03Si (MH+): 385.2058 Found: 385.2067 (l'S,2'S,2R ,3s)-Diastereomer 12 7,02-7.36 (m, lOH, arom), 5.09 (d, 1H, J=9.8, HI'), 4.95 (dq, IH, 1=9.8, 6.5, H2'), 4.56 (d, 1H, 1=9.7, H3), 3.41 (dq, IH, 1=9.8,6.2, H2), 2.91 (s, 3H, NCH3), 1.02 (d, 3H, 1=6.6, H3'), 0.60 (d, 3H, 1=6.2, H4), 0.29 (s, 3H, SiCH3), -0.26 (s, 3H, SiCH3). (l'S.2'S,2R .3R)- Diastereomer 20 7.02-7.36 (m, lOH, arom), 6.00 (d, IH,1=9.5, HI'), 4,96 (d, IH, 1=9.5, H3), 2.94 (m, 2H, H2, H2'), 2.86 (s, 3H, NCH3), 1.38 (d, 3H, 1=6.8, 62 H3'), 0.96 (d, 3H, 1=6.5, H4), 0.34 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3). (l'S.2'S.2R .3S)-19 and (l'S,2'S.2R,3R)-20 FTIR (neat film), em- 1: 2964 (w), 1636 (s), 1487 (w), 1451 (w), 1405 (w), 1369 (m), 1292 (w), 1251 (m), 1205 (w), 1077 (s), 851 (s), 795 (m), 692 (s), MS (CI:NH3): HRMS (CI:NH3): Calculated for C22H30N03Si (MH+): 384.1995 Found: 384.2015 TLC (50% ether-pet. ether): Diastereomer 18 0.61 (UV) Diastereomer 19 0.35 (UV) Diastereomer 20 0.35 (UV) Benzaldehyde 0.85 (UV) Cl'S,2'S.2R.3S2-Diastereomer 19 Deuterated at C3 7.02-7.36 (m, 1OH, arom), 5.09 (d, IH,1=9.8, HI'), 4.95 (dq, IH, 1=9.8,6.5, H2'), 3.41 (q, 1H, 1=6.2, H2), 2.91 (s, 3H, NCH3), 1.38 (d, 3H, 63 1=6.6, H3'), 0.60 (d, 3H, 1=6.2, H4), 0.29 (s, 3H, SiCH3), -0.26 (s, 3H, SiCH3). (l'S,2'S,2R,3R)-Diastereomer 20 Deuterated at C3 7.02-7.36 (m, 1OH, arom), 6.00 (d, lH,1=9.5, HI'), 2.94 (m, 2H, H2', H2), 2.86 (s, 3H, NCH3), 1.38 (d, 3H, 1=6.8, H3'), 0.96 (d, 3H, 1=6.5, H4), 0.34 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3). (1'S,2'S,2R.352-19 and (1'$,2'$,2R ,3R)-20 Deuterated at C3 FTm (neat film), em-I: 2964 (w), 1636 (s), 1487 (w), 1451 (w), 1405 (w), 1369 (m), 1292 (w), 1251 (m), 1205 (w), 1077 (s), 851 (s), 795 (m), 692 (s). HRMS (CI:CH4): Calculated for C22H29DN03Si (MH+): 385.2058 Found: 385.2055 TLC (50% ether-pet. ether): Diastereomer 18 0.61 (UV) Diastereomer 19 0.35 (UV) Diastereomer 20 0.35 (UV) Benzaldehyde 0.85 (UV) 64 576% 3 Desilylation of Racemic Anti Aldol Adduct 3 Racemic anti aldol adduct 3 (5.3 mg, 0.016 mmol, 1.0 equiv) was treated with KP.2H20 (15 mg, 0.16 mmol, 9.6 equiv) in MeOH (0.5 mL) at 35°C for 5 h. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and saturated brine. The aqueous layer was separated and extracted once more with ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography (40% ethyl acetate-hexanes) afforded 5 (2.6 mg, 76%). CH"N~ 6H3 !H3 U 4 • 676% Desilylation of Racemic Syn Aldol Adduct 4 Racemic syn aldol adduct 4 (7.2 mg, 0.022 mmol, 1.0 equiv) was treated with KP·2H20 (20 mg, 0.21 mmol, 9.5 equiv) in MeOH (0.5 mL) at 35°C for 5 h. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and saturated brine. The aqueous layer was separated and extracted once more with ethyl acetate (30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification of the residue by flash chromatography (40% ethyl acetate-hexanes) afforded 6 (3.5 mg, 76%). 65 CH 3 , ••_,CH 3 6OVPh N Et3N·3HF, CH3CN • 23 oC, 0.5 h CH 3 27 9 Desilylation of (l'S.2S.3R)-Anti Aldol Adduct 9 A solution of (1 'S,2S,3R)-anti aldol adduct 9 (21.5 mg, 0.067 mmol, 1 equiv) in CH3CN (1 mL) was treated with Et3N·HF (54 mg, 0.39 mmol, 5.9 equiv) for 30 min at 23°C. Concentration and purification of the residue by flash chromatography (ethyl acetate) afforded (1'S,2S,3R)-27 (17.3 mg, 98%) as a colorless oil. (1 'S,2S,3R)-Diol 27 Crotameric mixture) IH NMR (400 MHz, DMSO): 7.2-7.4 (m, 5H, arom), 5.25 (br, IH, OH), 4.51 (d, IH, 1=8.5, H3), 4.44 (d, IH, 1=8.8, H3), 4.13 (m, IH, HI'), 3.94 (m, IH, Hl'), 3,58 (m, 2H, H5'), 3.25 (m, 3H, H4'), 2.92 (dq, IH, 1=8.5,6.7, H2), 2.77 (dq, IH, 1=8.5,6.7, H2), 1.80 (m, 4H, H2', H3'), 0.73 (d, 3H, 1=6.7, H4), 0.68 (d, 3H, 1=6.7, CH3). FTIR (neat film), em-I: 3389 (s), 2966 (s), 1614 (s), 1449 (s), 1373 (w), 1332 (w), 1237 (w), 1185 (w), 1126 (w), 1044 (m), 997 (m). MS (CI:NH3): 66 HRMS (CI:NH3): Calculated for C15H22N03 (MH+): 264.1600 Found: 264.1593 TLC (EtOAc): Aldol product 9 0.56 (UV) Diol27 0.18 (UV) 67 • 18 h. 23°C 18 2190% Desilylation of CI'S,2'S,2S,3R)-Anri Aldol Product 18 A solution of (I'S,2'S,2S,3R)-anti aldol adduct 18 (30.0 mg, 0.078 mmol, 1 equiv) in CH3CN (1 mL) was treated with Et3N·3HF (105 mg, 0.76 mmol, 9.8 equiv) for 18 h at 23°C. Concentration and purification of the residue by flash chromatography (ether) afforded 21 (23.1 mg, 90%) as a colorless oil. (l'S,2'S.2S.3R)-Diol 21 Crotameric mixture) IH NMR (400 MHz, CDCI3): 7.08-7.35 (m, lOH, arom), 4.71 (d, lH,1=7.5, H3), 4.50 (br, lH, OH), 4.46 (d, lH, 1=8.3, HI'), 4.41 (d, IH, 1=8.6, HI'), 3.70 (dq, lH,1=8.6, 6.9, H2'), 3.08 (dq, IH, 1=7.2,6.5, H2), 2.98 (dq, IH, 1=7.5,6.5, H2), 3.75 (s, 3H, NCH3), 3.75 (m, IH, H2'), 3.73 (s, 3H, NCH3), 1.25 (d, 3H, 1=6.9, H3'), 0.98 (d, 3H, 1=6.5, H4), 0.95 (d, 3H, 1=6.9, H3'), 0.43 (d, 3H, 1=6.5, H4). FTIR (neat film), em-I: 3389 (m), 2978 (w), 1614 (s), 1484 (m), 1408 (w), 1373 (w), 1202 (w), 1108 (w), 1079 (w), 1044 (m), 1020 (m), 914 (w), 750 (m), 703 (s). 68 HRMS (CI:NH3): Calculated for C20H26N03 (MH+): 328.1913 Found: 328.1935 TLC (50% EtOAe-hexanes): Aldol product 18 0.52 Diol21 0.09 (1 'S,2'S,2S,3R)-Diol 21 Deuterated at C3 (rotameric mixture) IH NMR (400 MHz, CDCI3): 7.08-7.35 (m, lOH, arom), 4,50 (br, 1H, OH), 4.46 (d, 1=8.3, HI '),4.41 (d, 1H, 1=8.6, HI '),3.70 (dq, 1H, 1=8.6, 6.9, H2'), 3.08 (q, 1H,1=6.5, H2), 2,98 (q, 1H, 1=6.5, H2), 3.75 (5, 3H, NCH3), 3.75 (m, 1H, H2'), 3.73 (5, 3H, NCH3), 1.25 (d, 3H, 1=6.9, H3'), 0.98 (d, 3H, 1=6.5, H4), 0.95 (d, 3H, 1=6.9, H3'), 0.43 (d, 3H, 1=6.5, H4). FTIR (neat film), em-I: 3389 (m), 2978 (w), 1614 (5), 1484 (m), 1408 (w), 1373 (w), 1202 (w), 1108 (w), 1079 (w), 1044 (m), 1020 (m), 914 (w), 750 (m), 703 (5). MS (CI:NH3): HRMS (CI:NH3): Calculated for C20DH2SN03 (MH+): 329.1975 69 Found: 328.1969 TLC (50% EtOAc-hexanes): Aldol product 18 0.52 Diol21 0.09 70 60°C, 64 h 1870% + 19 7% 20 Desilylation of (1 'S,2'S,2R,3S)-19 and (1 'S,2'S,2R.3R)-20 A mixture of 19 and 20 (20.2 mg, 0.052 mmol, 1.0 equiv) was treated with KF·2H20 (30 mg, 0.32 mmol, 5.5 equiv) in MeOH (1 mL) at 23°C for 3 h. The reaction mixture was diluted with ethyl acetate and flushed through a silica gel plug (ethyl acetate, 2 cm x 2 cm), After the reaction mixture was concentrated in vacuo, the residue was purified by flash chromatography (80% ether-petroleum ether) affording a mixture of (1'S,2'S,2R,3S)-22 and (l'S,2'S,2R,3R)-23 (2:3 ratio, 14.2 mg, 84%) as a colorless oil. CI'S,2'S,2R.3s)-Oio122 1H NMR (400 MHz, CDCI3): 7.10-7.40 (m, 10H, arom), 4.82 (d, IH, 1=8.3, H3), 4.50 (d, lH, 1=9.3, HI '), 4.19 (dq, lH, 1=9.3,6.8, H2'), 3.33 (dq, IH, 1=8.1, 6.8, H2), 2.92 (s, 3H, NCH3), 1.96 (d, 3H, 1=6.8, H4), 1.02 (d, 3H, 1=6.8, H3'), 71 (1 'S.2'S,2R ,3R)-Diol 23 IH NMR (400 MHz, CDCI3): 7.00-7.40 (m, 10H, arom), 5.02 (d, 1=5.6, H3), 4.59 (d, IH, 1=9.3, HI '), 4.50 (br, IH, H2'), 3.00 (dq, IH, 1=7.1,5.6, H2), 2.75 (s, 3H, NCH3), 1.16 (d, 3H, 1=7.1, H4), 0.92 (d, 3H, 1=6.8, H3'). (1 'S,2'S,2R .3$)-Diol 22 and (1 'S,2'S,2R ,3R)- Diol 23 FTIR (neat film), em- 1: 3378 (m), 2978 (w), 1614 (s), 1484 (m), 1408 (w), 1373 (w), 1202 (w), 1108 (w), 1079 (w), 1044 (m), 1020 (m), 914 (w), 750 (m), 703 (s). HRMS (CI:NH3): Calculated for C20H26N03 (MH+): 328.1913 Found: 328.1918 TLC (50% EtOAe-hexanes): Aldol Adduct 19 0.35 Aldol Adduct 20 0.35 Dio122 0.09 Diol23 0.09 72 (1 'S,2'S,2R,3S)-Diol 22 Deuterated at C3 1H NMR (400 MHz, CDCI3): 7.10-7.40 (m, lOH, arom), 4.50 (d, IH, 1=9.3, HI'), 4.19 (dq, IH, 1=9.3,6.8, H2'), 3.33 (q, IH, 1=6.8, H2), 2.92 (s, 3H, NCR3), 1.96 (d, 3H, 1=6.8, H4), 1.02 (d, 3H, 1=6.8, H3'). (1 'S,2'S,2R.3R)-Dio123 Deuterated at C3 IH NMR (400 MHz, CDC)3): 7.10-7.40 (m, 10H, arom), 4.59 (d, 1H,1=9.3, HI'), 4.50 (br, 1H, H2'), 3.00 (q, IH, 1=7.1, H2), 2.75 (s, 3H, NCH3), 1.16 (d, 3H, 1=7.1, H4), 0.92 (d, 3H, 1=6.8, H3'). (1 'S,2'S,2R.3S2-Diol 22 and C1 'S,2'S,2R,3R)-DioI23 Deuterated at C3 FTIR (neat film), em- 1: 3378 (m), 2978 (w), 1614 (s), 1484 (m), 1408 (w), 1373 (w), 1202 (w), 1108 (w), 1079 (w), 1044 (m), 1020 (m), 914 (w), 750 (m), 703 (s). HRMS (CI:NH3): Calculated for C20H2SDN03 (MH+): 329.1975 Found: 328.1969 73 TLC (50% EtOAc-hexanes): Aldol Adduct 19 0.35 Aldol Adduct 20 0.35 Diol22 0.09 Diol23 0.09 74 o o 1 HO" X_ ptt" _OMe 1X ~OMe CICOCOCI, DMF CI/ ptt" CF3 CF3 (SI-Mosher Chloride (R)-(+)-MTAP (0.35 g, 1.71 mmol , 2.23 equiv, azeotropically dried with one portion of benzene) was treated with oxalyl chloride (151 ~L, 1.72 mmol, 2.56 equiv) and a catalytic amount of DMF (40 ~L) for 2 h at 23°C. Considerable gas evolution was observed. The reaction mixture was concentrated under vacuum (0.1 Torr) and used in the following reactions without further purification. CH 3 I 0. N , ....... 0 ' 'OH 2) (S)-Mosher chloride, 4 h 3' 2' 2868% (l'S,2R)- Mosher Ester 28 A solution of (S)-MTAPCI (1.49 mmol, 2.23 equiv) in CH2Cl2 (2 mL) was added by cannula to a mixture containing (lS)-N-methyl prolinol40 (77 mg, 0.67 mmol, 1.0 equiv), DMAP (120 mg, 0,98 mmol, 1.46 equiv), diisopropylethylamine (0.6 mL), 3-A molecular sieves (100 mg) and CH2Cl2 (2 mL). After 4 h at 23°C the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate) affording (1'S,2R)-27 (150 mg, 68%) as colorless oil. 75 (l'S,2R)- Mosher Ester 28. 7.20 (d, 2H, 1=8.6, arom), 7.00-7.15 (m, 3H, arom), 4.22 (dd, lH,1=5.4, 11.0, H5'), 3.96 (dd, 1H,1=4.8, 11.0, H5'), 3.41 (s, 3H, OCH3), 2.75 (dd, 1H, 1=4.8, 5.4, HI'), 2.12 (s, 3H, OCH3), 2.12 (m, 1H, H4'), 1.87 (m, 1H, H4'), 1.45 (m, 2H), 1.32 (m, 2H). FTIR (neat film), em-I: 2952 (w), 1750 (s), 1451 (w), 1272 (m), 1246 (m), 1168 (s), 1122 (m), 1081 (w), 1024 (m), 719 (m). MS (EI): HRMS (EI): Calculated for C16H21F3N03 (M+): 332.1474 Found: 332.1453 TLC (acetone): Amine 0.34 Mosher ester 28 0,72 76 .. 1) DMAP, CH 2CI 2, (f·PrhNEt 2) (S)-Mosher chloride, 4 h (l'R,2R)-Mosher Ester 29 A solution of (S)-MTAPCI (1.71 mmol, 2,55 equiv) in CH2Cl2 (2 mL) was added by cannula to a suspension containing (1R)-N-methyl prolino140 (77 mg, 0.67 mmol, 1.0 equiv), DMAP (120 mg, 0.98 mmol, 1.46 equiv), diisopropylethylamine (0.6 mL), 3-A molecular sieves (100 mg) and CH2Cl2 (2 mL). After 4 h at 23°C the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography (ethyl acetate) afforded (1'R,2R)-29 (162 mg, 73%) as a colorless oil. (1'R,2R)-Mosher Ester 29 7.20 (d, 2H, 1=8.6, arom), 7.00-7.15 (m, 3H, arom), 4,28 (dd, IH,1=5.4, 11.0, H5'), 3.91 (dd, IH,1=4.8, 11.0, H5'), 3.47 (s, 3H, OCH3), 2.78 (dd, IH, 1=4.8, 5.4, HI '), 2.10 (s, 3H, OCH3), 2.10 (m, IH, H4'), 1.87 (m, IH, H5'), 1.45 (m, 2H, H3'), 1.28 (m, 2H, H4'). FTIR (neat film), em- l : 2952 (w), 1750 (s), 1451 (w), 1272 (m), 1246 (m), 1168 (s), 1122 (m), 1081 (w), 1024 (m), 719 (m). 77 MS (EI): HRMS (EI): Calculated for C16H21F3N03 (M+): 332.1474 Found: 332.1473 TLC (acetone): GC (Chirasil Val Ill, no °C): Amine 0.36 Mosher ester 29 0.75 Mosher ester 28 51.84 min Mosher ester 29 53.02 min 78 NMR experiments • 30 16 (1'5. 2's)-Potassium Enolate 30 Potassium tert-butoxide (30.0 mg, 0.27 romol, 1.46 equiv) and C4DgO (0.4 mL) were combined in an NMR tube in a nitrogen-filled glovebox. The NMR tube was sealed with a septum and removed from the box. (l'S, 2'S)-O-Silyl ketene N,O-acetal 16 (0.040 mL, 45 mg, 0.185 romol, 1.0 equiv) was added dropwise to the reaction mixture. The NMR tube was shaken after each drop of enolate was added. A clear yellow solution resulted. (l'S. 2'$)-Potassium enol ate 30 IH NMR (400 MHz, C4DSO): 7.37-7.12 (m, lOH, arom), 4.68 (d, IH,1=1O.5, HI'), 4.05 (m, lH, H2'), 2.97 (q, IH, 1=6.3, H2), 2.32 (5, 3H, NCH3), 1.08 (d, 3H, 1=6.3, H3), 1.20 (s, 9H, Ot-Bu), 0.51 (d, 3H, 1=8.7, H3'), 0.15 (s, 3H, SiCH3), -0.27 (5, 3H, SiCH3). 29Si NMR (79 MHz, C4DSO): -8 79 Kinetics General Procedure for LiQuid Aldehydes (1 'S)-O-Silyl ketene N,O-acetal 7 (30 /J.L, -33 mg, 0.0154 mmol, 1 equiv) was weighed into a dry NMR tube (equipped with screw threads) sealed with two septa. 1,1diphenylethylene (12.6-10 /J.L, 12.9-10.2 mg, 0.071-0.056 mmol, -0.5 equiv) and C6D6 (400 /J.L) were added. The solution was subjected to three pump-freeze-thaw degas cycles, then aldehyde (0.0154 mmol, 1 equiv) was added by syringe. The septa were replaced with a Teflon seal. The solution was subjected to three more pump-freeze-thaw degas cycles. The solution was kept at -78°C until monitoring was started. The sample was protected from light when not in the NMR probe since the standard is slightly lightsensitive. General procedure for solid aldehydes Solid para-substituted benzaldehyde (1 equiv, 0.0154 mmol) was weighed into a dry NMR tube (equipped with screw threads) fitted with two septa. 1,I-diphenylethylene (12.6-1O.0/J.L, 12.9-10.2 mg, 0.071-0.056 mmol, -0.5 equiv), Q;D6 (400 /J.L) and (1'S)O-silyl ketene N,O-aceta17 (30 /J.L, -33 mg. 0.0154 mmol, 1 equiv) were syringed into the NMR tube. The septa were replaced with a Teflon seal. The solution was subjected to one pump-freeze-thaw degas cycle. The solution was kept at -78°C until monitoring commenced. All samples (except the one used for the 20°C benzaldehyde run) were kept in the NMR probe for the entire measurement period. The 20°C benzaldehyde sample was protected from light and immersed in a constant temperature bath between monitorings. 80 31 Q-Methoxybenzaldehyde Adduct 31 7.25 (d, 1H, 1=8.8, arom), 6.81 (d, 2H, 1=8.8, arom), 5.02 (dd, 1H, 1=3.2, 11.2, H5'), 4.82 (d, 1H, 1=9.7, H3), 4.00 (dt, 1H,1=3.0, 7.7, HI'), 3.60 (dt, 1H, 1=6.5,9.7, H4'), 3.33 (d, 1H, 1=10.8, H5'), 3.29 (s, 3H, OCH3), 3.03 (dt, 1H, 1=2.9, 7.9, H3'), 2.88 (dq, 1H, 1=6.7, 9.7, H2), 1.82 (m, 1H), 1.59 (m, 2H), 1.27 (m, 1H), 1.06 (d, 3H, 1=6.7, CH3), 0.34 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3)· FTIR (neat film), em-I: 2961 (m), 2879 (m), 1629 (s), 1510 (m), 1458 (m), 1427 (m), 1298 (w), 1247 (s), 1169 (w), 1112 (m), 1066 (m), 1030 (m), 983 (m), 911 (m), 875 (m), 849 (m), 797 (m). 350 (MH+). 81 HRMS (CI:CH4): Calculated for C18H28N04Si (MH+): 350.1788 Found: 350.1780 MP: 113-115°C TLC (30% ether-pet. ether): 31 0.16 p- Methoxybenzaldehyde 0040 1,1-Diphenylethylene 0.80 82 32 p-Chlorobenzaldehyde Adduct 32 7.12 (d, IH, 1=8.8, arom), 6.98 (d, 2H, 1=8.8, arom), 4.96 (dd, IH,1=3.2, 11.2, H5'), 4.66 (d, IH, 1=9.7, H3), 3.96 (dt, IH, 1=3.0,7.7, HI'), 3.48 (dt, lH, 1=6.5, 9.7, H4'), 3.32 (d, lH, 1=10.8, H5'), 2.94 (dt, 1H, 1=2.9, 7.9, H4'), 2.65 (dq, lH, 1=6.7,9.7, H2), 1.76 (m, 1H), 1.55 (m, 2H), 1.23 (m, 1H), 0.92 (d, 3H, 1=6.7, CH3), 0.30 (s, 3H, SiCH3), 0.08 (s, 3H, SiCH3). FTIR (neat film), em- 1: 2961 (w), 1624 (s), 1484 (w), 1453 (w), 1427 (s), 1252 (m), 1107 (m), 1066 (s), 1050 (m), 1009 (w), 906 (w), 875 (w), 854 (m), 797 (w). 354 (MH+). HRMS (CI:CH4): Calculated for C17H2SClN03Si (MH+): 354.1292 83 Found: 354.1288 MP: TLC (ether): 32 0.62 p-Chlorobenzaldehyde 0.85 l,l-Diphenylethylene 0.96 84 33 v-Cyanobenzaldehyde Adduct 7.03 (d, 1H, J=6.8, arom), 6.93 (d, 2H, J=7.1, arom), 4.92 (dd, lH, J=3.2, 10.8, H5'), 4.59 (d, lH, J=9.8, H3), 3.93 (dt, lH, J=3.0, 7.7, HI'), 3.40 (dt, IH, J=2.9, 9.4, H4'), 3.29 (d, IH, J=11, H5'), 2.93 (dt, 1H, J=2.9, 7.6, H4'), 2.55 (dq, 1H, J=6.8, 9.6, H2), 1.75 (m, 1H), 1.58 (m, 2H), 1.24 (m, 1H), 0.81 (d, 3H, J=6.6, CH3), 0.25 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3). FTIR (neat film), em- 1: 2959 (w), 2885 (w), 2231 (m), 1630 (s), 1429 (m), 1255 (m), 1113 (m), 1081 (m), 1049 (w), 991 (w), 912 (w), 870 (m), 854 (m), 796 (m). 345 (MH+). HRMS (CI:CH4): Calculated for C18H25N203Si (MH+): 345.1634 Found: 345.1643 85 MP: TLC (ether): 33 0.54 p-Cyanobenzaldehyde 0.85 l,l-Diphenylethylene 0.96 86 34 p- Nitrobenzaldehyde Adduct 7.84 (d, lH, 1=8.8, arom), 6.93 (d, 2H, 1=8.8, arom), 4.92 (dd, IH,1=3.2, 11.2, H5'), 4.64 (d, IH, 1=9.7, H3), 3.95 (dt, lH, 1=3.0, 7.7, HI '), 3.42 (dt, IH, 1=6.5,9.7, H4'), 3.30 (d, IH, 1=10.8, H5'), 2.95 (dt, lH, 1=2.9, 7.9, H4'), 2.56 (dq, IH, 1=6.7, 9.7, H2), 1.75 (m, IH), 1.58 (m, 2H), 1.26 (m, 1H), 0.81 (d, 3H, 1=6.7, CH3), 0.13 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3). FTIR (neat film), em-I: 2959 (w), 2874 (w), 1635 (s), 1609 (m), 1519 (s), 1456 (w), 1435 (m), 1345 (s), 1255 (m), 1113 (w), 1081 (m), 1049 (w), 986 (w), 912 (w), 849 (m), 838 (m), 796 (m). 365 (MH+). HRMS (EI): Calculated for C17H2SN20SSi (MH+): 365.1532 87 Found: 365.1537 MP: 160-162°C TLC (ether): 34 0.42 p- Nitrobenzaldehyde 0.79 1,1-Dipheny1ethy1ene 0.92 88 Deuterium Isotope Experiments o d'H(OJ .. n-BuLi. THF -78°C 95% Determination of Deuterium Enrichment of Benzaldehyde n~Butyllithium (0.59 mL, 2.5 Min hexanes, 1.475 mmol, 1.5 equiv) was added dropwise over 5 min to a deoxygenated solution of benzaldehyde (-1: 1 mixture of Q;HsCHO:C6fIsCDO, 100 ilL, 0.98 mmol, 1 equiv) in THF (2 mL) at -78°C. The reaction was kept at -78 °C for 2 h, then warmed to 0 °C for 15 min to ensure complete reaction. The reaction mixture was then partitioned between 3: 1 ethyl acetate-hexanes (10 mL) and H20 (2 mL). The organic layer was separated, dried with sodium sulfate, filtered and concentrated in vacuo, affording I-phenyl I-pentanol (152.6 mg, 95%). The percentage of deuterium present in the I-phenyl I-pentanol was determined by mass spectrometry. CH 3 , ."CH3 1.17:1 CsHsCDO:CsHsCHO CSH60 12 h. 60°C H'.(~O~Ph o CH, H(OJ 950% (0.88:1 d1 :do) Determination of the Deuterium Incorporation of 9 (1 'S)-O-Silyl ketene N,O-acetal 7 (112.3 mg, 0.526 mmol, 1.0 equiv) was added to a deoygenated solution of benzaldehyde (-1:1 mixture of C6HSCHO:C6HSCDO, 0.75 mL, 0.78 g, 7.3 mmol, 14 equiv) in benzene (1.5 mL). The foil-covered reaction flask 89 was heated at 60°C for 12 h, then the reaction mixture was cooled and concentrated in vacuo. Flash chromatography (50% ether-petroleum ether) afforded 9 (85 mg, 50%) as a white solid. Run 1 % Deuterium incorporation: 1-Phenyll-pentanol 54% Aldol adduct 9 47% I-Phenyll-pentanol 54% Aldol adduct 9 47% Run 2 % Deuterium incorporation: 90 References lKane, R. Ann. Physik Chem. 1838,44, 475. 2Reviews on stereose1ective aldol reactions: (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, l. (b) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; VoL 3, Chapter 2. 3The preference for Z configuration found with amide enolates is perhaps due to developing Al,3 strain present in the transition state leading to the E enolate: (a) Fataftah, Z. A.; Kopka, 1. E.; Rathke, M. W. J. Am. Chem. Soc. 1980,102, 3959. (b) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org. Chem. 1980,46, 1066. (c) Evans, D. A.; McGee, L. R. Tetrahedron Lett. 1980,21, 3975. (d) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980,21, 4233. (e) Takacs, J. M. Ph.D. Thesis, California Institute of Technology, 1981. 4Sogah, D. Y.; Hertler, W. R.; Webster, O. W.; Cohen, G. M. Macromolecules 1987, 20, 1473. 5This mechanism is controversial. An open transition state is proposed for fluoridecatalyzed aldol reactions: Noyori, R.; Nishida, 1.; Sakata, J.; Nishizawa, M. J. Am. Chem. Soc. 1980,102, 1223. 6(a) Hudrlik, P. F.; Peterson, D.; Chou, D. Synth. Commun. 1975, 5, 359. (b) Woodbury, R. P.; Rathke, M. W. J. Org. Chem. 1978,43, 881, and references therein. 91 70jima, 1.; Kogure, T. Organometallics 1982,1,1390. 8Myers, A. G.; Widdowson, K. L. 1. Am. Chem. Soc. 1990,112,9672. 9Creger, P. L. Tetrahedron Lett. 1972, 79. lOZimmerman, H. E.; Traxler, M. D. 1. Am. Chem. Soc. 1957,79, 1920. IlSchaefer, W. P.; Widdowson, K. L.; Myers, A. G. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1991, C47, 9672. 12Crystal structures of O-silyl enol ethers: (a) Seebach, D.; Maetzke, T.; Petter, W.; Klotzer, B; Plattner, D. A. 1. Am. Chem. Soc. 1991, 113, 1781. (b) Appel, R.; Hlinerbein, J.; Knoch, F. Angew Chem., Int. Ed. Eng/. 1983,22, 61. (c) Cheng, P.T.; Nyburg, S. C. Acta Crystallogr. Sect. B 1976, 32, 930. (d) Fenske, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 635. (e) Merzweiler, K.; Crossland, I.; Bock, K.; Norrostam, R. Acta Chem. Scand. Ser. B 1985,39,7. (f) Seebach, D.; Ertas, M.; Locher, R.; Schweizer, W. B. Helv. Chim. Acta. 1985, 68, 264. (g) House, H. 0.; Nomura, G. S.; VanDerveer, D.; Wissinger, J. E. 1. Org. Chem. 1986,51, 2408. (h) Mena, M.; Pellinghelli, M. A.; Royo, P.; Serrano, R.; Tiripiccihio, A. 1. Chem. Soc., Chem. Commun. 1988,1116. (i) Groth, P. Acta Chem. Scand. Ser. A. 1977,31, 641. (j) Brook, A. G.; Chatterton, W. 1.; Sawyer, J. F.; Hughes, D. W.; Vorspohl, K. Organometallics 1987, 6, 1247. (k) Brisse, F.; Thoraval, D.; Chan, T. H. Can. 1. Chem. 1986,64,739. (1) Maas, G.; Schneider, K.; Ando, W. 1. Chem. Soc., Chem. Commun. 1988, 72. 92 13For a theoretical study on the size of the Si-O-C bond angle see: Shambayati, S.; Blake, J. F.; Wierschke, S. G.; Jorgensen, W. L.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 697. 14This parallels an observation made in Chapter II, the larger ring siloxanes (7-9 membered rings) are stable to silica gel, while the smaller ring siloxanes are not. 15Chiral anti selective aldol reactions: (a) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976. (b) Masamune, S.; Sato, T.; Kim, B. M.; Wollman, T. A 1. Am. Chem. Soc. 1986, 108, 8279. (c) Gennari, c.; Bernardi, A; Colombo, L.; Scolastico, C. 1. Am. Chem. Soc. 1985, 107, 5812. (d) Helmchen, G.; Leikauf, U.; Taufer- Knopfel, I. Angew. Chem. Int. Ed. Engl. 1985, 24, 874. (e) Oppolzer, W.; Starkemann, C.; Rodriguez, I.; Bernardinelli, G. Tetrahedron Lett. 1991,32, 61. (f) Meyers, A I.; Yamamoto, Y. Tetrahedron 1984,40,2309. (g) Palazzi, c.; Colombo, L.; Gennari, C. Tetrahedron Lett. 1986,27, 1735. (h) Oppolzer, W.; Marco-Contelles, J. Helv. Chem. Acta. 1986, 69, 1699. (i) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 55,32, 173. (j) Corey, E. J.; Kim, S. S. Tetrahedron Lett. 1990, 31,3715. 16The complex {7·PhCHO} may not be an energy minimum but rather a point on the reaction-coordinate surface. 17These results are summarized in two papers: (a) Myers, A. G.; Widdowson, K. L.; Kukkola, P. K. J. Am. Chern. Soc., in press. (b) Myers, A. G.; Kephart, S. E.; Widdowson, K. L. J. Am. Chern. Soc., manuscript in preparation. 93 18All slopes and associated uncertainties were calculated using weighted-Ieast-squares formulas found in: Bevington, P. Data Reduction and Error Analysis for the Physical Sciences McGraw & Hill, New York, 1969; p. 92-118. Concentrations were calculated using the vinylic resonance of 1,1-diphenyl ethylene as the standard. Relative errors of inte gration of proton NMR spectra were assigned as 1-2% of val ue on the basis of peak shape and evidence of decomposition. The pulse delay for the sample was set at 20 seconds. Relative and absolute uncertainties were propagated following standard formulas outlined in: Skoog, D. A.; West, D. M. Fundamentals of Analytical Chemistry Holt, Rinehart, and Winston, 1976, pp. 42-88. The NMR probe temperature was calibrated using ethylene glycol according to formulas outlined in: Gordon, A. G.; Ford, R. A. The Chemist's Companion. Wiley & Sons, New York, 1972; p. 303. Volumes were assumed to be additive, except with solid al~ehydes where the NMR tube was precalibrated. This assumption was tested for benzaldehyde and appeared to be valid. 19Carpenter, B. K. Determination of Organic Reaction Mechanisms John Wiley & Sons, New York, 1984; p. 96. 20Review: Halevi, E. A. Progress in Physical Organic Chemistry 1963,1, 109. 21p-Methoxy benzaldehyde and benzaldehyde samples were monitored at 19.4 °C and 76.9 °C, respectively, and extrapolated back to 21.3 0c. All other p-substituted benzaldehydes were monitored at 21.3°C. 22It is interesting to compare these results with those of ref. 24 d and f, where a Hammett p of -1.52 was obtained in a kinetic study of the racemization of a tetracoordinated silane by a series of p-substituted benzaldehydes. 94 23Prof. John E. Bercaw, personal communication. 24Pseudorotation reviews: (a) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70. (b) Mislow, K. Acc. Chem. Res. 1970,3, 321. 25Mechanistic work on pseudorotation around silicon: (a) Klanberg, F.; Muetterties, E. L. Inorg. Chem. 1968, 7, 155. (b) Gibson, J. A; Ibbott, D. G.; Janzen, A F. Can. 1. Chem. 1973,51, 3203. (c) Farnham, W. B.; Harlow, R. L. 1. Am. Chem. Soc. 1981, 103,4608. (d) Stevenson, W. H., III; Martin, J. C. 1. Am. Chem. Soc. 1982, 104, 309. (e) Stevenson, W. H., III; Wilson, S.; Martin, J. C.; Farnham, W. B. 1. Am. Chem. Soc. 1985, 107, 6340. f) Stevenson, W. H., III; Martin, J. C. 1. Am. Chem. Soc. 1985,107, 6352. 26Theoretical work on pseudorotation around silicon: Deiters, J. A; Holmes, R. R. 1. Am. Chem. Soc. 1987,109, 1686. 27Berry, R. S. 1. Am. Chem. Soc. 1968,90,6722. see also 24 b and references therein. 28 An alternative turnstile mechanism for interconverting tbps has been proposed. However, structural and theoretical studies favor the Berry pseudorotational mechanism: (a) Muettereties, E. L. 1. Am. Chem. Soc. 1969,91, 4115. (b) Marsden, C. 1.; 1. Chem. Soc., Chem. Commun. 1984, 40. (c) Holmes, R. R.; Brown, R. K. 1. Am. Chem. Soc. 1977,99, 3326. (d) Holmes, R. R.; Day, R. 0.; Harland, J. J.; Sau, A. c.; Holmes, J. M. Organometallics 1984,3, 343. (e) Holmes, R. R.; Day, R. 0.; Chandrasekhar, V.; Harland, J. 1.; Holmes, J. M. Inorg. Chem. 1985,24, 2016. 95 29Lauterbur, P. C.; Ramirez, F. 1. Chem. Phys. 1960, 933. 30Review on 29Si NMR: Williams, E. A., Cargioli, J. D. Ann. Rep. NMR Spectroscopy 1970,9, 221. 31 The enantiomer is depicted for visual comparison of homochiral structures. 320-Silyl N,O-acetal16 was synthesized in an analogous manner to 7 in a 80% distilled yield. 33Schaefer, W. P.; Widdowson, K. L.; Myers, A. G. Acta Crysta!logr., Sect. C: Cryst. Struct. Commun. 1991, C47, 000. 34Hanson, K. R. 1. Am. Chem. Soc. 1966,88, 2731. 35Hoffmann, R.; Howell, J. M.; Muetterties, E. L. 1. Am. Chern. Soc. 1972,94, 3047. 36Huheey, J. E. Inorganic Chemistry Harper & Row: New York, 1983; p. 258. see also 24 e. 37(a) Laube, T.; Dunitz, J. D.; Seebach, D. Helv. Chem. Acta. 1985,68, 1373. (b) Bauer, W.; Laube, T.; Seebach, D. Chem. Ber. 1985,118, 764. 38Still, W. C.; Kahn, M.; Mitra, A. 1. Org. Chem. 1978,43, 2923. 96 39Kofron, W. G.; Baclawski, L. H. 1. Org. Chern. 1976,41, 1879. 40Chavdarian, C. G.; Sanders, E. B. Org. Prep. Proc. Int. 1981, 13, 389. 97 CHAPTER II Radical Cyclizations of O-Alloxy Dimethylsilyl Hemiselenoacetals 98 We wanted to study the cyclization of siloxane-linked radicals such as 1, as a potential stereoselective carbon-carbon bond forming reaction. Radical 1 is an especially attractive intermediate; the transition from inter- to intramolecular radical-olefin addition generally improves both yield and selectivity. We envisioned that 1 might be generated from an allylic alcohol and an aldehyde. Control of absolute stereochemistry of the cyclization products can then be achieved using optically active allylic alcohols. + ~OH R' 1 OH OH I R~ OH R' OH +~~R' '( ~R' CH 3 Both 6-exo and 7-endo cyclization of 1 can be envisioned. Previous studies with all-carbon chains demonstrate that 6-exo cyclization is kinetically favored. l This selectivity generally applies when the ring contains only first row elements; however, when silicon is included in the ring system the regiochemistry of radical attack is less predictable. 2 At the outset of our studies no data was available concerning the cyclizations of siloxanes such as 1, though results with related systems suggested that the regioselectivity 99 of radical attack is highly dependent upon the substitution of the allyl alcohol (vide infra).2 The increased tendency for endo attack in these cases, relative to all-carbon systems has been rationalized by trajectory analysis; longer bonds created by incorporating silicon in the ring make endo attack more favorable. 2h • Initial efforts to access the intermediate 1 by generation of the radical anion 2 in the presence of silyl chloride 3, led to the exclusive formation of dimeric pinacol products. To circumvent this problem, we decided to form the silicon-oxygen bond prior to radical generation. The hemiselenoacetal 6 seemed a nearly ideal precursor in this regard since the selenium-carbon bond is readily cleaved with trialkyltin radicals} This cleavage should be especially facile in the present case given the stability of the product radical. 100 + H3C H3C, .",CH 3 PhSeH .. I.~ pyr, Me2SiCI2 pyr R--1 "'H (10 equiv) SePh Si 0 / 'CI R~""'H SePh 4 5 ROH pyr ,CH 3 'S( 0 / 'OR R~""'H SePh 6 Trimethylsilyl hemiselenoacetals have been synthesized previously by reaction of an aldehyde with benzeneselenol, pyridine and chlorotrimethylsilane. 4 Modification of this procedure by substitution of chlorotrimethylslane with dichlorodimethylsilane (-10 equiv) afforded the monochlorosilyl intennediate 5, in high yields. Rather than attempt purification of this hydrolytic ally unstable intennediate, 5 was directly transfonned to siloxane 6 by reaction with an allylic alcohol. S Siloxanes 6 were stable to aqueous extraction but hydrolyzed readily on silica gel, and so they were used without purification. Small amounts of diphenydiselenide (-5%) and starting aldehyde «5%) were the only detectable impurities. This methodology appears to be fairly general and gave high yields of product with a number of allylic alcohols. The corrected yields for the products from reaction with allyl alcohol, (E)-cinnamyl alcohol, and methallyl alcohol were 93, 92, and 87%, respectively. Mixing aldehyde and benzeneselenol prior to the addition of silyl chloride (as opposed to combining the reagents all at once) appeared to accelerate the reaction. This mode of addition may prevent the fonnation of the less reactive silyl selenide. 6 The order of addition of 4 and allylic alcohols to the dichlorodimethylsilane is also important. 101 Addition of the allylic alcohol prior to the presumed benzeneselenol-aldehyde adduct (4), results in about 15% of the symmetrically substituted siloxane «CH3hSi(ORh). H3 C, ._,CH 3 Si 0/ '0 Ph~""H ~ SePh ~ BU3SnH, toluene, 60°C, AIBN, 6 h 862% 7 9 10 35%(3:1) J23-S.7Hz 11 J23 .. 2.SHz Hemiselenoacetals 7 and 9 reacted smoothly with tributyltin hydride to form both cyclization products and products resulting from simple reductive cleavage of selenium. The seven-membered ring 8 was the sole cyclization product obtained from reaction of hemiselenoacetal 7. In addition, small amounts (-5%) of hydrocinnamyl alcohol were formed, presumably resulting from competitive trapping of the radical intermediate with tributyltin hydride. The reaction of (E)-cinnamyl alcohol derivative 9 with tributyltin hydride produced a 3: 1 mixture of anti and syn diastereomers. As these six-membered ring siloxanes were sensitive to silica gel, they were converted directly to the corresponding acetonides for characterization (35%, two steps). The relative stereochemistry of each acetonide was determined by examining coupling constants between protons H2 and H3. The anti diastereomer, in which protons H2 and H3 are diaxial, exhibited the larger coupling constant. 102 The different regioselectivities observed with 7 and 9 can be rationalized by both electronic and steric factors. The radical derived from 7 attacks at the less hindered terminus of the double bond to form a more stable secondary radical. Longer siliconoxygen bonds also favor formation of the 7 -membered ring. The regioselectivity is different for 9, where both ends of the double bond are substituted, and the more stable benzylic radical is produced by 6-exo cyclization. It is not to be inferred that these radical cyclizations are reversible; since the thermodynamic stabilities of the product radicals may well be reflected in the relative stabilities of the respective transition states. Similar results have recently been observed by Koreeda7 during his investigation of the radical cyclizations of silyl ethers 12 and 14. With substrate 12 where the olefinic terminus is unsubstituted exclusive 7-endo attack is observed. However, exclusive 6endo attack is observed with the Z olefm 14. H3C, __,CH 3 R-O 13 C~.~ ) CI CH'-r.............. jH' °T ~ R 14 The ratio of cyclic products to simple reduction products was dependent on temperature, concentration, and solvent (Table I). 103 Table I. Influence of reaction variables on radical cyclization of 7 and 9 Substrate Temperature Cyclize~educeda (0C) [Bu3SnH] (mM) Solvent Yield (%) Ratio b anti:syn 7 30 1:5 5.9 toluene 7 60 9:1 5.9 toluene 71 c 7 110 6:1 5.9 toluene 59C 7 60 9:1 3.0 toluene 55e 7 60 2:3 5.9 THF 9 30 1:10 5.9 toluene 9 60 3:1 5.9 toluene 41d 3: 1 toluene 35 d 1.8:1 9 110 3:1 5.9 aDetermined by integration of 1H NMR of crude reaction mixtures. bDetermined by integration of the corresponding acetonides. qsolated yield of 7-membered siloxane 8. dlsolated yield of 1,3-diols. There appears to be a thermal barrier to cyclization, since reduction predominates below 60°C. The proportion of noncyclized products decreased upon lowering the concentration of tributyltin hydride. This is not surprising, since the formation of reduced product is expected to be a bimolecular process (fIrst order in both tributyltin hydride and substrate), while the cyclization is unimolecular (first order in substrate alone). This effect levels off at tributyltin hydride concentrations below 5.9 mM, perhaps because at that point the solvent competes effectively as a hydrogen atom donor. Solvent was also an important factor; increased amounts of reduction product resulted when tetrahydrofuran was used instead of toluene. The diastereoselectivity for the cyclization of 7 increases at lower reaction temperatures, favoring the anti isomer. This selectivity may be explained by invoking chair-like transition states such as A and S. In transition state A, both bulky substituents can adopt an equatorial orientation. In transition state S the olefInic substituent is axial. 104 The poor discrimination between anti and syn diastereomers is perhaps not surprising given the weak 1,3-diaxial interactions in S. 5 We have also studied group transfer radical cyclization with substrate 7. Primarily through the efforts of Curran,8 this reaction has become a valuable way to incorporate functionality in radical cyclizations. Curran's research has focused on the transfer of iodides. The group transfer of selenium, on the other hand, has received very little attention.9 H3 C, __,CH 3 Si 0/ ' 0 Ph~"'IH l SePh BU3SnSnBu3. hu. 30 h ~ benzene. 80°C 7 16 HO HO OH Ph~ + Ph~ OH 16 17 65% (3:1) 18 105 Irradiation of siloxane 7 with a tungsten lamp in the presence of a catalytic (10 mol%) amount of hexabutylditin gave almost quantitative yields of diastereomeric group transfer products 16. Since these products partially hydrolyzed on silica, they were not purified at this stage. Treatment of the product selenides with m-CPBA and triethylamine led to the olefins 17 and 18 in moderate yield. 10 The presence of the E olefin 18 among the products is almost certainly due to cleavage of the siloxane functional group prior to elimination to form the double bond. Only m-CBPA and t-BuOOH were screened as oxidants in the reaction and it is possible that other reagents (e.g., dimethyldioxirane, ozone) would lead to less siloxane cleavage. + HO OH Ph~ CH 2213% 3 Substrate 19 was examined to explore the possibility of generating trisubstituted double bonds using this methodology. This siloxane reacted smoothly upon irradiation to give high yields of group transfer products. Unfortunately these selenides eliminated to give the exocyclic olefin when treated with mCPBA in the presence of triethylamine. Only a small amount of the desired trisubstituted olefm 22 was isolated. 106 o (NPMB HO M~ AcNH yo~ o 4 steps + 3 CH OMe TBSO 23 OTBS 24 HO OH lNAO )lM~~O~ NH tu~- l'r--{ OCH 3 TBSO OTBS 2557% In summary, we have developed new methodology for reductively coupling an allylic alcohol and an aldehyde. Terminally unsubstituted allylic alcohols give l,4-diols in good to moderate yields. The mild reaction conditions are especially favorable for use with complex substrates, as exemplified by the transformation of 23 and 24 to the diol 25, a precursor in the synthesis of tunicaminyluraci1. 5 107 Experimental Section Melting points were recorded with a Biichi SMP-20 melting point apparatus and are uncorrected. Infrared spectra were recorded on either a Beckman 4240 Infrared spectrometer or a Perkin Elmer 1600 FTIR spectrometer. Data are represented as follows: frequency of absorption (cm- 1 ), and intensity of absorption (s=strong, m=medium, w=weak, br=broad). The IH NMR spectra were obtained on a lEOL JNMGX400 spectrometer (400 MHz), and peaks are reported in ppm (8 scale), using the residual solvent peak as reference (CHCl3:7.26, C6DsH:7.15). Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, m=multiplet, br=broad), integration, coupling constants in Hertz, and· assignment. Mass spectra and high resolution mass spectra were obtained from the UC Riverside Mass Spectrometry Facility. Photolyses .were performed with aGE 1000 W tungsten industrial lamp. Liquid chromatography was performed using a forced flow (flashchromatograpy)11 with the indicated solvent using JT Baker Silica Gel (40 ~m) or Merck Silica Gel 60 (230-400 mesh ASTM). Analytical thin-layer chromatography was performed using Merck pre-coated silica gel 60 F-254 plates (0.25 rnm, glass-backed, fluorescent at 254 nm). Tetrahydrofuran, and diethyl ether were distilled from sodium-benzophenone ketyl. N,N-Dimethylformamide, acetonitrile, methylene chloride, hexanes, pyridine, triethylamine, diisopropylamine, and chlorotrimethylsilane were distilled from calcium hydride. Benzene and toluene were distilled from sodium. All nonaqueous reactions were performed in flame-dried glassware under argon, unless otherwise noted. Deoxygenation of solutions was accomplished by evacuating and flushing the solutions with argon five times. Organic solutions were concentrated on a Biichi rotatory 108 evaporator at 10-20 Torr, unless otherwise specified. Solvents used in the workup and purification of compounds were HPLC-reagent grade and were used without further purification. Dichlorodimethylsilane (Petrarch) was distilled Hydrocinnamaldehyde was distilled under reduced pressure. from magnesium. 2-Propen-l-ol (allyl alcohol) and 2-rnethyl-2-propen-l-ol (rnethallyl alcohol) were distilled from CaH2 and stored over 3-A molecular sieves. All other reagents were obtained from commercial sources unless otherwise noted and used as received. 109 o Ph~H 1) PhSeH, pyr, 15 min 2) Me2SiCI2 (13 equiv), 16 h 3) allyl alcohol, pyr, tal, 1 h 793% Racemic Q-CAllyloxy) Dimethylsilyl Hemiselenoacetal Z Benzeneseleno}l2 (0.132 mL, 1.24 mmol, 1.04 equiv) was added dropwise to a solution of hydrocinnamaldehyde (0.161 g, 1.20 mmol, 1.0 equiv) in pyridine (10 mL). After 15 min, the light yellow solution was added by cannula to a deoxygenated solution of Me2SiCl2 (2.0 mL, 17 mmol, 14 equiv) in pyridine (10 mL). The solution was covered with foil, and allowed to stir at 23°C for 16 h, then the volatile components were removed under vacuum (0.1 Torr). The residue was taken up in a mixture of pyridine (2 mL), and toluene (10 mL) and a white solid precipitated out of solution. The suspension was treated with allyl alcohol (0.085 mL, 0.073 g, 1.04 equiv) for 1 h at 23°C, then the solution was concentrated in vacuo. The residue was partitioned between I: I ethyl acetate-hexanes (50 mL) and cold saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated affording a yellow oil (±)-7 (482.8 mg, 99%, 94% pure by weight). Racemic O-CAllyloxy) Dimethylsi.lyl Hemiselenoacetal Z 7.67 (m, 2H, arom), 7.07-7.23 (m, 8H, arom), 5.80 (m, IH, H2'), 5.49 (dd, 1= 6.3, 6.6, HI), 5.28 (m, 1H, H3'), 5.00 (m, 1H, H3'), 4.11 (m, 2H, HI'), 2.72 (m, 2H, H3), 2.25 (m, 2H, H2), 0.10 (s, 6H, SiCH3). 110 FTIR (neat film), em-I: 3060 (w), 2943 (w), 1643 (w), 1578 (m), 1490 (m), 1472 (m), 1449 (m), 1437 (m), 1255 (s), 1096 (s), 1038 (s), 914 (m), 861 (s), 797 (s), 732 (s), 691 (s). MS (FAB): 405 (MH+), 249 (MH+·SePh), 193 (MH+-SePh ·OC3H4). HRMS (FAB): Calculated for C20H2s02SeSi (MH+): 405.0789 Found: 405.0775 Hemiselenoacetal 7 0.36 (UV) (unstable) Hydrocinnamaldehyde 0.19 (UV) Diphenyl diselenide 0.66 (UV) 111 o Ph~H 1) PhSeH, pyr, 15 min 2) Me2SiCI2 (7 equiv), 10 h 3) cinnamyl alcohol, pyr, tol, 1 h Racemic Q-(Cinnamyloxy) Dimethylsilyl Hemiselenoacetal 9 Benzeneselenol 12 (0.264 mL, 2.48 mmol, 1.0 equiv) was added dropwise to a deoxygenated solution of hydrocinnamaldehyde (0.322 g, 2.4 mmol, 1.0 equiv) in pyridine (15 mL). After 15 min, the light yellow solution was added by cannula to a deoxygenated solution of Me2SiCh (2 mL, 17 mmol, 6.9 equiv) in pyridine (5 mL). The transfer was quantitated with one 5-mL portion of pyridine. The solution was covered with foil, and allowed to stir at 23°C for 10 h, then the volatile components were removed under vacuum (0.1 Torr). The residue was taken up in a mixture of pyridine (1 mL), and toluene (5 mL) and a white solid precipitated out of solution. The suspension was treated with (E)-cinnamyl alcohol (0.360 g, 2.68 mmol, 1.1 equiv) for 1 h at 23 °C, then the solution was concentrated in vacuo. The residue was taken up in hexanes (100 mL), filtered, and concentrated affording (±)-9 (1.106 g, 96%, 96% pure by weight) as a yellow oil. Racemic Q-(Cinnamyloxy) Dimethylsilyl Hemiselenoacetal 9 7.69 (m, 2H, arom), 6.95-7.30 (m, 13H, arom), 6.62 (d, 1H, 1=16.4, H3'), 6.19 (dt, 1=16.4,6.2, H2'), 5.54 (t, 1H, 1=7.5, HI), 4.30 (m, 2H, HI'), 2.77 (m, 2H, H3), 2.27 (m, 2H, H2), 0.17 (s, 6H, SiCH3). 112 FTIR (neat film), em- 1: 2943 (w), 1492 (m), 1472 (m), 1449 (m), 1431 (m), 1255 (s), 1076 (s), 1032 (s), 934 (m), 841 (s), 775 (s), 727 (s), 692 (s). MS (FAB): 483 (MH+), 325 (M+-SePh). HRMS (FAB): Calculated for C26H3102SeSi (MH+): 483.1259 Found: 483.1255 TLC (40% CH2Ch-hexanes): Hemiselenoacetal 9 0.30 (UY) (unstable) Hydrocinnamaldehyde 0.18 (UY) Diphenyl diselenide 0.66 (UY) Cinnamyl alcohol 0.04 (UV) 113 o Ph~H 1) PhSeH, pyr, 15 min 2) Me2SiCI2 (16 equiv), 10 h 3) methallyl alcohol, pyr, tal, 1 h 1987% Racemic O-<Methallyloxy) Dimethylsilyl Hemiselenoacetal 19 Benzeneselenol 12 (0.410 mL, 3.86 mmol, 1.03 equiv) was added dropwise to a deoxygenated solution of hydrocinnamaldehyde (0.501 g, 3.73 mmol, 1.0 equiv) in pyridine (15 mL). After 15 min, the light yellow solution was added by cannula to a deoxygenated solution of Me2SiCl2 (7.0 mL, 58 mmol, 16 equiv) in pyridine (5 mL). The transfer was quantitated with one 5-mL portion of pyridine. The solution was covered with foil, and allowed to stir at 23°C for 10 h, then the volatile components were removed under vacuum (0.1 Torr). The residue was taken up in a mixture of pyridine (1 mL), and toluene (5 mL) and a white solid precipitated out of solution. The suspension was treated with 2-methyl-2-propen-1-01 (methallyl alcohol, 0.325 mL, 0.380 g, 5.25 mmol, 1.3 equiv) for 1 h at 23°C, then the solution was concentrated in vacuo. The residue was taken up in hexanes (100 mL), filtered, and concentrated affording (±)-19 (1.4235 g, 91 %,95% pure by weight) as a yellow oil. Racemic Q-(Methallyloxy) Dimethylsilyl Hemiselenoacetal1.2 7.68 (m, 2H, arom), 7.15-6.89 (m, 8H, arom), 5.49 (t, 1H, 1=6.6, HI), 5.14 (s, 1H, H3'), 4.83 (s, 1H, H3'), 4.04 (m, 2H, HI'), 2.76 (m, 2H, H3), 2.27 (m, 2H, H2), 1.57 (s, 3H, CH3), 0.12 (s, 6H, SiCH3). 114 FTIR (neat film), em-I: 2943 (m),1578 (m), 1496 (m), 1431 (m), 1091 (s), 1044 (s), 867 (s), 797 (s), 732 (s). MS (FAB): 419 (MH+), 263 (MH+-SePh). HRMS (FAB): Calculated for C21H2702SeSi (MH+): 419.0946 Found: 419.0934 Hemiselenoacetal 19 0.41 (UV) (unstable) Diphenyl diselenide 0.66 (UV) Hydrocinnamaldehyde 0.19 (UV) 115 7 862% Racemic Siloxane 8 A deoxygenated solution of AIBN (4 mg, 0.02 mIllol, 0.06 equiv), and BU3SnH (0.240 mL, 259.7 mg, 0.892 mIllol, 2.2 equiv) in toluene (5 mL) was added rapidly dropwise to a deoxygenated solution of racemic hemiselenoacetal 7 (0.150 mL, 174 mg, 0.403 mIllol, corrected for impurity, 1 equiv) in toluene (150 mL) at 60 °C. After 6 h at 60 °C, the reaction mixture was cooled to 23 °C and concentrated under vacuum (0.1 Torr). A 1H NMR of the crude reaction mixture showed a 9: 1 ratio of cyclized:reduced product. The residue was purified by flash chromatography (40% CH2C12-hexanes) affording (±)-8 (63.0 mg, 62%) as a colorless oil. Racemic Siloxane 9 7.11 (m, 5H, arom), 3.80 (m, IH, H4), 3.65 (m, 2H, HI), 2.84 (m, IH, H6), 2.57 (m, IH, H6), 1.80 (m, IH, H5), 1.57 (m, IH, H5), 1.35 (m,4H, H2, H3), 0.20 (s, 3H, SiCH3), 0.17 (s, 3H, SiCH 3)· FTm (neat film), em- 1: 2921 (s), 1604 (w), 1495 (w), 1454 (w), 1368 (w), 1256 (s), 1090 (s), 1047 (s), 966 (m), 842 (m), 116 796 (s), 699 (s). MS (EI): HRMS (EI): Calculated for C14H2202Si (M+): 250.1389 Found: 250.1396 Siloxane 8 0.41 (UV) Herniselenoacetal 7 0.75 (UV) (unstable) BU3SnSePh 0.80 (UV) Hyclrocinnamaldehyde 0.52 (UV) 117 Racemic Acetonides 10 and 11 A deoxygenated solution of AIBN (2 mg, 0.01 mmol, 0.1 equiv) and BU3SnH (0.080 mL, 87 mg, 0.30 mmol, 2.4 equiv) in toluene (2 mL) was added dropwise over 5 min to a deoxygenated solution of racemic hemiselenoacetal 9 (62 mg, 0.12 mmol, corrected for impurity, 1 equiv) in toluene (60 mL). After 6 h at 60°C the reaction mixture was cooled and concentrated in vacuo. The residue was filtered through a pad of silica gel (1.5 cm x 2 cm, 40% CH2C12-hexanes) to r~move the higher Rftin species. The pad of silica was washed with ethyl acetate (110 mL) to ensure complete elution of the diols. After concentration in vacuo, the residue was further purified by flash chromatography (50% EtOAc-hexanes) to afford a mixture of anti and syn diols (14.1 mg, 42%). The diastereomers could be separated by thin-layer preparative chromatography (Rfin 50% ethyl acetate-hexanes syn = 0.23, anti = 0.22). The diols were converted to corresponding acetonides as follows. The mixture of diols (14.1 mg, 0.0519 mmol, 1 equiv) in CH2Cl2 (5 mL), was treated with CSA (5 mg, 0.021 mmol, 0.4 equiv) and 2,2-dimethoxypropane (1 mL, 847 mg, 8.13 mmol, 162 equiv) for 1 hat 23°C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (CH2C12) affording the two diastereomeric acetonides (±)-10 and (±)-11 as a 3:1 mixture (14.7 mg, 92%, 35% for two steps). The diastereomers could be separated by thin-layer preparative chromatography (Rf in CH2C12, syn = 0.42, anti = 0.41). 118 Racemic Acetonide 10 7.01-7.29 (m, lOH, arom), 3.74 (dt, 1H,1=8.7, 2.4, H3), 3.55 (dd, 1H,1=3.6, 12.0, HI), 3.45 (dd, 1H, 1=3.6, 12.0, HI), 3.11 (dd, IH,1=12.0, 13.9, H6), 2.76 (m, IH, H5), 2.68 (dd, IH, 1=3.8, 13.9, H6), 2.58 (m, IH, H5), 1.96 (m, IH, H4), 1.58 (s, 3H, CH3), 1.51 (m, IH, H4), 1.17 (s, 3H, CH3), 1.07 (m, IH, H2). FTIR (neat film), em- 1: 2925 (s), 1602 (w), 1495 (m), 1454 (s), 1380 (m), 1258 (s), 1199 (m), 1125 (m), 1058 (w), 986 (w), 858 (w), 750 (m), 699 (s). MS (EI): 310 (M+), 295 (MH+-C!-4), 234 (M+-C3H60 H20 ). HRMS (EI): Calculated for C21H2602 (M+): 310.1933 Found: 310.1938 Racemic Acetonide 11 6.95-7.30 (m, WH, arom), 3.58 (dd, IH, 1=5.3, 11.5, HI), 3.55 (dt, IH, 1=2.8, 9.1, H3), 3.45 (dd, 119 IH, J=11.2, 11.5, HI), 2.86 (m, 1H, H5), 2.74 (dt, IH, J=13.0, 7.6, H5), 2.38 (dd, IH, J=4.4, 13.8, H6), 1.84 (m, IH, H4), 1.81 (m, IH, H2), 1.74 (dd, IH, J=12.0, 13.9, H6), 1.72 (m, IH, H4), 1.53 (s, 3H, CH3), 1.28 (s, 3H, CH3). FTIR (neat film), em-I: 2940 (m), 1602 (w), 1495 (m), 1453 (m), 1379 (m), 1259 (w), 1196 (s), 1132 (m), 1052 (s), 979 (w), 859 (w), 744 (w), 699 (s). MS (EI): 310 (M+), 295 (MH+·Cf4), 234 (M+-C3Ht;O H20 ). HRMS (EI): Calculated for C21H2602 (M+): 310.1933 Found: 310.1938 TLC (20% EtOAe-hexanes): Acetonide 10 0.53 (UV) Acetonide 11 0.53 (UV) Hemiselenoacetal 9 0.58 (UV) (unstable) Diols 0.06 (UV) 120 ..CH 3 ,.' /Si, o 0 H3C Ph ~. "'H SePh 7 ~ 1) BU3SnSnBu3, hu, 30 h benzene, 80°C HO 2) m-CPBA, CH~12' -78. C ~ o I 3) Et3N, OMS, -78°C Ph 6 5 4 OH _ 3 1 + 2 ~23 °C, 10 h 17 65% (3:1) 18 Racemic Diols 17 and 18 Racemic hemiselenoacetal 7 (0.100 mL, 116 mg, 0.269 mmol, corrected for impurity, azeotropically dried with one portion of toluene (5 mL», BU3SnSnBu3 (0.010 mL, 0.012 mmol, 0.07 equiv) and benzene (60 mL) were combined in a 1oo-mL side-arm flask equipped with a reflux condenser. The reaction mixture was irradiated with a tungsten light bulb placed 10 cm away from the flask, which heated the solution to reflux. After 30 h, monitoring by thin-layer chromatography (Rfin CH2CI2, diphenyl diselenide = 0.91, 7 = 0.75, group transfer products = 0.58, 0.50, hydrocinnamaldehyde = 0.43) indicated the reaction was complete and the reaction mixture was concentrated under vacuum (0.1 Torr). A solution of the residue in CH2Cl2 (5 mL) was treated with mCPBA (200 mg, 1.159 mmol, 4.3 equiv) at -78°C for 1 h, then triethylamine (0.2 mL) was added. The reaction mixture was stirred at -78°C an additional hour, then the excess oxidant was quenched with dimethyl sulfide (1 mL). After another hour at -78°C, the solution was slowly warmed to 23°C and stirred for 10 h at that temperature. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (30 mL) and ethyl acetate (40 mL). The organic layer was separated and the aqueous layer was washed with three 40-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography (ether) affording (±)-17 and (±)-18 (33.7 mg, 3:1 ratio, 65% combined yield) as a yellow 121 solid. The isomers could be further separated by thin-layer preparative chromatography (Rfin 20% toluene-ethyl acetate trans = 0.31, cis = 0.28). Racemic Diol 17 7.10-7.34 (m, 5H, arom), 5.45 (d, 2H, 1=5.4, H2, H3), 3.81 (br, 1H, H4), 3.75 (s, 2H, HI), 2.60 (m, 2H, H6), 1.66 (m, 2H, H5). FTIR (neat film), em-I: 2921 (s), 1604 (w), 1495 (w), 1454 (w), 1368 (w), 1256 (s), 1090 (s), 1047 (s), 966 (m), 842 (m), 796 (s), 699 (s). MS (CI:NH3): 210 (M+NJ4+), 193 (MH+), 175 (MH+-H20), 157 (MH+-2H20). HRMS (CI:NH3): Calculated for C12H1702 (MH+): 193.1229 Found: 193.1220 Racemic Diol 18 7.10-7.34 (m, 5H, arom), 5.47 (m, 1H, H2), 5.33 (m, 1H, H3), 4.11 (q, 1H, 1=7.1, H4), 3.86 (m, IH, HI), 3.74 (m, 1H, HI), 2.55 (m, 2H, H6), 122 1.75 (m, lH, H5), 1.58 (m, lH, H5), 1.35 (br, IH, OH). FTIR (neat film), em-I: 3260 (w), 2919 (m), 2849 (m), 1602 (w), 1498 (w), 1449 (m), 1255 (m), 1020 (s), 797 (s), 744 (w), 691 (m). MS (CI:NH3): HRMS (CI:NH3): Calculated for C12H1702 (MH+): 193.1229 Found: 193.1224 TLC (ether): Dio117 0.14 (UV) Dio118 0.14 (UV) Group transfer products 0.78 (UV) (unstable) Hemiselenoacetal 7 0.84 (UV) (unstable) 123 + HO ~5A Ph- OH )1 6 .......... 4~_ CH 3 2213% 7 Group transfer reaction of Racemic Hemiselenoacetal 19 A solution of racemic hemiselenoacetal 19 (0.100 mL, 106 mg, 0.241 mmol, corrected for impurity, azeotropically dried with one portion of toluene (5 mL)), and BU3SnSnBu3 (0.010 mL, 0.020 mmol, 0.08 equiv).in benzene (50 mL) was irradiated with a 1000 W tungsten bulb, for 32 h at reflux until monitoring by thin-layer chromatography (Rf in CH2CI2, diphenyl diselenide = 0.91, 19 = 0.75, group transfer products = 0.62, 0.58, hydrocinnamaldehyde = 0.43) indicated the reaction was complete. The reaction mixture was concentrated under vacuum (0.1 Torr). A solution of the residue in CH2C12 (5 mL) was sequentially treated with m-CPBA (125 mg, 0.869 mmol, 3.61 equiv) and Et3N (0.1 mL) for 30 min at -78°C. The excess oxidant was quenched with dimethylsulfide (0.5 mL) and the reaction mixture was stirred an additional hour at -78°C. The reaction mixture was slowly warmed to 23°C and stirred for 10 h at that temperature. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and ethyl acetate (40 mL). The organic layer was separated and the aqueous layer was washed with three 40-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography (50% CH2C12-hexanes) giving (±)-20 (19.1 mg, 0.0725 mmol, 30%) and 124 a mixture of lower Rfdio1s and m-chlorobenzoic acid (23 mg). The lower Rfmixture was further purified by flash chromatography (50% ether-petroleum ether) affording (±)-21 (15.0 mg, 0.073 mmol, 30%), and (±)-22 (6.7 mg, 0.033 mmol, 13%) as clear, colorless oils. Racemic Siloxane 20 7.05-7.35 (m, 5H, arom), 4.84 (s, 1H, H7), 4.68 (s, IH, H7), 4.19 (m, 2H, HI), 3.77 (m, IH, H4), 2.79 (m, IH, H6), 2.57 (m, IH, H6), 2.16 (m, 2H, H3), 1.80 (m, IH, H5), 1.61 (m, IH, H5), 0.37 (s, 3H, SiCH3), 0.17 (s, 3H, SiCH3). FTIR (neat film), em-I: 2919 (w), 2849 (w), 1490 (w), 1449 (w), 1255 (m), 1091 (s), 1073 (s), 973 (m), 908 (m), 850 (s), 838 (s), 791 (s), 738 (w), 685 (m). 291 (MH++H20), 263 (MH+), 247 (MH+-CH4), 171 (M+-(CH3hSi(OHh). HRMS (CI:CH4): Calculated for ClSH2202Si (M+): 262.1389 Found: 262.1377 125 Racemic Diol 21 7.00-7.30 (m, 5H, arom), 4.92 (s, IH, H7), 4.72 (s, IH, H7), 3.74 (s, 2H, Hl), 3.49 (m, IH, H4), 2.72 (m, IH, H6), 2.55 (m, IH, H6), 2.06 (dd, IH,1=3.4, 13.9, H3), 1.95 (dd, IH,1=8.3, 13.9, H3), 1.60 (m, 2H, H5). FTIR (neat film), em-!: 3331 (s), 2919 (s), 2849 (m), 1649 (w), 1596 (w), 1496 (m), 1449 (m), 1049 (s), 1026 (s), 903 (m), 744 (m), 697 (s). 225 (MH++H20), 207 (MH+), 189 (MH+-H20), 171 (MH+-2H20). HRMS (CI:NH3): Calculated for C13H1902 (MH+): 207.1385 Found: 207.1391 Racemic Diol 22 6.90-7.30 (m, 5H, arom), 5.17 (d, IH, 1=8.0, H3), 4.18 (dt, IH, 1=5.5, 7.5, H4), 3.84 (d, IH, 1=12.0, HI), 3.64 (d, lH, 1=12.0, HI), 2.59 (m, 2H, H6), 1.77 (m, IH, H5), 1.61 (m, IH, H5), 1.61 (s, 3H, H7). 126 FTIR (neat film), em-I: 3331 (s), 2919 (m), 2861 (m), 6102 (w), 1490 (m), 1449 (m), 1026 (m), 997 (s), 744 (m), 691 (s). HRMS (CI:NH3): Calculated for C13H1902 (MH+): 207.1385 Found: 207.1384 TLC (ether): Siloxane 20 0.81 (UV) Diol21 0.44 (UV) Dio122 0.31 (UV) Group transfer products 0.88 (UV) (unstable) 127 References lea) Struble, D. L.; Beckwith A. L. J.; Gream, G. E. Tetrahedron Lett. 1968, 3701. (b) Beckwith A. L. J.; Gream, G. E.; Struble, D. L. Aust. 1. Chem. 1972, 1081. (c) Baldwin, J. E. 1. Chem. Soc., Chem. Commun. 1976, 107, 734. 2Systems studying 5-exo vs. 6-endo radical cyclizations in silicon-substitiuted radicals: (a) Stork, G. A.; Mook, R., Jr. 1. Am. Chem. Soc. 1983,105, 3741. (b) Stork; G. A.; Sher, P. M. 1. Am. Chem. Soc. 1983,105, 6765. (c) Nishiyama, H.; Kitajima, T.; Matasumoto, M.; Itoh, K. 1. Org. Chem. 1984,49,2298. (d) Wilt, J. W. Tetrahedron 1985,41, 3979. (e) Stork, G. A; Kahn, M. 1. Am. Chem. Soc. 1985, 107, 500. (0 Wilt, J. W. Tetrahedron 1985,41, 3979. (g) Kore~da, M.; George, 1. A. 1. Am. Chem. Soc. 1986,108, 8098. (h) Wilt, J. W.; Lusztyk, J.; Perran, M.; Ingold, K. U. 1. Am. Chem. Soc. 1988,107, 281. (i) Kurek-Tyrlik, A.; Wicha, J. Tetrahedron Lett. 1988, 29, 4001. (j) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. 1. Am. Chem. Soc. 1988, 110,5900. (k) Stork, G. A.; Mah, R. Tetrahedron Lett. 1989,30, 3609. (1) Tamoa, K.; Maeda, K.; Yamaguchi, T.; Ito, Y. 1. Am. Chern. Soc. 1989, 111, 4984. (m) Journet, M.; Smadja, W.; Malacria, M. Syn. Lett. 1990, 320. (n) Walkup, R. D.; Obeyesekere, N. U. Chern. Lett. 1990,31,1055. (0) Walkup, R. D.; Kane, R. R.; Obeyesekere, N. U. Tetrahedron Lett. 1990,31, 1531. (p) Agnel, G.; Malacria, M. Tetrahedron Lett. 1990,31,3555. (q) Journet, M.; Magnol, E.; Agnel, G.; Malacria, M. Tetrahedron Lett. 1990,31, 4445. (r) Curran, D. P.; Schwartz, C. E. 1. Am. Chern. Soc. 1990, 112, 9272. (s) Hutchinson, J. H.; Daynard, T. S.; Gillard, J. W. Tetrahedron Lett. 1991,32, 573. 128 3Generation of radicals from O-alkyl hemiseleno- or hemithio- acetals: (a) Yadav, V. K.; Fallis, A. G. Tetrahedron Lett. 1988,29, 897. (b) Yadav, V. K.; Fallis, A. G. Tetrahedron Lett. 1989,30, 3283. (c) De Mesmaeker, A.; Hoffmann, P.; Ernst, B.; Hug, P.; Winkler, T. Tetrahedron Lett. 1989,30,6307,6311. (d) De Mesmaeker, A.; Waldner, A.; Hoffmann, P.; Mindt, T.; Hug, P.; Winkler, T. Syn. Lett. 1990, 687. 4Methods for the synthesis of O-sHyl hemithio- and hemiseleno- acetals: (a) Chan, T. H.; Ong, B. S. Tetrahedron Lett. 1976, 319. (b) Dumont, W.; Krief, A. Angew. Chem., Int. Engl. 1977,16, 540. (c) Glass, R. S. Synth. Commun. 1976,6, 47. (d) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am. Chem. Soc. 1977, 99, 5009. (e) Liotta, D.; Paty, P. B.; Johnston, J.; Zima, G. Tetrahedron Lett. 1978,5091. (f) Sassaman, M. B.; Surya Prakash, G. K.; Olah, G. A. Synthesis 1990, 104. 5Myers, A. G.; Gin, D. Y.; Widdowson, K. L. J. Am. Chem. Soc. 1991, 113, 9661. 6This supports the mechanism suggested by Chan for O-trimethylsilyl hemiselenoacetal formation: see references 4 a and d. 7Systems studying 6-exo vs. 7-endo radical cyclizations in silicon-substitiuted radicals: (a) Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990,112,8175. (b) Hutchinson, J. H.; Daynard, T. S.; Gillard, J. W. Tetrahedron Lett. 1991,32,573. 8Group transfer radical reactions involving iodides: (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986,108, 2489. (b) Curran, D. P.; Kim, D. Tetrahedron Lett. 1986,27,5821. (c) Curran, D. P.; Chen, M.-H. J. Am. Chem. Soc. 1987,109,6558. 129 (d) Curran, D. P.; Chang, C.-T. 1. Org. Chem. 1989,54, 3140. (e) Barth, F.; Yang, c.-O. Tetrahedron Lett. 1990,31, 1121. (f) Curran, D. P. Synthesis 1988, 489. (g) Curran, D. P.; Chen, M.-H.; Sp1etzer, E.; Seong, c.; Chang, C.-T. 1. Am. Chem. Soc. 1989, 111, 8872. (h) Curran, D. P.; Chen, M.-H.; Kim, D. 1. Am. Chem. Soc. 1989, 111,6265. (i) Curran, D. P.; Chang, C.-T. Tetrahedron Lett. 1987,28, 1477. 9Byers, J. H.; Gleason, T. G.; Knight, K. S. 1. Chem. Soc., Chem. Commun. 1991, 355. 10Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.; Wendelborn, D. F. 1. Org. Chem. 1978, 13, 1697. llStill, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978,43, 2923. 12Foster, D. G. In Organic Syntheses, Collective Vol. 3 Horning, E. C., Ed.; John Wiley & Sons: New York, 1955; pp. 771-773. 130 CHAPTER III Synthesis of Hydroxy Carbonates from Epoxy Alcohols under Basic Conditions 131 It was necessary to synthesize the model compounds 2 and 4 to aid in the assignment of two stereo genic centers in the natural product neocarzinostatin. 1 0 }--o d5: r1 05: HPH '. OH ~ 11 ~ # • : I # ~ I # 2 3 1 • 4 Retrosynthetic analysis suggested that these compounds could be synthesized expeditiously from the corresponding optically active epoxy alcohols 1 and 3. The most general methodology for effecting the transformation of epoxy alcohols to hydroxy carbonates involves the Lewis acid-induced rearrangement of phenyl urethane derivatives. 2 Lewis acid Application of this procedure to the model compounds 1 and 3 led to intractable product mixtures, presumably due to facile epoxide opening at Cl. McCombie and Metz encountered similar problems in attempts to transform epoxy alcohol 5 to hydroxy carbonate 6, enroute to triol 7.3 Though unsuccessful in this conversion, they found that treatment of 5 with cesium carbonate-paraformaldehyde mixtures provided the 1,3dioxolane derivative 8 in good yield. This compound afforded the triol 7 upon acidic hydrolysis (6N HCI-MeOH). The extension of this approach by substitution of paraformaldehyde with carbon dioxide to produce hydroxy carbonates directly was investigated. 132 H ~1 Ph CH 20H 3 2 OH ...................... _-_ .. .-, OH Ph~O Ph~ o-{ H H OH 0 5 7 6 OH H Ph OH ~CH20H (CH 20 )n. CS~03 H OH Ph~O PhJyJ 0-1 H 95% 65 °C. 6 h OH 7 8 5 OH 6N HCI Scouting experiments established that treatment of 5 with carbon dioxide-cesium carbonate mixtures provided the desired C2-inverted hydroxy carbonate 6 as the major product along with three minor products 9, 10 and 11.4 OH Ph~O HO-( H Ph Ol .• -: CH 20H ~ 3 CS~03 (0.09 equiv) • 2 . H 5 (98% eel o 685% (98% eel C02. DMF. 36 oC, 13 h 98% o Ph" OH o--{ '~ /'0 H..... j''''H + Ph~O H 10 0-( o CH 20H 5% 11 Examination of the Mosher esters5 of the starting material 5 and the product 6 showed that the process was completely stereospecific, within experimental error. Hydrolysis of 6 afforded a triol which was found to be identical in all respects with authentic (lS,2R)7,6 confirming the absolute and relative stereochemistry of 6. 133 OH OH PhJY NaOH, MeOH Ph~O H 23°C, 15 min O--{ OH Observed [af3 s89 +20.2° (c 6.24, HzO) Literature [a]23 s89 +19.6° (c 6.24, H20) OH o 785% 6 o OH Ph, 0--( ~;O H- 1""CH 20H 23°C, 15 min H OH 9 771% o OH Ph"0--( X;O H.... OH PhJY NaOH, MeOH + T""H OH Ph~O NaOH, MeOH H 23°C, 15 min o--{ CH 20H Ph~ o 10 OH 11 OH 1281% The cis stereochemistry of 9 is suggested by the observation of a 5.1 Hz coupling between protons H2 and H3 in the 1H NMR spectrum. Saponification of 9 produced 7 confmning the assignment. Similarly, the trans stereochemistry of 10 is suggested by a 8.0 Hz coupling between protons H2 and H3. As expected, saponification of 10 and 11 produced the diastereomeric triol 8, supporting the assignments of these products. The major side product (9), is presumably derived from intramolecular carbonate equilibration. This process is rapid under the reaction conditions, thus a thermodynamic mixture of products results. The relative stability of carbonates is found to reflect that of the "parent" olefins. The more substituted carbonates (e.g., 9 and 10) are generally favored in the absence of overriding steric considerations. OH Ph~O H~ o--{ o 6 -- o o. [ p50 Ph ]= 9 134 The minor side products 10 and 11 are thought to arise primarily from Payne rearrangement (S~12)7 with subsequent reaction of 12 with carbon dioxide. 0 H Ph *( "': . H OH CH 20H base Ph H 5 f CS 2C03 H CO 2 :Jy.c Ph"O-{ H ·· .. 'H H CH 20H 12 10 OH Ph~O H 0-( 0 11 An alternative pathway involves attack of a carbonate anion on the cyclic carbonate. OH 0 (0 Ph~O H~ 0 - ( CS2C03 CO 2 0 6 ~-}o -CO2 Ph~O H~~ - Arc -- Ph"O-{ H b) ""'H OH Ph~O H CH~H 10 o-{ 0 11 Control experiments showed that direct conversion of 6 to 10 and 11 occurs, but is too slow to be the primary mode of formation of these products. The transformation of 5 to 6, 9, 10, and 11, was studied in detail to determine optimum reaction conditions (Table I). Proper catalyst preparation was found to be critical for reducing the amount of C2 inverted products. The optimum conditions for catalyst preparation involve heating the solid in vacuo, with cooling under one atmosphere of carbon dioxide (as opposed to cooling in vacuo). This procedure provided a very active catalyst. The rationale behind this catalyst activation procedure was to scavenge any cesium oxide produced in the heating process, by reaction with C02 to reform cesium carbonate. 135 Table I. Influence of Reaction Variables on the Transformation of S~, 9,10, and 11 Catalyst C02 pressure Temp (0C) (atm) Ratio of Productsa Time Yield Catalyst of 6 Preparation (h) 6 9 10 11 (%) CS2C03 (0.05 equiv) 3-A molecular sieves 1 SO 13 20 1.0 5.6 1.8 Ab 73 CS2C03 (0.05 equiv) 3-A molecular sieves 1 40 10 25 1.0 3.3 1.0 Be 8S CS2C03 (0.05 equiv) 3.4 3-A molecular sieves 40 13 25 1.0 3.3 1.0 B 7S CS2C03 (0.05 equiv) 54.4 3-A molecular sieves 40 13 20 4.0 1.0 1.2 B 71 CS2C03 (0.05 equiv) 1 40 24 20 1.0 1.8 1.8 B 74 K2CO] (1 equiv) 3-A molecular sieves BU4NCI (1 equiv) 1 40 12 25 1.0 15 5.0 B -d 80 24 B e 3-A molecular sieves KH (1 equiv) 1 70 12 Et3N (solvent) 1 80 24 2 1 12 4 -e aDetermined by integration of 1H NMR of crude reaction mixtures. bCatalyst flame-dried and cooled under vacuum. CCatalyst flame-dried and cooled under an atmosphere of C02. dlncomplete reaction. ~o reaction products detected. The relative amounts of Payne rearrangement products can also be decreased by increasing the pressure of carbon dioxide, although this had only a small effect on the rate of the reaction. Quantitating the effect of increased pressure of carbon dioxide was difficult because variations in stirring efficiency were encountered with different reaction vessels employed, a parameter found to be critical in this heterogeneous reaction. 136 The exact role of molecular sieves in the reaction is uncertain, but their incorporation causes a twofold increase in reaction rate. Both 3-A and 4-A molecular sieves were equally effective in accelerating the reaction, however sieves alone do not catalyze the reaction. The highest selectivity occurred with DMF as the solvent, although the reaction also occurred in nonpolar (toluene) and protic (isopropanol) solvents. A number of other bases were also examined as possible catalysts. Potassium hydride was effective, but greatly increased the amount of side products derived from Payne rearrangement. Potassium carbonate and tetrabutylammonium chloride mixtures were less effective than cesium carbonate as catalysts, and triethylamine did not promote the reaction. 0 H Ph JyH CS~03 (0.09 equiv), • . ·CH~H C02, DMF, 45°C, 6 h H OH o--{ Y-y0 Ph" + ""H Ph~O H CH~H 0 1064% 13 o-{ 1121% o 0-< CH~II.L /0 3 H' \"CH 3 CH;PH 1578% + C02, DMF, 72°C, 13 h OH 14 CH 3 : ~O CHl'b-{ o 1613% A variety of hydroxy epoxides of different substitution were studied. These substrates, unlike 6, showed no propensity for competitive Payne rearrangement. As 137 before, carbonate equilibration (presumably by intramolecular transesterification) occurred, producing a thermodynamic mixture of products. With substrate 13 the rearranged carbonate 10 predominated again reflecting the stability of the parent olefin. Epoxy alcohol 14 was examined as a substrate to test for the possibility of 6-exo opening of the epoxide, the relative steric hindrance at C 1 and C2 providing optimum opportunity for this mode of attack. However, only hydroxy carbonates 15 and 16 were observed, though not surprisingly higher reaction temperatures were required for the reaction to occur. The relative stereochemistry of hydroxy carbonate 15 was determined by nOe spectroscopy. 15 Irradiation of the hydroxy methylene protons led to a negative nOe of the me thine proton, supporting a cis relationship between these two substituents. Saponification of 15 and 16 produced the same triol (17), supporting the stereochemical assignment of 16. NaOH, MaOH 15 17 16 In an effort to determine the reaction mechanism, the transformation of 14 to 15 and 16 was monitored by NMR spectroscopy. The signals (l3C, 7Li external lock) of 138 epoxy alcohol 14 were gradually replaced by those of hydroxy carbonates 15 and 16. Thus, if carbonate 17 is an intermediate in the reaction, its concentration in solution must be quite low. n-BU~O-{O , 0 H .. "CH 3 CH 20H 14 17 15 Application of the methodology described above to epoxides 1 and 3 was found to produce the desired carbonates in high yield with complete stereospecificity, fulfilling the initial goals of the project. 1 This method is anticipated to be generally useful for the transformation of epoxy alcohols to hydroxy carbonates, especially with acid-sensitive substrates. 139 Experimental Section Melting points were recorded with a Biichi SMP-20 melting point apparatus and are uncorrected. Optical rotations were measured using a Jasco DIP-I80 Digital Polarimeter at the sodium D line (589 nm) and are reported as follows: [a]25 589, concentration (c (g/lOO mL)), and solvent. Infrared spectra were recorded with a Beckman 4240 Infrared spectrometer or a Perkin Elmer 1600 FTIR spectrometer. Data are represented as follows: frequency of absorption (cm- 1), and intensity of absorption (s=strong, m=medium, w=weak, br=broad). The 1H NMR spectra were obtained on a JEOL JNM-GX400 NMR spectrometer (400 MHz), and peaks are reported in ppm (0 scale) using the residual solvent peak as reference (CHCI3:7.26, C6D5H:7.15). Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, m=multiplet, br=broad), integration, coupling constants in Hertz, and assignment. Externally locked eLi), proton decoupled 13C NMR spectra were obtained on a JEOL FX-90Q NMR spectrometer (22.5 MHz) and are reported in ppm (0 scale) using the residual solvent peak as reference (DMF:162.7, 35.2, 30.1). Mass spectra and high resolution mass spectra were obtained from the UC Riverside Mass Spectrometry Facility. Liquid chromatography was performed using a forced flow (flashchromatography)8 with the indicated solvent using JT Baker Silica Gel (40 Jlm) or Merck Silica Gel 60 (230-400 mesh ASTM). Analytical thin-layer chromatography was performed using Merck pre-coated silica gel 60 F-254 plates (0.25 mm, glass-backed, fluorescent at 254 nm). Tetrahydrofuran and diethyl ether were distilled from sodium-benzophenone ketyl. N,N-Dimethylformamide, acetonitrile, methylene chloride, hexanes, pyridine, triethylamine, diisopropylamine, and trimethylchlorosilane were distilled from calcium 140 hydride. Benzene and toluene were distilled from sodium. t-Butyllithium in hexanes was titrated with diphenylacetic acid according to Kofron and Baclawski. 9 All nonaqueous reactions were performed in flame-dried glassware under argon, unless otherwise noted. Organic solutions were concentrated on a Blichi rotatory evaporator at 10-20 Torr, unless otherwise specified. Solvents used in the workup and purification of compounds were HPLC-reagent grade and were used without further purification. 141 1)t-8uLi (2 equiv), THF, -78 °C 2)n-pentanal, THF, -78 °C 55% Racemic 2-Methyl-1-hepten-3-01 t-BuLi (63 mL, 1.82 M in hexanes, 115 mmol, 2.0 equiv) was added over 20 min to a solution of 2-bromopropene (4.9 mL, 6.93 g, 57.3 mmol, 1.0 equiv) in tetrahydrofuran (100 mL) at -78 °e. After 1 h, n-pentanal (6.1 mL, 4.939 g, 57.34 mmol, 1.0 equiv) was added dropwise over 5 min. After an additional 40 min, the reaction mixture was warmed to 0 °e and quenched with saturated aqueous ammonium chloride solution (50 mL). The solution was partitioned between 1: 1 ethyl actetate-hexanes 100 mL) and brine (100 mL). The aqueous layer was extracted with 1:1 ethyl acetate-hexanes (2 x 100 mL) and the combined organic phases were dried over sodium sulfate. The solution was concentrated in vacuo and the residue was purified by flash chromatography (10% ether-petroleum ether~ 15% ether-petroleum ether) to afford pure racemic 2methyl-l-hepten-3-01 (4.02 g, 55%) as a clear, colorless oil. Racemic 2-Methyl-l-hepten-3-01 I H NMR (400 MHz, CDCI3): 4.81 (s, IH, HI), 4.21 (s, IH, HI), 4.02 (t, IH, 1=6.5, H3), 1.87 (s, IH, OH), 1.69 (s, 3H, H8), 1.51 (m,2H), 1.36 (m, 2H), 1.22 (m, 2H), 0.88 (t, 3H, 1=6.6, H7). FTm (neat film), em-I: 3378 (m), 2943 (s), 1449 (m), 1373 (m), 1002 (m), 891 (m). 142 MS (EI): 129 (MH+). HRMS (EI): Calculated for C8H160 (M+): 129.1268 Found: 129.1279 TLC (20% EtOAc-hexanes): 2-Methyl-l-hepten-3-ol 0.48 143 H r :L"? o °C, 20 min Ph' /H CH 20H 1 1360% Racemic Epoxy Alcohol 13 A solution of (Z)-3-phenyl-2-propen-1-oI 10 (0.77 g, 5.74 mmol, 1 equiv) in CH2Ch (6 mL) was treated with m-CPBA (1.71 g, 10.3 mmol, 1.8 equiv) for 20 min at o °C. Excess oxidant was quenched with saturated aqueous Na2S203 solution (10 mL). The reaction mixture was partitioned between CH2Cl2 (20 mL) and 5% aqueous NaOH solution (30 mL). The organic layer was separated, and the aqueous layer was extracted with one 10-mL portion of CH2CI2. The organic phases were combined and washed with aqueous 5% NaOH solution (30 mL). The aqueous' layer was washed with another 10mL portion of CH2Cl2. The combined organic layers were washed with half-saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (45% ethyl acetate-hexanes) to produce pure (±)-13 (0.52 g, 60%) as a colorless oil. Racemic epoxy alcohol 13 IH NMR (400 MHz, CDCI3): 7.11-7.40 (m, 5H, arom), 4.19 (s, 1H, H3), 3.55 (m, 1H, H2), 3.42 (m, 2H, HI), 1.75 (s, 1H, OH). FTIR (neat film), em-I: 3401 (s), 2978 (m), 1602 (w), 1490 (m), 1449 (m), 1032 (s), 938 (w), 885 (m), 779 (w), 744 (s), 697 (s), 615 (m), 550 (m). 144 MS (EI): 150 (M+), 132 (M+-H20), 119 (MH+-CH30H), 107 (C7H70+). HRMS (EI): Calculated for C9H902 «M-l)+): 149.0603 Found: 149.0600 TLC (50% EtOAc-hexanes): (2)-3-Phenyl-2-propen-l-ol 0.43 Epoxy alcohol 13 0.32 145 OH H Ph ~ o "': ' CHPH H CO 2 , DMF, 36 oC, 13 h 685% 98% o OH , Ph" 0--( ::k /'0 5 H. . t"'H 2 + 1 Ph~O H 1 10 b--{ o CH 20H 5% 11 (2R.3Sl-Hydroxy Carbonate 6 A 25-mL flask with a side-arm connection to vacuum/carbon dioxide was charged with anhydrous cesium carbonate (210.3 mg, 0.646 mmol, 0.09 equiv), powdered 3-A molecular sieves (0.50 g), and a teflon-coated stir bar. The mixture was vigorously flame-dried under vacuum (0.1 Torr), and cooled under an atmosphere of C02. A solution of (2S,3S)-3-phenyloxiranemethanoPl (5, 1.106 g, 7.37 mmol, 1.0 equiv, azeotropically dried with two portions of toluene (2 mL» in DMF (0.5 mL) was transferred via cannula to the catalyst flask; the transfer was quantitated with additional DMF (4 x 0.5 mL). The resulting suspension was warmed to 36°C, and reacted for 13 h under one atmosphere of carbon dioxide. The progress of the reaction can be conveniently monitored by thin-layer chromatography. The solution was neutralized with saturated aqueous ammonium chloride solution. The resulting suspension was partitioned between half saturated brine (100 mL)-saturated ammonium chloride (20 mL) and ethyl acetate (50 mL). The aqueous layer was extracted further with two 50-mL portions of ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated (since the hydroxy carbonates are quite polar, the aqueous layer should be checked by TLC to ensure that none of the products are left in the aqueous phase). 146 Purification of the residue by flash chromatography (20% ethyl acetate-toluene) afforded separately pure (2R ,3S)-6 (1.2172 g, 85%) and (2R ,3S)-9 (0.1121 g, 8%). A mixture of (2S,3S)-10 and (2S,3S)-1l (0.0733 g, 5% combined yield) were also isolated in a separate fraction. C2R,3s)-Hydroxy Carbonate 6 IH NMR (400 MHz, CDCI3): 7,15-7.40 (m, 5H, arom), 5.13 (t, 1H, 1=3.8, H3), 4.82 (m, 1H, H2), 4.53 (dd, 1H, 1=7.1,8.6, Hl), 4.21 (t, 1H, 1=8.6, Hl), 3.41 (s, 1H, OH). FTIR (neat film), em-I: 3420 (m), 1775 (s), 1476 (w), 1453 (w), 1398 (m), 1180 (s), 1081 (s). MS (EI): HRMS (EI): Calculated for ClOHlO04 (M+): 194.0579 Found: 194.0591 C2R.3s)-Hydroxy Carbonate 9 1H NMR (400 MHz, CDCI3): 7.23-7.54 (m, 5H, arom), 5.83 (d, 1H,1=5.1, H3), 4.98 (m, 1H, H2), 3.41 (m, 2H, HI), 1.48 (dd, 1H, 1=8.0, 8.6, OH). 147 FTIR (neat film), em-I: 3448 (m), 2931 (w), 1796 (s), 1496 (w), 1449 (m), 1373 (m), 1173 (s), 1061 (s), 767 (m), 706 (m). MS (EI): HRMS (EI): Calculated for ClOHlO04 (M+): 194.0579 Found: 194.0576 (2S.3S)-Hydroxy Carbonate 10 IH NMR (400 MHz, CDCI3): 7.23-7.54 (m, 5H, arom), 5.62 (d, IH, J=8.0, H3), 4.59 (m, rH, H2), 4.09 (m, IH, HI), 3.80 (m, IH, HI), 2.38 (t, IH, J=7.0, OH). FTIR (neat film), em-I: 3413 (s), 2936 (w), 1781 (s), 1476 (m), 1380 (m), 1169 (s), 1085 (m), 1065 (s). MS (EI): 194 (M+), 132 (M+-C02-H20), 120 (M+-C02CH20), 91 (C7H7+). HRMS (EI): Calculated for ClOHlO04 (M+): 194.0579 Found: 194.0586 (2S.3s)-Hydroxy Carbonate 11 148 IH NMR (400 MHz, CDCI3): 7.42 (m, 5H, arom), 4.84 (m, 2H, H2, H3), 4.33 (m, 2H, HI), 2.55 (d,1=4.0, IH, OR). FTIR (neat film), em-I: 3413 (s), 2942 (w), 1771 (s), 1476 (w), 1453 (w), 1398 (m), 1169 (s), 1081 (s). MS (EI): HRMS (EI): Calculated for ClOHlO04 (M+): 194.0579 Found: 194.0569 TLC (ether): Epoxy alcoholS 0.45 Hydroxy carbonate 6 0.51 Hydroxy carbonate 9 0.19 Hydroxy carbonate 10 0.31 Hydroxy carbonate 11 0.30 149 o 0--< C~~/>h(" 0 3 3 .••• CH 3 H 2 8 CH 20H 1578% CO 2 , DMF, 72°C, 16 h 1 + OH 14 1613% C2S,351-Hydroxy Carbonate 15 A 25-mL flask with a side-arm connection to vacuum/carbon dioxide was charged with anhydrous cesium carbonate (65.2 mg, 0.20 mmol, 0.12 equiv), powdered 3-A molecular sieves (2.32 g) and a teflon-coated stir bar. The mixture was vigorously flamedried under vacuum (0.1 Torr), and cooled under an atmosphere of C02. A solution of (2R,35)-epoxy alcohol 1411 (240.9 mg, 1.67 mmol, 1.0 equiv, azeotropically dried with toluene) in DMF (2.0 mL), was transferred via cannula to the catalyst flask; the transfer was quantitated with additional DMF (2 x 0.5 mL). The reaction mixture was warmed to 72°C, and heated for 16 h under one atmosphere of carbon dioxide. The solution was allowed to cool and the basic mixture was neutralized by the addition of saturated aqueous ammonium chloride solution (1 mL). The reaction mixture was partitioned between half-saturated brine (200 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was washed with a 40-mL portion of ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography (25% ethyl acetate-hexanes) produced pure (2S,3S)-15 (246.2 mg, 78%) as a colorless oil. The isomeric hydroxy carbonate (25,35)-16 (37.9 mg, 13%) was also isolated in a separate fraction. 150 C2S,3S)-Hydroxy Carbonate 15 1H NMR (400 MHz, CDCI3): 4,26 (dd, IH, 1=9,5,9.8, H3), 3.22 (dd, IH,1=5.5, 12.6, HI), 2.95 (dd, IH,1=6.4, 12.6, HI), 2.41 (dd, IH, 1=5.5,6.4, OH), 0.82-1.37 (m, 6H, CH2CH2CH2), 0.78 (t, 1=5.5, CH3, H7), 0.72 (s, 3H, CH3, H8). FTm (neat film), em-I: 3460 (m), 2943 (m), 1784 (s), 1461 (w), 1373 (w), 1296 (w), 1220 (w), 1067 (m), 773 (w). 189 (MH+), 127 (MH+-C02-H20), 109 (MH+C02-2H20 ). HRMS (CI:CH4): Calculated for C9H1704 (MH+): 189.1127 Found: 189.1132 C2S,3S)-HYdroxy Carbonate 16 IH NMR (400 MHz, CDCI3): 4.44 (d, IH, 1=8.1, HI), 4.11 (d, IH, 1=8.1, HI), 3.60 (m, IH, H3), 1.97 (br, IH, OH), 1.59 (m, 2H, CH2), 1.59 (s, 3H, H8), 1.47 (m, 2H, CH2), 1.36 (m, 2H, CH2), 0.95 (t, 3H, 1=6.6, H7). 151 FTIR (neat film), em-I: 3441 (m), 2958 (m), 2874 (m), 1771 (s), 1462 (m), 1366 (m), 1300 (m), 1216 (m), 1079 (s), 1027 (s), 776 (m). 189 (MH+), 127 (MH+-C02-H20), 109 (MH+C02-2H20 ). HRMS (CI:CH4): Calculated for C9H1704 (MH+): 189.1127 Found: 189.1131 TLC (50% EtOAe-hexanes): Epoxy alcohol 14 0040 Hydroxy carbonate 15 0.26 Hydroxy carbonate 16 0.32 152 o OH Ph" 0--( e~, DMF, 45 ae, 6 h A;O H~ T'''H + Ph~O H o-{ CH 20H 13 1064% o 11 21 % Reaction of CQ~2,CQ3 with Racemic Epoxy Alcohol 13 A solution of (±)-13 (156.0 mg, 1.04 mmol, 1.0 equiv, azeotropically dried with toluene) in DMF (1.0 mL) was added to a mixture of CS2C03 (41.5 mg, 0.127 mmol, 0.12 equiv) and 3-A molecular sieves (210.9 mg), which had been vigorously flame-dried under vacuum (0.1 Torr). The catalyst mixture was cooled, flushed with carbon dioxide and warmed to 45°C. After 6 h at 45°C the reaction mixture was partitioned between 1:1 ethyl acetate-hexanes (40 mL) and saturated aq':leous ammonium chloride solution (50 mL). The organic layer was separated and the aqueous layer was washed with a 40mL portion of 1: 1 ethyl acetate-hexanes. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (20% petroleum ether-ether) producing a 3: 1 mixture of (±)-lO and (±)11 (172.7 mg, 85%) as a colorless oil. 153 OH + 683% CO2 , DMF, 36 °e, 2 h 911% o )( ;0 OH Ph" 0--( 9 H" ,""H + Ph~O o-{ H CH 20H 10 o 6% 11 Equilibration of Hydroxy Carbonate 2 CS2C03 (30.2 mg, 0.09 mmol, 1.8 equiv) and 3-A molecular sieves were vigorously flame dried in vacuo then cooled under an atmosphere of C~. A solution of 9 (9.0 mg, 0.05 mmol, 1.0 equiv) in DMF (0.3 mL) was added to the catalyst flask by cannula. After heating 2 hat 35°C, the product distribution was 6 (83%),9 (11 %), and 10 and 11 (6% combined). ? OH D ..· : n-BU '0 ' 14 9C~- CH 3 D, : DMF, e02 n-BU CH 3 ,.''0 17 n-BU:;;y,0 -(0 , H 0 ·",CH 3 CH 20H 15 Reaction of Epoxy Alcohol 14 as monitored by DC NMR CS2C03 (47.2 mg, 0.145 mmol, 0.16 equiv) and 3-A molecular sieves (100.2 mg) were vigorously flamed dried and allowed to cool under an atmosphere of carbon dioxide. The mixture was quickly transferred in air to an NMR tube containing a solution of epoxy alcohol 14 (132 mg, 0.92 mmol, 1 equiv) in DMF (0.2 mL). Carbon dioxide was bubbled through the solution, using a long, steel needle, every 30 min. Less than 2% of 14 had 154 reacted after 12 h at 78°C. After the solution was heated at 78 °C for 12 h, approximately 50% of the starting material had been cleanly converted to hydroxy carbonates 15 and 16. There was no evidence of intermediate 17. Epoxy alcohol 14 Be NMR (22.S MHz, DMF): 74.0,58.5,52.5,32.7,28.0,22.7, 15.7, 13.8. Hydroxy carbonate 15 13C NMR (22.S MHz, DMF): 154,85.7,81.0,66.0,33.5,28.5, 23.0, 16.3, 13.5. 155 OH OH NaOH, MaOH Ph~O H~ o-{ 23°C, 15 min Ph),y! OH o 6 OH 7 85% Hydrolysis of (2R.3S)-Hydroxy Carbonate 6 A solution of (2R,3S)-hydroxy carbonate 6 (0.4697 g, 2.42 mmol) in MeOH (5 mL) was treated with 50% w/w aqueous NaOH (1 mL) for 15 min at 23°C. The reaction mixture was partitioned between saturated ammonium chloride solution (50 mL), saturated brine (50 mL), and ethyl acetate (100 mL). The aqueous layer was further extracted with two 100-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Purification of the residue by flash chromatography (ethyl acetate) afforded (1S,2R)-7 (0.3456 g, 85%, 105-106.5 °C) as a white, crystalline solid. o Ph" o-{ ~/'o H~ T""CH 20H OH NaOH.MeOH 23°C. 15 min H 9 OH Ph~ OH 7 71% Hydrolysis of (2R.3s)-Hydroxy Carbonate 2 A solution of (2R ,3S)-hydroxy carbonate 9 (8.2 mg, 0.042 mmol) in MeOH (1 mL) was treated with 50% w/w aqueous NaOH (0.2 mL) for 15 min at 23°C, The reaction mixture was partitioned between saturated ammonium chloride solution (20 mL), saturated brine (20 mL), and ethyl acetate (30 mL). The aqueous layer was further extracted with two 30-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash 156 chromatography (ethyl acetate) afforded (lS,2R)-15 (5.0 mg, 71%, mp 104-106 °C) as a white, crystalline solid. (lS.2R)- Trio115 IH NMR (400 MHz, CDCI3): 7.15-7.40 (m, 5H, arom), 4.89 (dd, IH, 1=3.6,4.8, HI), 3.86 (m, IH, H3), 3.77 (m, IH, H2), 3.70 (m, IH, H3), 2.60 (d, IH, 1=3.6, OH), 2.42 (d, 1H, 1=5.5, OH), 2.03 (t, IH, 1=7.5, OH). FTIR (Nujol mull), em-I: 3319 (s), 2908 (m), 1373 (m), 1243 (s), 1038 (s), 697 (s). MS (CI:NH3): HRMS (CI:NH3): Calculated for C9H1603N (M+NJ4+): 186.1130 Found: 186.1138 TLC (EtOAe): Optical Rotation: Hydroxy carbonate 6 0.67 Hydroxy carbonate 7 0.58 Triol15 0.25 Observed:[ex]23 S89 +20.2° (c 6.24, H20) Literature:[ex]23 S89 +19.6° (c 6.24, H20) 157 o OH Ph"O-{ A;O H- T""H + OH Ph~O H o-{ 23 °e, 15 min Ph~ OH o CH 20H 10 NaOH, MeOH OH 11 1273% Hydrolysis of C2S,3S)-Hydroxy Carbonates 10 and 11 A solution of (2S,3S)-10 and (2S,3S)-11 (39.0 mg, 0.20 mmol) in MeOH (1 mL) was treated with 50% w/w aqueous NaOH (0.2 mL) for 15 min at 23°C. The reaction mixture was partitioned between saturated ammonium chloride solution (20 mL), saturated brine (20 mL), and ethyl acetate (30 mL), The aqueous layer was further extracted with two 30-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Purification of the residue by flash chromatography (ethyl acetate) afforded (IS,2S)-12 (24.7 mg, 73%) as a colorless syrup. ClS,2S)-Triol12 IH NMR (400 MHz, CDCI3): 7.15-7.40 (m, 5H, arom), 4.78 (dd, IH,1=3.6, 4.8, HI), 3.80 (m, IH, H2), 3.64 (m, IH, H3), 3.56 (m, IH, H3), 2.81 (d, IH, 1=3.6, OH), 2.62 (d, IH, 1=5.5, OH), 1.96 (t, IH,1=7.5, OH). FTIR (neat film), em-I: 3342 (s), 2919 (m), 1655 (w), 1449 (m), 1378 (m), 1249 (m), 1096 (s), 1026 (s), 873 (w), 756 (m), 697 (s). 158 MS (CI:NH3): HRMS (CI:NH3): Calculated for C9H 1603N (M+NI4+): 186.1130 Found: 186.1130 TLC (EtOAc): Hydroxy carbonate 10 0.60 Hydroxy carbonate 11 0.60 Trio112 0.21 159 17 82% Hydrolysis of (2S.3S)-Hydroxy Carbonate 15 A solution of (2S,3S)-hydroxy carbonate 15 (6.0 mg, 0.032 mmol) in MeOH (1 mL) was treated with 50% w/w aqueous NaOH (0.2 mL) for 15 min at 23°C. The reaction mixture was partitioned between saturated ammonium chloride solution (20 mL), saturated brine (20 mL), and ethyl acetate (30 mL). The aqueous layer was further extracted with two 30-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Purification of the residue by flash chromatography (ethyl acetate) afforded (2S,3S)-17 (4.3 mg, 83%) as a white, crystalline solid. NaOH, MaOH 23°C, 15 min 16 17 95% Hydrolysis of C2S,3S>-Hydroxy Carbonate 16 A solution of (2S,3S)-hydroxy carbonate 16 (15.1 mg, 0.080 mmol) in MeOH (1 mL) was treated with 50% w/w aqueous NaOH (0.2 mL) for 15 min at 23°C. The reaction mixture was partitioned between saturated ammonium chloride solution (20 mL), saturated brine (20 mL), and ethyl acetate (30 mL). The aqueous layer was further extracted with two 30-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. Purification of the residue by flash chromatography (ethyl acetate) afforded (2S,3S)-17 (12.3 mg, 95%) as a colorless syrup. 160 (25,35)-Triol 17 IH NMR (400 MHz, CDCI3): 3,35 (m, IH, H3), 3.29 (dd, IH, 1=6.3, 7.3, HI), 3.22 (dd, IH, 1=6.3, 7.3, HI), 2.38 (s, 1H, OH), 1.89 (d, IH,J=4.6, OH), 1.77 (t, 3H,J= 6.25, OH), 1.48 (m, 2H, CH2), 1.25 (m, 4H, CH2CH2), 0.87 (t, 3H, 1=6,6, H7), 0.86 (s, 3H, CH3, H8). FTIR (neat film), em-I: 3378 (s), 2943 (s) 2861 (m), 1649 (w), 1461 (m), 1373 (m), 1320 (w), 1261 (w), 1044 (m). 180 (M++H20), 163 (MH+), 145 (MH+-H20), 127 (MH+-2H20), HRMS (CI:CH4): Calculated for CgH1903 (MH+): 163.1334 Found: 163.1327 TLC (EtOAe): Hydroxy carbonate 15 0.87 Hydroxy carbonate 16 0.87 Triol17 0.31 161 .. CICOCOCI, DMF 23 oC, 2 h (R)- Mosher Chloride (S)-(-)-Mosher acid (122.7 mg, 0.524 mmol, 1.0 equiv), oxalyl chloride (0.23 mL, 2.6 mmol, 5.0 equiv) and CH2Cb (3 mL) were combined in a lO-mL side-arm flask under argon. A l-cm capillary containing DMF was added and the solution was stirred for 1 h. The reaction mixture was concentrated under vacuum (0.1 Torr) and used without further purification in the following reactions. OH Ph~O . HO-{ o 2) (A)-Mosher chloride, 2 h, 23 °C 6 1981% C2'R.3'S.2S)-Mosher Ester 12 (R)-Mosher chloride (0.26 mmol, 4.7 equiv) in CH2Cb (5 mL) was added to a solution of DMAP (19.4 mg, 0.160 mmol, 2.76 equiv, azeotropically dried with two 1mL portions of toluene), and (2R,3S)-6 (11.2 mg, 0.058 mmol, 98% ee, 1 equiv) in CH2C12 (1 mL) at 0 °C. The reaction mixture was warmed to 23°C and stirred for 2 h at that temperature. The reaction was quenched with saturated aqueous citric acid solution (5 mL) and the aqueous layer was extracted with two 20-ml portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, fIltered, and concentrated. Purification of the residue by flash chromatography (7% ethyl acetate-toluene) gave (2'R,3'S,2S)-19 (19.2 mg, 81 %), as a clear oil. 162 C2'R,3'S,2S)-Mosher ester 19 7,53 (d, 2H, 1=6.5, arom), 6,82-7,10 (m, 8H, arom), 5,94 (d, IH, J=3,2, H3'), 3,84 (m, IH, H2'), 3,63 (t, 1H, 1=8,7, HI'), 3,25 (d, 3H, 1=1.6, OCH3), 3,10 (t, 1H,1=8,7, HI'), FTIR (neat film), em-I: 2952 (w), 1814 (s), 1758 (m), 1497 (w), 1453 (w), 1272 (m), 1243 (m), 1169 (s), 1122 (m), 1070 (m), 1016 (m), 766 (m), 722 (m), 700 (m), MS (EI): HRMS (EI): Calculated for C20H17F306 (M+): 410,0977 Found: 410,0986 TLC (40% EtOAe-hexanes): Mosher ester 19 0,57 (UV) Hydroxy carbonate 6 0.38 (UV) 163 o 1. FXh~'O ,. z MeO_ 3 Ph 2) (R)-Mosher chloride, 0.5 h, 0 °C :r.. H 0 b-{ o 2187% 20 (2S,2'S.3'R)-Mosher Ester 21 (R)-Mosher chloride (0.32 mmol, 6.4 equiv) in CH2Cl2 (5 mL) was added to a solution of DMAP (19.4 mg, 0.160 mmol, 3.14 equiv, azeotropically dried with two 1mL portions of toluene), and (2S,3R)-20 (9.8 mg, 0.051 mmol, 96% ee, 1.0 equiv) in CH2Cl2 (1 mL) at 0 °C. The reaction mixture was stirred for 30 min at that temperature. The reaction was quenched with saturated aqueous citric acid solution (5 mL) and the aqueous layer was extracted with two 20-ml portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography (7% toluene-ethyl acetate) gave (2S,2'S,3'R)-21 (17.9 mg, 87%), as a clear oil. (2S,2'S.3'R)-Mosher Ester 21 7.52 (d, 2H, 1=6.5, arom), 6.87-7.34 (m, 6H, arom), 6.67 (d, 2H, 1=7.6, arom), 5.89 (d, IH, 1=3.2, H3'), 3.81 (m, IH, H2'), 3.69 (dd, IH, 1=5.5,8.5, HI'), 3.44 (d, 3H, 1=1.6, OCH3), 3.02 (t, lH, 1=8.7, HI'). 164 FTIR (neat film), em-I: 2952 (w), 1814 (s), 1758 (m), 1497 (w), 1453 (w), 1272 (m), 1243 (m), 1169 (s), 1122 (m), 1070 (m), 1016 (m), 766 (m), 722 (m), 700 (m). MS (CI:NH3): HRMS (CI:NH3): Calculated for C20H21F3N06 (M+NJ-4+):428.1320 Found: 428.1310 TLC (40% EtOAe-hexanes): Mosher ester 21 0.57 (UV) Hydroxy carbonate 20 0.38 (UV) 165 1) DMAP, CH~12 2) (R)-Mosher chloride, 2 h, 23°C 5 H0" :xO *V 3' ,.": Ph . 'Z H 0 P OMe ., 'CF 3 2274% C2S.2'S.3'S)-Mosher Ester 22 (R)-Mosher chloride (0.262 mmol, 4.94 equiv) in CH2Cl2 (5 mL) was added to a solution of DMAP (14.0 mg, 0.115 mmol, 2.16 equiv, azeotropically dried with two 1mL portions of toluene), and (2S,3S)-5 (8.0 mg, 0.053 mmol, 98% ee, 1 equiv) in CH2Ch (1 mL) at 0 OCt The reaction mixture was warmed to 23°C and stirred for 2 h at that temperature. The reaction was quenched with saturated aqueous citric acid solution (5 mL) and the aqueous layer was extracted with two 20-ml portions of methylene chloride. The combined organic extracts were dried over sodium sulfate, fIltered, and concentrated. Purification of the residue by flash chromatography (10% ethyl acetate-toluene) gave (2S,2'S,3'S)-22 (14.2 mg, 74%), as a clear oil. C2S,2'S.3'S)-Mosher Ester 22 7.71 (d, 2H, J=7.5, arom), 6.95-7.34 (m, 8H, arom), 4.19 (dd, IH,J=12.0, 3.7, HI'), 3.92 (dd, IH, J=8.3, 5.6, HI'), 3.51 (s, 3H, OCH3), 3.41 (d, IH, 1=2.9, H3'), 2.79 (m, IH, H2'). FTm (neat film), em-I: 2952 (w), 1755 (s), 1490 (w), 1443 (w), 1267 (m), 1243 (m), 1167 (s), 1114 (m), 1079 (w), 1020 (m), 997 (m), 879 (w), 761 (w), 719 (m), 691 (m). 166 MS (CI:NH3): 385 (MH++H20), 367 (MH+), 189 (C9HgF30+).· HRMS (CI:NH3): Calculated for C19HlgF304 (MH+): 367.1157 Found: 367.1151 TLC (30% EtOAc-hexanes): Mosher ester 22 0.55 (UV) EpoxyalcoholS 0.18 (UV) 167 H *~ CH 0H 1) DMAP. CH2CI2 Ph' T i 2 H 2) (R)-Mosher chloride. 15 min. 0 °C 23 Ph H0 " :xO *t! 3' 'Z H 0 OMe ", P CF 3 24 71% C2S,2'R,3'R)-Mosher Ester 24 (R)-Mosher chloride (0.082 mmol, 1.3 equiv) in CH2Ch (0.2 mL) was added to a solution of DMAP (15.7 mg, 0.129 mmol, 1.97 equiv, azeotropically dried with two 1mL portions of toluene), and 23 (9.8 mg, 0.065 mmol, 96% ee) in CH2C12 (1 mL) at 0 0c. The reaction mixture was stirred at that temperature for 15 min. The reaction was quenched with saturated aqueous citric acid (5 mL) and the aqueous layer was extracted with two 20-ml portions of methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography (10% ethyl acetate-toluene) gave (2S,2'R,3'R)-23 (16.8 mg, 71 %), as a colorless oil. C2S,2'R.3'R)-Mosher Ester 24 7.70 (d, 2H, J=7.5, arom), 6.95-7.34 (m, 8H, arom), 4.23 (dd, IH, J=2.9, 12.2, HI '), 3.70 (dd, IH, J=5.4, 12.2, HI'), 3.41 (s, 3H, OCH3), 3.38 (d, IH, J=2.9, H3'), 2.74 (m, IH, H2'). FTIR (neat film), em-I: 2952 (w), 1755 (s), 1490 (w), 1443 (w), 1267 (m), 1243 (m), 1167 (s), 1114 (m), 1079 (w), 1020 (m), 997 (m), 879 (w), 761 (w), 719 (m), 691 (m). 168 MS (CI:NH3): HRMS (CI:NH3): Calculated for C19H18F304 (MH+): 367.1157 Found: 367.1161 TLC (30% EtOAc-hexanes): Mosher ester 23 0.55 (UV) Epoxy alcohol 22 0.18 (UV) 169 References l(a)Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. (b)Proteau, P. J. M. S. Thesis, California Institute of Technology, 1989. 2(a)Roush, W. R.; Brown, R. J.; DiMare, M. J. Org. Chem. 1983,48,5083. (b)Roush, W. R.; Brown, R. J. J. Org. Chem. 1982,47, 1371. (c)Corey, E. J.; Hopkins, P. B.; Munroe, J. E.; Marfat, A.; Hashimoto, S. J. Am. Chem. Soc. 1980,102,7987. (d)Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982,1040, 1109. 3McCombie, S. W.; Metz, W. A. Tetrahedron Lett. 1987,28,383. 4Myers, A. G.; Widdowson, K. L. Tetrahedron Lett. 1988,29, 6389. 5Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,34,2543. 6Delton, M. H.; Yeun, G. U. J. Org. Chem.1968, 33,2478. 7Payne, G. B. J. Org. Chem. 1962,27,3819. 8Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978,43, 2923. 9Kofron, W. G.; Bac1awski, L. H. J. Org. Chem. 1976,41, 1879. lOSmith, P. A. S.; Choi, S.-S. P. J. Org. Chem. 1981,20,3974. 170 IlGao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masmune, H.; Sharpless, K. B. 1. Am. Chern. Soc. 1987,109,5768. 171 Appendix I Spectral Catalog for Chapter One 172 ( , / ,. I i i , i i i i, Ii, iii i" ii' "I 9 8 7 ii" i, 6 j" j 5 "i'l' '."" 4 'i I" 3 i",' i, j " " " ' " 2 j 1 i'" i' i" j 0 i, I 100.62~ n : ...J II I I 1 J J I I I 65. 34 L-_- r - - -- -y----,------,- - - r - - - - - - -------,--- ---------r 4000 3500 3000 2500 2000 1500 1000 500 173 OSiEt3 CH,,~~CH' CH 3 H 1 __________~I__________~1__~~~~~~~~i_______ _ 'j'ili""'I""""'!""""'I';"""'I""""'!""""'/""""']""""'!""""'!""""']""" i"I,'j~ 10 9 8 I 6 5 4 ] 2 1 0 -1 82.21 IT 20.21~-------.-------~---------~----------------~------------------~------------- 3000 2500 2000 1500 1000 174 2 ----~'1,II"""j""""'I""""'j""""'j""""""ii,i"""""'"""""""""""""""""",,,"iil'i~ 10 9 8 7 6 ~ 5 3 2 1 0 81.62 IT ~~ 140S4J-;-----,4000 3500 3000 2500 2000 1500 1000 -1 175 3 iii' 8 " Ii. i 'f';' I I • • 7 i'5 iii 0 Ii' i j I I' 4 i, i •• I J i I iii 2 f 1 " oi 100.82 IT 1.05~----r------r------~-----r-----'------------'-------------~------------~ 4000 3500 3000 2500 2000 1500 1000 em-I 500 176 4 ____________ L -.....--r-r-r-r-r"""rrrr-r--r-r-r-rr-r--rrr-r-,rr.,....-~~.-rr-rl'T-rl~Ijr;'r;'~'~'~'-r'-r'TI~,~,~,~,~~'".,.'-'-'-r'-r,T'~I r--ro---Ir,r;'~~~-r-rl~,~,rr-~~-,--,-~';!:R"M~ 1 u 4 ') 1 104.12 IT 92.32~----~-----.-------r------r------~-------------r------------~------- 4000 3500 3000 2500 2000 1500 1000 em-I 51J0 177 5 l ..J'-I'-_'-~ ~ ' - - - - _ _---J'--''--- _ _ _ " III i, I , j l " 9 ii, I,' I' i, i i I I , 'I' I i I . I , "1' I i I i , I i '1" 8 7 6 5 i' Ii',' Iii" 4 _ _ __ , ii' , • , " II 3 iii, j , • i 2 i i i , •• i., i o i,ll, ii, - i ' I i II i -1 94.62 n 0.63~------_.-------.------._------r_------------_r--------------r_--------- 4000 3500 3000 2500 2000 1500 1000 178 6 " I i, i " " 10 i 'I' iii, i", i " 9 I I t I I I "" 7 8 I' I " II 6 I '" I i I I" 5 I. II I I I I I, I, I "1' I I 4 3 Ili'il"'II'J"i~f~ " 1 0 76.BO~ IT I I 24.43~-------r-------r------~------r--------------r--------------r---------- 4000 3500 3000 2500 2000 1500 1000 179 7 ~ ___ L il" to I j r~ii~'~'~~r~~i.~,~,~ij'I~~~I~'~~~il~-rll~~rrr-"'-~~""""~~~,rrl~'rrr~ii~'~'r i,,'~,rrr-rrr"1,~,.;,-;c;'.jI 7 6 2 <1 Cj 1 a -\ 108.06XT 1 1 1 1 1 , 4000 3500 3000 2500 2000 1500 r 1000 CID- 1 500 180 r 9 I , ,-, , " , -,,' I I-,,-,-,~r, r 1-,-, ' ,,- 4 -,' i·' I-T, I · 89.21- Energy \ \ 81.03+ 4000 3500 ,- - 1 3000 2~OO - " I 2000 1500 "I -- 1000 181 iii I iii iii iii i i Ii i , I , iii iii iii Ii 1iJ 9 8 PPM I I i i i ' i i i ' i i i i i i i ' i i i i I i I i I i i ' i i i i i i I i i i i i i i i I i i i i 1i i i i i i i i i Iii i i i i , , i i i i i i i I I i i , i i i i i 7 6 5 4 l 2 0-1 I 83.ao~ Energy· 1/ I 14.29+ 4000 - I I I 3500 3000 2000 1000 182 i 1 _.L.- .... -. 'I'--'-~r-,,",~~~·Ir-r-r-"""""----'--'-r-r--,--r-r-r-l-r-r-r-r-r-~r-r-~'~r-r--'--'.~I~~~~~~,~...,~'-'--'-'--'--'-"--r-r--'-' " I I " 81.59 :n ""l-r 4000 3500 --.-----,----,-----------.-----------.-------'-3000 2500 2000 1500 1000 183 18 l_U_J ~ r~"-'-r--r~1 5" r r-r-r"' ~rr-'r-T" '-r~ J .. 4.: 1 .. 1': ----------' ~ -rr"""T r-~r-r-"'--' '-rr-'--'--'--r-r"'-"--'-~'-~r'--'--'---' 1 -, 7 . rr-....--.-.....,-.......,.-· .. S - ~ - r-""""""""~rr--.--.- 1 .... 1 .......... r"T""".- .... .--, r-r~ ~ rD, --: 1 : ""-'-'--'--r"'-'- I ': <: '-'--1 1 r "---'-r-r~...-.-, '3 18 _~_l---' i I Ii,. Ii, I 9 I ii' 8 j • I i iii' 7 6 i, i" I, I I il'" 5 ii, I 4 iii. I" J j,' I I i 2 • I j 1 i I I o ...-.-- ........ 184 114.37 IT I ~ ! ~ i 1 I: I I 29. 46 1-- 18 -,- ----r--- --r ---- r-------r------ -------r------------j----------------, 4000 3500 3000 2500 2000 1500 CIII- 1 1000 500 88.85 IT 18 50.47~-----r_----_.------_.------._------------_r------------_.---------- 4000 3500 3000 2500 2000 1500 1000 185 -1-1~~-'--'r-r-"""'--rI--'Ir-rT-r-.-r 6 I 9 i •• I I , i , i I 3 I 5 j i ••• i i ' i i j • i • i • i i ' i i i . , i i , ( • i ~ • i • Iii i i 8 7 6 I' I •••• ; i' I 4 i I •• 3 Iii i.,. 2 i, i i •• , I j 1 liii~i 19 I J\ 6 i i i I I I i I i i I i I i I I i I I I i i 5 I I 3 ... l J.... ~ i , j I I ' j ' j i (i •• 1 I' j i' i., I ii ~I·iijijii,tii"""iliij'i"iibi"i'i'ii~""iii"~Ili"'I'i~"'ii.2 0 i iii 9 i i 186 toe.a, IT i r 19 and 20 I ~ I I 711.Ut--4000 r -3IlOO ---, ---lOGO r- - 2500 ,------ - , --- -- HOI l~O - ---- -r --1000 80.63 n 19 and 20 deuterated at C3 71. 13..lr----~----.- - - - , - - - - . . , 4000 3500 3000 2500 2000 1500 1000 187 21 I I I i 3 4 , , 9 ' i i ••• , I I ~ I. , I , , I ,\ 7 '\' , 6 I I ' t' 5 '(' i ,( 2 21 I I j ( o 188 102.86~ I IT 21 82.07~·--~1--~----~-----'-----'-----------'1-----------'----------~' 4000 3500 3000 2500 2000 1500 1000 em-I 500 88. 7!s~ IT I I I I I ~ JI I -1 . .~L 4000 21 -- , - -_ .. - r -.-- - T - - - " 3500 3000 2eOO 2000 ,. --1500 - -----1 --- - - - - - 1000 ---'C.-I 189 22 I I i iii 5 I i 4 I i I j I 3 - ,,,,, ~,~"", ====~~~~~-~1""~""11~' ~ , , , , , , , , , ~ , , , , , , , , , l ' , , , 'o;~; ~ I iiI I , i • I I • i , I ' '5 4 'i, I " I 3I" j" j, i '- X~~ '?"o .... OH 0 CH, CH 3 !H3 U 22 I '1"" 9 " , •• i" 8 I. I I I, I I 4 i , 3 i} "i'i"il~"i"I'il~'III"'il~ill"j"'~'jlri""~' i, j j f I I, tf' ,I il'" I' V ~ 190 eo .95~ :lOT I I I 22 and 23 I l 62.77 ........- -.....-~· --- r _ _~I_----r·--- - - - . . 1 4000 3500 3000 JI 2500 2000 1500 1 1000 22 and 23 I deuterated at C3 ~ ~ se.seL---,- --·,....---~-----r-· 4000 3500 3000 2500 2000 ---. - - - '-r -- .----------- -. - T-- -1500 1000 cm- I 500 191 ) ,-,-,,-, I . '-I 1 ,-,. 1-' 1 '-'-1 ' I ,-,-,.,-,-, ,-I-'-l-,-'-L,-r-r,-r-r-I I-" 'S , j 1-'-'-'-'-" I' ,-,-, '--'-'-''-,,-, .-,- I 98.13- 4000 I r-.-;~~ "I Energy 95.98+ ,-, I I r -1"- 3500 3000 1500 1000 192 .. bPM iliii"""!""""'I""""""""",,""""'I"ifll"'I""""'!""""""""""""""'""", Ijl~' ~ 8 7 C 5 4 J ~ 1 0 -1 10 , 82.52-j Energy r1I , I 75.00-j4000 I I 1 I" I I 3500 3000 2500 2000 1~00 1000 193 C H3 CH '.,__ 0 _ Si ........ N . o o_ ~CH3 6 H, ••. 3 CH 3 r 26 r"'-1-rl....,..,..-r-j--rrrrrrl-r-'I-r-'-1-r-,-,-.,-'{-' ,Tr .--:-rr-r-r,·,-,-,-r-r-n-r,-I-,-rl-,-r-'·<"I-II'-.--r-ri-r-r. I' r,-, "-,-r'- I ,-! r I, (1-,'-\ " ! I ,-.-,[-, I ,-n- ,-",",'J u 7 t, .-J j . J 1 IV , 62.67:H 58.92..1 1 4000 1 1 3500 :·jQOO 1 2tjOO 2000 1~OO 194 / / ~"'Irf to 9 i.,8 1 ; . 1 •• 1 •• ••• 11, Ii I.' , i i •• " j' 7 1 0 , . , ii" 'I i -I 98.79~ ST ' -----, ! i ....I I 16.55 J -- --I 4000 \ \ -I 3500 3000 2000 , r' 1500 1 1000 _._- em-I 500 195 I I I i I ~ I I I I I I I I I ) I I I I I I I I b' I I I I I I • , I ~ I , I CH 3 I I i I I I , ~ I , I , I , ~ I I I I I • , , I I k' , I I I I I I ' 1 'j~'~'~ I 1 ' I If' , I I I o I 0 /N~O 1 ,OM_ U"H /X Pit" CF 3 29 Ii Iii , i , , ~ , , , , , I , , , ~ Iii Iii, , , b' i , , , • I I , ~, , i , , , , , , ~" iii , , , , ~ , , , I , Iii 1 k Ii , , , , • , , 1 i , , I , 1 '6 I , i~ 196 83.68~ IT 28 I l ! ! l: 65.371--~--- ---, -.--.-.-,r-----.--------,------ .-.-- .-,-.------... I 4000 3500 3000 2500 28 2000 1500 29 co injection of 28 and 29 28 t r '"' 51.8 min CIII- J 1000 ~--28 29 t r - 53.0 min ~9 197 30 --~ii" . r I I,., a i I i, I I' 1 " " B I I., I I I Iii" 1 I i I t I i i i i i 1" 6 I'" 5 iii I. I \" 4 I" I Iii (i, i i " r' i , I . , i • • I i i . , i i i " , i ' , I • • , f ' i i " . , I , "1'" I 6 5 4 3 \ I' t. itt 2. oJ II'; , ii' I,' 2 t () , I 1 o i", (,',' I I ii, I i; i I; I t t I 0 i j ) j r 198 CH 3 , ._,CH 3 °-;-51'-"""'0 6 H,., N CH3 31 I' 9 " aI' 91.46 ~T 47.97~------~-------".--------r-------r---------------"t----------------r------------- 4000 3500 3000 2500 2000 1500 1000 199 CI 32 I ' i , i " " " " " " " " " " " " ' " 'l,i"""'I""""'I"I",', 'i' i,";""i"I""1 w 9 8 I 88.29 :n 44.80~--------~-------r 4000 3500 3000 654 J 2 'I" Ii " -1 CH 3 , ••,CH 3 6 200 0~S"'O H", N , CH3 CN 33 _ll._11~~ i i i j " iii 4 ~ , i, iii iii I Iii 2 i "'" 80 • .a~ IT I I 1 i I j II l \ I 74.02...l-r------,-4000 3500 I , 3000 , 2500 i L ,---- - - ' - - , - - " - ' - - - ' - , - - - - - 2000 1500 1000 em-I 201 CH 3 , .••,CH 3 6 0~Si'o H, ••. N . CH 3 34 88.85 IT ., I I 1 I I l I ~ I 69.81 ........ 1...-,- - , - 4000 3500 , 3000 ---I 2500 "-T,------r-- -2000 1500 -------r-----1000 em-I 202 Appendix II Spectral Catalog for Chapter Two 203 , H3C CH 3 ....... sf 0/ ' 0 Ph~""H ~I~ SePh 7 du J _LA~_._____~ ~rrrr""',TT"T"'-'-'-'~i rrrr-r-T'"T"T"""~,i'T"~n-r~'T~~TT"T"i i~'~'i~~'rl,I~'~I(~,~,......-r'I~'~j'''''~''''''',rr'~'~,i~'~,i..,.,-r,l""'~'~',.,-,~,.~,"1,.,-,~,Irr'~',."'''''''llrr,+,-;':;,'r, 10 ~ g 135. 82 IT tJ 4 L"j 2 .3 t 0 -1 1 ! I I lI I ~ I 92.40 --,----- 1-- - 4000 3500 r---,-- ----,---- - - - - - T - - - - - -- 3000 2500 2000 1500 -----,- 1000 em-I 500 204 92. IT 48 1 1I ~ 33.14 --T---"--- --,--.-----~----------~------.---~---------~CIII- 1 500 1500 1000 4000 3500 3000 2500 2000 205 -.-i- 85.124 IT I 1 6".75 , 4000 3500 '-,--' --.-- 3000 2500 ----.-,--- . _ - - ' -.....--.2000 1500 1000 em-I 500 206 -rj,-ro.-rjTO-r'-ljrT'-rT'-OT'-OTj-r~~ 10 ~ 8 rTO-rTO-r'-rT,-r,T','-r'-~-rTO~r~rT'-ro.-ro-~ 6 -I 92.68 IT 81. 25-----,----- r 4000 3500 I 3000 2500 I 2000 1500 1000 CIIl- 1 500 207 '~ f I ' 10 f, __- rr~ I -,--r-r-r-r,"T""""T""--r-r,"-.,--.-,,....,.-," ,.....,-.-,-r,-,-,"-"-"""""""'--'-'.,....,.,....,..... , ,.,...,,,-,-,-,.....,-.-. ~ rT-r-r-r-r-r-~r-~, t " 8 7 '" 5 ~ 1 2 1 0 ·1 78.87~--~------r-----r----~-----r---------~----------~------~~~ 4000 31500 3000 21500 2000 11500 1000 208 HO OH Ph~ 17 ~.' I~,~~," ~i"I~'~,~~~, rr-r-r--r," ~ii~,-,.",~~r~~T'~,~~~-r-rl" ~,,~,~~,~,,I'---'-'~~~"~,~,-,.,~,-,-,~,~," ,Ii~~-'-'~,~," ' ff~'c-rT~--T H g 1 L " 4 3 2 1 0 122.02 IT ! I -l I l I 1 . . . L-r4000 - 1- ------,- --------- r-- -- 3500 3000 2500 r-----------r--- ----- --,-------------, 2000 1500 1000 CII-I 500 209 HO Ph~ OH 18 ~~~~-rl~"~~~~~~~~~ii·~~~~'~I'~'~~~I~'~'~'~"~'~'~ii~~~~~~'~"~'~'~li~~~'~ "i 8 4 3 0 2. ] ~. J-T - ,- - "]- 4000 3500 3000 -.----,------------..1-----------,-2500 2000 1500 1000 ----r-500 210 H3 C, ."CH 3 Sf 0/ '0 I.. Ph~"H ~CH3 SePh 19 iii 9 Ii j I 4 i (i'i (, 3 2 , i - ( 1 87.94~ ST ....I I I 43.52.1..·· r"- --. 4000 -r 3500 - --1-- 3000 ---', 2500 '-1 2000 .- I 1500 - .---. , 1000 em-I 500 211 20 iii • i I i 8 I' 7 i iii o ,i I ' ~ 'i ii' I i i iii iii" 2 4 \ - ' 1 87.991 IT I lI 66.89 -..---r-----r-----r- ---r-------,--------,-4000 3500 3000 2500 2000 1500 1000 CID-I 500 HO OH 212 Ph~ 21 , -" "- '""'I~'~~~'-I~,~~~~I'"""~~~'-'-'--I~,I~I r-r-r-r-r-~'~'~'~,' I~~~r-.-.-~~-~~'' Ii'-"~''-'~,~,~,''-'''I~~~''-'~,' I~,~-::;:cg N 7 b ') 4 ~ 1 0 97.78 IT 73.32~----r------r------.------r-----'-------------'----'---------.-------------r- 4000 3500 3000 2500 2000 1500 1000 CIII-I 500 213 HO OH Ph~ CH 3 22 r-r'--~"""""'--'-rl~Ii~~~r-r-r'-'--"-r-r-r-r-r-r-rr-r-r-o--r-,........-r-r-I.-r-r-r-o--r-r-~I"'~~~'~, ',I~,~,~,~,,~,~,~,~,.,~,~,~,~,~~.,~,~~~~," ~,~,,.t,-~ Ii 'j 4 l b " -1 2 1 0 101. 22~ IT I I i I I 96.46~----'-------,r------r------~----~------------~-------------.--------------rL I 4000 3500 3000 2500 2000 1500 1000 cm-' 500 214 Appendix III Spectral Catalog for Chapter Three 215 OH CH3~CH3 CH 2 r 9 r r 8 6 r 2 r 5 ~p~ i , I , Ii o 116.55 U 48.18~----.-------.-------r------'-------r-- 4000 3500 3000 2500 2000 ------r-1500 1000 em-I 500 i 216 6 ili_ ili_ op .. i ~ BO.0~5 ; i i 5 I 2 r' 72,0:'l' 64.0BO !- \ ilK \ \r \ I ill . 58.053 III I ~ 'I, i:P \''\1 \ I 010.038 32.030 , _i ,I \,1 I ,: \ l... I I II \ 1/ I ~.- i i!~.022 i- ! I I I 111.015 .- I j 11.001 >- L 0.000 .000 3600 2800 !SOO 2000 CI'-! :;>00 800 600 217 : Ph OH 7 UI" ~' r r .r ~ - - ~ 1 ~ '- J-.r --' ~,-r-~·~'-rl-r~~~-.-r-r'-TI-r.-~~~-r-r'-~,,-r-r'-~~-'-r-r'-~r-r-r-r.-~~~-r 8 6 99.08 IT 70.88~------'-------r------r------'--------------r--------------r---------..000 3000 2!500 2000 1500 1000 o 218 Ph"O-{ )( ".'0 H.... T""CH~H H 9 93.51 IT 19.63~----r-----'------.----~r-----'------------'-------------.-----------~~ 4000 3500 3000 2500 2000 1500 1000 em-I 500 219 o Ph"~O--{;0 H"'" '{"'H CH 20H 10 OH 220 [ .A_ i 8 i 9 73.555/r-- - - , - !, --,------- ----,----- - -----.--- --- ---- - - . - - - -- -,--- --. IT' 72.432 ~ 71.309 r- I 70.186 89.063 ~ I ,,-~ 68.817 615.684 114.571 63.448 62.325 r ~, ~ ~ L~ ___ ___ --L_ 4000 3600 2BOO __ _ _ ---L-_. ____ 2000 ~ 1600 ____ _ 1200 BOO -I 221 OH OH Ph~ OH 12 9 6 8 76.81 :n 36.09~----~----~------~------r------r-------------'--------------r-----------~~ 4000 3500 3000 2500 2000 1500 1000 em-I 500 222 13 ~--~~~-'I-r~'-~'-~~-'---r.-'-'-~~~-.-r.-'-'-r-r~~-.-r-,~'-~~r.-__~-'-.-~ e 99.52 IT 69.95~-----r------'-------rl------'-------r--------------r--------------'--------------,- 4000 3500 3000 2500 2000 1500 1000 em-I 500 223 o o~ CH~"-L /'0 H' \"CH 3 3 CH~H 15 I I 9 I 5 I 6 8 79.57 :lOT 55.21J-----~-----,r_----_r------~----_,--------------r_------------,_----------J-~- 4000 3500 3000 2500 2000 1500 1000 em-I 500 224 OH 16 Ilf-'H -rl~~r>~I-r-r~~r>~-r-r~I-r-r~~rl~~r>-.-r-r.-.-~-.-r'-·r-,,-.-.-~-.-r'-'1~~ 9 8 71.9415 •.• 6 5 0 ~ q~ ~.~~ M.~~ 63.8315 ~ 61.808 59.7110 -l......-__ 2800 .... ,' 2000 -"-------~--.--~- 1BOO CM-1 1200 BOO 450 225 '~I-'-'-'-'-'I-'-'-'-'-'-'-'-'-'-'I-'-'-'-'-'I-'-'-'-'-'~-'-'~-r-.-r-'-'-r-r-r-r-r-r-r-r-r-.--I _r~~H 9 8 6 5 I 81.98 n 51.05~-----r------~------r-----~-------r--------------r-------------~------------~~ 4000 3500 3000 2500 2000 1500 1000 em-I 500 226 I 4 I' 9 I. i,' , ~' I i •• ii' ' •• I I I ., 7 b , Ii, I , • , , ~ , , , • , I"" • ,', I I Ii.,; i 4 I i J I' i., 2 j t_6" " , , , i -,~,~,~,~,~,~, 1 21 I "9 , ,-, '" ,~,~, I,r'~~ r-r-r-Ir-r-r-r-i-r-r-r-r-~ I I I 4 I i ••• , • ~ i , j , I , ii" 4 I , i, i ~...-.--.-~, ~,'~'~i2 I ' • i 1 " " " 1I • , , , - i , I i i • i j ~ --,-,,--r-r.,..,..,.,.--,-~, , , 227 r-; o Meo0'? F3 C Ph : Ph~O H' O-{ o 19 (blowup of 1H NMR spectrum) 111. 41 IT ~ \ I 67.77~---'-----'-----r-----~----~-----------'-----------~-------- 4000 3500 3000 2500 2000 1500 1000 ____r - em-I 500 228 22 ""1 9 ; j, iii ~~L 'l,---~lL- - - - -llJ~,-------__ " ,,-. k i,,' j,' j';' I" B Ii, I , •• ," I "1' I i , ' I iii" i ••• i , ; , , I • I i j , • _ ""'" I " '1 " , 0 1~T ~ 1 ~OMe X Ph .... -0' Ph CF 3 H 24 i , j , ii, i ",--llL~_,,--I_ _ _A'---'-_ _ _ '- ' - - - - - ,''--- ----~ j} i • , , ••• , , 0~ i • , iii , •• ~ , ii, I i , I ii, , i 4 •• I • , I ,I J i I ",., 2i i i , I \ Ii, 1 iii lit i' iii o I, I 229 22 (blowup of 'H NMR spectrum) ----~---- ---~----- 117.25 IT 1"9,of~ 1 ._ "'0- ~.x OMe Ph""- H Ph ~CF3 22 ----- ---,--.-------,-- 32.46 ........----.---,----·---.,--~---.._-----_r, 4000 3500 3000 2500 2000 1500 1000 ell-I 500 230 Index of Products for Chapter One Product Experimental Spectra (1 'S,2'S)- Pseudoephedrine Propionamide 34 172 1 36 173 2 37 174 3 44 175 4 44 176 5 47, 64 177 6 47,64 178 7 39 179 9 50 180 10 50 181 16 42 182 18 59 183, 184 19 59 185, 186 20 59 185, 186 21 67 187, 188 22 70 189, 190 23 70 189, 190 24 54 191 25 56 192 26 56 193 27 65 194 28 74 195, 196 29 76 196 231 Experimental Spectra 30 78 197, 198 31 80 198 32 82 199 33 84 200 34 86 199 Product 232 Index of Products for Chapter Two Product Experimental Spectra 7 109 203 8 115 204 9 111 205 10 117 206 11 117 207 17 120 208 18 120 209 19 113 210 20 123 211 21 123 212 22 123 213 233 Index of Products for Chapter Three Experimental Spectra Racemic 2-Methyl-l-hepten-3-o1 141 215 6 145 216 7 155 217 9 145 218 10 145, 152 219 11 145, 152 220 12 157 221 13 143 222 15 149 223 16 149 224 17 159 225 19 161 226, 227 21 163 226 22 165 228,229 24 167 228 Product