Synthetic and mechanistic studies on a silicon-mediated aldol reaction Citation Kephart, Susan E. (1995) Synthetic and mechanistic studies on a silicon-mediated aldol reaction. Master's thesis, California Institute of Technology. doi:10.7907/t9y9-zk34. https://resolver.caltech.edu/CaltechETD:etd-10312007-082516 Abstract No abstract submitted. Item Type: Thesis (Master's thesis) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Unknown, Unknown Thesis Committee: Unknown, Unknown Defense Date: 1 December 1994 Record Number: CaltechETD:etd-10312007-082516 Persistent URL: https://resolver.caltech.edu/CaltechETD:etd-10312007-082516 DOI: 10.7907/t9y9-zk34 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 4342 Collection: CaltechTHESIS Deposited By: Imported from ETD-db Deposited On: 13 Nov 2007 Last Modified: 16 Apr 2021 23:32 Thesis Files Preview PDF (Kephart_se_1995.pdf) - Final Version See Usage Policy. 7MB Repository Staff Only: item control page

Synthetic and Mechanistic Studies on a Silicon-Mediated Aldol Reaction Thesis by Susan E. Kephart In Partial Fulfillment of the Requirements for the Degree of Master of Science California Institute of Technology Pasadena, California 1995 (Submitted December 1, 1994) © 1995 Susan E. Kephart All Rights Reserved Table of Contents BACKGROUND RATE ACCELERATION BY SMALL RINGS Introduction Silacyclic O-silyl ketene N,O-acetals Silacyclobutane silyl enol ethers Silacyclobutanes with electron-withdrawing substituents KINETIC ISOTOPE EFFECT - NITROBENZALDEHYDE CLEAVAGE OF B-HYDROXY AMIDES MORE SILICON-MEDIATED ALDOL REACTIONS Pseudoephedrine auxiliary Chiral aldehydes Ephedrine auxiliary MECHANISTIC REASSESSMENT EXPERIMENTAL SECTION REFERENCES APPENDIX I: Catalog of spectra APPENDIX II: Coordinates and Crystal Structure for Silyl Ketene Acetal 8 15 22 27 31 38 38 47 53 57 63 180 186 299 FIGURES Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 List of Figures, Schemes, and Tables Co Oo NSN FF WH WW 13 27 31 35 36 45 50 52 57 58 59 61 62 iv SCHEMES Scheme I Scheme II Scheme III TABLES Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 . 29 48 51 17 19 28 32 37 39 41 44 49 53 List of. Abbreviations A angstrom Ac . acetyl Ar aryl aq aqueous bp boiling point Bu butyl C degrees Celsius C6D6 benzene-dg CI chemical ionization cm-l reciprocal centimeters Cy cyclopropyl 3) chemical shift in parts per million d days de diastereomeric excess DIBAL diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMEF N,N-dimethylformamide DMSO dimethy] sulfoxide € dielectric constant E entgegen ee enantiomeric excess EI electron impact equiv equivalent Et . ethyl Et,O EtOH EtOAc FAB GC hr HMDS HRMS kcal LAH LDA [M+] - MeOH mg MHz diethyl ether ethyl alcohol ethyl acetate fast atom bombardment Fourier transform gram . gas chromatography enthalpy hour hexamethyldisilazide high resolution mass spectroscopy Hertz iso infrared coupling constant rate constant kilocalories liter lithium aluminum hydride lithium diisopropylamide molar (moles/L) molecular ion methyl methyl alcohol milligram megahertz min mmol mol mp LL N nm NMR P pet. ether pH Ph PhCHO PMA ppm Pr minute milliliter millimole mole melting point microliter normal (concentration) nanometer nuclear magnetic resonance para Petroleum ether (bp: 30-60 °C) hydrogen ion concentration (log scale) phenyl benzaldehyde phosphomolybdic acid parts per million propyl pyridine rectus retention factor seconds entropy sinister tertiary tetrabutylammonium fluoride trigonal bipyramid TBS tert- Tf THF TLC TMS Torr viv wiv XS tert-butyldimethylsily1 tert-butyldiphenyl tertiary trifluoromethylsulfonyl tetrahydrofuran thin layer chromatography trimethylsilyl millimeters of mercury ultraviolet volume-to-volume ratio weight-to-volume ratio excess zusammen pseudorotation about ligand x List of Products Product First Appearance Experimental Procedure, Spectra, in Text, p. Pp: p- 8 9 65 187 9 9 67 189 10 10 69 191 11 10 69 193 12 12 72 195 13 12 72 195 14 11 76 197 15 11 78 199 20 16 83 204 21 16 85 206 22 16 87 208 24 18 89 210 25 18 91 | 212 26 18 93 214 27 22 96 216 28 22 98 218 29 23 100 — 30 23 100 . — 35 36 115 231 36 ; 36 115 233 37 41 118 235 38 39 40 41 42 43 44 45 46 47 48 49 50 52 53 54 55 56 57 58 59 60 . 61 Al 4l 41 4] 41 4l 4] AT 47 48 48 48 48 49 49 49 49 51 51 51 51 53 53 118 122 122 127 127 131 131 158 158 152 153 155 156 161 161 162 162 168 170 172 174 176 176 237 239 241 243 245 247 249 274 274 270 270 272 272 277 280 280 277 283 285 289 292 294 297 BACKGROUND In the past twenty years, the aldol addition reaction has been widely used to form carbon-carbon bonds stereoselectively.! Two new chiral centers are formed in this reaction, leading to four possible stereoisomers: M = Li, B, Zr, Ti, etc. O-silyl enol derivatives of aldehydes, ketones, and esters have been known to form aldol addition products with aldehydes in the presence of a coreactant such as fluoride ion? or Lewis acid3, or at high temperatures.4 Earlier work in the Myers group has shown that certain O-silyl ketene N,O-acetals (the O-silyl enol derivatives of amides) react with aldehydes to form predominantly anti aldol products.5 These reactions are uncatalyzed and occur at or below room temperature. For example, the O-triethylsilyl ketene N,O-acetal derivative of a simple N,N- dimethyl amide reacts cleanly with benzaldehyde at -30 °C to give an 80% yield of a 1.8:1 mixture of anti and syn aldol adducts (reaction 1).9 OSI(Et)3 0 OSi(Et)g O OSI(Et), CHa CN PhCHO, CH2Ch CH, : CH ee N aN | -30 °C, 7 hr | Ph * Ph (1) 80% 1.8:1 Stereoselectivity is improved dramatically by the use of a chiral auxiliary. (S)-Prolinol-derived O-silyl ketene N,O-acetal 1 reacts with benzaldehyde at room temperature to form anti aldol product 2 and syn aldol product 3 in a 39:1 ratio (reaction 2).5 1 9Chs 7° sCHs 0 _ f eS Si o— si_ No CH2Cly, PhCHO, H,,, pws 8 ec oan (2) 23 °C, 24h . 2 1% 3 1% X-ray crystal structures of 2 and 3 show a very short Si-O distance, suggesting the intermediacy of a pentacoordinate silicon species (Figure 1). H N ,; A \ N Le | —_—— a . e~ CH, r——~ CHs | ant oO | Re Oo IN H o—. a CH, | CHy CH, CH, Thoat Tehair Figure 1 The major, anti product could arise from a trigonal bipyramidal, boat-like transition state (similar to Tpoat), and the minor, syn product from a chair-like one (similar to T chair). While both proposed structures show bond formation to the same face of the enolate, orbital overlap is proposed to be greater in Tyoart. In both Tpoat and Tehair, the aldehyde is coordinated to the silicon atom in an equatorial position. This coordination mode could be the result of either aldehyde attack on an edge of the ground-state silicon tetrahedron, on attack on a face of the silicon tetrahedron followed by pseudorotation of this axial ligand in to an equatorial position (Figure 2). The original mechanism proposed for this silicon-mediated aldol reaction focused on facial attack followed by pseudorotation because edge attack was thought to be sterically unfavorable. 4 OH o— gis CHa H Thoat Face attack Figure 2 The original mechanism (Figure 3) begins with reversible aldehyde coordination through facial attack, followed by a rapid pseudorotation to place the aldehyde in a equatorial position. Rate-determining carbon-carbon bond formation then occurs from either Tpoat Or Tchair to give the observed aldol products.§ H H ye , CH CH Si-ons Oo- * o7 "0 p ‘CH, = "CHg 0 4 Ox LH A Vocn, fast Figure 3: Original Mechanism Proposed for Silicon-Mediated Aldol Reaction Several pieces of evidence were gathered to support this mechanism. The reaction proceeded well in solvents which were poor o donors (dichloromethane, benzene, hexane, acetonitrile) but was not observed in coordinating solvents (THF, DMF).°7 This implied that aldehyde coordination to silicon did occur. The rate of the reaction was approximately the same in both hexane and acetonitrile.6 Since these solvents differ greatly in polarity, _ this supported a transition state which was not highly polar. Kinetic analysis in benzene over a 60 °C range showed the reaction to be rigorously second order, first order in each reactant, with activation parameters AH? = 12.0 + 0.5 kcal/mol and AS? =—41 + 2 eu.6 The reaction order and large negative entropy of activation suggest an associative mechanism. Competition reactions between benzaldehyde-d and benzaldehyde-h with 1 yielded a secondary deuterium isotope effect, ky/kp = 0.76 + 0.05, indicating a later transition state involving carbon-carbon bond formation.® Kinetic analysis of the reaction of 1 with a series of para-substituted benzaldehydes showed that electron-withdrawing groups accelerate the reaction. A Hammet p value of 3.5 + 0.2 was determined, ruling out rate- determining aldehyde complexation (for which a p < 0 would be expected).6 However, the Hammet plot became nonlinear for p-nitrobenzaldehyde, possibly suggesting a.change in mechanism. The most subtle argument for the pseudorotational mechanism was based on the differing reactivity of 4, derived from (—) ephedrine, and its epimer 5, derived from (+) pseudoephedrine. No reaction of 4 with benzaldehyde was observed under 110 °C.8 (Reaction 3). CHg Ow cia CHG Ph st PhCHO 0 No Reaction Observed (3) CH3 we Up to 110 °C JX CHs CHg 4 The pseudoephedrine-derived epimer 5, however, smoothly adds to benzaldehyde at 60 °C to give the (25, 3R)-anti aldol adduct 6 in 70% yield.©? (Reaction 4) Lt . PhCHO, CH)Ch CH3 CHg (4) CH wwe nel MoGCHs / CHg si CHg Phy, o No 5 Lt > 7 7% CHg Ph CH; CH This (apparent) difference in reactivity was difficult to rationalize by considering the proposed transition structures Te and Tp (Figure 4) alone. However, if these structures are the result of a single pseudorotation from the proposed initial trigonal bipyramidal structures Ae and Ap, the difference can be explained.®!® Structure Ae, which would be formed by facial attack of the aldehyde opposite one of the silylmethyl groups, would suffer severe steric interaction between that silylmethyl group and a methyl group on the ephedrine ligand. In contrast, structure Ap would not experience as great a steric interaction. Thus it was reasoned that the non-reactivity of ephedrine-derived 4 supported the intermediacy of the trigonal bipyramidal structure A on the reaction pathway. This is a very involved argument, and one based on an absence of evidence. More direct evidence was needed to justify the inclusion of structure A in the proposed reaction mechanism. This evidence was provided by studying the rate of the silicon-mediated aldol reaction when the silicon atom was incorporated in small rings. =—=_—_=_=_=_=—=> v CH °S- H Ph Ae WOCHPh l —_—_—_> | ch, oN H Ph Tp A, Figure 4: Comparison of ephedrine (top) and pseudoephedrine (bottom) derived silyl ketene N,O-acetals in the proposed pseudorotational mechanism RATE ACCELERATION BY SMALL RINGS Introduction Only three of the possible trigonal bipyramidal isomers can form the proposed transition structure T by a single pseudorotation. Of those three, only two, structures A and B, arise directly from aldehyde attack on a face of the silicon tetrahedron. , H erent Ey Tat ons H = HC O, o~ Pca “CH; t _ OCH: ° yo CH3 | H o— sit cH | j cts H OH CH A T B Figure 5 Structure A has already been discussed. The most important difference between structure B and structure A is that both silylmethyl groups occupy equatorial positions in B. In the original mechanism shown in figure 3, the angle between these methyl groups is 90° both before and after pseudorotation. A mechanism involving B would require that they be separated by 120° on initial attack. If the methyl groups on the silicon atom were replaced by a small (4- or 5-membered) ring, structure B would be more strained than the tetrahedral . ground state, while trigonal bipyramid A would be stablilized relative to the ground state. The incorporation of phosphorus in a four- or five-membered ring is known to accelerate tbp formation to relieve ring strain.!! This causes rate enhancement in reactions in which the leaving group can attain an apical position through pseudorotation. When this is not possible rate retardation and ring-opening reactions are seen instead. A similar effect is also seen in the basic hydrolysis of 1-methylsilacyclobutane, which is 104-105 times faster than for triethylsilane.!2_Nucleophilic substitutions of silacyclobutanes are well known, and unlike acyclic or non-strained cyclic silanes, these reactions usually proceed with retention of stereochemistry.!3 Although this has been attributed to equatorial leaving, retention of stereochemistry is also consistent with tbp formation followed by pseudorotation to allow apical leaving. Silacyclic O-silyl ketene N,O-acetals To test the effect of small rings on the silicon-directed aldol reaction, silacyclopentane and silacyclobutane ketene N,O-acetals 8 and 9 were prepared in analogy to 1. Both reacted cleanly with benzaldehyde at accelerated rates to form mixtures of syn and anti aldol addition products (10-13). Figure 6: X-Ray structure of silacyclopentane ketene N, O-acetal 8 10 Silacyclopentane ketene N,O-acetal 8, formed by trapping the dianion of (S)-prolinol propionamide with 1,1-dichlorosilacyclopentane, was isolated as moisture- sensitive crystalline solid. X-ray crystal structure analysis performed by Dr. Joseph Ziller (University of California, Irvine) confirmed the Z-geometry of the double bond (Figure 6). Interestingly, the amide nitrogen is somewhat distorted from the expected planar hybridization. Kinetic studies (1H NMR) of the addition of this slightly strained (<CH>-Si-CH) = 98.3°) ketene N,O-acetal to benzaldehyde at 40 °C show approximately a tenfold rate acceleration over that of the dimethyl analog!9 at the same temperature (kg = 4.3 + 0.2 x 10-4 M-!s-l; ky = 4.2 + 0.9 x 10-4 M-ls-l), Unlike the dimethyl compound, which was strongly anti selective, the ratio of aldol addition products 10 and 11 is 1:1 (reaction 5)!4. Wy “ Om sje" O— Si Oo— Si ‘ NN 0 N O fe) CH + \ ° 40 °C, benzene-de : Ph | : Ph k = (4.3+0.2)x104 CHg CHg 8 10 11 NO Although the NMR spectra of 10 and 11 were extremely similar to those of the corresponding dimethyl compounds, an independent determination of the absolute stereochemistry was desired. Fortunately, these aldol products were somewhat stable to Silica gel and could be isolated by column chromatography. Anti adduct 10 was more Sensitive to hydrolysis and decomposition, but syn adduct 11 proved stable enough to obtain an X-ray structure.!5 The (S,S,S) stereochemistry and nine-membered ring conformation are essentially identical to that of dimethyl adduct 3!6: 11 superimposition of 3 and 11 X-ray quality crystals of 10 could not be prepared, but desilylation of both 10 and its anti dimethyl analog 2 yield the identical anti diol 14. Desilylation of both 11 and 3 yield identical syn diol 15. OH OH O OH O OH 10 or 2 EGN+ SHE ews Wor3 Eun: 3HF A - FoSiRp y Ph - F)SiRy y Ph CH CH; 14 15 Despite the change in stereoselectivity, which will be considered later, the structural similarity of the products indicates that there is no other change in the reaction mechanism. Thus, the moderately strained five-membered ring accelerates the silicon-directed aldol reaction, presumably by stabilizing the initially formed trigonal bipyramidal structure A relative to the strained ground state. A more dramatic effect is seen in the aldol reaction of the silacyclobutane homolog. Ketene N,O-acetal 9 results from trapping the (S)-prolinol propionamide dianion with 1,1- : dichlorosilacyclobutane. When reacted with an equimolar amount of benzaldehyde (0.25 M in CgD¢) at room temperature, the addition is complete almost immediately. In this case, the reaction is syn selective by almost 6 to 1 (reaction 6).14 12 oF QO me si” No ro a Foe, Bc iene Ann. AX, (6) CH3 <8 min, 100% 2 inane Que 15:85 9 12 13 Kinetic analysis (1H NMR) of this reaction was carried out at -80 °C. At this temperature the rate (ko = 2.6 + 0.1 x 10-4 M'!s"!)!4 is even faster than that of the dimethyl! analog! at 60 °C (ky = 1.5£0.2 x 10-4 M"!s-!). The activation parameters determined for 1 over the range 20-80 °C (AH# = 12.0 + 0.5 kcal/mol and AS? = -41 + 2 eu)6 can be used to extrapolate the rate of this reaction at -80 °C. The calculated value (kj ~ 1.2 x 10-10 M''s-!) is six orders of magnitude smaller than that of the silacyclobutane compound, indicating remarkable effect of the small ring. By incorporating the silicon atom in a four- membered ring, a million fold rate acceleration was achieved. Silacyclobutane ethers 12 and 13 were so sensitive to hydrolysis that they could not be isolated themselves, but desilylation of the crude reaction mixture gave syn diol 15 in 80% yield. No anti diol was recovered, however. This might be due to decomposition of anti adduct 12 before hydrolysis, perhaps through a retro-aldol mechanism. As will be discussed in the next section, retro-aldol reactions were observed in the desilylation of silacyclobutane enol ether-derived aldol products. Like the silacyclopentane adducts, the NMR spectra of the silacyclobutane adducts 12 and 13 are extremely similar to those of their dimethyl analogs, for which the absolute stereochemistry is known. Assuming that : silacyclobutane ketene N,O-acetal 9 follows the same reaction path as 1 in its addition to benzaldehyde, it is possible to rationalize the change in stereoselectivity with respect to the original pseudorotational mechanism. 13 The trend seen in the reactions of these three prolinol-derived O-silyl ketene N,O- acetals is that increased ring strain leads to increased syn selectivity. Dimethy] silyl 1 is overwhelmingly anti selective (syn:anti = 2:98), its silacyclopentane analog 8 is non- selective (syn:anti = 50:50), and silacyclobutane derivative 9 is moderately syn selective (syn:anti = 85:15). If all three are assumed to follow the proposed reaction path, the hypothetical transition state structures can be examined for causes. Figure 7 shows Structures Tpoat and Tchair and their analogs for the silacyclobutane case, Tpoat' and Tchair' . O— Si H O— Si H2 7 Ho” CH |, CH, |; Thoat Tehair oF _ wa A And os", —~ 12 o— si" —+ 13 BN AMY 5 H H H Thoat’ Tehair’ Figure 7: Comparison of proposed transition structures for the reactions of 1 and 9 with benzaldehyde In the dimethyl case, steric repulsion between the methyl groups may force the C- -Si-C angle to be greater than 90°, causing the equatorial O-Si-O angle to be distorted to less than 120°. This shift would increase z-overlap in the boat conformation, but decrease 14 m-overlap in the chair conformation. Thus anti products predominate. In the silacyclobutane case, the C-Si-C angle would be much closer to 90°, so the equatorial O-Si- O angle may be wider than before. This improves m-overlap in the chair conformation, making carbon-carbon bond formation more favorable for structure Tehair' than for Structure Tehair. In addition, the ring hydrogens would now be constrained to lie close to the equatorial plane, where steric repulsion with the aldehyde proton may become significant.!7 Along with this steric repulsion, the greater O-Si-O bond angle would reduce overlap in the boat conformation. Both of these factors disfavor anti product formation, so the reaction becomes syn selective. The silacyclopentane case lies between these two extremes. The ring hydrogens would not be as close to the equatorial plane, but the C-Si-C bond angle may remain somewhat distorted. The 1:1 ratio of syn and anti products indicates that, for this substrate, the proposed chair-like and boat-like transition states may be approximately equal in energy. Incorporation of the silicon atom in a small ring was found to accelerate the silicon- directed aldol reaction of O-silyl ketene N,O-acetals derived from (S)-prolinol propionamide. This supports the proposed reaction pathway in which the silicon-bound alkyl groups remain disposed apically-equatorially rather than the pathway in which they are, even temporarily, disposed diequatorially. The rate acceleration is accompanied by a dramatic change in stereoselectivity, which can be‘fationalized by considering distortion of the tbp-like transition state by the small ring and by steric interactions between ring and aldehydic hydrogens. The million-fold rate acceleration seen with the silacyclobutane functional group suggested that the rates of other carbon-carbon bond forming reactions involving pentavalent silicon could also be enhanced. The next step was to apply this aldol | methodology to the reactions of other carbonyl-derived organosilicon species, specifically silyl enol ethers of ketones and esters. 15 Silacyclobutane silyl enol ethers Amide enolates are generally more nucleophilic than ester or ketone enolates, so it was uncertain if the silacyclobutane methodology could be used to make this uncatalyzed silicon-directed aldol reaction feasible for less reactive carbonyl compounds. The reaction of O-trimethylsilyl ketene acetals derived from esters with aromatic aldehydes at very high temperatures had been reported‘, and work by others both inside and outside the Myers group has shown that O-silacyclobutane ketene acetals do react faster and at lower temperatures than their non-cyclic analogs.!4!8 For example, the reaction of O-trimethylsilyl ketene acetal 16 with benzaldehyde is reported to require heating at 150 °C (neat, 18 hr) for completion and affords the addition product 17 in 81% yield.4 (Reaction 7) In contrast, the methylsilacyclobutane derivative 18 reacted completely and cleanly with benzaldehyde within 4 hours at 27 °C (0.2 M each, benzene) to give adduct 19 quantitatively.!4 (Reaction 8) He .CHs HaQy Clg * Si Si su™ ~~~ (@) oO CH 3 ° CHa PhCHO SCH; (7) CH3O 150°C, 18 hr CH30 al CH, H3C CHg 16 17 81% si PhCHO, C Si oO” ~CHg EHO, C66 Oo OO ~CHg (8) S CHy 27°C, 4hr co NV CHO ~Ph 18 19 100% 16 No precedent was available for the thermal, non-catalyzed aldol reaction of ketone silyl enol ethers with aldehydes, so it was uncertain if even a 106 rate acceleration due to a silacyclobutane group would make the reaction energetically accessible. Cyclohexanone was chosen as the first enol ether precursor for study because the enolate geometry is constrained to be E, and because many references are available on catalyzed reactions of its trimethylsiloxy derivative. Enolization with lithium diisopropylamide followed by trapping with the appropriate trialkyl silyl chloride gave silacyclobutane enol ethers 20 and 21 as well as dimethylphenyl silyl 22, which was used as a control. The TMS enol ether 23 is commercially available. 1-Phenyl silacyclobutane enol ether 20 was observed to react with benzaldehyde at room temperature, although very slowly (ty/2 ~4 days, 0.8 M each, CgD¢) to give predominantly syn products (12:1 syn:anti). This promising result led to a series of sealed-tube reactions carried out at higher temperatures. The results are summarized in table 1. As anticipated, the dimethylalkyl enol ethers did not react, even at elevated temperatures. Dimethylphenylsilyl enol ether 22 showed slow hydrolysis to cyclohexanone, while trimethylsilyl enol ether 23 remained unchanged even after eight days at 150 °C. The phenylsilacyclobutane enol ether 20 was more reactive and more selective than the methyl-substituted analog 21, indicating a possible electronic effect. The increased susceptibility to hydrolysis of 22 over 23 may also be a manifestation of this effect. 17 Table 1. Sealed tube reactions of cyclohexanone enol ethers with aldehydes? Enol Ether Benzaldehyde Isobutyraldehyde LO 100 °C, 33.5 hr 88% yield (0% unreacted) 5.0:1 syn:anti syn: 5.78¢ (d, J = 3.2 Hz) anti: 5.37 (d, J = 8.1 Hz) 100 °C, 337 hr 58% yield (9% unreacted) 1.6:1 syn:anti> syn: 4.05 (dd, J = 3.0, 8.4 anti: 4.73 (dd, J = 4.5, 6.0 Hz) Hz) (\ > 100 °C, 84 hr 100% yield (0% unreacted) 2.1:1 syn:anti 100 °C, 303 hr 32% yield (49% unreacted) 1.4:1 syn:anti> om eK CH 3 syn: 5.70 (d, J = 3.1 Hz) syn: 4.00 (dd, J = 2.7, 8.1 Hz) anti: 5.32 (d, J = 7.8 Hz) anti: 4.13 (dd, J = 4.2, 6.6 Hz) Si~CHg: syn 0.32, anti 0.29 Si-CHs: syn 0.47, anti 0.39 21 HaCy CHs Sj 150 °C, 201.5 hr 150 °C, 201.5 hr om NO ALDOL PRODUCTS NO ALDOL PRODUCTS (71% unreacted)4 (81% unreacted)4 22 He, CHs Si 150 °C, 201.5 hr 150 °C, 201.5 hr O” ~CHg NO ALDOL PRODUCTS NO ALDOL PRODUCT, S (100% unreacted) (100% unreacted). ~ 23 0.5 M solutions in C6Dg6, 0.1 M cis-dichloroethylene used as internal standard. bStereochemical “assignments for isobutyraldehyde adducts based on coupling constants. “Chemical shift for the formerly aldehydic proton in parts per million, relative to cis-dichloroethylene 5=5.605 ppm. 4Hydrolysis to cyclohexanone observed. 18 The silacyclobutane enol ethers reacted much faster with benzaldehyde than with isobutyraldehyde, and with greater stereoselectivity. The syn and anti assignments of the benzaldehyde adducts have been confirmed by desilylation and comparison of the melting points, NMR chemical shifts, and FTIR spectra to the literature values for the resulting B- keto alcohol. Desilylation of the isobutyraldehyde adducts, however, led to decomposition by retro-aldol reactions. Thus, the syn and anti assignments are based on the coupling constants, in analogy to those reported for the aldol adducts of trimethylsiloxy cyclopentene and isobutyraldehyde: erythro (syn) 3.80, d, J = 8 Hz; threo(anti) 3.56, dd, J = 4, 7 Hz (CCl4).!9 These assignments also correlate the shifts of the silyl methyl singlets for the aldol adducts of 21. The anti singlet appears at higher field than the syn in the benzaldehyde case, and this relationship is also seen in the isobutyraldehyde case as assigned based on coupling constants. Silyl enol ethers of 3-pentanone were studied next to determine the effect of double bond geometry on the aldol reaction. Kinetic deprotonation of 3-pentanone by lithium diisopropylamide and trapping the enolate mixture with 1-phenyl or 1-methyl-1- chlorosilacyclobutane gave enol ethers 24 and 25 with isomer ratios ~2:1 E to Z. The same procedure was used to generate dimethylphenyl silyl enol ether 26, but distillation of the crude enol ether caused isomerization to a mixture which was 4:1 Zto E. A Z-rich mixture of enol ether 24 was adventitiously obtained when a second batch isomerized on distillation. Presumably, these isomerizations were caused by basic impurities present during distillation. Table 2 summarizes the results of a series of sealed-tube reactions of these enol ethers. 19 Table 2. Sealed-tube reactions of 3-pentanone enol ethers with aldehydes? Enol Ether Benzaldehyde Isobutyraldehyde 15:85E/Z 100 °C, 92.5 hr 100 °C, 243 hr o Si 86% yield (0% unreacted) 2.8:1 syn:anti 66:34E/Z 100 °C, 103.4 hr 95% yield (5% unreacted) 64% yield (28% unreacted) 4,2:1 anti:syn> 100 °C, 103.5 hr 64% yield (30% unreacted) 24 ~ CHg 7.6:1 syn:anti 2.6:1 anti:syn syn: 5.23° (d, J = 6.9 Hz) syn: 3.96 (dd, J = 2.4, 9.0Hz) anti: 5.04 (d, J = 9.6 Hz) anti: 4.00 (dd, J = 5.0, 6.4Hz) 69:31 E/Z (\ 100 °C, 196 hr 100 °C, 197 hr a 86% yield (14% unreacted) 32% yield (35% unreacted) Oo” Sk Ha 5.3:1 syn:anti 1.5:1 anti:syn CHg NN syn: 5.12 (d, J=7.0 Hz) | syn: 3.854 (dd, J= 2.4, 9.3Hz) anti: 4.91 (d, J = 9.6 Hz) anti: 3.89 (dd, J = 5.1,6.3Hz) 95 CHs Si~CHs3: syn 0.17, anti 0.11 Si-CH3: syn 0.25, anti 0.21 \5 150 °C, 201.5 hr 150 °C, 201.5 hr om NO ALDOL PRODUCTS NO ALDOL PRODUCTS cH ; (73% unreacted)® 3 SQ clean reaction to 3-pentanone and new product 26 CH3 “0.5 M solutions in CgDg¢, 0.1 M cis-dichloroethylene used as internal standard. >Stereochemical assignments for isobutyraldehyde adducts based on coupling constants. °Chemical shift for the formerly aldehydic proton in parts per million relative to cis-dichloroethylene 8=5.605 ppm. “Chemical shift of formerly aldehydic proton in parts per million, relative to benzene-dg 5=7.150 ppm. *Hydrolysis to 3- pentanone is observed. As before, the stereochemical assignments for the isobutyraldehyde adducts are based on the coupling constants, in this case in analogy to those reported for the corresponding alcohol: erythro (syn) 3.48, dd, J = 3, 8 Hz; threo(anti) 3.41, t, J=7 Hz.20 The non-cyclic control 26 did not react with benzaldehyde after eight days at 20 150 °C, but it did react with isobutyraldehyde to produce the starting 3-pentanone and a new, silicon-bearing product. This reaction was complete after 83 hours, and showed no change on extended heating. This new product could be the enol ether of isobutyraldehyde: 7 CHy O— Si= CH, New product? = ‘CHg CH, H The reaction of silacyclobutane enol ethers 24 and 25 with isobutyraldehyde was considerably slower and much less syn selective than with benzaldehyde. In fact, these reactions were anti selective, even more so than the cyclohexanone enol ethers. Their reactions with benzaldehyde, however, were still moderately syn selective. The phenyl- substituted silacyclobutane was once again more reactive than the methyl-substituted equivalent. The enolate geometry has a noticeable effect on the rate and stereoselectivity of these reactions. In every case, the E isomer was consumed faster than the Z isomer. For example, in the reaction of the Z-rich mixture of 24 with benzaldehyde, all the E isomer was consumed after only 9.5 hours, only one-tenth the total reaction time. In the reaction with the E-rich mixture, the E-isomer was consumed in the first 39 hours. The greater reactivity of the E isomer is consistent with the shorter reaction times seen for the cyclohexanone-derived silyl enol ethers. Assuming no isomer interconversion, the . Stereoselectivity of each isomer is also different, which can be rationalized by the proposed pseudorotational mechanism. 21 It was proposed in the discussion of the amide-derived ketene N,O-acetals that a Z isomer would react from a boat-like transition state to give anti products and from a chair- like transition state to syn products. For the E isomer, this situation is reversed, and the . boat-like transition state would give the syn adduct. In the reactions of 24 with benzaldehyde, the greater overlap of the boat transition state seems to determine the syn selectivity of the E isomer, while the weak syn selectivity of Z isomer is attributable to the destabilization of the boat conformation by steric interference from the ring hydrogens as discussed earlier. The anti selectivity of both isomers in the reactions with isobutyraldehyde may be due to the steric bulk of the isopropyl group. One question which remains unresolved is whether the Z enol ethers are reacting directly, or whether they first equilibrate to E isomers under reaction conditions. Since E to Z isomerization was a problem on distillation of the enol ethers, it is possible that isomerization in the reverse direction could also occur. During the course of the sealed- tube reactions, the E/Z ratio was observed to decrease uniformly. Fast isomer equilibration followed by a slower reaction of the E isomer with aldehyde would be expected to show a constant E/Z ratio. However, slow isomer equilibration followed by fast consumption of £ enol ether would show consumption of the two isomers at different rates as seen. To determine whether slow isomer equilibration occurs, a sealed sample of the E-rich mixture of 24 was studied by high temperature 1H NMR under reaction conditions. The spectrum showed no change in the isomer ratio, chemical shifts, or peak shapes up to 90 °C (monitoring above 90 °C was hampered by the solution refluxing in the tube above the level of the probe). Furthermore, the isomer ratio after heating to 100 °C for 2 hours was identical to the room temperature ratio. Attempts to observe spin saturation transfer2! at 75 °C were inconclusive. In summary, the rate accelerating effect of the silacyclobutane group was studied in the reactions of ketone-derived silyl enol ethers, and shown to induce the silicon-directed 22 aldol reaction in ordinarily unreactive carbonyl species. Even so, the reaction rates are very _slow, even at 100 °C, and diastereoselectivity is modest. The reaction is cleaner and faster with benzaldehyde; addition to isobutyraldehyde is plagued by side reactions and impractically slow rates. Furthermore, the stereochemistry of the isobutyraldehyde adducts needs to be resolved. Enol ether geometry has a significant effect on the rate and stereoselectivity, as shown in the reactions of 3-pentanone-derived enol ethers. The E isomer is more reactive and more syn-selective, which suggests preference of the boat-like transition state, although the chair-like transition state is favored in some cases. Silacyclobutanes with electron-withdrawing substituents The increased reactivity of phenyl-substituted silacyclobutane enol ether 20 over its methyl-substituted analog 21 suggested that electron-withdrawing groups on silicon might accelerate the reaction by making the silicon center more susceptible to nucleophilic attack. To test this, chlorine-substituted silacyclobutane enol ethers 27 and 28 were synthesized. oa oc . on 27 28 Enol ethers 20 and 21 had been obtained by enolization of cyclohexanone with _ lithium diisopropylamide and trapping of the lithium enolate with the appropriate 1-alkyl-1- chlorosilacyclobutane. For 27 and 28, however, a procedure using milder, trialkylamine bases was developed.. Early NMR experiments showed that cyclohexanone and 23 dichlorosilacyclobutane reacted in the presence of an equivalent of triethylamine to give two enol ether products, 29 and 30 (reaction 9). No reaction was seen in the absence of triethylamine. cS) Si + * +4 EtgN + (9) US CDCly H Cl Cl ~ 70% Several experiments to optimize this reaction were performed. The order of addition was shown to have little effect on the rate or product distribution. As well as triethylamine, diisopropylethylamine, N-methylpiperidine, and pyridine each acted as effective bases. Pyridine was chosen for further study because the byproduct, pyridinium chloride, was insoluble and thus the enol ether products were easier to observe by NMR. The effect of amine stoichiometry was also studied. In the presence of one to five equivalents of pyridine, a product ratio of about 6:1 of 29 and 30 was obtained. However, in pyridine as solvent, only the monoadduct, 29 was observed. Enol ethers 27 and 28 were isolable in moderate yield (see experimental) Although chlorine substitution could not be confirmed by NMR, when added to one equivalent of silver triflate both immediately form an insoluble white precipitate. The mass spectra of these compounds are also consistent with the proposed silyl chloride structures. Both 27 and 28 react with benzaldehyde at room temperature (reactions 10 and ~ 11). Since the silylated aldol adducts were unstable to column chromatography, desilylation with fluorine and isolation of the B-keto alcohols was used to determine the stereoselectivities of these reactions. Cyclohexanone enol ether 28 was somewhat anti 24 Selective (1:2.1 syn:anti) while cyclopentanone enol ether 27 was syn selective (5.5:1 syn:anti). Both reactions also produced significant amounts of the o,B-unsaturated ketone, possibly from an HC] catalyzed elimination. When 27 was reacted in pyridine rather than methylene chloride, formation of the enone was suppressed (2% rather than 32%). Pyridine could serve as an HCl trap by forming insoluble pyridinium chloride. As expected, chlorine substitution on silicon led to rate acceleration. The room-temperature half life in the reaction of 20 with benzaldehyde is about four days; for 28 it is less than one day. (\ Oo OH O 4H Si So) 1. PhCHO, 1.5 hr, 27 °C Z o *a 2. EtsNeSHF ph + Ph (10) H In CH,Cl, 25%, 5.5:1 syn:anti 32% . 27 InCsHsN 25%, 3.0:1 syn:anti 2% Sj O OH ; O H o~ ~c)_ 1. PRCHO, 1 d, 27 °C, CgD5N 2. EtgNeSHF oh + arn H (11) 52 % 15% 28 syn:anti = 1:2.1 Since the aldol addition was rapid compared to enol ether formation, a one-pot enolization-aldol procedure was developed. For example, dichlorosilacyclobutane, “cyclohexanone, and benzaldehyde were stirred in pyridine for eight hours at 70 °C. On desilylation, the B-keto alcohols were obtained in 52% yield and the enone in 29% yield (reaction 12). This procedure, however, led to little stereoselectivity. Product ratios were 25 generally 1:1.5 syn:anti. No reaction was seen in the absence of dichlorosilacyclobutane or with either isobutyraldehyde or pivalaldehyde. In the latter two cases, only enol ether formation was observed. Similar results were obtained using dimethyldichlorosilane. Heating for 29 hours at 50 °C led to 50% yield of the aldols (1:1.9 syn:anti) and 11% of (\ 1.PhCHO,CsHsN, 9 OH Oo 4 + Si 70 C, 8 hr Ph + 4A Ph (12) cl” ~c 2. EtsNeSHF 52% 29% syn:anti = 1:1.6 the enone. Silacyclobutane enol ethers with substituents even more electron-withdrawing than chlorine were also desired. Silacyclobutane compounds bearing tert-butoxy and diisopropyl amine groups had been isolated before, but attempted syntheses of silacyclobutane triflates from triflic acid or triflic anhydride had led to ring opening rather than substitution on silicon.22 Thus, an alternate substitution procedure using silver triflate was developed. To test whether silver triflate would displace a silacyclobutane-bound chlorine atom, dichlorosilacyclobutane itself was reacted with two equivalents of dry silver triflate. After only five minutes at room temperature, the product, a dense colorless liquid which could be distilled and handled under argon but fumed violently on exposure to air, was formed in 82% yield. The }3C NMR of this liquid shows a characteristic trifluoromethyl . quartet and only two other signals. The mass of the liquid recovered is too great to be due to a mono-triflate product, so this liquid is assumed to be silacyclobutane ditriflate. 26 Unfortunately, satisfactory mass spectral data on this very reactive product could not be obtained. A mixture of cyclohexanone-derived enol ether 28 in pyridine-ds and silver triflate was allowed to equilibrate for two hours and then treated with benzaldehyde (2 days, 27 °C). After desilylation, the B-keto alcohols were isolated in 37% yield with a 1:1 syn:anti ratio and the enone isolated in 1% yield. Compared to the same reaction without triflate substitution (only 1 day at 27 °C, 52% aldol adducts, 15% enone), this does not seem to be an improvement. The chloride and triflate-substituted silacyclobutane enol ethers, while more reactive that their alkyl-substituted analogs, gave poor stereoselectivity in their reactions with benzaldehyde and no reaction with other aldehydes. These reactions were plagued by elimination of the aldol adducts to o,B-unsaturated ketones, although the amount of elimination could be reduced by using pyridine as solvent. 27 KINETIC ISOTOPE EFFECT - NITROBENZALDEHYDE Previous experiments had determined a kinetic isotope ratio of ky/kp = 0.76 for the reaction of 1 with benzaldehyde.® This, along with other evidence, suggested that the transition state for this reaction involved carbon-carbon bond formation. The theoretical minimum kinetic isotope effect is 0.71, in the case of rate-determining rehybridization of a carbon atom from sp? to sp3. A late transition state was also supported by the determination of a Hammet p value of 3.5 for the reaction of para-substituted benzaldehydes with 1.° If aldehyde coordination were the rate-determining step, electron- withdrawing substituents would be expected to slow the reaction, leading to a negative p value. For para-nitrobenzaldehyde, however, the Hammet plot became non-linear, possibly indicating a change of mechanism to rate-limiting aldehyde complexation. -2 CN x NO, -3-4 o~ -44 > Cl ~ = 30 H £ -5- -6 MeO p=35+02 -7 T T -0.4 -0.2 0 0.2.0.4 40.6 0.8 1 Opara Figure 8: Hammet Plot for the reactions of 1 with para-substituted benzaldehydes (From ref. 10) 28 To learn more about the mechanism of this reaction, the secondary kinetic isotope effect for the addition of para-nitrobenzaldehyde to 1 needed to be determined. In order to run a competition reaction between deuterated and non-deuterated p-nitrobenzaldehyde it was first necessary to obtain the labelled aldehyde. Since p-nitrobenzaldehyde-d was not commercially available, and since the published preparative procedure23 seemed unnecessarily lengthy, a few alternate routes were first explored (Table 3) Table 3. Attempted syntheses of p-nitrobenzaldehyde-d Scheme outcome ref. OCH, I p-nitrobenzoic 24 1) ci 1) HC — NH*Cr° acid only OoN 2) LIAID, p-nitrobenzoic 25 LiA(O'Bu)3D acid only 2) OnN complex 1) "BuLi, — 78 °C or 'BuLi, -100 °C mixture with 26 2) DMF-d reduction of nitro group None of these procedures, however, produced satisfactory results, so the labelled aldehyde -was ultimately synthesized by the literature procedure?3, as shown in Scheme I. Recrystallized pnitrobenzaldehyde is first protected as the dithiane using propane dithiol and HCl gas. The crystalline dithiane was deprotonated with catalytic sodium 29 hydroxide in D2O and deuterated with DCl in D2O. Finally, the protecting group was removed with bromine followed by lead diacetate. This procedure gave the desired p-nitrobenzaldehyde-d in good yield and with very high deuterium incorporation (>96% D by both NMR and HRMS). Scheme | O () H a S b,c —_—_—_—_—_—_—_> H — OoN OoN iS de D D ———— OoN ON Reagents and conditions: (a) 1.0 equiv HS(CH2)3SH, HCl (g), CHCl, 0 °C, 5 min then rt, 30 min, 96% crude, 83% recrystallized from EtOH; (b) 0.11 equiv NaOH in D2O, dioxane, rt, 1 hr; (c) 0.21 equiv 20 wt.% DCl in D,O, rt, 15 min, 83% recrystallized from EtOH, >97% D; (d) 4.3 equiv Br2, H2O/HOAc/dioxane, rt, 5 min; (e) excess Pb(OAc)2°3H20, H20, rt, 20 min, 71%, >96% D Once the deuterated aldehyde had been obtained, the deuterium isotope effect was determined by a competition reaction. Silyl ketene N,O-acetal 1 was allowed to react with an excess of a 1:1 mixture of labeled and unlabeled aldehyde (equation 13). 30 H (D) fe) fe) CHs CHs 7 CH ts CH3 ‘Oo NO> NO» fe) fe) \ 48 : 52 CH, (13) benzene, 15 °C, 2 hr 40 min NO, 1 46% 51:49 D:H Mass spectroscopic analysis of the initial aldehyde mixture and the isolated aldol adducts both showed 50% deuterium incorporation, within experimental error. Thus the rate constant ratio, ky/kp, is very close to 1 for this reaction, indicative of a transition state in which no rehybridization is occurring on the deuterium-bearing carbon. This secondary isotope effect is consistent with rate-determining aldehyde coordination for p- nitrobenzaldehyde, as was suggested by the Hammet plot. The large, positive Hammet p value (3.5) originally calculated for the reaction of 1 with para-substituted benzaldehydes showed that electron-withdrawing groups accelerated the silicon-mediated aldol reaction and suggested a mechanism in which carbon-carbon bond formation was the rate-limiting step. However, the anomalous result with p-nitrobenzaldehyde suggested that for some aldehydes, coordination can be so slow as to become the rate-determining step. The secondary deuterium isotope effect calculated for p-nitrobenzaldehyde is consistent with a transition state in which carbon-carbon bond formation is not occurring, and confirms that aldehyde coordination may be rate-limiting. 31 CLEAVAGE OF B-HYDROXY AMIDES Since the discovery of the highly diastereoselective silicon-mediated aldol reactions of amide derivatives of (S)-prolinol and (+)-pseudoephedrine 1 and 5 (Figure 9), an important concern has been the removal of these chiral auxiliaries after the reaction H3C H3C —— si Oo-— si. ‘5 PhCHO, hexanes, sea 23 °C, 10 hr vA , CHg CH, CH, 1 2 77% 3 2% from (S)-prolinol (2S,3R) (28,35) HaQ CHg me CH Oo; oe Phi, “ nh Pha, ee PhCHO, CH,Ch, we cH 60 °C, 64 hr 3b Pha, Hg CH, CH, Ch, CH3 5 6 70% 7 71% (2S,3R) (2R,3S) from (+)-pseudoephedrine Figure 9. Highly diastereoselective aldol reactions using B-hydroxy amide auxiliaries.56 Previous attempts to remove the prolinol auxiliary focused on cleaving the amine by reductive methods, but gave very poor results.27 Very little had been done on the pseudoephedrine system, so a wide variety of techniques were explored to remove this auxiliary from both the silylated and desilylated aldol adducts, as shown in table 4 Table 4. Selected cleavage attempts - Pseudoephedrine auxiliary 32 reagent outcome ref, Ph, 2OR on . LIE CHa w no reaction 28 N=Al CHg . Ph JN I i CH30 CH CH3 CH3 R = (CH3)2Si or R= H Na2O2 or KO2 desilylation or no reaction 29 NaOMe/ MeOH desilylation or no reaction 30 Et,OtBF,- two new products, 31 neither is ethyl ester 10% HCl, desilylation, 32 H20, 85 °C, acid with epimerization 26 hr, (1:1 anti:syn) 5% HCl, desilylation, 32 dioxane, reflux, acid with epimerization 3-17 hr (1:1 anti:syn) Attempts to transamidate using Weinreb's aluminum amide complex,?8 to oxidize using sodium peroxide or potassium superoxide,?9 and to transesterify using sodium methoxide in methanol3? or triethoxytetrafluoroborate3! gave either no reaction, desilylation only, or undesired products. Acidic hydrolysis conditions gave some of the desired carboxylic acid, but with complete epimerization. The conditions shown in the last entry of table 4, 5% HCl in refluxing dioxane, were those used by Evans and McGee to remove a prolinol-derived chiral auxiliary after 33 zirconium-mediated, syn-selective aldol reactions. Under these conditions, hydrolysis of a comparable benzaldehyde adduct gave the syn acid with less than three percent epimerization (equation 14).32 MEMO e) OH O OH 5% HCl, dioxane 18% Ph wo Ph 14 At reflux, 4 hr < 3% anti (14) CH, CH; Although these conditions yielded much more epimerization for the pseudoephedrine system, this paper did provide a useful clue for further experiments. Evans suggests that the first step in the acidic hydrolysis mechanism is an N->O acyl transfer, followed by slow, acid-catalyzed cleavage of the resulting B-amino ester. Treatment of the reaction solution with aqueous sodium bicarbonate after acyl transfer gave much faster, base-catalyzed ester cleavage.32 If the same mechanism is operating in the acid-catalyzed hydrolysis of the pseudoephedrine aldol adducts, then a pseudoephedrine ester could be an intermediate. Base-catalyzed hydrolysis of similar esters is known to occur. N-methyl ephedrine esters give anti-selective aldol adducts under TiCl, catalysis, and these aldol adducts can then be cleaved using sodium hydroxide with 4:1 methanol-water as solvent (equation 15).33 fe) OH JA 1. NaOH, 4/1 MeOH-H,0, 1 rh ° = Ph room temp, 15 hr moo 60% (15) I —CHs 2. CHNo an 94% ee CH3 N(CHs)o 34 These conditions were also successful for removal of the pseudoephedrine chiral auxiliary. Diol 31 is derived by desilylation of (25, 3R) anti aldol adduct 6 with triethylamine trihydrofluoride in acetonitrile. When refluxed with 5 equivalents of sodium hydroxide (0.33 M) in a solution of four parts methanol to one part water, 31 gives a quantitative yield of (25S, 3R)-3-hydroxy-2-methyl-3-phenylpropionic acid 32 and 81% recovery of the auxiliary (equation 16). Similar results can be obtained using the silylated aldol adducts themselves, but the yields are slightly lower, perhaps because desilylation is slow under basic conditions. The resulting silyl side product is slightly acidic and thus difficult to separate from the B- hydroxy acid itself. This side product appears to be a polymer: the 'H NMR shows multiple peaks around 0 ppm, and the 13C NMR has broadened, low intensity peaks in the 0 ppm region. Because of the difficulty removing this impurity, it is preferable to first remove the dimethyl silyl group with triethylamine trihydrofluoride and then subject the purified diols to the hydrolysis conditions. Ph, OH Ph, OH L O OH 5 NaOH, pee IL CH3 A, 4/1 MeOH-H20, HOT S~ ~Ph st CHg NH (16) | = reflux, 16 hr CH I CH3 CH, 3 CH; 31 32 100% 81% 98% anti Although the N-methyl ephedrine esters could be removed at room temperature, the pseudoephedrine amides required heating to reflux for several hours. The difference in reactivity is probably due to the different relative concentrations of amide and ester forms. Under basic conditions the N-acylated form is more stable,34 but the O3N acy] transfer is blocked for N-methyl ephedrine. This acyl transfer would be facile for a hypothetical 35 pseudoephedrine ester, however. Under alkaline conditions, the amide form of the pseudoephedrine auxiliary would predominate, but a trace of the ester form would exist. Thus, alkaline cleavage of B-hydroxy amides probably involves a slow, reversible NO ° acyl transfer, followed by a much faster ester hydrolysis step, as shown in figure 10. The proposed pseudoephedrine ester intermediate has not been observed, however. When the hydrolysis reaction is stopped before completion, the only other species observed is " unreacted diol. Phy, Ph, ~90 OH Ph N A - HO CHs Lay bt, bt, CH3 “3 + HeO 31 \ - OH OH su Ph, Ph, _-O : Ph AK fast . z : NH <~—_—_. CH H+, CHs CHy NH l O OH wy § . CHg Figure 10. Proposed mechanism for alkaline hydrolysis of B-hydroxy amides. Precedent for very rapid basic cleavage of B-amino esters can also be found from the Evans group. When treated with aqueous sodium bicarbonate at room temperature, prolinol-derived B-amino esters 33 are cleaved completely in only five minutes; the rapidity of this reaction is attributed to a catalytic, hydrogen-bonding role for the amine nitrogen (figure 11).35 36 O ok _ om OH HO / HCO3 fe) i a ' ae ak + NH rt, 5 min fe) H —-o R NH H 33 Figure 11. Rapid basic hydrolysis of B-amino esters (from ref. 35) The enantiomeric purity of the resulting B-hydroxy acids was determined by esterification with diazomethane and chiral GC analysis of the resulting B-hydroxy methyl esters. The (25, 3R) geometry of 6, the major product of the silicon-mediated aldol reaction between benzaldehyde and (+)-pseudoephedrine derived silyl ketene N,O-acetal 5, was confirmed by X-ray crystallography.3° After desilylation, hydrolysis of the resulting diol 31, and esterification with diazomethane, Methyl (2S, 3R)-3-hydroxy-2-methyl-3- phenylpropionate was obtained in > 93% ee (see table 5). The enantiomeric silyl ketene N,O-acetal 34, derived from (—)-pseudoephedrine, was also reacted with benzaldehyde to give both anti diastereomers 35 and 36 (see p. 39), which were also hydrolyzed in the same manner. The major (2R, 3S) adduct 35, which is spectroscopically identical to 6, gave the opposite enantiomer of the methyl ester, as indicated by a distinct, different peak in the chiral GC trace. On the other hand, the minor product 36, on hydrolysis and esterification gave the same enantiomer of the methyl ester as 6, the (25, 3R) enantiomer, in =90% ee. Even though 36 appears to be two compounds in the NMR spectra, hydrolysis shows it to be a single diastereomer, perhaps existing in rotameric forms. The prolinol auxiliary can also be removed under slightly more basic conditions, but auxiliary recovery is poor. All these results are summarized in table 5. 37 Table 5. Pseudoephedrine and Prolinol Auxiliary Cleavage. Substrate Refix Yield Ratio Yield Yield Ester (Concentration) NaOH Time = Acid Anti:Syn@ Auxiliary Ester? _ee® Phy, _-OH L fe) OH , CH; 2A, Seq 16hr 100% 98:2 81% 85% 93.6% CH; CHg 0.33 M 31 (0.066 M) HG «CH, Phy, O77 oN o 869 5eq l6hr 77%4 96:4 11% NA NA peu pp 0.33 M | i CH3 CH; 6 (0.066 M) H3aQ CH, oS Seq 17hr 100% >98:2 84% 80% 84.3% Ph CH,” oon 0.33 M CH, CHg 35 (0.066 M) HeQ .cHy Phe -O7 SN, / ag 9 ~O Seq 19hr 88%! 93:7 65% 62% 89.5% CH,” OA 0.33 M E CH3 CH3 36 (0.066 M) Le HQ CHs o— Si. ~“ d . not O O Seq 24hr 78% >98:2 N/A N/A AA recovered Ph 0.45 M CHy 2 (0.09 M) “Based on integration of 1H NMR spectrum. When available, GC ratios agree. bYield of methyl ester after treatment with diazomethane. “Determined by capillary GC on Chirasil-Val column at 110 °C. Average of three runs. ¢Uncorrected for the presence of polymeric silyl impurities. 38 MORE SILICON-MEDIATED ALDOL REACTIONS Pseudoephedrine. Auxiliary With an efficient auxiliary-cleavage technique now in hand, it made sense to explore the scope of aldol reactions available using the pseudoephedrine auxiliary. As was seen in the case of cyclohexanone-derived silacyclobutane enol ethers 20 and 21, substrates which react smoothly with benzaldehyde are often unreactive to non-aromatic aldehydes. Earlier work studied the reaction of (+)-pseudoephedrine propionamide-derived silyl ketene N,O- acetal 5 with benzaldehyde only (reaction 4). As reported, the yield for this reaction was 70% for the major product and 7% for the minor product.® In this case, the products crystallized out of solution after stirring at 60 °C for more than two days. The concentration of each reactant had to be very high; the small amount of methylene chloride present at the beginning of the reaction certainly had evaporated by the end. On further study, this proved to be an extremely capricious reaction. Table 6 summarizes several attempts to reproduce the results shown in reaction 4. Both hands of the chiral auxiliary were used so that the hydrolysis products could be compared and so that the ee after hydrolysis could be assessed. Attempts to reproduce the published conditions (entry 1) exactly (entries 2, 3, and 7) led to a wide variation in the times at which crystallization of the reaction solution occurred (36, 18, and 64 hours), and also in the final yield. 39 Table 6. Reactions of pseudoephedrine-derived silyl ketene acetals with benzaldehyde. Phy, o> Sit CHy Phy, -O> si Phy, CH ° ww CHy 5 6 from (+) pseudoephedrine major product minor oduct (2S, 3R) (2R, 3S) CHs HG CH Hs, CH3 Pha 70 sin CHs Pho ~O— ee | Pha 0 SK ae o PhCHO Tf : AAA 34 35 36 from (-) pseudoephedrine major product minor product , (2R, 3S) (28, 3R) silyl ketene acetal PhCHO conditions products entry eq. conc. eq. solvent temp. time major minor 1 5 1.0 16M 1.1 CHCl, 60°C 64hr¢ 70% 7%> 2 5 1.0 19M 1.1 CH2Cly = 60°C 36hr¢ = 54% 3 5 1.0 2.7M 1.1 none 60 °C 18-hr¢ 38% 4 5 1.0 2.5M 1.5 none 60 °C 47 hr 25% 5 5 10 13M 5.0 none 80 °C 4 hr 36% 6 5 1.0 14M 4,2 none 80 °C 8 hr 46% 7 34 1.0 LIM 1.1 CH2Cly 60°C 64hr¢ 34% 8 34 1.0 2.6M 1.1 none 120°C 1 hr 39% 9 34 1.0 10M 1.0 CH2Cl, 130°Ce Shr 48% 10 34 1.0 11M 1.0 CH2Cly =105°C* 16hr 57% 11 34 1.0 11M 1.0 toluene 115°C 13.5hr 40% 12 34 1.0 13M 5.0 none 80 °C 4 hr 53% 71% 13 34 1.0 13M 5.0 none 85 °C 3 hr 48% 14 34 1.0 13M 5.0 none 85 °C 12 hr 52% 12% 15 34 1.0 13M 5.0 none 90 °C 45hr 55% 16 34 1.5 29M 1.0 none 80 °C 12hr¢ = 26% 17 34 2.0 2.2M 1.0 toluene — 100°C 6 hr 44% 34% “Reaction mixture had solidified by this time. Widdowson, K.L., Ph.D. Thesis, California Institute of Technology, 1992, pp. 24 & 70. ©Reaction run in a sealed tube. dan extremely viscous solution which had stopped stirring by this time. 40 At very high concentrations of reagents (no solvent, ~1:1 ratio of ketene acetal to benzaldehyde) this reaction becomes very viscous as it progresses, hindering efficient Stirring. In the presence of nucleation sites the product will crystallize from solution. When this happens, the solution becomes essentially solid, and stirring stops completely. It can be assumed that reaction stops on crystallization of the solution. Since the time at which crystallization occurs seems to be almost random, the extent of reaction also varies widely. Two reactions (entries 9 and 10) were run in pressure tubes with methylene chloride as the solvent. This avoided the high viscosity and tendency to crystallize of the neat reactions, but also allowed higher reaction temperatures. The best yield, 57% of the major product, was obtained in a pressure tube reaction. (In most cases, the minor product was not isolated.) Toluene was used as a solvent for some higher temperature reactions (entries 11 and 17). Several reactions were run without any solvent at all, in hopes that the higher concentration of reagents would accelerate the reaction. The most reproducible results, however, were obtained using an excess of benzaldehyde as solvent (entries 12-15). With a fivefold excess of benzaldehyde, 55% yield of the major product could be isolated after heating only 4.5 hours at 90 °C (entry 15). Although this is lower than the reported yield (70%) for this reaction, it is achieved in a much shorter reaction time. In brief, even though the published results may be difficult to reproduce, these conditions give a slight loss in yield offset by considerable savings in time. The (—)-pseudoephedrine-derived silyl ketene acetal 34 was reacted with other aldehydes, with somewhat surprising results (table 7). As was seen in the prolinol system, aliphatic aldehydes also required higher temperatures and more time to react than benzaldehyde, Most of the reactions were run with excess aldehyde and no other solvent, with the exception of the hydrocinnamaldehyde experiment. Because this aldehyde was 41 both too high boiling to remove under vacuum and difficult to separate from the aldol adducts by column chromatography, an excess of enolate 34 was used, with toluene as solvent. Ketene acetal 34 is easily removed from the aldol adducts by chromatography. For the volatile aldehydes, isobutyraldehyde and pivalaldehyde, the reactions were run in sealed pressure tubes to prevent evaporation. Table 7. Reactions of 34 with aldehydes. eq. products? aldehyde eq. 34 RCHO _ conditions (2R, 3S) (2S, 3R) Oo : 1.0 5.0 no solvent? 35 36 H 80 °C, 4 hr 53% 1% O 2.0 1.0 toluene 37 38 H 100 °C, 6 hr 45% 45% O CHg 1.0 3.5 no solvent 39 40 H sealed tube . 22% 48% CH 120 °C,18.5 hr 3 O 1.0 5.0 no solvent 41 42 H 80 °C, 16.5 hr 9% 63% O ; CH 1.0 5.0 no solvent 43 44 H sealed tube 5% 48% ST ou, 100 °C, 42 hr “Based on isolated yields of silylated aldol adducts after column chromatography on silica gel. Entry 12 from table 6. 42 In all of these experiments, both anti diastereomers were obtained (the stereochemical assignments will be discussed shortly). Unlike the prolinol system, in which both major and minor products resulted from attack of aldehyde on the same face of the enolate double bond, it appears that the pseudoephedrine ketene acetal 34 is easily attacked from both faces of the double bond. In fact, the greater the steric bulk of the aldehydes, the more likely they were to add to the “less favored” face of the ketene acetal. As a result, there is a complete inversion in the sense of diastereoselectivity from benzaldehyde to pivalaldehyde. In the former case, the de is 76% for the (2R, 3S) isomer; in the latter it is 81% favoring the (2S, 3R) isomer. None of the syn isomers were observed. As discussed earlier, the stereochemistry of the aldol adducts was assigned by hydrolysis of the pseudoephedrine chiral auxiliary, esterification with diazomethane, and chiral GC analysis of the methyl esters. The major product of the benzaldehyde reaction, 35, was identical by 'H NMR and FTIR spectra to the (1'S, 2'S, 25, 3R) isomer 6 derived from (+)-pseudoephedrine,*® implying that 35 is the enantiomeric (1'R, 2'R, 2R, 35) isomer, as shown. It appears as a single spot on TLC analysis, and elutes as a single band off a silica gel column. After hydrolysis and esterification, only the (2R, 35) methyl ester is obtained, the enantiomer of that derived from 6. On the other hand, minor product 36 elutes as two bands off a silica gel column and appears as two spots on TLC analysis, but 2-D TLC shows those spots convert into each other. The 'H NMR spectrum of 36 also appears to contain two isomers in an approximately equal ratio. However, upon hydrolysis and esterification with diazomethane, 36 yields only the anti ester (with very minor syn impurities). This ester is identical by chiral GC to the ester derived from cleavage of (1'S, 2'S, 25, 3R) aldol adduct 6 or diol 31, the major aldol adduct from the reaction of the (+)-pseudoephedrine silyl ketene acetal 5 (see table 5). Thus 36 can confidently be assigned the (1'R, 2'R, 25, 3R) 43 geometry as the other possible anti aldol adduct. This compound apparently exists in equilibrium between two conformers in solution. It should be noted that this minor product was Originally identified as a mixture of anti and syn isomers. !0 The stereochemical assignments for the hydrocinnamaldehyde, isobutyraldehyde, cyclohexanecarboxaldehyde, and pivalaldehyde adducts were made based on the assumption that the nature of the pendant alkyl group does not affect the conformation around the nine-membered siloxy ring, and thus similarities between NMR spectra of these adducts and the benzaldehyde adducts could be used to assign stereochemistry. Those products which appeared as a single spot on silica gel and as a single product in the 1H NMR spectrum were assigned the (2R, 35) geometry (37, 39, 41, and 43). Those which appeared as two interconverting spots on silica gel and which exhibited a mixture of conformers in the 1H NMR spectrum were assigned the (25, 3R) geometry (38, 40, and 42). An interesting exception to this rule was the major pivalaldehyde adduct 44. This highly crystalline product (mp: 143-145 °C) elutes as a single spot on TLC analysis. In benzene-d, the 'H NMR spectrum of 44 appears to contain only a single isomer, but in chloroform-d the 'H NMR spectrum of 44 appears to contain two isomers in approximately a 2:1 ratio. The similarity of the chloroform spectrum to that of the minor benzaldehyde adduct implies that it is the (2S, 3R) anti aldol adduct, which adopts two conformers in chloroform solution, but which exists as a single conformer in the less polar benzene solution. These aldol adducts were subjected to the hydrolysis conditions discussed in the previous section. The results are shown in table 8. In general, a greater degree of epimerization was observed, and yields were much poorer, perhaps due to the volatility of the resulting acids and esters. Table 8. Cleavage of (—)-pseudoephedrine aldol adducts.¢ Substrate Reflux Time - Yield Ratio Acid — Anti:Syn? Yield Yield Auxiliary Ester¢ Ester eet 37 38 39 40 41 42 43 Pry 078K Phyo SL Li CH3 CH3 CH; Ho _-CHs [e) fe) “a . CH CHs CH CHs CH3* Ph CH CHs t H CH3 CH3 CHs HsQ CH, CH3 ' 2 H CH3 CH3 CHs3 » 20.5 hr 20.5 hr 9.5 hr 9.5 hr ll hr tl hr 5 days 3 days 100% 82:18 97%é 93:7 78 %é 96:4 98%e 94:6 53%e 90:10 713% 88:12 T6%f 92:8 TANS 91:9 83% 90% 78% 73% 98% 24% 87% 23% not isolated 29% not isolated 50% 71% 100% 70.7% 100% 83.4% 100% “Conditions: 5 equivalents of 0.33 M NaOH in 4:1 MeOH-H20. Refluxed in oil bath for indicated time. Based on integration of 1H NMR spectrum. When available, GC ratios agree. Yield of methyl ester after treatment with diazomethane. Based on silylated aldol adduct. “Determined by capillary GC on Chirasil- Val column. Average of three runs. “Uncorrected for the presence of polymeric silyl impurities.. /Based on diol derived from desilylation with triethylamine trihydrofluoride. 45 Pivalaldehyde adducts 43 and 44 were especially difficult to cleave. To avoid contamination with the polymeric silyl impurity mentioned earlier, they were first treated with triethylamine trihydrofluoride to remove the silyl group, then purified by a short silica plug before hydrolysis. | Under the same conditions which gave complete hydrolysis of benzaldehyde-derived diol 31 in 16 hours, the pivalaldehyde-derived diols required several days to react. The (2R, 35) isomer 43 still showed traces of the unreacted diol after refluxing for five days. In contrast, hydrolysis of the silylated isobutyraldehyde adducts 39 and 40 were complete by TLC in less than 10 hours. The pivalaldehyde adducts also showed the greatest difference in reactivity between the two diastereomers, which must be a steric effect. It is clear from the 'H NMR spectra that the pivalaldehyde-derived acids assume a very different solution conformation than their benzaldehyde analogs. In general, the stereochemistry of aldol adducts is assigned by invoking intramolecular hydrogen bonding between the B-hydroxyl proton and the carbonyl oxygen. This results in a vicinal coupling constant between the o and £ protons of 2-6 Hz for the syn isomer and 7—10 Hz for the anti isomer (figure 12),! Figure 12. Hydrogen-bonding paradigm for assigning aldol adduct stereochemistry. 46 This hydrogen-bonding rule accurately describes the 3-hydroxy-2-methyl-3- phenylpropionic acids derived from cleavage of the benzaldehyde adducts; the syn acid has Jo,3 = 4.5 Hz, and the anti has J23 = 8.9 Hz. On the other hand, the 3-hydroxy-2,4,4- trimethyl pentanoic acids derived from cleavage of the pivalaldehyde adducts have an anti coupling constant of 2.1 Hz, which is smaller than the syn coupling of 3.2 Hz. These experimental values are in good agreement with the literature (See ref. 1). Therefore, these acids must experience steric strain which prevents regular, intramolecular hydrogen bonding. Thus it is not unreasonable to suggest that the diols derived from desilylation of 43 and 44 also experience some steric strain which both prevents intramolecular hydrogen bonding and hinders hydrolysis by sodium hydroxide. The enantiomeric purity of the methyl esters was determined by chiral GC. For the (2R, 35) isobutyraldehyde adduct 39 an ee of 70.7% was found, but the (2S, 3R) isomer 40 gave enantiomerically pure ester to the limits of GC detection. Similar results were obtained for the cyclohexanecarboxaldehyde adducts. Adduct 41 gave (2R, 35) methyl ester with ee of 83.4%; 42 gave enantiomerically pure (25, 3R) methyl ester. It is questionable whether these values are significant, however, because the yields of the esters were very low (<50%). The methyl esters resulting from cleavage of hydrocinnamaldehyde adducts 37 and 38 could not be separated under reasonable GC conditions. 47 Chiral aldehydes - The next question approached in the study of silicon-mediated aldol reactions was whether a chiral aldehyde would produce matching and mismatching effects on reaction with a silyl ketene N,O-acetal bearing a chiral auxiliary. The prolinol system was chosen for study since the reactions of 1 were much faster than its pseudoephedrine analogs 5 and 34. The aldehydes chosen for this purpose were (2R)- and (2S)-3-tert-butyldiphenyl- siloxy-2-methyl propionaldehydes 45 and 46. As shown in Scheme II, these aldehydes are easily synthesized in three steps from commercially available starting materials. Methyl (R)-(—)- or (S)-(+)-3-hydroxy-2-methyl propionate was refluxed in a benzene solution of the Weinreb N-methyl-N-methoxy aluminum complex (3.0 equiv) to give the corresponding N-methyl-N-methoxy amides in 70% and 60% yield, respectively. The B-hydroxy group was then protected with tert-butyldiphenylsilyl chloride (1.25 equiv) in the presence of imidazole (2.5 equiv) in DME (91% and 80% yields after column chromatography). The protected amides were reduced with lithium aluminum hydride in ether at -78 °C to give the desired aldehydes in 64% and 71% yields after silica gel chromatography. Reduction at higher temperatures gave cleavage of the TDS protecting group. Overall yields were 41% for the R isomer 45 and 34% for the S isomer 46. 48 Scheme Il. O OH O OH O OTDS a CH b CH c co ae AA 70% 91% 64% CH, CHO CH ° CHsO CH ° 47 49 O OTDS CH, 45 O OTDS CHg 46 O OH O OH , O OTDS a Cc A CH CH CH,0 a aN — pe 3“, = 60% | = 80% | z, 71% CH3 CH30 CHs CH,0 CH; 48 50 Reagents and conditions (TDS = SiPhgt-Bu): (a) 3.0 equiv CH3(CH30)N-AI(C1)CH3, CgHg, reflux, 2 hr; (b) 1.25 equiv TDSCI, 2.5 equiv imidazole, DMF, 31 °C, 3 hr; (c) 1.0 equiv LiAlHy, Et2O, —78 °C, 1.5 hr. Both (S)- and (R)-prolinol propionamide O-silyl ketene N,O-acetals 1 and 51 were prepared according to the standard procedure.!° Each of these silyl ketene acetals was reacted with both enantiomers of the chiral aldehyde at room temperature (30 °C) for 24 49 hours. In each case, only one aldol adduct was observed. Isolated yields from 24% to 42% were obtained, but with no definitive correlation between yield and reactant geometry. The results are shown in table 9. Table 9. Aldol reactions of prolinol-derived silyl ketene acetals and chiral aldehydes.4 Aldehyde fe) OTDS o . «OTDS 45 46 : R Silyl Ketene Acetal (8) : (8) CHg CH H3C H3C CH ' _aCHs \ (ahs \ 0 oO OTDS oO 0 OTDS O vA 2 4 1(S) ws CH3 CHg CHg CHg 52 28% 53 32% (2S, 3R, 4R) (2S, 3R, 45S) H3C HgC CH3 ° | oCHy ° Hg Y o-—— Si o— Si Om aaah CH 7 es Lf 9 OTDS fo No OTDS E O : : i ? we { | { , i CG CHs CHy CH, CH, CHy 31 () 54 24% 55 42% (2R, 3S, 4R) (2R, 3S, 48) “Conditions: 1.0 equiv each of ketene acetal and aldehyde, 0.5 M in CH2Cly, 30 °C, 24 hours. Purification by flash column chromatography. The 2, 3-anti configuration of each aldol adduct is suggested by a coupling constant of 10 Hz between those two protons in each isomer. For comparison J23 = 9.7 Hz in anti aldol adduct 2, and J2,3 = 3.8 Hz for syn adduct 3. The absolute stereochemical assignments for carbons 2 and 3 are only tentative — they have been drawn in analogy to 2. 50 As expected, enantiomeric reagents gave enantiomeric products (52/55 and 53/54). However, the yields of these enantiomeric reactions were not identical. The (S) enolate + (R) aldehyde combination gave 52 in only 28% yield, but the (R) enolate + (S) aldehyde combination gave 42% yield of enantiomeric 55. This is probably due to the purity of (R) aldehyde 45, since the yield of 54 is also lower than that of 53. The reactions of (S) aldehyde 46 were repeated at 0 °C in hopes of enhancing diastereoselectivity. After 44 hours at 0 °C, the (S) + (S) combination of 1 and 46 afforded 42% of (2S, 3R, 4S) adduct 53. The (R) + (S) combination of 51 and 46 gave 48% of adduct 55 after 55 hours at 0 °C. Thus it appears that aldehyde geometry has little effect on the rate and outcome of the reaction. The rate of reaction is roughly comparable to that of isobutyraldehyde with 1 (58% after 26 hours at room temperature).!0 Examination of models suggests that, for the proposed boat transition state, both enantiomers of the aldehyde can minimize steric interactions by adopting a configuration in which only the a-hydrogen atom is brought close to the reacting face of the silyl ketene acetal, as shown in figure 13. H H SX H Se H 77) CH weeeg tty | “ —< | of cH o—— six H Oo—— Six | OTBS | CHg CH; Figure 13. Possible transition state geometry for the reactions of chiral aldehydes 45 and 46 with silyl ketene acetal 1. 31 Aldol adducts 53 and 55 were completely desilylated using triethylamine trihydrofluoride to triols 56 and 57 in 61% and 64% yield, respectively. When subjected to the alkaline hydrolysis conditions discussed earlier 56 and 57 afforded (S)- and (R)- prolinol in 78% and 58% yield, respectively. The acidic conditions of the work up, however, caused the resulting 5-hydroxy acids to cyclize, and only 6-lactones were recovered. On hydrolysis, triol 56 produced an 83:12:5 mixture of three lactones in 80% yield. Purification by chromatography gave 61% of major product 58. Hydrolysis of triol 57 also afforded a 67:25:7 ratio of lactones in 71% yield, but none of these products were identical to 58. Recrystallization from ether gave major lactone product 59 in 35% yield. These results are summarized in scheme III. Scheme III HC 1 .CHg O o-— sic aN OH CHg O fe) OTDS O OH OH oO EtgNe3HF AK 1. NaOH CH3CN, rt, 26 hr : Ht OH CHy CHg CH3 CHg CH3 53 56 61% 58 61% H3C “1 aCHs O Si a N ws CHy OTDS 4 OH “ EtN+3HF : a7 NaOH | c CH3CN, rt, 26 hr 4 A “OH Hg CH CHg CH, CH3 55° 57 64% 59 35% 52 The stereochemistry of lactone 58 is supported by the coupling constants observed in the 1H NMR spectrum. As shown in figure 14, the axial-axial relationship between the proton on carbon 4 and the axial proton on carbon 5 is indicated by a large coupling constant of 10.8 Hertz. The smaller couplings between protons 2 and 3 and between protons 3 and 4 (3.0 and 1.0 Hz) suggest axial-equatorial relationships. A very small "w" coupling (0.9 Hz) between the equatorial proton on carbon 5 and the proton on carbon 3 is also present. A similar pattern of coupling constants is also present in lactone 59, but the relatively small coupling between protons 3 and 4 (4.3 Hz) is not consistent with the geometry at carbon 4 as assigned. If the hydroxyl group were axial instead of equatorial, as shown, the coupling constants would be consistent, but this would imply (2, 3)-syn geometry for aldol adduct 55 and triol 57. Thus the exact stereochemistry of lactone 59 is still in question. a . U ro “w* Hyt.-°4.3 Hz? CHg 59 Figure 14. 'H NMR coupling constants of lactones 58 and 59. 353 Ephedrine auxiliary In contrast to earlier observations, the dimethyl silyl ketene N,O-acetal derived from (-)-ephedrine propionamide 4 was found to react smoothly with benzaldehyde at room temperature to give moderate yields of both anti aldol adducts 60 and 61. This ketene acetal is more reactive than the pseudoephedrine analogs 5 and 34, which require elevated temperatures to react. (See table 6) The combined yield of products is roughly comparable to the pseudoephedrine reaction (about 70%), but the diastereoselectivity is poorer. A product ratio of 47:24 was obtained in comparison to 70:7 as reported in reference 5. Table 10 summarizes the results of several experiments using the ephedrine auxiliary. Table 10. Reactions of (—)-ephedrine-derived 4 with benzaldehyde. CH Haq sCHs HQ CH; Ph OW si ow CHg o— SL o— Si A PhCHO mae ee CH, CH, 4 60 61 from (—)-ephedrine major product minor product (2R,3S) (2S,3R) silyl ketene acetal PhCHO conditions products entry eq. conc. eq. solvent temp. time major minor 1 4 1.04 15M 1.0 C6De6 31°C Sdays 45% 13% 2 4 1.09 27M 1.0 none 31°C 19 hr? 45% 14% 3 4 1.0¢ 2.7M 1.0 none 31°C 46 hro 37% 17% 4 4 1.0¢ 13M 5.0 PhCHO 31°C 20 hr 43% 19% 5 4 1.0¢ 2.7M 1.0¢ none 31°C 22hre = 336% 15% 6 4 1:0 2.7M 1.0 none 31°C 45 hr’ 47% 24% “First batch of ketene acetal 4. "Reaction had crystallized by this time; stirring stopped. Second batch of ketene acetal 4. Distilled 1 day before use to ~85% purity. “Second batch of ketene acetal 4. Redistilled one hour before use to ~95% purity. © Benzaldehyde distilled immediately before use. 54 The minor product, 61, was assigned (2, 3)-anti stereochemistry based on a vicinal coupling constant of 9.7 Hz in the 1}H NMR spectrum. On desilylation and alkaline hydrolysis of the ephedrine auxiliary, the anti acid is obtained almost exclusively. After treatment with diazomethane, the methyl ester is obtained in a 97:3 anti:syn ratio. An ee of 83.0% for the anti ester was determined by chiral GC analysis. Furthermore, the anti ester co-elutes with the ester derived from cleavage of the major (+)-pseudoephedrine adduct 6, a compound with (2S, 3R)-stereochemistry confirmed by X-ray crystal structure analysis.3° Thus 61 is assigned (25, 3R)-stereochemistry. The major product 60 (mp: 151-153 °C) exhibits a 'H NMR spectrum with curiously broadened peaks, except in the aromatic region, which is well defined. Because of this, it is difficult to make stereochemical assignments at this stage. On desilylation and auxiliary removal, however, the anti acid is again obtained almost exclusively, with only 3% epimerization to the syn acid After treatment with diazomethane, the anti methyl ester is formed in 100% ee, according to chiral GC analysis. This ester co-elutes with that obtained from cleavage of the major (—)-pseudoephedrine adduct 35. Since 35 is the enantiomer of 6, it is known to have (2R, 3S) stereochemistry. Thus the major (—)-ephedrine adduct 60 is also assigned the (2R, 3S) stereochemistry. Satisfactory FTIR, 13C NMR, and HRMS data has been obtained for both aldol adducts, both silylated and desilylated. Since earlier experiments suggested that the ephedrine propionamide ketene acetal 4 did not react with benzaldehyde, it is possible that these positive results were due to some catalytic impurity rather than the intrinsic reactivity of the reagents. In an attempt to rule this out, the first batch of 4 was set aside after the first two reactions (entries 1 and 2, table 10), and a fresh batch prepared. This second batch was distilled to about 85% purity from the crude and used in aldol reactions the following day. (This is approximately as pure as the silyl ketene acetals used in the pseudoephedrine and prolinol experiments. The enolates 55 are very moisture sensitive and difficult to get absolutely pure by distillation.) Freshly distilled benzaldehyde was also used in these reactions (entries 3 and 4, table 10). The results from these two runs were not significantly different those of the first two. Two more experiments were run, using reagents redistilled immediately (less than 1 hour) before use, again yielding similar results (entries 5 and 6, table 10). Four of these experiments were run using a 1:1 ratio of reagents and no other solvent. In these four cases, (entries 2, 3, 5,and 6, table 10) the yields of major and minor aldol adducts 60 and 61 were almost identical, but reaction times varied from 19 to 46 hours. At the indicated reaction time, stirring had stopped because so much of the crystalline product had formed that the reaction mixture was essentially solid. In each of these cases, the reaction mixture became extremely viscous after only a few hours, and stirring was severely impaired. As was seen in the pseudoephedrine case (table 6), the time at which crystallization occurs is highly variable, possibly depending on the availability of nucleation sites in the reaction environment. Furthermore, the longer reaction times indicate when crystallization was first observed, not necessarily when crystallization occurred. It is reasonable to assume that little reaction occurs after crystallization, so the actual reaction times could be many hours shorter. In general, the aldol reactions of (—)-ephedrine-derived 4 are no less reproducible than those of its pseudoephedrine analogs 5 and 34. The question remains why Dr. Paivi Kukkola, who did the original experiments with ephedrine compound 4, failed to observe any aldol reaction. Although she ran the reaction several times, under varied conditions, it appears she followed the reaction by TLC only. According to her notebook, she eluted with either diethyl ether, 4:1 ethyl acetate-pet. ether, or 3:1 ethyl acetate-pet. ether. All of these solvent systems are so polar that the aldol adducts 60 and 61 co-elute or nearly co-elute with benzaldehyde. Furthermore, she Stained her TLC plates with ninhydrin, perhaps an unfortunate choice. While ninhydrin . 36 stains ephedrine propionamide strongly and the silyl ketene acetal 4 moderately, it stains the products only very faintly, if at all. Thus it is quite possible she actually observed the aldol adducts under UV, but since they did not stain, she may-have attributed the spot to unreacted benzaldehyde. The product spots stain well in PMA, and in a less polar solvent (40% ether in pet. ether), the two aldol adducts 60 and 61 are slightly separated from each other and well separated from benzaldehyde. In conclusion: the silicon-mediated aldol reaction of ephedrine-derived silyl ketene N,O-acetal 4 with benzaldehyde is real and reproducible. The reaction occurs at lower temperatures than the pseudoephedrine analogs, but stereoselectivity is not as good. The reaction was not observed in Dr. Kukkola's experiments, probably due to a poor choice of TLC conditions. 57 MECHANISTIC REASSESSMENT It is interesting to note that in the ephedrine case, as well as the pseudoephedrine case, only anti aldol adducts are observed, indicating that aldehyde attack occurs on both faces of the enolate double bond. This is inconsistent with the pseudorotational mechanism originally proposed for the prolinol system, in which attack occurs on only one face of the double bond. To account for these results, and alternative, ene-type reaction mechanism has been proposed.37 In one type ene reaction3® an allylic hydrogen atom is transferred to a carbonyl oxygen in a concerted, pericyclic mechanism involving a six-membered transition state. (figure 15) Entropies of activation for intermolecular ene reactions are typically on the order of —30 eu.39 In the proposed ene-type mechanism for the silicon-mediated aldol reaction, an enolic silicon atom is transferred to a carbonyl oxygen, also in a concerted, pericyclic fashion. No pseudorotational steps are involved. Ene Reaction AS * =~30 eu \I/ \l/ Ene-Type Mechanism for Silicon-directed Aldol Reaction AS # =- 41 eu Figure 15. Comparison of the ene and ene-type reaction mechanisms 58 In order to derive reasonable transition states for this ene-type mechanism, it is first necessary to consider the ground state conformation of the starting silyl ketene acetals. Unlike the silacyclopentane ketene acetal 8, the pseudoephedrine and ephedrine silyl ketene acetals 5, 34, and 4 were liquids rather than solids. Since a crystal structure could not be obtained, a ground state conformation was calculated using molecular modeling. Figure 16 shows the lowest-energy conformer for the (~-)-pseudoephedrine enolate 34.40 Figure 16. Calculated minimum energy conformation for 34 As was seen in the crystal structure of 8 (figure 6), the molecule is somewhat concave. One face of the enolate double bond is somewhat blocked by one of the silyl alkyl groups, and one face of the silicon tetrahedron (defined by the two oxygen atoms and the forward silyl methyl group) is almost directly over the nitrogen methyl group. The back face of the silicon tetrahedron (defined by the two oxygen atoms and the other silyl methyl group), however, is on the "outside" and completely unhindered. 59 ms set Ph om IN, Oo “Oo I = CHg CH, (2S, 3A) Favored for R = Aldehyde approaches back (less hindered) face Ys CO Nets CH3 CHy CH 1:1-mixture for R = Aldehyde approaches front (more hindered) face CHg H ct “a 2CHs On Ph O o “o CH3 4H cH" _ CH, CHg (2R, 3S) Favored for R = QD Figure 17. Possible transition states for ene-type mechanism 60 If the aldehyde were to attack the less hindered, back face of the silicon tetrahedron, a boat-like transition state would lead directly to the (2S, 3R) anti aldol adduct, as shown in figure 17. This seems to be the preferred addition mode for sterically bulky aldehydes such as pivalaldehyde, cyclohexane carboxaldehyde, and isobutyraldehyde. If, for whatever reason, the aldehyde were to approach the more hindered, front face of the silicon tetrahedron, the boat-like transition structure seen at the bottom of figure 17 would lead directly to the (2R, 3S) anti aldol adduct, which is preferred for only benzaldehyde. A 1:1 mixture of the two anti aldol adducts was obtained in the reaction of hydrocinnamaldehyde, indicating that both transition structures are equal in energy for this substrate. Although these transition structures can be used to rationalize the experimental results, they do require the amide oxygen to leave from an equatorial position.4! On the other hand, a concerted mechanism would explain why the hypothetical pentacoordinate silicon intermediate proposed by the pseudorotational mechanism was never observed. !9 The concerted, ene-type mechanism also nicely explains the tremendous rate acceleration observed when the silicon atom is constrained in a small ring. In the original, pseudorotational mechanism, rate determining carbon-carbon bond formation occurs after, and in a separate step from, aldehyde coordination. Aldehyde coordination opposite one of the silyl methylene groups relieves ring strain by decreasing the bond angle between those silyl methylene groups. However, in the original mechanism this relief of ring strain happens before the proposed rate-limiting step (figure 18). Thus, only a modest rate acceleration would be expected with the small rings due to destabilization of the tetrahedral ground State relative to the dimethylsilyl analog. The transition state itself would not be expected to be significantly stabilized by the small ring (although the intermediate formed on initial aldehyde coordination would be). 61 H CHI “cH3 SAT ot 4 SP Son CH Sion | ro) CHS on NNO o— si” W ‘CH3 —> v OCH2 “ : | CH3 _— o—sx GG _—_— products . “— H Ox pH fast O. 3H fast l CH3 slow ; CH3 CH3 fo} 7) O— Si Voch2 x . = _—_—— o— siz \ —. products OH faster | H Just as fast L H just as slow Figure 18. Rate comparison for pseudorotational mechanism. Since relief of ring strain is not involved in transition state, only modest rate acceleration expected. In contrast, a concerted mechanism would be consistent with significant rate acceleration in the presence of a small ring. The dramatic increase in reaction rate from the dimethylsilyl enolate 1 to the silacyclobutane enolate 9 strongly suggests that C-Si-C bond angle rehybridization is occurring in the transition state. Since a separate, rate-limiting aldehyde coordination step had been ruled out by the large positive Hammet p value (3.5) determined earlier,!° a single step mechanism in which aldehyde coordination and C-C bond formation occur simultaneously could be operating (figure 19). 62 - iE: RH Ch Ph o H CHy— six oR 8 Ph Palais oS So 6 ——- + products CH Char 7 3: Wi CH 3 i) R CH, H - 4 i R H © Che € H OO ph io "CH o\Si \ PA 6 3 |——+ products faster YP jeorN-cHs | faster CHa 4 cn is g | 3 Rf CHs = — Figure 19. Rate comparison for concerted mechanism. Since relief of ring strain is involved in the transition state, significant rate acceleration is expected. The pseudorotational mechanism satisfactorily rationalized the high anti selectivity for the silicon-mediated aldol reactions of N,N-dimethyl amides and the very strong facial selectivity of prolinol-derived silyl ketene N,O-acetal 1. However, the facial selectivity of the silicon-mediated aldol reactions of pseudoephedrine-derived silyl ketene N,O-acetals 5 and 34 was found to be dependent on the steric bulk of the aldehyde. This, along with the observation that ephedrine-derived silyl ketene N,O-acetal 4 does react with benzaldehyde under conditions similar to the other enolates, suggests that another, non-pseudorotational mechanism, may be operating. The million fold increase in reactivity seen with the silacyclobutane compounds is also consistent with a mechanism in which relief of ring strain occurs in the rate-determinin g step. Thus, a concerted, pericyclic reaction mechanism is a plausible alternative to the original pseudorotational mechanism. 63 EXPERIMENTAL SECTION General Procedures. All reactions were performed in flame-dried round bottom or modified Schlenk (Kjeldahl shape) flasks fitted with rubber septa under a positive pressure of dry argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Where necessary (so noted), solutions were deoxygenated by alternate evacuation for 10-15 seconds and ~ flushing with argon (more than three iterations). Organic solutions were concentrated by rotary evaporation below 30°C at ca. 25 Torr (water aspirator). Flash column chromatography was performed as described by Still et al.42 employing 230-400 mesh silica gel. Analytical and preparative thin layer chromatography were performed using glass plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure to ultraviolet light (noted as 'UV') and/or by immersion in a staining solution (p-anisaldehyde or PMA as indicated) followed by heating on a hot-plate. Materials. Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran and diethyl ether were distilled from sodium benzophenone ketyl. Methanol was distilled from magnesium turnings. Dichloromethane, N,N-diisopropylamine, triethylamine, toluene, benzene, and acetonitrile were distilled from calcium hydride. All aldehydes were distilled from calcium hydride at reduced pressure and stored under argon and over 4A molecular sieves less than a week before use. All silyl chloride compounds, with the exception of TDSCI, were distilled from calcium hydride (at reduced pressure if necessary), and stored under argon. Cyclohexanone and 3-pentanone were distilled from calcium hydride immediately before use. The molarity of n-butyllithium 64 solutions was determined by titration using diphenylacetic acid as an indicator (average of three determinations). Instrumentation. Infrared (IR) spectra were obtained with a Perkin-Elmer 1600 FT-IR spectrophotometer referenced to a polystyrene standard. Data are presented as follows: frequency of absorption (cm-!), intensity of absorption (s = strong, m = medium, w = weak, br = broad), and assignment (when appropriate). Proton and carbon nuclear magnetic resonance (1H NMR and !3C NMR) spectra were recorded with a Bruker AM-500 (1H, 500 MHz; 13C, 125 MHz), JEOL JX-400 (1H, 400 MHz; 13C, 100 MHz), or General Electric QE-300 (1H, 300 MHz; !3C, 75 MHz) NMR spectrometer. Chemical shifts are expressed in parts per million (5 scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvent (CHCl, 6 7.26; C6Ds5H, 6 7.15). Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, coupling | constant (Hz), and assignment (H#). Elemental analyses were performed in the analytical laboratories of the Arnold and Mabel Beckman Laboratories of Chemical Synthesis. High resolution mass spectra were obtained from the University of California, Riverside Mass Spectrometry Facility and from the Midwest Center for Mass Spectrometry at the University of Nebraska, Lincoln. X-ray crystallographic analyses were obtained from the Arthur Amos Noyes Laboratory of Chemical Physics X-ray Facilities, Division of Chemistry and Chemical Engineering, California Institute of Technology, and from the University of California, Irvine Department of Chemistry X-ray Laboratory. Melting points were recorded with a Biichi SMP-20 melting point apparatus and are uncorrected. 65 OH fe) 1) LDA, THF, - 78 °C Ow CHs [ \ . 2) -—78°C si’ . ci” ~cl Silacyclopentane (1'S)-O-Silyl Ketene N,O-acetal 8 n-Butyllithium (23.2 mL, 2.50 M solution in hexanes, 57.9 mmol, 2.2 equiv) was added dropwise over 10 min to a deoxygenated solution of diisopropylamine (8.48 mL, 60.5 mmol, 2.3 equiv) in tetrahydrofuran (300 mL) at -78 °C. The solution was warmed to 0 °C and held at that temperature for 10 min. After the solution was recooled to -78 °C, a solution of (1'S)-prolinol propionamide (4.1355 g, 26.3 mmol, 1 equiv) in tetrahydrofuran (12 mL) was added by cannula. The transfer was quantitated by rinsing the amide flask with three 3-mL portions of tetrahydrofuran. After stirring the solution at ~78 °C for 1.5 hours, dichlorosilacyclopentane (4.896 g, 31.6 mmol, 1.2 equiv) was added dropwise over 5 minutes. The solution was stirred at ~78 °C for 2 more hours, then allowed to warm to 27 °C. The solvent was removed under vacuum (0.4 Torr), and the residue taken up in toluene (12 mL), from which a white solid precipitated. The Supernatant was decanted by cannula and the precipitate washed with two aliquots of toluene (6 mL each). The combined toluene layers were concentrated (0.4 Torr) to an oily _ yellow solid which was purified by sublimation (0.4 Torr, dry-ice condenser, 100-120 °C oilbath), yielding 8 (3.0818 g, 12.9 mmol, 49%) as colorless, moisture sensitive, needle- like crystals. The Z-configuration was confirmed by X-ray crystal structure analysis (performed by Dr. Joseph Ziller, University of California, Irvine). ~ 1H NMR (300 MHz, C¢Dg), 5: 13C NMR (75 MHz, CeDe), 8: 66 0.6-0.9 (m, 5H, H-3'a, H-4, H-7), 1.2-1.4 (m, 3H, H-2', H-3'b), .1.5-1.7 (m, 4H, H-5, H-6), 1.90 (q, 1H, J = 6.4 Hz, H-2), 2.67-2.80 (m, 1H, H-4'a), 2.81-2.87 (m, 1H, H-4'b), 3.25-3.40 (m, 2H, H-1', H-5'a), 3.54 (dd, J=1.7, 9.3 Hz, H-5'b), 3.78 (q, 1H, J =6.4 Hz, H-2) 9.1 (C-5), 10.2 (C-6), 11.0 (C-3), 25.0 (C-4), 25.3 (C-7), 25.9 (C-3'), 28.3 (C-2'), 50.8 (C-4'), 62.7 (C-1'), 71.1 (C-5'), 77.4 (C-2), 151.7 (C-1) 67 OH Oo 1) LDA, THF, — 78 °C ot 2) \.7% ,-78°C Si. ? ci” ~cl Silacyclobutane (1'S)-O-Silyl Ketene N.O-acetal 9 n-Butyllithium (23.0 mL, 2.50 M solution in hexanes, 57.5 mmol, 2.3 equiv) was added dropwise over 10 min to a deoxygenated solution of diisopropylamine (7.71 mL, 55 mmol, 2.2 equiv) in tetrahydrofuran (300 mL) at -78 °C. The solution was warmed to 0 °C and held at that temperature for 15 min. After the solution was recooled to -78 °C, a solution of (1'S)-prolinol propionamide (3.930 g, 25 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added by cannula over 25 min. The transfer was quantitated by rinsing the amide flask with three 3-mL portions of tetrahydrofuran. After stirring the solution at -78 °C for 2 hours, a solution of dichlorosilacyclobutane (4.6138 g, 32.7 mmol, 1.3 equiv) in tetrahydrofuran (10 mL) was added by cannula over 20 minutes. The solution was stirred at ~78 °C for 50 minutes, then allowed to warm to 27 °C. The solvent was removed under vacuum (0.4 Torr), and the residue taken up in toluene (15 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of toluene (5 mL each). The combined toluene layers were concentrated (0.4 Torr) and distilled (short path, 0.15 Torr, 77-95 °C) yielding 9 (2.544 g, 11.3 mmol, 45%) as a colorless, extremely moisture-sensitive liquid of 93% purity. (The major contaminant is an N-silylated diisopropylamine adduct which could not be separated by distillation) 1H NMR (400 MHz, C¢Do), 5: 13C NMR (100 MHz, CDg), 8: FTIR (neat), cm-!: 68 0.81 (m, 1H, H-3'a), 1.05-1.35 (m, 3H, H-2', H-3'b), 1.45-1.85 (m, 6H, H-4, H-5, H-6), 1.92 (d, 3H, J =6.4 Hz, H-3), 2.69 (m, 1H, H-4'a), 2.82 (m, 1H, H-4'b), 3.36 (m, 2H, H-1', H-S5'a), 3.53 (d, 1H, J=7.3 Hz, H-5'b), 3.80 (q, 1H, J=6.4 Hz, H-2) 10.5 (C-3), 12.4 (C-5), 21.8 (C-4), 21.9 (C-6), 24.3 (C-3'), 27.6 (C-2'), 50.2 (C-4'), 62.2 (C-1'), 70.3 (C-5'), 77.4 (C-2), 150.7 (C-1) 2929 (s), 2772 (m), 1669 (s), 1334 (s), 1128 (s), 1045 (m), 889 (m), 719 (m) 69 6 6 Cy. Cy. () () : 8 Om cient ‘Ll \ = O PhCHO, CgHe Sek + XQ CHa 24 hr, 27 °C ° oP AA , F oH CH 4 crude anti : syn = 50 : 50 8 10 20% 11 30% Silacyclopentane Aldol Adducts: (1'S, 25, 3R)-Anti 10 and (1'S, 2S, 35)-Syn 11 A solution of benzaldehyde (0.767 mL, 7.54 mmol, 1.05 equiv) in benzene (10 mL) was added over 6 minutes to a solution of silacyclopentane (1'S)-O-silyl ketene N,O- acetal 8 (1.72 g, 7.19 mmol, 1 equiv) in benzene (40 mL) at 27 °C. After Stirring at 27 °C for 21 hours, the solution was concentrated under vacuum (0.4 Torr) and purified by flash column chromatography (30% ethyl acetate in hexanes eluent). Anti adduct 10 (0.4865 g, 1.41 mmol, 20%) was isolated as colorless, feathery crystals which decomposed on exposure to air. Syn adduct 11 (0.7492 g, 2.17 mmol, 30%) was isolated as a colorless, crystalline solid, mp 157-161 °C. The (1'S, 25, 35) geometry of 11 was confirmed by X-ray crystal structure analysis. }5 Silacyclopentane (1'S, 25, 3R)-Anti Aldol Adduct 10 ‘Y NMR (300 MHz, CDs), 8: 0.47-0.61, 0.65-0.85, 0.96 (3m, 1H, 2H, 1H respectively, H-5, H-8), 1.01 (d, 3H, J = 6.6 Hz, H-4), 1.19-1.60, 1.82 (2m, 7H, 1H, respectively, 13C NMR (75 MHz, CoDg), 8: FTIR (neat), cm-!: MS (CI/NH3), m/z: HRMS (CI/NH3), m/z: TLC (50% Et2O in Pet. Ether), Rr: 70 H-2', H-3', H-6, H-7), 2.86 (dq, 1H, J = 6.7, 9.7 Hz, H-2), 2.98 (br t, 1H, J = 7.4, H-4'a), 3.41 (d, 1H, J= 10.8 Hz, H-S'a), 3.52 (at, 1H, J = 6.5, 9.4 Hz, H-4'b), 3.96 (t of d, 1H, J = 3.0, 7.5 Hz, H-1'), 4.88 (d, 1H, J =9.7 Hz, H-3), 5.09 (dd, 1H, J = 3.2, 10.9 Hz, H-5'b), 7.03-7.19, 7.25- 7.32 (2m, 3H, 2H respectively, aromatic H) 6.4, 11.8, 13.6, 25.1, 25.2, 25.7, 28.9, 47.9, 49.5, 59.6, 63.4, 82.9, 127.6, 128.4, 128.9, 129.0, 143.6, 173.9 2934 (m), 1636 (s, C=O), 1431 (s), 1250 (w), 1204 (w), 1110 (s), 1075 (s), 1028 (m), 990 (m), 911 (w), 840 (m), 807 (m), 741 (w), 700 (s) 346 (MH*) Calcd for C}9H2g03NSi (MH*): 346.1838 Found: 346.1837 Anti Adduct 10: 0.25 (PMA) Syn Adduct 11: 0.18 (PMA) 71 Silacyclopentane (1'S, 25, 35)-Syn Aldol Adduct 11 1H NMR (300 MHz, C6Do), 5: 13C NMR (75 MHz, CsDo), 5: FTIR (neat), cm-!: MS (CI/NH3), m/z: HRMS (CI/NH3), m/z: 0.36-0.57, 0.71, 0.86 (3m, 2H, 1H, 1H, respectively, H-5, H-8), 1.07 (d, 3H, J=6.8 Hz, H-4), 1.2-1.8 (3m, 8H total, H-2', H-3', H-6, H-7), 2.81 (dq, 1H, J = 3.6, 6.8 Hz, H-2), 3.05 (br t, 1H, J =7.6 Hz, H-4'a), 3.17 (dt, 1H, J =5.7, 10.3 Hz, H-4'b), 3.31 (d, 1H, J = 10.6 Hz, H-S'a), 4.02 (t of d, 1H, J =2.7, 8.2 Hz, H-1'), 4.90 (br d, 1H, J =9.2 Hz, H-5'b), 5.48 (d, 1H, J =3.5 Hz, H-3), 7.07-7.30 (m, 5H, aromatic H) 8.9, 9.0, 9.3, 25.17, 25.21, 25.5, 27.6, 46.4, 48.2, 58.3, 61.5, 73.0, 125.6, 127.1, 128.4, 142.2, 171.6 2936 (s), 2872 (m), 1634 (s, C=O), 1450 (s), 1422 (s), 1379 (m), 1250 (m), 1097 (s), 1076 (s), 1025 (s), 989 (m), 913 (m), 877 (m), 853 (m), 754 (m), 701 (s) 346 (MH+), 239 (MH+- C7H,0) Calcd for CjgH2g03NSi (MH?+): 346.1838 Found: 346.1821 72 Cl O~ gi" \ Oo 7 PhCHO, CgDg Qu CHa “93 °C,<8min, 2' 100% 9 Silacyclobutane Aldol Adducts: (1'S, 2S, 3R)-Anti 12 and (1'S, 25, 35)-Svn 13 An initial 300 MHz 'H NMR spectrum was recorded for a solution of silacyclobutane silyl ketene acetal 9 (31.6 mg, 0.14 mmol, 1 equiv) in deuterated benzene (0.50 mL). Benzaldehyde (15.7 iL, 0.15 mmol, 1.1 equiv) was injected, the sample was immediately replaced in the NMR probe, and a second spectrum taken. Less than 8 minutes after aldehyde injection, only aldol products (12:13 = 1:6) and excess benzaldehyde are visible in the NMR spectrum. Note: 12 and 13 are extremely moisture-sensitive and were not isolated. Silacyclobutane (1'S, 25, 3R)-Anti Aldol Adduct 12 ‘H NMR (300 MHz, C¢Dg), 5: 0.97 (d, 3H, J = 6.6 Hz, H-4), 1.20-1.75 (m, 10 H, H-2', H-3', H-5, H-6, H-7), 2.82 (dq, 1H, J = 6.6, 9.6 Hz, H-2), ~3.00 (br t, 1H, J = 7.8, H-4'a, partially obscured by syn resonance at 3.02) 3.34 (d, 1H, J=10.8 Hz, H-5'a), 3.48 (dt, 1H, 73 J = 6.3, 9.4 Hz, H-4'b), 4.95 (d, 1H, J =8.1 Hz, H-3), 5.18 (dd, 1H, J =3.0, 10.8 Hz, H-5'b) resonance for H-1' probably obscured by syn peak at. 3.94. C NMR (75 MHz, CeD¢), 8: 12.6, 13.0, 18.2, 21.7, 24.7, 28.5, 47.4, 49.0, 59.1, 61.4, 81.0, 127.2, 128.6, 129.0, 142.8, 173.3 Silacyclobutane (1'S, 25, 3s)-Syn Aldol Adduct 13 ‘H NMR (300 MHz, C6Do), 8: 1.04 (d, 3H, J = 6.6 Hz, H-4), 1.20-1.75 (m, 10 H, H-2', H-3', H-5, H-6, H-7), 2.79 (dq, 1H, J = 3.6, 6.9 Hz, H-2), 3.02 (br t, 1H, J =7.8 Hz, H-4'a), 3.09 (dq, 1H, J =5.7, 10.5 Hz, H-4'b), 3.27 (d, 1H, J = 10.5 Hz, H-5'a), 3.94 (dt, 1H, J =3.3, 8.1 Hz, H-1'), 4.98 (dd, 1H, J = 3.3, 10.5 Hz, H-5'b), 5.55 (d, 1H, J = 3.6, H-3) '3C NMR (75 MHz, C¢Dg), 8: 8.9, 12.3, 21.1, 21.5, 25.4, 27.9, 46.2, 48.2, 58.3, 60.5, 72.4, 125.6, 127.1, 128.5, 142.1, 171.8 74 ow, si" . . o—s o—s ‘5 fe) No fe) No — ewe OA + pA ott 40 °C, benzene-dg i Ph i Ph k = (4.340.2)x107 CHs CHs 8 10 11 Kinetic Analysis of Silacyclopentane ketene acetal 8 at 40 °C Silacyclopentane ketene acetal 8 (31.8 mg, 0.13 mmol, 1 equiv) was weighed into an NMR tube capped with a septum, dissolved in benzene-dg (0.420 mL), and cis-stilbene (10.0 LL, 0.056 mmol, 0.44 equiv) added as an internal reference. The exact concentration of 8 was determined from an initial 400 MHz 'H NMR spectrum taken at 27 °C. Benzaldehyde (12.9 uL, 0.127 mmol, 1.0 equiv) was added, and further spectra taken in an NMR probe warmed to 40 °C. The appearance of two product protons in the region 4.6—-5.7 ppm was followed for 10 hours (80% conversion). The rate constant was derived from a plot of ({E],—-[P])! vs. t. k = (4.29+0.18)x10-4 M-ls-! 75 = = cl * ¥ é at . O~ gj: . Sj Si il oS No oo N oO PhCHO vA ott —80 °C, benzene-dg cant OA Ph k = (2.640.1)x104 uO Que 2 Huse 9 12 13 _ Kinetic Analysis of Silacyclobutane ketene acetal 9 at —80 °C Silacyclobutane ketene acetal 9 (30.4 mg, 0.135 mmol, 1.0 equivalents) was weighed into an NMR tube capped with a septum, dissolved in toluene-dg (0.420 mL), and cis-stilbene (10.0 WL, 0.056 mmol, 0.42 equiv) added as an internal reference. The exact concentration of 9 was determined from an initial 400 MHz 'H NMR spectrum taken at 27 °C. The sample was frozen in liquid nitrogen, benzaldehyde (13.7 WL, 0.135 mmol, 1.0 equiv) added, and further Spectra taken in an NMR probe cooled to —80 °C. The appearance of two product protons in the region 4.9-5.6 ppm was followed for 8 hours (65% conversion). The rate constant was derived from a plot of ((E}],-{P])"! vs. t. k = (2.58+0.09)x10-* M-!s-1 76 o 9 EtsN*3HF, benzene A, 27°C, 1.5 hr Authentic (1'S, 2S, 3R)-Anti Diol 14 Triethylamine trihydrofluoride (0.248 mL, 1.52 mmol, 3.0 equiv) was added toa solution of dimethylsilyl (1'S, 25, 3R)-anti aldol adduct 21° (161.9 mg, 0.51 mmol, 1 equiv) in benzene (10 mL) at 27 °C. After stirring 1.5 hr, the solution was concentrated and the residue was purified by flash column chromatography (100% ethyl acetate) to yield anti diol 14 (118.5 mg, 0.45 mmol, 89%) as a colorless gel. 'W NMR (400 MHz, CDCls), 6: Major rotamer: 1.15 (d, 3H, J=7.0 Hz, H-4), 1.61, 1.72-1.85, 1.96 (3m; 1H, 2H, 1H, respectively; H-2', H-3'), 2.91 (quintet, 1H, J =6.6 Hz, H-2), 3.26, 3.34, 3.63 (m; m; br d, J=11.1 Hz; 1H, 2H, 1H, respectively; H-4', H-5'), 4.09 (m, 1H, H-1'), 4.32 (br s, 1H, H-6), | 4.54 (br s, 1H, H-5); 4.77 (d, 1H, J=5.9 Hz, H-3), 7.26-7.35 (m, 5H, aromatic H) 77 FTIR (neat), cm-!: 3374 (s, br, —OH), 2969 (m), 2872 (m), 1612 (s, C=O), 1441 (s), 1076 (w), 1048 (m), 766 (m), 702 (s) TLC (20% acetone in ethyl acetate), Rg: — Anti Diol 14: 0.22 (PMA) (50% ethyl acetate in toluene), Ry: 0.05 (PMA) (100% ethyl acetate), Ry: 0.15 (PMA) CH { CH, O—~ Si. 0 Hg oe) Que 78 EtsNe3HF, benzene 27 °C, 2 hr Authentic (1'S, 2S, 35)-Syn Diol 15 Triethylamine trihydrofluoride (43.5 tL, 0.27 mmol, 3.0 equiv) was added to a solution of dimethylsilyl (1'S, 25, 35)-syn aldol adduct 31° (28.4 mg, 0.09 mmol, 1 equiv) in benzene (10 mL) at 27 °C. After stirring 2 hours, the solution was concentrated and the residue was purified by flash column chromatography (100% ethyl acetate) to yield syn diol 15 (18.4 mg, 0.07 mmol, 79%) as a colorless, crystalline solid. 'H NMR (500 MHz, CDC13), 8: Major rotamer: 1.13 (d, 3H, J = 7.0 Hz, H-4), 1.72 (br s, 1H, H-6), 1.57, 1.80, 1.86, 2.02 (4m, IH each, H-2', H-3'), 2.75 (dq, 1H, J = 4.2, 7.0 Hz, H-2), 3.32 (dt, LH, J= 7.2, 10.2 Hz, H-5'a), 3.47, 3.62 (2m, 1H each, H-4'), 4.15 (dg, 1H, J = 2.6, 6.2 Hz, H-1'), 4.24 (br s, 1H, H-5), 4.60 (br d, LH, J = 6.1 Hz, H-S'b), 5.05 (d, 1H,J = 4.1 Hz, H-3), 7.27, 7.34 (2m, 5H total, aromatic H) 79 C NMR (100 MHz, CDCl), 5: 10.9, 24.0, 27.9, 45.1, 47.8, 60.7, 65.9, 74.3, 126.0, 127.2, 127.9, 141.9, 176.7 FTIR (neat), cm-!: 3372 (m, br, -OH), 2969 (m), 2876 (m), 1608 (s, C=O), 1454 (s), 1438 (m), 1079 (w), 1041 (m), 767 (m), 702 (s) TLC (50% ethyl acetate in hexanes), (10% MeOH in dichloromethane), (10% acetone in ethyl acetate), (20% acetone in ethyl acetate), (25% ethyl acetate in toluene), (50% ethyl acetate in toluene), (100% ethyl acetate), Ry: Syn Diol 15: 0.05 (PMA) 0.43 (PMA) 0.25 (PMA) 0.31 (PMA) 0.03 (PMA) 0.05 (PMA) 0.05 (PMA) 80 o— si OH "4 ° EtsNe3HF, benzene O OH CHs CH, 10 14 76% Desilylation of Silacyclopentane (1'S, 25, 3R)-Anti Aldol Adduct 10 Triethylamine trihydrofluoride (0.236 mL, 1.45 mmol, 3.0 equiv) was added'to a solution of silacyclopentane (1'S, 2S, 3R)-anti aldol adduct 10 (166.9 mg, 0.48 mmol, 1 equiv) in benzene (10 mL) at 27 °C. After stirring 4 hours, the solution was concentrated and the residue was purified by flash column chromatography (100% ethyl acetate) to yield anti diol 14 (96.7 mg, 0.37 mmol, 76%) as a colorless gel. 1H NMR and FTIR spectra of ths compound were identical to those of the authentic anti diol obtained from the dimethylsilyl analog. The diol product also co-eluted with authentic 14 under several TLC conditions. 81 O-—— Si OH o 9 EtgNe3HF, benzene Qo 69H An 27 °C, 1 hr 45 min Ne 11 15 Desilylation of Silacyclopentane (LS, 25, 35)-Syn Aldol Adduct 11 Triethylamine trihydrofluoride (0.105 mL, 0.65 mmol, 3.0 equiv) was added to a solution of silacyclopentane (1'S, 25, 35)-syn aldol adduct 11 (74.5 mg, 0.22 mmol, 1 equiv) in benzene (10 mL) at 27 °C. After stirring 1 hour 45 minutes, the solution was concentrated and the residue was purified by flash column chromatography (100% ethyl acetate) to yield syn diol 15 (86.1 mg, >100%, contaminated with silica gel?) as a colorless solid. 'H NMR and FTIR spectra of ths compound were identical to those of the authentic syn diol obtained from the dimethylsilyl analog. The diol product also co-eluted with authentic 15 under several TLC conditions. 82 | OH sin O P 1. PhCHO, CgHg, 31 °C vA ory 2. EtsNe3HF, 0-31 °C ire} <= Ph On — oe 9 15 80% Desilylation of Silacyclobutane Aldol Adducts Silacyclobutane silyl ketene acetal 9 (0.7519, 3.34 mmol, 1.06 equiv) was added to a solution of benzaldehyde (0.322 mL, 3.17 mmol, 1 equiv) in benzene (30 mL) at 31 °C (warm room). The solution was stirred at 31 °C for 10 minutes, then cooled to 0 °C, and treated with triethylamine trihydrofluoride (1.63 mL, 10.0 mmol, 3.15 equiv). After stirring 1 hr 15 min at 0 °C, the reaction mixture was warmed to 31 °C and held at that temperature for 45 min. The solution was concentrated, and the residue was purified by flash column chromatography (20% acetone in ethyl acetate), affording diol 15 (0.6678 g, 2.54 mmol, 80%) as a colorless crystalline solid. The syn stereochemistry was confirmed by comparison of the NMR, IR,-and TLC data with that from an authentic sample derived from the dimethyl analog. 83 8 r{\ . si_10-% 12 O 1)LDA,THF,-78°C =O aL) ; 4 15 13 2) <> 78°C eo; 14 si o- Ci Ph 5 3 4 20 92% Silylphenyl-Silacyclobutane Enol Ether 20 n-Butyllithium (4.38 mL, 2.51 M solution in hexanes, 11 mmol, 1.1 equiv) was added dropwise over 4 min to a deoxygenated solution of diisopropylamine (1.68 mL, 12 mmol, 1.2 equiv) in tetrahydrofuran (50 mL) at -78 °C. After stirring 10 min at -78 °C, . the solution was warmed to 0 °C and held at that temperature for 10 min. The reaction mixture was recooled to —78 °C and cyclohexanone (1.04 mL, 0.9815 g, 10 mmol, 1 equiv) was added by syringe over 5 min. Stirring was continued at ~78 °C for 1 hour, then 1-phenyl-1-chloro-1-silacyclobutane (2.27 g, 2.00 mL, 12.4 mmol, 1.24 equiv) was added over 3 min. The solution was warmed to 27 °C and concentrated under vacuum (i Torr). The residue was taken up in pentane (10 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of pentane (5 mL each). The combined pentane layers were filtered under argon through a fine frit to remove suspended precipitate, concentrated (1 Torr), and distilled (short path, 11 mTorr, 78-80 °C) providing enol ether 20 (2.2433 g, 9.2 mmol, 92%) as _acolorless liquid. 1H NMR (300 MHz, CeDg), 8: 13C NMR (75 MHz, C¢Do), 8: FTIR (neat), cm-!: MS (CI/NH3), m/z: HRMS (CI/NHs3), m/z: 84 1.35 (m, 2H, H-4), 1.45-1.77 (m, 7H, H-5, H-7, H-9, H-8a), 1.90 (m, 2H, H-3), 2.11 (m, 3H, H-6, H-8b), 5.11 (t of t, 1H, J =3.9, 1.5 Hz, H-2), 7.22 (m, 3H, H-12, H-13, H-14), 7.73 (m, 2H, H-11, H-15) 14.6 (C-8), 18.9 (C-7, C-9), 22.5 (C-4), 23.4 (C-5), 24.1 (C-3), 30.2 (C-6), 104.9 (C-2), 128.3 (C-12, C-14), 130.4 (C-13), 133.9 (C-11, C-15), 136.1 (C-10), 150.5 (C-1) 2929 (s), 1669 (m), 1428 (m), 1365 (m), 1265 (m), 1181 (s), 1168 (s), 1123 (s), 987 (m), 910 (s), 853 (m), 739 (s), 699 (s) 245 (MH*) Calcd for Cjs5H2,;OSi (MH*): 245.1362 Found: 245.1354 85 8 74 39 Oo a iL 1) LDA, THF, - 78 °C 2) CHs 10 1 2) <> 78°C 6 2 Sf °7 Cl~ S CH 5 3 4 21 73% Silylmethyl-Silacyclobutane Enol Ether 21 n-Butyllithium (4.38 mL, 2.51 M solution in hexanes, 11 mmol, 1.1 equiv) was added dropwise over 5 min to a deoxygenated solution of diisopropylamine (1.68 mL, 12 mmol, 1.2 equiv) in tetrahydrofuran (50 mL) at -78 °C. After stirring 10 min at ~78 °C, the solution was warmed to 0 °C and held at that temperature for 10 min. The reaction mixture was recooled to —78 °C, and cyclohexanone (1.04 mL, 0.9815 g, 10 mmol, 1 equiv) was added by syringe over 4 min. Stirring was continued at -78 °C for 1 hour, then 1-methyl-1-chloro-1-silacyclobutane (1.52 g, 1.6 mL, 12.6 mmol, 1.26 equiv) was added over 5 min. The solution was warmed to 27 °C and concentrated under vacuum (35 Torr). The residue was taken up in pentane (10 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of pentane (5 mL each). The combined pentane layers were filtered under argon through a fine frit to remove suspended precipitate, concentrated (35 Torr), and distilled (short path, 38 Torr, 74-79 °C) yielding enol ether 21 (1.3253 g, 7.3 mmol, 73%) as a colorless liquid. 1H NMR (300 MHz, C¢Dg), 5: 13C NMR (75 MHz, CeDo), 8: FTIR (neat), cm-!: MS (CI/NH3), m/z: HRMS (CI/NHs3), m/z: 86 0.28 (s, 3H, H-10), 1.19 (m, 2H, H-7a, H-9a), 1.39 (m, 2H, H-7b, H-9b), 1.51 (m, 6H, H-4, H-5, H-8), 1.96 (m, 2H, H-3), 2.06 (m, 2H, H-6), 5.06 (t of t, 1H, J=3.9, 1.4 Hz, H-2) ~1.3 (C-10), 14.1 (C-8), 19.4 (C-7, C-9), 22.7 (C-4), 23.4 (C-5), 24.1 (C-3), 30.2 (C-6), 104.4 (C-2), 150.5 (C-1) 2932 (s), 2841 (m), 1671 (m), 1366 (m), 1266 (w), 1252 (m), 1182 (s), 1121 (m), 987 (m), 916 (s), 865 (m), 780 (m) 183 (MH*) Calcd for C}gHigOSi (MH*): 183.1205 Found: 183.1197 87 7 8 Haha OH 0 9 11 Oo 1) LDA, THF, — 78 °C om 1S 1 14 6 2 2) Si, a: 78°C eS 13 CI” ~Ph 5 3 4 22 69% Phenyldimethyl Silyl Enol Ether 22 ~ Cyclohexanone (0.644 mL, 6.2 mmol, 1 equiv) was added dropwise over 6 min to a deoxygenated solution of lithium diisopropyl amide (0.7322 g, 6.8 mmol, 1.1 equiv) in tetrahydrofuran (40 mL) at —78 °C. The solution was warmed to 0 °C and held at that temperature for 10 min. The reaction mixture was recooled to —-78 °C, and phenyl- dimethylchlorosilane (1.233 mL, 7.5 mmol, 1.2 equiv) was added by syringe over 4 min. The solution was allowed to gradually warm to 27 °C overnight. Solvent was removed under reduced pressure (100 Torr), and the residue was taken up in pentane (10 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of pentane (3 mL each). The combined pentane layers were concentrated (100 Torr) and distilled (Kugelrhor, 30-35 Torr, 120-150 °C) furnishing enol ether 22 (0.9916 g, 4.27 mmol, 69%) as a colorless liquid. 'H NMR (300 MHz, Ce6Do), 8: 0.41 (s, 6H, H-7, H-8), 1.35 (m, 2H, H-4), 1.46 (m, 2H, H-5), 1.89 (m, 2H, H-3), 2.06 (m, 2H, H-6), 4.97 (t of t, 1H, J=3.9, 1.4 Hz, H-2), 7.21 13C NMR (75 MHz, CD), 5: FTIR (neat), cm-!: 88 (m, 3H, H-11, H-12, H-13), 7.63 (m, 2H, H-10, H-14) -0.8 (C-7, C-8), 22.6 (C-4), 23.4 (C-5), 24.1 (C-3), 30.3 (C-6), 104.2 C-2), 128.1 (C-11, C-13), 129.6 (C-12), 129.6 (C-12), 133.7 (C-10, C-14), 138.5 (C-9), 150.8 (C-1) 2931 (m), 1717 (w), 1591 (w), 1428 (m), 1366 (w), 1339 (w), 1253 (s), 1186 (s), 1119 (s), 1049 (m), 986 (w), 893 (s), 832 (s), 787 (s), 7279 (m), 699 (s), 650 (w) 89 7 15 6{ \8 ud 16 * si Si, /™ ie) 1) LDA, THF, - 78 °C oO” ~Ph oO Ph To oo HsC 2 NN 4 + Hon 1012 cH, | 2 <> ° 1 3 9 11 13 ) gf + 78°C Cl” ~Ph as 67:33 24 81% Silyiphenyl-Silacyclobutane Enol Ethers 24 n-Butyllithium (4.38 mL, 2.51 M solution in hexanes, 11 mmol, 1.1 equiv) was added dropwise over 5 min to a deoxygenated solution of diisopropylamine (1.68 mL, 12 mmol, 1.2 equiv) in tetrahydrofuran (100 mL) at —78 °C. The solution was warmed to 0 °C and held at that temperature for 10 min. The reaction mixture was recooled to -78 °C, and 3-pentanone (1.01 mL, 0.861 g, 10 mmol, 1 equiv) was added by syringe over 3 min. Stirring was continued at —78 °C for 1 hour, then 1-phenyl-1-chloro-1- silacyclobutane (2.0 mL, 2.25 g, 12 mmol, 1.2 equiv) was added over 3 min. The mixture was stirred at —-78 °C for 1.5 hours more, then warmed to 27 °C. Solvent was removed under vacuum (1 Torr), and the residue was taken up in pentane (10 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of pentane (S mL each). The combined pentane layers were filtered under argon through a fine frit to remove suspended precipitate, concentrated (1 Torr), and distilled (short path, 16-17 mTorr, 110-117 °C) affording enol ether mixture 24 (1.8902 g, 8.13 mmol, 81%) as a colorless liquid along with N-silylated diisopropylamine as an impurity (8%). The isomer ratio was determined by ‘H NMR 90 analysis to be 67% E, 33% Z. (Note: This enol ether is prone to isomerize on Standing or distillation to a mixture which is ~20% E, ~80% Z.) 1 NMR (300 MHz, CeDe), 5: + Ejisomer: 1.08 (t, 3H, J = 7.5 Hz, H-1), 1.42 (d, 3H, J=6.9 Hz, H-5), 1.49-1.70 (m, 5H, H-6, H-8, H-7a), 2.0-2.2 (m, 3H, H-2, H-7b), 4.84 (q, 1H, J=7.0 Hz, H-4), 7.22 (m, 3H, aromatic H), 7.73 (m, 2H, aromatic H) Zisomer: 0.99 (t, 3H, J=7.4 Hz, H-9), 1.49-1.70 (m, 5H, H-14, H-16, H-15a), 1.64 (d of t, 3H, J=6.7, 1.4 Hz, H-13), 2.0-2.2 (m, 3H, H-10, H-15b), 4.57 (q of t, 1H, J = 6.7, 1.1 Hz, H-12), 7.22 (m, 3H, aromatic H), 7.73 (m, 2H, aromatic H) '3C NMR (75 MHz, CsDo), 8: Eisomer: 11.8 (C-1), 11.8 (C-5), 14.5 (C-7), 19.0 (C-6, C-8), 24.4 (C-2), 101.46 (C-4), 128.29, 130.4, 133.8, 136.1, 152.6 (C-3) Zisomer: 11.1 (C-9), 11.9 (C-13), 14.2 (C-15), 19.6 (C-14, C-16), 30.0 (C-10), 101.49 (C-12), 128.32, 130.5 , 133.9, 135.9, 153.2 (C-11) FTIR (neat), cm-!: 2970 (s), 2932 (m), 1670 (m), 1429 (m), 1266 (w), 1197 (s), 1115 (s), 1083 (m), 1064 (m), 907 (m), 867 (m), 854 (m), 699 (m) . 91 16 6{ \a s( 17 sk 9 Pr 18 O. 1) LDA, THF, - 78 °C O” ~CHg QO CHs 2) ~78°C 1 3 10 12 14 Si’ CI” ~CH, os 70:30 25 52% Silylmethyl-Silacyclobutane Enol Ethers 25 n-Butyllithium (6.57 mL, 2.51 M solution in hexanes, 16.5 mmol, 1.1 equiv) was added dropwise to a deoxygenated solution of diisopropylamine (2.52 mL, 18 mmol, 1.2 equiv) in tetrahydrofuran (100 mL) at ~78 °C. The solution was warmed to 0 °C and held at that temperature for 10 min. The reaction mixture was recooled to —78 °C, and 3-pentanone (1.51 mL, 15 mmol, 1.0 equiv) was added by syringe over 5 min. Stirring was continued at —78 °C for 1.5 hours, then 1-methyl-1-chloro-1-silacyclobutane (2.6 g, 21.3 mmol, 1.4 equiv) was added over 10 minutes. The solution was allowed to warm to 27 °C, concentrated under vacuum (90 Torr), and the residue taken up in hexanes (25 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of hexanes (6 mL each). The combined hexane layers were filtered under argon through a fine frit to remove suspended precipitate, concentrated (40 Torr), and distilled (short path, 35 Torr, 53-55 °C) yielding enol ether mixture 25 (1.3201 g, 1.15 mmol, 52%) as a colorless liquid. The isomer ratio was determine by 'H NMR analysis to be 70% E, 30% Z. 92 1 NMR (300 MHz, Cs5De), 5: Eisomer: 0.28 (s, 3H, H-9), 1.05 (t, 3H, J=7.5 Hz, H-1), 1.1-1.3 (m, 2H, H-6a, H-7a), 1.46 (d, 3H, J=6.9 Hz, H-5), 1.3-.55 (m, 3H, H-6b, H-8b, H-7a), 1.95-2.15 (m, 3H, H-2, H-7b), 4.78 (q, 1H, J = 6.9 Hz, H-4) Zisomer: 0.26 (s, 3H, H-18), 1.00 (t, 3H, J = 7.5 Hz, H-10), 1.1-1.3 (m, 2H, H-15a, H-17a), 1.3-1.55 (m, 3H, H-15b, H-17b, H-16a), 1.60 (d of t, 3H, J = 6.6, 1.4 Hz, H-14), 1.95-2.15 (m, 3H, H-11, H-16b), 4.55 (q of t, 1H, J=6.6, 1.1 Hz, H-13) '3C NMR (75 MHz, CeDo), 8: Eisomer: —1.4 (C-9), 11.75 (C-1), 11.80 (C-5), 14.0 (C-7), 19.6 (C-6, C-8), 24.3 (C-2), 101.2 (C-4), 153.3 (C-3) Zisomer: —1.6 (C-18), 11.0 (C-10), 11.9 (C-14), 13.8 (C-16), 20.2 (C-15, C-17), 30.0 (C-11), 100.9 (C-13), 152.7 (C-12) FTIR (neat), cm:!: 2968 (s), 2935 (s), 2877 (m), 1670 (m), 1253 (m), 1200 (s), 1123 (s), 1107 (m), 1083 (m), 1064 (m), 914 (s), 873 (m), 789 (s), 663 (m) 93 6 7 1314 HQ CH; Hs, Cis Si Py “~~ Ph 9) 1) LDA, THF, — 78 °C fe) Ph fe) re eer = Hy. 2A 4 + HO8 JAM chy 2 <> ° 1 ~~ 3 8 10 12 ) gf +— 78°C Ci” ~Ph os 82:18 26 83% ~ Phenyldimethyl Sil 1Enol Ethers 26 n-Butyllithium (6.57 mL, 2.51 M solution in hexanes, 16.5 mmol, 1.1 equiv) was added dropwise to a deoxygenated solution of diisopropylamine (2.52 mL, 18 mmol, 1.2 equiv) in tetrahydrofuran (100 mL) at -78 °C. The solution was warmed to 0 °C and held at that temperature for 10 min. The reaction mixture was recooled to -78 °C, and 3- pentanone (1.51 mL, 15 mmol, 1.0 equiv) was added by syringe over 5 min. Stirring was continued at —-78 °C for 25 minutes, then dimethylphenylchlorosilane (3.23 mL, 3.33 g, 19.5 mmol, 1.3 equiv) was added over 3 minutes. The solution was allowed to warm to 27 °C and concentrated under vacuum (100 Torr). The residue was taken up in pentane (20 mL), from which a white solid precipitated. The supernatant was decanted by cannula and the precipitate washed with two aliquots of pentane (6 mL each). The combined pentane layers were filtered under argon through a fine frit to remove suspended precipitate, concentrated (50 Torr), and the residue distilled (short path, 35 Torr, 47- 81 °C) to give enol ether mixture 26 (2.7593 g, 12.5 mmol, 83%) as a colorless liquid. The isomer ratio was determined by 'H NMR analysis to be 82% E, 18% Z. A second distillation (short path, 35 Torr, 75-86 °C) afforded 26 with an isomer ratio of 20% E, 80% Z. 94 'H NMR (300 MHz, CeDg), 8: Eisomer: 0.40 (s, 6H, H-6, H-7), 1.07 (t, 3H, J=7.5 Hz, H-1), 1.40 (d, 3H, J = 6.9 Hz, H-5), 2.08 (q, 2H, J=7.5 Hz, H-2), 4.68 (q, 1H, J=6.9 Hz, H-4), 7.20 (m, 3H, aromatic H), 7.63 (m, 2H, aromatic H) Zisomer: 0.38 (s, 6H, H-13, H-14), 0.94 (t, 3H, J=7.4 Hz, H-8), 1.61 (d of t, 3H, J = 6.6, 1.4 Hz, H-12), 1.95 (q of t, 2H, J=7.4, 1.2 Hz, H-9), 4.52 (q of t, 1H, J= 6.6, 1.0 Hz, H-11), 7.20 (m, 3H, aromatic H), 7.63 (m, 2H, aromatic H) C NMR (75 MHz, CsD¢), 8: E isomer: —0.9 (C-6, C-7), 11.8 (C-1), 11.9 (C-5), 24.5 (C-2), 100.5 (C-4), 128.1, 129.8, 133.7, 138.7, 153.6 (C-3) Zisomer: —-0.6 (C-13, C-14), Hd (C-8), 29.8 (C-9), 101.1 (C-11), 128.2, 129.9, 133.6, 138.5, C-10 not visible, C-12 may be obscured by peak at 11.9 FTIR (neat), cm:!: 2966 (m), 1677 (m), 1428 (m), 1253 (s), 1194 (s), 1118 (s), 1084 (s), 1064 (s), 878 (s), 832 (s), 811 (s), 786 (s), 739 (m), 699 (s) 95 General Procedure for Sealed-Tube Aldol Reactions: Silyl Enol Ethers 20 to 26 Tables 1 and 2 Silyl enol ether (20 to 26, 0.25 mmol, 1 equiv), aldehyde (benzaldehyde or isobutyraldehyde, 0.25 mmol, 1 equiv), and cis-dichloroethylene (3.8 UL, 4.9 mg, 0.05 mmol, 0.2 equiv) were injected into a septum-capped, sealable NMR tube under argon. Enough benzene-d¢ (400-420 tL) was added to bring the total volume to 0.500 mL. ~ Under positive argon pressure, the septum was replaced with a vacuum adapter, and the solution degassed by three freeze-pump-thaw cycles in liquid nitrogen and under high vacuum (<50 mTorr). The tube was then sealed permanently under vacuum, so excess pressure would not develop on heating. An initial 'H NMR spectrum was recorded, then the sealed tube was completely submerged in an oil bath (100 °C for silacyclobutane enol ethers 20, 21, 24, and 25; 150 °C for dimethyl silyl enol ethers 22, 23, and 26) and held at that temperature for the times indicated in tables 1 and 2. Relevant product 'H NMR signals are listed in the tables. 96 Si, EtsN 1 cy ci” ~cl ; 20H 60 °C, 4 days 27 25% Chlorosilyl Silacyleobutane Enol Ether 27 Dichlorosilacyclobutane (3.25 mL, 3.61 g, 25.6 mmol, 1.3 equiv) was added dropwise over 2 minutes to triethylamine (20 mL, 143 mmol, 7.2 equiv) under argon, causing white fumes to develop. After stirring at 27 °C for fifteen minutes until fuming stopped, cyclopentanone (1.77 mL, 1.68 g, 20 mmol, 1 equiv) was added rapidly. The reaction mixture was warmed to 60 °C, and stirred for four days at this temperature. Over this time copious white precipitate formed. After four days, the solution was concentrated under vacuum (1 Torr), and the white solid residue washed with four aliquots (10 mL each) of dry ether. Each aliquot was transferred by cannula to a fine porosity filter frit. The combined ether fractions were filtered under argon, concentrated under vacuum (1 Torr) , and distilled under reduced pressure (short path, 1.8 Torr, 62-63 °C) to yield enol ether 27 (0.9732 g, 5.1 mmol, 25%) as a yellow liquid. 1H NMR (300 MHz, C¢Dg), 5: 1.47-1.71 (m, 8H, H-4, H-6, H-7), 2.11-2.18 (m, 2H, H-3), 2.25-2.32 (m, 2H, H-5), 4.88 (quintet, J=2.1, 1H, H-2) C NMR (75 MHz, CsDo), 8: HRMS (ED, m/z: 97 12.66 (C-7), 21.44 (C-4), 24.95 (C-6), 28.82 (C-3), 33.19 (C-5), 105.23 (C-2), 152.73 (C-1) Calcd for CgH13035CISi: 188.0425 Found: 188.0420 Calcd for CgH,3035CISi: 190.0394 Found: 190.0395 98 * 1 or Soy ENS cHof | H 27 °C, 3 days 5 28 26% 8 CL 74 3 Si <1 2 3 4 Chlorosilyl Silacylcobutane Enol Ether 28 Triethylamine (3.48 mL, 2.53 g, 25 mmol, 1.01 equiv) was added to a solution of dichlorosilacyclobutane (3.0 mL, 3.4922 g, 24.7 mmol, 1.0 equiv) in dry dichloromethane (20 mL) under argon at 27 °C. The solution fumed on amine contact. After stirring five minutes, cyclohexanone (2.59 mL, 2.45 g, 25 mmol, 1.01 equiv) was rapidly added. The reaction mixture was stirred at 27 °C under argon for three days, during which time a white precipitate formed. After 3 days, the solution was concentrated under vacuum (1 Torr) and the yellow residue dissolved in dry ether (2 mL). The liquid portion was removed by cannula to a fine porosity filter frit, and filtered under argon pressure. The residual white solid was washed with three aliquots of ether (5 mL each)which were also passed through the same filter frit. The combined etherial fractions were concentrated under vacuum (1 Torr) and then distilled at reduced pressure (Kugelrhor, 0.3 Torr, 75-80 °C) to yield enol ether 28 (1.299 g, 6.4 mmol, 26%) as a pale brown liquid. 1H NMR (300 MHz, C6Do), 8: 13C NMR (75 MHz, C¢D¢), 8: FTIR (neat), cm-!: HRMS (ED), m/z: 99 1.50-1.57 (m, 2H, H-8), 1.65-1.97 (m, 8H, H-4, H-5, H-7), 2.00-2.15 (m, 4H, H-3 and H-6), 5.07 (t of t, J= 1.4, 3.9 Hz, H-2) 12.36 (C-8), 21.95 (C-7), 22.85, 23.58 (C-4 and C-5), 25.04 (C-3), 29.23 (C-6), 106.13 (C-2), 148.63 (C-1) 2934 (s), 2860 (m), 2842 (m), 1673 (s), 1442 (m), 1336 (m), 1265 (m), 1165 (s), 1138 (m), 1123 (m), 1047 (m), 991 (s), 920 (s), 853 (s), 722 (s), 689 (s) Calcd for CoH;3035ClSi: 202.0581 Found: 202.0575 Calcd for CoH)3035C1Si: 204.0551 Found: 204.0551 100 Mt Si. | Si va <_—— ; (\ EtsN, CDCls , 4 8 ’ a oy 27 °C, 3 days H ~ 70% 29 2:1 30 Enolization with Triethylamine: NMR Experiment Cyclohexanone (65.3 WL, 61.8 mg, 0.63 mmol, 1 equiv) was added to a solution of dichlorosilacyclobutane (75 uL 88.9 mg, 0.63 mmol, 1 equiv) in deuteriochloroform (0.5 mL) in a septum-capped NMR tube under argon. Monitoring for one hour by 1H NMR showed no reaction. Triethylamine (87.8 WL, 63.7 mg, 0.63 mmol, 1.0 equiv) was then added, bringing the final concentration of each reactant to 0.9 M. The tube was allowed to stand at 27 °C and the reaction periodically monitored by 1H NMR. After 3 days, a crystalline precipitate had formed and two sets of vinylic proton signals had appeared (tt at 4.82 and 4.78 J = 1.2, 3.8 Hz for both) which were attributed to enol ethers 29 and 30 respectively. Integration of these signals indicated at 2:1 ratio of products with about 70% conversion of cyclohexanone. !3C NMR at this time also indicated formation of two enol products with peaks at 148.4, 148.1, 105.7 and 104.5. 101 oO ? 7 Si, sin, + (\ n R3N, CH2Clp rn ¢ ° 7k CI 27 °C, 12 hr H 29 30 R3N = diisopropylethylamine 5:1 N-methylpiperidine 10:1 pyridine 4:1 General Procedure: Trialkyl Amine Bases To a solution of dichlorosilacyclobutane (200 uL, 244 mg, 1.73 mmol, 1 equiv) in dichloromethane (1.38 mL) under argon was added 1 equiv of either diisopropylethylamine (301 wL, 233 mg, 1.73 mmol), N-methylpiperidine (210 wh, 171 mg, 1.73 mmol) or pyridine (140 uL, 137 mg, 1.74 mmol), causing brief fuming. Cyclohexanone (179 pL, 169 mg, 1.73 mmol, 1.0 equiv) was then added. After stirring 12 hours at 27 °C, an aliquot was removed and the product ratios determined by 'H NMR, as indicated above. Only the pyridine solution formed a precipitate during this time. The other two solutions turned yellow but remained clear. 102 Oo se - Sin . (\ n equiv. pyridine, CH»Ch O% ¢! A a 9 or Cl 27 °C, 7 hr H 29 30 n=1 4:] n=0 no reaction n=5 6:1 n=10 100:0 (no other solvent) General Procedure: Stoichiometry of Pyridine To a solution of dichlorosilacyclobutane (200 uL, 244 mg, 1.73 mmol, 1.1 equiv) in dichloromethane (either 1.27, 0.653, or 0 mL) under argon was added either 0, 5, or 10 equivalents of pyridine (0, 0.653, or 1.27 mL), causing fuming on amine-silyl chloride contact. Cyclohexanone (163 WL, 154 mg, 1.57 mmol, 1 equiv) was added and the reactions stirred at 27 °C for 7 hours. An aliquot was then removed and the product ratios were determined by 'H NMR, as shown above. No reaction was observed in the absence of amine, and only the monoadduct 30 was observed in the reaction with neat pyridine. 103 Oo ~Ccl O OH OO YH H 1. PhCHO, 1.5 hr, 27 °C 2 82 2. EtsNe3HF 6 6 Pho 4 611 12 Ph 4 3 10 9 27 In CH,Cl, 25%, 5.5:1 syn:anti 32% In C;H;N 25%, 3.0:1 syn:anti 2% Aldol Reactions of Silyl Enol Ether 27 Benzaldehyde (52.6 WL, 54.9 mg, 0.52 mmol, 1.0 equiv) was added to a solution of enol ether 27 (90UL, 98.2 mg, 0.52 mmol, 1 equiv) in either dichloromethane or pyridine (0.5 mL). The solutions were stirred at 27 °C for 1.5 hours, then triethylamine trihydrofluoride (169 mL, 166.9 mg, 1.04 mmol, 2.0 equiv) was added by syringe. The reaction mixtures were partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and concentrated. The products were separated by column chromatography (20% ether in petroleum ether). The enone was isolated as a yellow crystalline solid (CH2Cl: 28.8 mg, 0.17 mmol, 32%. CsHs5N: 1.5 mg, 0.009 mmol, 1.7%). The aldol adducts were obtained together as a yellow oil and the isomer ratio determined by 'H NMR of the oil. (CH2Cly: 24.3 mg, 0.13 mmol, 25%, 5.5:1 syn: anti. CsH N: 24.3 mg, 0.13 mmol, 25% 3:1 syn:anti). Enone 1H NMR (300 MHz, CDCI), 6: 3C NMR (75 MHz, CDCl,), 8: FTIR (neat), em-!: Syn Aldol Adduct 'H NMR (300 MHz, CDCI3), 5: 104 2.03 (quintet, J=7.5 Hz, 2H, H-10), 2.41 (t, J=7.9 Hz, 2H, H-11), 2.98 (t of d, J =2.7, 7.2 Hz, 2H, H-9), 7.32-7.45 (m, 4H, aromatic H), 7.51-7.62 (m, 2H, H-12, aromatic H) 20.15 (C-10), 29.31 (C-9), 37.76 (C-11), 128.64, 129.26, 130.45, 132.23 (aromatics), 135.48 (C-12), 136.01 (C-8), 208.06 (C-7) 2969 (s), 2954 (s), 1712 (s, C=O), 1622 (s, C=C), 1572 (m), 1489 (m), 1448 (s), 1402 (m), 1321 (m), 1306 (m), 1290 (m), 1276 (m), 1235 (s), 1175 (s), 1128 (m), 1078 (m), 1028 (m), 783 (s), 750 (s), 696 (s) 1.6-2.5 (m, 7H, H-2, H-3, H-4, H-5), 2.55 (br s, 1H, OH), 5.30 (d, J=2.8 Hz, 1H, H-6), 7.22—7.40 (m, 5H, aromatics) 13C¢ NMR (75 MHz, CDC}), 8: FTIR (neat), cm-!: Anti Aldol Adduct ‘WH NMR (300 MHz, CDCI), 8: C NMR (75 MHz, CDCI), 8: TLC (40% Et2O in pet. ether), Ry: 105 20.45 (C-4), 22.74 (C-3), 39.18 (C-5), 56.10 (C-2), 71.50 (C-6), 125.53, 127.30, 128.33, 142.68 (aromatics), 220.49 (C-1) (5:1 syn:anti mixture): 3452 (br, -OH), 2965 (m), 2880 (m), 1736 (s, C=O), 1494 (m), 1451 (m), 1403 (m), 1333 (m), 1273 (m), 1199 (m), 1155 (s), 1104 (m), 1025 (s), 969 (m), 840 (m), 729 (s), 701 (s) 1.6-2.5 (m, 7H, H-2, H-3, H-4, H-5), 4.57 (br s, 1H, OH), 4.70 (d, J = 9.2 Hz, 1H, H-6), 7.22-7.40 (m, 5H, aromatics) 20.39 (C-4), 26.98 (C-3), 38.72 (C-5), 55.31 (C-2), 75.21 (C-6), 126.54, 127.97, 128.41, 141.38 (aromatics), 201.00? (C-1) Enone 0.54 (strong UV, anisaldehyde) Synadduct 0.23 (anisaldehyde) Anti adduct 0.19 (anisaldehyde) 106 \Se O OH Qo 4H Oo” cl 1. PhCHO, 1 d, 27 °C, CsDgN . 2 9 _, 2: BteNsSHF 6 7Ph Oth 5 3 12 10 28 52% 15% syn:anti = 1:2.1 Aldol Reactions of Silyl Enol Ether 28 Benzaldehyde (48.8 L, 50.9 mg, 0.48 mmol, 1 equiv) was added to a solution of chlorosilyl enol ether 28 (90 LL, 96.9 mg, 0.48 mmol, 1 equiv) in pyridine-ds (410 wL) under argon. The sample was allowed to stand at 27 °C for one day, with periodic monitoring by 1H NMR. A crystalline, colorless precipitate formed in this time. After one day, triethylamine trihydrofluoride (78.2 uL, 77.4 mg, 0.48 mmol, 1 equiv) was added, and the reaction mixture partitioned between saturated ammonium chloride solution and 15% ethyl acetate in hexanes. The organic layer was dried over sodium sulfate, filtered, concentrated, and the three products separated by column chromatography (15% ethyl acetate in hexanes), The enone (13.5 mg, 0.07 mmol, 15%) was isolated as a yellow oil. The syn aldol adduct (19.7 mg, 0.10 mmol, 20%) was isolated as a white crystalline solid (mp 99-101 °C), and the anti aldol adduct (31.6 mg, 0.15 mmol, 32%) as a white solid (mp 66-67 °C). Enone 1H NMR (300 MHz, C¢D6), 5: 1H NMR (300 MHz, CDCI), 8: 13C NMR (75 MHz, CDCI), 5: FTIR (neat), cm-!: 107 1.18 (m, 2H, H-11), 1.33 (m, 2H, H-12), 2.26 (t, J =6.7 Hz, 2H, H-13), 2.39 (t of d, J = 2.2, 6.4 Hz, 2H, H-10), 7.02-7.17 (m, 5H, aromatics), 7.80 (t, J = 2.2 Hz, 1H, H-14) 1.62 (m, 2H, H-11), 1.77 (m, 2H, H-12), 2.40 (t, J =6.7 Hz, 2H, H-13), 2.70 (t of d, J=2.3, 6.4 Hz, 2H, H-10), 7.14-7.28 (m, 5H, aromatics), 7.37 (t, J = 2.3 Hz, 1H, H-14) 23.21 (C-11), 23.71 (C-12), 28.77 (C-10), 40.16 (C-13), 128.16, 128.36, 130.13, 136.49 (aromatics), 135.38 (C-14), 135.42 (C-9), 201.50 (C-8) 2940 (s), 2865 (m), 1682 (s, C=O), 1593 (s, C=C), 1573 (m), 1491 (m), 1446 (s), 1317 (m), 1257 (s), 1203 (m), 1143 (s), 1068 (m), 822 (m), 762 (m), 719 (m), 697 (s) 108 n Aldol Adduct 1H NMR (300 MHz, Ce6Do), 8: 0.84 (m, 1H, H-4a), 1.14 (q of t, J= 3.8, 13.1, 1H, H-4b), 1.24, 1.42, 1.54 (3m, 1H, 1H, 2H, respectively, H-3 and H-5), 1.73 (t of d, J = 6.0, 13.4 Hz, 1H, H-6a), 2.12 (m, 2H, H-6b and H-2), 3.11 (d, J = 3.2 Hz, 1H, exchanges with D.O, OH. In CDCl: 3.02, d, J = 3.3 Hz), 5.39 (t, J = 2.4 Hz, 1H, H-7. In CDCl: 5.40, t, J = 2.6 Hz), 7.16 (m, 3H, aromatics), 7.32 (m, 2H, aromatics) 13C NMR (75 MHz, CDCI), 8: 24.74 (C-4), 25.87 (C-5), 27.83 (C-3), 42.55 (C-6), 57.07 (C-2), 70.44 (C-7), 125.64, 126.84, 128.02, 141.42 (aromatics), 214.67 (C-1) FTIR (neat), cm7!: 3547 (br,-OH), 2933 (m), 1696 (s, C=O), 1447 (s), 1313 (m), 1132 (s), 1060 (s), 985 (m), 699 (s) Anti Aldol Adduct 'H NMR (300 MHz, CeDo), 5: 0.81 (m, 2H, H-4), 1.10 (m, 2H, H-5), 1.25, 1.35 (2m, 1H each, H-3), 1.65 (t of d, J = 5.0, 13.5, 1H, H-6a), 2.13 (m, 1H, H-6b), 2.24 (m, 1H, H-2), 4.14 (d, J =2.8, 1H, exchanges with DO, OH. In CDCl;: 3.97, d, J = 2.7), 4.76 (dd, 13C NMR (75 MHz, CDC13), 5: FTIR (neat), cm-!: TLC 30% EtOAc in hexanes), Rr: 109 J =2.8, 8.6 Hz, 1H, H-7. In CDCl: 4.78, dd, J = 2.4, 8.7), 7.16 (m, 3H, aromatics), 7.32 (m, 2H, aromatics) 24.38 (C-4), 27.57 (C-5), 30.54 (C-3), 42.35 (C-6), 57.16 (C-2), 74.35 (C-7), 126.79, 127.58, 128.08, 140.79 (aromatics), 215.20 (C-1) 3510 (br, -OH), 2936 (m), 1696 (s, C=O), 1451 (s), 1129 (m), 1042 (m), 746 (m), 702 (s) Enone 0.60 (Strong UV, anisaldehyde) Synadduct 0.46 (anisaldehyde) Antiadduct 0.36 (anisaldehyde) 110 1. PhCHO, CsHeN, OH Oo 4 Si 70°C, 8 hr __ Pht y4 Ph CI” ~cl 2. EtgNe3HF 52% 29% syn:anti = 1:1.6 One-Pot Enolization-Aldol Addition with Dichlorosilacyclobutane Cyclohexanone (207 uL, 196 mg, 2.0 mmol, 1 equiv) and benzaldehyde (203uL, 212 mg, 2.0 mmol, 1.0 equiv) were added to a solution of dichlorosilacyclobutane (270LL, 320 mg, 2.26 mmol, 1.13 equiv) in pyridine (970 wL) under argon. The reaction mixture was stirred at 70 °C until no more cyclohexanone could be detected by TLC (8 hours). After cooling to 0 °C, the solution was treated with triethylamine trihydrofluoride (750uUL, 241 mg, 4.6 mmol, 2.3 equiv). The reaction mixture was partitioned between Saturated ammonium chloride solution (10 mL) and ethyl acetate (5 mL). The aqueous layer was separated and extracted further with two 5-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated; the products were isolated by flash column chromatography (20% ethyl acetate in hexanes). The enone was isolated as yellow crystalline solid (107.1 mg, 1.04 mmol, 29%), the syn aldol adduct as colorless needles (81.3 mg, 0.40 mmol, 20%), and the anti aldol adduct as a colorless solid (131.8 mg, 0.65 mmol, 32%) 111 0 1. PhCHO, CsHgN 0 OH Oo H HsCy {CH 50 °C, 29 hr - A 4 Z + Si Ph Ph cI” Cl 2. EtsNeSHF - 50% 11% syn:anti = 1:1.9 One-Pot Enolization-Aldol Addition with Dimethyldichlorosilane Cyclohexanone (207 tL, 196 mg, 2.0 mmol, 1 equiv) and benzaldehyde (203 uL, 212 mg, 2.0 mmol, 1.0 equiv) were added to a solution of dimethyldichlorosilane (279 uL, 297 mg, 2.3 mmol, 1.15 equiv) in pyridine (970 pL) under argon. The reaction mixture was stirred at 50 °C until no more cyclohexanone could be detected by TLC (29 hours). After cooling to 0 °C, the solution was treated with triethylamine trihydrofluoride (750uL, 241 mg, 4.6 mmol, 2.3 equiv). The reaction mixture was partitioned between saturated ammonium chloride solution (10 mL) and ethyl acetate (5 mL). The aqueous layer was separated and extracted further with two 5-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated; the products were isolated by flash column chromatography (20% ethyl acetate in hexanes). The enone was isolated as yellow oil (41.8 mg, 0.22 mmol, 11%), the syn aldol adduct as colorless needles (71.3 mg, 0.35 mmol, 18%), and the anti aldol adduct as a colorless solid (133.1 mg, 0.65 mmol, 32%) 112 2 \ 2 AgOTT, Et,0 “\ 1 Si Si, Ci” ~ci > 27°C, 5 min Tio” ~oTt Silacyclobutane ditriflate Silacyclobutane dichloride (0.491 mL, 564.4 mg, 4.0 mmol, 1 equiv) was added to ~ a suspension of silver triflate (2.17 g, 8.45 mmol, 2.2 equiv) in dry ether (15 mL). Thick white precipitate formed immediately. The solution was stirred under argon at 27 °C for approximately five minutes, then transferred by cannula to a fine porosity filter frit and filtered under argon. The residual solid was rinsed twice with 5-mL aliquots of ether, and the combined ether fractions were concentrated under reduced pressure (150 Torr), then distilled (Kugelrhor, 35 Torr, 90-100 °C) to yield silacyclobutane ditriflate (1.2109 g, 3.29 mmol, 82%) as a colorless liquid, density 1.63 g/mL. Proton and carbon NMR of this liquid are consistent with substitution on silicon. ‘H NMR (300 MHz, C6Do), 8: 1.38 (m, 2H, H-2), 1.55 (m, 4H, H-1) C NMR (75 MHz, C6D¢), 5: 11.30 (C-2), 24.19 (C-1), 118.76 (q, J = 318 Hz, CF3) 113 Si, ol 1. PhCHO, CsDsN O - OH Hi H + AgOTf 27 °C, 2 days = Ph + 4 Ph 2. EtsNe3HF 28 37% 1% syn:anti = 1.06:1 Aldol Reaction of Silyl Enol Ether 28 with silver triflate Silyl enol ether 28 (90 tL, 96.9 mg, 0.48 mmol, 1 equiv) was added to a solution of silver triflate (123.6 mg, 0.48 mmol, 1.0 equiv) in pyridine-ds (400 uL), protected from light, and stirred at 27 °C for 2 hours 15 minutes, giving a clear solution. Benzaldehyde (49 wL, 51 mg, 0.48 mmol, 1.0 equiv) was added, causing a white precipitate to fall out of solution. The supernatant was transferred by cannula to a dry NMR tube under argon and the reaction monitored periodically by 'H NMR. After standing in the dark at 27 °C for 2 days, the solution was treated with triethylamine trihydrofluoride (78 wL, 77 mg, 0.48 mmol, 1.0 equiv). The reaction mixture was partitioned between saturated ammonium chloride solution (10 mL) and ethyl acetate (5 mL). The aqueous layer was separated and extracted further with two 5-mL portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated; the products were isolated by flash column chromatography (20% ethyl acetate in hexanes). The enone (0.9 mg, 0.005 mmol, 1%) was isolated as a yellow oil; the syn aldol adduct (19 mg, 0.093 mmol, 19%) as a colorless solid; and the anti (17.9 mg, 0.88 mmol, 18%) as a colorless solid. 114 benzene, 15 °C, 2 hr 40.min NO» 1 46% 51:49 D:H Deuterium isotope experiment Dimethy] silyl ketene acetal 1 (40 WL, 40.7 mg, 0.19 mmol, 1.0 equiv) was added to a deoxygenated solution of 4-nitrobenzaldehyde (48:52 mixture of NO2zCs6H4gCDO: NO2C6H4CHO, exact ratio determined by mass spectrometry. 438.6 mg, 2.89 mmol, 14 equiv) in benzene (4 mL) cooled to 15 °C in an ice/water bath. The reaction was stirred at 15°C for 2 hours, 40 minutes. Aldol adducts were then isolated by flash column chromatography (50% ether in petroleum ether) as a white solid (16.8 mg, 0.087 mmol, 46%). Exact deuterium incorporation was determined by mass spectrometry. Mass Spectral Results Aldehyde Aldol adducts Run % D % H %D % H H reference 0 100 0 , 100 D reference 100 0 97 3 Run | 48 52 51 49 Run2 48 52 51 49 Run 3 48 52 Sl 49 115 CH, HQ CHs Haq .CHs ; ‘ Si. 1 Si. Pha O~ sit CH Phot Lo Philo \ 5 PhCHO fe) No . oo : O 80°C, 4hr as - A2k CH3™” CH," Ph CHa" 5. N Ph 3 A on 7. 271 3 7 2, 12 3 ~ CHg CH,z CH, CH; CH, 4 4 34 35 53% 36 7% (2R, 35) (2S, 3R) (—)-Pseudoephedrine~Benzaldehyde Aldol Adducts 35 and 36 Benzaldehyde (523 uL, 546 mg, 5.14 mmol, 5 equiv) and the O-silyl N,O-ketene acetal derived from (—)-pseudoephedrine propionamide 34 (285.3 mg, 1.03 mmol, 1 equiv) were combined in a 10-mL Schlenk tube under argon. The solution was stirred in an 80 °C oil bath for 4 hours, then excess benzaldehyde was removed under vacuum (1 | Torr). Purification by flash column chromatography (30% ethyl acetate in hexanes) afforded major product 35 (209.0 mg, 53%) as a colorless solid (mp: 156-161 °C) and minor product 36 (28.3 mg, 7%) as a colorless oil. The major product, 35, has 'H NMR and FTIR spectra identical to the (1'S, 2°S, 25, 3R) isomer derived from (+)-pseudoephedrine, (See Marsh, R.E.; Schafer, W.P.; Widdowson, K.L.; Myers, A.G. Acta. Crystallogr., 1992, C48, 1948.) implying that 35 is the enantiomeric (1'R, 2'R, 2R, 3S) isomer, as shown. Upon TLC analysis, 36 appears as two spots, but 2-D TLC shows those spots inter convert into each other. The 'H NMR spectrum of 36 also appears to contain two isomers in an approximately equal ratio. Upon hydrolysis, however, 36 yields only the anti acid (with very minor syn impurities), implying that it is the other anti aldol adduct, the (1'R, 2'R, 25, 3R) isomer, perhaps existing in equilibrium between two conformers. 116 1'R, 2'R, 2R, 3S) Anti Aldol Adduct 35 4H NMR (300 MHz, CDCls), 8: 13C NMR (75 MHz, CDCI), 5: FTIR (neat), cm-!: 0.06 (s, 3H, Si-CH3), 0.09 (s, 3H, Si-CH3), 0.87 (d, J=6.5 Hz, 3H, H-4), 0.88 (d, J=7.1 Hz, 3H, H-3'), 3.19 (s, 3H, N-CH3), 3.29 (dq, J = 6.6, 9.7 Hz, 1H, H-2), 4.52 (d, J=9.6 Hz, 1H, H-1'), 4.70 (d, J=9.7 Hz, 1H, H-3), 5.28 (dq, J=7.1, 9.6 Hz, 1H, H-2'), 7.27~7.41 (m, 10H, aromatics) ~3.99 (Si-CH3), -3.85 (Si-CH3), 13.27 (C-4), 14.15 (C-3'), 29.33 (N-CH3), 44.30 (C-2), 55.09 (C-2'), 77.42 (C-1'), 80.73 (C-3), 126.74, 126.92, 127.62, 127.69. 128.19, 128.22, 141.63, 142.56 (aromatics), 177.34 (C-1) 3029 (w), 2979 (m), 2936 (w), 2878 (w), 1639 (s, C=O), 1491 (w), 1455 (m), 1406 (m), 1372 (w), 1290 (w), 1258 (s), 1230 (w), 1206 (w), 1139 (w), 1080 (s), 1051 (s), 1027 (m), 934 (m), 883 (s), 866 (s), 855 (s), 800 (m), 743 (m), 700 (s) 117 ('R, 2'R, 2S, 3R) Anti Aldol Adduct 36 1H NMR (300 MHz, CDCls), 6: FTIR (neat), cm*!: TLC (30% EtOAc in hexanes), Rr: Appears as ~1:1 mixture of isomers -0.31 (s, 3H, Si-CH3), 0.02 (s, 3H, Si-CH3), 0.15 (s, 3H, Si-CH3), 0.22 (s, 3H, Si-CH3), 0.85 (d, J =6.6 Hz, 3H, H-4), 0.89 (d, J=6.6 Hz, 3H, H-4), 0.97 (d, J=6.8 Hz, 3H, H-3'), 1.24 (d, J=7.0 Hz, 3H, H-3'), 3.01 (s, 3H, N-CH3), 3.07 (dq, J = 6.6, 9.6 Hz, 1H, H-2), 3.08 (dq, J=7.0, 9.5 Hz, 1H, H-2'), 3.31 (s, 3H, N-CH3), 3.51 (dq, J = 6.7, 9.7 Hz, 1H, H-2), 4.74 (d, J=9.5 Hz, 1H, H-3), 4.75 (d, J = 9.9 Hz, 1H, H-3), 4.86 (d, J=9.9 Hz, 1H, H-1'), 5.05 (d, J =6.7, 9.9 Hz, 1H, H-2'), 5.70 (d, J=9.5, 1H, H-1'), 7.25-7.88 (m, 20H, aromatics) 2970 (m), 1637 (s, C=O), 1491 (w), 1452 (w), 1375 (m), 1256 (m), 1079 (s), 852 (s), 800 (s), 700 (s) 35: 0.33. (UV and PMA) 36: 0.15 and 0.48 (UV and PMA) 118 a rp 9g 37 45% oo 2- (2R, 3S): He CH" aoe | 1 3' Om gia CHg CH3 CHg \ Ph ag 5 5 PhCHsCHsCHO 4. wr toluene, 100 °C, 6 hr CH," 3 A ots CHg Phot o— si © 38 45% 34 e Aah ~ (2S, 3R) CHs™ 13 Ph (—)-Pseudoephedrine~Hydrocinnamaldehyde Aldol Adducts 37 and 38 Hydrocinnamaldehyde (122.8 pL, 125.1 mg, 0.933 mmol, 1 equiv) was added to a solution of the O-silyl N,O-ketene acetal derived from (—)-pseudoephedrine propionamide 34 (517.4 mg, 1.86 mmol, 2 equiv) in dry toluene (250 uL) in a 10 mL Schlenk tube. The solution was stirred in a 100 °C oil bath for 6 hours. Purification of the reaction mixture by flash column chromatography (30% ethyl acetate in hexanes) afforded separately 37 (174.4 mg, 45%) as a colorless oil and 38 (171.2 mg, 45%) also as a colorless oil. Product 37 was assigned the (1'R, 2'R, 2R, 3S) geometry based on the similarity of its 'H NMR spectrum to the corresponding benzaldehyde adduct. Upon TLC analysis, 38 appears as two spots, but 2-D TLC shows those spots convert into each other. The 'H NMR spectrum of 38 also appears to contain two isomers in an approximately 1.3:1 ratio. Upon hydrolysis, however, 38 yields only the anti acid (with very minor syn 119 impurities), implying that it is the other anti aldol adduct, the (1'R, 2'R, 2S, 3R) isomer, perhaps existing in equilibrium between two conformers. | CR, 2'R, 2R, 3S) Anti Aldol Adduct 37 1H NMR (300 MHz, CDCls), 6: 0.11 (s, 3H, Si-CH3), 0.14 (s, 3H, Si-CH3), 0.85 (d, J=7.1 Hz, 3H, H-3'), 1.12 (d, J=6.5 Hz, 3H, H-4), 1.74 (m, 1H, Ph-CH2-CH>-), 2.00 (m, 1H, Ph-CH,-CH>-), 2.55 (ddd, J = 4.9, 11.9,13.4 Hz, 1H, Ph-CH>~), 2.80 (ddd, J = 5.0, 12.1, 13.4 Hz, 1H, Ph-CH>-), 3.07 (s, 3H, N-CHs3), 3.08 (dq, J =6.4, 9.7 Hz, 1H, H-2), 3.88 (t of d, J = 2.3, 9.2 Hz, 1H, H-3), 4.48 (d, J=9.6 Hz, 1H, H-1'), 5.22 (dq, J=7.1, 9.6 Hz, 1H, H-2'), 7.18-7.50 (m, 10 H, aromatics) FTIR (neat), cm: 3026 (w), 2960 (w), 2875 (w), 1643 (s, C=O), 1492 (w), 1454 (m), 1406 (m), 1375 (w), 1290 (w), 1257 (m), 1216 (w), 1138 (w), 1090 (s), 1029 (w), 977 (w), 932 (w), 873 (m), 853 (m), 847 (m), 799 (m), 747 (w), 700 (s) HRMS (FAB), m/z: Caled for C24H3403NSi (MH*+): 412.2308 Found: 412.2305 120 (1'R, 2'R, 28. 3R) Anti Aldol Adduct 38 1H NMR (300 MHz, CDCI), 8: 3C NMR (75 MHz, CDCh), 8: Appears as ~1.3:1 mixture of isomers -0.10 (s, 3H, Si-CH3), 0.04 (s, 3H, Si-CH3), 0.11 (s, 3H, Si-CH3), 0.13 (s, 3H, Si-CH3), 0.90 (d, J=6.7 Hz, 3H, H-3'), 1.07 (d, J=6.6 Hz, 3H, H-4), 1.11 (d, J=6.6 Hz, 3H, H-4), 1.25 (d, 7.0 Hz, 3H, H-3'), 1.75 (m, 3H, H-2 and two of Ph-—CH2—-CH>~), 2.02 (m, 2H, Ph~-CH.—CH>-), 2.60 (m, 2H, Ph-CH~), 2.89 (m, 2H, Ph-CH)-), 2.95 (s, 3H, N-CH3), 3.02 (dq, J=7.0, 9.6 Hz, 1H, H-2'), 3.20 (s, 3H, N-CH3), 3.22 (dq, J =6.7, 9.8 Hz, 1H, H-2), 3.82 (t of d, J = 2.2, 9.6 Hz, 1H, H-3), 3.92 (t of d, J=2.3, 9.6 Hz, 1H, H-3), 4.69 (d, J = 10.0 Hz, 1H, H-1'), 4.88 (dq, J = 6.7, 10.0, 1H, H-2'), 5.62 (d, J = 9.6 Hz, 1H, H-1'), 7.17-7.51 (m, 20 H, aromatics) Appears as ~1.3:1 mixture of isomers -6.08 (Si-CH3), -3.27 (Si-CH3), -0.92 (Si-CH3), 0.98 (Si-CH3), 13.32 (C-3'), 14.79 (C-4), 14.95 (C-4), 15.83 (C-3'), 26.93 (N-CH3), 31.83 (N-CH3), 32.14, 36.47, 36.72, 41.54 (Ph-CH2—-CH)~), 42.39 (C-2), 43.88 (C-2), 56.36 (C-2'), 68.90 (C-2'), 74.78 (C-3), 77.22 (C-3), 78.32 (C-1'), 79.18 (C-1'), 125.81, 125.89, FTIR (neat), cm-!: HRMS (FAB), m/z: TLC (20% EtOAc in hexanes), Ry: 121 126.98, 127.48, 127.82, 128.13, 128.34, 128.37, 128.43, 128.67, 140.75, 141.87, 142.03, 142.86 (aromatics), 175.79 (C-1), 176.50 (C-1) 2936 (w), 1637 (s, C=O), 1453 (w), 1356 (w), 1256 (m), 1078 (m), 873 (w), 845 (m), 799 (m), 699 (s) Caled for C24H3403NSi (MH+): 412.2308 Found: 412.2303 37: 0.35 (UV and PMA) 38: 0.56 and 0.22 (UV and PMA ) 122 HsC, 3CHg Pho one L : 39 22% e 2A CH; —_2R, 35) CHs ors 2Nifo3 Ph On Sian CH, CH3 CH3 CHg \ . 4 CHa” 120 °C, 18.5 hr CHs Ph 1' Oo; i a 40 48% 34 ~ 2 CH; (28, 3) CH a NY 3 . 3) = CH, CH3 CHg 4 ’ (—)-Pseudoephedrine—Isobutyraldehyde Aldol Adducts 39 and 40 Isobutyraldehyde (600 WL, 476.4 mg, 6.61 mmol, 3.6 equiv) and the O-silyl N,O-ketene acetal derived from (—)-pseudoephedrine propionamide 34 (509.7 mg, 1.84 mmol, 1 equiv) were combined in a sealable pressure tube under argon. The solution was subjected to three freeze-pump-thaw degas cycles, evacuated, sealed, and heated in a 120 °C oil bath for 18.5 hours. Excess aldehyde was removed in vacuo. Purification by flash column chromatography (25% ethyl acetate in hexanes) afforded minor product 39 (142.4 mg, 22%) as a colorless, crystalline solid (mp: 121-127 °C) and major product 40 (310.3 mg, 48%) as a colorless oil which crystallized on standing to a colorless solid (mp: 96-98 °C). The minor product, 39, was assigned the (1'R, 2'R, 2R, 3S) geometry based on the similarity of its 'H NMR spectrum to the corresponding benzaldehyde adduct. The major product, 40, appears as two spots on TLC analysis, but 2-D TLC shows those spots convert into each other. The 'H NMR spectrum of 40 also appears to contain two isomers 123 in an approximately 1:1 mixture of isomers. Upon hydrolysis, however, 40 yields only the anti acid (with minor syn impurities), implying that it is the other anti aldol adduct, the (1'R, 2'R, 2S, 3R) isomer, perhaps existing in equilibrium between two conformers. (LR, 2'R, 2R, 3S) Anti Aldol Adduct 39 ~ lH NMR (300 MHz, C¢Dg), 8: 1 NMR (300 MHz, CDCI), 5: 0.02 (s, 3H, Si-CH3), 0.06 (s, 3H, Si-CH3), 0.60 (d, J=7.2 Hz, 3H, H-3'), 0.80 (d, J=6.8 Hz, 3H, one of -CH(CH3)2), 0.83 (d, J = 6.7 Hz, 3H, one of —CH(CH3)2), 1.13 (d, J=6.5 Hz, 3H, H-4), 1.70 (quintet of d, J=1.7, 6.7 Hz, 1H, —CH(CH3)2), 2.64 (s, 3H, N-CH3), 3.02 (dq, J=6.5, 9.9 Hz, 1H, H-2), 3.80 (dd, J = 1.8, 9.9 Hz, 1H, H-3), 4.34 (d, J=9.6 Hz, 1H, H-1'), 5.58 (dq, J =7.2, 9.6 Hz, 1H, H-2'), 7.04-7.16 (m, 3H, aromatics), 7.29-7.32 (m, 2H, aromatics) 0.05 (s, 3H, Si-CHs), 0.07 (s, 3H; Si-CH3), 0.82 (d, J=7.2 Hz, 3H, H-3, 0.88 (d, J=6.7 Hz, 3H, one of -CH(CHs)s), 0.89 (d, J = 6.8 Hz, 3H, one of —CH(CH3)s), 1.06 (d, J =6.5 Hz, 3H, H-4), 1.89 (quintet of d, J=1.7, 6.7 Hz, 1H, ~CH(CH3)), 3.01 (s, 3H, N-CH3), 3.14 (dq, J =6.5, 9.9 Hz, 1H, H-2), 3.69 (dd, J=1.7, 9.9 Hz, 1H, H-3), 4.44 (d, J=9.6 Hz, 1H, H-1), 13C NMR (75 MHz, CDC}), 8: FTIR (neat), cm-): HRMS (FAB), m/z: 124 5.18 (dq, J = 7.2, 9.6 Hz, 1H, H-2'), 7.22-7.36 (m, 5H, aromatics) ~4.23 (Si-CH3), -3.56 (Si-CH3), 13.00 (C-3'), 13.40 (one of -CH(CH3)2), 14.10 (one of —CH(CH3)2), 20.68 (C-4), 29.21 (N-CH3), 39.45 (C-2), 53.32 (-CH(CH3)2), 54.80 (C-2'), 76.96 (C-1'), 81.22 (C-3), 126.86, 127.56, 128.11, 141.66 (aromatics), 177.41 (C-1) 2964 (m), 2937 (w), 2875 (w), 1643 (s, C=O), 1490 (w), 1455 (m), 1406 (m), 1376 (w), 1366 (w), 1291 (m), 1258 (s), 1146 (m), 1114 (m), 1096 (s), 1071 (s), 1047 (s), 975 (w), 932 (w), 879 (s), 853 (s), 799 (s), 701 (s) Calcd for Cj9H3203NSi (MH*): 350.2151 Found: 350.2152 (UR, 2'R, 2S, 3R) Anti Aldol Adduct 40 'H NMR (300 MHz, CDCl), 8: Appears as ~1:1 mixture of isomers —0.24 (Si-CH3), 0.03 (Si-CH3), 0.04 (Si-CH3), 0.12 (Si-CH3), 0.86 (d, J=6.7 Hz, 3H, 13C NMR (75 MHz, CDCI), 8: 125 CH-CH3), 0.89 (d, J= 6.8 Hz, 3H, CH-CH3), 0.90 (d, J=6.7 Hz, 3H, CH-CH3), 0.94 (d, J=6.8 Hz, 3H, CH-CHs), 0.98 (d, J=7.0 Hz, 3H, CH-CH3), 1.01 (d, J=6.8 Hz, 3H, CH-CHs3), 1.07 (d, J = 6.6 Hz, 3H, CH-CH3), 1.23 (d, J=7.0 Hz, 3H, CH-CH3), 1.85 (quintet of d, J=1.8, 6.7 Hz, 1H, -CH(CH3)), 1.93 (quintet of d, J= 1.9, 6.7 Hz, 1H, -CH(CH3),), 2.93 (s, 3H, N-CH3), 2.99 (dq, J = 6.5, 9.7 Hz, 1H, H-2), 3.00 (dq, J =7.0, 9.5 Hz, 1H, H-2'), 3.17 (s, 3H, N-CH3), 3.18 (m, 1H, H-2), 3.66 (dd, J=1.8, 9.8 Hz, 1H, H-3), 3.75 (dd, J=1.9, 10.0 Hz, 1H, H-3), 4.67 (d, J = 10.2 Hz, 1H, H-1'), 4.96 (dq, J =6.7, 10.2 Hz, 1H, H-2'), 5.59 (d, J =9.6 Hz, 1H, H-1'), 7.21-7.50 (m, 5H, aromatics) Appears as ~1:1 mixture of isomers ~6.34° (Si-CH3), -3.51 (Si-CH3), -1.37 (Si-CH3), 0.40 (Si-CH3), 12.71 (-CH-CHs3), 13.39 (-CH-CH3), 13.60 (-CH-CH3), 14.05 (-CH-CH3), 15.07 (-CH-CH3), 15.62 (-CH-CH3), 20.41 (-CH-CH3), 20.44 (-CH-CH3), 28.95 (N-CH3), 29.03 (N-CHs3), 39.79 (C-2), 40.47 (C-2), 55.71 (-CH-(CH3)), 68.98 (C-2'), 74.57 (C-1'), 79.41 (C-1'), 81.01 FTIR (neat), cm-!: HRMS (FAB), m/z: TLC (25% EtOAc in hexanes), Ry: 126 (C-3), 82.13 (C-3), 126.88, 127.34, 127.92, 128.02, 128.28, 128.63, 140.71, 142.84 (aromatics), 175.88 (C-1), 176.96 (C-1) 2964 (s), 2875 (m), 1644 (s, C=O), 1486 (m), 1455 (m), 1410 (m), 1376 (s), 1295 (m), 1257 (s), 1228 (m), 1203 (m), 1182 (m), 1136 (s), 1051 (s), 979 (w), 933 (w), 857 (s), 799 (s), 701 (s) Calcd for Cy9H3203NSi (MH*): 350.2151 Found: 350.2154 39: 0.22 (UV and PMA) 40: 0.38 and 0.16 (UV and PMA) 127 41 9% (2R, 3S) Ph Om Sis CHg 5 \ ae 7 wee 80 °C, 16.5 hr CH \ ’ CH 42 63% 34 (2S, 3R) (—)-Pseudoephedrine—Cyclohexanecarboxaldehyde Aldol Adducts 41 and 42 Cyclohexanecarboxaldehyde (1.116 mL, 1.033 g, 9.21 mmol, 5 equiv) and the O-silyl N,O-ketene acetal derived from (—)-pseudoephedrine propionamide 34 (511.2 mg, 1.84 mmol, 1 equiv) were combined in a 10 mL Schlenk tube under argon. The solution was heated in a 80 °C oil bath for 16.5 hours. Excess aldehyde was removed in vacuo. Purification by flash column chromatography (10-430% ethyl acetate in hexanes) afforded minor product 41 (62.8 mg, 9%) as a colorless, crystalline solid (mp: 121-126 °C) and major product 42 (451.9 mg, 63%) as a slightly yellow oil. The minor product, 41, was assigned the (1'R, 2'R, 2R, 35S) geometry based on the similarity of its 'H NMR spectrum to the corresponding benzaldehyde adduct. The major product, 42, appears as two spots on TLC analysis, and the 'H NMR spectrum of ‘42 also appears to contain two isomers in an approximately 1:1 ratio. The 1H NMR spectrum of 42 is also very similar to that of the minor benzaldehyde adduct, which also appears as two isomers. Furthermore, 42 yields only the anti acid (with minor syn 128 impurities) upon hydrolysis, implying that it is the other anti aldol adduct, the (I'R, 2'R, 25, 3R) isomer, perhaps existing in equilibrium between two conformers. (UR, 2'R, 2R, 3S) Anti Aldol Adduct 41 1 NMR (300 MHz, CDCls), 5: 13C NMR (75 MHz, CDCI), 8: FTIR (neat), cm-!: 0.05 (s, 3H, Si-CH3), 0.07 (s, 3H, Si-CH3), 0.81 (d, J=7.1 Hz, 3H, H-3'), 1.05 (d, J=6.5 Hz, 3H, H-4), 1.08-1.80 (m, 11H, cyclohexyl H), 3.00 (s, 3H, N-CH3), 3.22 (dq, J =6.5, 9.9 Hz, 1H, H-2), 3.66 (dd, J=1.4, 9.9 Hz, 1H, H-3), 4.43 (d, J=9.6 Hz, 1H, H-1'), 5.18 (dq, J = 7.1, 10.0 Hz, 1H, H-2'), 7.26-7.39 (m, 5H, aromatics) -4.09 (Si-CH3), -3.40 (Si-CH3), 13.12 (C-4), 14.16 (C-3'), 23.93 (cyclohexyl —CH2-), 26.23 (cyclohexyl —CH»-), 26.49 (cyclohexyl —CH>-), 26.59 (cyclohexyl —CH —-), 29.17 (cyclohexyl -CH)-), 31.30 (N-CH3), 38.55 (cyclohexyl —-CH-), 39.58 (C-2), 54.84 (C-2'), 77.00 (C-3), 81.30 (C-1'), 126.93, 127.61, 128.16, 141.75 (aromatics), 178.14 (C-1) 2928 (s), 2853 (m), 1642 (s, C=O), 1490 (w), 1451 (m), 1406 (m), 1375 (w), 1290 (w), 1256 (s), 1218 (w), 1145 (m), 1082 (s), 1069 (s), 1021 (m), HRMS (FAB), m/z: 129 973 (w), 934 (w), 898 (w), 871 (m), 840 (m), 797 (m), 700 (m) Calcd for C22H36NO3Si (MH*): 390.2464 Found: 390.2469 (1'R, 2'R, 28, 3R) Anti Aldol Adduct 42 1 NMR (300 MHz, CDCls), 5: 13C NMR (75 MHz, CDC1,), 3: Appears as ~1:1 mixture of isomers -0.20 (s, 3H, Si-CH3), 0.03 (s, 3H, Si-CH3), 0.04 (s, 3H, Si-CH3), 0.11 (s, 3H, Si-CH3), 0.88 (d, J=6.7 Hz, 3H, H-3'), 1.00 d, J=6.5 Hz, 3H, H-3'), 1.06 (d, J=6.5 Hz, 3H, H-4), 1.22 | (d, J=7.0 Hz, 3H, H-4), 1.12-1.87 (m, 22H, cyclohexyl H), 2.92 (s, 3H, N-CH3), 2.99 (dq, J=7.0, 9.5 Hz, 1H, H-2), 3.07 (dq, J = 6.5, 9.7 Hz, 1H, H-2), 3.16 (s, 3H, N-CH3), 3.25 (dq, J=6.6, 9.8 Hz, 1H, H-2'), 3.63 (dd, J = 0.8, 9.4 Hz, 1H, H-3), 3.72 (dd, J = 1.3, 9.9 Hz, 1H, H-3), 4.66 (d, J= 10.2 Hz, 1H, H-1'), 4.95 (dq, J=6.7, 10.2 Hz, 1H, H-2'), 5.59 (d, J=9.6 Hz, 1H, H-1'), 7.21-7.49 (m, 10H, aromatics) Appears as ~1:1 mixture of isomers FTIR (neat), em-!: HRMS (FAB), m/z: TLC (20% EtOAc in hexanes), Ry: 130 -6.24 (Si-CH3), -3.46 (Si-CH3), -—1.26 (Si-CH3), 0.50 (Si-CH3), 12.77 (-CH-CH3), 14.16 (-CH-CH3), 15.07 (CH-CH3), 15.62 (-CH-CH3), 24.03 (cyclohexyl -CH>-), 24.12 (cyclohexyl —CH2-), 26.14 (cyclohexyl —CH?-), 26.20 (cyclohexyl —CH2-), 26.54 (cyclohexyl -CH>-), 26.65 (cyclohexyl -CH»2-), 30.82 (N-CH3), 30.96 (N-CH3), 39.07 (cyclohexyl -CH-), 39.36 (cyclohexyl -CH-), 39.50 (C-2), 41.52 (C-2), 55.67 (C-2'), 68.98 (C-2'), 74.56 (C-3), 79.38 (C-3), 80.90 (C-1'), 82.11 (C-1'), 126.88, 127.33, 127.94, 128.00, 128.24, 128.63, 140.69, 142.86 (aromatics), 176.09 (C-1), 177.11 (C-1) 2929 (s), 2853 (s), 1642 (s, C=O), 1485 (m), 1452 (s), 1411 (m), 1376 (s), 1296 (m), 1255 (s), 1204 (w), 1109 (s), 1071 (s), 1028 (s), 975 (w), 935 (m), 898 (m), 866 (s), 847 (s), 798 (s), 735 (w), 701 (s), 558 (m) Calcd for Cy7H3gNO3Si (MH*): 390.2464 Found: 390.2465 41: 0.18 (UV and PMA) 42: 0.39 and 0.11 (UV and PMA) 131 Photo SK ae f 6S 43 5% CHg (2R, 3S) CH3” >» CHs cH 3 CH, om Seu CH, 5 3 CH3 CHg CHg \ CH; 4 Ph ae O CH3 7 + wer 100 °C, 42 hr CH,* ’ H.C Us o 9 44 48% CH a N 1 Y 3 3 1 13 CH, CH3 CH3 CHg 4 1 @) nk ie) to Sun (—)-Pseudoephedrine—Pivalaldehyde Aldol Adducts 43 and 44 Pivalaldehyde (797 WL, 632.3 mg, 7.34 mmol, 5 equiv) and the O-silyl N,O-ketene acetal derived from (—)-pseudoephedrine propionamide 34 (407.3 mg, 1.47 mmol, 1 equiv) were combined in a sealable pressure tube under argon. The solution was subjected to three freeze-pump-thaw degas cycles, evacuated, sealed, and heated in a 100 °C oil bath for 42 hours. Some crystallization occurred on cooling The supernatant was carefully removed and the crystals rinsed with cold hexanes. This afforded aldol adduct 44 (162.2 mg, 30%) as colorless, needle-like crystals (mp: 143-145 °C). Excess aldehyde was removed from the supernatant in vacuo. Purification by flash column chromatography (20% ethyl acetate in hexanes) afforded minor product 43 (24.9 mg, 4.7%) as a colorless solid (mp: 158-162 °C) and more of the major product 44 (95.1 mg, 18%) as a colorless solid (mp: 140-143 °C). The minor product, 43, was assigned the (1'R, 2'R, 2R, 3S) geometry based on the similarity of its 4H NMR spectrum to the corresponding major benzaldehyde adduct. 132 The major product, 44, appears as a single spot on TLC analysis. In benzene-dg the 1H ' NMR spectrum of 44 appears to contain only a single isomer, but in chloroform-d the 1H NMR spectrum of 44 appears to contain two isomers in an approximately 2:1 ratio. The similarity of this spectrum to that of the minor benzaldehyde adduct implies that 44 is the (1'R, 2'R, 2S, 3R) anti aldol adduct, which equilibrates between two conformers in chloroform solution, but which does not in the less polar benzene solution. (1'R, 2'R, 2R, 3S) Anti Aldol Adduct 43 1H NMR (300 MHz, CDC1s), 8: 13C NMR (75 MHz, CDCl), 8: FTIR (neat), cm-!: 0.05 (s, 3H, Si-CH3), 0.08 (s, 3H, Si-CH3), 0.80 (d, J =7.2 Hz, 3H, H-3'), 0.98 (s, 9H, -C(CH3)3), 1.20 (d, J = 6.4 Hz, 3H, H-4), 3.00 (s, 3H, N-CH3), 3.22 (dq, J = 6.4, 9.4 Hz, 1H, H-2), 3.56 (d, J=9.4 Hz, 1H, H-3), 4.46 (d, J=9.5 Hz, 1H, H-1'), 5.19 (dq, J =7.2, 9.5 Hz, 1H, H-2'), 7.24-7.38 (m, SH, aromatics) -3.70 (both Si-CH3), 14.40 (C-3'), 15.82 (C-4), 27.20 (-C(CH3)3), 29.32 (N-CH3), 36.55 (-C(CH3)3), 39.45 (C-2), 54.79 (C-2'), 77.12 (C-1'), 84.65 (C-3), 126.94, 127.63, 128.20, 141.80 (aromatics), 178.13 (C-1) 2961 (m), 2872 (w), 1637 (s, C=O), 1490 (w), 1456 (w), 1403 (m), 1380 (w), 1361 (w), 1340 (w), 133 1291 (m), 1252 (m), 1219 (w), 1139 (m), 1107 (s), 1088 (s), 1066 (s), 1028 (m), 946 (w), 932 (w), 876 (m), 846 (m), 796 (m), 702 (m) HRMS (FAB), m/z: Calcd for Co9H3403NSi (MH*): 364.2308 Found: 364.2307 CUR, 2'R, 2S, 3R) Anti Aldol Adduct 44 'H NMR (300 MHz, C¢Do), 8: Appears as only one product. 0.14 (s, 3H, Si-CH3), 0.30 (s, 3H, Si-CH3), 0.91 (s, 9H, -C(CH3)3), 1.18 (d, J=6.5 Hz, 3H, H-4), 1.34 (d, J= 6.8 Hz, 3H, H-3'), 2.79 (s, 3H, N-—CH3), 2.86 (dq, J =7.0, 9.5 Hz, 1H, H-2'), 2.92 (dq, J=6.5, 9.2 Hz, 1H, H-2), 3.65 (d, J =9,.2 Hz, 1H, H-3), 5.99 (d, J=9.5 Hz, 1H, H-1’), 7.05-7.39 (m, 5H, aromatics) 1 NMR (300 MHz, CDCI,), 8: Appears as ~2:1 mixture of isomers. major: 0.04 (s, 3H, Si-CH3), 0.16 (s, 3H, Si-CH3), 0.97 (s, 9H, -C(CH3)3), 1.16 (d, J=6.5 Hz, 3H, H-4), 1.21 (d, J/=6.9 Hz, 3H, H-3'), 2.99 (dq, J = 6.9, 9.6 Hz, 1H, H-2'), 3.08 (dq, J=6.5, 9.2 Hz, 1H, H-2), 3.16 (s, 3H, 134 N-CH3), 3.53 (d, J=9.2 Hz, 1H, H-3), 5.68 (d, J=9.6 Hz, 1H, H-1'), 7.22-7.50 (m, 5H, aromatics) minor: —0.22 (s, 3H, Si-CH3), 0.07 (s, 3H, Si-CH3), 0.91 (d, J = 6.7 Hz, 3H, H-3'), 1.05 (s, 9H, —C(CH3)3), 1.21 (d, J=6.9 Hz, 3H, H-4), 2.93 (s, 3H, N-CH3), 3.31 (dq, J = 6.8, 9.6 Hz, 1H, H-2), 3.68 (d, J = 9.6 Hz, 1H, H-3), 4.66 (d, J=10.1 Hz, 1H, H-1'), 4.98 (dq, J=6.7, 10.2 Hz, 1H, H-2'), 7.22-7.50 (m, 5H, aromatics 13C NMR (75 MHz, CDCI), 8: Appears as ~2:1 mixture of isomers. major: —6.08 (Si-CH3), -0.99 (Si-CH3), 14.76 (CH- CH3), 15.48 (CH-CH3), 27.12 (-C(CH3)3), 36.23 (N-CH3), 41.39 (C-2), 41.46 (-C(CH3)3), 68.89 (C-2'), 75.10 (C-1'), 85.40 (C-3), 127.01, 127.91, 128.06, 143.15 (aromatics), 177.10 (C-1) minor: —3.46 (Si-CH3), 0.74 (Si-CH3), 15.71 (CH- CH3), 16.50 (CH-CHs3), 26.80 (-C(CH3)3), 36.31 (N-CH3), 40.46 (C-2), 55.86 (C-2'), 79.53 (C-1'), 84.34 (C-3), 127.38, 128.30, 128.66 (aromatics), 176.81 (C-1) FTIR (neat), cm-!: HRMS (FAB), m/z: TLC (30% EtOAc in hexanes), Ry: 135 2944 (m), 2877 (w), 1632 (s, C=O), 1484 (m), 1454 (m), 1410 (w), 1375 (m), 1360 (m), 1291 (w), 1256 (s), 1103 (s), 1083 (s), 1062 (s), 953 (w), 930 (w), 911 (w), 854 (s), 796 (s), 718 (m), 705 (m) Found: 364.2322 43: 0.47 (UV and PMA) 44: 0.57 (UV and PMA) 136 HsC, CH, — Si. Ph O ag fe) No 5eq0.33MNaQH O- OH 4/1 MeOH/H20, CH3* R reflux HO R CHg CHs CHy General Procedure for Hydrolysis of Pseudoephedrine Auxiliary: The silylated anti aldol adducts were dissolved in 5 equiv of a 0.33 M solution of NaOH in 4:1 methanol-water, then heated to reflux until TLC showed only the acid as a long, low Ry streak. When complete, the cooled reaction mixture was concentrated in vacuo to remove methanol. The remaining basic solution was extracted with three 10-mL portions of dichloromethane. The organic extracts were dried over sodium sulfate, filtered, and concentrated to yield the pseudoephedrine auxiliary. The remaining aqueous layer was acidified with 1 N aqueous hydrochloric acid to pH < 2, saturated with solid sodium chloride, and extracted with several (> 5) portions of dichloromethane (15-20 mL). These organic extracts were dried over sodium sulfate, filtered, and concentrated to yield the crude carboxylic acids and a polymeric silyl contaminant. 137 9 OH CHN, O OH os Et,0, 27°C co CH; CH General Procedure for Esterification of Acids A solution of diazomethane in ether was prepared by slow addition of N-methyl-N- nitroso-p-toluenesulfonamide (Diazald®) to a stirred solution of 40% potassium hydroxide in water in the presence of catalytic 2-(2-ethoxyethoxy)ethanol while heatin g to reflux. The resulting yellow solution was distilled in glass apparatus with non-ground glass joints and collected and stored over potassium hydroxide. This ether solution of diazomethane was added dropwise by fire-polished pipette to a solution of the crude acid in dry ether (15 mL) at 27 °C until the acid solution remained a persistent yellow color. The reaction mixture was allowed to stir open to the atmosphere at 27 °C until the yellow color dissipated (5-10 minutes). Concentration of this solution and purification by flash column chromatography yielded the pure methyl esters. 138 Hydrolysis of Benzaldehyde Adduct 35 Hydrolysis of (2R, 35) benzaldehyde aldol adduct 35 (205.1 mg, 0.53 mmol) according to the general procedure for 17 hours afforded (—)-pseudoephedrine (73.2 mg, 0.44 mmol, 83.6%) as a crystalline solid and a crude mixture of (2R, 3S)-3-hydroxy-2- methyl-3-phenylpropionic acid with the polymeric silyl contaminant (99.6 mg, 0.55 mmol based on acid, >100%, uncorrected for impurity) as a crystalline solid film. The 1H NMR spectrum of this crude acid shows <2% of the syn acid, relative to the anti isomer. Esterification of this acid mixture with diazomethane and purification by flash column chromatography (50% ethyl acetate in hexanes) gave methyl (2R, 3S)-3-hydroxy-2-methy]l- 3-phenylpropionate (85.1 mg, 0.44 mmol, 83% from 35) as a colorless oil. The 'H NMR spectrum of this purified methyl ester also shows <2% of the syn ester. Chiral GC analysis showed the anti ester to have an ee of 84.3% Hydrolysis of Benzaldehyde Adduct 36 Hydrolysis of (25, 3R) benzaldehyde aldol adduct 36 (59.5 mg, 0.155 mmol) according to the general procedure, for 19 hours afforded (—)-pseudoephedrine (16.7 mg, 0.101 mmol, 65.2%) and a crude mixture of (2S, 3R)-3-hydroxy-2-methyl-3- phenylpropionic acid with the polymeric silyl contaminant (24.7 mg, 0.137 mmol based on acid, 88%, uncorrected for impurity). The 'H NMR spectrum of this crude acid shows 7% of the syn acid, relative to the anti isomer. Esterification of this acid mixture with diazomethane and purification by flash column chromatography (20% ethyl acetate in hexanes, silica gel) gave methyl (25, 3R)-3-hydroxy-2-methyl-3-phenylpropionate (18.6 mg, 0.095 mmol, 62% from 36) as a colorless oil. The 1H NMR spectrum of this 139 purified methyl ester also shows 7% of the syn ester. Chiral GC analysis showed the anti ester to have an ee of 89.5%. This ester was identical to that derived from the major (+)-pseudoephedrine aldol adduct 6. o OH © OH oon wn, CH, CH, (2R, 38) (28, 3R) 4H NMR (300 MHz, CDCl), 5: 1.02 (d, J=7.2 Hz, 3H, -CH3), 2.84 (dq, J=7.2, 8.9 Hz, 1H, H-2), 4.76 (d, J =8.9 Hz, 1H, H-3), 6.44 (br s, D2O exchangeable, 2H, —OH), 7.28-7.40 (m, 5H, aromatics) 3C NMR (75 MHz, CDCl), 3: 14.38 (-CH3), 67.21 (C-2), 76.41 (C-3), 126.78, 128.22, 128.56, 141.15 (aromatics), 180.77 (C-1) FTIR (neat), cm-!: 3378 (br, -OH), 1712 (s, C=O), 1494 (w), 1456 (m), 1408 (m), 1258 (m), 1203 (m), 1125 (w), 1089 (w), 1014 (m), 913 (w), 764 (m), 701 (s) TLC (30% EtOAc in hexanes), Rr: Acid: streaks, depends on concentration (PMA) Methyl Ester: 0.23 (PMA) 140 © OH © OH CH;O~ + 5° Ph CHjO~ 1+ 3 Ph CH, CH, QR, 3S) (28, 3R) Methyl (2R, 35)- and (25, 3R)-3-Hydroxy-2-Methyl-3-Phenylpropionate 4H NMR (300 MHz, CDCI), 5: 0.97 (d, J=7.5 Hz, 3H, ~CH-CH3), 2.79 (dq, J =7.2, 8.7 Hz, 1H, H-2), 3.13 (br d, J = 3.6 Hz, D2O exchangeable, 1H, -OH), 3.70 (s, 3H, -OCH3), 4.72 (dd, J =2.7, 8.7 Hz, 1H, H-3), 7.20-7.40 (m, 5H, aromatics) 13C NMR (75 MHz, CDCls), 8: 14.26 (-CH-CH3), 47.06 (C-2), 51.77 (-OCH3) 76.23 (C-3), 126.57, 127.89, 128.32, 141.49 (aromatics), 176.14 (C-1) FTIR (neat), cm: 3457 (br, -OH), 2979 (m), 2951 (m), 1736 (s, C=O), 1494 (w), 1456 (s) 1436 (m), 1375 (m), 1342 (m), 1309 (m), 1249 (m), 1199 (s, C-O), 1170 (s, C-O), 1124 (m), 1089 (m), 1073 (m), 1053 (m), 1034 (m), 1023 (m), 908 (m), 768 (s) 704 (s) 611 (m) . GC (Chirasil-Val, 110°C), min: (2, 3S) 10.9 (25,3R) 113 141 Hydrolysis of Hydrocinnamaldehyde Adduct 37 Hydrolysis of (2R, 3S) hydrocinnamaldehyde aldol adduct 37 (77.1 mg, 0.187 mmol) according to the general procedure for 20.5 hours afforded (-)-pseudoephedrine (25.6 mg, 0.155 mmol, 82.9%) and a crude mixture of (2R, 3S)-3-hydroxy-2-methy]-5- phenylpentanoic acid with the polymeric silyl contaminant (42.9 mg, 0.206 mmol based on acid, >100%, uncorrected for impurity). The 1H NMR spectrum of the crude acid shows an anti:syn ratio of 82:18. Esterification with diazomethane and purification by filtration through a short silica gel plug (100 % ethyl acetate) gave methyl (2R, 3S)-3-hydroxy-2- methyl-5-phenylpentanoate (37.6 mg, 0.169 mmol, 90.4% from 37) as a slightly yellow oil. This methyl ester could not be cleanly separated from its enantiomer on the chiral GC column (Chirasil—Val), so the ee was not determined. Hydrolysis of Hydrocinnamaldehyde Adduct 38 Hydrolysis of (2S, 3R) hydrocinnamaldehyde aldol adduct 38 (59.2 mg, 0.128 mmol) according to the general procedure for 20.5 hours afforded (-)-pseudoephedrine . (16.5 mg, 0.100 mmol, 78.0%) and a crude mixture of (2S, 3R)-3-hydroxy-2-methyl]-5- phenylpentanoic acid with the polymeric silyl contaminant (25.8 mg, 0.124 mmol based on acid, 96.8%, uncorrected for impurity). The 'H NMR spectrum of the crude acid shows an anti:syn ratio of 93:7. Esterification with diazomethane and purification by filtration through a short silica gel plug (100% ethyl acetate) gave methyl (2S, 3R)-3-hydroxy-2- methyl-5-phenylpentanoate (20.9 mg, 0.094 mmol, 73.4% from 38) as a slightly yellow oil. This methyl ester could not be cleanly separated from its enantiomer on the chiral GC column (Chirasil—Val), so the ee was not determined. 142 fe) OH 0 OH HO" 4 3 Ph HO" 1 3 Ph CH3 (2R, 3S) CH, (2S, 3R) 2R, 35S)- and (2S, 3R)-3-Hydroxy-2-Methyl-5-Phenylpentanoic Acids ‘H NMR (300 MHz, CDCl), 8: FTIR (neat), cm7!: TLC (20% EtOAc in hexanes), Ry: 1.24 (d, J=7.2 Hz, 3H, -CH3), 1.84 (m, 2H, PhCH2CH)-), 2.58 (quintet, J=7.0, Hz, 1H, H-2), 2.71 (ddd, J = 6.9, 9.4, 13.7 Hz, 1H, one of PhCH>-), 2.87 (ddd, J =5.5, 9.5, 13.5 Hz, 1H, one of PhCH»-), 3.72 (ddd, J =3.5, 6.5, 9.5 Hz, 1H, H-3), 5.94 (br s, 2H, -OH), 7.16-7.37 (m, 5H, aromatics) 3500 (br, -OH), 3025 (m), 2942 (m), 1707 (s, C=O), 1496 (w), 1458 (m), 1406 (w), 1260 (m), 1203 (m), 1030 (m), 937 (w), 804 (m), 749 (m), 700 (s) Acid: streaks, depends on concentration (PMA) Methyl Ester: 0.28 (PMA) 143 9 OH Oo OH CHy CH, (2R, 3S) (2S, 3R) - Methyl (2R, 35S)- and (2S, 3R)-3-Hydroxy-2-Methyl-5-Phenylpentanoate _ 1H NMR (300 MHz, CDCl), 5: 1.21 (d, J=7.2 Hz, 3H, -CH-CH3), 1.76 (m, 2H, PhCH2CH?-), 2.55 (dq, J =6.4, 7.1, Hz, 1H, H-2), 2.69 (d, J=6.9 Hz, 1H, -OH), 2.70 (ddd, J = 6.9, 9.6, 13.7 Hz, 1H, one of PhCH), 2.87 (ddd, J=5.5, 9.6, 13.9 Hz, 1H,one of PhCH), 3.67 (ddd, J =3.5, 6.5, 8.7 Hz, 1H, H-3), 3.70 (s, 3H, -OCH3), 7.16-7.33 (m, 5H, aromatics) 13C NMR (75 MHz, CDCh), 5: 14.34 (-CH-CH3), 31.88 (PhCH)-), 36.62 (PhCH,CH)-), 45.19 (C-2), 51.76 (-OCH3) 72.61 (C-3), 125.84, 128.38, 128.43, 141.87 (aromatics), 176.42 (C-1) FTIR (neat), cm-!: 3448 (br, -OH), 2950 (m), 1734 (s, C=O), 1603 (w), 1496 (w), 1456 (m), 1436 (m), 1357 (w), 1262 (m), 1199 (m, C-O), 1167 (m, C-O), 1044 (m), 935 (w), 748 (w), 700 (s) 144 Hydrolysis of Isobutyraldehyde Adduct 39 Hydrolysis of (2R, 3S) isobutyraldehyde aldol adduct 39 (94.7 mg, 0.271 mmol) _ according to the general procedure for 9.5 hours afforded (-)-pseudoephedrine (44.0 mg, 0.266 mmol, 98.3%) and a crude mixture of (2R, 35)-3-hydroxy-2,4-dimethylpentanoic acid with the polymeric silyl contaminant (31.2 mg, 0.213 mmol based on acid, 78.6%, uncorrected for impurity) as a yellow oil. The 1H NMR spectrum of the crude acid shows an anti:syn ratio of 96:4. Esterification with diazomethane and purification by flash column chromatography (20% ethyl acetate in hexanes) gave methyl (2R, 35)-3-hydroxy-2,4- dimethylpentanoate (10.3 mg, 0.064 mmol, 23.7% from 39) as a colorless oil. Chiral GC analysis showed the anti ester to have an ee of 70.3% Hydrolysis of Isobutyraldehyde Adduct 40 Hydrolysis of (25, 3R) isobutyraldehyde adduct 40 (117.4 mg, 0.336 mmol) according to the general procedure for 9.5 hours afforded (-)-pseudoephedrine (48.3 mg, 0.292 mmol, 86.9%) and a crude mixture of (2S, 3R)-3-hydroxy-2,4-dimethylpentanoic acid with the polymeric silyl contaminant (48.3 mg, 0.330 mmol based on acid, 98.3%, uncorrected for impurity) as a yellow oil. The 1H NMR spectrum of the crude acid shows an anti:syn ratio of 94:6. Esterification with diazomethane and purification by flash column chromatography (20% ethyl acetate in hexanes, silica gel) gave methyl (2S, 3R)-3- hydroxy-2,4-dimethylpentanoate (12.3 mg, 0.076 mmol, 22.8% from 40) as a colorless oil. Chiral GC analysis showed the anti ester to enantiomerically pure (100% ee). 145 fe) OH fe) OH 23 CH3 Nh HO" 3 HO" 17 3 CH3 CH; CH, CH | (2R, 35) (2S, 3R) 2R - and (25, 3R)-3-Hydroxy-2,4-Dimethylpentanoic Acid 1H NMR (300 MHz, CDCly), 8: 0.92 (d, J= 6.7 Hz, 3H, —CH3), 0.98 (a, J=6.8 Hz, 3H, -CH3), 1.23 (d, J=7.2 Hz, 3H, -CH3), 1.79 (m, 1H, -CHMe}), 2.67 (quintet, J = 7.0 Hz, 1H, H-2), 3.43 (“t”, J=5.9 Hz, 1H, H-3), 6.23 (br s, 2H, -OH) 3C NMR (75 MHz, CDCl), 5: 14.60 (-CH3), 16.14 (-CH3), 19.74 (-CH3), 30.72 (-CHMez), 42.65 (C-3), 78.06 (C-2), 181.16 (C-1) FTIR (neat), cm7!: 3410 (br, -OH), 2964 (s), 1711 (s, C=O), 1465 (m), 1388 (m), 1261 (s), 1204 (m), 1133 (m), 1097 (m), 1035 (m), 998 (m), 966 (m), 898(w), 804 (m), 658 (w) TLC (30% EtOAc in hexanes), Re: Acid: streaks, depends on concentration (PMA) Methyl Ester: 0.33 (PMA) 146 Oo OH Oo OH CH,0~ 4 3 CH,07 1 3 CH, CHg CH, CHg (2R, 35) (25S, 3R) Methyl (2R,3S)- and (2S, 3R)-3-Hydroxy-2,4-Dimethylpentanoate 'H NMR (300 MHz, CDCls), 8: 0.92 (d, J = 6.7 Hz, 3H, _CH3), 0.96 (d, J = 6.8 Hz, 3H, —CH3), 1.20 (d, J=7.2 Hz, 3H, -CHs3), 1.71 (quintet of d, J = 5.4, 6.8 Hz, 1H, -CHMe?), 1.65 (br s, 1H, -OH), 2.66 (dq, J =6.6, 7.2 Hz, 1H, H-2), 3.38 (t, J=5.8 Hz, 1H, H-3), 3.71 (s, 3H, -OCH3) 13C NMR (75 MHz, CDCl), 8: 14.79 (-CH3), 16.34 (-CH3), 19.75 (-CH3), 30.99 (-CHMez), 42.50 (C-3), 51.76 (-OCHs), 78.21 (C-2), 176.88 (C-1) FTIR (neat), cm-!: 3504 (br, -—OH), 2961 (s), 2878 (m), 1724 (s, C=O), 1459 (m), 1437 (m), 1376 (m), 1260 (s), 1199 (s, C—O), 1171 (s, C—O), 1134 (m), 1100 (m), 1040 (m), 1003 (m), 965 (w), 892 (w), 851 (w), 803 (m) — GC (Chirasil-Val, 55 °C), min: (2R, 3S) 7.36 (2S, 3R) 7.74 147 Hydrolysis of Cyclohexanecarboxaldehyde Adduct 41 Hydrolysis of (2R, 3S) cyclohexanecarboxaldehyde aldol adduct 41 (74.7 mg, 0.192 mmol) according to the general procedure for 11 hours afforded (—)-pseudoephedrine (amount undetermined) and a crude mixture of (2R, 3S)-3-hydroxy- 2-methy]-3-cyclohexanepropionic acid with the polymeric silyl impurity (19.0 mg, 0.102 mmol based on acid, 53%, uncorrected for impurity) as a yellow oil. The 1H NMR spectrum of this crude acid shows an anti:syn ratio of 90:10. Esterification of the crude acid mixture and purification by flash column chromatography (20% ethyl acetate in hexanes) gave methyl (2R, 3.$)-3-hydroxy-2-methyl-3-cyclohexanepropionate (11.0 mg, 0.055 mmol, 28.6% based on 41) as a colorless oil. The 1H NMR spectrum of the methyl ester shows an anti:syn ratio of 86:14, perhaps as an artifact of the very poor yield of acid. Chiral GC analysis showed the anti ester to have an ee of 83.4%. Hydrolysis of Cyclohexanecarboxaldehyde Adduct 42 Hydrolysis of (2S, 3R) cyclohexanecarboxaldehyde aldol adduct 42 (200.7 mg, 0.515 mmol) according to the general procedure for 11 hours afforded (—)-pseudoephedrine (amount undetermined) and a crude mixture of (25, 3R)-3-hydroxy- 2-methyl-3-cyclohexanepropionic acid with the polymeric silyl impurity (70.5 mg, 0.379 mmol based on acid, 73.5%, uncorrected for impurity) as a yellow oil. The 'H NMR spectrum of this crude acid shows an anti:syn ratio of 88:12. Esterification of the crude acid mixture and purification by flash column chromatography (20% ethyl acetate in hexanes) gave methyl (2S, 3R)-3-hydroxy-2-methyl-3-cyclohexanepropionate (51.6 mg, 0.258 mmol, 50.0% based on 42) as a colorless oil. The 1H NMR spectrum of the methyl 148 ester also shows an anti:syn ratio of 88:12. Chiral GC analysis showed the anti ester to be ' enantiomerically pure (100% ee) CH, (2R, 35S) (2S, 3R) 2R, 35)- and (2S, 3R)-3-Hydroxy-2-Methyl-3-Cyclohexylpropionic Acid 4H NMR (300 MHz, CDCI), 5: 1.00-1.32 (m, 4H), 1.24 (d, J=7.2 Hz, 3H, —CH3), 1.40-1.49 (m, 1H), 1.61-1.68 (m, 3H), 1.74-1.82 (m, 3H), 2.71 (quintet, J = 6.9 Hz, 1H, H-2), 3.42 (t, J=5.9 Hz, 1H, H-3), 6.30 (br s, 2H, —OH) '3C NMR (75 MHz, CDCl), 6: 14.73 (-CH3), 25.97, 26.26, 26.29 (cyclohexyl -CH)._), 40.74 (cyclohexyl —CH), 41.89 (C-3), 77.66 (C-2), 181.25 (C-1) FTIR (neat), cm: 3394 (br, -OH), 2927 (s), 2853 (s), 1708 (s, C=O), 1450 (m), 1406 (w), 1259 (m), 1204 (m), 1101 (m), 1028 (m), 982 (w), 892 (w), 803 (s) TLC (100% toluene), Ry: Acid: streaks, depends on concentration (PMA) Methyl Ester: 0.34 (PMA) 149, (2S, 3R) Methyl 2R, 3S)- and (2S, 3R)-3-Hydroxy-2-Methy]-3-Cyclohex ylpropionate 'H NMR (300 MHz, CDCl), 5: 13C NMR (75 MHz, CDCl), 8: FTIR (neat), cm-!: GC (Chirasil-Val,.55 °C), min: 1.03-1.18 (m, 5H), 1.20 (d, J=7.2 Hz, 3H, —CH3), 1.24-1.38 (m, 1H), 1.58-1.66 (m, 2H), 1.73—-1.82 (m, 3H), 2.43 (br s, 1H, -OH), 2.69 (dq, J =6.2, 7.1 Hz, 1H, H-2), 3.36 (t, J= 5.8 Hz, 1H, H-3), 3.70 (s, 3H, -OCH3) 14.81 (-CH3), 26.01, 26.28, 26.31, 26.89, 29.91 (cyclohexyl —CH>_), 40.97 (cyclohexyl —CH), 41.82 (C-3), 51.69 (-OCH3), 77.71 (C-2), 176.90 (C-1) 3490 (br, -OH), 2928 (s), 2853 (s), 1732 (s, C=O), 1451 (s), 1375 (m), 1259 (s), 1199 (s, C-O), 1172 (s, C-O), 1103 (s), 1036 (s), 992 (m), 891 (w), 872 (w), 850 (w), 803 (m) (2R, 3S) 13.1 (2S,3R) 13.6 150 Hydrolysis of Pivalaldehyde Adduct 43 The minor (2R, 35) pivalaldehyde. aldol adduct 43 (22.8 mg, 0.063 mmol, 1 equiv) was treated with triethylamine trihydrofluoride (101 mg, 102 pL, 0.63 mmol, 10 equiv) in acetonitrile (1.0 mL) for 12 hours at 27 °C. Purification by filtration through a short silica plug (100% ethyl acetate) yielded crude diol (16.9 mg, 0.055 mmol, 87.6%) as a white solid. This diol was then subjected to the standard hydrolysis conditions for 5 days. After the standard aqueous extraction procedure, (2R, 3S)-3-hydroxy-2,4,4- trimethylpropionic acid (6.7 mg, 0.042 mmol, 76.4% from diol) was isolated as a crystalline film. The 'H NMR spectrum of this acid shows an anti:syn ratio of 92:8. (—)-Pseudoephedrine (7.0 mg, 0.042 mmol, 77.0% from diol) was also recovered. Hydrolysis of Pivalaldehyde Adduct 44 The major (25, 3R) pivalaldehyde aldol adduct 44 (89.9 mg, 0.247 mmol, 1.0 equiv) was treated with triethylamine trihydrofluoride (169 mg, 171 uL, 1.04 mmol, 4.2 equiv) in acetonitrile (10 mL) for 10 hours at 27 °C. Purification by filtration through a Short silica plug yielded crude diol (32.2 mg, 0.105 mmol, 42.4%) as a white solid. This diol was subjected to the standard hydrolysis conditions for 3 days. After the standard aqueous extraction procedure, (25, 3R)-3-hydroxy-2,4,4-trimethylpropionic acid (12.4 mg, 0.077 mmol, 73.7% from diol) was isolated as a crystalline film. The 1H NMR Spectrum of this acid shows an anti:syn ratio of 91:9. (—)-Pseudoephedrine (17.3 mg, 0.105 mmol. 100% from diol) was also recovered. 151 Oo OH 90 OH 24 CH 2 CHg HOW 13 HO” 1 . CH i CHg CH, CHg CH3 CH (2R, 3S) (2S, 3R) (2R, 3S)- and (25, 3R)-3-Hydroxy-2,4,4-Methylpropionic Acids 4H NMR (300 MHz, CDCl), 6: 0.94 (s, 9H, -C(CH3)3), 1.40 (d, J=7.2 Hz, 3H, —CHCH3), 2.78 (dq, J = 2.0, 7.3 Hz, 1H, H-2), 3.25 (d, J = 2.1 Hz, 1H, H-3) 13C NMR (75 MHz, CDCl), 8: 18.16 (-CHCH3), 26.07 (-C(CH3)3), 36.02 (-CMes3), 82.46 (C-3), 181.60 (C-1) FTIR (neat), cm-!: 3287 (very br, -OH), 2961 (s), 2682 (m), 2607 (m), 1694 (s, C=O), 1465 (s), 1349 (m), 1289 (s), 1220 (s), 1198 (s), 1119 (m),1055 (m), 976 (s), 811 (w), 730 (w) 152 CHy = CHs Oo OH jal OH clo AY CH,0 clo om A, CH, | CgHeg, reflux, 2 hr CHO CH, 4 (R) 47 70% N-methoxy-N-methyl (2R)-3-Hydroxy-2-Methylpropionamide 47 Triethylaluminum (2.0 M in toluene, 30 mL, 60 mmol, 3.0 equiv) was added dropwise via cannula to a solution of N,O-dimethyl hydroxylamine hydrochloride (5.85 g, 60 mmol, 3.0 equiv) in dry benzene (60 mL) at 0°C. After stirring at 0°C for 10 minutes, the solution was warmed to 27 °C and stirred 1 hour, 45 minutes further. To this aluminum amide complex was added a solution of methyl (R)-(—)-3-hydroxy-2-methyl propionate (2.3626 g, 2.22 mL, 20 mmol, | equiv) in dry benzene (40 mL) via dropping funnel over 40 minutes. When the addition was complete, the solution was heated to reflux for 2 hours. After cooling to 0 °C, 1 N HCl (30 mL) was added to quench excess aluminum amide complex. The layers were separated and the aqueous layer extracted further with three 30-mL portions of dichloromethane . The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by flash column chromatography (100% ethyl acetate-—>30% methanol in ethyl acetate) affording (R) propionamide 47 (2.0572 g, 13.98 mmol, 69.9%) as a pale yellow oil. 153 CHy CH o OH pm » OH cHi0 A? CHO Cl CHa ae, (S) 48 60% N-methoxy-N-methyl (2,5)-3-Hydroxy-2-Methylpropionamide 48 Triethylaluminum (2.0 M in toluene, 54.1 mL, 108.3 mmol, 3.0 equiv) was added dropwise via cannula to a solution of N,O-dimethyl hydroxylamine hydrochloride (10.56 g, 108.3 mmol, 3.0 equiv) in dry benzene (100 mL) at 0 °C. After stirring at 0 °C for 15 minutes, the solution was warmed to 27 °C and stirred 1 hour further. To this aluminum amide complex was added a solution of methyl (S)-(+)-3-hydroxy-2-methyl propionate (4.264 g, 4.00 mL, 36.1 mmol, { equiv) in dry benzene (25 mL) via dropping funnel over 30 minutes. When the addition was complete, the solution was heated to reflux for 1 hour, 40 minutes. After cooling to 0°C, 1 N HCl (80 mL) was added to quench excess aluminium complex. The layers were separated and the aqueous layer extracted further with three 30-mL portions of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by flash column chromatography (100% ethyl acetate) affording (S) propionamide 48 (3.1789 g, 21.6 mmol, 59.8%) as a colorless oil 154 Propionamides 47 and 48 1H NMR (300 MHz, CeDo), 8: 1.06 (d, J=7.1 Hz, 3H, H-4), 2.81 (s, 3H, N-—CH3), 2.89 (m, 2H, one H-3 and —-OH), 3.03 (s, 3H, N-OCH3), 3.60 (m, 1H, one H-3), 3.80 (m, 1H, H-2) C NMR (75 MHz, CeDo), 8: 13.94 (C-4), 31.87 (N-CH3), 38.32 (N-OCH3), 61.12 (C-2), 64.92 (C-3), 176.68 (C-1) FTIR (neat), cm: 3417 (br, -OH), 2976 (m), 2940 (m), 2880 (w), 1634 (s, C=O), 1464 (m), 1392 (m), 1325 (w), 1118 (m), 1070 (m), 1035 (m), 991 (m) 155 | O”~ NH o OH en a o OTS ) | DMF, 27 °C, 3 hr ; | CH30 CH3 Ph CHO CH3 4 47 49 91% N-methoxy-N-methyl (2R)-3-(tert-Butyldipheny!)Siloxy-2-Methylpropionamide 49 tert-Butyldiphenyl silyl chloride (2.36 g, 2.24 mL, 9.53 mmol, 1.25 equiv) was added to a solution of (R) hydroxy amide 47 (1.1222 g, 1.00 mL, 7.63 mmol, 1 equiv) and imidazole (1.298 g, 19.1 mmol, 2.5 equiv) in DMF (7.6 mL). After Stirring 3 hours at 27 °C, the solution was diluted with ether (20 mL), then washed sequentially with saturated aqueous solutions of citric acid (20 mL), sodium bicarbonate (20 mL), and sodium chloride (20 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by flash column chromatography (hexanes>40% ethyl acetate in hexanes), affording (R) siloxy amide 49 (2.6785 g, 6.95 mmol, 91.0%) as a colorless oil which crystallizes on standing. 156 7° ~ NH OTDS fe) OC) Oo OH Ph ot J + 3 cl CHon 3 i J | DMF, 27 °C, 12.5 hr pt: CH30 CH3 Ph CH30 CH3 4 48 50 80% N-methoxy-N-methyl (2S)-3-(tert-Butyldiphenyl)Siloxy-2-Methylpropionamide 50 tert-Butyldiphenyl silyl chloride (5.92 g, 5.60 mL, 23.9 mmol, 1.25 equiv) was _ added to a solution of (S) hydroxy amide 48 (2.8130 g, 2.50 mL, 19.11 mmol, 1 equiv) and imidazole (3.253 g, 47.8 mmol, 2.5 equiv) in DMF (19.1 mL). After stirring 12.5 hours at 27 °C, the solution was diluted with ether (25 mL), then washed sequentially with saturated aqueous solutions of citric acid (15 mL), sodium bicarbonate (15 mL), and sodium chloride (15 mL). The organic layer was dried over sodium sulfate, filtered, concentrated affording (5) siloxy amide 50 (5.91 g, 15.33 mmol, 80.2%) as a colorless oil which crystallizes on standing. Siloxy Amides 49 and 50 'H NMR (300 MHz, CeDo), 8: ‘1.01 (d, J = 7.0 Hz, 3H, H-4), 1.14 (s, 9H, ~C(CH3)3), 2.93 (s, 3H, N-CH3), 3.18 (s, 3H, N-OCH3), 3.23 (m, 1H, H-2), 3.65 (dd, J = 5.8, 9.4 Hz,1H, H-3), 4.15 (dd, J = 8.8, 9.2 Hz, 1H, 137 H-3), 7.18—7.28 (m, 6H, aromatics), 7.75-7.85 (m, 4H, aromatics) 3C NMR (75 MHz, CeDo), 8: 13.89 (C-4), 19.46 (-CMe3), 27.02 (-C(CH3)3), 32.06 (N-CH3), 38.33 (N-OCH3), 61.04 (C-2), 66.74 (C-3), 127.79, 128.05, 129.94, 133.82, 134.22, 135.94, 136.12 (aromatics), 175.76 (C-1) FTIR (neat), cm-!: 3071 (m), 3049 (m), 2960 (s), 2933 (s), 2857 (s), 1661 (s, C=O), 1472 (s), 1427 (s), 1388 (s), 1361 (w), 1318 (w), 1260 (w), 1168 (m), 1152 (m), 1112 (s), 998 (s), 824 (s), 739 (s), 703 (s), 689 (s), 614 (s) HRMS (FAB), m/z: Calcd for C22H3,;03NSi (MH*): 386.2151 Found, 49: 386.2150 Found, 50: 386.2150 TLC (30% EtOAc in hexanes), Re: Amides 49 and 50: 0.35 (UV and PMA) 158 fe) OTDS oC OTDS CHa LiAIH,, EtpO 2 ~78°C, 1.5 hr 1 y 3 CH,0 CH3 CH3 4 49 45 64% (2R)-3-(tert-Butyldiphenyl)siloxy-2-Methylpropionaldehvde 45 Lithium aluminum hydride (1.0 M in ether, 2.1 mL, 2.1 mmol, 1.0 equiv) was added to a solution of (R) siloxy amide 49 (804.6 mg, 2.09 mmol, 1 equiv) in dry ether (20 mL) at -78 °C. After stirring at -78 °C for 1.5 hours, excess lithium aluminium hydride was quenched with a saturated solution of citric acid in THF (30 mL) at —78 °C. After warming to 27 °C, the solution was diluted with ether (20 mL), and washed sequentially with saturated aqueous solutions of citric acid (10 mL), sodium bicarbonate (10 mL), and sodium chloride (10 mL). The organic layer was dried, filtered, concentrated, and purified by flash column chromatography (10%—30% ethyl acetate in ‘ hexanes), affording (R) aldehyde 45 (436.0 mg, 1.34 mmol, 64.9%) as a colorless oil. fe) OTDS O OTDS CHyw LIAIH,, EtpO 2 ~78°C, 1.5hr 1 8 CH,O CH CH, 4 50 46 71% (2S)-3-( tert-Butyldiphenyl)siloxy-2-Methylpropionaldehyde 46 Lithium aluminum hydride (1.0 M in ether, 5.14 mL, 5.14 mmol, 1.0 equiv) was added to a solution of (S) siloxy amide 50 (1.98 g, 5.14 mmol, 1 equiv) in dry ether (50 159 mL) at ~78 °C. After stirring at -78 °C for 1.5 hours, excess lithium aluminium hydride was quenched with a saturated solution of citric acid in THF (50 mL) at -78 °C. After warming to 27.°C, the solution was diluted with ether (50 mL), and washed sequentially with saturated aqueous solutions of citric acid (25 mL), sodium bicarbonate (25 mL), and sodium chloride (25 mL). The organic layer was dried, filtered, concentrated, and purified by flash column chromatography (10%—50% ethyl acetate in hexanes, silica gel), affording (S) aldehyde 46 (1.1908 g, 3.65 mmol, 70.9%) as a colorless oil. Siloxy Aldehydes 45 and 46 1H NMR (300 MHz, C6Do), 8: 0.80 (d, J=7.1 Hz, 3H, H-4), 1.09 (s, 9H, —C(CH3)3), 2.05 (m, 1H, H-2), 3.57 (dd, J = 6.0, 10.3 Hz, 1H, H-3), 3.63 (dd, J =4.8, 10.3 Hz, 1H, H-3), 7.16-7.23 (m, 6H, aromatics), 7.66-7.71 (m, 4H, aromatics), 9.48 (d, J = 1.5 Hz, 1H, aldehyde H) '3C NMR (75 MHz, CeDo), 8: 10.20 (C-4), 19.40 (-CMe3), 26.94 (-C(CHs3)3), 48.82 (C-2), 64.18 (C-3), 128.10, 128.20, 129.72, 130.10, 133.60, 135.94, 136.06, (aromatics), 202.43 (C-1) FTIR (neat), cm-!: 3071 (w), 3050 (w), 2959 (s), 2931 (s), 2858 (s), . 1738 (s, C=O), 1589 (w), 1472 (m ), 1462 (m), 1428 (s), 1391 (w), 1362 (w), 1330 (w), 1307 (w), 1260 (w), 1188 (w), 1112 (s), 1035 (m), 1008 (w), TLC (30% EtOAc in hexanes), Rr: 160 998 (w), 961 (w), 937 (w), 823 (s), 805 (s), 740 (s), 702 (s), 614 (s) . Amides 49 and 50: 0.35 (UV and PMA) Aldehydes 45 and 46: 0.56 (UV and PMA) 161 CH m4 aCHg rc o— Si Om gin Hs \ OTDS OTDS fe) ‘o 1 4 CHeCly \ : 30 °C, 24 hr : | CH = 3 CH3 CHg CHg 1 (5) 45 (R) 52 28% (25, 3R, 4R) (1'S, 2S, 3R, 4R) Aldol Adduct 52 The silyl ketene acetal derived from (S)-prolinol propionamide 1 (102.6 mg, 100 LL, 0.48 mmol, 1 equiv), was syringed into a tared, empty 10-mL Schlenk tube under argon, then weighed. A solution of (R) aldehyde 45 (157.2 mg, 0.48 mmol, 1.0 equiv) in dry dichloromethane (1.0 mL) was then added by syringe. After stirring at 30 °C for 24 hours, the reaction solution was concentrated and purified by flash column chromatography (40%-»90% ether in pet. ether), affording aldol adduct 52 (73.0 mg, 0.135 mmol, 28.2%) as a viscous, colorless oil. . HgC on dw CHs ° sf 0 OTDS fe) oO OTDS vA i 30 °C, 24 hr i E CH3 CH3 CH3 CHg 1 (S) 46 (S) 53 32% (2S, 3R, 45) 1'S, 2S, 3R. 4S) Aldol Adduct 53 By the preceding procedure, (S) silyl ketene acetal 1 (212.8 mg, 213 WL, 1.0 mmol, 1 equiv) and (S) aldehyde 46 (326.0 mg, 1.0 mmol, 1.0 equiv) in dry dichloromethane (2.0 mL) produced aldol adduct 53 (171.1 mg, 0.317 mmol, 31.7%) as a viscous, colorless oil. 162 He .CHg CH, — sic O~ fw CHy YP si 9 —OTDS £ Q “oO oOTDS = O CH2Clp ? z + —— vA. 30°C, 24hr ( | CHg CHs CH, CHg3 51 (R) 45 (R) 54 24% (2R, 3S, 4R) (1'R, 2R, 35, 4R) Aldol Adduct 54 By the same procedure, (R) silyl ketene acetal 51 (106.1 mg, 100 uL, 0.50 mmol, 1 equiv) and (R) aldehyde 45 (162.5 mg, 0.50 mmol, 1.0 equiv) in dry dichloromethane (1.0 mL) produced aldol adduct 54 (64.8 mg, 0.12 mmol, 24%) as a viscous, colorless oil. Hog ,CH CH 3 3 o- Si fe) OTDS fe) QO OTDS CHoClo f oe AV 30°C, 24hr — { myo? CHg CH, CHy CHs 51 (R) 46 (S) 55 42% (2R, 38S, 48) UR, 2R. 35, 4S) Aldol Adduct 55 By the same procedure, (R) silyl ketene acetal 51 (222.9 mg, 213 uL, 1.05 mmol, 1 equiv) and (S) aldehyde 46 (341.5 mg, 1.05 mmol, 1.0 equiv) in dry dichloromethane (2.1 mL) produced aldol adduct 55 (235.7 mg, 0.437 mmol, 42%) as a viscous, colorless oil with a strong peanut odor. 163 H3C 1 .CH3 O~ si oC OTDS cue roe) OTDS Oo 2wil2 + ow —_—_—e— \ CHs CHg . CH3 CHg 1 (S) 46 (S) 53 42% (2S, 3R, 4S) (1'S, 2S, 3R, 45) Aldol Adduct 53 (Low Temperature Conditions) A solution of the silyl ketene acetal derived from (S)-prolinol propionamide 1 (948 mg, 905 WL, 4.45 mmol, 1.08 equiv) and (S) aldehyde 46 (1.3365 g, 4.09 mmol, 1 equiv) in dry dichloromethane (4.0 mL) was stirred under argon for 44 hours at 0 °C. After concentration and purification by flash column chromatography (40%— 100% ether in pet. ether), aldol adduct 53 (171.1 mg, 0.317 mmol, 31.7%) was recovered as a viscous, colorless oil. eG CHs CHg ose O~ ds CH3 / fs 9 OTDS £ 9 O- OTDS : O aw CH2Cla Po. z + —_- owe i 0°C,55hr ( , H CH3 CHg CH, CH3 51 (R) 46 (S) 55 48% (2R, 3S, 45) (1'R, 2R, 35, 45) Aldol Adduct 55 (Low Temperature Conditions) A solution of the silyl ketene acetal derived from (R)-prolinol propionamide 51 (929.1 mg, 890 UL, 4.36 mmol, 1.10 equiv) and (S) aldehyde 46 (1.2933 g, 3.96 mmol, 1.0 equiv) in dry dichloromethane (4.0 mL) was stirred under argon for 55 hours at 0 °C. After concentration and purification by flash column chromatography (50%—100% ether in pet. ether), aldol adduct 55 (1.034 g, 1.92 mmol, 48.5%) was recovered as a viscous, colorless oil with a strong peanut odor. 164 HG aCHg Hs aCHs , 0 Si , 0-— Sk 5 o OTDS "4/9 “9g ons 1' 2 4 i \S CHa CH, 6 CHa CH 3 4 6 7 o 4 6 7 52 (2S, 3R, 4R) 55 (2R, 35, 45) C'S, 25, 3R, 4R) Aldol Adduct 52 and (1'R, 2R, 3S, 4S) Aldol Adduct 55 'H NMR (300 MHz, CeDg), 8: '3C NMR (75 MHz, CgDg), 5: 0.10 (s, 3H, Si-CH3), 0.35 (s, 3H, Si-CH3), 0.80 (d, J=6.9 Hz, 3H, H-7), 1.10 (d, J = 6.5 Hz, 3H, H-6), 1.20 (m, 1H, H-2'), 1.21 (s, 9H, -C(CH3)3), 1.36 (m, 2H, H-2', H-3'), 1.72 (m, 1H, H-3’), 1.98 (m, 1H, H-4), 2.76 (dq, J = 6.5, 10.0 Hz, 1H, H-2), 2.94 (t of d, J=3.0, 8.5 Hz, 1H, H-4'), 3.28 (d, J=10.9 Hz, 1H, H-5'), 3.37 (dt, J=6.4, 9.3 Hz, 1H, H-4'), 3.59 (dd, J = 6.3, 9.9 Hz, 1H, H-5S), 3.72 (dd, J = 8.2, 9.9 Hz, 1H, H-5), 3.93 (t of d, J=2.9, 7.4 Hz, 1H, H-1'), 4.23 (dd, J= 1.4, 10.0 Hz, 1H, H-3), 4.94 (dd, J =3.1, 10.9 Hz, 1H, H-5'), 7.20-7.27 (m, 6H, aromatics), 7.77—7.82 (m, 4H; aromatics) —5.86 (Si-CH3), -1.04 (Si-CH3), 9.05 (C-7), 12.88 (C-6), 19.43 (-CMe3), 24.75 (C-2'), 27.18 (-C(CH3)3), 28.62 (C-3'), 37.77 (C-4), 41.51 FTIR (neat), cm-!: HRMS (FAB), m/z: TLC (30% EtOAc in hexanes), Ry: 165 (C-2), 48.89 (C-4'), 58.95 (C-1'), 61.98 (C-5'), 67.05 (C-5), 77.04 (C-3), 128.07, 130.00, 130.05, 134.22, 135.93, 136.03 (aromatics), 173.69 (C-1) 3071 (w), 3049 (w), 2963 (m), 2933 (m), 2879 (m), 2858 (m), 1638 (s, C=O), 1472 (m), 1428 (s), 1256 (m), 1130 (m), 1110 (s), 1084 (s), 1049 (s), 990 (w), 912 (w), 872 (w), 855 (m), 838 (m), 825 (m), 799 (m), 739 (w), 703 (s), 690 (w), 614 (m) Calcd C39H4604NSi2 (MH+): 540.2982 Found, 52: 540.2966 Found, 55: 540.2977 Aldehydes 45 and 46: 0.56 (UV and PMA) Aldol Adducts 52 and 55: 0.22 (UV and PMA) 53 (25S, 3R, 45) 166 : 2 4 2 { 1 3 5 4 ' CHs CH 3 4 6 7 54 (2R, 3S, 4R) (1'S, 25, 3R, 4S) Aldol Adduct 53 and (1'R, 2R, 3S, 4R) Aldol Adduct 54 ‘HY NMR (300 MHz, CsDg), 8: 13C NMR (75 MHz, C6Dz), 8: 0.10 (s, 3H, Si-CH3), 0.22 (s, 3H, Si-CH3), 0.86 (d, J=6.9 Hz, 3H, H-7), 1.16 (s, 9H, -C(CH3)3), ~1.16 (d, 3H, H-6, partially obscured), ~1.18 (m, 1H, H-2', partially obscured), 1.50 (m, 2H, H-2', H-3'), 1.73 (m, 1H, H-3'), 2.07 (sextet of d, J=1.3, 6.7 Hz, 1H, H-4), 2.98 (t of d, J=2.9, 8.6 Hz, 1H, H-4'), 3.17 (dq, J = 6.5, 10.1 Hz, 1H, H-2), 3.27 (d, J=10.9 Hz, 1H, H-5'), 3.39 (dt, J= 6.5, 9.4 Hz, 1H, H-4'), 3.61 (dd, J=6.4, 10.1 Hz, 1H, H-5), 3.79 (dd, J=1.3, 10.1 Hz, 1H, H-3), 3.92 (dt, J = 2.9, 7.4 Hz, 1H, H-1'), 4.90 (dd, J =3.2, 10.9 Hz,1H, H-S'), 7.22 (m, 6H, aromatics), 7.79 (m, 4H, aromatics) ~6.16 (Si-CH3), -1.10 (Si-CH3), 13.22 (C-7), 16.33 (C-7), 19.35 (-CMes3), 24.70 (C-2'), 27.07 FTIR (neat), cem-!: HRMS (FAB), m/z: TLC (30% EtOAc in hexanes), Ry: 167 (-C(CH3)3), 28.57 (C-3'), 37.36 (C-4), 42.55 (C-2), 49.00 (C-4'), 58.85 (C-1'), 61.92 (C-5'), 64.67 (C-5), 81.67 (C-3), 128.04, 130.01, 133.91, 134.20, 135.97 (aromatics), 174.21 (C-1) | 3071 (w), 3049 (w), 2961 (s), 2932 (s), 2879 (s), 2858 (s), 1634 (s, C=O), 1471 (s), 1462 (s), 1428 (s), 1390 (w), 1372 (w), 1337 (w), 1311 (Ww), 1286 (w), 1257 (s), 1202 (w), 1188 (w), 1162 (Ww), 1112 (s), 1076 (s), 1050 (s), 990 (m), 912 (m), 872 (m), 855 (s), 839 (s), 800 (s), 740 (m), 703 (s), 614 (m) Caled for C39H4gO4NSi2 (MH*): 540.2982 Found, 53: 540.2966 Found, 54: 540.2968 Aldehydes 45 and 46: 0.56 (UV and PMA) Aldols Adducts 53 and 54: 0.23 (UV and PMA) 168 HC 1 .CH3 Si : f- Oo OTDS oO OH OH EtgN¢3HF ; : . ——__—— 1 2k 4 ' i = CH3CN, 27 °C, 26 hr 2' 1 : 3 z / 5 CH3 CHg ; | CHg — CHg 53 56 61% (1'S, 2S. 3R. 4S) Triol 56 Triethylamine trihydrofluoride (553.9 mg, 560 UL, 3.436 mmol, 2.0 equiv) was added to a solution of silylated aldol adduct 53 (927.3 mg, 1.718 mmol, 1 equiv) in dry acetonitrile (25 mL). After 26 hours at 27 °C, the solution was concentrated and partitioned between hexanes (15 mL) and distilled water (10 mL). The hexane layer was further washed with distilled water (2 x 10 mL). The combined aqueous layers were saturated with solid sodium chloride and extracted with dichloromethane (3 x 10 mL). The combined dichloromethane layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by filtration through a short silica plug (ethyl acetate) to give triol 56 (257.1 mg, 1.048 mmol, 61%) as a colorless oil. 'H NMR (300 MHz, CeDo), 8: 0.81 (d, J=7.0 Hz, 3H, H-7), 1.09 (d, J = 7.0 Hz, 3H, H-6), 1.30 (m, 4H, H-2', H-3'), 1.79 (ddq, J = 5.0, 5.4, 7.0 Hz, 1H, H-4), 2.44 (dq, J=4.4, 7.0 Hz, 1H, H-2), 2.74 (m, 1H, -OH), 2.86 (m, 1H, H-4'), 3.30 (m, 1H, H-4'), 3.43 (dd, J=6.3, 11.1 Hz, 1H, H-5'), 3.48 (m, 1H, 13C NMR (75 MHz, CDCl), 8: FTIR (neat), cm7!: HRMS (FAB), m/z: TLC (10% MeOH in EtOAc), Ry: 169 H-3), 3.67 (dd, J = 3.5, 11.1 Hz, 1H, H-5'), 3.75 (d, J=5.3 Hz, 2H, H-5), 3.97 (m, 1H, H-1), 4.42 (br s, 1H, -OH), 5.23 (br d, J=7.9 Hz, 1H, —OH) 14.50 (C-6), 14.70 (C-7), 24.17 (C-2'), 27.97 (C-3'), 38.56 (C-4), 39.36 (C-2), 48.02 (C-4'), 60.59 (C-1'), 65.70 (C-5), 66.69 (C-5'), 79.59 (C-3), 177.17 (C-1) 3370 (s, br, -OH), 2966 (m), 2927 (m), 2877 (m), 1604 (s, C=O), 1458 (s), 1040 (m), 989 (m) Calcd for Cj2H2404N(MH?+): 246.1705 Found: 246.1702 Aldo! Adduct 53: 0.65 (UV and PMA) Triol 56: 0.18 (PMA, not UV active) 170 ~ HgC 3 ' Chg o— Si (9) QO OTDS : EtsNeSHF ( AY CH3CN, 27 °C, 26 hr 2! \ CH, CHg 55 | 57 64% vt. 'R. 2R. 3S. 48) Triol 57 Triethylamine trihydrofluoride (594.5 mg, 601 UL, 3.688 mmol, 2.0 equiv) was added to a solution of silylated aldol adduct 55 (995.3 mg, 1.844 mmol, 1 equiv) in dry acetonitrile (25 mL). After 26 hours at 27 °C, the solution was concentrated and partitioned between hexanes (15 mL) and distilled water (10 mL). The hexane layer was further washed with distilled water (2 x 10 mL). The combined aqueous layers were saturated with solid sodium chloride and extracted with dichloromethane (3 x 10 mL). The combined dichloromethane layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by filtration through a short silica plug (ethyl acetate) yielding triol 57 (289.2 mg, 1.179 mmol, 63.9%) as a colorless oil. 1H NMR (300 MHz, CeDg), 8: 0.89 (d, J = 7.0 Hz, 3H, H-7), 1.07 (d, J = 6.9 Hz, 3H, H-6), 1.76-1.87 (m, 3H, H-4, H-2', H-3"), 1.94-2.03 (m, 2H, H-2', H-3), 2.78 (dq, J =7.1, 8.0 Hz, 1H, H-2), 3.49 (dd, J = 5.8, 11.2 Hz, 1H, H-5'), 3.50 (m, 1H, H-4'), 3.61 (d, J =5.8 Hz, 2H, H-5), 3.65 (m, 1H, H-4’, 3.80 13C NMR (75 MHz, CDCI), 8: FTIR (neat), cm*!: HRMS (FAB), m/z: TLC (10% MeOH in EtOAc), Ry: 171 (dd, J=3.6, 11.2 Hz, 1H, H-5'), 3.94 (dd, J = 3.0, 8.2 Hz, 1H, H-3), 4.18 (m, 1H, H-1'), 4.40 (br s, 1H, -OH) 9.71 (C-7), 13.72 (C-6), 24.17 (C-2'), 27.92 (C-3'), 36.86 (C-4), 41.08 (C-2), 48.06 (C-4'), 59.88 (C-1'), 64.79 (C-5'), 65.88 (C-5), 74.88 (C-3), 176.84 (C-1) 3380 (br, s, -~OH), 2968 (m), 2880 (m), 1600 (s, C=O), 1455 (s), 1376 (w), 1335 (w), 1247 (w), 1192 (w), 1158 (w), 1114 (w), 1043 (s), 983 (m), 901 (w) Calcd for Cy2H2404N(MH?+): 246.1705 Found: 246.1706 Aldol Adduct 55: 0.65 (UV and PMA) Triol 57: 0.18 (PMA, not UV active) 172 oO 6 OH CH 9 OH OH 1 2 Cww 1. NaOH os z 2. Ht . 3 OH CH, CHs CH3 7 56 58 61% Lactone 58 . (1'S, 2.5, 3R, 45) Triol 56 (253.5 mg, 1.033 mmol, 1 équiv) was dissolved in a 0.33 M solution of sodium hydroxide in 4:1 methanol-water (15.6 mL, 5.17 mmol, 5.0 equiv) and refluxed for 18 hours. The solution was concentrated to dryness in vacuo, acidified with 1 N aqueous HCI (10 mL), then extracted with dichloromethane (3 x 15 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated to yield a crude lactone mixture (119.2 mg, 0.827 mmol, 80.0%) as a yellow, non-viscous liquid. The 'H NMR spectrum of this crude product shows a 83:12:5 ratio of three products. Purification of the crude mixture by flash column chromatography. (100% ether) afforded major lactone 58 (90.4 mg, 0.627 mmol, 60.7%) as a colorless oil. The acidic aqueous layer was saturated with solid sodium chloride, basified with solid sodium hydroxide to pH > 10, and extracted with dichloromethane (3 x 15 mL). The “* Organic extracts were dried over sodium sulfate, filtered, and concentrated to yield (S)-prolinol (81.3 mg, 0.804 mmol, 77.8%) as a colorless oil. 'H NMR (300 MHz, C6Dg), 5: 0.71 (d, J=6.8 Hz, 3H, H-7), 1.31 (d, J =7.2 Hz, 3H, H-6), 1.59 (dddq, J = 1.0, 5.7, 12.0, 6.8 13C NMR (75 MHz, C6De), 8: FTIR (neat), cm7!: HRMS (ED), m/z: TLC (100% Et,0), Ry: 173 Hz, 1H, H-4), 2.08 (dq, J = 3.0, 7.1 Hz, 1H, H-2), 3.39 (br s, 1H, H-3), 3.74 (br s, 1H -OH), 3.79 (ddd, J = 0.9, 5.9, 10.8 Hz, 1H, H-5eq), 4.15 - (dd, J = 10.8, 11.8 Hz, 1H, H-5,,) 12.77(C-7), 13.21 (C-6), 33.91 (C-4), 42.90 (C-2), 70.68 (C-5), 70.98 (C-3), 174.36 (C-1) 3448 (br, -OH), 2974 (m), 2907 (m), 1718 (s, C=O), 1417 (w), 1414 (w), 1377 (w), 1349 (w), 1249 (w), 1193 (m), 1167 (s, C—O as. St.), 1125 (m), 1037 (s, C—O sy. st.), 975 (m) Caled for C7H1203 (M°+): 144.0786 Found: 144.0783 Lactone 58: 0.25 (PMA, not UV active) Lactone 59 174 59 35% By the proceeding procedure, triol 57 (283.7 mg, 1.156 mmol, 1 equiv) was refluxed with sodium hydroxide (0.33 M in 4:1 MeOH-H,0, 17.4 mL, 5.8 mmol, 5.0 equiv) for 18 hours. After the aqueous workup, a crude lactone mixture (118.2 mg, 0.82 mmol, 70.9%) is recovered as a crystalline film. The 1H NMR spectrum of this crude product shows a 67:25:7 ratio of three products, none of which are identical to lactone 58. Recrystallization from ether afforded major lactone 59 (59.0 mg, 0.409 mmol, 35.4%) as colorless needles (mp: 91-92 °C). (R)—Prolinol (68.1 mg, 0.673 mmol, 58.2%) was also recovered as a colorless oil. 1H NMR (300 MHz, C¢Dg), 5: 0.41 (d, J=7.2 Hz, 3H, H-7), 1.10 (d, J=7.0 Hz, 3H, H-6), 1.48 (br s, 1H, -OH), 1.56 (dddq, J = 4.2, 5.5, 9.7, 7.1 Hz, 1H, H-4), 1.95 (dq, J=4.5, 7.0 Hz, 1H, H-2), 3.01 (t, J/=4.3 Hz, 1H, H-3), 3.10 (dd, J=9.4, 11.4 Hz, 1H, H-5,,), 3.77 (dd, J = 5.6 Hz, 1H, H-5Seq) 13C NMR (75 MHz, CsDs), 8: FTIR (neat), cm-!; TLC (100% Et,0), Rp: 175 11.56 (C-7), 14.58 (C-6), 36.63 (C-4), 38.76 (C-2), 69.72 (C-5), 74.13 (C-3) 3492 (s, sharp, -OH), 2985 (m), 2962 (m), 2929(m), 2895 (m), 1744 (s, C=O), 1725 (s, C=O), 1452 (m), 1400 (m), 1267 (m), 1178 (s), 1164 (s, C-O as. st.), 1118 (m), 1074 (m), 1030 (m, C-O sy. st.), 989 (s), 737 (m), 620 (m) Lactone 59: 0.20 (PMA, not UV active) 176 CH3 HG CH Hag CHa \ ‘ Si. ' Si. Phe Om ci CH Pha’ LO Phat Lom : ‘ ” PhCHO 0 ~o 9 ~o 31 °C, 45 hr 24 * Ak | 3 3 3' = , CH CH3 CH3 CH, CH3 4 4 4 60 47% 61 24% (2R, 3S) (2S, 3R) (—)-Ephedrine—Benzaldehyde Aldol Adducts 60 and 61 Benzaldehyde (1.209 g, 1.158 mL, 11.39 mmol, 1.0 equiv) and the O-silyl ketene N,O-acetal derived from (—)-ephedrine propionamide 4 (3.1595 g, 3.00 mL, 11.39 mmol, 1 equiv) were combined in a 25 mL Schlenk tube under argon. The solution was stirred at 31 ° for 45 hours, by which time the products had crystallized from solution. Purification by flash column chromatography (30% ether in pet. ether) afforded separately major product 60 (2.03 g, 5.30 mmol, 46.5%) as a colorless, crystalline solid (mp: 151-153 °C) and minor product 61 (1.07 g, 2.79 mmol, 24.5%) as a colorless oil which crystallized on standing to a colorless solid (mp: 70-76 °C). (1'R, 2'S, 2R, 3S) Anti Aldol Adduct 60 'H NMR (300 MHz, C¢Do), 8: -0.03 (s, 3H, Si-CH3), 0.31 (s, 3H, Si-CH3), 0.86 (br s, 3H, H-3'), 0.99 (d, J=6.7 Hz, 3H, H-4), 2.66 (slightly br s, 3H, N-CH3), 3.19 (br s, 1H, H-2), 4.91 (br s, 2H, H-1', H-2'), 5.14 (br d, J=8.2 Hz, 1H, H-3), 7.04-7.33 (m, well resolved, 10 H, aromatics) 1H NMR (300 MHz, CDCI,), 5: '3C NMR (75 MHz, CDCl), 8: FTIR (neat), cm-!: HRMS (FAB), m/z: 177 0.10 (slightly br s, 3H, Si-CH3), 0.25 (sharp s, 3H, Si-CH3), 0.74 (d, J= 6.5 Hz, 3H, H-4), 1.26 (d, J=5.8 Hz, 3H, H-3'), 2.52 (slightly br s, 3H, N-CHs3), 3.16 (slightly br dq, J =7.1, 8.2 Hz, 1H, H-2), 4.90 (d, J = 8.7 Hz, 1H, H-3), 5.07 (m, 2H, H-1', H-2'), 7.24-7.43 (m, well resolved, 10 Hi) —4.35 (Si-CH3), —3.19 (Si-CH,), 15.85 (C-4), 17.10 (C-3'), 30.71 (N-CHs3), 45.24 (C-2), 55.20 | (C-2'), 75.24 (C-1'), 78.70 (C-3), 126.78, 127.27, 127.56, 127.60, 128.13, 139.89, 142.51 (aromatics), 177.07 (C-1) 3063 (w), 3025 (w), 2973 (m), 2935 (w), 2890 (w), 1634 (s, C=O), 1494 (m), 1475 (m), 1454 (s), 1410 (m), 1372 (m), 1352 (m), 1296 (m), 1260 (s), 1223 (m), 1130 (s), 1071 (s), 1029 (m), 944 (m), 893 (s), 868 (s), 803 (s), 765 (m), 722 (m), 700 (s), 655 (m) Calcd for Cz2H3903NSi (MH*+): 384.1995 Found: 384.1996 UR, 2'S, 25,.3R) Aldol Adduct 61 1H NMR (300 MHz, C¢Do), 5: 'H NMR (300 MHz, CDCl), 8: 13C NMR (75 MHz, CDCl), 8: FTIR (neat), cm-l: 178 0.00 (s, 3H, Si-CH3), 0.11 (s, 3H, Si-CH3), 0.75 (d, J=7.5 Hz, 3H, H-3'), 1.03 (d, J=6.5 Hz, 3H, H-4), 2.95 (s, 3H, N-CH3), 3.23 (dq, J = 6.6, 9.8 Hz, 1H, H-2), 4.80 (d, J= 9.7 Hz, 1H, H-3), 4.96 (dq, J = 4.2, 7.5 Hz, 1H, H-2'), 6.16 (d, J=4.1 Hz, 1H, H-1'), 7.07-7.45 (m, 10H, aromatics) 0.06 (s, 3H, SiCH3), 0.15 (s, 3H, SiCH3), 0.888 (d, J =7.9, 3H, H-39, 0.891 (d, J =6.5, 3H, H-4), 3.29 (s, 3H, NCH), 3.37 (dq, J = 6.6, 9.6, 1H, H-2), 4.69 (d, J =9.7, 1H, H-3), 4.78 (dq, J=42, 7.4, 1H, H-2'), 5.86 (d, J=4.1, 1H, H-1'), 7.21-7.44 (m, 10H, aromatics) -6.55 (Si-CH3), -1.29 (Si-CH3), 11.48 (C-3'), 13.21 (C-4), 33.49 (N-CH3), 45.00 (C-2), 56.03 (C-2'), 71.24 (C-1'), 81.74 (C-3), 125.19, 126.56, 126.61, 127.69, 128.03, 128.20, 141.60, 142.70 (aromatics), 176.41 (C-1) 3062 (w), 3030 (w), 2982 (m), 2937 (w), 1631 (s, C=O), 1493 (m), 1454 (m), 1404 (m), 1292 (w), 1258 (s), 1230 (w), 1206 (w), 1150 (m), HRMS (FAB), m/z: TLC (60% Et O in pet ether), Ry: 179 1124 (m), 1082 (s), 1038 (s), 1028 (s), 1016 (m), 928 (w), 886 (s), 866 (s), 852 (s), 802 (s), 771 (w), 735 (m),700(s) Calcd for C22H3903NSi (MH*): 384.1995 Found: 384.1992 60: 0.54 (UV and PMA) 61: 0.58 (UV and PMA) 180 REFERENCES 181 1. Review of aldol reactions: Heathcock, C. H. in Asymmetric Synthesis; Morrison, J.D., Ed.; Academic Press: New York, 1984; volume 3, Chapter 2. 2. a) Kleschick, W.A.; Buse, C.T.; Heathcock, C.H. J. Am. Chem. Soc. 1977, 99, 247. b) Noyori, R.; Yokoyama, K.; Sakata, J.; Kuwajima, L; Nakamura, E.; Shimizu, M. J. Am. Chem. Soc. 1977, 99, 1265. ce) Nakamura, E.; Shimizu, M.; Kuwajima, L; Sakata, J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983,48, 932. d) Kuwajima, L; Nakamura, E. Acc. Chem. Res. 1985, 18, 181. 3. a)Mukaiyama, T.; Banno, K.; Nasaka, K. J. Am. Chem. Soc. 1974, 96, 7503. b) Heathcock, C.H.; Davidsen, S.K.; Hug, K.T.; Flippin, L.A. J. Org. Chem. 1986, 5/, 3027. c) Sato, S.; Matsuda, I.; Izumi, Y. Tetrahedron Lett. 1986, 27, 5517. d) Reetz, M.T.; Vougioukas, A.E. Tetrahedron Lett. 1987, 28,793. e) Mukai, C.; Hashizume, S.; Nagami, K.; Hanaoka, M. Chem. Pharm. Bull. 1990, 38, 1507. 4. Creger, P.L. Tetrahedron Lett. 1972, 79. 5. Myers, A.G.; Widdowson, K.L. J. Am. Chem. Soc. 1990, 112, 9672. 6. Myers, A.G.; Widdowson, K.L.; Kukkola, P.J. J. Am. Chem. Soc. 1992, 114, 2765. 7. Later experiments showed that the reaction did occur in THF. Hou Chen, unpublished results. 182 8. Later experiments showed that 4 does react with benzaldehyde. For a further discussion of the reactivity of 4, see p. 53 9. The minor product, (2R,3S)-anti aldol adduct 7 was originally misidentified as a mixture of this and the (2R,3R)-syn adduct. (ref. 10) Later work showed it to be 7 exclusively. See p. 36. (10. Widdowson, K.L., Ph.D. Thesis, California Institute of Technology, 1992. 11. Pentacoordinate phosphorus reviews: (a) Westheimer, F.H. Acc. Chem. Res. 1968, 1,70. (b) Holmes, R.R. Pentacoordinated Phosphorus; American Chemical Society: Washington, D.C., 1980; Vol. 2. 12. Sommer, L.H.; Bennett, O.F.; Campbell, P.G.; Weyenberg, D.R. J. Am. Chem. Soc. 1957, 79, 3295. Although the authors propose a tbp intermediate, they do not invoke pseudorotation. 13. Barton, T. J. “Carbocyclic Silanes” in Comprehensive Organometallic Chemistry; Pergamon Press: Oxford, 1982; p. 205, and references therein. 14. Myers, A.G.; Kephart, S.E.; Chen, H. J. Am. Chem. Soc. 1992, 114, 7922. 15. Marsh, R.E.; Schaefer, W.P.; Kephart, S.E.; Myers, A.G. Acta. Crystallogr. C. 1993, 49, 185. 183 16. Crystal structures of 2 and 3: Schaefer, W. P.; Widdowson, K.L.; Myers, A.G. Acta. Crystallogr. C. 1991,47, 2575. 17. This is similar to the "neopentyl effect" seen in the hydrolysis of a-methylated cyclic phosphinate esters. Hawes, W.; Trippett, S. Chem. Commun. 1968, 577. 18. Denmark, S.E.; Greidel, B.D.; Coe, D.M. J. Org. Chem. 1993, 58, 988. 19. Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1983, 105, 1598. 20. Evans, D.A.; Nelson, J.V.; Vogel, E.; Taber, T.R. J. Am. Chem. Soc. 1981, 103, 3099. 21. a)Forsen, S.; Hoffman, R.A. J. Chem. Phys., 1963, 39, 2892. b)Campbell, I.D.; Dobson,C.M.; Ratcliffe, G.; Williams, R.J.P. J. Magn. Resonance 1978, 397. c) Led, J.J.; Gessmar, H. J. Magn. Resonance 1982, 444. 22. Hou Chen, unpublished results 23. a) Bull, H.G.; Koehler, K.; Pletcher, T.C.; Oritz, J.J.; Cordes, E.H. J, Am. Chem. Soc. 1971, 93, 3002. b) Seebach, D.; Erickson, B.W. J. Org. Chem. 1961, 31, 4303. 24. Nahm, S.; Weinreb, S.M Tetrahedron Lett. 1981, 22, 3815. 184 _ 25. Brown, H.C.; Subba Rao, B.C. J. Am. Chem . Soc. 1958, 80, 5377. 26. Smith, J.G.; Dibble, P.W.; Sandborn, R.E. J. Org. Chem. 1986, 51, 3762. Kobrich, G.; Buck, P. Chem. Ber. 1970, 103, 1412. 27. Nathaniel Finney, unpublished results. 28. Levin, J.1.; Turos, E.; Weinreb, S.N. Synth. Commun. 1982, 12, 989. 29. Vaughn, H.L.; Robbins, M.D. J. Org. Chem. 1975, 40, 1187. 30. Evans, D.A.; Bartroli, J.; Shih, T.L.J. Am. Chem. Soc. 1981, 103, 2127. 31. a) Hanessian Tetrahedron Lett. 1967, 1549. b) Menezes, R.; Smith, M.B. Synth. Commun. 1988, 78, 1625. 32. Evans, D.A.; McGee, L.R. J. Am. Chem. Soc. 1981, 103, 2876. 33. Gennari, C.; Bernardi, A.; Colombo, L.; Scolastico, C. J. Am. Chem. Soc. 1985, 107, 5812. 34. Phillips, A.P.; Baltzly, R. J. Am. Chem. Soc. 1947, 69, 200. 35. Evans, D.A.; Takas, J.M.; McGee, L.R.; Ennis, M.D.; Mathre, D.J.; Bartroli, J. Pure and Appl. Chem. 1981, 53, 1109. 185 36. Marsh, R.E.; Schafer, W.P.; Widdowson, K.L.: Myers, A.G. Acta. Crystallogr., 1992, C48, 1948. 37. Ene-type mechanism originally proposed by Vijaya Subramanian. 38. Reviews of the ene reaction: a) Hoffmann, H.M.R. Angew. Chem. Int. Ed. Engl. 1969, 8, 556. b) Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. 39. Franzus, B. J. Org. Chem. 1963, 28, 2954. 40. Lowest energy conformation resulting from a Monte Carlo Conformational search using the MM2 force field and the program Macromodel v. 3.5x 41. Equatiorial leaving from trigonal bipyramidal silicon has often been invoked to explain retention of stereochemistry after nucleophilic displacement on chiral silacyclobutanes. See ref. 13. 42. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923. 43. Kofron, W. G.; Baclawski, L.M. J. Org. Chem. 1976, 41, 1879. 186 APPENDIX I Catalog of Spectra 187 \ Was +YOLVYadO 9099 L6AON81 OLO0 LLIM3S SAId Jd YWN 4d 26 HoT NN welS~o 188 GE NMR , QE PLUS SEKI68. 020 23NOV9 1 SEK-I-46 ENOLATE 13 Cans OPERATOR: SEK O~ gj" \ O NTN CH3 8 Sreve| ae es ee t T if T T t ] t T Li i] Lj T T T T T T | T T T q T T T T T t T | T T Lr 220 200 180 160 140 199 ana an en an an 0. 76.93~ XT 48.64 1 1 1 T T 1 T T 4000 3500 3000 2500 2000 4500 cuca, 1000 CHCl cm 500 : 3 92/08/05 21: 02 X: 4 scans, 4.0cm-i, flat 189 T- 0 } e € 4 G s) Z 8 6 Ov serrtirrr prs tere pet ttt tt tt tt tt tt tt tt td tt tt tt dd Be EST 00° 0c 9¢ Ov i a rc HOT Ny —N (e) \ “SO ‘i avS-I-yas 190 SEK-I-54. 13 a O—~sj’ nlliesneeorinin nein line HS 20 20700 196 190 485 160 175 170 165 100 155 150 145 140 135 130 125 120 145 1414 105 100 95 90 8 BO 75 70 65 60 55 50 45 au 25 4 25 20 15 10 5 0 AS @3.40- aT 4 - -2.13L T T T T 7 T T T 4000 3500 3000 2500 2000 14500 21000 cm 500 Sek- 154 92/03/17 22: 18 X 4 scan, 4.0cm-1, flat 191 AIS *YOLVYsdO ‘9099 HL 24u @l-I-yg9s - L6AONE? 120 '@LIMIS SN 1d 3d YWN 39 ve an OT ®HO Ud Yr re} oO “is —o 192 | GE NMR QE PLUS s SEKI78. 200 o—si_ ; 23NO0V91 ANTI? JA OPERATOR: SEK N : Ph CH3 10 OD 4 200 150 1.00 50 O PPM 69 .66- xT 59.36 T T 1 T T T T I 4000 3500 3000 2500 2000 4500 4000 cm! 500 92/06/09 413: 42 Xx: 4 scans, 4.0cm-4, flat SEK-I-93 anti 193 Mas *YOLVYadO 9q99 Ht JOOTVNAS “ESY CE-I-NIS cONV PS? QO€0 “€6INAS SA 1d 3d YWN 39 GE NMR QE PLUS - SEKI93. 300 Oo— Si, 25JAN92 NX Oo O SEK-I-93 RF3 = SYN ALDOL : 13C Céd6 N Ph OPERATOR: SEK CH 11 T T q ] T q T T | T T T T | T T T 200 150 100 50 PPM 89.87. ; | | 39.72 700.4 I em! - | | 28.10 t 4 T T T T t T 4000 3500 3000 + #2500 2000 4500 1000 cm! 500 92/06/09 13:33 xX: 4 scans, 4.0cm-4, flat SEK~I-70 syn Wdd Il- 0 Lt ¢ € v S putin = J | 1 L | | | on ee ee 9 L 8 6 OL 1 —- | 4 = | i | a oe L eee L L | | 1 1 195 — | _/ iL =<\ ot & Wdd 8+ O'S f° ; 43S siouvaaco " OAHIGWZN3E ONV 31VIONS Si-T-¥3s 34 f rai L6AONPF 1 0¢c0°SLIMIS e ®HQ HQ "9 Ud. ~A_ UN Y le Yur oe Ct ~~ oN aa — I@D, — | 196 = meg O- Si o , Ph OA, i = CH CH3 3 SyNiAati 2 621 ; GE NMR QE PLUS SKI160. 100 OS JUN92 Ke omy e | An salertelsannlldniac Hensal L a TWO BO 1 (eo Ih 1 Ie HB & BM HB 6 10 een 197 SEK-1I-71.ANTI.DIOL.CDCL3 AL N : Ph From PPM 10 9 8 7 6 1 a -1 SEKI82,001 04DEC91 SEK-I-82 ANTI DIOL? YH COCLI/THS OPERATOR: SEK re A a Ge i ( NK \O 198 From 30.54 T T T T T T T T™ 4000 3500 3000 2500 2000 1500 4000 cm 500 SER TZ 91/14/24 22: 12 X: 46 scans, 4.0cm-4, flat 400.00 xT _ Si. fe] 3 \ From N : CH, 0.00 T T tT T T T T T , 4000 3500 3000 2500 2000 41500 1000 cm! 500 SEK - I-92 91/12/04 17: 23 xX 4 scans, 4.0cm-1, flat OH oe) uO <= Ph 199 CH3 15 He ois o “No From N Y “ Cy ee Ne DDO DDD) eerie peeceeiesce peerrricrerr poco poceercecre poorericicre poree|erercre Perret (pret 4 3 ot T 3.0 : i \6 4 % 7 & OH Oo uO = CH3 15 Ph ee a s . 200 GE NMR QE PLUS SEKI83. 001 O4DEC91 a€K-I-03 sYm DIOUt 4H COCLa/ THe OPERATOR: SEX 201 OH O OH A Ph 89.59- CH3 xT 15. 7 _ From N ¥ Cty 41.94 “T~ T T T T “T T — 4000 3500 3000 2500 2000 41500 4000 ca! §00 SEKI 94/44/24 42:54 X%: 4 scans, 4.0cm-4 89,58~ &T ~ ° rel No From _N ¥ oH 74.57 tT T T T 1 — - “ 1 4000 3500 3000 2500 2000 1500 1000 cm 500 91/14/24 44: 46 ¥: 4 scans, 4.0cm-1, flat 18.03 T T q T T 4000 3500 3000 2500 2000 . i 1500 i 1000 T cm §00 202 203 SEK~-1-55. LOWER .AF .SPOT.CDCL3 Wdd om b~ Q L ¢ i v & 204 HAS ‘YOLVYadO 9099 HL YYOLWEL/930 08-82 INOTLOVY' vVl-I-WIS c6AVWCL OLO“vvLIXS SA ld 3d YANN 39d < 0¢ tS) Ny, "ny 205 do) Si o7 GE NMR | QE PLUS SKI144. 100 12MAY92 SEK—I-144 FRACTION i . 20 wyeteapge 11 oom OPERATOR: SEK Ov ] T tT T T T | TT T | T T T J | a 200 150 100 50 0 PPM 74.584 xT 8.75 sy T T Li T T T T 4000 3500 3000 2500 2000 4500 4000 cm! 500 SEK» 1-144} 92/05/43 44: 48 flat X% 4 scans, 4.0cm-4, 206 N38 ‘YoLVUsdo _ 9089 Hi SHAMS") S3009-c9 eNOTLOVYS 91 1-I~-N38 COUVNGL 020 9ILIXS SNId JO YWN 39 be 1? “ PHO. LO a \ OO 207 ; SS = GE NMR a QE PLUS Si aol, SKI116. 200 O CH3 19MAR92 - SEK-I~-116 FRACTIONZ €3-44 DEG 1.8 mH isc cape OPERATOR; SEK i) | I 1 T ere Ls 44.44 T T T T t T 4000 3500 3000 2500 2000 4500 4000 cm! 500 SEK Ie Feline . 92/03/18 23: 39 X: 4 scans, 4.0cm-1, flat 208 ~Wdd I~ 0 pili {ott | | eee ee | Lot | [of J! | as ee | a oe oe | ae oe | a ee oe | | {i of ot | { po Po tL L 4 € Vv G 9 L 8 6 Ol | WY —_- | 17 (a6 x (x) (e) IG a rx) N | zo O GE NMR QE PLUS SEKI99. 200 11FEB92 SEK~I-99 DISTILLED 60 UL 59.0 MG vac COCLa OPERATOR: SEK 22 1) meee “ is a 210 7m eo «je ke OD «(1tD BGGE4CB 0-2 0" g0.00-1 1.72 T T T t T t 4000 3500 3000 2500 2000 1500 4000 cm! 500 SEK~-1-99 92/05/14 15: 24 Xx 4 scans, 4.0cm-1 210 Was *YOLVYAdO 9099 HI JIWYS WNISTHO eSl~I-ywas COAVWS | LOO eSlINS SN 1d Ad YWN 49d ap) | + <3 Gi GE NMR 07 Spy 7 No, QE PLUS 6) skI152.019 15MAY92 H3C NN + Ho cts Hitt ee CHg 24 on | | _ AALS SELLER LI Oe | 65 .07-~ %T 41.94 —t T T T T 1 T T 4000 3500 3000 2500 2000 . 14500 1000 cm 500 SER-1-150 92/05/23 16:54 X: 4 scans, 4.0cm-4, flat 212 Wdd Il- 0 | C € v G NS) L ¥ 6 Ut bd | iit [i a wo Lo hooebLreet L iL teek I. Le $@ NN HoT NOH + ofH fHO Oo fo) x O / \ Oo 213 Shou! ON cig 56) : GE NMR H3C NN + He DK ots QE PLUS SKTI126. 100 : : 28MAY92 CHg SEK-I-126 Vic cene OPERATOR: SEK 25 T tT T T T T T | T T t if qT T T T T T T T T r T I T T T I T T T T T <5 T q T T T | T T , T T uJ T T T T T T TT 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 75.53- aT 36.34 T — T T T T T T 4000 3500 3000 2500 2000 41500 4000 cm! 500 92/05/28 14: 46 X: 46 scans, 4.0cm-41, flat SEK I 4126 214 MBS ‘YOlVHAdO 9089 Ht a3 vI1si¢ tei-I-x3s Z6NdVez O10 CELINS SNI1d 3d YAN 39 we bt ror ‘ vy s+ pb a tt tt iy a's coe a. 97 ®HO Sy HoT NOTH + WW da 9 $ GHD "OFH tus ‘yey HO 9 OfH 215 oo " GE NMR : QE PLUS SKI133. 100 Ha CHs HQ. os _2SAPR92 - Si tie cae Of ph 7 ‘pp OPERATOR: SEK H3 A + Hg S\ CH3 26 T T T T T T T T T T T | T T T T TT T T t T T | T q v J T T ap T T T T qT T | T T T t T T T T T t T ~T 2 WO IR WO 146 120 100 > 4 ® 9 =2B 7° 37.82 T —— T T T T T T 4000 3500 3000 2500 2000 4500 41000 cm 500 92/05/28 414: 27 X% 46 scans, 4.0cm-4, flat SEK I 133 216 Wdd +8'+ 98+ 88" LZ WIS ?¥OLYYSdO 9099 HI , SHAN $°1/930 69-z9 : H @ NOLLOVYS $E2-I~NIS G6AONG2 020 “SECIS < SN 1d 30 YAWN 39 27 " T 217 GE NMR QE PLUS SKI235. 200 25NOV92 Wdd 0 L 4 € vo ; 218 NIS 'woLvEsdO _ 67009 HI WHS "0/930; 08-SL dB BLI-I-N3as 26d aSC0 OLOSLLIXS SN Id 3d YWN 39 (Op ly 87 1 ‘ 2 = GE NMR : : QE PLUS Si oO” “c ~SKI178. 100 . O4SEP92 H BE Ta-sare. ao 13c cOCLa OPERATOR: BEX 28 A | as 48.92 T T “T T T T T 4000 3500 3000 2500 2000 41500 1000 cm 500 92/09/04 21: 00 xX 4 acans, 4.0cm-1, flat SEK-I-178 Wdd 0 220 WIS + ¥OLlVERdS $109 _Ht eau SE2~-I-N3S _ 660450E0 c00 “8SEcINS SNId FO YWN 39 Ud Oo HW ) GE NMR ZA h QE PLUS P SKI238. 200 O3DEC92 SEK-{-298 OPERATOR: 8€K a ee re a a ee ee es a me 2d \ te 40 YO 100 w& 4 @ POM 56 .97- aT | 49.63 1 1 1 1 1 ~ : L_ 4000 3500 3000 2500 2000 41500 4000 cm! 500 92/12/03 16: 05 xX 4 scans, 4.0cm-4, flat SEK-I-238 rf2 Neat Film S 9 jJ— 222 M38 'YOLVaadO "87009 HE yeesy @b2-I-N3S c60340E0 £00 8ECINS SN Id 3d YWN 49d vo <7 rt ch. FF 9°F er 0's 2S y- 4 1 rt { i i 1 1 i 1 1 L L 1 l fiat a oo ape jopys nue x! x= One ° Ud H “4 jopye ués 0 £ GE NMR QE PLUS SKI238. 300 O03DEC92 SEK-I-298 130 cocis OPERATOR: SEK 52.65 T T T T t T T tT 4000 3500 3000 2500 2000 4500 1000 cm 500 92/42/03 17: 18 X% 4 scans, 4.0cm-4 SEK-I-238 rf38&4 Neat Film Ph GE NMR QE PLUS $KI213.001 260CT92 S£K-1-213 PF 1H ce06 OPERATOR: 8£K an a a : a Cuth, i | 3 t 1 6 Poy GE NMR QE PLUS SKI213.004 260CT92 SEK-I-213 1H cous OPERATOR: SEK WO i A $ 7 6 S ToT tt 4 PET TTT > 2 ra 1 é may a“ GE NMR QE PLUS O H SKI213.300 260CT92 SEK-T-213 2 a ; Ph Moe coca S OPERATOR: SEK | o n i. 1 be 1 uae rf T TF | T T T T T T T T T T T T T T T T T T T i] T T T T T v T I t T T ] T T T i T qT T | T T T “T ana oan 129 1aA TAN 1997 inn Rn RO An 20 A PPM 91.77- aT 24,89 T T t T T T T T 4000 3500 3000 2500 2000 1500 . 1000 cnt 500 92/12/19 12: 42 X: 4 scans, 4.0cm-4 SEK-I-243 rf3 enone GE NMR QE PLUS Ph oe SKI215. 003 280CT92 peei-8 1 1H ceoe OPERATOR: SEK J Sa en § 8 FF 6 5 4 8 > 1 ™ Ge) J) GE NMR QE PLUS SKI228.004 19NOV92 SEK-I-228 nF 4 1K coca, OPERATOR: BEK JJ Lhe | A A De ee q 7 OG 6 A 3 1 oo a oon 82.11- 227 SKI215. 400 20DEC92 ac coca OPERATOR: SEK PPM 59.58 92/12/20 15: 59 X: 4 scans, SEK-I~215 rf4 syn T T 3500 3000 —— em 500 228 qw yy. GE NMR QE PLUS. SKI215. 004 280CT92 SEK-I-215 RF. 1H céDe OPERATOR: SEK GE NMR QE PLUS SKI228.005 19NOV92 RExet-eze 1H COLE OPERATOR: SEK GE NMR QE PLUS SKI2 15.500 20DEC92 BEK-I-215, RFS ANTE vac coca OPERATOR: SEX TTT ] TTT T TT T | tet T | TT T T TTT | TTT i a | i TTT | T T™T ] req tv q Le | Lae ie | T UO wd 19% 1H 40 12 (et BG 8B AB 0 -20 PPM 92.94- aT 73.10 t —T T T T T T T 4000 3500 3000 2500 2000 _ 4500 1000 cm! 500 92/12/20 16: 10 X: 4 scans, 4.0cm-4, flat SEK-I-2415 rf5 anti TIO "ny OTE 230 GE NMR Qe PLUS SKI241. 001 17DEC92 SEK-I-241 DISTILLED 1H cAOe OPERATOR: SEK 1.8 1.7 1.5 1.3 1.2 &t,0 ae j i} { T u T T T T T T i T T T T T T T T T T T T T T T T T T T T T T T T T T T T T 10 8 7 6 5 4 3 2 1 GE NMR QE PLUS SKI241, 100 17DEC92 SEK-I-241 OISTILLED 1ac cape OPERATOR: SEK ~CF, 1 T Try Le es 126 124 122 120 118 +16 v4 1912 110 uy the “ OO 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM ‘ ie anes “TW " = N _- (S€ ‘YZ) 43S: ¥OLVYSdO Se 61909 HI @ Lods Le-II-y38 E6AVN60 HO 200 L¥0ZxS “ SNid 3d YNN 39 Ud Haq CHa Phe OSI T 0 No CHy*” “on CH; CHg 35 (2R, 3S) P-E] 86.46 xT 41.98 t T T T T T 4000 3500 3000 2500 2000 4500 1000 cm! 500 93/07/21 16: 14 X: 4 scan, 4.0cm-4, flat SEK-II-47 sp.2 232 L- 0 : € v S 9 L 8 6 Li Pe tt isa) N (YE ‘SZ) 9¢ 438 t¥OLYNIa0 PHO “Ho i Ud ALN of HO Le TI=N3S : Yr . E6AVNG60 u “L00°LyOCHS oN G0 Ud SN 1d 30 : euo® ey YAN 39d 72.64 HG hs o— SiN 36 (2S, 3R) 4000 93/07/21 46: 07 4.0cm-1, SEK-II-47 sp 4 X: 4 scan, T 3500 flat T 3000 T 2500 U T 2000 4500 4000 T cm” 500 234 235 o°sS S’¢ 0°93 s‘9 OL GZ £ fo Joa 1 foo rt 1 os (SE ‘NZ) Le FHO = FHO Ud Nv HO oO. oO ig——07 ud £1909 2 dS Ze-IT-Nas "T CH," Haq CHg o— Si i @) i CH3 CH, 37 (2R, 3S) 38.8414. pe ey 93/04/28 14: 34 X 4 scan, 4.0cm-4, flat SEK-II-37 sp2 rm 1 4000 3500 3000 2500 2000 4500 Ph 236 237 43S “HOLVESu0 a 67909 HL t LodS 9¢-TI-3a8 -E6AVWBO 100 9¥02uS SNid 30 YWN 39 OO (YE ‘S7) 8¢ ®HO "HO “NN "HO O e) oie ey 238 Haq CH3 SK2040. 100 2 O2MAY93 Ph oS sK-11-49 re) re} Toe coca wwe OPERATOR: SEK cH NT NS Ph CH3 CH3 38 (2S, 3R) “T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T i T T T T T T T T T T T T TT T T. 220 200 180 160 140 120 100 80 60 40 20 ) -20 PPM 92.69- xT 69.944 T r ee eR ae a ane maa tama Sana a eae eee 4000 3500 3000 2500 2000 4500 1000 cm 500 93/05/03 40: 20 X: 4 scan, 4.0cm-41, flat SEK~II-40 sp4 239 43S *BOlvYsdO “e900 HI ; Z-LOds Le-TI-y3s E6AVWL @ 200 °190¢mMS -SAId Jd YWN 39 C 240 SK2061. 200 2 7MAY93 Cs eit . 43¢ coca o— Si UPERATOR. sk CH3 CH3 CH3 39 (2R, 3S) I T T | T T T iH T 220 200 180 160 140 120 100 80 60 40 20 0 20 PPM 93.99- xT 43.34- T T T T T mi T T 4000 3500 ~ 3000 2500 2000 1500 1000 cm §00 93/05/22 416: 10 X: 41 scan, 4.0cm~-1, flat SEK~II-61 spe dd 241 WAS '¥OlvHadO £1909 HE 4 LOds '9~TI-H3S E6AVNNL Z 100 1902xS SA Id 3d YWN 39 (YE ‘S7) OP "HO SHO HO 3 N HO HO oO Oo Ng —0 Ud eHO” Sey 242 SK2061. 100 27MAY93 - Toe cdeta GPERATOR. SEK CH3 CH3 CH3 40 (2S, 3R) if ; , T r T T T T T | T T T T T T T | T + T T T T T T T T T T TTT T T T T T T T T 1 T T T t T T T T T T T T 220 200 180 160 140 120 100 80 60 40 20 0 ~20 89.28-4 aT 34.96- t t t T T T T T 4000 3500 - 3000 2500 2000 1500 1000 cm! 500 93/05/22 15: 50 X: 4 scan, 4.0cm-4 SEK-II-61 spi 243 Aas +yOlvuadd £3000 HL @ Logs $o-II~-yas CBAVWIS 200 S90¢HS SAd 3D YAN 39 bo 244 HQ CHa Si 2065: 200 Ph omen 7MAY93 Oo Oo If-6s = coca : ATOR: 9ER CH” N CHa 41 (2R, 3S) T y T T T T T T T T T T TF T T T T T T T CTT T wv T T | TT T T T T T T T T T T T TT | TT T aan T ] T 220 200. 180 160 140 «1120 100 80 60 40 20 0 20. PPM 90.484 xT oo | 47.03 T T T T T 7 1 — 4000 3500 3000. 2500 2000 4500 4000 em 800 93/05/27 14: 36 X: 4 scan, 4.0cm-1, flat SEK-II-65 spe 245 Aas *yOLVYadO £1009 HI 1 10ds S&-IT-w3s - ECAVWIOS L00°S902¢MS ~Snid qd) - YWN 39 9 CH (2S, 3R) A 246 SK2065. 10 27MAY93 SEK-IT-65 SPor 1 Vac cocLs OPERATOR 3EK 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 87.364 XT 1.06- 1 T T T 1 — T 2000 4500 1000 cm 500 T 4000 3500 - 3000 2500 93/05/27 414: 27 X: 1 scan, 4.0cm-41, flat SEK-II-65 sp4 247 N3S tYOLV¥adO £7909 HL z 104s ¥L-II-NIS EENnry2 020 vLoeyS SN1d 3d YWN 39 Ee S 9 a ee ne OW (SE ‘Y) cp € fHO fH = FHO HO I HO fHO i 6 oO ON ge 9 Ud eyoY Sey | ~CHz CH3 CHy — 43 (2R, 3S) A —20 220 200 180 160 140 tl. i 1 4000 3500 3000 2500 93/06/24 413: 34 X> 1 scan, 4.0cm-4, flat SEK-II-74 sp2 120 t 2000 60 20 1000 cm 248 SEK +4 spots ches PPM 500 249 NAS *YOLVYadO NIVOY 9089 Hi . £009Z00 HONS STVISAYD ; vin lI-938 e6NNrrZ v00 '¥L0euS SAId Jo YANN 39 ve ww HO “Ud 250 43S wOLYYadO . E1909 HL ay he HSIN SWISAYD vi-II~y3as CENN Ve?) C00 vL02xS SN1d 30 YAWN 39. ww HO Ud Ph CHa” . n stnateaseinaananees spatinaa .. OT TT Too -20 220 200 180 160 140 120 100 i { 80 60 if ' 5 4000 3500 . 3000 2500 2000 4500 93/06/24 413: 22 ; X: 4 scan, 4,.0cm-1, flat SEK-II-74 sp4 40 20 0 251 SK2074. 100 24JUN93 sEK-II-14 SPOTt © Hk AT 13¢ cocLa OFERATUR: SEK ’ PPM 252 MAS ¥O1lVead0 €1909 Ht GIov v2l-1I-398 E6100L0 LOO vVelLcUS: SN1d 3d YAN 3d Es (ye ‘s2) (s¢ “y2) PHO OH 253 x fe) OH fe AL 9.100 R93 HO Ph ~— CH3 2EK (2S, 3R) T T T if T T T i v T T T T T T q T T T | T T T T T T T T T T T T T T T T T T T T “T T T T T T T | T T T T T 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 66.91-4 xT 50.64 T T T T T T T T 4000 3500 3000 2500 2000 4500 4000 cm! 500 93/03/06 19: 12 2: 4 scan, 4.0cm—1, flat SEK-I-289 acid 254 (YE ‘SZ) (S€ ‘YZ) wa8_ twoLvUadO : ; . fH HO ‘67009 Ht : M98 Boum - Ud . OfHO Ud OFHO B6NNPLO | Yor : Loo 9902%S | HOO HOO SA 1d 30 YWN 39 255 O OH AK SK2066.100 CH30 : Ph 01JUN93 (2R, 3S) (25, 3R) 96 .27- aT ~3.73- T tT T T T T 1 T 4000 3500 3000 2500 2000 1500 41000 cm 500 93/06/04 10:45 X 4 scan, 4.0cm-4, flat SEK-II-66 ester 256 438 *YOLVYSdO : " B1000 HL HSYA_OIoy . Ee TI-ns EGAVWSO L00“€vO?NS SN id 30 YWN 49. (YE ‘SZ) Ud a aa Ud HO ie) 257 wo AA, H3 (25, 3R Qi 86. 16-bo on aq pe , Pp nr nee nce enti pence een 4000 3800 3000 2500 2000 4500 4000 cm 500 93/05/04 24: 07 X: 4 scan, 4.0cm-4, flat SEK-II-44 acid 4d L— 0 4 4 =| _ —_— AIS ‘¥OLVYsdO (YE ‘$Z) (S€ ‘YZ) o§-II-N3S €610002 Ud OFHO / Ud OfHo £00 0S0ZMS YN SATd 30 - HO 00 HO O YWN 49 . 259 SK2050. 300 230CT93 I jou CH3,0 Ph / CH30 ; Ph CH3 CH3 -(2R, 3S) (2S, 3R) n 1 abi fa L A ‘ 1 T T T i T T T T T T if T T T T | T T T | T T T T T T T T T T T T T T T | T T T T T T T T T T T T T T | T 220 200 180 160 120 100 80 60 40 20 0 -20 PPM 84.27- xT 58.60 T rT 1 1 T —- r 4000 3500 3000 2500 2000 1500 1000 93/10/49 24: 32 xX: 4 scan, 4.0cm-41, flat SEK-II-50 ester T cm! 500 260 (S€ ‘¥Z) fHO _ 43S 'YoLvuzu0 61909 HI HSYA_OIOV OL-TI-N3S SENN +O L00°0202¢xS OH [@) Adhere O SN1d JO. YWN 39 261 fn Oca Ae ee » OO TUN “yt t War FERAL LER CH3 CH3 CH3 CH3 (2R, 3S) (25, 3R) T T T T T T T T T T T T T T T | T F T 1 T T T T T ¥ T T T T T | T T T T T T T ] T T T T T T T { t Y “ey “ye . 220 200 180 160 140 120 100 80 oi 40 eu 0 “PO PRM 87.39-] XT 44.42. , r 1 1 : cn 1 —y 1 4000 3500 ~ 3000 2500 2000 - 4500 1000 cm 500 93/06/05 12: 26 X: 4 scan, 4.0cm-4, flat SEK-II-70 acid 262 438 *¥OLVH3d0 £7009 HI Q3NAN109 YI1S3 3H Gl-TI-N38 e6nnrse 700 0L0z¢yS SN 1d 30 ~ YWN 39 ®HO fH (YE ‘ S@) ®HO HO ®HO (S€ ‘YZ) GHD 263 SK2070. 300 265UN93 * SEK-EI-70 - MEESTER 13¢ cocus OPERATOR: SEK A A OS 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 82.17-| aT | 27 .53- 1 , vey nn ie . ' Soe 4000 3500 ~ 3000 2500 2000 4500 4000 cm! 500 93/06/25 415: 45 X: 4 scan, 4.0cm-1, flat SEK-II-70 ester 0) L C c v G 9 i ii l I ii | i 1 | | J | ii i | t 1 i i | i it if J | H | it ii | I i L i { i { i { EE a = oO N a - ee ff wae yA Lyysda BIG) Hl HEV O20¥ (SE ‘YZ) BONA LO f49 LOO -2l02uS . H SAd FO OH YAWN 39 io Olt. 265 fr oan Or a uf fdr: a ae rose FERAL ER O OH HO Otte H3 (2S, 3R (2R, 3S) ns T T T T T T T TT 1 T T T | T T T ] T T T T T T T T T T T T T T T T T T T ] T v T Torry Tr rey u 220 200 180 160 140 120 100 80 060 40 ye w ATU PM 96. 22- XT 10.69 , 1 1 I 1 . 4000 3500 3000 2500 2000 4500 1000 em! 500 93/06/09 09: 36 X: 4 scan, 4.0cm-1 SEK-II-72 acid 266 (YE ‘SZ) (SE ‘NZ) ®HO 43S ‘YoLvYEazdO €1909 HL Cl-II-n38 e6ennrsz 600 €20zyS | | Ho OO “SNATd FO YWN 39 CH (2S, 3R) (2R, 3S) Se 220 200 180 160 140 420 100 80 60 -20 89.34~ aT 31.451 1 1 T 1 1 1 4000 3500 * 3000 2500 2000 1500 1000 93/06/25 16: 40 X: 4 scan, 4.0cm-1, flat SEK-II-73 ester cm! 267 Wo reuse SK2072.301 O4JUL93 SEK-IT-72 PPM 500 L— 0 | Z € 4 S 9 L —_L l l 1 I } 1 ii l | i I i 1 l 1 J ! if | i ! 1 1 | L i L L | L l 1 I | L 1 iT J I i] 1 I L nr ioe} a Tr W3S wOLVHadO ° (we ‘S a) (S € ‘Y @) £ aeaatt | Bo 1 “HQ HO fH Or I-II-H3S : €6190SZ | fH9 OH Z00 SL ZyS HO oO SN1d 3d YWN 39 Us O OH CH HO 3 CH, | HO os H CHs CH3 CHg (2S, 3R) 78.82- xT 34.26- if T LJ T 4000 3500 - 3000 2500 2000 1500 93/10/25 15:34 xX 4 scan, 4.0cm-4, flat SEK-II-148 acid 269 SK2 148. 200 250CT93 SEK-II-148 acID : _. 13 ¢ cpeL3 OPERATOR: SEK 270 MAS t¥Olvugdo 9099 HL 3aNWA 109 ~ S$0-II-y3s ce Inrel L100 ‘S80¢uS SN 1d 3d YWN 39 wo SP Lp fH OfHO G9 Of SEHD 271 SK2086. 100 12JUL93 SEK-II-06 ‘COLUMNED 1ac caos OPERATOR: 8&K CHg CH A Sn aN l CH30 CH CH30 47 48 Qua Hg he | A IT A A Oe aa 220 200 180 160 140 120 100 80 60 40 20 0 —20 PPM 92.99- xT 3.19 T T T i T 4000 3500° 3000 2500 2000 4500 oi ep ne a ee 93/07/04 410: 57 X: 4 scan, 4.0cm-4, flat SEK-II-77 amide dd I+ Li 272 “WAS :¥OLVYTdO 9099 HL yOrva g@-II-a3s C6 INFSL 200 8802xS SN 1d 3d . YAN 39 a Os oP fHO OfHO HO OfHO Netu9 Pre) SaLO fe) SGLO O 273 o . OTDS O OTDS |. 109 JL93 CH CH ~ 3 ; ry CH,0 CHg | CHgO CHg 49 50 | ie Oe A A A Us Oe ee ee ee 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 87.70- XT 41.23 T T T Li T T T T 4000 3500 - 3000 2500 2000 41500 1000 cm” 500 93/07/02 23: 48 Xx: 1 scan, 4.0cm-4, flat SEK-II-79 274 | _) wae uedyyage | 8099 HI QSNWNIG.: aqAH AAW Ne-TT-wge Ce INGSO 100 0802S SATd 30 YWN 39 oP Sp ®HO ETS) SdLO O SALO re) 275 SK2083. 200 O8JUL93 o OTDS o OTDS sre 1c cape OPERATOR: SEK H H CHg CHg 45 46 1 ee T TTT T T T T T TOT T T TT T T T T T T T T T T TTT T T my T T TT T TT T T TTT T T T T tT? 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 81.46- xT ae bi ~1.47- T T t T ! oe T — on a TT 4000 3500 ~ 3000 2500 2000 1500 1000 cm 500 93/07/05 15: 34 X: 4 scan, 4.0cm-4, flat SEK-II-80 aldehyde Ovl ogt 276 ldV . Wdd s2"- ol zL'9 Wows WO/Mdd ses. WO/ZH 90'SEL ' ?31VOS lod 0062 = YaMod Wdd 10Z*y == AONANDIYd -LYVAINGON 9b—GYVORVIS $Y3a71dN0d30 te 09 = NIV @zl 0 «3218 IWNTd 24 20 = 3218 INES 14 y voz = 3ZIS SIuO 14 LULe = HIGIM 23 . OoSzl = HLGIM $4 091661 ‘00E = O3u4 24 129067 ‘Sz = O3Nd bd Sau ot - alVa NIds ZH 00°OL §=™ ~SNOVOUE ANTI 982 - 3218 Vive . = “S0OV 40 ‘ON o3s 99° = GAIL JPA. OSSN 26°18 mr SAIL “OOV 2 ta a 2 ° 2 ™ Peas raan 2 a 938N OF ‘OL. 938N_09°0c — = ld ‘Iddl/X31dHOSUIdAK WOS8D JAILISNIS JSVHd : ‘MIs. FYOLWEURdO 9089 361 2 iods eo-II-y3s -e6inreo lvd‘eg0zys SNid JO YWN 39 Op ° SP fHO fH9 SCLO Oo SALO O td v S 9 l 1 I i i | l l l | | 1 1 ] i | 1 ] i i | i i 1 L l i L L [ | i] | iT L | I l i ! 1 —S—— ry a é~ 6 N (Sp ‘SE ‘NZ Ss (Yp ‘YE ‘SZ) ZS “Was ‘woivuzuo ®HO = FHO 9099 HI z € lods N 10-11-9138 _e€é6 inrg2 : cout I I £00 °L602yS = = ; » Salo OL OY \ 5 SAd Elv) Is——O cunt” a YWN 39 euD® Le HO be 278 SK208 1.220 O8JUL93 HgC BS HG sCH3 , : i aCHs . OPERATOR: 9cK ( GH, CHs CH3 CHg 52 (25, 3R, 4R) 55 (2R, 3S, 45S) OT Tt 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 84.324 xT 16.03: T T T T T y oT 4000 3500° 3000 2500 2000 4500 1000 cm 500 93/07/06 22:37 . xX 4 scan, 4.0cm-1, flat SEK-II-81 sp 2 Wdd 0 02 Or 09 og O01 O21 279 vn nn ee es | es en ees 0 ee ee wT Ll ldV * cm T TT | es Wad 02 '- OL { 60'e Wowd ; \ ' WO/Ndd_S2S¥’ WO/ZH 98 "SEL | { 23 WS’ 10d ; 006z = wMod ( ' Wadd 102") = AQNSNOSNS ' DILVINGOH Bi-ONVONVIE !WaTuNoDga be og = NIvo 4 92h = 3ZI8 WNI4 24 { ¥20L0- = SZIS “IWNI3 13 ey © 3218 SIMO 24 ev0z © = 3218 SIMO |4 LULZ = HiOmA 24 O0SZs = HLGIM 14 { oolesi "006 == baud z4 vegoer'Sk = = ORNS Id { *3AW3S@0 Sau Ob = 31¥" NIvs ( } ZH 00"0t = eNgYOud 3NI7 | 9s2 = sts Yiva z = "svo¥ Jo ‘ON q O38 99° = SAIL JAR" | O38 26°18 » SAIL ‘dOv , o 7] 7) = 2 ° ° ° 2 Ovreuunns a a 938N_ 08°02 mw bd Idd1/X31dWO9U3dAH WSS JAILISN3S 3SVHd 338 !WOLVURdo (sp ‘SE ‘UY SS (Yb ‘YE ‘ST) 7S { z tows fu9 «| «fFHO \e-TI-38 . £6 1NF80 Iva°l802eyS 1) Sd 30 ; sao 4200, «COO F saio OQ. 0 YWN 39 | 4 280 (YP ‘SE NT) pS (Sp ‘YE SZ) Es See | | HO HO "438 Rolvugde / \ : : 9g99 Hi N Corr & lods : 96-TI-)38 i i es intr? SaLO fe) fo) = SdLO fe) oO £00 '960zyS Ngo” ‘“is—o . yw € aan SN'1d 30 | PHOT de no" oH WN 39 es 281 SK2096. 300 ' 24JUL93 H3C . -HaC . oo 1 CHg 1 wCHg OPERATOR: EK Oo Oo OTDS f 0 ‘Oo oTDS CH3 CHg 6 CH3 CH 53 (28S, 3K, 45) 54 (2R, 3S, 4R) ee a ite pa | eaten T T T T T T T T T T T T T T T T t T T T T T T T T T T T T T T T T T T T T TT T T T i T Ly T T T T T t T T 220 200 180 160 140 120 100 80 . 60 40 “20 0 -20 PPM 80.74- xT 3.93 T 1 T T —T T ~—— _ 4000 3500 ~ 3000 2500 2000 4500 1000 em 500 93/07/26 09: 43 X: 4 scan, 4.0cm-4, flat SEK-II-96 spot 3 282 idV Wdd 06 ‘= ol L398 woud WO/Ndd Sesr » WO/ZH 98 'SEt ‘JWSS Lo4d ogee = - YaM0d Wdd $02"y = AONANDAYY LVINGON Sl-GuVONVLS 'Y3TdNOD3d te o9 = Nivo eet = 3ZIS WNI4 23 y2ot == 3421S IWNId 14 ey = 3ZIS SIYO 24 Broe = 4218 OI¥0 1d 2bL@ = HIGIM 24 oos2el = HIGIM L4 O9L661 “OOF = O3N4 24 t2e06y “Sz = Oud L4 *3AUaSEO Sd¥ 6t = 3ivd NIds ZH 00'O1 | * ONGYONS 3NT1 . 9s¢ = aZIs viva z = "S0OV JO ‘ON a aS 98° = OWIl 3194034 VESW 26°18 =, 3WIL ‘ddov 93SN 00 Fal = a! D3SN oO 'L = ed J4aSN 0028 = wd D3SN OO Ly = gd O3SW 00 008 = sd OaSW 02°2 = +0 938W seit = €¢0 O3SN OF Ot = ?éd 33SN_ 08 02 = td Idd /XF1dWOSYSdAH W985 3ATLISN3S 3SVHd WAS 'YOLVYRdO 9099 & logs 96-II-y3S C6 INCE? LVG'960¢xS SATd 3d YWN 49 r PPM (Up ‘SE ‘YT) PS GYD «= -FHO fu” HN (Sb ‘WE ‘STZ) €s ®HO oot SOLO oO (} 283 438 YOLVUIdO $099 HL Yorn LOl-TI-35 CE INLE LOO'LOL?MS SN Id 30 YNN 39 Ee 284 SK2101. 200 01AUG93 SEK-1T-101 JOR 13¢ coca OPERATOR: 96K OH C 56 H3 CHg3 A OO 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 87.3544 xT 70.44) . 1 1 1 “T > 1 T 2500 2000 1500 1000 cm! 500 4000 3500 3000 93/08/02 16: 25 X 4 scan, 4.0cm—-1, flat SEK-II-101 major 285 NaS YoLlvuzdo 81909 HI w INT 138V04 lé-II-n38 eeintr]? €00°L60zZHS SN Id 30 YNN 39. ei Ade. ° ve oF 09 08 OOL Ocl Ovl 091 t L t LL | Lb a a 2 1 | L | L L on oe Sy ne eS DE Oe 286 Po iL 5 $ t f ; i lav sade taenaienmdates ai “ “re br NOV ve a SNEED Tver Thr PTO meeten Fo TUW ne TET DVT Ena Uwe ae OU CONN WOUeT PPM 1 Wdd $2°— OL L zL'8 WOU WO/Wdd SZS¥ * - _ WO/ZH 99"SEL : 231VO8 LOtd { oeez = ——_-u3Mod Wdd Loz"¥ = AONaNOSug | | IVTNOOW BI~CU¥ONVIS “Ya TdNODgC ts 09 Nive \ @zZL 0 = 3ZIS IWNId z4 . v20t 0 3218 ‘IWNIA U4 | Sf = -BZTs SIN 23 @yoz == 3218 OTNO U4 LUL2 | = HIGIM z4 O0Szt = HLOTH t4 09661008 «= = aud zd } L. \2goer Sz. = 0343 1a 'SAW3SE0 . Sdu 6h = (31¥H NIds ZH 00°OL = SNGYOUS SNTT . ™ 9S2 : at z “sod 40 “ON . tb <P 935 98° = SAIL J1DA0RN | SISN 26 °1e ™ SWIL “OS¥ wh ~ D38N OF ‘OL L. 938N_09°0z 9S 14d1/X3 1ANOOUIAAH WOSD JAILISN3S 38¥Hd NS ?¥oLvu3do ; —— 1009 961 . ®HQ "HQ ; o 2 o e e ° s oanearann a a ; yOrvH LOl“TI-N3S EBONVLO aad : Lyd‘ lol2ys _ said 3 | , HO YWN 39 TT 287 $K2091. 300 24JUL93 SEK-11-01 | tac cons OPERATOR: SEK DD 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 87.74 xT 10.93 “T T t T T T t tT 4000 3500" 3000 2500 2000 4500 1000 cm 500 93/07/24 10: 34 X: 4 scan, 4.0cm-1, flat SEK-II-91 baseline PPM 288 GE NMR QE PLuSs SK2091. DAT 24JUL93 SEK-II~94 “BASEL INE~ cock 3 OPERATOR. SEK QuIcK COSY HYPERCOMPLEX/TPPL P2 = 9.50 us: te ® vd SE. os = 200.00 MSEC Da 1a 368.00 USEC . Ss ° 3 & m a AcQ TIME = $88 42 MSEC RECYCLE TIME = $2. séc WO. OF ACQS, = 1 OATA SIZE = 4024 LINE @ROADNG = +00 HZ - SPIN RATE - 19 RPS *] OBSERVE . FY FREQ = 300. 199760 ‘ F2 FREQ = 300 199760 a - Fr WITH = = 2717 2 wiOTH = 2717 o -s Fi f1 ORIG SIZE = 3024 £2 ORIG SIZE = a 2 2s6 FINAL SIZE = 512 F2 FINAL SIZE = 512 GAIN = 4Tet PLOT SCALE. a 108.09 HZ/cM 9620 PPM/CM F FROM 812 To -.30 PPM i 3 2 1 0 PPM GE NMR QE PLus SK2091.DAT 24JUL93 - sEK-II-91 BASELINE" 13¢ CDCL3 UPERATOR. sEK PHASE SENSEI (VE acm . HYPERCOMPLEK/7P?! ' USEC vSEC ° a (eobeoeee aca EI . 8182 mn \ : RECYCLE TIME = eo it KO) OF Acus «+ 2 { OATA SIZE - 258 LINE BROADNG = 14 60 WZ SPIN RATE = 19 RPS VOSERVE Fy S 490021 f2 FREQ = sou 139760 DECUUPLE A STANUARD-1o Muli 2s. FREQUENCY = 4 201 PPK POWER: ' PLOT SCALE 198 @o nZ‘om 4525 FPM/cM FROM au to - 25 PPM . eh. Lh pe vntiaedtarmmeesirecer elle apy a nanny as r rent snot APT ¥ as cad T T T T—1—T J T Ss ee ee T i 120 100 80 60 40 20 0 PRM ~ sid dienadthte pias ele: ae i wr 4 it | : | m | Lol 7 A, a Or ywevedionns ase pehieh hentia Alinta sacha dita hlihid den hdathh hack ni delhateaticalbtenin thesia het tidhinbaaiati sa - T—1 Tot Wdd 289 MBS -YOLVY3dO 9099 Ht 1OdS YOrVW MY - 2tl—II-x3s E6ONVeI €00 2b es -SATd Jd. YAWN 39 BO HO fHO 8s fu9 290 SK2112.300 12 AUG93 SEK~II-112 AW MAJOR SPOT 13C cép6 OPERATOR: SEK O CH O OH CHg 58 T T T | T T T T | T T T T ] T T T T | T T T T | T —T 200 150 100 50 0 PPM 40. 45- 1 + 1 4000 3500° 3000 2500 T . 2000 4500 93/08/41 49: 38 xX: 4 scan, 4.0cm-4, flat SEK-II-1412 acid OV Lo 1 1 291 ° idvV Wdd S2°- OL e1°8 woud WO/Ndd S2SP ° WO/ZH 98 "Set TAOS Lod 0ReZ = YaMOd Wdd L0@"P = AONSNOSYS NOTLVINGOW 9I~GUVGNVLS ‘Yaz 1dNOD3d t¥ og = NIVO get = 3ZIS IWNIJ 24 F201 = 3ZIS IWNId td “OF = 3ZIS SIyo 24 8v02 = 32ZIS 9Iyo 13 LLL@ = HIGIM 24 ooset = HIGIM tJ o9l66t 'O0E- == O3YG 25 Les0Gy “Si = 0344 14 *JAUaSEO Sdu 6t = 3lVY¥ NIdS ZH 00.01 = ONdVONd JNIT 9S2 = a2Is viva z = SDOV 30 “ON 33S 98° = WIL 3104034 QSSH 26°18 = SWIL “DOV 23SN oo rel = SI 33SN Oe't = $80 33SN 00 '2e = 1a D3SN 00 'le = 90 DISW 94008 = $6 SASW 02°72 = +d DASW Sacl = €0 S3SN OF OL = ed S3SN 02°02 = ld Iddl/X31dNODYSdAH WSO GAILISNIS 3svHd M3S + YOLvyadO 9q99 281 40dS YOrvW MY etl-YI-yM3s IVG elt exs YWN 39 DD, 8s EHO HO. HO Laka li 292 MAS *¥OLVHadO - 9q99 HL G3ZIVWIsAyosY HS¥M_GIOV ElLI-TI-ygs EGONVIL. 200 ELL 2yS SAid JO YAWN 39 30 6S fHO HOy,, fH” 293 SK2119. 200 re) 21AUG93 REID aah weds the CH, OPERATOH uEK o 4" tay OH CH; A 220 200 180 160 140 120 100 80 60 40 20. Qa ~20 PPM 48.03-L ae ee erm ee unmet ea one ene ete men pees eee cane at on 4000 3500 ~° 3000 2500 2000 4500 4000 em 500 93/08/46 14:04 ¥:-4 scan, 4.0cm-1, flat SEK-II-443 acid rextal 294 Wdd Io AIS + YOLVYEsdO sg39 HL daZIVWLSAdoay . @ LOdS GVI-TINN3S C6ONVS? 120 SLLEMS SN Td Jd YAN 39 Ud (SE “NZ) 09 PHO "HO N fHO 6 0 Ng -—-0 Ud PHO ‘yey 295 dd E207 24 gu 3d SN Id JO YWN 39 Ee 9 Lt — ot (SE ‘NZ) 09 EHD "Ho A N fH 6. Oo L Nig Ud eH” ey 296 Oe no oR EER 2 AG fa tt-vt eed fK t HE he PC LeeD ‘ We TERAD B Haq CHs Pho 07S o ‘9 CH; N | CH3 CH3 60 (QR, 3S) DD 220 200 tsa 160 140 6d Y “aul BPM 80 .76- xT 20.57 1 1 — r 1 4000 3500" 3000 2500 4500 1000 cm! 500 93/08/25 241: 03 X%: 4 scan, 4.0cm-1, flat SEK-II-1415 sp2 recrystal tn 297 WIS tYOLWHRdO . 9089 Ht 1 logs @tI-TI-43s __ e6onvsz 100 “SL LZys SNid 30 YWN 39 %6 (YE “SZ) HO = FHO Ud ana HO Nig —0 Ud fH hey, 298 $K2115. 100 24AUG93 eG oH oremons Ph om! o Oo CHg we Ph CH3 CH; 61 (2S, 3R) ¥ rT T TTY T TF T T T TT T T T T T T T T T ee or T TTT T TT ae T TT ij T TT T TT T a T TOT T T 220 200 180 160 140 120 100 80 60 40 20 0 -20 PPM 91.43 aT 1 ~ 3.98 Tr ™— 1 T T T T T 4000 3500° 3000 2500 2000 1500 1000 cm! 500 33/08/24 08: 52 G 4 scan, 4.0cm-4, flat 3EK-II-415 spi 299 APPENDIX II Coordinates and Crystal Structure of Silacyclopentane Silyl Ketene Acetal 8 300 TITL AM1 in P2(1)2(1)2(1) Preliminary Data CELL 1 ORTHOGONAL COORDINATES / ewes ewe eee ew tee wee ew twee wee ewww ow + eattl S11 5 0.00000 0.00000 0.00000 it 01 4 0.17960 0.92507 -1.33334 O 02 4 -1.06371 0.74182 1.04912 AL Nl 3 0.11533 2.71270 1.10946 | NT CHa Cl 1 0.47727 2.32259 -1.34749 C2 1 -0.31216 3.09952 -0.30127 C3 1 0.02696 4.61088 -0.37543 8 C4 1 1.12119 4.78950 0,68449 C5 1 0,62030 3.88536 1.80685 C6 1 -0.69002 1,81013 1,80684 C7 1 -1.07669 1.91875 3.07420 C8 1 -1.85319 0.85222 3.78436 C9 1 -0.69038 -1,.66274 -0.43400 ClO 1 0.47384 ~-2.60649 0,04429 Cll Ll 1,26162 -2.02650 1.11101 cl2 ol 1.54037 -0,56947 0,87709 HIA 2 0.29250 2.67817 -2,21981 HIB 2 1.41305 2,43973 -1,16792 H2A 2 -1,25234 2.94488 -0,41849 H3A 2s -0.73641 5.15313 -0.16382 H3B 202=—0,34375 = 4, 84199 -1, 25172 H4a 2 1.19669 5,70073 0,97702 H4B 2 1.97066 4.49101 0.35154 HSA 2 = -0,08095 4.31544 2.30175 HSB 2 1.32870 3.65024 2.41051 H7A 2 -0.86516 2.71644 3,56468 H8A 2. -2,05342 1.11458 4.68590 H8B 2 ~~ = -2,67157 0.69997 3,30612 H8G 2) = --1.33326 = 0.04525 3.79388 H9A 62) -0.86715 = -1.73766 = - 1.37456 HOB 2 = «=-1.49597 --1.83880 0.05756 H10A 2 1.04932 -2.77886 -0,70461 H10B 2 0.11204 -3,44498 0,34030 H11A 2 2.09251 -2.49781 1.20610. H11B 2 = 0, 77696 = -2,11253 1, 93516 H12A 2 2.30966 -0,46002 0,31346 H12B 2 1.68025 -0.09015 1,69703 LINK SI1 ol 1 LINK STIl 02 L LINK 01 ¢l 1 LINK ¢l H1A 1 LINK Cl HIB LINK N12 1 LINK Cl €2 1 LINK G2 H2A 1 LINK ¢2 C3 1 LINK C3 H3A 1 LINE 63 H3B 1 LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK LINK END x) Ch C4 N1 Ch C5 cS 02 N1 C6 C7 C7 G8 c8 c8 Sil C9 C9 cg C10 C10 C10 Cll cil Stl G11 C12 C12 C4 H4A H4B C5 cS HSA HSB C6 cé C7 H7A c8 H8A H8B H8C C9 H9A HOB C10 H1OA H10B cll HI1A H11B C12 12 H1L2A H12B RO RR ee ee ee ee te et pe pe pt 301 302