Enantioselective Construction of Quaternary Stereogenic Carbons by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes Scott E. Denmark,* Tyler W. Wilson, Matthew T. Burk, and John R. Heemstra, Jr. Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801 Received September 17, 2007; E-mail: denmark@scs.uiuc.edu The development of catalytic, enantioselective methods for the construction of quaternary stereogenic centers represents a continu- ing challenge in organic chemistry. 1 Creating these centers rapidly and selectively is difficult because of the steric repulsion that is encountered in the C-C bond-forming event. Moreover, achieving high levels of enantiotopic face selectivity is difficult because of the relatively similar steric environments presented by the non- hydrogen substituents. The need for more general methods is underscored by a growing number of biologically active natural products and pharmaceutical agents that possess quaternary ste- reogenic carbon atoms. Quaternary stereogenic centers can be generated through the aldol addition of R,R-disubstituted enolates to aldehydes, and given the edifice of work on catalytic, enantioselective aldol-type reactions, this strategy seems logical. 2 However, this approach is limited by the need for and inability to obtain geometrically defined R,R- disubstituted enolate or enolate equivalents. 3 To solve this problem and empower the aldol addition for the selective synthesis of quaternary centers would require either (1) controlling the geometry of disubstituted enolates, (2) developing other nucleophile classes, or (3) identifying catalysts that dominate the facial selectivity. Herein we describe an aldol addition process that combines the latter two strategies. A class of nucleophiles that avoids the issues associated with enolate geometry is the silyl ketene imine (1). The key structural feature of these species is the pair of orthogonal substituent planes which imparts an axis of chirality when R 1 and R 2 are dissimilar. 4 Aldol-type reactions of these nucleophiles would generate -hy- droxy nitriles (2) containing an R-quaternary stereogenic center (Scheme 1). 5 These compounds are versatile synthetic intermediates due to the wide range of functionalities that are accessible through manipulation of the cyano group. 6 Although silyl ketene imines (SKIs) are well-known, only a few reports have described their use as nucleophiles. 7 Frannett et al. established that SKIs undergo exothermic additions to both alde- hydes and acid chlorides. 8 More recently, Fu et al. have described the enantioselective acylation of SKIs, catalyzed by a chiral 4-(pyrrolidino)pyridine derivative. 9 Recent studies from these laboratories have described the SiCl 4 - promoted, Lewis base catalyzed, enantioselective aldol-type addition reactions of enoxysilane derivatives with aldehydes. 10 Generally, the products are isolated in good yield and with high diastereo- and enantioselectivities; however, the formation of only secondary and tertiary stereocenters has been achieved. Quaternary centers have proven more difficult to create because of the reduced reactivity of the R,R-disubstituted enolate equivalents with this catalyst. 10c We hypothesized that a silyl ketene imine might be suitable to participate in this reaction because a significant portion of their steric bulk resides in a plane perpendicular to and distal from the nucleophilic carbon. To test this hypothesis, SKI 3a was prepared (by lithiation of R-phenylpropionitrile followed by trapping with TBSCl) and its reactivity was assayed in the addition to benzaldehyde (4a) using the SiCl 4 /bisphosphoramide catalyst system (Table 1, entry 1). Gratifyingly, nitrile product 6aa was isolated in good yield and with high levels of both diastereo- and enantioselectivity. Further- more, in situ IR studies with 1-naphthaldehyde revealed that complete conversion was achieved in less than 50 s at -68 °C with catalyst loadings as low as 1 mol %! In contrast, the analogous silyl ketene acetal derived from ethyl 2-phenylpropanoate proved unreactive under identical reaction conditions. In light of this promising result, a wide range of disubstituted silyl ketene imine structures was next surveyed. The first series of nucleophiles investigated the scope of the aldol addition with respect to the aryl substituent of the silyl ketene imine (Table 1). Electron-rich, electron-poor, and hindered aryl-substituted ketene imines were prepared and then tested in the addition to 4a. Each nucleophile reacted at a comparable rate, and the aldol products were isolated in high yields and with excellent selectivities. The nitrile products derived from the additions of electron-rich and electron-poor aryl-substituted ketene imines exhibited higher di- astereo- and enantioselectivities than those observed with hindered aryl substituents, most likely because of an achiral background reaction for slower reacting substrate 3d. The next survey of nucleophile structure examined the scope of this process with respect to the alkyl substituent of the SKI (Table 2). First a series of R-alkylbenzylnitrile-derived ketene imines 3e-g Scheme 1 Table 1. Aldol Addition Reaction of Aryl-Substituted SKIs with Benzaldehyde a entry SKI R 1 R 2 product yield % b dr c er c 1 3a Ph Me 6aa 87 95:5 d 98.5:1.5 2 3b 4-CF3C6H4 Et 6ab 73 97:3 99.5:0.5 3 3c 4-MeOC6H4 Me 6ac 90 99:1 99.1:0.9 4 3d 2-MeC6H4 Me 6ad 74 87:13 d 94.2:5.8 e a Reactions employed 1.1 equiv of SiCl4, 1.2 equiv of silyl ketene imine, 0.05 equiv of (R,R)-5 at 0.25 M in CH2Cl2 at -78 °C for 2 h. b Yield of analytically pure material. c Determined by CSP-SFC. d Determined by 1 H NMR analysis. e Determined by CSP-HPLC after derivatization with 3,5- dinitrobenzoyl chloride. Published on Web 11/08/2007 14864 9 J. AM. CHEM. SOC. 2007, 129, 14864-14865 10.1021/ja077134y CCC: $37.00 © 2007 American Chemical Society