Enantioselective construction of quaternary stereogenic carbons by the Lewis base catalyzed additions of silyl ketene imines to aldehydes

Article abstract of DOI:10.1021/ja077134y

Silyl ketene imines derived from a variety of α-branched nitriles have been developed as highly useful reagents for the construction of quaternary stereogenic centers via the aldol addition reaction. In the presence of SiCl₄ and the catalytic a

Full text of DOI:10.1021/ja077134y

Published on Web 11/08/2007
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.
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 SiCl4/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.
Table 1. Aldol Addition Reaction of Aryl-Substituted SKIs with
Benzaldehydea
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 R1 and R2 are dissimilar.4
Aldol-type reactions of these nucleophiles would generate â-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
entry
SKI
R1
R2
product
yield %b
drc
erc
1
2
3
4
3a Ph
Me
Et
6aa
6ab
6ac
6ad
87
73
90
74
95:5d
97:3
99:1
98.5:1.5
99.5:0.5
99.1:0.9
3b 4-CF3C6H4
3c
3d 2-MeC6H4
4-MeOC6H4 Me
Me
Scheme 1
87:13d 94.2:5.8e
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 1H
NMR analysis. e Determined by CSP-HPLC after derivatization with 3,5-
dinitrobenzoyl chloride.
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 SiCl4-
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
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
9
14864
J. AM. CHEM. SOC. 2007, 129, 14864-14865
10.1021/ja077134y CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
was prepared and tested in the addition to 2-naphthaldehyde (4b).
The results show that, although steric bulk can be well tolerated at
this position, the presence of an R-branched substituent leads to a
drop in both the diastereomeric and enantiomeric purity of the
product (compare entries 1-3 to entry 4). More importantly, a
synthetically useful allyl-substituted silyl ketene imine 3h was well
tolerated in the reaction providing a nitrile product in good yield
and high selectivity (entry 5). To further expand on the nucleophile
scope, two dialkyl-substituted SKIs that do not contain an aryl ring
were prepared and tested in the addition to 4b. The cyclohexane-
derived ketene imine 3i provided an aldol product with a nonste-
reogenic quaternary carbon in good yield and enantioselectivity
(entry 6). Silyl ketene imine 3j, containing disparate alkyl groups,
reacted to give a 60:40 mixture of enantiomerically enriched
diastereomers in good yield (entry 7). The high enantiomeric ratio
observed within each diastereomer suggests that the source of the
low dr was the insufficient steric differentiation in the alkyl
substituents of the silyl ketene imine.
and high selectivities (entries 5 and 6). Additionally, only a slight
diminution in the enantioselectivity was observed for the electron-
rich heteroaromatic aldehyde, 2-furaldehyde (entry 7). Despite the
high rate of reaction observed for the addition of SKIs to aromatic
aldehydes, aliphatic aldehydes remain unreactive.11
The absolute and relative configurations of the products were
established by single-crystal X-ray crystallography for the nitrile
product 6da, obtained from the addition of SKI 3a to 4-bromoben-
zaldehyde.12 The S-configuration at the alcohol center confirms that
the nucleophile adds to the Re face of the aldehyde, in agreement
with the sense of asymmetric induction observed in other reaction
manifolds reported for this catalyst.10c
In conclusion, a novel Lewis base catalyzed aldol reaction for
the construction of quaternary stereogenic centers via the addition
of SKIs to aromatic aldehydes has been described. The products
are isolated in good yields and with excellent diastereo- and
enantioselectivities. Furthermore, the reaction exhibits broad sub-
strate scope in both the SKI and the aromatic aldehyde. Future work
will focus on new classes of ketene imine nucleophiles and other
electrophiles.13
Table 2. Aldol Addition Reaction of Aryl, Alkyl-Substituted, and
Dialkyl-Substituted SKIs with 2-Naphthaldehydea
Acknowledgment. We are grateful to the National Science
Foundation (NSF CHE-0414440 and 0717989) for generous
financial support. J.R.H. acknowledges the U of I for a Seemon H.
Pines Graduate Fellowship.
Supporting Information Available: Full characterization of all
aldol products along with representative procedures for the addition
reactions. This material is available free of charge via the Internet at
http://pubs.acs.org.
entry
SKI
R1
R2
product
yield %b
drc
erc
1
2
3
4
5
6
7
3a
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Ph
Me
Et
i-Bu
i-Pr
allyl
6ba
6be
6bf
6bg
6bh
6bi
90
78
90
73
79
85
92
98:2
97:3
99:1
61:39
94:6
N/A
98.7:1.3
92.7:7.3
99.6:0.4
78.9:21.1d
97.5:2.5
91.2:8.8
92.1:7.9e
References
(1) For recent reviews, see: (a) Trost, B. M.; Chunhui, J. Synthesis 2006,
369-396. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363-5367. (c) Denissova, I.; Barriault, L. Tetrahedron 2003,
59, 10105-10146. (d) For a recent monograph, see: Quaternary Stereo-
centers: Challenges and Solutions for Organic Synthesis; Christoffers,
J., Baro, A., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(2) For reviews on catalytic asymmetric aldol reactions, see: (a) Carreira, E.
M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; Chapter 29.1. (b)
Carreira, E. M.; Fettes, A.; Marti, C. Org. React. 2006, 67, 1-216. (c)
For a recent monograph, see: Modern Aldol Reactions; Mahrwald, R.,
Ed.; Wiley-VCH: Weinheim, Germany, 2004.
-(CH2)5-
i-Pr Me
3j
6bj
60:40
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 Enantiomeric ratio
of the minor diastereomer was 71.4:28.6. e Enantiomeric ratio of the minor
diastereomer was 96.6:3.4.
To further elaborate the scope of this reaction, a survey of the
aldehyde structure was undertaken (Table 3). The addition of SKI
3a to a wide range of aromatic aldehydes 4c-i was examined, and
in general, the aldol products were isolated in high yields and with
excellent selectivities. Electron-poor and electron-rich aromatic
aldehydes reacted with similar rates and selectivities to benzalde-
hyde (entries 1-3). Hindered aromatic aldehydes, such as 2-tolu-
aldehyde and 1-naphthaldehyde, also yielded products in good yields
(3) For a discussion on quaternary carbon synthesis via aldol reaction, see:
ref 1d, Chapter 3.
(4) However, studies on both N-alkyl and N-aryl ketene imines reveal a low
barrier to racemization; see: (a) Jochims, J. C.; Lambrecht, J.; Burkert,
U.; Zsolnai, L.; Huttner, G. Tetrahedron 1984, 40, 893-903. (b)
Lambrecht, J.; Gambke, B.; Seyerl, J.; Huttner, G.; Nell, G.; Herzberger,
S.; Jochims, J. C. Chem. Ber. 1981, 114, 3751-3771.
(5) For an example of this catalytic, enantioselective process, see: Kuwano,
R.; Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000, 603, 18-29.
(6) Tennant, G. In ComprehensiVe Organic Chemistry; Barton, D. H. R., Ollis,
W. D., Sutherland, I. O., Eds.; Pergamon: New York, 1979; Vol. 2, pp
539-550.
(7) (a) West, R.; Gornowicz, G. A. J. Am. Chem. Soc. 1971, 93, 1714-1720.
(b) Watt, D. S. Synth. Commun. 1974, 4, 127-131.
Table 3. Aldol Reaction of R-Phenylpropionitrile-Derived SKI 3a
with Aromatic Aldehydesa
(8) (a) For additions to aldehydes, see: Cazeau, P.; Llonch, J.-P.; Simonin-
Dabescat, F.; Frainnet, E. J. Organomet. Chem. 1976, 105, 145-156. (b)
For additions to acid chlorides, see: Cazeau, P.; Llonch, J.-P.; Simonin-
Dabescat, F.; Frainnet, E. J. Organomet. Chem. 1976, 105, 157-160.
(9) Mermerian, A. H.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 949-952.
(10) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2007, in press.
(b) Denmark, S. E.; Fujimori, S. In Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, Germany, 2004; Vol. I, Chapter 7. (c)
Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem.
Soc. 2005, 127, 3774-3789.
(11) The reduced reactivity of aliphatic aldehydes can be attributed to an
unfavorable equilibrium that exists between the activated aldehyde
complex and an inactive R-chlorotrichlorosilyl ether; see ref 10c.
(12) The crystallographic coordinates of 6da have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 659734. These
data can be obtained free of charge from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-
336-033; www.ccdc.cam.ac.uk/conts/retrieving.html or deposit@ccdc.cam.
ac.uk.
entry
R1
product
yield %b
drc
erc
1
2
3
4
5
6
7
4-CF3C6H4 (4c)
4-BrC6H4 (4d)
4-CH3O2CC6H4 (4e)
4-CH3OC6H4 (4f)
2-CH3C6H4 (4g)
1-naphthyl (4h)
2-furyl (4i)
6ca
6da
6ea
6fa
6ga
6ha
6ia
88
93
93
78
84
76
92
>99:1d
99:1
>99:1
96:4
>99:1
>99:1
99:1
99.3:0.7
98.9:1.1
98.6:1.4
96.6:3.4
99.2:0.8
98.4:1.6
94.9:5.1
a Reactions employed 1.1 equiv of SiCl4, 1.2 equiv of 3a, 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 1H NMR
analysis.
(13) Preliminary results from reactions of SKIs with R,â-unsaturated aldehydes
show exclusive 1,4-addition with moderate diastereoselectivity.
JA077134Y
9
J. AM. CHEM. SOC. VOL. 129, NO. 48, 2007 14865