Asymmetric synthesis of syn- and anti-1,3-amino alcohols

Article abstract of DOI:10.1021/ja026292g

The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes. Reduction of the β-hydroxy-N-sulfinyl imine products with catecholborane and LiBHEt₃ provides syn- and

Full text of DOI:10.1021/ja026292g

Published on Web 05/14/2002
Asymmetric Synthesis of syn- and anti-1,3-Amino Alcohols
Takuya Kochi, Tony P. Tang, and Jonathan A. Ellman*
Center for New Directions in Organic Synthesis, Department of Chemistry, UniVersity of California,
Berkeley, California 94720
Received March 22, 2002
Table 1. Preparation of â-Hydroxy-N-sulfinyl Imines 2
The addition of nucleophiles to N-sulfinyl imines is used
extensively for the asymmetric synthesis of a broad range of amine-
containing compounds.1 In contrast, despite the importance of
metalloenamines as enolate equivalents,2 the chemistry of metallo-
enamines derived from N-sulfinyl imines has not previously been
reported. Herein we describe the highly diastereoselective addition
of a metalated tert-butanesulfinyl imine to aldehydes (Figure 1).
We further describe the highly diastereoselective reduction of the
â-hydroxy-N-sulfinyl ketimine products to obtain N-sulfinyl deriva-
tives of either syn- or anti-1,3-amino alcohols, which are present
in many molecules of pharmaceutical and biological interest.3 To
our knowledge this is the first method to be reported for the
stereoselective synthesis of both the syn- and anti-1,3-amino
alcohols from a common synthetic intermediate.4
entry
R
additive
product
dra
yield (%)b
1
2
3
4
5
6
7
8
Et
Et
Et
i-Bu
i-Pr
t-Bu
Ph
-
2a
2a
2a
2b
2c
2d
2e
2e
86:14
96:4
93:7
96:4
98:2
98:2
76:2
92:8
80
84
62
75
88
64
66
79
MgBr2
ZnBr2
MgBr2
MgBr2
MgBr2
MgBr2
ZnBr2
Ph
a Diastereomeric ratios. b Isolated yields of diastereomerically pure
material.
Hydrolysis of the addition product 2c with acetic acid in
MeOH/H2O afforded â-hydroxy ketone 3c in quantitative yield with
1-2% racemization (eq 1). The absolute configuration of 3c was
determined by comparison of the optical rotation to the literature
value, confirming that the sense of induction is the same for
additions to both aliphatic and aromatic aldehydes. tert-Butane-
sulfinamide was also isolated in 99% yield and without racemization
(>99% ee). Hydrolysis of 2e similarly proceeded in quantitative
yield with <2% racemization.
Figure 1. Addition of metalated N-sulfinyl imine 1 to aldehydes (M )
MgBr or ZnBr).
We first examined the metalation of tert-butanesulfinyl ketimine
1 followed by addition to propionaldehyde (Table 1). Deprotonation
of 1 with LDA in THF followed by reaction with propionaldehyde
afforded â-hydroxy sulfinyl imine 2a in 80% yield and with 86:14
dr (entry 1). Changing the solvent to toluene or diethyl ether resulted
in lower diastereoselectivities. However, the addition of metal salts
resulted in a dramatic increase in diastereoselectivity. Specifically,
addition of MgBr2 and ZnBr2 afforded 2a with ratios of 96:4 and
93:7, respectively, with the addition of MgBr2 providing the highest
yield (entry 2). Using the optimal conditions, the metalloenamine
of 1 was next added to an R-branched aldehyde (entry 4), a
â-branched aldehyde (entry 5), and an R,R-dibranched aldehyde
(entry 6). The addition reactions proceeded with high diastereo-
selectivity for each aldehyde substrate (96:4 to 98:2), and dia-
stereomerically pure 2b-d were obtained in high yields after
chromatography. Notably, addition of the metalloenamine of 1 to
benzaldehyde proceeded with highest stereoselectivity when ZnBr2
(entry 8) rather than MgBr2 (entry 7) was added. The sense of
induction for the addition to aldehydes was confirmed by X-ray
crystallography of product 2e from addition to benzaldehyde and
can be predicted by the mnemonic in Figure 1.
The reduction of â-hydroxy-N-sulfinyl imines 2 was next
examined. A number of reducing agents were first screened for
the reduction of 2c (Table 2). The N-sulfinyl 1,3-amino alcohol
syn-4c was obtained with the highest selectivity (96:4 syn/anti) by
reduction with catecholborane at -10 °C, with the diastereomeri-
cally pure material isolated in 84% yield after chromatography.
Alternatively, reduction of 2c with LiBHEt3 at -78 °C provided
the anti product 4c in 83% yield. Reduction of 2c with LiBH(s-
Bu)3 provided the same yield and selectivity observed for LiBHEt3.
The generality of the optimal reducing conditions was demonstrated
by reducing â-hydroxy N-sulfinyl imines 2a-e (Table 3). For all
substrates, very high diastereoselectivities and good yields were
observed for reductions with both catecholborane and LiBHEt3.5
To understand the origin of the reduction stereoselectivities, the
reduction of the C-3 epimer of 2e was investigated. Reduction with
catecholborane provided the anti-1,3-amino alcohol product with
86:14 diastereoselectivity, while reduction with LiBHEt3 provided
the syn-1,3-amino alcohol with 90:10 diastereoselectivity. Clearly,
the selectivity of the reduction is primarily controlled by the
stereochemistry of the N-sulfinyl group rather than by the stereo-
chemistry of the alcohol.6 The opposite diastereoselectivity for the
* To whom correspondence should be addressed. E-mail: jellman@
uclink.berkeley.edu.
9
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J. AM. CHEM. SOC. 2002, 124, 6518-6519
10.1021/ja026292g CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reduction of â-Hydroxy-N-sulfinyl Imine 2c with Various
Reducing Agents
membered ring intermediate 6 analogous to the stereoselective
reduction of â-hydroxy ketones reported by Evans and Hoveyda.7
Isomerization from the E- to the Z-imine would presumably result
in the observed reversal in the stereoselectivity of the catecholborane
reduction.
In conclusion, the first application of metalloenamines derived
from N-sulfinyl imines is reported for the highly diastereoselective
addition to aldehydes. The reduction of the resulting â-hydroxy
sulfinyl imines 2 with catecholborane and LiBHEt3 provides syn-
and anti-1,3-amino alcohols, respectively, with very high diastereo-
meric ratios. The addition chemistry of metalloenamines derived
from N-sulfinyl R-substituted ketimines, aliphatic ketimines, and
aldimines is currently under investigation, as is the addition of
carbon-based nucleophiles to â-hydroxy imines 2.
reductant
NaBH4
NaCNBH3
catecholborane
LiBHEt3
solvent
THF
THF/AcOH
THF
THF
THF
major isomer
dra
yield (%)b
anti-4c
syn-4c
syn-4c
anti-4c
anti-4c
66:34
83:17
96:4
>99:1
>99:1
45
78
88
83
83
LiBH(s-Bu)3
a Diastereomeric ratios. b Isolated yields of diastereomerically pure
material.
Acknowledgment. We gratefully acknowledge the NSF for
financial support. T.P.T. also thanks Pharmacia for a graduate
research fellowship. The Center for New Directions in Organic
Synthesis is supported by Bristol-Myers Squibb as a Sponsoring
Member and Novartis as a Supporting Member. We thank Dr. Fred
Hollander and Dr. Allen Oliver of the UC Berkeley CHEXRAY
facility for carrying out the X-ray diffraction studies.
Table 3. Highly Diastereoselective Reduction of
â-Hydroxy-N-sulfinyl Imines 2
Supporting Information Available: Synthetic procedures, char-
acterization, and stereochemical determination of new compounds
(PDF). An X-ray crystallographic file in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
R
reductant
major isomer
dra
yield (%)b
Et
catecholboranec
syn-4a
anti-4a
syn-4b
anti-4b
syn-4c
anti-4c
syn-4d
anti-4d
syn-4e
anti-4e
95:5
>99:1
96:4
>99:1
96:4
>99:1
96:4
>99:1
96:4
94
69
84
85
88
83
89
91
84
73
d
LiBHEt3
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