those containing easily removable N-protecting groups,
continues to be a major research focus in synthetic organic
chemistry.5 At the same time, reduction strategies that
circumvent the use of transition metals and metal hydrides
have attracted significant attention in recent years due to the
increasing demand for environmentally friendly, inexpen-
sive, and efficient synthetic methods. The aluminum-based
Meerwein-Schmidt-Ponndorf-Verley (MSPV) reduction6-8
is a reaction that not only satisfies these criteria but also
holds substantial promise for further asymmetric develop-
ments. While employing an inexpensive and innocuous
metal, this reaction proceeds under relatively mild conditions
and utilizes simple secondary alcohols, such as 2-propanol,
as the reducing agent.9 A catalytic protocol for our aluminum-
based enantioselective MSPV reduction of ketones employ-
ing a chiral complex formed in situ between enantiomerically
pure 2,2′-dihydroxy-1,1′-binaphthyl (BINOL),10 AlMe3, and
2-propanol has recently been reported.11,12 In this paper, we
disclose a highly enantioselective reduction of N-phosphinoyl
ketimines based on the use of this reagent combination.
40 °C results in an increase in enantioselectivity (99% ee),
but a decrease in conversion to 50% (Table 1, entry 2).
Ultimately, increasing the concentration (to 80 mM) and
temperature (to 60 °C) with 1.2 equiv of (S)-BINOL/AlMe3
affords the desired amide 11 in 92% conversion with
excellent selectivity (96% ee, Table 1, entry 5). The use of
a catalytic amount of the (S)-BINOL/AlMe3 mixture only
affords a commensurate conversion of the imine, suggesting
a single-turnover event (Table 1, entry 6).
Table 2. Reaction Scope of the MSPV Reduction of Ketimines
Table 1. Optimization of the MSPV Reduction of Ketimine 1
entry
T (°C)
X equiv
conversiona (%)
eeb (%)
1
2
3
4
5
6
25
40
60
80
60
60
1.0
1.0
1.0
1.0
1.2
0.1
0
50
85
99
92
8
c
99
91
84
96
c,d
a Isolated. b Determined by chiral HPLC (Chiralcel OD-H column).
a Determined by GC at 20 h. b Determined by chiral HPLC (Chiralcel
OD-H column). c Not determined. d 80 mM in imine.
The conditions of Table 1, entry 5, are highly selective
for a wide range of structurally diverse N-phosphinoylimines.
For example, alkyl aryl ketimines 1-6 were all reduced in
good yield and excellent selectivity (Table 2, entries 1-6).
The R,â-unsaturated imines 7 and 8 were also reduced with
superb selectivity (Table 2, entries 7 and 8). The doubly
The identification of a viable imine electrophile to pair
with our aluminum system was a critical first step. Encour-
aged by our recent success in the addition of acyl anions to
N-diphenylphosphinoyl imines,13 we reasoned that these
electrophilic compounds might also undergo MSPV reduc-
tion. Furthermore, these imines have recently been employed
as electrophiles in a number of asymmetric transforma-
tions,14,15 and the resulting amides are easily converted into
useful intermediates.16 Hence, we were gratified to observe
the stereoselective reduction of imine 1 by 2-propanol in the
presence of stoichiometric amounts of (S)-BINOL and AlMe3
during our initial experiments (Table 1). While reaction 1
does not proceed at room temperature (Table 1, entry 1),
quantitative conversion is observed at 80 °C, albeit in 84%
ee (Table 1, entry 4). Lowering the reaction temperature to
(9) For reviews, see: (a) de Graauw, C. F.; Peters, J. A.; van Bekkum,
H.; Huskens, J. Synthesis 1994, 1007-1017. (b) Graves, C. R.; Campbell,
E. J.; Nguyen, S. T. Tetrahedron: Asymmetry 2005, 16, 3460-3468.
(10) Brunel, J. M. Chem. ReV. 2005, 105, 857-897.
(11) Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed.
2002, 41, 1020-1022.
(12) Cohen, R.; Graves, C. R.; Nguyen, S. T.; Martin, J. M. L.; Ratner,
M. A. J. Am. Chem. Soc. 2004, 126, 14796-14803.
(13) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363-4366.
(14) For examples, see: (a) Sugi, K. D.; Nagata, T.; Yamada, T.;
Mukaiyama, T. Chem. Lett. 1997, 26, 493-494. (b) Masumoto, S.; Usuda,
H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
5634-5635 and references therein. (c) Weix, D. J.; Shi, Y.; Ellman, J. A.
J. Am. Chem. Soc. 2005, 127, 1092-1093. (d) Weinreb, S. M.; Orr, R. K.
Synthesis 2005, 8, 1205-1227.
(15) For recent examples of the asymmetric reduction of phosphinoyl
imines, see ref 5b,h,j,k.
(16) Kenner, G. W.; Moore, G. A.; Ramage, R. Tetrahedron Lett. 1976,
17, 3623-3626.
(6) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 444,
221-238.
(7) Ponndorf, W. Z. Angew. Chem. 1926, 39, 138-143.
(8) Verley, M. Bull. Soc. Chim. Fr. 1925, 37, 871-874.
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Org. Lett., Vol. 8, No. 6, 2006