Asymmetric reduction of prochiral ketones using in situ generated oxazaborolidines derived from amino alcohols of (1R)-camphor as catalysts

Article abstract of DOI:10.1016/S0957-4166(00)00320-7

Chiral oxazaborolidines generated in situ from 1,2-amino alcohols and amino alcohol derivatives derived from (1R)-(+)-camphor and borane or trimethyl borate were used as catalysts for the enantioselective reduction of prochiral ketones. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00320-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3553–3560
Asymmetric reduction of prochiral ketones using in situ
generated oxazaborolidines derived from amino alcohols of
(1R)-camphor as catalysts
,
†
V. Santhi and J. Madhusudana Rao*
Organic Chemistry Division, Regional Research Laboratory [CSIR], Trivandrum 695019, India
Received 10 July 2000; accepted 15 August 2000
Abstract
Chiral oxazaborolidines generated in situ from 1,2-amino alcohols and amino alcohol derivatives
derived from (1R)-(+)-camphor and borane or trimethyl borate were used as catalysts for the enantio-
selective reduction of prochiral ketones. © 2000 Published by Elsevier Science Ltd.
1
. Introduction
Enantioselective reduction of prochiral ketones to enantiomerically pure secondary alcohols is
an important reaction in asymmetric synthesis. Many methods are available in the literature for
1
,2
the enantioselective reduction of ketones. Although the catalytic asymmetric reduction using
3
1
,3,2-oxazaborolidines as catalyst and borane as the reducing agent has received much attention
4
since the initial reports by Itsuno et al., there are only a few isolated reports on the use of
borane complexes of 1,2-amino alcohols derived from (1R)-(+)-camphor in the asymmetric
5
–8
reduction of prochiral ketones.
Herein we report the results obtained by an indepth study of the enantioselective reduction of
prochiral ketones catalyzed by in situ generated oxazaborolidines. Oxazaborolidines were
generated from the reaction of 1,2-amino alcohols synthesized from (1R)-(+)-camphor with
borane or trimethyl borate.
*
Corresponding author. Fax: (91)40-7173757, 7173387; e-mail: janaswamy@iict.ap.nic.in
Present address: Natural Products Laboratory, Indian Institute of Chemical Technology [CSIR], Hyderabad
00007, India.
†
5
0
957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00320-7

3554
V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
2
. Results and discussion
.1. Enantioselectivity
2
1
,2-Amino alcohols derived from (1R)-(+)-camphor with different orientations of the ꢀOH
and ꢀNH groups provide opportunities to study the effect of the structure of the catalyst
precursor on the enantioselectivity of the reduction. There are eight possible isomers that can be
prepared from camphor. Pavia et al. and Chittenden et al. synthesized seven of these isomers.
We prepared three isomers, cis-endo-endo and cis-exo-exo amino alcohols (1, 2 and 3) using
modified reported procedures (Fig. 1).
2
9
10
Figure 1.
These were treated with borane or trimethyl borate to generate the catalysts. The borane
reductions were performed as described in Section 4 (Scheme 1).
Scheme 1.
Similarly, catalysts from other isomers were also prepared (Fig. 2).
Figure 2.
The results obtained for the asymmetric reduction of prochiral ketones (Scheme 2) are
summarized in Tables 1 and 2.
Scheme 2.

V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
3555
Table 1
Results of enantioselective reduction of prochiral ketones using cis-endo-endo amino alcohol derived
oxazaborolidines as catalysts
It is evident from the above results that the cis-3-endo-amino-2-endo-hydroxybornane and
borane derived oxazaborolidine is an efficient catalyst for the asymmetric reduction of ketones.
The very low value of enantioselectivity observed for cis-2-endo-amino-3-endo-hydroxybornane
can be explained on the basis of steric factors. The free borane cannot coordinate with the
nitrogen atom of the oxazaborolidine moiety because of the steric repulsion of the methyl group
on the camphor skeleton thus facilitating free borane reduction.
The configuration of the products was found to be S when cis-exo-exo amino alcohol derived
oxazaborolidines were used as catalysts.
11
As expected, with the substituted amino alcohols low ee’s were obtained for the products.

3556
V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
Table 2
Results of enantioselective reduction of prochiral ketones using cis-exo-exo amino alcohol derived
oxazaborolidines as catalysts
2
.2. Effect of other factors on the enantioselectivity of asymmetric reduction
After carrying out these reductions, we were interested in studying the effect of various
parameters on the enantioselectivity of asymmetric ketone reduction. The catalyst 4a was taken
as the standard and acetophenone was taken as the model substrate for these studies.
2
.2.1. Temperature
Early reports on the effect of temperature on oxazaborolidine catalyzed reductions show a
12
decrease in the enantioselectivity of the product with a decrease of temperature. We carried out
the oxazaborolidine reduction of acetophenone at various temperature and the results are
summarized in Table 3.
It is evident from the study that good enantioselectivity is obtained only at room temperature.
At −78 and 65°C reaction leads to low ee of the product. The catalyst may not be stable at 65°C
and at −78°C the catalyst formation may be slow. In both cases free borane reduction may occur
at a faster rate leading to low enantioselectivity of the product.

V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
3557
Table 3
Effect of temperature on enantioselectivity of reduction
a
b
Entry
Temperature (°C)
ee (%)
Yield (%)
1
2
3
4
5
−78
0 to −10
rt (25)
45
50
65
93
25
6
45
76
84
80
80
65
a
Determined by comparison with standard specific rotation values.
Isolated yield.
b
2
.2.2. Catalyst–substrate ratio
Increase in concentration of the catalyst to substrate is known to increase the asymmetric
induction in some cases. The effect of catalyst concentration on the enantioselectivity of the
acetophenone reduction was studied by using 1, 5, 10 and 20 mol% of the catalyst. The results
are tabulated in Table 4.
Table 4
Effect of catalyst concentration on the enantioselectivity of reduction
a
b
Entry
Catalyst mol (%)
ee (%)
Yield (%)
1
2
3
4
5
0
1
5
10
20
0
79
80
90
76
99
78
69
87
86
a
Determined by comparison with standard specific rotation values.
Isolated yield.
b
It can be concluded from the study that good ee is obtained using 10 mol% of the catalyst.
13
When we carried out the reaction, adding the ketone to the catalyst borane complex, we
obtained a racemic secondary alcohol.
2
.2.3. Chirality of the catalyst precursor
To study the effect of chirality of the catalyst precursor on the asymmetric reduction of
acetophenone, the amino alcohols were prepared from (1S)-(−)-camphor according to a
5
reported procedure. Oxazaborolidines were generated from these amino alcohols by treatment
with borane and the reduction of acetophenone was carried out in situ (Scheme 3).
The results are summarized in Table 5.
From Table 5 it is clear that chirality of the starting material also plays an important role
in the enantioselectivity of the reduction product.

3558
V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
Scheme 3.
Table 5
Effect of chirality of starting material on enantioselectivity
a
b
Entry
Catalyst
ee (%)
Configuration
Yield (%)
1
2
8
10
42
46
R
S
78
76
a
Determined by comparison with standard specific rotation values.
Isolated yield.
b
3
. Conclusion
This paper gives the results of our investigation into the catalytic enantioselective reduction of
prochiral ketones catalyzed by the in situ generated oxazaborolidines generated from 1,2-amino
alcohols and substituted amino alcohols derived from (1R)-(+)-camphor. The effect of various
parameters such as temperature, catalyst–substrate ratio and chirality of the catalyst precursor
on the enantioselectivity of the reduction were also studied.
4
. Experimental
4
.1. General experimental details
(
1R)-(+)-Camphor was purchased from M/S Fluka. 1,2-Amino alcohols of (1R)-(+)-camphor
5,9,10
were prepared according to the reported procedure.
BH ·Me S was purchased from Aldrich
3
2
Chemical Company, and made up to 2 M in dry THF and used for the reactions. All reactions
were carried out under anhydrous conditions. Optical rotations were recorded on a Jasco DIP
1
3
70 digital polarimeter at ambient temperature (24–27°C). H NMR spectra were recorded on
a Bruker 300 MHz instrument using CDCl as the solvent and TMS as the internal standard. All
3
secondary alcohols were identified by spectral analysis. Enantiomeric excesses and configura-
tions of secondary alcohols were determined by optical rotation measurements. The ee values
obtained were further confirmed by studying the NMR spectra of (R)-MTPA esters of the
1
4
secondary alcohols.

V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
3559
A typical procedure for the asymmetric reduction using oxazaborolidines is described with cis
-endo-amino-2-endo-hydroxybornane 1 as the starting material.
3
The amino alcohol (0.034 g, 0.2 mmol) was dissolved in 3 mL of dry THF in a three necked
RB flask fitted with a septum, an argon source and a pressure equalizing funnel. To this 0.3
mmol of 2 M BH ·Me S in THF was added and the mixture stirred for one hour at room
3
2
temperature. After the amino alcohol was fully consumed (monitored by TLC) another 1.4
mmol of 2 M BH ·Me S was added and the reaction mixture was stirred for a further 10
3
2
minutes. To this acetophenone (0.240 g, 2 mmol) in 4 mL THF was added dropwise. On
completion of the reaction (2 h) the excess borane was destroyed by dropwise addition of cold
water (2 mL). The reaction mixture was extracted with ether (4×5 mL). The organic layers were
pooled together, washed with distilled water, brine, dried over anhydrous Na SO and concen-
2
4
trated. The crude product was purified by column chromatography with silica gel (100–200
mesh) using a hexane–EtOAc mixture as the eluent to afford the alcohol in 85% yield
2
5
[
h] =+39.9 (literature value +42.9). This was again confirmed by the NMR spectra of the
D
1
4
MTPA ester of the alcohol.
4
.2. Reaction with trimethyl borate
The amino alcohol (0.034 g, 0.2 mmol) was dissolved in 3 mL of dry THF in a three necked
RB flask fitted with a septum, an argon source and a pressure equalizing funnel. To this 0.26
mmol of trimethyl borate was added and the mixture stirred for one hour at room temperature.
After the amino alcohol was fully consumed (monitored by TLC), the excess trimethyl borate
was evaporated off, 1.4 mmol of 2 M BH ·Me S was added and the reaction mixture was stirred
3
2
for a further 10 minutes. To this acetophenone (0.240 g, 2 mmol) in 4 mL THF was added
dropwise. On completion of the reaction (2 h) the reaction mixture was worked up as described
in the above experiment.
Acknowledgements
V.S. thanks the CSIR, New Delhi for a research fellowship. The authors thank Dr. G. Vijay
Nair, [Director RRL], Dr. M. S. Nair and Dr. P. Shanmugam of the Organic Chemistry
Division, RRL, Trivandrum for useful discussions.
References
1
2
. Singh, V. K. Synthesis 1992, 7, 605.
. Itsuno, S. In Organic Reactions; Paquette, L. A., Ed.; Enantioselective Reduction of Ketones. John Wiley: New
York, 1998; Vol. 52, p. 395.
3
. (a) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475 and references cited therein. (b) Deloux, L.;
Srebnik, M. Chem. Rev. 1993, 93, 763 and references cited therein. (c) Corey, E. J.; Helal, C. J. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 1986 and references cited therein.
4
5
6
7
8
9
. Hirao, A.; Itsuno, S.; Nakahama, S.; Yamazaki, N. J. Chem. Soc., Chem. Commun. 1981, 315.
. Nakanishi, S.; Kondo, K.; Takemoto, K. Chem. Express 1987, 2, 41.
. Tanaka, K.; Matsui, M.; Suzuki, H. J. Chem. Soc., Chem. Commun. 1991, 1311.
. Quallich, J. G.; Blake, J. F.; Woodall, T. M. J. Am. Chem. Soc. 1994, 116, 8516.
. Yang, T. L.; Lee, D. S. Tetrahedron: Asymmetry 1999, 10, 405.
. Daniel, P.; Pavia, A. A. Bull. Soc. Chem. 1971, 3, 1060.

3560
V. Santhi, J. M. Rao / Tetrahedron: Asymmetry 11 (2000) 3553–3560
1
1
1
1
0. Chittenden, R. A.; Cooper, G. H. J. Chem. Soc. (C) 1970, 49.
1. Santhi, V.; Rao, J. M. Synth. Commun., in press.
2. Stone, B. G. Tetrahedron: Asymmetry 1994, 5, 465.
3. Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E.
J. J. J. Org. Chem. 1993, 58, 2880.
14. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 54, 2543. (b) Little, D. R.; Moellar, K. D. J. Org.
Chem. 1983, 48, 4487.
.