Chiral oxazaborolidines bearing a 1- or 2-naphthylmethyl group as catalysts for the enantioselective borane reduction of ketones: Experimental and quantum chemical calculations

Article abstract of DOI:10.1016/S0957-4166(98)00079-2

Two new catalysts for the enantioselective reduction of ketones, chiral 1,3,2-oxazaborolidines substituted at carbon 4 by a 1- or 2-naphthylmethyl group, have been prepared from the related amino alcohols, by treatment with borane in tetrahydrofuran, and

Full text of DOI:10.1016/S0957-4166(98)00079-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1091–1095
Chiral oxazaborolidines bearing a 1- or 2-naphthylmethyl group
as catalysts for the enantioselective borane reduction of ketones:
experimental and quantum chemical calculations
Zongxuan Shen,∗ Wei Huang, Jianwen Feng and Yawen Zhang
School of Chemistry and Chemical Engineering, Suzhou University, Suzhou 215006, PR China
Received 5 January 1998; accepted 13 February 1998
Abstract
Two new catalysts for the enantioselective reduction of ketones, chiral 1,3,2-oxazaborolidines substituted at
carbon 4 by a 1- or 2-naphthylmethylgroup, have been prepared from the related amino alcohols, by treatment with
borane in tetrahydrofuran, and the effectiveness of these two catalysts has been investigated. The stereochemical
outcomes were verified by means of quantum calculations using the AM1 computational method. © 1998 Published
by Elsevier Science Ltd. All rights reserved.
Chiral 1,3,2-oxazaborolidine catalysts have been successfully employed for the asymmetric borane
reduction of ketones in recent years.1 Many new catalysts, derived from natural or unnatural starting
materials, have been prepared in order to find more effective and economic catalysts.1 At the same time,
a number of papers on structure–enantioselectivity relationships of the catalyst have been published.2
Some papers on quantum chemical research in this field have appeared,3 after Corey had suggested their
mechanism for this reduction.4
According to Corey, the borane reduction of prochiral ketones using chiral 1,3,2-oxazaborolidines as
catalysts consists of four steps: I, formation of the borane adduct 3; II, coordination of the ketone to be
reduced to borane adduct 3 forming 4; III, stereospecific transformation of a hydride from BH3 to the
carbonyl carbon; IV, release of the product regenerating the catalyst.
It has been indicated that to achieve high enantioselectivity in the asymmetric borane reduction, one
face of the oxazaborolidine should be totally blocked. In order to verify the above hypothesis, we prepared
two new chiral oxazaborolidine catalysts bearing a 1- or 2-naphthylmethyl group at position 4 (2a and
2b), from the (R)-β-amino alcohols 1a and 1b in situ, by treatment with borane. Then the effectiveness
of these two catalysts was investigated through the reduction of a series of prochiral ketones. The reason
for the choice of 1- and 2-naphthylmethyl as the substituents is that they are similar in electronic nature
∗
Corresponding author. E-mail: yjhx@nsad.suda.edu.cn
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00079-2

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Table 1
Asymmetric reduction of prochiral ketones with 2a/2b (0.05 equiv.) and borane (1 equiv.)
while the 1-naphthylmethyl group is more bulky than the 2-naphthylmethyl group and hence the catalyst
2a may be the better one of the two.
The syntheses of the chiral β-amino alcohols 1a and 1b were achieved using a procedure similar to that
described in the literature.5 The structures of 1a and 1b were confirmed by elemental analyses, 1H NMR
and IR.6 The borane reduction of prochiral ketones catalyzed by the in situ formed oxazaborolidines 2a
and 2b was performed as described before,5 using 0.05 equiv. of 1a or 1b and 1 equiv. of borane in THF
at 30°C. The results are summerized in Table 1. It was shown that both 2a and 2b have high abilities
to induce chirality in the product secondary alcohol molecules for the tested ketones, including aralkyl,
alkyl and halogen-containing ketones. In particular, excellent results were obtained in the reduction of
p-methylacetophenone and p-methoxyacetophenone when 2a was employed as the chiral catalyst. These
two ketones were reduced to the corresponding secondary alcohols in 100% e.e. Obviously, catalyst 2a
displayed higher stereoselectivity than catalyst 2b, which is different from 2a only in the substitution
position of the naphthyl group. These results are in accordance with expectation.
Experimental results have been verified by quantum chemical calculations. Energy calculations were
made for each of the four steps shown in Scheme 1 by means of the computational AM1 method, using
the reduction of butyrophenone with borane and catalyst 2a or 2b as the models. The optimized structures
4a, 4b, 5a and 5b are shown in Fig. 1. In 4a and 4b, the catalyst is coordinated to the carbonyl lone pair
which is syn to the propyl group and anti to the phenyl group, leading to the formation of (S)-secondary
alcohol. The total energy and heat of formation of each optimized structure was summerized in Table 2,
and the enthalpies of each step are shown in Table 3.
One can see from the data in Table 3 that both steps I and III are exothermic reactions, while steps II
and IV are endothermic. The release of the reduction product from 5 regenerating the catalyst (step IV,
the most endothermic step) may be rate-determining. This is in accordance with the experimental results
reported by Corey, who had demonstrated, in the borane reduction of acetophenone and its derivatives
using 6 as a catalyst, that neither ketone–catalyst coordination nor hydride transfer to carbonyl steps
are rate-limiting.7 By comparing the enthalpies of the pairs IIa/IIb and IVa/IVb, one would find that
the formation of complex 4a is more favorable than the formation of 4b, and the release of the product
regenerating the catalyst from 5a is more readily accomplished than from 5b. In conclusion, catalyst 2a
is more effective than catalyst 2b.

Z. Shen et al. / Tetrahedron: Asymmetry 9 (1998) 1091–1095
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Scheme 1. The mechanism of the oxazaborolidine catalyzed enantioselective borane reduction of ketones
Acknowledgements
We thank Professor Cao Yang for helpful discussion over the quantum chemical calculations and we
are grateful to the National Natural Science Foundation of China and the Natural Science Foundation of
Jiangsu Education Commission for financial support.
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6. (R)-2-Amino-3-(1-naphthyl)-1,1-diphenyl-1-propanol 1a, recrystallized from ethanol, m.p. 96–97°C, [α]2D5 +135 (c=1 in
1
CHCl3). Elemental anal. calcd for C25H23NO: C, 84.95; H, 6.56; N, 3.96; found: C, 84.80; H, 6.56; N, 4.00. H NMR
(δ ppm, CDCl3): 0.93–1.82 (b, 2H), 2.85 (dd, 1H), 3.10 (dd, 1H), 4.30 (dd, 1H), 4.69–4.80 (b, 1H), 7.04–7.54 (m, 10H),
7.56–7.98 (m, 7H). (R)-2-Amino-3-(2-naphthyl)-1,1-diphenyl-1-propanol 1b, recrystallized from ethanol, m.p. 148–149°C,

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Z. Shen et al. / Tetrahedron: Asymmetry 9 (1998) 1091–1095
Fig. 1. The optimized structures of 4a, 4b, 5a and 5b
Table 2
Energies of optimized structures (kJ mol−1
)

Z. Shen et al. / Tetrahedron: Asymmetry 9 (1998) 1091–1095
1095
Table 3
Enthalpies of each reaction step
[α]2D5 +49.5 (c=1 in CHCl3). Elemental anal. calcd for C25H23NO: C, 84.95; H, 6.56; N, 3.96; found: C, 84.86; H, 6.43; N,
3.95. 1H NMR (δ ppm, CDCl3): 1.17–1.25 (b, 2H), 2.62–2.84 (m, 2H), 4.21–4.30 (m, 1H), 4.59–4.69 (b, 1H), 7.22–7.48
(m, 10H), 7.65–7.83 (m, 7H).
7. Corey, E. J.; Link, J. O.; Bakshi, R. K. Tetrahedron Lett. 1992, 33, 7107.