A practical stereoselective synthesis of chiral hydrobenzoins via asymmetric transfer hydrogenation of benzils

Article abstract of DOI:10.1021/ol990226a

(matrix presented) Asymmetric reduction of benzil with RuCl[(S,S)-Tsdpen)(η⁶-p-cymene) in a mixture of formic acid and triethylamine proceeds with a substrate/ catalyst molar ratio of 1000-2000 to give (R,R)-hydrobenzoin quantitatively with high diastereomeric (97% de) and enantiomeric purities (>99% ee), in which the benzoin intermediate with a chirally labile stereogenic center is converted to one major stereoisomer, (R,R)-product, via dynamic kinetic resolution.

Full text of DOI:10.1021/ol990226a

ORGANIC
LETTERS
1999
Vol. 1, No. 7
1119-1121
A Practical Stereoselective Synthesis of
Chiral Hydrobenzoins via Asymmetric
Transfer Hydrogenation of Benzils
Kunihiko Murata,† Kazuya Okano,‡ Miwa Miyagi,‡ Hiroshi Iwane,‡
Ryoji Noyori,§ and Takao Ikariya*†
Department of Applied Chemistry, Graduate School of Science and Engineering,
Tokyo Institute of Technology and CREST, Japan Science and Technology
Corporation, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552 Japan,
Tsukuba Research Center, Mitsubishi Chemical Corporation, 8-3-1,
Chuo, Ami, Inashiki, Ibaraki, 300-03, and Department of Chemistry and Research
Center for Materials Science, Nagoya UniVersity, Chikusa, Nagoya 464-8602 Japan
tikariya@o.cc.titech.ac.jp
Received August 11, 1999
ABSTRACT
Asymmetric reduction of benzil with RuCl[(S,S)-Tsdpen)(η6-p-cymene) in a mixture of formic acid and triethylamine proceeds with a substrate/
catalyst molar ratio of 1000−2000 to give (R,R)-hydrobenzoin quantitatively with high diastereomeric (97% de) and enantiomeric purities (>99%
ee), in which the benzoin intermediate with a chirally labile stereogenic center is converted to one major stereoisomer, (R,R)-product, via
dynamic kinetic resolution.
Chiral 1,2-diols, especially, hydrobenzoins are useful building
blocks for the syntheses of various biologically active
compounds as well as chiral ligands and auxiliaries in
stereoselective organic syntheses.1 These important chiral
hydrobenzoins have been prepared by resolution of racemic
hydrobenzoins,2 by stereoselective pinacol coupling of (η6-
o-substituted benzaldehyde)Cr(CO)3 with samallium iodide,3
and by Sharpless asymmetric dihydroxylation of trans-
stilbene.1a,4,5 Although asymmetric reduction of readily
available R-diketones to chiral 1,2-diols would be a promis-
ing and widely applicable approach, no practical reduction
systems have been reported except for oxazaborolidine-
catalyzed reductions of benzils with borane/methyl sulfide,6
which give chiral hydrobenzoins together with meso-1,2-
† Tokyo Institute of Technology.
‡ Mitsubishi Chemical Corporation.
§ Nagoya University.
(1) (a) Wang, Z.-M.; Sharpless, K. B. J. Org. Chem. 1994, 59, 8302-
8303 and references therein. (b) Halterman, R. L.; Jan, S.-T.; Nimmons,
H. L.; Standlee, D. J.; Khan, M. A. Tetrahedron 1997, 53, 11257-11276.
(c) Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998, 63, 9351-
9357. (d) Donnoli, M.-I.; Superchi, S.; Rosini, C. J. Org. Chem. 1998, 63,
9392-9395. (e) Kim, K.-S.; Park, J., II.; Ding, P. Tetrahedron Lett. 1998,
39, 6471-6474. (f) Superchi, S.; Contursi, M.; Rosini, C. Tetrahedron 1998,
54, 11247-11254. (g) Ishimazu, K.; Monda, K.; Yamamoto, Y.; Akiba,
K. Tetrahedron 1998, 54, 727-734. (h) Tunge, J. A.; Gately, D. A.; Norton,
J. A. J. Am. Chem. Soc. 1999, 121, 4520-4521.
(2) (a) Kawashima, M.; Hirayama, A. Chem. Lett. 1991, 763-766. (b)
Edwards. P. J.; Entwistle, D. A.; Ley, S. V.; Owen, D. R.; Perry, E. J.
Tetrahedron: Asymmetry 1994, 5, 551-556.
(3) (a) Taniguchi, N.; Kaneta, N.; Uemura, M. J. Org. Chem. 1996, 61,
6088-6089. (b) Taniguchi, N.; Uemura, M. Tetrahedron 1998, 54, 12775-
12788.
(4) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(5) Hanessian, S.; Meffre, P.; Girard, M.; Beaudoin, S.; Sanceˆau, J.-Y.;
Bennani, Y. J. Org. Chem. 1993, 58, 1991-1993.
10.1021/ol990226a CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/04/1999

diols because of an inherent preference for the formation of
the meso-isomers in the borane reduction. Chiral Ru-BINAP
complexes effect the asymmetric hydrogenation of 1,2-
diketones to give a mixture of chiral 1,2-diol with an
excellent enantiomeric excess (ee) and meso-isomer. How-
ever, meso-isomer is the major product because the substrate
control in the second hydrogenation step of the hydroxy
ketone intermediate favors meso-diol formation.7,8 Here, we
describe the first practical asymmetric reduction of 1,2-
diketones to chiral 1,2-diols catalyzed by well-defined chiral
Ru(II) catalysts, RuCl(Tsdpen)(η6-arene) (1) (TsDPEN, N-(p-
toluenesulfonyl)-1,2-diphenylethylenediamine)9 with the for-
mic acid/triethylamine mixture as a hydrogen source.10
Asymmetric reduction of benzil (2a) catalyzed by the
chiral Ru complex (S,S)-1b proceeds homogeneously at 40
°C with a substrate:catalyst molar ratio (S/C) of 1000 in a
DMF solution of HCOOH/N(C2H5)3 (benzil:HCOOH:
N(C2H5)3 molar ratio ) 1:4.4:2.6, 0.95 M) to give almost
quantitatively chiral (R,R)-hydrobenzoin (4a) with excellent
diastereomeric (dl:meso ) 98.6:1.4) and enantiomeric purities
(>99% ee) (Scheme 1). The p-cymene and mesitylene
stereoselectivity although less reactivity at 40 °C. However,
when the temperature was increased to 60 °C, the yield went
from 5% to 22% without a significant loss in the selectivity.
RuCl(Tscydn)(η6-p-cymene) 1e (TsCYDN, N-(p-toluene-
sulfonyl)-1,2-cyclohexanediamine) is also usable. Formic
acid is the best hydrogen donor for this reduction. Attempted
reduction using a 0.05 M solution of 2-propanol containing
(S,S)-1b (S/C ) 100, 30 °C, 24 h) gave (S)-benzoin with a
10% ee and 42% yield, but hydrobenzoin was not produced.10
DMF is used to maintain the homogeneity of the reaction
mixture, but is not crucial for the catalysis to be efficient
and practical. In fact, the reaction of benzil with a S/C of
1000 (1.6 M) in a mixture of HCOOH and N(C2H5)3
containing (S,S)-1b (2a:HCOOH:N(C2H5)3 molar ratio )
1:4.4:2.6) proceeded heterogeneously at the early stages of
the reaction because of the low solubility of 2a. After 24 h
at 40 °C, (R,R)-4a (dl:meso ) 98.4:1.6, >99% ee) was
formed stereoselectively in quantitative yields. Enantiomeri-
cally pure (R,R)-hydrobenzoin was obtained in 84% isolated
yield by simple evaporation of triethylamine, washing with
water, and crystallization from ethanol from a 10-g-scale
reaction. In the absence of triethylamine, no conversion of
benzils was observed. The addition of triethylamine to the
reaction mixture resulted in a significant increase in the
conversion of the benzils. A formic acid:triethylamine molar
ratio of 4.4:2.6 to 4.4:4.4 gave the best catalyst performance
in terms of reactivity and stereoselectivity.
Scheme 1
Various benzil derivatives bearing substituents on aromatic
rings were able to be stereoselectively reduced to the chiral
hydrobenzoins with high ee’s and in good yields. Table 1
Table 1. Asymmetric Transfer Hydrogenation of Benzils and
Benzoin Catalyzed by Chiral Ru(II) Catalysts with Formic Acida
yield
(%)b
ee
Ru cat. ketone solvent t (h)
dl:mesob (%)c confd
(S,S)-1a
(S,S)-1b
(S,S)-1b
(S,S)-1c
(S,S)-1d
(S,S)-1d e
(S,S)-1e
(S,S)-1b
(S,S)-1bf
(S,S)-1bg
(R,R)-1b
(S,S)-1b
(S,S)-1bi
(S,S)-1b
(S,S)-1bl
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
3a
DMF
DMF
DMF
DMF
DMF
DMF
DMF
-
-
-
-
-
24 100
24 97
30 100
90.4:9.4 >99 R,R
98.6:1.4 >99 R,R
98.6:1.4 >99 R,R
98.1:1.9 >99 R,R
99.9:0.1 >99 R,R
98.1:1.9 >99 R,R
93.8:6.2 >99 R,R
98.4:1.6 >99 R,R
98.1:1.9 >99 R,R
24
24
24
24
96
5
22
47
complexes 1b and 1c effected the reaction equally well, while
the benzene complex 1a was more reactive but less selective.
The hexamethylbenzene complex 1d showed extremely high
24 100
24 84
(6) (a) Quallich, G. J.; Keavey, K. N.; Woodall, T. M. Tetrahedron Lett.
1995, 36, 4729-4732. (b) Prasad, K. R. K.; Joshi, N. N. J. Org. Chem.
1996, 61, 3888-3889.
24 100(84)h 97.9:2.1 >99 R,R
24 100
98.0:2.0 >99 S,S
96.7:3.3 >99 R,R
94.4:5.6 >99j R,R
94.2:5.8 >99 R,Rk
98.2:1.8 >99 R,R
(7) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988,
110, 629-631.
48
48
67
75
DMF
-
DMF
24 100
24 100
(8) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994; Chapter 2.
(9) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 7562-7563. (b) Takehara, J.; Hashiguchi, S.;
Fujii, A.; Inoue, S.; Ikariya, T.; Noyori, R. J. Chem. Soc., Chem. Commun.
1996, 233-234. (c) Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics
1996, 15, 1087-1089. (d) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-2522. (e) Uematsu, N.;
Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996,
118, 4916-4917. (f) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, A.;
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288. (g) Hashiguchi,
S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 288-290. (h) Matsumura, K.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738-8739. (i)
Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102. (j) Murata,
K.; Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186-2187.
a The reaction of benzil (1.05 g, 5.0 mmol) was carried out with a S/C
molar ratio of 1000, benzil:HCOOH:N(C2H5)3 molar ratio ) 1:4.4:2.6 in
0.95 M DMF solution at 40 °C, unless otherwise noted. b Yields and dl:
meso ratios were determined by 1H NMR. c Unless otherwise noted,
determined by HPLC analysis using a Daicel Chiralcel OJ column. d Unless
otherwise noted, determined from the sign of rotation of the isolated product.
e At 60 °C. f Reaction with a S/C molar ratio of 2000. g Reaction of benzil
(11.0 g, 52.3 mmol). h Isolated yield in parentheses. i The reaction was
carried out with a S/C ratio of 200 and benzil:HCOOH:N(C2H5)3 molar
ratio ) 1:4.4:4.4 in a 1.2 M DMF solution at 35 °C. j Determined by HPLC
analysis using a Daicel Chiralcel OD column. k Determined by X-ray crystal
structural analysis of the salt with (S,S)-1,2-diaminocyclohexane. l Racemic
3a:HCOOH:N(C2H5)3 molar ratio ) 1:3.1:2.6 in a 1.2 M DMF solution.
1120
Org. Lett., Vol. 1, No. 7, 1999

lists some examples. The benzils with electron-donating
substituents (2b and 2c) were reduced with excellent enan-
tioselectivity but lower reactivity,9 while the reduction of
p-fluorobenzil (2d) proceeded rapidly as expected, giving a
product with a high ee.
Scheme 4
The success of the asymmetric reduction of benzils with
the formic acid and triethylamine mixture relies strongly on
the nature of benzoins 3 with a configurationally labile
stereogenic center and the chiral structure and mechanism-
based functional group discrimination ability of the chiral
Ru complexes. Thanks to a sufficiently rapid stereomutation
of 3 under the reaction conditions, the dynamic kinetic
resolution of benzoins allows the diastereo- and enantio-
selective synthesis of chiral hydrobenzoins 4. Thus, the
reaction of racemic benzoin 3a with a S/C of 1000 in a
mixture of formic acid and triethylamine containing (S,S)-
1b (1b:HCOOH:N(C2H5)3 molar ratio ) 1:3.1:2.6) at 40 °C
gave (R,R)-4a quantitatively (dl:meso ) 98.2:1.8, >99% ee)
after 24 h (Scheme 2, Table 1). The products contained the
metric transfer hydrogenation of benzils or hydrobenzoins
with formic acid as the hydrogen source. The coordinatively
saturated nature of the diamine-based Ru(II)-arene com-
plexes 1 with an excellent carbonyl group discrimination
ability as well as structural factors of the substrate is
responsible for the excellent stereoselective outcome of this
reduction.6,7,13,14 The CO2 byproduct is potentially recyclable
by using a rapid CO2 hydrogenation method under super-
critical CO2 conditions.15 Overall, the high rate of the reaction
and operational simplicity attained here can make this
reduction of readily available ketones practical. A 100-g-
scale reduction of 2 or racemic 3 leads successfully to
optically pure 4a with an 80% isolated yield after one
recrystallization from ethanol.
Scheme 2
Acknowledgment. We thank Professor Takeshi Nakai of
Tokyo Institute of Technology and Dr. Makoto Tokunaga
of RIKEN for valuable discussions.
same de and ee values as those attained at 4% conversion
after 0.25 h. These results imply that the (S,S)-catalyst favors
the reaction of (R)-benzoin. Computer-aided analysis of the
reduction indicated that the rate of the reduction of (R)-
benzoin with (R,R)-1b proceeds 55 times faster than the (S)-
isomer.11 The slow-reacting (S)-isomer undergoes a rapid
racemization (Scheme 3).12 Similarly, when racemic methyl
Supporting Information Available: The [R]D values of
the reaction products and the experimental procedure for the
transfer hydrogenation reaction of 2a with Ru catalyst 1b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL990226A
(10) Asymmetric transfer hydrogenation of benzil by in situ generated
diamine-based Ru catalyst using 2-propanol as a hydrogen source gave chiral
hydrobenzoin with moderate enantiomeric purity (dl:meso ) 31:69, 50%
ee). Schwink, L.; Ireland, T.; Pu¨ntener, K.; Knochel, P. Tetrahedron:
Asymmetry 1998, 9, 1143-1163.
Scheme 3
(11) For computer-aided analysis of dynamic kinetic resolution, see:
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995, 68,
36-56 and references therein.
(12) The racemization strongly depends on the reaction conditions and
the catalyst used. Future experiments will attempt to determine the
mechanism of the interconversion of the enantiomeric 3.
(13) Preliminary experiments showed that hydrogenation of 2a catalyzed
by a combined catalyst system of RuCl2[(R)-binap][(R,R)-dpen] and KO-
t-Bu gave racemic 3a in 20% yield. No hydrobenzoin was obtained.
Conditions: 2a:Ru cat:KO-t-Bu molar ratio ) 200:1:2.2, H2 10 atm,
2-propanol/DMF ) 5/1.5, 30 °C, 24 h. Two-component Ru catalyst, see:
(a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.;
Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. Engl. 1998, 37, 1703-1707. (b) Ohkuma, T.; Koizumi, M.; Doucet,
H.; Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529-13530.
(14) Hydrogenation of 2a catalyzed by Ru2Cl4[(R)-tolbinap]2‚(C2H5NH2)
gave a mixture of benzoin in 3% yield and hydrobenzoin with dl:meso )
5:95 in 12% yield. Conditions: S/C ) 200, H2 40 atm, CH3OH:CH2Cl2 )
5:1, 30 °C, 20 h. Ru-BINAP catalyst, see: Ikariya, T.; Ishii, Y.; Kawano,
H.; Arai, T.; Saburi, M.; Yoshikawa, S.; Akutagawa, S. J. Chem. Soc., Chem.
Commun. 1985, 922-924.
ether 5 was reduced with the (S,S)-catalyst (5:HCOOH:
N(C2H5)3 molar ratio ) 1:3.1:2.6, S/C ) 1000) at 40 °C,
for 24 h, a 92:8 mixture of the syn alcohol, (1R,2R)-6 (98.0%
ee) and the anti alcohol, (1R,2S)-6 (57.4% ee) was obtained
(Scheme 4).
(15) (a) Jessop, P. G.; Ikariya, T.; Noyori, R. Nature 1994, 368, 231-
233. (b) Jessop, P. G.; Hsiao, Y.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1994, 116, 8851-8852.
In summary, this work presents the first asymmetric
synthesis of enantiomerically pure hydrobenzoins via asym-
Org. Lett., Vol. 1, No. 7, 1999
1121