Highly stereocontrolled reduction of 1,3-cyclopentanediones using oxazaborolidine -BH3

Article abstract of DOI:10.1016/S0957-4166(00)00378-5

Highly enantioselective reduction of 1,3-cyclopentanediones was conducted using an oxazaborolidine derived from L-threonine and a borane complex to give either 1,3-cyclopentanediols or 3-hydroxycyclopentanones in high enantiomeric purity by choosing appropriate reduction conditions. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00378-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3883–3886
Highly stereocontrolled reduction of 1,3-cyclopentanediones
using oxazaborolidineꢀBH3
Makoto Shimizu,* Shunsuke Yamada, Yoshifumi Fujita and Fumiko Kobayashi
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 4 September 2000; accepted 18 September 2000
Abstract
Highly enantioselective reduction of 1,3-cyclopentanediones was conducted using an oxazaborolidine
derived from
L-threonine and a borane complex to give either 1,3-cyclopentanediols or 3-hydroxy-
cyclopentanones in high enantiomeric purity by choosing appropriate reduction conditions. © 2000
Elsevier Science Ltd. All rights reserved.
Widespread occurrence of cyclopentane derivatives in many biologically interesting materials1
coupled with recent interest in the oxazaborolidine-mediated selective reduction2 prompts us to
report our results from asymmetrization of 1,3-cyclopentanediones using such a reduction
methodology. For the preparation of useful chiral synthons possessing multiple stereogenic
centers leading to the synthesis of cyclopentanoides, asymmetrization of meso-compounds offers
one of the most convenient approaches.3 We have already reported that meso-dicarboxylic
anhydrides are readily converted into chiral monoesters by the action of zinc reagents in the
presence of a cinchona alkaloid as a chiral auxiliary,4 and have also disclosed very recently that
the oxazaborolidine-mediated reduction is a useful tool for the reduction of meso-imides, leading
to a short-step synthesis of (+)-deoxybiotin, a precursor of (+)-biotin, with high enantiomeric
excess.5 However, difficulty was encountered in the selective reduction of 1,3-diketones to
1,3-diols or b-hydroxy ketones due to the susceptibility of b-hydroxy ketones towards further
reduction into 1,3-diols. We have now found that the reduction of 1,3-cyclopentanediones with
BH3–oxazaborolidine derived from
L
-threonine leads to the formation of either 1,3-diols or
b-hydroxy ketones by choosing appropriate reduction conditions.
* Corresponding author. Tel/fax: +81 59 231 9413; e-mail: mshimizu@chem.mie-u.ac.jp
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00378-5

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M. Shimizu et al. / Tetrahedron: Asymmetry 11 (2000) 3883–3886
An initial examination was carried out for the bis-reduction using diacetylindane 5 as a
substrate under the conditions previously reported,6 except oxazaborolidine 2, which we have
developed,7 was used. As shown in Table 1, the substituent on the boron atom of the
oxazaborolidine 2 was found to be very important in the control of enantioselectivity. Among
the derivatives screened, the use of methyl substituted analogue 2 (R=Me) proved to be the
most effective, and the use of a stoichiometric amount of the oxazaborolidine 2 (R=Me) was
also crucial for the control of the diastereoselectivity (entry 4). We then turned our attention to
the stereocontrolled reduction of cyclic substrates, and the results are also summarized in Table
1.
Table 1
Bis-reduction of 1,3-cyclopentanedione 1 to 1,3-diol 3a
Entry
Diketone
R in ligand 2
2 (equiv.)
BH3 complex
% eeb
Yield (%)c
dl:mesod
1
2
3
4
5
6
7
8
9
5
5
5
H
0.1
0.1
0.1
1.0
0.1
1.0
0.1
1.0
0.1
1.0
BH3ꢀSMe2
BH3ꢀ SMe2
BH3ꢀSMe2
BH3ꢀSMe2
BH3ꢀTHF
BH3ꢀTHF
BH3ꢀSMe2
BH3ꢀSMe2
BH3ꢀSMe2
BH3ꢀSMe2
8
92
66
97
90
\99
83
98
56
\99
48
44
46
74
89
83
72
80
56
62
36:64
23:77
22:78
69:31
65:35
\99:1
78:22
\99:1
79:21
\99:1
Me
n-Bu
Me
Me
Me
Me
Me
Me
Me
5
1a
1a
1a
1a
1b
1b
10
a The reaction was carried out according to the typical procedure, see Ref. 9.
b Determined by HPLC using a chiral stationary column (Daicel OD).
c Isolated yields. Determination of the absolute configurations of the products, see Ref. 8.
d Determined by HPLC (Kanto Chemicals Mightysil and/or Daicel OD column).
In the presence of a catalytic amount of oxazaborolidine 2 (R=Me), the reduction proceeded
to give the diol in good yield with good enantioselectivity, although the diastereoselectivity was
not high (entry 5). In contrast, when a stoichiometric amount of 2 was used, both diastereo- and
enantioselectivities were excellent, and the reduction gave essentially enantiomerically pure diols
(entries 6, 8, and 10).9 The poor diastereoselectivities observed in the cases with the use of a
catalytic amount of 2 may be due to the competing non-diastereoselective reduction of the
initially formed hydroxy ketone with BH3 itself. With these findings in mind we next applied the
present procedure to the mono-reduction of 1,3-pentanediols, and the results are shown in Table
2.
As shown in Table 2, reduction in the absence of additives gave the mono-reduction product
4a with moderate enantiomeric purity in moderate yield. In order to improve both product

M. Shimizu et al. / Tetrahedron: Asymmetry 11 (2000) 3883–3886
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Table 2
Mono-reduction of 1,3-cyclopentanedione 1 to b-hydroxy ketone 4a
Entry
1
Additive (equiv.)
BH3ꢀTHF (equiv.)
Time (h)
Yield (%)b
% eec
1
2
3
4
5
6
7
8
9
1a None
1.1
1.1
2.0
2.0
2.0
2.0
2.0
4.0
2.0
3.0
1
19
19
3
1
1
58
64
40
29
70
48
44
40
71
63d
78
88
86
84
84
92
94
96
88
90
1a N,N-Diethylaniline (0.1)
1a N,N-Diethylaniline (0.5)
1a N-Ethyl-N-methylaniline (0.5)
1a N,N-Diethylaniline (0.5)
1a N-Ethyl-N-isopropylaniline (0.5)
1a N,N-Diisopropylaniline (0.5)
1b N,N-Diethylaniline (2.0)
1c N,N-Diethylaniline (0.5)
1d N,N-Diethylaniline (0.75)
1
19
19
19
10
a The reaction was carried out according to the typical procedure, see Ref. 12.
b Isolated yields. Determination of the absolute configurations of the products, see Ref. 10.
c Determined by HPLC using a chiral stationary column (Daicel OD).
d No hydroboration at the allyl substituent was observed under the present conditions.
yields and enantiomeric purities, we carried out the reduction under a variety of conditions.
Although it was not trivial to stop the reduction at the mono-reduction stage under the typical
reduction conditions, the presence of certain amine additives could retard the second reduc-
tion.11 Among the amines screened aniline derivatives were found to be effective.6 The presence
of N,N-diethylaniline improved the enantiomeric purity of the mono-reduction product up to
88% ee, and N,N-diisopropylaniline was also effective (entries 2 and 7). In terms of the product
yield, the reaction carried out in a short reaction period gave better results, although the
enantioselectivity was somewhat lowered (entries 3 and 5). This is due to over-reduction leading
to the formation of diols and some other unidentified products. In the presence of N,N-diethyl-
aniline other 1,3-cyclopentadione derivatives 1b–d underwent enantioselective mono-reduction
to give hydroxy ketones 4b–d with good enantiomeric purities.12 In the absence of added amines,
the second reduction was relatively fast, giving the diol 3 with good enantiomeric purity and the
hydroxy ketone 4 with moderate enantiomeric purity. This is due to the kinetic resolution of the
hydroxy ketone 4, in which the second reduction increases the enantiomeric purity in favor of
the diol 3 not of the remaining hydroxy ketone 4. Therefore, the added amine possesses two
roles, the control of enantioselectivity of the first reduction and the suppression of the second
one.
In conclusion, the present methodology using asymmetrization of cyclopentan-1,3-diones
demonstrates the power of the oxazaborolidine-mediated reduction of symmetrical molecules to
give a very useful class of compounds with high enantiomeric excess in a single step. The
presence of the added amine makes the selective formation of the mono-reduction product

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M. Shimizu et al. / Tetrahedron: Asymmetry 11 (2000) 3883–3886
feasible. Thus, both 1,3-diols and b-hydroxy ketones may be prepared by choosing appropriate
reduction conditions.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research on Priority Area from the
Ministry of Education, Science, Sports, and Culture of the Japanese Government.
References
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201–204. (d) Corey, E. J.; Bakshi, R. K.; Shibata. S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109,
7925–7926. (e) Trost, B. M.; Shimizu, M. J. Am. Chem. Soc. 1983, 105, 6757–6759, and references cited therein.
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1990, 1, 477–511. (c) Harada, T.; Oku, A. Synlett 1994, 95–104, and the references cited therein.
4. Shimizu, M.; Matsukawa, K.; Fujisawa, T. Bull. Chem. Soc. Jpn. 1993, 66, 2128–2130.
5. Shimizu, M.; Nishigaki, Y.; Wakabayashi, A. Tetrahedron Lett. 1999, 40, 8873–8876.
6. Quallich, G. J.; Keavey, K. N.; Woodall, T. M. Tetrahedron Lett. 1995, 36, 4729–4732.
7. (a) Shimizu, M.; Kamei, M.; Fujisawa, T. Tetrahedron Lett. 1995, 36, 8607–8610. (b) Shimizu, M.; Tsukamoto,
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8. Absolute configurations of the products were determined by comparison with the authentic samples prepared via
baker’s yeast reduction of cyclopentan-1,2-diones followed by further reduction with NaBH4 and appropriate
functional group transformations. Cf. Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J. Org. Chem. 1987, 52,
3223–3232.
9. A typical procedure for the reduction of 1,3-diketones into 1,3-diols: A mixture of (2S,3R)-2-amino-3-
(t-butyldimethylsiloxy)-1,1-diphenylbutanol (74.2 mg, 0.2 mmol) and methylboronic acid (13.2 mg, 0.22 mmol) in
,
THF (3.0 mL) was heated at 50°C for 5 h in the presence of molecular sieves 4 A (1.0 g). The resulting mixture
was cooled to 0°C and to it was added a solution of 1a (40.4 mg, 0.2 mmol) in THF (3.0 mL). A solution of
BH3·SMe2 complex (0.1 mL, 1.0 mmol) in THF (3.0 mL) was added to the mixture over 3 h at 0°C. After stirring
for 13 h at rt, the reaction mixture was quenched by adding 2N HCl, and the repeated extraction with ethyl
acetate was followed by usual work-up which gave a crude oil that was purified on preparative TLC (eluent:
n-Hex/AcOEt=2/1) to give the diol 3a as a colorless oil (33.0 mg, 80%).
10. Absolute configurations of the products were determined by comparison with the authentic samples prepared via
baker’s yeast reduction of cyclopentan-1,2-diones. See Refs. 1a,b and 8.
11. (a) Cai, D.; Tschaen, D.; Shi, Y. J.; Verhoeven, T. R.; Reamer, R. A.; Douglas, A. W. Tetrahedron Lett. 1993,
34, 3243–3246. (b) Shi, Y. J.; Cai, D.; Dolling, U. H.; Douglas, A. W.; Tschaen, D. M.; Verhoeven, T. R.
Tetrahedron Lett. 1994, 35, 6409–6412. (c) Periosamy, M.; Kanth, J. V. B.; Prasad, A. S. B. Tetrahedron 1994,
50, 6411–6416. (d) Falorni, M.; Collu, C.; Giacomelli, G. Tetrahedron: Asymmetry 1996, 7, 2739–2742. (e)
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12. A typical procedure for the reduction of 1,3-diketones into b-hydroxy ketones: Compound 2 (R=Me) was
prepared as above. The resulting solution of 2 (R=Me) was cooled to 0°C and to it was added a mixture of 1a
(40.4 mg, 0.2 mmol) and N,N-diethylaniline (1.5 mL, 0.02 mmol) in THF (3.0 mL). A solution of BH3·THF
complex (0.22 mL, 0.22 mmol) in THF (0.6 mL) was added to the mixture during 45 min at 0°C. After stirring
for 19 h at rt, the reaction mixture was quenched by adding 2N HCl. Usual work-up followed by purification on
preparative TLC (eluent: n-Hex/AcOEt=2/1) gave the b-hydroxy ketone 4a as a colorless oil (25.9 mg, 64%).
.
.