Oxazaborolidine-catalyzed enantioselective reduction of α-methylene ketones to allylic alcohols

Article abstract of DOI:10.1021/jo8011013

(Chemical Equation Presented) Oxazaborolidine-catalyzed enantioselective reduction of α-methylene ketones was efficiently carried out by using borane-diethylaniline as a stoichiometric reducing agent. The combination of this method and subsequent hydrogen

Full text of DOI:10.1021/jo8011013

Oxazaborolidine-Catalyzed Enantioselective
Reduction of r-Methylene Ketones to Allylic
Alcohols
Jun-ichi Matsuo,* Takaaki Kozai, Osamu Nishikawa,
Yu Hattori, and Hiroyuki Ishibashi*
DiVision of Pharmaceutical Sciences, Graduate School of
Natural Science and Technology, Kanazawa UniVersity,
Kakuma machi, Kanazawa 920-1192, Japan
FIGURE 1. Tacalcitol (1R,24-(R)-dihydroxycholecalciferol).
jimatsuo@p.kanazawa-u.ac.jp
SCHEME 1. Reduction of 24-Oxochoresterol Derivative
ReceiVed May 20, 2008
because the sizes of the aliphatic alkyl groups on the 24-keto
group were not sufficiently differentiated. Stereoselective reduc-
tion of such ketones has been left as an important problem, and
some indirect methods have been reported. For example,
DeNinno reported a method involving oxazaborolidine-catalyzed
reduction of acyl dithianes and reductive removal of the dithiane
group.6 Cho reported 3-catalyzed reduction of p-tolylthiomethyl
ketones followed by oxidation to sulfoxide, alkylation, and
reductive removal of the sulfinyl group.7 Crich reported 3-cat-
alyzed reduction of R,R-disubstituted R-nitroketones followed
by removal of the nitro group using AIBN and Bu3SnH.8
Oxazaborolidine-catalyzed enantioselective reduction of R-m-
ethylene ketones was efficiently carried out by using
borane-diethylaniline as a stoichiometric reducing agent.
The combination of this method and subsequent hydrogena-
tion of thus-formed allylic alcohol improved stereoselectivity
in the reduction of 24-oxocholesteryl ester to 24-(R)-
hydroxycholesteryl ester.
Tacalcitol (1R,24-(R)-dihydroxycholecalciferol, 1) is a phar-
macologically active vitamin D3 analogue (Figure 1).1,2 We have
been studying efficient synthesis of 1 from 24-oxocholesterol
(2a),3 and reduction of the 24-keto group of 2a with high facial
selectivity is a difficult issue that remains to be solved. The
difficulty was exemplified by reduction of 24-oxocholesteryl
benzoate (2b) with sodium borohydride, which gave the
corresponding alcohol 4b as a mixture of equal amounts of 24-
(R) and 24-(S)-isomers. Even oxazaborolidine 3-catalyzed
reduction4,5 of 2b with catecholborane gave alcohol 4b in 61%
yield with moderate selectivity (24-R/S ) 76:24, Scheme 1)
FIGURE 2. Ternary complex of oxazaborolidine 3, borane, and
R-methylene ketone 5.
We considered that enone 5 would be a more suitable
substrate for oxazaborolidine 3-catalyzed reduction since lone
pair electrons that were anti to the C-C double bond would
selectively coordinate to boron (Figure 2)9 and thus-formed
allylic alcohol would be easily hydrogenated to a saturated one.
However, there has been only one example of oxazaborolidine-
(1) Review: Nishikawa, O. Medchem News 1994, 4, 85–90.
(2) (a) Matsui, T.; Nakao, Y.; Kobayashi, N.; Kishihara, M.; Ishizuka, S.;
Watanabe, S.; Fujita, T Int. J. Cancer 1984, 33, 193–202. (b) Matsunaga, T.;
Yamamoto, M.; Ohta, T.; Kiyoki, M.; Ohba, T.; Naruchi, T.; Hosoi, J.; Kuroki,
T. J. Dermatol. 1990, 17, 135–142.
(3) (a) Morisaki, M.; Koizumi, N.; Ikekawa, N.; Takeshita, T.; Ishimoto, S.
J. Chem. Soc., Perkin Trans. 1 1975, 1421–1424. (b) Nishikawa, O.; Ishimaru,
K.; Takeshita, T.; Tsuruta, H. U.S. Patent 4,298,537, 1981. (c) Nishikawa, O.;
Ishimaru, K.; Takeshita, T.; Ysuruta, H. U.S. Patent 4,388,243, 1983. (d)
Okamoto, M.; Tabe, M.; Fujii, T.; Tanaka, T. Tetrahedron: Asymmetry 1995, 6,
767–778.
(4) Review: (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012. (b) Itsuno, S. Org. React. 1998, 52, 395–576. (c) Itsuno, S. In
ComprehensiVe Asymmetric Catalysts; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: New York, 1999; Vol. 3, pp 289-315. (d) Wallbaum, S.;
Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475–1504. (e) Cho, B. T.
Tetrahedron 2006, 62, 7621–7643.
(5) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551–5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926.
(6) DeNinno, M. P.; Perner, R. J.; Lijewski, L. Tetrahedron Lett. 1990, 31,
7415–7418.
(7) (a) Cho, B. T.; Kim, D. J. Tetrahedron 2003, 59, 2457–2462. (b) Cho,
B. T.; Choi, O. K.; Kim, D. J. Tetrahedron: Asymmetry 2002, 13, 697–703.
(8) Crich, D.; Ranganathan, K.; Rumthao, S.; Shirai, M. J. Org. Chem. 2003,
68, 2034–2037.
(9) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153–9156.
6902 J. Org. Chem. 2008, 73, 6902–6904
10.1021/jo8011013 CCC: $40.75 2008 American Chemical Society
Published on Web 08/07/2008

TABLE 2. Effect of Aminesa
SCHEME 2. Oxazaborolidine 7-Catalyzed Reduction of
r-Methylene Ketone 6
entry
ligand
reaction time (h)
yield (%)
% ee
1
2
3
4
5
iPr2NPh
5
2
1
4
2
22
46
71
22
0
92
88
91
85
iPrEtNPh
Et2NPh
Me2NPh
2,6-lutidine
a Enantioselective reduction of 9 to 10 by using 3 (10 mol %) and
BH3-amine complex (1 equiv) in THF at 4 °C.
borane-diethylaniline showed better enantioselectivity (92% ee)
and the use of 25 mol % of the catalyst 3 gave 10 in 88% yield
with 94% ee (entry 3). The increased amount of the catalyst 3
contributed to shortening of the reaction time: the use of 10
mol % of 3 required a long reaction time (2 h), whereas the
reduction was completed within 5 min when 25 mol % of 3
was employed. Lowering the reaction temperature did not
improve the enantioselectivity (-10 °C: 61% yield, 92% ee;
-20 °C: 10% yield, 51% ee). The absolute configuration of 10
was determined by comparison with the reported sign of optical
rotation.15 In Corey’s transition state model,4a as expected, the
isopropenyl group adopts the position anti to lone pair electrons
which coordinate to boron (Figure 2). When solvents other than
THF were employed in 3-catalyzed reduction of 9 with
borane-diethylaniline, neither better chemical yields nor better
enantioselectivities were observed in toluene (31%, 62% ee),
TABLE 1. Effect of Reducing Agents
entry
L2BH (equiv)
conditionsa
yield (%)
% ee
63
1
2
BH3-THF (1.0)
BH3-Me2S (1.0)
BH3-Et2NPh (1.0)
4 °C, 10 min
4 °C, 5 min
4 °C, 2 h
19
29
83
3
75 (88)b
92 (94)b
86
4c
catecholborane (1.5) -78 °C, 3.5 h 90
a After the slow addition (1.5 h) of 9. b The catalyst 3 (25 mol %)
was employed. Conditions: 4 °C for 5 min. c Dichloromethane was used
as solvent.
t
CH2Cl2 (22%, 51% ee), BuOMe (57%, 74% ee), Et2O (75%,
84% ee), dimethoxyethane (69%, 80% ee), CH3CN (trace), and
EtNO2 (trace).
In order to investigate the effect of amines16 that coordinated
to borane, various borane-amine complexes17 were prepared
by mixing 1.2 equiv of borane-Me2S18 and 1 equiv of amine
in THF at room temperature for 1 h followed by removal of
excess borane-Me2S in vacuo. The 3-catalyzed reduction of 9
with BH3-diethylaniline complex prepared by this method gave
results similar to those obtained with commercially available
borane-diethylaniline13 (Table 2, entry 3 vs Table 1, entry 3).
Investigation of the effects of N-substituents of N,N-substituted
anilines revealed that there was no notable influence on
enantioselectivity, whereas chemical yield of 10 was influenced
by the amine ligands (entries 1-4). The use of dimethylaniline
and 2,6-lutidine gave 10 in low yields because they coordinated
to borane more strongly than did diethylaniline and their
complexes reduced 9 more slowly than did borane-diethylaniline.
Scope and limitations of the present method were surveyed
by using 25 mol % of catalyst 3 and commercially available
borane-diethylaniline13 (Table 3). Various alkyl isopropenyl
ketones 11a-d were reduced by the present method to give
the corresponding allylic alcohols 12a-d in good yields with
around 90% ee’s (entries 1-4). Alkyl vinyl ketone 11e was
reduced by the present method in 81% yield with 70% ee (entry
5). The absolute configuration of 12e was determined by
hydrogenation of 12e to 1-phenylpentan-3-ol (H2, Pd/C, EtOH)
and by comparison with the reported sign of optical rotation.19
catalyzed R-methylene ketones:10 Corey reported that vinyl
ketone 6 was reduced by oxazaborolidine 7-catalyzed reduction
to afford 8 in a low yield (30%) with moderate enantioselectivity
(76% ee, Scheme 2). They introduced an Me3Si or n-Bu3Sn
group at the ꢀ-position of R,ꢀ-unsaturated ketone 6 for size-
differentiation and inhibition of side reactions.11 We report here
an efficient method for enantioselective reduction of R-meth-
yleneketonesbyoxazaborolidinecatalysiswithborane-diethylaniline.
Prior to the preparation of 24-(R)-hydroxycholesterol, suitable
reaction conditions were explored for the reduction of R-me-
thylene ketone 9 using 10 mol % of oxazaborolidine catalyst
311 (Table 1). First, various borane complexes, including
borane-THF, borane-Me2S,12 borane-diethylaniline,13 and
catecholborane, were employed. It was found that reduction with
the relatively reactive reducing agents, borane-THF and
borane-Me2S, gave 10 in 19% and 29% yields, respectively
(entries 1 and 2), while the reaction with the mild reducing
agents, borane-diethylaniline and catecholborane, gave 10 in
75% and 90% yields, respectively (entries 3 and 4). Milder
reducing agents gave allyl alcohol 10 in better chemical yields
because they minimized side reactions.14 It was noted that
(10) Corey, E. J.; Guzman-Perez, A.; Lazerwith, S. E. J. Am. Chem. Soc.
1997, 119, 11769–11776.
(11) A solution of 3 in toluene was prepared by the reported procedure, see:
Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.;
Corley, E. G.; Desmond, R. Org. Synth. 1997, 74, 50.
(12) Mincione, E. J. Org. Chem. 1978, 43, 1829–1830.
(15) Shibata, T.; Nakatsuki, K.; Soai, K. Inorg. Chim. Acta 1999, 296, 33–
36.
(13) Purchased from Aldrich. For employment of borane-diethylaniline in
oxazaborolidine-catalyzed reduction, see: (a) Periasamy, M.; Kanth, J. V. B.;
Prasad, A.S. B. Tetrahedron 1994, 50, 6411–6416. (b) Salunkhe, A. M.;
Burkhardt, E. R. Tetrahedron Lett. 1997, 38, 1523–1526.
(16) (a) Cai, D.; Tschaen, D.; Shi, Y.-J.; Verhoeven, T. R.; Reamer, R. A.;
Douglas, A. W. Tetrahedron Lett. 1993, 34, 3243–3246. (b) Falorni, M.; Collu,
C.; Giacomelli, G. Tetrahedron: Asymmetry 1996, 7, 2739–2742. (c) Yeung,
Y.-Y.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 10346–10347.
(17) Brown, H. C.; Murray, L. T. Inorg. Chem. 1984, 23, 2746–2753.
(18) The use of borane-THF complex did not give a satisfactory result.
(19) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986,
108, 6071–6072.
(14) It is known that BH3-THF complex reduces R,ꢀ-unsaturated carbonyl
compounds with a formation of saturated carbinols. (a) Klein, J.; Dunkelblum,
E Tetrahedron Lett. 1966, 604, 7–6049. (b) Klein, J.; Dunkelblum, E. Tetrahedron
1968, 24, 5701–5710. (c) Dunkelblum, E.; Levene, R.; Klein, J. Tetrahedron
1972, 28, 1009–1024.
J. Org. Chem. Vol. 73, No. 17, 2008 6903

TABLE 3. Oxazaborolidine 3-Catalyzed Enantioselective
Reduction of Various r-Methylene Ketones 11a-e to Allylic
Alcohols 12a-e with Borane-Diethylaniline
byoxazaborolidine3-catalyzedreductionwithborane-diethylaniline
in THF. It was found that diethylaniline made the reactivity of
borane suitable for reduction of R-methylene ketones. The
present method will be useful for oxazaborolidine-catalyzed
reduction of R-methylene ketones because the introduction and
removal of trimehylsilyl or tributylstannyl group at the ꢀ-posi-
tion of enones are not required. The combination of the present
procedure and hydrogenation of the C-C double bond is an
effective method for preparing chiral secondary alcohols in high
enantiomeric purity compared with reduction of aliphatic
isopropyl ketones.
entry
11
R1
R2
12
yield (%)
% ee
1
2
3
4
5
11a
11b
11c
11d
11e
Ph(CH2)3
Me
Me
Me
Me
H
12a
12b
12c
12d
12e
83
82
82
85
81
90
CH3(CH2)6
c-HexCH2
c-Hex(CH2)2
Ph(CH2)2
92
87a
95b
70
Experimental Section
a ee was determined by HPLC after derivatization to
p-methoxybenzoate. b ee was determined by HPLC after derivatization
to benzoate.
General Procedure for Oxazaborolidine 3-Catalyzed
Enantioselective Reduction of r-Methylene Ketones with
Borane-Diethylaniline. To a stirred solution of 3 (0.5 M in
toluene,11 0.29 mL, 0.145 mmol) in THF (2 mL) was added
BH3-Et2NPh (0.1 mL, 0.576 mmol) at 4 °C (ice-water), and the
solution was stirred for 30 min at 4 °C. A solution of 9 (101.4 mg,
0.581 mmol) in THF (5 mL) was then added through a cannula for
1.5 h at 4 °C, and complete disappearance of 9 was confirmed by
TLC analysis (it took 5 min at 4 °C). The reaction was quenched
with 1 N hydrochloric acid, and the mixture was extracted with
ethyl acetate (three times). The combined organic extracts were
washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The crude product was purified with
preparative TLC (hexane/ethyl acetate ) 7:1) to afford 1021 (90.3
mg, 88%) as a colorless oil. The enantiomeric excess (94% ee)
was determined by HPLC analysis using a chiral column (Daicel
Chiralpak AS-H 46 × 150 mm, 254 nm UV detector, room
temperature, eluent: hexane/i-PrOH ) 20:1, flow rate: 0.5 mL/min,
retention time (min) 8.1 (S isomer), 8.6 (R isomer)): [R]23D ) +26.2
SCHEME 3. Stereoselective Synthesis of 15 from 13
1
(c 1.20, CHCl3); H NMR (270 MHz, CDCl3) δ 1.51 (1H, brs),
1.75 (3H, s), 1.83-1.91 (2H, m), 2.58-2.76 (2H, m), 4.04-4.14
(1H, m), 4.87-4.88 (1H, m), 4.96-4.97 (1H, m), 7.16-7.31 (5H,
m); 13C NMR (67.8 MHz, CDCl3) δ 17.6, 31.9, 36.5, 75.2, 111.2,
125.8, 128.4, 128.4, 142.0, 147.4.
It was then found that the absolute configuration of 12e was R
and even the vinyl group tended to adopt the same position as
the 2-propenyl group in the transition state as shown in Figure
2.
Oxazaborolidine 3-catalyzed reduction of 13 under optimized
reaction conditions gave allylic alcohol 14 in 87% yield with
high facial selectivity (24-R/S ) 97.5:2.5) (Scheme 3).20
Stereoselective synthesis of 24-(R)-hydroxycholesteryl acetate
15 was accomplished by regioselective hydrogenation of the
exo-methylene group of 14 by using H2 and Wilkinson’s catalyst
(84% yield).
Acknowledgment. The authors are grateful for the financial
support from Takeda Science Foundation and a Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan.
Supporting Information Available: Experimental proce-
dures and full characterization of data for all new compounds;
1H and 13C NMR spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Thus, highly enantioselective reduction of 2-propenyl ketones
to the corresponding allylic alcohols was efficiently carried out
JO8011013
(20) For asymmetric reduction of a compound similar to 13 with (R)-(+)-
binaphthol-LiAlH4, see: Ishiguro, M.; Koizumi, N.; Yasuda, M.; Ikekawa, N.
J. Chem. Soc. Chem. Commun. 1981, 115–117.
(21) Bonnert, R. V.; Jenkins, P. R. J. Chem. Soc., Perkin Trans. 1 1989,
413–418.
6904 J. Org. Chem. Vol. 73, No. 17, 2008