Bronsted acid catalyzed asymmetric reduction of ketones and acyl silanes using chiral anti -pentane-2,4-diol

Article abstract of DOI:10.1021/ol1006532

Ketones and acyl silanes were reduced to the corresponding alcohols by a simple procedure employing anti-1,3-diol and a catalytic amount (5 mol %) of 2,4-dinitrobenzenesulfonic acid in benzene at reflux. Asymmetric induction reached up to >99% ee when a chiral pentane-2,4-diol of 97% ee was used.

Full text of DOI:10.1021/ol1006532

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2294-2297
Brønsted Acid Catalyzed Asymmetric
Reduction of Ketones and Acyl Silanes
Using Chiral anti-Pentane-2,4-diol
Jun-ichi Matsuo,* Yu Hattori, and Hiroyuki Ishibashi
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and
Health Sciences, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
jimatsuo@p.kanazawa-u.ac.jp
Received March 19, 2010
ABSTRACT
Ketones and acyl silanes were reduced to the corresponding alcohols by a simple procedure employing anti-1,3-diol and a catalytic amount
(5 mol %) of 2,4-dinitrobenzenesulfonic acid in benzene at reflux. Asymmetric induction reached up to >99% ee when a chiral pentane-2,4-diol
of 97% ee was used.
Ketone reduction to the corresponding secondary alcohol is
undoubtedly an important and fundamental reaction in
organic synthesis. A number of methods for the reduction
of ketones and reducing agents have been developed,1 and
asymmetric reduction has also been studied extensively over
the past few decades.2 Meerwein-Ponndorf-Verley (MPV)
reduction, which has long been known from the independent
discoveries of Meerwein, Ponndorf, and Verley, has distinc-
tive usefulness in organic synthesis.3 Various modifications
and improvements of the MPV reduction have been studied
by using metal alkoxides (usually aluminum alkoxides) as
reducing agents.4 A metal ion activates the carbonyl group
to be reduced and also promotes hydrogen transfer from the
C-H bond of the alcohol. We report here a metal-free
asymmetric reduction of ketones that uses a chiral anti-1,3-
diol under the catalysis of a Brønsted acid. In this reduction,
the 1,3-diol works as a reducing agent and does not give an
acetal. Remarkably, a higher reactivity of acyl silanes than
aliphatic ketones is noted.
In the course of our study on stereoselective reduction of
24-oxocholesterol derivatives,5 we tried to prepare a chiral
acetal 3 derived from 24-oxocholesteryl benzoate 1 and
(2S,4S)-pentane-2,4-diol 2 in order to test the diastereose-
lective reduction of acetal 3 with aluminum hydride reagents,
as reported by Yamamoto.6 Acetalization employing diol 2
and pyridinium p-toluenesulfonate (PPTS) in benzene at
reflux with continuous azeotropic removal of water gave
(4) (a) Evans, D. A.; Nelson, S. G.; Gagne, M. R.; Muci, A. R. J. Am.
Chem. Soc. 1993, 115, 9800–9801. (b) Fujita, M.; Takarada, Y.; Sugimura,
T.; Tai, A. Chem. Commun. 1997, 1631–1632. (c) Ooi, T.; Miura, T.;
Maruoka, K. Angew. Chem., Int. Ed. 1998, 37, 2347–2349. (d) Ooi, T.;
Itagaki, Y.; Miura, T.; Maruoka, K. Tetrahedron Lett. 1999, 40, 2137–
2138. (e) Campbell, E. J.; Zhou, H.; Nguyen, S. T. Org. Lett. 2001, 3,
23912393. (f) Campbell, E. J.; Zhou, H.; Nguyen SonBinh, T. Angew.
Chem., Int. Ed. 2002, 41, 1020–1022.
(1) (a) Handbook of Reagents for Organic Synthesis, Oxidizing and
Reducing Agents; Burke, S. D., Danheiser, R. L., Ed.; Wiley: New York,
1999. (b) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Ed.;
Pergamon Press: New York, 1991; Vol. 8.
(2) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Ed.; Springer: New York, 1999. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994. (c)
Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40–73.
(3) Review: Wilds, A. L. Org. React. 1944, 2, 178–223.
(5) Matsuo, J.; Kozai, T.; Nishikawa, O.; Hattori, Y.; Ishibashi, H. J.
Org. Chem. 2008, 73, 6902–6904.
(6) (a) Mori, A.; Fujiwara, J.; Maruoka, K.; Yamamoto, H. Tetrahedron
Lett. 1983, 24, 4581–4584. (b) Mori, A.; Fujiwara, J.; Maruoka, K.;
Yamamoto, H. J. Organomet. Chem. 1985, 285, 83–94.
10.1021/ol1006532  2010 American Chemical Society
Published on Web 04/22/2010

acetal 3 in only 8% yield, probably due to steric hindrance7
around the carbonyl group of 1 (Scheme 1). In the screening
Table 1. Effect of Diols and an Additive in DNBSA-Catalyzed
Reduction of Ketone 5 to Alcohol 6a
Scheme 1. Brønsted Acid Controlled Selectivity between
Acetalization and Reduction of Ketone 1 with Diol 2 (97% ee)
of other catalysts for the acetalization,8 it was unexpectedly
found that the use of 2,4-dinitrobenzenesulfonic acid (DN-
BSA) did not give the desired acetal 3 but gave alcohol 4
directly in 23% yield (24-R/S ) 88.5:11.5, Scheme 1). Thus,
diol 2 reduced ketone 1 by the catalysis of DNBSA. Brønsted
acid-catalyzed reduction of ketones with alcohols1b,9 has not
been reported to date, and the observed high stereoselectivity,
which is better than that of Corey-Bakshi-Shibata (CBS)
reduction10 (24-R/S ) 76:245), prompted us to investigate
this reduction in more detail.
a General conditions: diol (1.1 equiv), DNBSA (5 mol %), 5 (0.3 mmol),
benzene (10 mL), reflux, 2 h, a Dean-Stark apparatus. b Isolated yield.
c Not determined. d 97% ee. e 49% ee (R). f Octanethiol (1.1 equiv) was
used as an additive. g 48% ee (R). h A Dean-Stark apparatus was not used.
First, various 1,3-diols including 2 were employed in the
DNBSA-catalyzed reduction of ketone 5 to the corresponding
alcohol 6 in order to investigate what structural factors in
diols were needed for reduction of the ketone (Table 1). The
use of 1,3-propanediol and 2 gave 6 in 9% and 27% yields,
respectively, whereas meso-syn-1,3-diol 7 gave the corre-
sponding acetal 8 in 55% yield along with a trace amount
of 6 (entries 1-3). Since the use of anti-1,2-diol and anti-
1,4-diol did not give the reduction product 6,11 the anti-1,3-
diol structure was essential for smooth reduction of the
ketone. The employment of (()-anti-diol 9, which did not
have any hydrogens at its 3-position, did not give 6 but
afforded ꢀ-alkoxy ketone 10 in 32% yield (entry 4). When
a sterically demanding (()-diol 11 was used, the yield of
reduction product 6 increased to 46% yield (entry 5). Next,
an additive to improve efficiency in reduction of ketone 5
with diol 2 was explored. After extensive trials, it was found
that addition of 1.1 equiv of octanethiol improved the yield
of alcohol 6 to 62% yield.12 In this case, ꢀ-octylthio ketone
12 and ꢀ-octylthio alcohol 13 were also isolated in 52% and
15% yields, respectively (entry 6, vide infra). Under non-
dehydrative conditions (without continuous removal of water
by a Dean-Stark apparatus), 57% yield of alcohol 6 was
obtained. Thus, continuous removal of water was not
necessarily required for the present reduction.
A plausible mechanism for Brønsted acid catalyzed
reduction of ketones with anti-(2S,4S)-pentane-2,4-diol 2 is
shown in Scheme 2. Acetalization of ketone 14 with diol 2
Scheme 2. Plausible Mechanism for DNBSA-Catalyzed
Reduction of Ketone 14 to Alcohol 19 by Using anti-1,3-Diol 2
(7) Dauben, W. G.; Gerdes, J. M.; Look, G. C. J. Org. Chem. 1986, 51,
4964–4970.
(8) Acetalization using TsOH gave 3 in 12% yield along with 4% yield
of 4.
(9) For the combined use of aluminum alkoxides and Brønsted acids,
see : (a) Kow, R.; Nygren, R.; Rathke, M. W. J. Org. Chem. 1977, 42,
826–827. (b) Akamanchi, K. G.; Varalakshmy, N. R. Tetrahedron Lett.
in the presence of Brønsted acid gives acetal 17 via
oxocarbenium ion 16. DNBSA, a strong Brønsted acid, also
catalyzes stereoselective ring cleavage of 17 to regenerate
oxocarbenium ion 16.6,13 Oxocarbenium ion 15 bearing two
1995, 36, 3571–3572
.
(10) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–
2012. (b) Itsuno, S. Org. React. 1998, 52, 395–576.
(11) (2R,3R)-Butane-2,3-diol and (2S,5S)-hexane-2,5-diol were employed
for anti-1,2-diol and anti-1,4-diol, respectively.
Org. Lett., Vol. 12, No. 10, 2010
2295

methyl groups in equatorial positions is formed by C-C bond
rotation in 16 as well as directly by reaction with ketone 14
and diol 2. Then 1,5-hydride transfer proceeds via the six-
membered transition state shown in oxocarbenium ion 15 to
afford ꢀ-alkoxy ketone 18.14,15 Brønsted acid-catalyzed
elimination of the ꢀ-alkoxy ketone 18 gives alcohol 19 and
enone 20. The involvement of ꢀ-alkoxy ketone 18 and enone
20 was suggested by isolation of the ꢀ-alkoxy ketone 10
and the ꢀ-alkylthio ketone 12, respectively, as mentioned
above (Table 1, entries 4 and 6).16 The effect of octanethiol,
which improved the efficiency of the reduction of ketone
14 to alcohol 19, can be explained by decreasing competitive
reduction of enone 20 with diol 2 by its transformation to
ꢀ-alkylthio ketone 21, whose steric circumstance around the
carbonyl group is more crowded than that of 20. In the case
of diol 11 (Table 2, entry 5), the competitive reduction of in
situ-formed enone is diminished to some extent because of
its steric hindrance.
Table 2. DNBSA-Catalyzed Asymmetric Reduction of Various
Ketones 22a-e and Acyl Silanes 22f-j with Chiral Diol 2a
The scope and limitations and also asymmetric induction
of the present DNBSA-catalyzed reduction of ketones 22
with diol 2 were investigated (Table 2). Aliphatic methyl
ketones having secondary alkyl groups 22a-d gave the
corresponding alcohols 23a-d in moderate yield and with
high asymmetric induction (82-93% ee, entries 1-4). tert-
Butyl ketone 22e gave alcohol 23e in >99% ee in spite of
a low chemical yield (21%, entry 5). Interestingly,
reduction of acyl trimethylsilanes17 22f,g proceeded
smoothly in the absence of octanethiol18 to give alcohols
23f,g in 81-84% yields and in 98% ee (entries 6 and 7).19
Reduction of acyl tert-butyldimethylsilane 23h and acyl
dimethylphenylsilane 23i,j also proceeded efficiently to
afford the corresponding alcohols in high yields and in
high ees (entries 8-10). The observed higher efficiency
of the reduction of acyl silanes compared with ketones,
in the absence of octanethiol, is caused by the higher
(12) Various thiols were tested, and more nucleophilic thiols gave better
results: PhSH (40%), p-MeOC6H4SH (50%). The effect of octanethiol was
not observed when diol 11 was used instead of 2 because conjugate addition
of thiol to in situ formed enone was difficult.
(13) Acetals were not obtained from anti-1,3-diol when DNBSA was
used as a Brønsted acid catalyst.
(14) For Lewis acid-promoted 1,5-hydride transfer of oxocarbenium ion,
see: (a) Shaw, P. E. J. Org. Chem. 1966, 31, 2116–2119. (b) Martin, O. R.;
Rao, S. P.; El-Shenawy, H. A.; Kurz, K. G.; Cutler, A. B. J. Org. Chem.
1988, 53, 3287–3292.
a General conditions: ketone 22 (0.4 mmol), 2 (97% ee, 1.1 equiv),
DNBSA (5 mol %), octanethiol (1.1 equiv), benzene (10 mL), reflux, a
Dean-Stark apparatus. b Isolated yield unless otherwise mentioned.
c Determined by chiral HPLC (see the Supporting Information). d Determined
by 1H NMR analysis using an internal standard. e Octanethiol was not used.
(15) Aluminum reagent-catalyzed reductive cleavage of chiral acetal 17
to ꢀ-alkoxy ketone 18 was reported by Yamamoto and Ishihara. See: (a)
Ishihara, K.; Hanaki, N.; Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 7074–
7075. (b) Ishihara, K.; Hanaki, N.; Yamamoto, H. Synlett 1993, 127–129.
(c) Ishihara, K.; Hanaki, N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115,
10695–10704.
reactivity of acyl silanes. The latter can be ascribed to its
raised HOMO level, caused by the interaction between
C-Si bond (σC-Si) orbital and nonbonding orbital of
carbonyl oxygen (nO).20 As shown in Scheme 2, highly
asymmetric selectivity induced by chiral diol 2 is ex-
plained by location of the larger substituent of ketone (RL)
in the equatorial position of the intermediate 15.
(16) Enone was isolated when (4S*,6S*)-2,8-dimethylnonane-4,6-diol
was employed instead of 2.
(17) Review : (a) Ricci, A.; Degl’Innocenti, A. Synthesis 1989, 647–
660. (b) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci,
A. J. Organomet. Chem. 1998, 567, 181–189. (c) Cirillo, P. F.; Panek, J. S.
Org. Prep. Proc. Int. 1992, 24, 553–582.
(18) In the presence of octanethiol, alkenylsulfide was obtained. See:
Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Peri, F.; Ricci,
A. J. Chem. Soc., Perkin Trans. 1 1996, 280, 3–2809.
(19) For asymmetric reduction of acyl silanes, see: (a) Buynak, J. D.;
Strickland, J. B.; Hurd, T.; Phan, A. J. Chem. Soc., Chem. Commun. 1989,
89–90. (b) Soderquist, J. A.; Anderson, C. L.; Miranda, E. I.; Rivera, I.;
Kabalka, G. W. Tetrahedron Lett. 1990, 31, 4677–4680. (c) Takeda, K.;
Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1, 237–239. (d) Arai, N.; Suzuki,
K.; Sugizaki, S.; Sorimachi, H.; Ohkuma, T. Angew. Chem., Int. Ed. 2008,
47, 1770–1773.
In summary, we have developed a Brønsted acid-catalyzed
asymmetric reduction of ketones and acyl silanes that uses
(20) (a) Bock, H.; Alt, H.; Seidl, H. J. Am. Chem. Soc. 1969, 91, 355–
361. (b) Yoshida, J.; Itoh, M.; Matsunaga, S.; Isoe, S. J. Org. Chem. 1992,
57, 4877–4882.
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Org. Lett., Vol. 12, No. 10, 2010

chiral anti-pentane-2,4-diol 2 as a reducing agent. DNBSA
was found to be an effective Brønsted acid, and addition of
octanethiol improved the efficiency of the reduction of
ketones, whereas reduction of acyl silanes proceeded smoothly
in the absence of octanethiol. The metal-free procedure for
the present asymmetric reduction of ketones and acyl silanes
is convenient for preparing optically active secondary alco-
hols.
Education, Culture, Sports, Science, and Technology, Japan.
We thank Teijin Pharma Ltd. for financial support.
Supporting Information Available: Detailed experimen-
tal procedures and full spectroscopic characterization data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
OL1006532
Org. Lett., Vol. 12, No. 10, 2010
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