Enantioselective borohydride reduction of aliphatic ketones catalyzed by ketoiminatocobalt(iii) complex with 1-chlorovinyl axial ligand

Article abstract of DOI:10.1246/cl.2012.780

For the enantioselective borohydride reduction of aliphatic ketones, the optically active ketoiminatocobalt(II) catalysts was successfully designed based on their axial ligand. Instead of chloroform for the aryl ketone reduction, various axial ligand precursors were examined for the aliphatic ketone. Consequently, 1, 1, 1-trichloroethane was found to be the most effective activator of the cobalt(II) complexes to generate the corresponding 1-chlorovinyl cobalt(III) derivatives as the reactive intermediate. Several aliphatic ketones were successfully reduced to afford the corresponding secondary alcohols with high enantioselectivities.

Full text of DOI:10.1246/cl.2012.780

doi:10.1246/cl.2012.780
780
Published on the web July 28, 2012
Enantioselective Borohydride Reduction of Aliphatic Ketones Catalyzed
by Ketoiminatocobalt(III) Complex with 1-Chlorovinyl Axial Ligand
Tatsuyuki Tsubo, Hsiu-Hui Chen, Minako Yokomori, Kosuke Fukui, Satoshi Kikuchi, and Tohru Yamada*
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522
(Received May 9, 2012; CL-120402; E-mail: yamada@chem.keio.ac.jp)
For the enantioselective borohydride reduction of aliphatic
the metal-complex-catalyzed system, though non-metal cata-
lysts, chiral Lewis bases10 and chiral Brønsted acids,11 for the
asymmetric reduction have also been recently reported. The
enantioselective reduction of aliphatic ketones still needs to be
developed for asymmetric synthesis. In this communication, we
address one of the solutions for this problem based on the
rational design of a reactive intermediate derived from cobalt(II)
complex catalysts.
ketones, the optically active ketoiminatocobalt(II) catalysts was
successfully designed based on their axial ligand. Instead of
chloroform for the aryl ketone reduction, various axial ligand
precursors were examined for the aliphatic ketone. Conse-
quently, 1,1,1-trichloroethane was found to be the most effective
activator of the cobalt(II) complexes to generate the correspond-
ing 1-chlorovinyl cobalt(III) derivatives as the reactive inter-
mediate. Several aliphatic ketones were successfully reduced to
afford the corresponding secondary alcohols with high enantio-
selectivities.
Under the original conditions of the enantioselective
borohydride reduction for aromatic ketones catalyzed by
optically active ketoiminatocobalt(II) complexes, CHCl3 was
employed as a unique solvent to achieve a high enantioselec-
tivity as well as reactivity.12 At least a catalytic amount of
chloroform was required to realize a high enantioselectivity.
This observation means that the effect of CHCl3 is not only due
to being a suitable solvent, but CHCl3 itself reacted as an
activator with the cobalt complex to generate an essential
reactive intermediate that catalyzed the present reduction with
the borohydride.13 The FAB-MS analysis of the cobalt complex/
borohydride solution suggested that cobalt-hydride (M + 1) and
dichloromethyl-cobalt-hydride (M + 1 + 83) were generated in
the reaction mixture. Based on the experimental or analytical
examinations, the DFT calculations of the model system also
afforded a reasonable transition-state (TS) with the dichloro-
methyl group on the cobalt complex (Figure 1). As a result, the
mechanism of the present reaction was proposed as follows: the
original cobalt(II) complex reacts with CHCl3 in the presence of
the hydride to generate the dichloromethyl-cobalt-hydride
intermediate with the sodium cation (Na+). Carbonyl substrates
would be captured by the sodium cation, which leads to
activation and stereochemical alignment of the carbonyl. The
cobalt hydride intermediate would eventually attack the carbonyl
via a quasi-six-membered TS to afford the reduced product with
a high selectivity. Therefore, it is reasonable to consider that the
(di)chloroalkyl group on the axial site would have a significant
effect on both the reactivity and selectivity.
The enantioselective reduction of carbonyl or imine
derivatives is one of the most reliable methods to provide
various optically active compounds.1 Enzymatic processes2 have
been employed to prepare small molecules, such as optically
active synthetic building blocks, though specificity on the
substrates seems to be problematic as well as the efficiency
related to the reaction time and/or reactor volume. Enantio-
selective reductions catalyzed by optically active metal-com-
plexes are promising alternative processes for a wide variety of
substrates and rather large molecules with a high efficiency.
Various combinations of metal-complex catalysts with hydride
reductants have been reported;3 e.g., oxazaborolidine/borane,4
ferrocenylphosphine-Rh/hydrosilane,5 BINAP-Ru/hydrogen or
a secondary alcohol,6 and other metals.7,8 From our research
group, optically active cobalt(II) complexes with a conventional
reductant, sodium borohydride, have been proposed as an
effective system for the catalytic enantioselective reduction of
ketone and imine derivatives to afford the corresponding
secondary alcohols and amines in high-to-excellent yields with
high enantioselectivities.9 Although the aryl carbonyl deriva-
tives are suitable substrates to achieve a high enantioselectivity,
aliphatic ketones, such as 1-adamantyl methyl ketone, was
converted into the reduced product in 89% yield, but with only
41% ee (Scheme 1). The highly enantioselective reduction of
aliphatic ketones was limited to only a few methods, including
Based on the proposed mechanism for the aliphatic ketone
reduction, various haloalkanes were examined as an activator
precursor of an effective intermediate (Figure 1). Various di- or
H
H
(B)
(A)
O
OH
H
H
O
O
R
O
N
O
N
O
R
O
H
H
Co
N
N
97% ee
OH
CHCl3
O
O
cat. Co( )-Complex 1
Na+
Na+
Co
Co
N
N
O
O
O
R CCl3
NaBH4, EtOH, THFA, CHCl3
Cl
Cl
R
C
C
Cl
Cl
1a : R = 2,4,6-trimethylphenyl
1b : R = Me
41% ee
H
Figure 1. (A) TS proposed by DFT calculation. (B) A new design
for cobalt complex catalysts.
Scheme 1. Enantioselective reductions of aromatic and/or ali-
phatic ketones (the original system).9h
Chem. Lett. 2012, 41, 780-782
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

781
Table 1. Examination of various trihaloalkanes as an activatora
Table 2. Enantioselective borohydride reduction of aliphatic
O
OH
ketonesa
(R,R)-1a (5 mol%)
Haloalkane (20-25 mol%)
(S,S)-1a (5 mol%)
CH3CCl3 (20 mol%)
O
OH
NaBH4, Alcohol(s)
THF
R
R
2a
3a
NaBH4, MeOH
THF
2
3
Entry
Haloalkane
Yield/%
ee/%
OH
OH
OH
1
2
3
4b
5b
6
®
quant.
85
97
94
51
98
75
91
13
40
28
29
29
45
64
85
CHCl3
CHBr3
CHl3
85% yieldb
88% ee
16 h
83% yieldb
81% ee
72 h
84% yield
87% ee
24 h
OBn
3c
CCl4
3a
3b
OH
OH
OH
CH2Cl2
CH3CCl3
CH3CCl3
7
8c
83% yield
86% ee
22 h
85% yieldc
80% ee
24 h
63% yieldd
90% ee
48 h
aReaction conditions: ketone 2a (0.25 mmol), (R,R)-1a (12.5 ¯mol,
5 mol %), NaBH4 (0.38 mmol, 1.5 equiv), EtOH (0.38 mmol), THFA
(5.25 mmol), haloalkane (50 mmol, 20 mol %), THF (6.5 mL) at 0 °C
for 24 h. Yields are of material isolated by silica gel chromatography.
Enantiomeric excess was determined by HPLC analysis of
1-naphthoate derivative (Chiralpak IB). bHaloalkane (63 mmol,
25 mol %). cReaction conditions: NaBH4 (0.50 mmol, 2.0 equiv),
MeOH (3.0 mmol, 12 equiv), CH3CCl3 (50 mmol, 20 mol %), THF
(6.5 mL) at ¹20 °C for 24 h.
3d
OH
3e
3f
3i
OH
OH
Ph
97% yielde
80% ee
12 h
65% yieldf
61% ee
22 h
16% yield
85% ee
Ph
96 h
3g
3h
aReaction conditions: ketone 2 (0.25 mmol), (S,S)-1a (12.5 ¯mol,
5 mol %), NaBH4 (0.50 mmol, 2.0 equiv), MeOH (3.0 mmol, 12 equiv),
CH3CCl3 (50 mmol, 20 mol %) at ¹20 °C. Yields are of material
isolated by silica gel chromatography. Enantiomeric excess was
determined by HPLC analysis of 1-naphthoate derivative (Chiralpak
IB). Absolute configuration of 3a was determined by specific optical
rotation. bCH3CCl3 (75 mmol, 30 mol %) was used. c(R,R)-1a was used
and the modified borohydride (NaBH4 0.75 mmol and MeOH
4.5 mmol in THF 6 mL) was added in three portions every 3 h. dThe
reaction was run at ¹30 °C. e(R,R)-1a, NaBH4 (0.38 mmol, 1.5 equiv),
MeOH (2.3 mmol, 9 equiv) were used. The yield was based on GC
trihaloalkanes were screened as an activator for the cobalt(II)
complex 1a in the presence of a borohydride modified by EtOH
and tetrahydrofurfuryl alcohol (THFA) in THF. Without any
haloalkane, 1-adamantyl methyl ketone (2a) was reduced to
1-(1-adamantyl)ethanol (3a) with only 13% ee (Table 1,
Entry 1). As a result of examining the effect by halogen atoms,
chlorine was found to work the most effectively among the three
haloforms, i.e., CHCl3, CHBr3, and CHI3 (Entries 2-4). Several
carbon chloride derivatives, such as CCl4 and CH2Cl2 (Entries 5
and 6 and see Supporting Information14), were next examined.
Most of them did not improve the enantioselectivity and were
less effective or slightly better than CHCl3. When 1,1,1-
trichloroethane was employed as the activator, the enantio-
selective reduction effectively proceeded to provide the reduced
product 3a in 75% yield with 64% ee (Entry 7). After
optimization of the reaction conditions, the enantioselectivity
was enhanced with replacement of the borohydride modifier
from EtOH/THFA to MeOH. The corresponding alcohol 3a was
obtained in 91% yield with 85% ee at ¹20 °C (Entry 8).
The optimized conditions were then successfully applied to
the catalytic enantioselective borohydride reduction of various
aliphatic ketones. The present scope is shown in Table 2.
Tertiary alkyl ketones were reduced into the corresponding
alcohols 3 with over 80% ee. The adamantyl ketones 2a-2c and
noradamantyl ketone 2d were converted into the optically active
alcohols with 81-88% ee. The methyl 1-methylcyclohexyl
ketone (2e) was also an applicable substrate; the product 3e
was obtained in 85% yield with 80% ee. Though the reactivities
for the reductions of the more bulky substrates 2f and 2g were
low, high enantioselectivities were also observed; especially,
3-methyl-3-phenyl-2-butanol (3f) was obtained with 90% ee.
The simple tertiary alkyl ketone 2h was smoothly converted into
3h with 80% ee. When the secondary alkyl ketone 2i was
employed in the same system, a moderate enantioselectivity was
observed (61% ee).
f
conversion. (S,S)-1b was used.
An ESI-MS analysis of the reaction mixture of the cobalt(II)
complex/borohydride was performed in the presence of 1,1,1-
trichloroethane to reveal the structure of the reactive intermedi-
ate (Figure 2). After the solution color of the cobalt catalyst
changed from yellow (cobalt(II) complex) to red after treatment
with the borohydride in the presence of 1,1,1-trichloroethane,
a peak at m/z 877 was observed in the negative mode.
It could be assigned as the cobalt(III) complex containing
dichloroethyl group on the axial site based on the previous
observation in the original CHCl3 solvent system. Also, the
isotopic pattern corresponding to the molecule containing two
chlorine atoms was definitely observed, whereas in the positive
mode, the peak at m/z 879 or neighborhood derived from
dichloroethyl-cobalt was not detected. The peak observed at
m/z 843 could be assigned as (M+ + CH2CCl; 782 + 35 +
24 + 2), and these observations could be explained as follows:
Initially, the dichloroethylcobalt(III) 4a could be derived from
the original cobalt(II) complex with 1,1,1-trichloroethane in the
presence of the borohydride, similar to the original cobalt
catalyst system with chloroform. The proton of the terminal
methyl on dichloromethyl group should be acidic enough due to
the two chlorine atoms on the ¡-position and cobalt(III) atom on
the ¢-position to be removed in the reaction system (Scheme 2).
The chloride was then released. The molecular weight of the
resulting structure 5a, 1-chlorovinyl group on cobalt(III) com-
Chem. Lett. 2012, 41, 780-782
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

782
H
A
B
N
O
N
O
Co
O
O
+
C50H57ClCoN2O4
m/z: 843.33
Cl
O
Cl
Co
O
Co
H
N
O
N
O
N
O
N
O
-
-
O
O
C
51H57ClCoN2O6
O
O
C50H56Cl2CoN2O4
m/z: 877.29
m/z: 887.32
Cl
Cl
Figure 2. ESI-MS in positive (A) and negative (B) modes.
Verlag, New York, 1999, Vol. 1, Chap. 6.
4
a) S. Itsuno, K. Ito, A. Hirao, S. Nakahama, J. Chem. Soc., Chem.
Commun. 1983, 469. b) E. J. Corey, R. K. Bakshi, S. Shibata, J. Am.
Chem. Soc. 1987, 109, 5551. c) E. J. Corey, R. K. Bakshi, S. Shibata,
C.-P. Chen, V. K. Singh, J. Am. Chem. Soc. 1987, 109, 7925. d) E. J.
Corey, C. J. Helal, Angew. Chem., Int. Ed. 1998, 37, 1986.
a) M. Sawamura, R. Kuwano, Y. Ito, Angew. Chem., Int. Ed. Engl. 1994,
33, 111. b) Y. Nishibayashi, K. Segawa, K. Ohe, S. Uemura, Organo-
metallics 1995, 14, 5486. c) R. Kuwano, M. Sawamura, J. Shirai, M.
Takahashi, Y. Ito, Bull. Chem. Soc. Jpn. 2000, 73, 485. d) B. Tao, G. C.
Fu, Angew. Chem., Int. Ed. 2002, 41, 3892. e) S. Gladiali, E. Alberico,
Chem. Soc. Rev. 2006, 35, 226.
CH CCl
3
-HCl
3
NaBH
4
N
O
N
O
N
O
N
N
O
N
O
Co
1a
Co
Co
O
O
O
O
O
O
O
H
H
Cl
Cl
Cl
H
H
H
5
4a
5a
Scheme 2. Leaving process of hydrogen chloride from dichloro-
methyl-cobalt complex.
6
a) T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1995, 117, 2675. b) R. Noyori, T. Ohkuma, Angew. Chem.,
Int. Ed. 2001, 40, 40. c) T. Ohkuma, M. Koizumi, K. Muñiz, G. Hilt, C.
Kabuto, R. Noyori, J. Am. Chem. Soc. 2002, 124, 6508. d) C. A.
Sandoval, T. Ohkuma, K. Muñiz, R. Noyori, J. Am. Chem. Soc. 2003,
125, 13490. e) T. Ohkuma, C. A. Sandoval, R. Srinivasan, Q. Lin, Y.
Wei, K. Muñiz, R. Noyori, J. Am. Chem. Soc. 2005, 127, 8288. f) H.
Ooka, N. Arai, K. Azuma, N. Kurono, T. Ohkuma, J. Org. Chem. 2008,
73, 9084. g) C. A. Sandoval, Y. Li, K. Ding, R. Noyori, Chem.®Asian J.
2008, 3, 1801.
For recent works on hydrosilylation, see: a) O. Riant, N. Mostefaï, J.
Courmarcel, Synthesis 2004, 2943. b) B. K. Langlotz, H. Wadepohl,
L. H. Gade, Angew. Chem., Int. Ed. 2008, 47, 4670. c) X.-C. Zhang, Y.
Wu, F. Yu, F.-F. Wu, J. Wu, A. S. C. Chan, Chem.®Eur. J. 2009, 15,
5888. d) T. Inagaki, L. T. Phong, A. Furuta, J.-i. Ito, H. Nishiyama,
Chem.®Eur. J. 2010, 16, 3090. e) A. Albright, R. E. Gawley, J. Am.
Chem. Soc. 2011, 133, 19680. f) F. Yu, X.-C. Zhang, F.-F. Wu, J.-N.
Zhou, W. Fang, J. Wu, A. S. C. Chan, Org. Biomol. Chem. 2011, 9,
5652.
For recent works on transfer hydrogenation, see: a) W. Baratta, M.
Ballico, A. Del Zotto, K. Siega, S. Magnolia, P. Rigo, Chem.®Eur. J.
2008, 14, 2557. b) N. Meyer, A. J. Lough, R. H. Morris, Chem.®Eur. J.
2009, 15, 5605. c) A. Mikhailine, A. J. Lough, R. H. Morris, J. Am.
Chem. Soc. 2009, 131, 1394.
a) T. Nagata, K. Yorozu, T. Yamada, T. Mukaiyama, Angew. Chem., Int.
Ed. Engl. 1995, 34, 2145. b) K. D. Sugi, T. Nagata, T. Yamada, T.
Mukaiyama, Chem. Lett. 1997, 26, 493. c) Y. Ohtsuka, T. Ikeno, T.
Yamada, Tetrahedron: Asymmetry 2000, 11, 3671. d) Y. Ohtsuka, T.
Kubota, T. Ikeno, T. Nagata, T. Yamada, Synlett 2000, 535. e) Y.
Ohtsuka, K. Koyasu, T. Ikeno, T. Yamada, Org. Lett. 2001, 3, 2543. f) Y.
Ohtsuka, K. Koyasu, D. Miyazaki, T. Ikeno, T. Yamada, Org. Lett. 2001,
3, 3421. g) Y. Ohtsuka, D. Miyazaki, T. Ikeno, T. Yamada, Chem. Lett.
2002, 31, 24. h) T. Yamada, T. Nagata, K. D. Sugi, K. Yorozu, T. Ikeno,
Y. Ohtsuka, D. Miyazaki, T. Mukaiyama, Chem.®Eur. J. 2003, 9, 4485.
i) A. Kokura, S. Tanaka, T. Ikeno, T. Yamada, Org. Lett. 2006, 8, 3025.
plex, is 843. This hypothesis can be supported by the negative
mode ESI-MS analysis. A free chloride anion could coordinate
to another axial site to generate the corresponding ate-complex
containing two chlorine atoms. Consequently, the isotopic
pattern was observed. Furthermore, the peak observed at m/z
887 could be assigned as the 1-chlorovinyl cobalt(III) complex
5a with a formate anion in place of the chloride anion (formic
acid was employed as the solvent for ESI-MS measurement).
The obtained cobalt(III) complex could form a similar quasi-six-
membered transition-state with the sodium cation, chlorine
atom, and carbonyl substrate to achieve a high reactivity and
high selectivity similar to the mechanism proposed in the
previous report.12
7
In summary, the catalytic enantioselective borohydride
reduction of dialkyl ketones was successfully developed using
the newly designed cobalt(III) complex in the presence of 1,1,1-
trichloroethane. Further studies regarding the details of the
catalyst structure will be discussed in a continuing paper.
8
9
This work is partially supported by the MEXT-Supported
Program for the Strategic Research Foundation at Private
Universities, 2008-2012.
References and Notes
1
M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keßeler, R. Stürmer, T.
Zelinski, Angew. Chem., Int. Ed. 2004, 43, 788.
2
a) D. Zhu, Y. Yang, J. D. Buynak, L. Hua, Org. Biomol. Chem. 2006, 4,
2690. b) D. Zhu, Y. Yang, L. Hua, J. Org. Chem. 2006, 71, 4202. c) J. C.
Moore, D. J. Pollard, B. Kosjek, P. N. Devine, Acc. Chem. Res. 2007,
40, 1412. d) F. R. Bisogno, I. Lavandera, W. Kroutil, V. Gotor, J. Org.
Chem. 2009, 74, 1730. e) T. Matsuda, R. Yamanaka, K. Nakamura,
Tetrahedron: Asymmetry 2009, 20, 513. f) A. M. C. Bizerra, G.
de Gonzalo, I. Lavandera, V. Gotor-Fernández, M. C. de Mattos, M.
da Conceicão F. de Oliveira, T. L. G. Lemos, V. Gotor, Tetrahedron:
Asymmetry 2010, 21, 566.
10 L. Zhou, Z. Wang, S. Wei, J. Sun, Chem. Commun. 2007, 2977.
11 Z. Zhang, P. Jain, J. C. Antilla, Angew. Chem., Int. Ed. 2011, 50, 10961.
12 a) I. Iwakura, M. Hatanaka, A. Kokura, H. Teraoka, T. Ikeno, T. Nagata,
T. Yamada, Chem.®Asian J. 2006, 1, 656. b) A. Kokura, S. Tanaka, H.
Teraoka, A. Shibahara, T. Ikeno, T. Nagata, T. Yamada, Chem. Lett.
2007, 36, 26.
13 C. Qiuhao, L. G. Marzilli, N. B. Pahor, L. Randaccio, E. Zangrando,
Inorg. Chim. Acta 1988, 144, 241.
14 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
3
For comprehensive reviews, see: a) H. Nishiyama, K. Itoh, in Catalytic
Asymmetric Synthesis, 2nd ed., ed. by I. Ojima, Wiley VCH, New York,
2000, Chap. 2. b) H. Nishiyama, in Comprehensive Asymmetric
Catalysis, ed. by E. N. Jacobsen, A. Pfaltz, H. Yamamoto, Springer-
Chem. Lett. 2012, 41, 780-782
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/