New efficient organic activators for highly enantioselective reduction of aromatic ketones by trichlorosilane

Article abstract of DOI:10.1021/ol0613822

Aryl ketones were reduced to the corresponding alcohols with excellent enantioselectivity (up to 99.7% ee) by Cl₃SiH in the presence of a catalytic amount of N-formyl-α′-(2,4,6-triethylphenyl)-L-proline as an activator. Both carboxyl group at the α-position of the activator and 2,4,6-triethylphenyl group at the α′-position were critical for the high enantioselectivity.

Full text of DOI:10.1021/ol0613822

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3789-3792
New Efficient Organic Activators for
Highly Enantioselective Reduction of
Aromatic Ketones by Trichlorosilane
Yoshihiro Matsumura,* Kanako Ogura, Yoshimi Kouchi, Fumiaki Iwasaki,† and
Osamu Onomura
Graduate School of Biomedical Sciences, Nagasaki UniVersity,Bunkyo-machi, Nagasaki
852-8521, Japan
matumura@net.nagasaki-u.ac.jp
Received June 6, 2006
ABSTRACT
Aryl ketones were reduced to the corresponding alcohols with excellent enantioselectivity (up to 99.7% ee) by Cl3SiH in the presence of a
catalytic amount of N-formyl-r′-(2,4,6-triethylphenyl)- -proline as an activator. Both carboxyl group at the -position of the activator and
2,4,6-triethylphenyl group at the r′-position were critical for the high enantioselectivity.
L
r
Enantioselective reduction of ketones has been one of central
topics in asymmetric synthesis over the past two decades.1
Although a variety of reducing reagents have been used for
the purpose,2 there have been few studies on the use of
trichlorosilane (Cl3SiH),3 which is an economical and easy
to handle reagent.4,5 Because Cl3SiH does not have the ability
to reduce ketones by itself, appropriate activators are
necessary for the reduction of ketones by Cl3SiH with high
efficiency. Organic chiral activators are in particular of
interest in this respect because they provide a route for
asymmetric reduction of ketones. We have reported a first
enantioselective reduction of ketones by Cl3SiH using chiral
N-formylpyrrolidines (1q,r) as organic activators (up to 43%
ee),4 and recently isoquinolinyloxazoline (2) was reported
to work well as a chiral activator (up to 94% ee).6,7
† Tsukuba Research Laboratory, Tokuyama Corporation, 40 Wadai,
Tsukuba, 300-4247, Japan.
(1) Some recent reviews, see: (a) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97-102. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int.
Ed. 1998, 37, 1986-2012. (c) Noyori, R.; Ohkuma, T. Angew. Chem., Int.
Ed. 2001, 40, 40-73. (d) Riant, O.; Mostefai, N.; Courmarcel, J. Synthesis
2004, 2943-2958.
We report herein new efficient organic activators 3-6
(Figure 1), which allow the reduction of aromatic ketones 7
(2) ) Recent representative literatures. B-H reagents: (a) Yamada, T.;
Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno, T.; Ohtsuka, Y.; Miyazaki, D.;
Mukaiyama, T. Chem. Eur. J. 2003, 9, 4485-4509. Hydrogen transfer
reactions: (b) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1996, 118, 2521-2522. Hydrogenation: (c) Ohkuma,
T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei, Y.; Muniz, K.; Noyori,
R. J. Am. Chem. Soc. 2005, 127, 8288-8289. Si-H reagents: (d) Tao, B.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3892-3894. (e) Evans, D. A.;
Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003,
125, 3534-3543. (f) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A.
J. Am. Chem. Soc. 2003, 125, 8779-8789. (g) Gade, L. H.; Ce´sar, V.;
Bellemin-Laponnaz, B. Angew. Chem., Int. Ed. 2004, 43, 1014-1017.
(3) For non-enantioselective reduction, see: (a) Kira, M.; Sato, K.;
Sakurai, H. J. Org. Chem. 1987, 52, 948-949. (b) Kobayashi, S.; Yasuda,
M.; Hachiya, I. Chem. Lett. 1996, 407-408.
Figure 1. Organic activators for Cl3SiH to reduce ketones.
(4) Iwasaki, F.; Onomura, O.; Mishima, K.; Maki, T.; Matsumura, Y.
Tetrahedron Lett. 1999, 40, 7507-7511.
10.1021/ol0613822 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

by Cl3SiH to afford the corresponding alcohols 8 with up to
99.7% ee (Scheme 1).
Table 1. Enantioselective Reduction of Ketone 7a by Cl3SiH
in the Presence of Activatorsa
Scheme 1
Chiral activators cis-3-5, trans-3-5, cis-6, and 1u used
in this study were prepared according to the methods shown
in Supporting Information. With those organic activators in
hand, we first compared the efficiency of 1u, cis- and trans-
4, and cis-6 as the activator in the reduction of 7a to 8a by
Cl3SiH. The results are shown in Table 1, which also shows
the results using 1p,s,t as comparison.
a 7a (0.3 mmol), Cl3SiH (0.9 mmol), and activator (0.03 mmol) in CH2Cl2
(1.5 mL) at room temperature for 24 h. b The reported data in ref 4.
c Determined by HPLC. d Identified by comparison of the HPLC data with
that of a commercially avilable authentic sample.
Noticeable points in Table 1 are as follows: (a) The
existence of an R-methoxycarbonyl group on a pyrrolidine
ring (1s) decreased the yield of product 8a (entries 1 and 2).
(b) The reduction of 7a using N-formyl-L-proline (1t)
afforded 8a in 55% yield (entry 3), which was higher than
the yield (39%) in a case using ester 1s (entry 2). This result
suggests an importance of hydrogen bonding between the
carboxyl group of 1t and the carbonyl group of 7a or some
interaction between the carboxyl group with Cl3SiH. (c)
Moderate enantioselectivity (42% ee) was observed in the
reduction using 1u, suggesting an importance of the π-π
interaction12 between the activator and aromatic ketones
(entry 4). (d) R′-Arylated proline ester cis-6 showed a high
selectivity (70% ee), but the yield was very low (3%) (entry
5). This result suggested an importance of both the π-π
interaction and some steric factor. (e) cis-R′-Arylproline (cis-
4) was found to be highly efficient (entry 6), whereas trans-
R′-arylproline (trans-4) resulted in a low yield of 8a with
low enantioselectivity (entry 7).
Next, we checked the substituent’s effect on the R′-
aromatic ring using activators cis-3-5 and trans-3-5 (Table
2). The results showed an advantage of the cis isomer in
Table 2. Enantioselective Reduction of Ketone 7a by Cl3SiH
in the Presence of R′-Arylproline Derivativesa
(5) (a) Akutagawa, S. J. Synth. Org. Chem. Jpn. 1986, 44, 513-518.
(b) Okamoto, H.; Kato, S. Bull. Chem. Soc. Jpn. 1991, 64, 2128-2130. (c)
Zulehler, W.; Neure, B.; Rau, G. Ullmann’s Encyclopedia of Industrial
Chemistry; VCH: Weinheim, 1993; Vol. A23, pp 721-741.
(6) Malkov, A. V.; Stewart Liddon, A. J. P.; Ram´ırez-Lo´pez, P.; Bendova´,
L.; Haigh, D.; Koe`ovsk×c6, P. Angew. Chem., Int. Ed. 2006, 45, 1432-
1435.
(7) Enantioselective reduction of imines was also achieved by Cl3SiH
using organic activators: 1r (up to 66% ee),8 N-formyl-N-methyl-L-valine
arylamide (up to 92% ee),9 N-formyl-L-pipecolinic acid derivative (up to
96% ee),10 and N-picolinoyl-(2S)-(diphenylhydroxymethyl)pyrrolidine (up
to 80% ee).11
(8) ) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.;
Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525-2527.
(9) (a) Malkov, A. V.; Mariani, A.; MacDougall, N. K.; Kocˇovsky´, P.
Org. Lett. 2004, 6, 2253-2256. (b) Malkov, A. V.; Stoncˇius, S.; MacDou-
gall, K. N.; Mariani, A.; McGeoch, G. D.; Koe`ovsk×c6, P. Tetrahedron
2006, 62, 264-284.
a 7a (0.3 mmol), Cl3SiH (0.9 mmol), and activator (0.03 mmol) in CH2Cl2
(1.5 mL) at room temperature for 24 h. b Determined by HPLC. c Identified
by comparison of the HPLC data with that of a commercially available
authentic sample.
(10) Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett.
2006, 5, 999-1001.
(11) Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y. Tetrahedron
Lett. 2006, 47, 3751-3754.
(12) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112,
5525-5534.
comparison with the trans isomer, and as a result, the most
promising activator among the ones examined was cis-2,4,6-
triethylphenyl-L-proline (cis-5).
3790
Org. Lett., Vol. 8, No. 17, 2006

The solvent effects were examined to optimize the
reduction of 7a by Cl3SiH using cis-5, showing that the
reduction depended on the solvent as shown in Table 3. The
Table 5. Reactivity of Recovered cis-5 in the Reduction of
Ketone 7aa
iteration time
yield (%) of 8a
ee (%) (config)
1
2
3
4
5
90
89
91
90
91
95 (R)
95 (R)
94 (R)
95 (R)
95 (R)
Table 3. Solvent Effect in the Reduction of 7a by Cl3SiH in
the Presence of cis-5a
entry
solvent
h
yield (%) of 8a
ee (%) (config)
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
CCl4
AcOEt
THF
toluene
MeCN
Et2O
24
6
74
90
87
70
0
82
73
57
95 (R)
95 (R)
76 (R)
81 (R)
a 7a (0.3 mmol), Cl3SiH (0.9 mmol), and cis-5 (0.03 mmol) in CHCl3
(1.5 mL) at room temperature for 6 h.
12
24
24
24
24
24
85 (R)
51 (R)
46 (R)
and of acetylferrocene 7m to 8m in 99.7% ee at -60 °C
(Scheme 2).
a 7a (0.3 mmol), Cl3SiH (0.9 mmol), and cis-5 (0.03 mmol) in solvent
(1.5 mL) at room temperature.
Scheme 2
condition using CHCl3 as a solvent (entry 2) gave the best
result.
On the basis of those results, various aryl ketones 7b-k
were reduced by Cl3SiH using an activator cis-5 in CHCl3.
The results are summarized in Table 4, which involves the
Table 4. Enantioselective Reduction of Ketones 7a-k by
Cl3SiH in the Presence of Activator cis-5 in CHCl3 for 6 h at
Room Temperaturea
yield (%)
of 8a-k
ee (%)b
(config)c
entry
ketone
Ar
R
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
Ph
Ph
Ph
4-ClPh
2-ClPh
Me
Et
90
90
90
93
61
91
93
91
91
94
93
95 (R)
95 (R)
95 (R)
97 (R)
96 (R)
94 (R)
97 (R)
93 (R)
96 (R)
93 (R)
95 (R)
Also, by using this method, we succeeded in the prepara-
tion of an optically active lactone 9 from keto ester 7n in
93% yield with 97% ee (Scheme 3). Lactone 9 is an
n-Pr
Me
Me
Me
Me
Me
Me
Me
Me
4-FPh
4-NO2Ph
4-MePh
2-MePh
4-t-BuPh
4-PhPh
Scheme 3
9
10
11
7j
7k
a 7a-k (0.3 mmol), Cl3SiH (0.9 mmol), and activator (0.03 mmol) in
CHCl3 (1.5 mL) at room temperature for 6 h. b Determined by HPLC.
c Identified by comparison of the optical rotation of the products with the
reported data or by comparison of the HPLC data with those of authentic
samples.
important intermediate for a preparation of a wide variety
of biologically active substance.13
result of reduction of 7a.
In summary, we present a new effective organic activator,
N-formyl-R′-(2,4,6-triethylphenyl)-L-proline, cis-5, for Cl3-
SiH to reduce aryl ketones with excellent enantioselectivity.
Both a carboxyl group at the R-position and a 2,4,6-
triethylphenyl group at the R′-position of cis-5 are critical
As shown in Table 4, the stereoselectivity for the reduction
of ketones 7a-k to corresponding alcohols 8a-k was very
high (93-97% ee) and the absolute configuration of enan-
tiomerically enriched alcohols was R in every case.
An activator cis-5 was reusable several times without any
loss of its activity as shown in Table 5.
This method was applicable to highly enantioselective
reduction of 4′-(allyloxycarbonyl)acetophenone 7l to 8l
without any reduction of the C-C double bond in 97% ee
(13) (a) Brown, H. C.; Kulkarni, S. V.; Racherla, U. S. J. Org. Chem.
1994, 59, 365-369. (b) Kamal, A.; Sandbhor, M.; Shaik, A. A. Tetrahe-
dron: Asymmetry 2003, 14, 1575-1580. (c) Hilborn, J. W.; Lu, Z. H.;
Jurgens, A. R.; Fang, Q. K.; Byers, P.; Wald, S. A.; Senanayake, C. H.
Tetrahedron Lett. 2001, 42, 8919-8921.
Org. Lett., Vol. 8, No. 17, 2006
3791

for the high enantioselectivity. Further study on the applica-
tion of this method to nonaromatic ketones and the mecha-
nistic aspect is currently under investigation.
Supporting Information Available: CIF file of the X-ray
structure of trans-5; characterization data for activators 1u,
cis- and trans-3-5, and their precursors cis- and trans-11-
15, alcohols 8a-8m, and lactone 9; and experiments
involving electrochemical oxidation. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This study was supported by a Grant-
in Aid for Scientific Research on Priority Areas from Mext
(no. 444, Advanced Molecular Transformations of Carbon
Resources) and the Tokuyama Science Foundation.
OL0613822
3792
Org. Lett., Vol. 8, No. 17, 2006