A catalytic enantioselective conjugate addition of cyanide to enones

Article abstract of DOI:10.1021/ja801201r

The first synthetically useful catalytic enantioselective conjugate addition of cyanide to enones is described. The optimized conditions involved a Gd catalyst (5 or 10 mol %) derived from ligands 3 or 4 and a 1:1 ratio of TBSCN and 2,6-dimethylphenol. Th

Full text of DOI:10.1021/ja801201r

Published on Web 04/18/2008
A Catalytic Enantioselective Conjugate Addition of Cyanide to
Enones
Yuta Tanaka, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo113-0033, Japan
Received February 18, 2008; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Optimization of the Reaction Conditions
The asymmetric conjugate addition of cyanide to R,ꢀ-unsaturated
carbonyl compounds is a highly versatile reaction. Significant
progress was recently made in the catalytic asymmetric variant
using R,ꢀ-unsaturated carboxylic acid derivatives (imides1 and
N-acylpyrroles2). Synthetically useful catalytic asymmetric conju-
gate addition of cyanide to enones, however, has yet to be
developed.3 This sharp contrast with respect to substrates is due
to the ambident characteristics of enones. There are two possible
reaction pathways from enones, 1,2-addition and 1,4-addition.
Therefore, differentiation of the two pathways, in addition to
enantioselection, is necessary. Catalytic control of even one of these
two factors, however, is not an easy task. Here, we report the first
synthetically useful catalytic enantioselective conjugate addition
of cyanide to enones.
Previously, we developed an asymmetric conjugate addition of
cyanide to R,ꢀ-unsaturated N-acylpyrroles using the Gd catalysts
derived from ligands 1 and 3 in the presence of TMSCN and HCN
or 2,6-dimethylphenol (DMP).2 The active catalysts were poly-
metallic complexes 5 with defined higher-order structures (Gd:1
) 2:3 and/or 4:5 + oxo, and Gd:3 ) 5:6 + oxo + OH) generated
through modular self-assembly.4 These complexes are multifunc-
tional; gadolinium cyanide (or isocyanide) generated through
transmetalation from TMSCN acting as a nucleophile, and an acidic
proton (Z in 5) incorporated from the protic additives acting as a
turnover accelerator.4
entry
ligand
conditions
yield (%)e
9a/10a
ee (%)g
1
1
TMSCNc
63%
19/81f
15h
rt, 15 min
2
3
4
5
6
7
8
3
3
3
3
3
3
3
TMSCNc
62%
67%
70%
40%
44%
37%
77%
52/48f
18/82f
100/0
72/28
27/73
27/73
100/0
40
53
84
90
93
47
92
rt, 18 h
TMSCN + HCNd
rt, 18 h
TMSCN + DMPb
rt, 1 h
TMSCN + DMPb
-20 °C, 24 h
TMSCN + DMPb
-40 °C, 45 h
HCNb
-20 °C, 41 h
TBSCN + DMPb
-20 °C, 24 h
a Gd(OiPr)3 (10 mol %) + 1 (20 mol %) or Gd(OiPr)3 (10 mol %) +
3 (15 mol %); rt ) room temperature. b Standard conditions. c Run
using 1.5 equiv. d Reaction run using 1 equiv of TMSCN and 1 equiv of
HCN. e Combined yield of 9a and 10a. f The 1,2-product was silylated
in the reaction mixture. g The ee of 9a determined by chiral GC.
h (R)-9a was obtained.
in enantioselectivity (entries 4-6). Although TMSCN was com-
pletely converted to HCN under those conditions,9 use of pure HCN
produced much less satisfactory results (entry 7 vs 5), suggesting
a key role of the silyl group for high 1,4-selectivity and enanti-
oselectivity. Thus, the effects of the silyl group structure were
studied using TBSCN in the presence of DMP (entry 8). As a result,
the catalyst activity and 1,4-selectivity significantly improved,
giving 9a as the sole regioisomer in 77% yield with 92% ee.
Substrate scope was evaluated under the optimized reaction
conditions (Table 2). Excellent to high enantioselectivity was
produced not only from methyl ketones, but also from linear,
branched, aryl, and cyclic enones. In the case of R,ꢀ-disubstituted
enone 8 h and cyclic enones 8i, 8j, and 8k, the catalyst derived
from electronically tuned ligand 4 afforded significantly higher
enantioselectivity than 3.10 The catalyst loading could be reduced
to 5 mol % (entries 2, 4, and 6). In all entries, the reactions were
completely 1,4-selective. The products can be converted to
synthetically useful keto carboxylic acid derivatives through acid
hydrolysis without racemization.10
We applied the Gd catalysts to an asymmetric conjugate addition
of cyanide to enones. 3-Hepten-2-one (8a) was selected as a model
substrate for initial optimization (Table 1). Preliminary ligand
screening demonstrated a remarkable difference between the
catalysts derived from 1 or 2 and 3, and identified 3 as the more
promising ligand in terms of regioselectivity (9a/10a) and enan-
tioselectivity (entries 1 and 2). Conversely, Gd-1/2 were completely
1,2-selective enantioselective catalysts at -60 °C; TMS-protected
cyanohydrin (TMS-10a) was produced in 80% yield with 84% ee
using 5 mol % of Gd-2 (9 h in propionitrile, 9a/10a ) 1/>30).5
The effects of protic additives were then studied using Gd-3.6
The addition of HCN did not change the reaction rate, however,
but produced markedly lower 1,4-selectivity (entry 3). In contrast,
a 1:1 ratio of TMSCN and DMP facilitated the reaction with
complete 1,4-selectivity as well as improved enantioselectivity
(70% yield and 84% ee; entry 4).7 Lowering the reaction temper-
ature, however, decreased 1,4-selectivity8 with a gradual increase
In addition to high enantioselectivity and wide substrate scope,
it is noteworthy that the asymmetric rare earth metal catalyst
selectively produced the 1,4-adducts from enones. Specifically, new
reaction conditions using a 1:1 ratio of TBSCN and DMP were
effective.7 To gain insight into the origin of the pathway-selectivity,
mechanistic information was collected, leading to two important
findings.
9
6072 J. AM. CHEM. SOC. 2008, 130, 6072–6073
10.1021/ja801201r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Catalytic Asymmetric Rearrangement of Cyanide
Table 2. Catalytic Enantioselective Conjugate Addition of Cyanide
to Enones
of the reaction in some entries of Table 2 (e.g., entries 4 and 6).
The cyanohydrin was gradually converted to the 1,4-product
according to the reaction progress. Therefore, the complete 1,4-
selectivity depended on the ability of the enantioselective catalyst
to promote both reversible 1,2-cyanation/retro-cyanation and ir-
reversible 1,4-cyanation.15
In conclusion, we developed the first synthetically useful
catalytic enantioselective conjugate addition of cyanide to
enones. Combining the previous results,5 both R-cyanohydrins
(1,2-adducts) and ꢀ-cyano ketones (1,4-adducts) can be produced
selectively from enones with high enantioselectivity. Studies
are ongoing to improve catalyst turn-over and to extend these
findings to quaternary carbon synthesis.
Acknowledgment. Financial support was provided by Grant-
in-Aid for Specifically Promoted Research from MEXT and
Grant-in-Aid for Scientific Research (B) from JSPS. We thank
Dr. Akihiro Sato and Dr. Sanae Furusho in JASCO International
Co., Ltd. for ESI-QFT-MS measurement.
Supporting Information Available: Experimental procedures
and characterization of the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442.
(b) Sammis, G. M.; Danjo, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
126, 9928. (c) Mazet, C.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2008,
47, 1762.
(2) (a) Mita, T.; Sasaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005,
127, 514. (b) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho,
S.; Kanai, M.; Shibasaki, M. Tetrahedron 2007, 63, 5820.
(3) (a) Dehmlow, E. V.; Sauerbier, C. Liebigs Ann. Chem. 1989, 181, (up to
17% ee). (b) Dehmlow, E. V.; Sauerbier, C. Pol. J. Chem. 1994, 68,
2199, (up to 4% ee).
a Ligand 3 was used. b Reaction run using 5 mol % of catalyst. In
other entries, 10 mol % of catalyst was used. c Ligand 4 was used.
d Combined yield of cis (major) and trans isomers and enantiomeric
excess of the cis isomer. e Reaction run using 2.5 equiv of TBSCN and
2.5 equiv of DMP. f The absolute configuration was determined to be
(S).
(4) Review: Shibasaki, M.; Kanai, M. Org. Biomol. Chem. 2007, 5, 2027.
(5) For the catalytic enantioselective cyanosilylation of ketones using Gd-2,
see: Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.;
Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908.
(6) For examples of the acceleration effects of protic additives in catalytic
asymmetric conjugate addition reactions: (a) Kitajima, H.; Katsuki, T.
Synlett 1997, 568. (b) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow,
J. S. J. Am. Chem. Soc. 1999, 121, 1994.
First, whereas the Gd-3 catalyst in the presence of TMSCN and
DMP was a proton-containing poly-Gd complex (5: generated
through protonolysis of 6),11 ESI-MS studies indicated that the
asymmetric catalyst under the current optimized conditions was
an O-t-butyldimethylsilylated complex (7).10 This structural infor-
mation is consistent with the experimental results; the silyl group
significantly affected the reaction rate and regio- and enantiose-
lectivities (Table 1, entries 5, 7, and 8). Together, the silylated
complex might be a more efficient 1,4-selective catalyst than the
proton-containing complex.12 The complex contained a more robust
silyl group when TBSCN was used (7) than when TMSCN was
used (6), leading to stabilization of the silylated, 1,4-selective
asymmetric catalyst.
Second, the Gd complex can enantioselectively convert free
cyanohydrins to the corresponding 1,4-products.13 Thus, treatment
of racemic cyanohydrin 10a under the reaction conditions produced
1,4-product 9a in 87% yield with 85% ee (Scheme 1).14 No reaction
proceeded in the absence of the catalyst, indicating that the catalyst
promoted retro-cyanation from the cyanohydrin (1,2-adduct) and
the subsequent irreversible asymmetric 1,4-addition of cyanide.
Cyanohydrin formation was detected by TLC analysis in the middle
(7) In the previous catalytic enantioselective conjugate addition of cyanide to
R,ꢀ-unsaturated N-acylpyrroles (ref 2b), use of a slight excess of TMSCN
to DMP was critical for high catalyst turnover and enantioselectivity, and
the conditions of TMSCN:DMP ) 1:1 were not effective. On the other
hand, application of the previous conditions (2.5 equiv of TMSCN and 2
equiv of DMP) to the cyanation of enones resulted in partial formation of
TMS-protected cyanohydrin (9a/TMS-10a ) 75/25 in 65% combined yield
at room temp). For detailed comparison between the previous and present
reaction conditions (i.e., effects of the remaining TMSCN), see Supporting
Information.
(8) This tendency indicates that 10a and 9a are kinetic and thermodynamic
products, respectively: Nagata, W.; Yoshioka, M. Org. React. 1977, 25,
255.
(9) DMP was completely silylated based on TLC analysis.
(10) See Supporting Information for details.
(11) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 16438.
(12) Consistent with this hypothesis, preincubation of the Gd complex with a
catalytic amount of TBSCN (10 mol %) produced markedly improved 1,4-
selectivity (93/7) using TMSCN + DMP (1:1) as the cyanation reagent at
-20 °C (cf. Table 1, entry 5). For further experimental support for this
hypothesis, see Supporting Information.
(13) Analogous asymmetric rearrangement (1,2- to 1,4-adduct) of alkynyl groups
was recently reported: Nishimura, T.; Katoh, T.; Takatsu, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 14158.
(14) On the other hand, TMS cyanohydrins were intact.
(15) For a relevant pathway-selective asymmetric catalysis, see: Oisaki, K.;
Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 7439.
JA801201R
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J. AM. CHEM. SOC. VOL. 130, NO. 19, 2008 6073