Catalytic enantioselective conjugate addition of cyanide to α,β-unsaturated N-acylpyrroles

Article abstract of DOI:10.1021/ja043424s

A catalytic enantioselective conjugate addition of cyanide to α,β-unsaturated N-acylpyrroles was developed using the chiral gadolinium catalyst generated from Gd(OⁱPr)₃ and D-glucose-derived ligand 2. Generally high enantioselectivit

Full text of DOI:10.1021/ja043424s

Published on Web 12/18/2004
Catalytic Enantioselective Conjugate Addition of Cyanide to r,â-Unsaturated
N-Acylpyrroles
Tsuyoshi Mita,† Kazuki Sasaki,† Motomu Kanai,*,†,‡ and Masakatsu Shibasaki*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Tokyo 113-0033, Japan, and PRESTO,
Japan Science and Technology Agency, Japan
Received October 30, 2004; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
The conjugate addition of cyanide to R,â-unsaturated carboxylic
acid derivatives is one of the most useful reactions in organic
chemistry. The resulting â-cyano adducts can be converted to
γ-aminobutyric acids (GABA analogues) under reducing conditions,
1,2-dicarboxylic acids via hydrolysis, and â-amino acids via Curtius
rearrangement. Specifically, the catalytic enantioselective version
of this reaction provides very important chiral building blocks for
pharmaceuticals. Up to now, only one catalytic enantioselective
conjugate addition of cyanide has been reported; Jacobsen’s group
obtained excellent enantioselectivity from â-aliphatic-substituted
Figure 1. Chiral ligands (1 and 2) and the working hypothesis for the
R,â-unsaturated imides using the chiral salen-Al complex as a
transition-state model of the Strecker reaction (3) and the conjugate addition
(4).
catalyst.1 On the other hand, substrates with a â-aryl or â-vinyl
substituent were unreactive in their system. Thus, there is high
demand for a reaction with broader substrate generality. In this
Table 1. Optimization of the Reaction Conditions
communication, we report the catalytic enantioselective conjugate
addition of cyanide to various â-substituted R,â-unsaturated N-
acylpyrroles, including â-aryl, â-vinyl, and R,â-disubstituted
derivatives, using a chiral gadolinium complex.
We recently developed a catalytic enantioselective Strecker
reaction of N-phosphinoyl ketoimines using a chiral gadolinium
complex prepared from Gd(OiPr)3 and ligand 2 in a 1:2 ratio.2 Both
catalyst activity and enantioselectivity were significantly improved
in the presence of protic additives, such as 2,6-dimethylphenol or
HCN. Structural information of the asymmetric catalyst suggested
that the active catalyst is a proton-containing 2:3 complex of Gd
and 2,2 and the reaction would proceed through an intramolecular
cyanide transfer to an activated imine from the gadolinium cyanide
(3).3 Because of the topologic analogy of the reaction pattern (1,4-
addition), we planned to extend our catalysis to the conjugate
addition of cyanide to R,â-unsaturated carboxylic acid derivatives
(4).
a Isolated yield. b Determined by chiral HPLC. c With 10 mol % catalyst,
Targeting cinnamic acid derivatives as substrates, we started our
1 equiv of TMSCN, and 2 equiv of HCN (instead of 2,6-dimethylphenol).
optimization using 5 mol % catalyst, 1.5 equiv of TMSCN, and 1
equiv of 2,6-dimethylphenol, observing the effects of the carbonyl
obtained using 10 mol % catalyst, 1 equiv of TMSCN, and 2 equiv
of HCN (entry 8).5
substituents of the substrates (Y in Table 1) on the reactivity and
enantioselectivity (entries 1-6). Although ethyl cinnamate and
cinnamoyl imidazolide did not produce any products, benzylidene
malonate 5, oxazolidinone 6, and N-acylpyrrole 7a4 produced the
corresponding adducts at ambient temperature, albeit with low to
moderate enantioselectivity. When the reaction temperature was
decreased to -20 °C, the enantioselectivity of the product from
N-acylpyrrole 7a was significantly improved to 74% ee, with
diminishing chemical yield (entry 6). Higher enantioselectivity (81%
ee) was produced using a catalyst derived from the electronically
tuned 2, although the yield was still moderate (entry 7). Finally,
HCN was determined to be a better protic additive than 2,6-
dimethylphenol; high chemical yield and enantioselectivity were
The optimized reaction conditions were applied to other sub-
strates containing â-aryl, vinyl, and alkyl substituents (Table 2).
Excellent enantioselectivity was obtained from a wide range of R,â-
unsaturated N-acylpyrroles.6 The reaction also proceeded from R,â-
disubstituted substrate 7i with high enantioselectivity, although
diastereoselectivity requires further improvement.7 Thus, this reac-
tion significantly expanded the substrate generality of the catalytic
enantioselective conjugate addition of cyanide to R,â-unsaturated
carboxylic acid derivatives.
Because of the synthetic versatility of the cyanide and N-
acylpyrrole,4 short-step synthesis of a broad range of chiral
pharmaceuticals should become possible using this reaction as a
key step. Selected examples are shown in Scheme 1. First, a
â-phenyl-substituted GABA analogue,8 which has inhibitory activity
† The University of Tokyo.
‡ PRESTO.
9
514
J. AM. CHEM. SOC. 2005, 127, 514-515
10.1021/ja043424s CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Conjugate Addition of Cyanide
to R,â-Unsaturated N-Acylpyrroles
Scheme 1. Conversion of the Products to Useful Compounds
pharmaceuticals and their lead compounds were achieved. Detailed
mechanistic studies and efforts to further improve the efficiency
are in progress.
Acknowledgment. Financial support was provided by Kuraray
Co. Ltd., PRESTO of Japan Science and Technology Agency (JST),
and Grant-in-Aid for Specially Promoted Research of MEXT. We
thank Ms. Sugita, Mr. Qin, and Dr. Matsunaga for helpful advice
regarding R,â-unsaturated N-acylpyrrole synthesis.
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.
(2) (a) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004,
45, 3147. (b) Kato, N.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2004, 45, 3153. (c) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
(3) Kinetic studies and labeling experiments supported this reaction mechanism
in the catalytic enantioselective cyanosilylation of ketones using the
gadolinium complex: Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima,
Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 9908.
(4) (a) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2004, 126, 7559. (b) Evans, D. A.; Borg, G.; Scheidt, K.
A. Angew. Chem., Int. Ed. 2002, 41, 3188.
a Isolated yield. b Determined by chiral HPLC. c With 1 equiv of
TMSCN. d With 0.5 equiv of TMSCN. e The reaction experiment was
performed at room temperature. f Ratio of trans/cis. g Absolute configuration
was determined as shown in the above scheme. h Enantiomeric excess of
trans isomer. The absolute configuration was determined to be (2R,3R).
i Enantiomeric excess of cis isomer. The absolute configuration was
determined to be (2S,3R).
(5) Catalysts prepared from other lanthanide alkoxides produced less satisfac-
tory results.
(6) General Procedure: Gd(OiPr)3 (0.2 M in THF, 75 µL, 0.015 mmol) was
added to a solution of 2 (13.8 mg, 0.030 mmol) in THF (0.3 mL) at 0 °C.
The mixture was stirred at 45 °C for 1 h, and then the solvent was
evaporated at ambient temperature. After drying the resulting precatalyst
under reduced pressure (<5 mmHg) for 1.5 h, substrate 7f (53.1 mg, 0.30
mmol) in propionitrile (500 µL) was added at room temperature, then
cooled to -20 °C. After 20 min, TMSCN (20 µL, 0.15 mmol) was added,
and after 10 min, HCN (4 M in propionitrile stock solution, 150 µL, 0.60
mmol) was added to start the reaction.
(7) The cyanide addition proceeded with high enantioselectivity. Lack of the
diastereoselectivity is due to the nonstereoselective protonation of the
intermediate enolate.
(8) Sytinsky, I. A.; Soldatenkov, A. T. Prog. Neurobiol. 1978, 10, 89.
(9) For a procedure from the lactam to â-phenyl-substituted GABA analogue,
see: Sobocinska, M.; Zobacheva, M. M.; Perekalin, V. V.; Kupryszewski,
G. Pol. J. Chem. 1979, 53, 435.
in the nervous system, was synthesized in four steps from 8a
through hydrogenation of the cyanide and lactam formation.9
Second, pregabalin,10 an important anticonvulsant drug, was
synthesized in two steps from 8f. Third, trans-cyclopentanedicar-
boxylic acid, a useful chiral building block, was synthesized in two
steps from trans-8i.
In conclusion, we developed a catalytic enantioselective conju-
gate addition reaction of cyanide to R,â-unsaturated N-acylpyrroles
using the chiral gadolinium catalyst generated from Gd(OiPr)3 and
D-glucose-derived ligand 2. This reaction expands the previous
substrate scope significantly; substrates with â-aryl and â-vinyl
substituents and R,â-disubstituted substrates can now be used. Using
this reaction as a key step, short-step syntheses of several
(10) Pregabalin has a (3S) configuration: (a) Silverman, R. B.; Andruszkiewicz,
R.; Yuen, P.-W.; Sobieray, D. M.; Franklin, L. C.; Schwindt, M. A. U.S.
Patent 5,563,175, 1996. For recent catalytic enantioselective synthesis of
pregabalin, see: (b) Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219, and
ref 1a. For a practical synthesis of (ent)-ligand 2, see: (c) Kato, N.; Tomita,
D.; Maki, K.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2004, 69, 6128.
JA043424S
9
J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 515