Highly enantioselective, catalytic conjugate addition of cyanide to α,β-unsaturated imides

Article abstract of DOI:10.1021/ja034635k

(Salen)Al-Cl complex 1a catalyzes the asymmetric conjugate addition of hydrogen cyanide to α,β-unsaturated imides in high yields and enantioselectivities. The cyanide adducts can readily be converted into a variety of useful chiral building blocks, including α-substituted-β-amino acids and β-substituted-γ-aminobutyric acids. Mechanistic data obtained thus far point to a cooperative bimetallic mechanism for nucleophile and electrophile activation. Copyright

Full text of DOI:10.1021/ja034635k

Published on Web 03/25/2003
Highly Enantioselective, Catalytic Conjugate Addition of Cyanide to
r,â-Unsaturated Imides
Glenn M. Sammis and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received February 12, 2003; E-mail: jacobsen@chemistry.harvard.edu
While significant advances have been made in the development
of catalyst systems for enantioselective 1,2-cyanations of aldehydes,
ketones,1 and imines,2 no asymmetric catalysts for 1,4-additions to
R,â-unsaturated carbonyl compounds have been identified to date.
Such methodology would provide access to difunctional intermedi-
ates that are readily converted to a variety of useful chiral building
blocks, including â-substituted-γ-aminobutyric acids and R-sub-
Figure 1.
stituted-â-amino acids (Scheme 1). We describe here the application
of readily available (salen)AlIII catalysts to the conjugate addition
Scheme 1
of hydrogen cyanide to R,â-unsaturated imides with high enanti-
oselectivity.
We initiated the study with a screen of known chiral cyanation
and conjugate addition catalysts in reactions of HCN or TMSCN
with R,â-unsaturated acid derivatives. Chiral aluminum salen
catalysts (e.g., 1a,b) were of particular interest given their proven
activity in the asymmetric cyanation of imines3 and conjugate
Table 1. Conjugate Addition of TMSCN to R,â-Unsaturated Imides
addition of HN3 to R,â-unsaturated imides (Figure 1).4 Using imide
2c as a model substrate,5 we found that complex 1a promoted the
conjugate addition of HCN in 90% ee, but with very low conversion
(1-2 turnover numbers). Systematic variation of solvent, cyanide
source, order of addition, and reaction temperature led to substantial
improvement in reactivity,6 with product 3c generated in 90%
isolated yield and 97% ee under optimal conditions.7 The method
used for generation of HCN proved to be a particularly important
reaction parameter: no reaction was observed when HCN alone
was used as a cyanide source, but good reactivity was obtained
with HCN generated in situ from TMSCN and an alcohol such as
2-propanol8 (vide infra).
Generally good results were obtained with imide substrates
bearing aliphatic â-substituents (Table 1).9 Enantioselectivity was
found to be largely insensitive to the steric properties of the
substituent, with products 3a and 3g generated in similar yield and
ee. A significant substrate-dependence on reactivity was observed,
however, and slower-reacting imides such as 2g and 2h required
elevated temperatures and catalyst loadings to attain full conversion
(method B). Imide derivatives bearing unsaturated â-substituents
(R ) aryl, vinyl, alkynyl) proved unreactive, even under forcing
conditions.
time
(h)
isolated
yield (%)
eeb
(%)
product
R
methoda
3a
3b
3c
3d
3e
3f
Me
Et
A
A
A
A
A
A
B
B
26
26
26
26
26
48
48
48
92
95
90
91
93
96
90
70
98c
97
97
94
96
95
97
87
nPr
iPr
iBu
(CH2)3CHCH2
3g
3h
tBu
CH2OBn
a Reactions were carried out on a 0.5 mmol scale. Method A: 10 mol %
(S,S)-1a (see ref 10), 2.5 equiv of TMSCN, 2.5 equiv of 2-propanol, 0.2
mL of toluene, 24 °C. Method B: 15 mol % (S,S)-1a, 4 equiv of TMSCN,
4 equiv of 2-propanol, 0.4 mL of toluene, 45 °C. b The ee was determined
by chiral HPLC on a Pirkle L-Leucine column. c Absolute stereochemistry
was determined by conversion of 3a to the known γ-amino acid (ref 11).
enantioenriched R-substituted-â-amino acid derivatives (Scheme
3).16 Compound 3c was accessed by the catalytic, enantioselective
addition of HCN to imide 2c. Curtius rearrangement of the derived
acid 6 was accomplished using diphenylphosporyl azide (DPPA)17
in tert-butyl alcohol to afford the Boc-protected cyano amide 7.
Hydrolysis of the nitrile in hydrochloric acid afforded the amino
acid product in excellent yield and with minimal racemization.
Spectroscopic studies revealed that the chloride complex (1a) is
converted to two distinct species under the reaction conditions. Upon
addition of TMSCN, 1a is transformed to a new complex that we
hypothesize to be (salen)Al-CN complex 1c.18,19 Addition of imide
to complex 1c results in formation of a new (salen)Al-imidate
complex (1d). Initial rate studies reveal a second-order kinetic
This new methodology can be applied in a straightforward
manner to the synthesis of pregabalin (5, (S)-3-isobutyl-γ-ami-
nobutyric acid), an anticonvulsant drug that has been identified as
a promising treatment for neuropathic pain.12,13 In general, â-sub-
stituted-γ-amino acids are difficult to synthesize, with the current
manufacturing process for pregabalin involving a racemic 1,4-
cyanation followed by late-stage classical resolution.14,15 Cyanide-
adduct (S)-3e was prepared in 96% ee on the gram scale (Scheme
2). Selective imide hydrolysis provided carboxylic acid 4, and nitrile
reduction over platinum oxide afforded γ-amino acid 5 in excellent
yield without deterioration of enantiomeric purity. The overall yield
from commercially available materials was thus 62% over six steps.
Cyanide adducts (3) can also be applied toward the synthesis of
9
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J. AM. CHEM. SOC. 2003, 125, 4442-4443
10.1021/ja034635k CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of Pregabalin (5)
References
(1) For reviews, see: (a) Mori, A.; Inoue, S. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New
York, 1999; Chapter 28. (b) Vachal, P.; Jacobsen, E. N. In ComprehensiVe
Asymmetric Catalysis Supp. 1; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; in press.
(2) For leading references, see: (a) Yet, L. Angew. Chem., Int. Ed. 2001, 40,
875-877. (b) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012-10014.
(3) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315-
5316.
(4) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-
8960.
(5) For a practical synthesis of these substrates, see: Goodman, S. N.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 4703-4705.
(6) Best results were obtained through the use of concentrated toluene
solutions. Similar enantioselectivities, but slower reaction rates, were
obtained in TBME and chlorobenzene. Use of excess TMSCN (g2.5
equiv) proved necessary for the attainment of complete conversion of the
imide substrate, with improved rates and comparable enantioselectivities
achieved with higher cyanide concentrations.
(7) General procedure (method A): Aluminum complex 1a (60.7 mg, 0.1
mmol) and the imide 2 (1 mmol) were combined in a 25 mL Schlenk
flask under N2. Toluene (0.4 mL) and TMSCN (333 µL, 2.5 mmol) were
added by syringe, and the mixture was heated gently until the yellow
solution became homogeneous. The reaction flask was then placed in a
water bath at ambient temperature, and 2-propanol (193 µL, 2.5 mmol)
was added dropwise over 2 min. The system was sealed, and the mixture
was stirred for the specified length of time. Solvents were removed in
vacuo with a K2CO3 solution trap. The residue was purified by flash
chromatography to afford pure product 3.
Scheme 3. Synthesis of R-Substituted-â-Amino Acid
(8) Comparable results were obtained using ethanol or tert-butyl alcohol.
(9) No reactivity was observed with imides bearing R-substitution.
(10) Best results were obtained when the catalyst was dried azeotropically with
toluene prior to use.
(11) Andruszkiewicz, R.; Barrett, A. G. M.; Silverman, R. B. Synth. Commun.
1990, 20, 159.
(12) (a) Taylor, C. P.; Vartanian, M. G.; Yuen, P. W.; Bigge, C.; Suman-
Chauhan, N.; Hill, D. R. Epilepsy Res. 1993, 14, 11-15. (b) Silverman,
et al. U.S. Patent 6,262,120, 2001.
(13) Field, M. J.; McCleary, S.; Hughes, J.; Singh, L. Pain 1999, 80, 391-
398. For an excellent review on 3-substituted GABA analogues with CNS
activity, see: Bryans, J. S.; Wustrow, D. J. Med. Res. ReV. 1999, 19,
149-177.
(14) Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote,
T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E.
J.; Karrick, G. L. Org. Process DeV. 1997, 1, 26-38. For alternative
approaches, see: (a) Brenner, M.; Seebach, D. HelV. Chim. Acta 1999,
82, 2365-2379. (b) Andruszkiewicz, R.; Siverman, R. B. Synthesis 1989,
953-955. (c) Serfass, L.; Casara, P. J. Bioorg. Med. Chem. Lett. 1998, 8,
2599-2602.
(15) For selected examples of asymmetric catalytic approaches to 3-aryl-γ-
amino acids, see: (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.;
Wittenberger, S. J.; Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215-
10216. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257-4259. (c)
Mazzini, C.; Lebreton, J.; Alphand, V.; Furstoss, R. J. Tetrahedron Lett.
1997, 38, 1195-1196. (d) Doyle, M. P.; Hu, W. Chirality 2002, 14, 169-
172.
dependence on catalyst concentration.20 Taken together, these
preliminary data are consistent with a bimetallic, dual activation
mechanism involving cyanide delivery from the complex (1c) to
the electrophile bound as the imidate complex (1d).21
In summary, this represents the first example of asymmetric
catalysis of cyanide conjugate addition reactions. The methodology
has been applied successfully in the synthesis of important classes
of chiral γ- and â-amino acids. Mechanistic data obtained thus far
point to a cooperative bimetallic mechanism for nucleophile and
electrophile activation. Current studies are being directed toward
the development of more reactive and general systems through
independent optimization of the nucleophile-delivery and Lewis acid
activation functions of the catalyst system. Our results from these
efforts will be reported in due course.
(16) For representative alternative routes, see: (a) Juaristi, E. EnantioselectiVe
Synthesis of â-Amino Acids; Wiley-VCH: New York, 1997. For comple-
mentary asymmetric, catalytic approaches, see: (b) Davies, H. M. L.;
Venkataramani, C. Angew. Chem., Int. Ed. 2002, 41, 2197-2199. (c)
Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F. J. Am.
Chem. Soc. 2002, 124, 1866-1867.
(17) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151-
2157.
(18) Titration of a solution of (salen)Al-Cl with TMSCN led to formation of
a precipitate, and TMSCl remained in solution. Direct characterization of
the Al-containing product has been hampered by its low solubility.
(19) This complex does not form upon treatment of 1a with HCN, consistent
with the observation that the conjugate addition reaction does not take
place with pregenerated HCN (vide supra). However, catalytic activity is
restored if TMSCN (1 equiv relative to imide) is added.
(20) Spectroscopic and kinetic data are provided as Supporting Information.
(21) Closely analogous mechanisms have been revealed in epoxide ring-opening
reactions catalyzed by metal salen complexes. See: Jacobsen, E. N. Acc.
Chem. Res. 2000, 33, 421-431.
Acknowledgment. This work was supported by the NIH (GM-
43214) and by a predoctoral fellowship from the National Science
Foundation to G.M.S. We thank Dr. Hiroshi Danjo for important
preliminary experiments, and Mr. Mark Taylor and Mr. Qinghao
Chen for helpful discussions.
Supporting Information Available: Complete experimental pro-
cedures and chiral chromatographic analyses of racemic and enantio-
merically enriched products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA034635K
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