A highly enantioselective chiral Lewis base-catalyzed asymmetric cyanation of ketones.

The control of absolute configuration of quaternary stereocenters represents a great challenge in asymmetric catalysis.1-3 A conceptually direct and attractive approach is to transform prochiral ketones to chiral building blocks containing a quaternary stereocenter by a catalytic asymmetric C-C bond formation. The realization of this approach, however, has proven to be a formidable task.1,2d,3 Achieving synthetically useful enantioselectivity with unconjugated aliphatic ketones is particularly challenging since the two alkyl substituents of the ketone closely resemble each other both electronically and sterically. We describe here the development of a highly enantioselective cyanation of dialkyl ketones catalyzed by an organic chiral Lewis base. Guided by our recent discovery that readily available modified cinchona alkaloids are highly effective chiral Lewis base catalysts for desymmetrization of cyclic anhydrides,4 we undertook the development of a chiral Lewis base-catalyzed asymmetric cyanation of ketones in view of its significance in asymmetric synthesis.5 Our investigation started with the development of an efficient amine-catalyzed cyanation of ketones. Poirier reported that the treatment of unconjugated aliphatic ketones 1 with 20 equiv of diisopropylamine (3, R4 ) i-Pr) and 5-10 equiv of methyl cyanoformate (4, R3 ) Me) afforded tertiary cyanohydrin carbonates 2 (R3 ) Me) in good yield.6 A large excess secondary amine 3 was used, presumably because deprotonation of 5 or 6 by a second equivalent of 3 will decompose 3 to carbamate 7 (Scheme 1). However, in principle, the reaction could be catalytic in a tertiary amine, which cannot undergo this proton transfer. Although, Poirer reported that excess Et3N was much less effective than diisopropylamine in promoting the conversion of 1 to 2,6 we observed at 25 °C that cyanation of 2-heptanone with 10 mol % amine and 1.5 equiv of NCCO2Me in THF proceeded in 3540% conversion with Et3N, and the conversion was further improved to 84% with DABCO. Encouraged by these results, we turned to the enantioselective conversion of 1 to 2 catalyzed by a tertiary chiral amine, such as natural and modified cinchona alkaloids (Figure 1), as shown in the proposed catalytic cycle (Scheme 2). Asymmetric cyanation of 2-heptanone (1a) with 1.2 equiv of methyl cyanoformate and 10 mol % of the chiral amine in CHCl3 at 25 °C gave 2 (R1 ) n-C5H11, R2 ) R3 ) Me) in the following conversion and ee: quinidine (66%, 2.6% ee), DHQD-CLB (63%, 17% ee), QHQDPHN (83%, 27% ee), (DHQD)2PYR (86%, 11% ee), (DHQD)2PHAL (80%, 22% ee), (DHQD)2AQN (94%, 27% ee). With (DHQD)2AQN as the catalyst, the enantioselectivity of the asymmetric cyanation can be improved from 27% ee to 40% ee by employing ethyl cyanoformate and performing the reaction at -24 °C. The substitution of ethyl cyanoformate with benzyl cyanoformate or the employment of other common organic solvents such as dichloromethane, ether, toluene, and acetonitrile resulted in deteriorated enantioselectivity for the asymmetric cyanation of 2-heptanone (see Supporting Information for details). Most importantly, a variety of acyclic and cyclic dialkyl ketones, both R-substituted and R,R-disubstituted, are transformed to tertiary cyanohydrin carbonates in good to excellent enantioselectivity and in synthetically useful yield with either DHQDPHN or (DHQD)2AQN as the catalyst (Table 1). Enantioselective cyanation of the sterically hindered R,R-disubstituted ketones has been reported previously only once with tert-butyl methyl ketone using an enzymatic method.7,8 Particularly noteworthy is that, for the first time, a catalytic asymmetric cyanation of a cyclic ketone * To whom correspondence should be addressed. (1) For excellent reviews, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (b) Fuji, K. Chem. ReV. 1993, 93, 2037. (2) For recent examples of catalytic creation of quaternary stereocenters see: (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228. (b) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (c) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532. (d) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (3) While this manuscript was in preparation, Shibasaki and co-workers reported the first highly enantioselective cyanosilylation of ketones catalyzed by transition metal complexes prepared via a multistep synthesis from D-glucal. See: (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412. (b) Hamashima Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 691. (4) Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542. (5) For reviews, see: (a) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649. (b) Effenberger, F. Angew. Chem., Int. Ed. 1994, 33, 1555. (c) North, M. Synlett 1993, 807. (6) (a) Poirier, D.; Berthiaume, D.; Boivin, R. P. Synlett 1999, 1423. (b) Berthiaume, D.; Poirier D. Terahedron 2000, 56, 5995. (7) Griengl, H.; Klempier, N.; Pöchlauer, P.; Schmidt, M.; Shi, N.; Zabelinskaja-Mackova, A. A. Tetrahedron 1998, 54, 14477. Scheme 1. Decomposition of Secondary Amines to Carbamates 7