Organic Chemistry Portal
Organic Chemistry Highlights

Monday, July 24, 2006
Douglass Taber
University of Delaware

Catalytic Enantioselective Construction of Alkylated Stereogenic Centers

One of the simplest ways to construct alkylated ternary centers is enantioselective catalytic hydrogenation. Xumu Zhang of Pennsylvania State University has devised (Angew. Chem. Int. Ed. 2005, 44, 4933. DOI: 10.1002/anie.200501332) a chiral Rh catalyst that reduces allyl phthalimides such as 1 with high ee. This appears to be a general method for preparing β-methyl chiral amines.

Hydroformylation homologates an alkene such as 3 into either the branched product 4 or the linear product 5. Jerzy Klosin of Dow Chemical, Midland, MI has developed (Angew. Chem. Int. Ed. 2005, 44, 5834. DOI: 10.1002/anie.200501478) a chiral Rh catalyst that converts 3 into 4 with high selectivity and high ee.

Epoxides such as 6 are now readily available using the Jacobsen kinetic resolution. Geoffrey W. Coates of Cornell University has prepared (J. Am. Chem. Soc. 2005, 127, 11426. DOI: 10.1021/ja051874u) a Co catalyst that efficiently carbonylates such epoxides, leading to the β-lactone 7. β-Lactones such as 7 are known to react with lithium dialkyl cuprates with clean inversion at the secondary center.

Stereogenic centers can also be established by desymmetrization of prochiral anhydrides such as 9. Yoshimitsu Nagao of the University of Tokushima has found (Angew. Chem. Int. Ed. 2005, 44, 5838. DOI: 10.1002/anie.200501408) that the organocatalyst 10 effects the opening of 9 with high enantioselectivity. Note that thioesters such as 11 are cleanly homologated to the corresponding ketones with Cu-catalyzed Grignard reagents or lithium dialkyl cuprates.

Control of absolute configuration in the alkylation of acyclic ketone enolates has been a long-standing problem in organic synthesis. John F. Hartwig of Yale University has reported (J. Am. Chem. Soc. 2005, 127, 17192. DOI: 10.1021/ja0566275) an Ir catalyst that mediates enantioselective bond formation between silyl enol ethers such as 12 of methyl ketones, and allylic carbonates. Barry M. Trost of Stanford University has described (J. Am. Chem. Soc. 2005, 127, 17180. DOI: 10.1021/ja055968f) a complementary approach.

Shu Kobayashi of the University of Tokyo has reported (Org. Lett. 2005, 7, 4729. DOI: 10.1021/ol051965w) the remarkable aldol reaction of both cyclic (e.g. 15) and acyclic ketone silyl enol ethers with aqueous formaldehyde. With a chiral bismuth catalyst, the homologation proceeds at room temperature in good yield and high ee.

The most active area of investigation has been enantioselective conjugate addition. In a particularly important development, Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen have shown (J. Am. Chem. Soc. 2005, 127, 9966. DOI: 10.1021/ja053020f) that while α,β-unsaturated esters are mediocre substrates for Cu-catalyzed conjugate addition, the corresponding α,β-unsaturated thioesters work well.

Another advance that will be of general utility is the organocatalyst-mediated chiral conjugate addition of aldehydes such as 19 to enones such as 20, developed independently by Karl Anker Jorgensen of Aarhus University (J. Am. Chem. Soc. 2005, 127, 18296. DOI: 10.1021/ja056120u), by Yujiro Hayashi of Tokyo University of Science (Angew. Chem. Int. Ed. 2005, 44, 4212. DOI: 10.1002/anie.200500599) and by Samuel H. Gellman of the University of Wisconsin (J. Am. Chem. Soc. 2005, 127, 11598, DOI: 10.1021/ja0532584; Org. Lett. 2005, 7, 4253, DOI: 10.1021/ol0517729).

D. F. Taber, Org. Chem. Highlights 2006, July 24.