Organic Chemistry Portal
Organic Chemistry Highlights

Monday, June 20, 2005
Douglass Taber
University of Delaware

Enantioselective Construction of Single Stereogenic Centers

Single enantiomer synthesis is of increasing importance in pharmaceutical production. It is essential that practical and scalable procedures be developed for controlling the absolute configuration of new stereogenic centers as they are formed. Severally particularly important developments have recently been reported.

A challenge of long standing has been the enantioselective addition of a propargyl anion to an aldehyde. Teck-Peng Loh of the National University of Singapore has reported (Chem. Commun. 2004, 2456. DOI: 10.1039/b411653d) that the well-known allyl transfer from a defined secondary alcohol works well also with allenyl alcohols such as 1. The reaction proceeds to give a product 3 of inverted absolute configuration compared to the donor. The enantiomerically-pure alcohol 1 was prepared by resolution, but Chan-Mo Yu of Sungkyunkwan University has described (Chem. Commun. 2004, 2494. DOI: 10.1039/b407387h) the preparation of alcohols such as 1 by the enantioselective reduction of the corresponding ketones.

Erick Carreira of ETH H÷nggerberg has reported (Org. Lett. 2004, 6, 4575. DOI: 10.1021/ol048035h) a catalytic procedure for the reduction of nitroalkenes such as 4 to the nitroalkane 5 with high enantiomeric excess. He has also reported (Angew. Chem. Int. Ed. 2005, 44, 612. DOI: 10.1002/anie.200461879) that the enantiomerically-enriched nitroalkane can be converted to the corresponding nitrile 6 without loss of stereochemical purity.

An alternative route to nitriles of high enantiomeric excess, based on the conjugate addition of Me3Si-CN to an activated amide 7, has been reported (J. Am. Chem. Soc. 2004, 126, 9928. DOI: 10.1021/ja046653n) by Eric Jacobsen of Harvard University. The key to success in this case was dual catalysis, with a chiral Al complex and a chiral Er complex.

Another advance in conjugate addition has been reported (Org. Lett. 2004, 6, 4877. DOI: 10.1021/ol048071g) by Toshiro Harada of Kyoto Institute of Technology. The organocatalyst 10 efficiently mediates the addition of ketene silyl acetals to enones such as 9. In this case, it was use of the dimethylsilyl group that led to success.

The enantioselective conjugate addition of alkyl groups to enones has required the use of dialkyl zinc reagents. Now, Ben Feringa of the University of Groningen has found (J. Am. Chem. Soc. 2004, 126, 12784. DOI: 10.1021/ja046632t) that with ferrocene-based chiral Cu catalysts, one can achieve conjugate addition with ordinary alkyl Grignard reagents.

The work on organocatalytic aldol reaction continues unabated. In a recent advance, Armando Cˇrdova of Stockholm University has found (Angew. Chem. Int. Ed. 2004, 43, 6528. DOI: 10.1002/anie.200460678) that (S)-proline also will catalyze the Mannich reaction with high enantiomeric excess. Acyclic ketones also participate efficiently.

D. F. Taber, Org. Chem. Highlights 2005, June 20.