Organic Chemistry Portal
Organic Chemistry Highlights

Monday, January 23, 2006
Douglass Taber
University of Delaware

Catalytic Enantioselective Aldol/Mannich Reactions Leading to Extended Arrays of Stereogenic Centers

There are several strategies now available for the catalytic construction of isolated oxygenated and aminated stereogenic centers in high enantiomeric excess (Enantiocontrolled Construction of Oxygenated and Aminated Stereogenic Centers 2006 Jan 9). Processes for the catalytic enantioselective construction of extended arrays of aminated, oxygenated and alkylated stereogenic centers have also been developed (Enantioselective Construction of Arrays of Stereogenic Centers 2005 June 27).

The enantioselective element can be complexed with the nucleophile, with the acceptor, or both. A powerful approach is to use the chiral ligand sphere around a catalytic transition metal as the controlling element. Hisao Nishiyama of Nagoya University has recently (J. Am. Chem. Soc. 2005, 127, 6972. DOI: 10.1021/ja050698m) developed such an approach. Silane-mediated reduction of an unsaturated ester in the presence of an aldehyde and a chiral Rh catalyst delivered the anti aldol product 2 in high diastereoselectivity and enantioselectivity.

In a complementary approach, Matthew D. Shair of Harvard University has found (J. Am. Chem. Soc. 2005, 127, 7284. DOI: 10.1021/ja051759j) that Cu*-catalyzed decarboxylation of malonate thioesters such as 3 in the presence of an aldehyde led to the syn aldol product 4 in high diastereoselectivity and enantioselectivity.

Enantomerically-pure secondary amines can condense with reactive ketones to make enantiomerically-pure enamines. Essentially simultaneously, Dieters Enders at the RTWH, Aachen, (Angew. Chem. Int. Ed. 2005, 44, 1210. DOI: 10.1002/anie.200462428) and Carlos F. Barbas III at Scripps (Org. Lett. 2005, 7, 1383. DOI: 10.1021/ol0502533) described the highly diastereoselective proline-catalyzed condensation of the acetonide 5 of dihydroxy acetone with aldehydes such as 6 to give the differentially-protected anti aldol product 7 in high ee.

In a remarkable series of three papers, Armando Córdova of Stockholm University has expanded on the proline-mediated condensation of activated aldehydes such as 8. In the first paper (Tetrahedron Lett. 2005, 46, 2839. DOI: 10.1016/j.tetlet.2005.02.116), enantioselective Mannich reaction is described. Homocondensation with an aryl amine 9 gave the four-carbon array 10 in high ee. Condensation with other activated imines such as 12 also proceeded efficiently.

In the following paper (Tetrahedron Lett. 2005, 46, 3363. DOI: 10.1016/j.tetlet.2005.03.084), Professor Córdova reported that condensations such as 5 with 6 (above) proceed more quickly and in higher yield and ee when a small quantity of water is deliberately added to the reaction mixture. He also reported the proline-catalyzed Mannich condensation of 5. In the final paper of the series, (Tetrahedron Lett. 2005, 46, 3965. DOI: 10.1016/j.tetlet.2005.04.047), co-authored by Jan E. Bäckvall, Professor Córdova reported oxidation of benzylic amines such as 14 to the imine, with subsequent in situ Mannich condensation with 16 to give 17.

D. F. Taber, Org. Chem. Highlights 2006, January 23.