Organic Chemistry Portal
Organic Chemistry Highlights

Monday, August 15, 2005
Douglass Taber
University of Delaware

Michael Reactions for Enantioselective Ring Construction

An abiding ambition of the organic synthesis chemist is to form a ring in high yield and with high enantiocontrol, using an inexpensive catalyst. The Michael reactions described here come close to achieving that goal.

Intermolecular Michael reactions continue to be developed. Karl Anker Jĝrgensen of Aarhus University, Denmark, has found (Angew. Chem. Int. Ed. 2004, 43, 1272. DOI: 10.1002/anie.200353364) that the organocatalyst 3 mediates the addition of 2 to 1 with high enantiomeric excess. What is more, under the reaction conditions the intial Michael addition is followed by an aldol condensation, to give 4 as essentially a single diastereomer.

The intramolecular Michael reaction is also a powerful transformation. In the cyclizations reported by Tetsuaki Tanaka of Osaka University (J. Org. Chem. 2004, 69, 6335. DOI: 10.1021/jo0492923), the stereochemical outcome is controlled by the chirality of the sulfoxide. Remarkably, subsequent alkylation or aldol condensation leads to one or two additional off-ring stereocenters with high diastereocontrol. Note that the high stereoselectivity in the cyclization is only observed with the (Z)-unsaturated ester.

The absolute course of the intramolecular Michael reaction can also be mediated by organo catalysts. Benjamin List of the Max-Planck-Institut, Mülheim, has shown (Angew. Chem. Int. Ed. 2004, 43, 3958. DOI: 10.1002/anie.200460578) that 9 is particularly effective. Michael addition followed by intramolecular aldol condensation gives the trans bicyclic enone 11 in high ee.

Tandem intramolecular Michael addition – intramolecular alkylation can lead to cyclopropanes. Matthew J. Gaunt of the University of Cambridge has shown (Angew. Chem. Int. Ed. 2004, 43, 2681. DOI: 10.1002/anie.200454007) that this intramolecular Michael addition also responds to organocatalysis. In this case, the catalyst, a quinine-derived amine, covalently binds to the substrate, then is released at the end of the reaction.

D. F. Taber, Org. Chem. Highlights 2005, August 15.