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Monday, April 18, 2005
Douglass Taber
University of Delaware

Heterocycle Construction by Grubbs Metathesis

Grubbs metathesis has proven to be a powerful tool for the rapid construction of complex heterocycles. Shengming Ma of the the Shanghai Institute of Organic Chemistry reports (J. Org. Chem. 2004, 69, 6305. DOI: 10.1021/jo0493121) a concise assembly of the tetracycle 4. Exposure of the symmetrical triene 1 to the second-generation Grubbs catalyst (G2) led first to ene-yne metathesis, then to diene metathesis, to give the triene 2. Addition of maleimide 3 proceeded with substantial diastereocontrol, to give 4.

Many macrocyclic lactams have potent physiological activity. Daesung Lee of the University of Wisconsin has taken advantage (Org. Lett. 2004, 6, 4351. DOI: 10.1021/ol048136f) of the conformational preference of diacyl hydrazides such as 8 to prepare, by Grubbs cyclization of 8 and then again of 10, the 8-8 system 11. Exposure of 11 to Na in liquid ammonia reduced the N-N bond and opened the epoxide, to deliver macrocyclic lactam 12.

Faced with the preparation of BILN 2061 18, a hepatitis C NS3 protease inhibitor, Anne-Marie Faucher of Boehringer Ingelheim (Canada) in Quebec adopted (Org. Lett. 2004, 6, 2901. DOI: 10.1021/ol0489907) a ring-closing metathesis approach. To this end, it was necessary to prepare the enantiomerically-enriched amino acid 14. Remarkably, Knowles hydrogenation of 13 proceeded efficiently, without concomitant reduction of the very reactive monosubstituted alkene. For the cyclization of 15 to 17, the Hoveyda metathesis catalyst 16 proved the most efficient. Note that although a large ring is being formed, it is sufficiently constrained that only the desired Z-alkene 17 is observed.

D. F. Taber, Org. Chem. Highlights 2005, April 18.