Use of a novel [ 4 + 2 ] phosphine catalyzed annulation toward the total synthesis of corynantheine indole alkaloids

ORGN 432

Reymundo A. Villa, rvilla@chem.ucla.edu, Department of Chemistry and Biochemistry, University of California Los Angeles, 605 Charles E. Young Drive East, Los Angeles, CA 90095 and Ohyun Kwon, ohyun@chem.ucla.edu, Department of Chemistry and Biochemistry, University of California, Los Angeles, 605 Charles E. Young Drive East, Los Angeles, CA 90095.
Indole alkaloids, hirsutine and hirsuteine, show antihypertensive, negative chronotropic, and antiarrhythmic activity. We have chosen to synthesize hirsuteine and hirsutine since it was discovered quite recently that both compounds exhibit anti-influenza A virus activity and also because an enantioselective total synthesis of hirsuteine has not yet been accomplished. The key reaction in our synthesis is the phosphine-catalyzed [4+2] annulation of 2-methyl-2,3-butadienoate 4 with 2-indolylimine 3 to build the tricyclic intermediate 5. Upon C ring formation via Friedel-Crafts acylation/reduction/alkylation, the D ring a,b-unsaturated ester was utilized in a diastereoselective Michael addition of sodiodimethylmalonate in methanol. The resulting tetracyclic intermediate 10 contains all the requisite carbon atoms with correct stereochemistry of hirsuteine/hirsutine and, therefore, brings us close to the conclusion of the planned total synthesis. The concise 9-step synthesis of 10 showcases the power of the [4+2] annulation in the area of indole alkaloid natural product synthesis.

 

New Reactions and Methodology, Total Synthesis, Materials, Devices and Switches, Lipids, Nucleotides and Mimetics
8:00 PM-10:00 PM, Tuesday, March 27, 2007 Hyatt Regency Chicago -- Riverside Center, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, March 26, 2007 Hyatt Regency Chicago -- Riverside Center, Sci-Mix

Division of Organic Chemistry

The 233rd ACS National Meeting, Chicago, IL, March 25-29, 2007