Use of the Intramolecular Heck Reaction for Forming Congested Quaternary Carbon Stereocenters. Stereocontrolled Total Synthesis of (±)-Gelsemine

• Published in: Journal of the American Chemical Society 2005-12, Vol.127 (51), p.18054-18065
• Main Authors: Madin, Andrew, O'Donnell, Christopher J, Oh, Taeboem, Old, David W, Overman, Larry E, Sharp, Matthew J
• Format: Article
• Language: English
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Indoles - chemical synthesis; Indoles - chemistry; Organic chemistry; Preparations and properties; Pyrans - chemical synthesis; Pyrans - chemistry; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Stereoisomerism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja055711h

Intramolecular Heck reactions of α,β-unsaturated 2-haloanilides derived from azatricyclo[4.4.0.02,8]decanone 5 efficiently install the congested spirooxindole functionality of gelsemine. Depending upon the Heck reaction conditions and the nature of the β-substituent, either products having the natural or unnatural configuration of the spirooxindole group are formed predominantly. Efforts to elaborate the hydropyran ring of gelsemine from the endo-oriented nitrile substituent of pentacyclic Heck product 18 were unsuccessful. Important steps in the ultimately successful route to (±)-gelsemine (1) are as follows:  (a) intramolecular Heck reaction of tricyclic β-methoxy α,β-unsaturated 2-iodoanilide 68 in the presence of silver phosphate to form pentacyclic product 69 having the unnatural configuration of the spirooxindole fragment, (b) formation of hexacyclic aziridine 80 from the reaction of cyanide with intermediate 79 containing an N-methoxycarbonyl-β-bromoethylamine fragment, (c) introduction of C17 by ring-opening of the aziridinium ion derived from aziridine 80, and (d) base-promoted skeletal rearrangement of pentacyclic equatorial alcohol 82 to form the oxacyclic ring and invert the spirooxindole functional group to provide hexacyclic gelsemine precursor 83.