Total Synthesis of (−)- and ent-(+)-Vindoline and Related Alkaloids

• Published in: Journal of the American Chemical Society Vol. 128; no. 32; pp. 10596 - 10612
• Main Authors: Ishikawa, Hayato, Elliott, Gregory I, Velcicky, Juraj, Choi, Younggi, Boger, Dale L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 16-08-2006
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Chemistry; Cyclization; Exact sciences and technology; General and physical chemistry; Molecular Structure; Stereoisomerism; Vinblastine - analogs & derivatives; Vinblastine - chemical synthesis; Vinblastine - chemistry; Pentacyclic compound; Intramolecular reaction; Alkaloid; Cycloaddition; Molecular structure; Natural product; Stereochemistry; Tandem reaction; Chemical synthesis; Total synthesis; Enantiomer(-); Successive reaction
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja061256t

A concise 11-step total synthesis of (−)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C−C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).