Structural Determination of (−)-SCH 64874 and Hirsutellomycin by Semisynthesis

• Published in: Journal of organic chemistry Vol. 82; no. 1; pp. 353 - 371
• Main Authors: Tokuyama, Hidetoshi, Yamada, Kaori, Fujiwara, Hideto, Sakata, Juri, Okano, Kentaro, Sappan, Malipan, Isaka, Masahiko
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.01.2017
• Subjects: Alkaloids - chemical synthesis; Alkaloids - chemistry; Carboxylic Acids - chemistry; Molecular Structure; Piperazines - chemical synthesis; Piperazines - chemistry; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.6b02452

The structure of a C 2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the β-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric β-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (−)-deacetylaranotin core with two enantiomeric β-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the β-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4′–C6′ syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2′ stereocenter, was determined by introduction of four possible side chains into the bisdethiodi­(methylthio)­deacetylaranotin core. We found that the stereochemistry of C2′ converged with that of the thermodynamically stable form influenced by the core structure.