Total Synthesis of Cryptophycin-24 (Arenastatin A) Amenable to Structural Modifications in the C16 Side Chain

• Published in: Journal of organic chemistry 2000-11, Vol.65 (23), p.7792-7799
• Main Authors: Eggen, MariJean, Mossman, Craig J, Buck, Suzanne B, Nair, Sajiv K, Bhat, Laxminarayan, Ali, Syed M, Reiff, Emily A, Boge, Thomas C, Georg, Gunda I
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Depsipeptides; Peptides, Cyclic - chemical synthesis; Structure-Activity Relationship
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo000767+

Two efficient protocols for the synthesis of tert-butyl (5S,6R,2E,7E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-8-phenyl-2,7-octadienoate, a major component of the cryptophycins, are reported. The first utilized the Noyori reduction and Frater alkylation of methyl 5-benzyloxy-3-oxopentanoate to set two stereogenic centers, which became the C16 hydroxyl and C1‘ methyl of the cryptophycins. The second approach started from 3-p-methoxybenzyloxypropanal and a crotyl borane reagent derived from (−)-α-pinene to set both stereocenters in a single step and provided the dephenyl analogue, tert-butyl (5S,6R,2E)-5-[(tert-butyldimethylsilyl)oxy]-6-methyl-2,7-octadienoate, in five steps. This compound was readily converted to the 8-phenyl compound via Heck coupling. The silanyloxy esters were efficiently deprotected and coupled to the C2−C10 amino acid fragment to provide desepoxyarenastatin A and its dephenyl analogue. The terminal olefin of the latter was further elaborated via Heck coupling. Epoxidation provided cryptophycin-24 (arenastatin A).