Total synthesis of the cytotoxic cyclodepsipeptide (-)-doliculide: the "ester" effect in acyclic 1,3-induction of deoxypropionates.
The total synthesis of the marine cyclodepsipeptide (-)-doliculide is described. An acyclic (2S,4S,6R)-trimethyl alkanoic acid precursor to the "hydrocarbon" portion of doliculide was synthesized starting with l-ascorbic acid based on a stereocontrolled iterative conjugate addition of lithium dimethylcuprate to acyclic delta-Cmethyl alpha,beta-unsaturated ester derivatives. syn/syn selectivity was achieved by relying on 1,3-induction in preferred folded conformations that avoid 1,5-syn-pentane interactions in the transition states. The nature of the ester moiety seems to play an important role in determining the syn/anti ratios of C-methyl adducts. The 1-methyl-1-cyclopentyl ester group was found to confer the best syn selectivity to the cuprate addition products, especially in seven-carbon enoates.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, Canada H3C 3J7. stephen.hanessian@umontreal.ca
Mascitti
Vincent
V
Giroux
Simon
S
D000818:Animals; D002625:Chemistry, Organic / Q000379:methods; D047630:Depsipeptides; D004951:Esterification; D006801:Humans; D066298:In Vitro Techniques; D008387:Marine Toxins / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D047630:Depsipeptides; D008387:Marine Toxins; D010456:Peptides, Cyclic; C424144:doliculide