CYTOCHALASIN C SUPPORT STUDIES II
Abstract
The results of research directed towards the total synthesis of Cytochalasin C, a member of a group of fungal metabolites processing a high level of biological activity, are detailed. The synthetic strategy employs an intramolecular Diels-Alder reaction of a chiral (Z)-diene for construction of the tetrahydroisoindolone nucleus. A conjugate addition/alkylation reaction of a chiral vinyl sulfone with (beta)-keto ester dianions ultimately yields a tetracyclic precursor for an enolate-assisted intraannular fragmentation reaction to construct the 11-membered macrocycle. The absolute configuration of the vinyl sulfone required for construction of the macrocycle has been established by a correlation to (R)-3-methyl cyclohexanone. Results of Horner-Emmons olefination reactions aimed at synthesis of Z-trisubstituted alkenes are detailed. Extremely high Z selectivity results from use of highly electrophilic phosphonates. Model studies indicated that (beta)-keto amides undergo Aldol/elimination reactions with methyl glyoxylate to predominantly furnish Z-trisubstituted (alpha)-(beta)-unsaturated amides. The resultant triply-activated vinyl amides serve as highly reactive electrophilic dienophiles. An intramolecular Diels-Alder reaction of a chiral triply-activated (alpha)-(beta)-unsaturated amide/Z-dienyl amide occurred in situ to stereospecifically furnish the isoindolone nucleus of Cytochalasin C possessing the requisite chirality at all five stereocenters.
Degree
Ph.D.
Subject Area
Organic chemistry
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