New methodologies directed towards the total synthesis of cytochalasin C and D
Abstract
The presented thesis elucidates the empirical results directed towards the total synthesis of cytochalasins C and D. These cytochalasins are fungal metabolites possessing high levels of biological activity and are therefore of medicinal interest. The overall synthetic strategy comprises the use of an intramolecular Diels-Alder reaction of a chiral E,Z-diene. The synthesis of these cytochalasans are dissected into two zones and two key bonds: Western Zone; Eastern Zone; Northern Bond and the Southern Bond. The use of allylsilanes for the preparation of cytochalasin D is investigated. Thiolester intermediated cyclizations are investigated for the purpose of using a Ramberg-Backlund type strategy. These investigations prompted further interest in the area of the preparation of electrophilic and nucleophilic mercaptanylations with a $\beta$-trimethylsilylethane thiol derived reagents; along with mass spectral analysis of these intermediates. Efficient methodology was discovered and research is currently underway. The use of a conjugate addition of an allylpotassium to a chiral vinyl sulfone with subsequent refunctionalization affords a methodology of latent $\alpha$-sulfonyl anions. The necessary aldehyde precursor for intramolecular construction of the northern bond of the tetrahydroisoindoline nucleus was investigated. The southern bond could then form to yield a tetracyclic ring system with subsequent enolate-assisted intraannular fragmentation to the desired 11-membered macrocycle. Mass spectral analysis of these intermediates is included. The preparation and reaction proclivities of $\alpha$-sulfonyl anions of $\alpha$-heterosubstituted sulfones were investigated. This area of chemistry involved the preparation of $\alpha$-sulfonyl anion and "protection" with CIMMe$\sb3$ (M = Si, Ge, or Sn; or a halogen) so as to reserve the center for latent refunctionalization. The fluoride-induced regeneration of the $\alpha$-sulfonyl anion is used to form five-membered rings and the $\alpha$-bromo sulfones for the intramolecular chiral acyl transfer methodology. Mass spectral analysis of these intermediates is included.
Degree
Ph.D.
Advisors
Fuchs, Purdue University.
Subject Area
Organic chemistry
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