Date of Degree

10-2014

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor(s)

David R. Mootoo

Subject Categories

Organic Chemistry

Keywords

Carbapyranoside, FR65814, OSW-1, Metathesis, Oxocarbenium, Pharmacological, Synthesis

Abstract

Highly oxygenated cyclohexanes comprise the structures of a number of pharmacologically interesting molecules, including potently bioactive natural products and carbapyranosides. The latter, which are unnatural analogues of carbohydrates in which the ring oxygen of the parent sugar is replaced with a methylene group, have attracted interest as hydrolytically stable mimetics of their parent O-glycosides. This research reports the development of two general methodologies for the synthesis of highly oxygenated cyclohexanes: (1) Oxocarbenium Ion Cyclization (OCC) and (2) Ring Closing Metathasis (RCM).

Chapter one gives a review of the literature on the synthesis for highly oxygenated cyclohexanes.

Previous results from this laboratory have shown that OCCs on cyclic oxocarbeniums derived from 1-thio-1,2-O-isopropylidene precursotrs are highly stereoselective for cyclohexanes and tetrahydropyrans with cis 3,4-diols. To expand the scope of the OCC methodology, the goal was to evaluate the OCCs on non-cyclic oxocarbenium ions derived from mixed thioacetal precursors. Chapter two describes reactions with alkene nucleophiles. In particular, the OCC on an alkene-mixed thioacetal precursor aimed at the cyclohexane core of the immunosuppressive agent FR65814, was examined. This study revealed that OCCs on non-cyclic oxocarbenium ions could deliver cyclohexanes with trans 3,4-diols in high stereoselectivety. As for the previous observations on OCCs with cyclic oxocarbenium ions, these results can be explained in terms of conformational arguments.

Chapter three discusses OCCs for non-cyclic oxocarbenium ions and enol-ether nucleophiles. These reactions were expected to give highly oxygenated cyclic enol ether precursors for carba- and C- pyranosides with trans 3,4-diols. However, in all cases, complex mixtures of products that suggested multiple deleterious pathways from the initial formed cyclization intermediates, was observed. This result contrasts to the successful OCCs involving cyclic oxocarbenium ions and enol ethers, and suggests that conformational rigidity is an important requirement for OCCs involving enol ether nucleophiles. Therefore, the OCC strategy appears to be limited to the synthesis of carba- and C- pyranosides with cis-3,4-vicinal diols.

Chapter four describes a more general synthesis of carbapyranosides, which is based on the RCM of an enol ether - alkene substrate. This reaction delivers a six-membered cyclic enol ether in which the enol ether oxygen is exocyclic, and contrasts with a related cyclization from the Postema group that provides C-1-substituted glycals, i.e. cyclic enol ethers with an endocyclic enol ether oxygen. This RCM strategy for carbapyranosides was applied to the carba-arabinose and carba-xylose analogues of the sugar residues in the potent antitumor steroidal glycoside OSW-1.

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