Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Amos B. Smith, III

Abstract

Polyketides constitute a group of highly structurally diverse and biologically active natural products. Synthetic efforts toward two families of polyketides, namely irciniastatins and nahuoic acids, are represented in this thesis, in conjunction with the development of Anion Relay Chemistry (ARC) tactic as a useful tool for polyketide construction.

Chapter one describes the design and synthesis of seven novel irciniastatin analogues, achieved by structural simplification of the tetrahydropyran core as well as by functional group variation of the C(11) substituent of irciniastatin A. These analogues are in turn evaluated against several cancer cell lines; all possess antiproliferative activity in nanomolar range.

Chapter two describes the extension of the ARC tactic to achieve effective [1,5]-vinyl Brook rearrange via incorporation of conformational constraints. Three types of restrained linchpins are designed, synthesized and validated for both alkylation and cross coupling reactions. Density Functional Theory (DFT) calculation also provides insight into the mechanism of such reactions.

Chapter three presents the first total synthesis of a member of the nahuoic acid family, namely Ci(Bii), in a longest linear sequence of 16 steps. Nahuoic acids are highly hydroxylated and cis-decalin-scaffold-containing polyketides. These acids are the first series of natural products isolated to date that exhibit S-adenosylemethionine (SAM) competitive inhibition activity against SETD8 enzyme. Our synthesis highlights a titanium-catalyzed asymmetric Diels–Alder reaction to generate the cis-decalin skeleton, Type II ARC tactic to construct the polyol chain, and a late-stage strategic large fragment union via a Micalizio alkoxide-directed alkyne-alkene coupling.

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