Title

Synthesis of polyketide-derived natural products from carbohydrates: Application of the (2,3)-Wittig rearrangement of carbohydrate-derived alpha-alkoxy tertiary allylic ethers to the syntheses of Adda and rapamycin

Date of Award

1996

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

James Kallmerten

Keywords

Wittig rearrangement, organic chemistry

Subject Categories

Organic Chemistry

Abstract

Considerable effort has focused on the development of synthetic methodology to effectively construct the unique structural subunits found within biologically active, polyketide-derived natural products. One successful approach begins with carbohydrates as chiral building blocks from which the complex structure and stereochemistry of polyketide-related intermediates can be elaborated. This dissertation describes the development of a synthetic strategy which utilizes carbohydrates in combination with the (2,3) -Wittig rearrangement for the synthesis of polyketide-derived natural products.

The synthesis of the novel $\beta$-amino acid (2S, 3S, 8S, 9S)-Adda, a component of hepatotoxic cyclic peptides, such as the microcystins, nodularin and motuporin, isolated from fresh water cyanobacteria is described. The present approach uses the (2,3) -Wittig rearrangement of a carbohydrate-derived tertiary allylic ether to establish the stereochemistry at the C$\rm\sb6,\ C\sb8$ and C$\sb9$ stereocenters of Adda.

A stereoselective and efficient synthesis of an advanced C$\sb{24}$-C$\sb{42}$ fragment of rapamycin from a carbohydrate template is presented. This fragment was rapidly assembled by serial sigmatropic rearrangements of carbohydrate-derived allylic ethers. The (2,3) -Wittig rearrangement was used to install the C$\sb{29}$ trisubstituted olefin and the C$\sb{31}$ and C$\sb{32}$ chiral centers of the target compound. Subsequently, the (3,3) -Claisen rearrangement was employed to introduce the cyclohexyl unit and the C$\sb{35}$ methyl group of rapamycin.

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