Title

Part~I. The total synthesis of 18-deoxynargenicin A(1). Part~II. Studies toward the synthesis of the pseudomonic acids

Date of Award

1989

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

James Kallmerten

Keywords

Organic chemistry

Subject Categories

Organic Chemistry

Abstract

Part I of this thesis describes the total synthesis of 18-deoxynargenicin A$\sb1$. 18-Deoxynargenicin A$\sb1$, produced by Saccharopolyspora hirsuta is a member of a small class of macrolide antibiotics known as the nargenicins. 18-Deoxynargenicin A$\sb1$ exhibits activity against drug-resistant strains of Staphylococcus, and pronounced activity against streptococci. This synthesis of enantiomerically pure 18-deoxynargenicin A$\sb1$ represents the first total synthesis of any member of the nargenicin macrolides.

The densely functionalized cis-fused decalin nucleus was generated in a rapid and efficient manner in nine steps from benzoquinone. Central to the success of this synthetic effort was the establishment of the 11-oxatricyclo (4.4.1.0) undecene ring system. This ring system, unique to the nargenicin macrolides, was introduced by a novel intramolecular epoxide opening.

The remote stereochemistry of the macrolide ring was introduced in a convergent manner. By addition of a chiral seven-carbon fragment to the (+/$-$) cis-decalin nucleus, the remote stereochemistry of the macrolide sidechain and the ether bridge of the nucleus were incorporated in one synthetic operation, to afford a separable mixture of diastereomers.

The three-carbon ester portion of the 18-deoxynargenicin A$\sb1$ macrolide system was introduced stereospecifically. The closure of the ten-membered lactone ring, while entropically disfavored, was successfully performed, using high-dilution conditions.

Ongoing studies in this area consist of investigation of methods for the stereocontrolled incorporation of the C$\sb{14}$-C$\sb{19}$ sidechain. Synthetic methodology developed in this synthesis of 18-deoxynargenicin A$\sb1$ will be applied to the synthesis of the remaining nargenicin congeners.

Part II describes two unique approaches for the synthesis of the pseudomonic acids. These naturally occurring compounds represent a small class of compounds produced by Pseudomonas fluorescens, which exhibit antimicrobial activity against gram-positive bacteria.

Synthetic strategies focused on the stereospecific generation of the C$\sb9$-C$\sb{14}$ sidechain via enolate Claisen rearrangement of an allylic glycolate. Utilization of this methodology would introduce the E-double bond and the remote stereochemistry of the sidechain in one synthetic operation. This strategy for the incorporation of the sidechain was not attempted by us, due to the inefficiency in the construction of the pyran nucleus.

The glycolate Claisen strategy was utilized by a group at Hoffmann-La Roche to generate the C$\sb9$-C$\sb{14}$ sidechain of pseudomonic acid C; a total synthesis of pseudomonic acid C was ultimately achieved.

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