Approaches directed toward the total synthesis of Bruceantin

Michael Hobart Nantz, Purdue University

Abstract

This thesis describes approaches toward the synthesis of Bruceantin, a quassinoidal antileukemia agent. The original approach required addition of a C$\sb8$ (Z)-dienyl nucleophile (B,C-ring precursor) to a coumalate ester (D ring). The subsequent (Z)-diene intramolecular Diels-Alder reaction for the adduct was designed as the key step utilizing a chiral pentadienylic methyl substituent to impart diastereofacial selectivity. An efficient synthesis of the C$\sb8$-diene was developed utilizing an acetylide-epoxide coupling strategy with subsequent triple bond reduction to either the (Z) or (E) diene. Studies were conducted on the addition of representative carbon nucleophiles to methyl coumalate. A strong tendency for regiospecific 1,6-conjugate addition was observed in the addition reactions. Coupling of the C$\sb8$-diene to methyl coumalate by means of a ketone enolate or silyl enol ether was unsuccessful due to base lability of the diene fragment. A revised approach entailed use of a 3-carboxycyclopentenone as a dienophile for the same dienyl fragment tethered to the 3-carboxy moiety. In the execution of this approach, methods for carboxycyclopentene synthesis were developed. Condensation of sulfone-activated methylene compounds with cis-1,4-dichloro-2-butene yielded cyclopentenes readily transformed to 3-carboxycyclopentenones. Thermolysis of the pentenone-diene substrate failed to initiate intramolecular cycloaddition. Activation of the cycloaddition reaction was sought through in situ cyclopentadienone generation. A method was developed for smooth generation of 3-carboxycyclopentadienone which was shown to undergo cycloaddition with various dienes intermolecularly at temperatures $\sim$100$\sp\circ$C lower than the corresponding cyclopentenone. However, the requisite pentadienone-diene substrate failed to undergo intramolecular cycloaddition. Competitive decomposition and dimerization at elevated temperatures prevailed.

Degree

Ph.D.

Advisors

Fuchs, Purdue University.

Subject Area

Organic chemistry

COinS