Studies directed toward the synthesis of the tremorgenic indole alkaloid penitrem D

Richard Allen Hartz, University of Pennsylvania

Abstract

Chapter One of this dissertation focuses on the tremorgenic indole alkaloid family of natural products. Numerous indole alkaloids with a structure similar to penitrem D have been isolated. These compounds share common biological activities as well as common biosynthetic origins. Chapter One concludes with a presentation of research previously performed in the Smith Group germane to the penitrem D synthetic venture. Retrosynthetically penitrem D can be dissected into three key intermediates. An indole coupling procedure, developed in the Smith Group, was used to join ($-$)-67 and ($-$)-97. Epoxide ($-$)-65 was attached at a later point via the Stork metalloenamine protocol. Chapter Two describes a second and third generation synthesis of lactone (+)-68 in enantiomerically enriched form. Introduction of the vicinal quaternary methyl groups in an efficient, stereocontrolled fashion presented a major challenge for the assembly of (+)-68. In the second generation synthesis a chiral lithium amide was used to deprotonate ketone 104; the enantioselectively was 80%. Treatment of ($-$)-100 with KO-t-Bu resulted in the formation of the extended enolate which was then alkylated with Mel at the $\alpha$-position to install the second quaternary methyl group. This 19 step synthesis of lactone (+)-68 proceeded in 0.5% overall yield on a preparative scale. A third generation synthesis of lactone (+)-68 was subsequently developed to address the problem of low overall yield in the second generation approach. This route began with enantiomerically pure Wieland-Miescher ketone. Unlike our first two routes to (+)68, which employed enolate chemistry to install the second quaternary center, this route utilized a directed Simmons-Smith cyclopropanation followed by a dissolving metal reduction to effect this transformation. This 15 step synthesis of lactone (+)-68 proceeded in 8.3% overall yield. The asymmetric synthesis of aniline ($-$)-67 is presented in Chapter Three. A chiral lithium amide was used to deprotonate ketone 104 enantioselectively in 80% ee as in the second generation synthesis of (+)-68. The highlights of the remainder of the synthesis include a (2+2) -photocycloadditon, Robinson annulation, and Semmler-Wolff reaction resulting in a 4.2% overall yield for this 18 step route. The coupling of aniline ($-$)-67 with lactone ($-$)-97 is also described.$\sp*$ ftn$\sp*$Please refer to the dissertation for diagrams.

Subject Area

Organic chemistry

Recommended Citation

Hartz, Richard Allen, "Studies directed toward the synthesis of the tremorgenic indole alkaloid penitrem D" (1996). Dissertations available from ProQuest. AAI9627933.
https://repository.upenn.edu/dissertations/AAI9627933

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