Studies directed toward the synthesis of the tremorgenic indole alkaloid penitrem D
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.
Hartz, Richard Allen, "Studies directed toward the synthesis of the tremorgenic indole alkaloid penitrem D" (1996). Dissertations available from ProQuest. AAI9627933.