Progress toward the synthesis of a Xenia diterpenoid common intermediate and the preparation of inotilone derivatives

Abstract

Xenia diterpenoid natural products (or xenicanes), isolated from the crude organic extracts of coelentrates, have been shown to possess cytotoxic, antiangiogentic, antimicrobial and anti-inflammatory effects against a number of animal cell lines. Structurally, these molecules feature a nine-membered ring containing an endocyclic (E)-olefin between C-6 and C-7 and trans substituents at C-2 and C-3. Snowden proposed the synthesis of a common xenicane intermediate employing tandem Reformatskii/Grob chemistry. Such a route can allow for a divergent synthesis of a library of Xenia diterpenoids. The synthetic strategy mandates beginning from the 1,3-ketol trans-3-hydroxy-2-vinyl-2-methylcyclopentan-1-one, a common motif found in the synthesis of medium-sized carbocycles and natural products. An array of cyclic-2,2-disubstituted-1,3-alkanediones were reduced to the corresponding 1,3-ketols using NaBH₄/DME or LTBA/THF to study reaction progress and diastereomeric outcomes. These analyses show that both reducing systems favor formation of the cis-ketol; the degree of diastereoselectivity was largely found to be a function of steric bulk in the 2-position. Additionally, both reducing systems minimize over-reduction to the corresponding diol, though this effect is more pronounced with LTBA/THF. In the investigation of conjugate reduction conditions for the synthesis of Snowden's common intermediate, Stryker's reagent was found to effect reductive aldol cyclization of our enoate dione starting materials to the corresponding ⍶-hydroxy ester. Experimentation with catalytic quantities of Stryker's reagent using hydrosilanes as the stoichiometric reductant on enoate ketone substrates offered excellent conversions at room temperature with little control of diastereoselectivity. Attempts to expand the bicyclic products via Wharton-type Grob fragmentation resulted in diastereomeric racemization and/or saponification of the ester moiety. Suppression of the COX-2 isoenzyme has been found to lessen the risk of colorectal cancer onset in epidemiological studies. The natural product inotilone, isolated by Hertweck in 2006 and first synthesized by Snowden in 2007, acts as a potent COX-2 inhibitor. An array of structurally related analogs was prepared by the Mukaiyama aldol reaction of 5-methyl-3-trimethylsiloxyfuran and commercially available benzaldehyes in 14-71% yield. These derivatives will be screened against a number of cancer cell lines to assess biological activity relative to the parent inotilone compound.