Sunday, July 1, 2012

Corey's Total Synthesis of (+/-)-Retigeranic Acid A (1985)

In the previous post, we discussed a very recent synthesis of the trans-hydrindanone 4, a synthetic building block that intersects with Corey's route to retigeranic acid A, published in 1985. In this post, we will examine Corey's now classic work directed at this unique and complex pentacyclic sesterterpenoid, first isolated in 1965 from a Himalayan lichen. The conversion of the cyclohexenone 1 into the bicyclic enone 3 was first described by the laboratory of Barry Snider (then at Princeton) in 1980. In this powerful transformation, the Lewis acid acts as an initiator of a cation-olefin cyclization that proceeds via the intermediacy of the zwitterionic species 2. Two 1,2-hydride migrations then give rise to the bicyclic enone 3 in a process reminiscent of the biosynthesis of steroids and terpenes. Seven subsequent operations were then required to secure the diene component (5) of a critical Diels-Alder cycloaddition step. In the event, exposure of 5 to a dienophile with heating (98 - 105 degrees C) furnished a diastereomeric mixture of products from which the desired tricarbocyclic intermediate 6 was isolated in good yield (61%) after preparative HPLC purification.
Intermediate 6 was then advanced in a relatively straightforward way (5 steps) to the ketene 7 and this species smoothly underwent intramolecular [2+2] cycloaddition with the pendant exocyclic alkene to give the cyclobutanone 8 in excellent yield. Notably, this  reaction installs, with complete stereocontrol, the challenging all-carbon quaternary center of the eventual triquinane system. Construction of the triquinane substructure (from 8) now requires a ring expansion of the cyclobutanone and a ring contraction of the cyclohexene. The former is accomplished by addition of a lithio derivative to the western carbonyl followed by cuprous triflate-mediated thio-pinacol rearrangement and desulfurization, resulting in the advanced pentacycle 11.
In the endgame of the synthesis, dihydroxylation of 12 (obtained from 11) and oxidative glycol cleavage of the intermediate diol affords a seco keto aldehyde (13) that, under remarkably mild conditions, undergoes intramolecular aldol cyclization to forge the triquinane carbon skeleton. Finally, Pinnick oxidation (sodium chlorite) of retigeranic aldehyde furnishes the sesterpenoid target molecule in racemic form. It is interesting to note that no additional synthetic advancements targeting any pentacyclic sesterpenoid have been described in the literature since Wender's synthesis of retigeranic acid, published 22 years ago (in 1990). Additionally, retigeranic acid A is the only member in its natural product class that has been synthesized in a laboratory.

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