Sunday, March 23, 2014
In a previous post, we highlighted some distinctive steroidal natural products that were isolated from marine sponges. Terpios hoshinota is a noteworthy example of an encrusting sponge that overgrows hard corals on a relatively large scale in the seas surrounding Okinawa, Japan. Terpios outbreaks are commonly referred to as the ‘black disease’ of corals. Indeed, the dispersal of this so-called coral-killing sponge raises concerns for coral survival in the Indo-West Pacific region. In 2003, in a search for the hypothetical toxic compound secreted by the invasive sponge, Uemura and co-workers isolated 400 micrograms of the polyhalogenated C-nor-D-homosteroid nakiterpiosin from 30 kilograms of T. hoshinota. Nakiterpiosin inhibits the growth of P388 mouse leukemia cells with an IC50 of 10 ng/mL and was recently identified as an antimitotic agent that targets microtubules. This novel chemotherapeutic lead compound interacts directly with tubulin, inhibits microtubule polymerization, enhances tubulin acetylation and reduces the viability of paclitaxel-resistant cancer cells. In 2009, Chuo Chen’s research group at The University of Texas, Southwestern Medical Center, completed a practical and highly convergent total synthesis and structural revision of nakiterpiosin. Chen’s synthetic campaign is discussed below.
C-nor-D-homosteroids are skeletally rearranged 6,6,5,6 fused tetracyclic structures in which the C-ring is contracted and the D-ring is expanded by one carbon atom, relative to the natural steroidal connectivity. Biomimetic approaches that provide synthetic access to this unique carbon framework were pioneered by chemists at Merck in the early 1950’s. The biomimetic skeletal reorganization involves C13 à C12 bond migration accompanied by a concerted deprotonation of H17. This general strategy has been subsequently developed and refined by a number of research groups, culminating in its application in an efficient synthesis of cyclopamine by Giannis and co-workers in 2009. One early example of a designed rearrangement of a steroid into a C-nor-D-homosteroid skeleton was reported by R. Hirschmann and co-workers at Merck Research Laboratories (sequence shown below). The Merck group subjected the C12 para-toluenesulfonylhydrazone derivative of the abundant plant sterol hecogenin to a Bamford-Stevens rearrangement. The strongly basic thermolytic reaction conditions promoted the aforementioned bond migration (C13 à C12) with extrusion of nitrogen to deliver in high yield the endocyclic olefinic product as a single stereoisomer. A related cationic ring contraction/expansion was developed by the laboratory of Giannis in the course of their synthesis of cyclopamine. The Giannis protocol proceeds via the intermediacy of a C12-O-triflate and affords a mixture of exo- and endocyclic double bond regioisomers.
Chen’s convergent synthetic strategy to access nakiterpiosin, which does not require a commercially available steroidal raw material, involves retrosynthetic bond disconnection of the internal cyclopentanone C-ring, leading to the advanced western (highlighted below in blue) and eastern (red) substructural fragments, 1 and 2, respectively. A carbonylative Stille coupling and a photo-Nazarov cyclization reaction were projected to cross-couple the two advanced intermediates and then forge the five-membered C-ring. Global deprotection of the silyl groups would then complete the total synthesis of this rare C-nor-D-homosteroid.
The synthesis of the tricyclic enol triflate building block 1 relied upon a critical intramolecular Diels-Alder (IMDA) reaction. To begin, a Noyori reduction under transfer hydrogenation conditions was utilized to establish the C6 stereochemistry of intermediate 3. Next, addition of a vinyl Grignard reagent to the Weinreb amide 3 secured a dienophilic enone which, upon exposure to Lewis acidic conditions at low temperature, underwent stereoselective intramolecular [4+2] cycloaddition to provide the exo product 4 exclusively. Dihydroxylation of 4 under Upjohn conditions precluded decomposition via a retro-Diels-Alder pathway and bromide was then introduced by SN2 displacement of an electron-deficient aryl sulfonate. The latter transformation occurred with concomitant installation of the acetonide group resident in intermediate 5. Oxidative cleavage of the diol then gave rise to the bis-hemiacetal 6, which underwent regioselective ionic reduction of the less hindered hemiacetal functionality. Silyl etherification of the intact hemiacetal preceded conversion of the ketone into its corresponding enol triflate, thus completing the synthesis of the western substructural fragment 1. The stannane component 2 was synthesized in 16 steps from a benzoic acid derivative by a sequence that featured a stereocontrolled Mukaiyama aldol reaction.
The endgame of the Chen group’s synthetic campaign involved merger of the advanced intermediates 1 and 2 under carbonylative Stille coupling conditions to afford the aryl vinyl ketone 7. The photo-Nazarov cyclization of 7, involving disruption of aromaticity, surprisingly, proceeded efficiently in the absence of a Lewis acid catalyst to deliver the annulation product 8 as a mixture of C9 epimers (epimeric position indicated by an asterisk). Fortunately, diastereomeric 8 converged to a single stereoisomer upon treatment with diisopropylamine in methanol and global deprotection of the penultimate precursor with a fluoride source furnished fully synthetic nakiterpiosin.