Sunday, April 27, 2014

A Practical Semisynthetic Approach to a Complex Disecopregnane Steroid with Antiviral and Antitussive Bioactivity

            The dried roots of Cynanchum stauntonii have been administered in accordance with the Chinese Pharmacopoeia to relieve cough and to promote the elimination of phlegm. The main chemical component of C. stauntonii roots that elicits the antitussive, airway smooth muscle relaxant effects was recently identified as an architecturally complex 13,14:14,15-disecopregnane steroidal glycoside. Cynatratoside B (structure shown above) was shown to exhibit potent inhibition of acetylcholine-induced tracheal contractions, which ultimately gives rise to the antitussive, expectorant and anti-inflammatory effects observed upon oral administration of C. stauntonii extracts. The disecosteroidal aglycone portion of cynatratoside B contains an internal nine-membered lactone fused to a western A/B monounsaturated decalin. In addition, the eastern cis-fused D/E bis-furan system is densely functionalized and poses a significant synthetic challenge. In 1983, Mitsuhashi and co-workers speculated that the biogenesis of this unique type of carbon skeleton might involve a Grob-type fragmentation, culminating in scission of the C13-C14 bond of a hirundigenin-type biosynthetic precursor (as depicted above). The laboratory of Weisheng Tian at the Shanghai Institute of Organic Chemistry was inspired by this biogenetic hypothesis to investigate the biomimetic ferrous-mediated homolytic b-fragmentation of a related hydroperoxide species, itself accessible through implementation of key Schenck ene reaction. These synthetic investigations have led to the first chemical synthesis of the complex disecopregnane steroid, glaucogenin D. An overview of their successful synthetic campaign is provided below.
            Tian’s group has pioneered the development of a robust Baeyer-Villiger-type oxidative degradation of plant-derived steroidal sapogenins (e.g. tigogenin) that generates the pregnane triol 1 and related derivatives on kilogram scale. Their Baeyer-Villiger protocol was previously applied to rockogenin acetate to produce a key western domain intermediate in the course of Tian’s tour de force chemical synthesis of cephalostatin 1. En route to glaucogenin D, the pregnane derivative 1 is next advanced to the monosilylated tetraol 2 by a seven-step sequence involving implementation of Meystre’s hypoiodite method to accomplish oxidative functionalization of the unactivated angular methyl group at C18. Oxidative cleavage of the D14,15 olefin of 2 then induces a complex oxidative skeletal rearrangement, resulting in formation of the polycyclic D-seco steroid 3. It should be noted that the ozonolysis of 2 proceeds with outstanding synthetic efficiency on 17-gram scale. Next, a variation of Meystre’s hypoiodite-mediated intramolecular free radical C-H functionalization reaction, using (diacetoxyiodo)benzene, is applied to intermediate 3. This synthetic approach efficiently accomplishes chemoselective oxidation of the C20 ether of 3 to forge the highly complex cage-like product 4, containing a unique consecutive ketal/acetal/ketal connectivity. Next, b-elimination of 4 under acidic conditions converts one of the ketal linkages into an enol ether (5) and the acetal at C15 of 5 is then selectively reduced by a three-step sequence, culminating in the hexacyclic  hirundigenin-type derivative 6.
            Cleavage of the C13-C14 bond of the advanced intermediate 6 is now required to form the nine-membered lactone ring of the target structure. A Schenck ene reaction/ferrous-mediated homolytic b-fragmentation strategy was projected to achieve this synthetic goal. In the event, the Schenck ene reaction of 6 efficiently produces the a-alkoxy hydroperoxide 7 with excellent regio- and stereoselectivity. Subsequent exposure of 7 to Fe(II) in the presence of the stabilized radical trap reagent, TEMPO, induces a sequence involving homolytic cleavage of the peroxide followed by alkoxy radical b-fragmentation to produce a tertiary carbon-centered radical which is finally trapped by TEMPO to afford the desired lactone 8 in 70% yield. The fragmented product 8 contains a C13-TEMPO substituent on the alpa face of the D/E bis-furan domain that is processed through the entirety of the endgame sequence. Stereoselective keto-hydroxylation of the olefin of 8 is achieved in two steps to secure the oxygenated trans-decalin 9. Next, a Grieco selenoxide syn-elimination sequence introduces the requisite unit of unsaturation across C5-C6. The resultant enone 11 is then dehydroxylated with samarium iodide to produce the conjugated enol 12 and subsequent Luche reduction of 12 primarily furnishes the C7b-allylic alcohol. Finally, thermal elimination of the TEMPO substituent selectively generates the D/E-exocyclic C12-C13 olefin, which is isomerized upon exposure to a ruthenium catalyst to the requisite endocyclic bis-furan enol ether system of glaucogenin D. The first chemical synthesis of glaucogenin D was completed in 25 steps from the readily available plant-derived sapogenin, tigogenin. The route is highly practical in terms of its conciseness, given the complexity involved, and features several fascinating biomimetic oxidative rearrangements and/or fragmentations of the steroidal carbon skeleton.

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