Saturday, August 9, 2014

Asymmetric Synthesis of the Torgov Diene: Application to Total Synthesis of Estrone

Igor Torgov (1912 - 2007)
            Igor Vladimirovich Torgov was a Soviet chemist who served as the head of steroid chemistry at the Institute of Natural Compounds Chemistry of the Soviet Academy of Sciences (currently the Shemyakin Institute of Bioorganic Chemistry). Dr. Torgov’s famous reaction is a carbocyclization of an achiral diketone (discussed in detail below) that provided an early pathway for the total chemical synthesis of steroid hormones, and is still used for the industrial-scale production of certain steroids at the factories of Schering AG in Berlin, Germany. The product of the Torgov cyclization, the Torgov diene, is a steroidal D8,14 dienone which serves as a synthetic precursor to a range of estrol and estradiol derivatives including estrone. Torgov’s synthetic methodology provides expedient access to racemic steroids. However, since its original disclosure in 1963, the development of an enantioselective variant of the Torgov cyclization has remained elusive. Torgov and co-workers were eventually able access enantiopure steroid intermediates by resorting to an enantioselective reduction of a key intermediate, mediated by S. cerevisiae yeast culture. But the use of fermenting yeast reduction suffers from drawbacks that include large reaction volumes and difficulties encountered during extraction of water-soluble products. Additionally, in the late 1990s, workers at Schering reported studies toward the development of a catalytic asymmetric version of the Torgov cyclization, but high selectivity and turnover numbers were not achieved. Consequently, enantioselectivity in the Torgov process for steroid production has been considered a classic unsolved problem for organic chemists.
            Very recently, Benjamin List’s laboratory at the Max Planck Institute disclosed a report describing a catalytic asymmetric version of the Torgov cyclization (see above, conversion of 1 à ‘Torgov’s diene’). Mechanistically, the Torgov cyclization involves (1) isomerization of intermediate 1 to the endocyclic D8,9 isomer A (2) Prins-type cation-olefin cyclization (3) deprotonation of the ensuing carbocation to give the alcohols B and, finally, (4) isomerization and dehydration of B, which furnishes the intact Torgov diene. List and co-workers recognized that the chirogenic, stereo-determining step is likely the cyclization of intermediate A and that this transformation might be catalyzed by an enantiopure Brønsted acid. Upon screening of a range of acids, a novel chiral disulfonimide (DSI) (shown above, see box) emerged that was uniquely able to deliver the requisite diene at low temperature and with high enantioselectivity. A gram-scale Torgov cyclization of intermediate 1, catalyzed by the unique pentafluorothio- and nitro-containing DSI, proceeded in high yield to furnish Torgov’s diene with an enantiomeric ratio of 96.5:3.5. A single recrystallization provided essentially optically pure material (>99.9:0.1 e.r.). Moreover, the precious DSI could be recovered from the reaction in 88% yield. List’s group then repeated a two-step procedure that was previously developed by E. J. Corey’s laboratory to diastereoselectively reduce Torgov’s diene to estrone methyl ether (3). Methyl ether deprotection yielded fully synthetic (+)-estrone, thus completing the shortest route to the bioactive steroid reported to date.
            List’s achievement in the enantioselective chemical synthesis of estrone is rivaled in its conciseness only by the work of E. J. Corey’s group, which has previously disclosed no less than three (!!!) distinct enantioselective processes. The first, reported in 2004 (chemistry not shown), uses a catalytic enantioselective Diels-Alder reaction as the key step. The second, outlined in the scheme above, proceeds through the intermediacy of Torgov’s diene. In this work, the achiral diketone 1 is first reduced enantioselectively using oxazaborolidine catalysis in combination with the reductant catecholborane. A single recrystallization of the product from ethyl acetate-hexane affords highly enantioenriched 4 (99% ee). Torgov cyclization of mono-ketone 4 then proceeds efficiently in methanolic hydrochloric acid and the ensuing optically active dienol 5 is oxidized to Torgov’s diene by the IBX reagent. Finally, the same two-step reductive sequence from above, borrowed by List and co-workers, efficiently converts Torgov’s diene into estrone methyl ether. An alternate enantioselective total synthesis of Torgov’s diene, reported by Corey’s group in 2008, is discussed here. We should note that, these days, (+)-estrone is commercially available from Sigma-Aldrich for about $1.75/gram.

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