Igor Torgov (1912 - 2007)
Saturday, August 9, 2014
Asymmetric Synthesis of the Torgov Diene: Application to Total Synthesis of Estrone
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.