Friday, May 30, 2014

A Facile One-Pot Cascade Sequence for the Enantioselective Construction of Synthetic Steroids

            Bor-Cherng Hong’s group has developed expedient organocatalytic approaches to highly substituted cyclopentanes  and, more recently, to complex 14b-steroid derivatives. The development of convenient methods for the rapid assembly of optically active steroids from readily available synthetic building blocks, suitable to compete with classical semisynthetic approaches, is a long sought goal of organic chemists, dating back to the pioneering studies of Deslongchamps, Corey and others. Quite recently, Karl Anker Jørgensen’s group at Aarhus University (Denmark) has made an important contribution in this area. Hong’s laboratory at National Chung Cheng University (Taiwan) has now disclosed a powerfully expedient strategy to access the steroidal nucleus (5, shown below) that exploits enantioselective organocatalysis in conjunction with ‘telescoping,’ one-pot process development techniques.
            To begin, a double Michael addition sequence between the nitroalkane 1 and enal 2, catalyzed by the Jørgensen-Hayashi catalyst 3, proceeds in a stereocontrolled fashion via the intermediacy of homochiral iminium (Int-I) and enamine (see TS-I) species, to ultimately furnish the tetrasubstituted cyclohexanes (3), obtained as a diastereomeric mixture at the nitro-bearing carbogenic position. Direct addition of para-toluenesulfonic acid (pTsOH) to the reaction mixture then promotes a Robinson-type dehydrative cyclization of 3, which efficiently generates the tricyclic enone 4. Chloroform is then removed from the reaction mixture in vacuo and tetrahydrofuran (THF) and 1,8-diazabicycloundec-7-ene (DBU) are sequentially added to the crude trans-decalin 4.  Curiously, upon exposure of 4 to DBU, only the b-nitro diastereomer engages in intramolecular Henry cyclization (as depicted in TS-II) to afford the synthetic steroid derivative 5. Fortunately, the subsequent addition of tetra-nbutylammonium fluoride (TBAF) to the reaction medium promotes isomerization of a-nitro epimer of 4 to the more reactive b-configuration, thereby facilitating the shuttling of additional 4 to the desired product 5 through the intermediacy of TS-II. Although this fascinating one-pot enantioselective sequence has only been demonstrated on milligram scale, the highly functionalized 14b-steroid 5 should be suitable for elaboration into a range of bioactive natural products including cardenolides, bufadienolides and pregnane glycosides.

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