Friday, July 13, 2012

Synthesis of B-Ring-Modified Steroids

It is difficult to envision a practical way to migrate the steroidal C19 angular methyl group from its position at the A/B ring junction onto C6 of the B-ring (with retention of configuration). Recently, a fascinating synthetic sequence was reported in Organic Letters that manages to accomplish just that (exact overall transformation shown above). The authors plan to use their chemistry to synthesize members of the cyclocitrinol natural product family. The methodology also provides stereocontrolled access to novel and therapeutically relevant B-ring (C6)-modified pregenolone derivatives.
The C19 angular methyl group is first functionalized by converting pregnenolone acetate (1) to its corresponding bromohydrin derivative. This provides the substrate for subsequent implementation of Meystre's hypoiodite C-H functionalization reaction (discussed here). Reduction of the lactol acetate product with concomitant elimination then gave 19-hydroxy pregnenolone acetate. This intermediate was converted into a cyclopropane derivative via the intermediacy of its corresponding mesylate. The cyclopropanated steroid was then exposed to Lewis acidic conditions (boron trifluoride diethyl etherate) which promoted rearrangement to a cyclopropyl-methyl cation species (shown above in brackets). Finally, regioselective nucleophilic ring-opening by formic acid efficiently generates the B-ring-modified steroid 2. Molecular entities derived from 2 are novel and potentially interesting from a pharmaceutical development persective. Moreover, they are not easily obtained by other known synthetic methods.

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