Catalyst-Directed Diastereoselective Isomerization of Allylic Alcohols for the Stereoselective Construction of C(20) in Steroid Side Chains: Scope and Topological Diversification

The stereoselective construction
of C20 in steroidal derivatives
by a highly diastereoselective Ir-catalyzed isomerization of primary
allylic alcohols is reported. A key aspect of this strategy is a straightforward
access to geometrically pure steroidal enol tosylate and enol triflate
intermediates for subsequent high yielding stereoretentive Negishi
cross-coupling reactions to allow structural diversity to be introduced.
A range of allylic alcohols participates in the diastereoselective
isomerization under the optimized reaction conditions. Electron-rich
and electron-poor aryl or heteroaryl substituents are particularly
well-tolerated, and the stereospecific nature of the reaction provides
indifferently access to the natural C20-(R) and unnatural
C20-(S) configurations. Alkyl containing substrates
are more challenging as they affect regioselectivity of iridium-hydride
insertion. A rationale for the high diastereoselectivities observed
is proposed for aryl containing precursors. The scope of our method
is further highlighted through topological diversification in the
side chain and within the polycyclic domain of advanced and complex
steroidal architectures. These findings have the potential to greatly
simplify access to epimeric structural analogues of important steroid
scaffolds for applications in biological, pharmaceutical, and medical
sciences.