Concise Enantioselective Total Synthesis of Cardiotonic Steroids 19-Hydroxysarmentogenin and Trewianin Aglycone

The
expedient and scalable approach to cardiotonic steroids carrying
oxygenation at the C11- and C19-positions has been developed and applied
to the total asymmetric synthesis of steroids 19-hydroxysarmentogenin
and trewianin aglycone as well as to the assembly of the panogenin
core. This new approach features enantioselective organocatalytic
oxidation of an aldehyde, diastereoselective Cu­(OTf)2-catalyzed
Michael reaction/tandem aldol cyclizations, and one-pot reduction/transposition
reactions allowing a rapid (7 linear steps) assembly of a functionalized
cardenolide skeleton. The ability to quickly set this steroidal core
with preinstalled functional handles and diversity elements eliminates
the need for difficult downstream functionalizations and substantially
improves the accessibility to the entire class of cardenolides and
their derivatives for biological evaluation.