Synthesis of Bufadienolide Natural Products and Analogs via Singlet Oxygen Oxidation and Late-Stage Modification

In this work, we describe the synthesis of three new bufadienolide natural products cinobufotalin, bufotalin, and 5β-hydroxybufotalin and four new analogs of resibufogenin, bufalin, telocinobufagin, and marinobufogenin. This was achieved by developing a unified pathway that features installation of the characteristic α-pyrone ring onto steroid scaffolds with or without C5 oxygenation, and introduction of D-ring oxidation through a photochemical singlet oxygen [4 + 2] cycloaddition/endoperoxide rearrangement to furnish 14β,16β-bis-epoxides. Following a regioselective scandium(III) trifluoromethanesulfonate-catalyzed House-Meinwald rearrangement previously used to synthesize cinobufagin, these intermediates were elaborated to, cinobufotalin (13 steps LLS, 8.0% yield), bufotalin (12 steps LLS, 5.9% yield), and 5β-hydroxybufotalin (14 steps, 1.3% yield). This strategy was further extended to access new analogs of resibufogenin (26), bufalin (25), telocinobufagin (30), and marinobufogenin (29). Altogether, these studies describe the development of a general platform for accessing natural and unnatural bufadienolides from readily available androstenedione 5.