Work

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

Year: 2026

Type: article

Abstract: 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 .

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.6c00124

Authors: Colin Tichvon, Nasma Ibrahim, Kevin Kong, Pavel Nagorny

Institution: University of Michigan

Language: English

Topic: Organic Chemistry Synthesis Methods

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences

Awards: G81577471, G9000145372