Formal Synthesis of (−)-Englerin A and Cytotoxicity Studies of Truncated Englerins

An efficient formal synthesis of (−)‐englerin A (1) is reported. The target molecule is a recently isolated guaiane sesquiterpene that possesses highly potent and selective activity against renal cancer cell‐lines. Our enantioselective strategy involved the construction of the BC ring system of compound 1 through a RhII‐catalyzed [4+3] cycloaddition reaction followed by subsequent attachment of the A ring through an intramolecular aldol condensation reaction. As such, this strategy allows the synthesis of truncated englerins. Evaluation of these analogues with the A498 renal cancer cell‐line suggested that the A ring of englerin is crucial to its antiproliferative activity. Moreover, evaluation of these analogues led to the identification of potent growth‐inhibitors of CEM cells with GI50 values in the range 1–3 μM. An enantioselective RhII‐catalyzed [4+3] cycloaddition reaction between disubstituted furan 9 and chiral diazoester 10 constitutes the key steps in the synthesis of englerin A (1) and in the synthesis of truncated englerins (such as compound 17).