Importance of a 4-Alkyl Substituent for Activity in the Englerin Series

The ring closing metathesis/transannular etherification approach to the englerin nucleus was adapted to provide two key intermediates for analogue synthesis: the 4-desmethyl ?(5,6) tricycle and the 4-oxo ?(5,6) tricycle. The former was elaborated to 4-desmethyl englerin A and the latter served as a common precursor for englerin A, 4-ethyl englerin A, and 4-isopropyl englerin A. 4-Desmethyl englerin A was less active than the natural product by an order of magnitude, but the 4-ethyl and 4-isopropyl analogues were comparable in activity to englerin A. These results are consistent with the premise that the 4-alkyl group enforces the binding conformation of the cinnamoyl ester substituent. Furthermore, they suggest that 4-alkyl englerin structures may prove to be useful tool compounds.

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