The crambescidin family of natural products, characterized by a pentacyclic guanidinium core often tethered to a polar side chain, exhibit significant and unique cytotoxicity profiles.

The synthesis of crambescidins that vary in substitution at C14 is described. The key step of the synthetic route is Pd-catalyzed cleavage of a pentacyclic cinnamyl ester to generate core acid 1 as a key intermediate. Core acid 1 was directly esterified with various electrophiles to complete the first total synthesis of crambescidin 431 (2) and various crambescidin analogues. Cytotoxicities of these analogs have been obtained and a rudimentary SAR for the crambescidin side chain developed. Core acid 1 decomposes to form crambescidin 359 (3). Detailed examination of the decomposition of core acid 1 to generate 3 have lead to an improved understanding of the behavior of the pentacyclic core of the crambescidin alkaloids.