Synthesis of 2-hexyl-5-ethylfuran-3-sulfonic acid (HEFS) – natural antithrombosis agent from Eisenia earthworms

[Figure not available: see fulltext.] A total synthesis of 2-hexyl-5-ethylfuran-3-sulfonic acid (HEFS) is reported. HEFS is an important natural product isolated as a major metabolite from Eisenia earthworms. It acts as an anticoagulant, blood platelet aggregation inhibitor, antiulcer agent, and vasoconstriction inhibitor in vertebrates. Several possible synthetic routes to HEFS were tested, and a simple four-step approach was proposed. The discovered route begins with Grignard ethynylation of 1-heptanal, followed by Weinreb amide alkynylation. Bromocyclization of the resultant ketopropargylic alcohol affords key intermediate 3-bromo-5-ethyl-2-hexylfuran. Finally, one-pot metal–halogen exchange and sulfonylation furnish synthetic HEFS.