Enantioselective synthesis of the tricyclic core of the GKK1032 fungal metabolites

Access restricted to the OSU CommunityAn enantioselective synthesis of the core of the GKK1032 fungal metabolites (1- 3) in the form of fused tricycle 155 is described. The synthetic route to 155 proceeded from (R,R)-pseudoephedrine propionamide (66) over 15 steps. The key step in this sequence was the 1,1,1,3,3,3-hexafluoroisopropanol induced cation-olefin cyclization of 1 ,7-diene 77 to form the highly substituted cyclohexanecarboxaldehyde 40. A three-step conversion of aldehyde 40 to intramolecular Diels-Alder (IMDA) substrate 144 was followed by a thermally induced IMDA cycloaddition of 144 to afford fused tricycle 155. [chemical diagrams] Attempts to form the macrocycle found in GKK1032 A₂ (1) by Dieckmann condensation between the ethyl ester and the lactone found in 155 were unsuccessful. However, the versatile design of this route will enable the use of aldehyde 40 (11 steps, 15% yield from 66) as a common intermediate for the synthesis and evaluation of multiple substrates for the required macrocyclization en route to the ultimate targets, GKK1032 A₂ (1) and GKK1032 B (3), with minimal alteration of the synthetic sequence. One macrocyclization proposal that will be discussed features an intramolecular Friedel Crafts alkylation between the 3-acyl pyrrole and the benzyl chloride contained within fused tricycle 157. [chemical diagrams