Total Synthesis of Altemicidine

Abstract

Altemicidin (1), which was isolated from the Actinomycetestrain Streptomyces sioyaensis SA-1758 by Takeuchi et al. in 1989, exhibits anti-brine shrimp activity as well as acaricide and antitumor activity. The total synthesis of altemicidin was accomplished on the basis of original strategy involving, (1) an intramolecular Mizoroki-Heck reaction of bromopyridine 19 for the construction of the five-membered ring, and (2) the stereoselective partial reduction of methyl pyridinium salt 23 leading to the hexahydro-6-azaindene skeleton.

Bromopyridine 19 was synthesized from cyano pyridine 17 through an addition reaction with a,b-unsaturated aldehyde 6 followed by protection of the resulting alcohol with a TIPS group. The intramolecular Mizoroki-Heck reaction of 19 was performed by adopting the optimized conditions using Pd(OAc)₂ and P(2-furyl)₃as the catalyst in CH₃CN at 130 °C under irradiation of microwave, resulting in formation of cyclization product 20. While product 20 was found to be the wrong diastereomer, treatment of the corresponding ester 21 with TBAF effected inversion of the configuration of the hydroxyl group. Then the stereoselective partial reduction of the pyridine ring was achieved through reduction of methyl pyridinium salt 23 with NaBH₄, protection of the hydroxyl group with a TES group, and hydrogenation of tetrahydropyridine 27 catalyzed by Pd/C. Finally, the total synthesis of altemicidin was accomplished by elaboration of the functional groups (17 steps in total, 1.8% overall yield).