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A second-generation strategy for construction of (+)-nodulisporic acids A and B based on the development of a new, effective modular indole synthesis exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic is disclosed. This strategy evolved due to the considerable acid instability of the C(24) hydroxyl group observed in several advanced intermediates during our first-generation approach.

A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-nodulisporic acid D were achieved.

[structure: see text] Construction of the heptacyclic core of (-)-nodulisporic acid D, a representative member of a recently discovered class of architecturally complex, ectoparasiticidal indole alkaloids, has been achieved. The modular synthetic strategy comprises an expedient, stereocontrolled synthesis of a tricyclic western hemisphere, in conjunction with union of an eastern hemisphere, exploiting the 2-substituted indole synthetic protocol introduced and developed in our laboratory.

[structure: see text] A stereocontrolled total synthesis of (+)-nodulisporic acid F, the simplest member of a family of novel ectoparasiticidal agents, has been achieved. Highlights of the effective modular synthetic strategy include anionic union of a tricyclic lactone with o-toluidine via our 2-substituted indole synthetic protocol, an optimized C-ring construction protocol, and a late-stage installation of the alpha,beta-unsaturated carboxylic acid side chain via the B-alkyl Suzuki-Miyaura cross-coupling tactic.