Chapter 2 Synthesis of geldanamycin using glycolate aldol reactions

Publisher Summary This chapter describes the process of successful total synthesis of heat shock protein 90 (Hsp90) inhibitor, geldanamycin. Geldanamycin was first isolated as a crystalline antimicrobial compound from culture filtrates of the soil bacterium, Strep. Hygroscopicus. Two new aldol reactions, as general solutions to anti and syn 1, 2 diol formations, were developed for this route. More efficient, convergent approaches, as alternatives to the linear route, have been designed and attempted without success. Important information concerning the installation of the para -quinone has been obtained. UV analysis has been used to correlate ortho and para quinones, both in model systems and with the final ansamycin lactam products. The initial lack of attention can be attributed to its ambiguous stereochemistry, more challenging oxygenation pattern, and the unique presence of the additional methoxyl group on the quinone at C17. The impetus to surmount these challenges has been the more recent revelation of its ability to bind and inactivate the oncogenic kinase chaperone, Hsp90. This finding opens up huge opportunities for geldanamycin and its analogs as a new class of well-selective, therapeutic agents.