Total synthesis of Hsp90 inhibitor geldanamycin

Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates folding, transport, and degradation of client proteins. It also plays a key role in the conformational maturation of oncogenic signaling proteins. Hsp90 ATPase binding region's role in cancer and protein maintenance as well as its broad range of functions make it a significant therapeutic target for anticancer drug development. Natural product geldanamycin is the first reported Hsp90 inhibitor. It is currently under development as a therapeutic agent for cancers associated with abnormally elevated levels of receptor tyrosine kinase activity. A major focus of this project involved the development of an efficient method for the synthesis of the C11-C21 fragments of reblastatin and geldanamycin. Specifically, a reliable Sc(OTf)3 promoted reductive opening of stereochemically well defined aryl pyranosides was developed. This methodology, which effects a formal deoxygenation of the benzylic position, provides useful, enantioenriched building blocks for the syntheses of ansamycin natural products including geldanamycin. In completing the synthesis of this natural product target, we also demonstrated the utility of newly developed chiral (E)-crotylsilane reagents for the synthesis of the C5-C10 fragment of geldanamycin.The total synthesis of Hsp90 inhibitor geldanamycin was achieved in 20 linear steps with 2.0% overall yield from commercially available 2-methoxyhydroquinone. This synthesis was highlighted by a regio- and stereoselective hydroboration a Sc(OTf)3/Et3SiH-mediated pyran-ring opening an enantioselective crotylation to simultaneously install the ( E)-trisubstituted olefin and the C10 and C11 stereocenters a chelation controlled asymmetric acetylide additon and an intramolecular copper(I)-mediated aryl amidation to close the 19-membered macrolactam.A Rh(I) promoted cycloisomerization reaction of allenylsilanes was developed to access carbocyclic and heterocyclic cross-conjugated tirenes which possess a vinylsilane functionality.