Total synthesis of the Hsp90 inhibitor geldanamycin.
An enantioselective synthesis of the Hsp90 inhibitor geldanamycin was achieved in 20 linear steps and 2.0% overall yield from 2-methoxyhydroquinone. The synthesis is highlighted by a regio- and stereoselective hydroboration reaction; a Sc(OTf)(3)/Et(3)SiH-mediated pyran ring-opening reaction; an enantioselective crotylation to simultaneously install the C8-C9 (E) -trisubstituted olefin, the C10 and C11 stereocenters; a chelation-controlled asymmetric metallated acetylide addition; and an intramolecular copper(I)-mediated aryl amidation reaction to close the 19-membered macrolactam.
Qin
Hua-Li
HL
Department of Chemistry and Center for Chemical Methodology and Library Development, Metcalf Center for Science and Engineering, Boston University, Boston, MA 02215, USA.
Panek
James S
JS
D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006873:Hydroquinones / Q000737:chemistry*; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D013237:Stereoisomerism
C438644:2-methoxy-1,4-hydroquinone; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; D003300:Copper; C001277:geldanamycin