A solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of (-)-saframycin A.
A 10-step solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogues of saframycin A is described. The synthetic route, which bears analogy to solid-phase peptide synthesis, involves the directed condensation of N-protected alpha-amino aldehyde reactants. A novel dual linker was developed for attachment of intermediates to the solid support via a C-protective group, a substituted morpholino nitrile derivative. The route employs a novel diastereospecific cyclorelease mechanism, supports structural variation at multiple sites in the saframycin core, and obviates the need for chromatographic purification of the products or any intermediate. To demonstrate the feasibility of structural variation at multiple sites, a matrix of 16 saframycin A analogues was prepared by parallel synthesis with simultaneous variation of two sites. This work is notable not only as a preliminary step toward large-scale library construction but also as an example of the use of sequential stereoselective C-C bond-forming reactions on the solid phase for the preparation of natural product analogues.
Myers
Andrew G
AG
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. myers@chemistry.harvard.edu
Lanman
Brian A
BA
D000470:Alkaloids / Q000138:chemical synthesis*; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D002625:Chemistry, Organic / Q000379:methods; D007546:Isoquinolines / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D007546:Isoquinolines; C026925:saframycin A