Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin: asymmetric glycolate aldol reactions and biological evaluation |
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Authors: | Andrus Merritt B Meredith Erik L Hicken Erik J Simmons Bryon L Glancey Russell R Ma Wei |
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Affiliation: | Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, Utah 84602-5700, USA. mbandrus@chem.byu.edu |
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Abstract: | The total synthesis of (+)-geldanamycin (GA), following a linear route, has been completed using a demethylative quinone-forming reaction as the last step. Key steps include the use of two new asymmetric boron glycolate aldol reactions. To set the anti-C11,12 hydroxymethoxy functionality, (S,S)-5,6-bis-4-methoxyphenyldioxanone 8 was used. Methylglycolate derived from norephedrine 5 set the C6,7 methoxyurethane stereochemistry. The quinone formation step using nitric acid gave the non-natural o-quino-GA product 55 10:1 over geldanamycin. Other known oxidants gave an unusual azaquinone product 49. o-Quino-GA 55 binds Hsp90 with good affinity but is less cytotoxic compared to GA. |
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