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Asymmetric aldol reactions using catalytic d(+)-proline: a new, economic and practical approach to a commonly employed C1-C6 keto-acid synthon of the epothilones |
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| Authors: | Yansong Zheng |
| Institution: | a Department of Medicinal Chemistry, University of Mississippi, University, MS 38677, USA b National Center for Natural Products Research, School of Pharmacy, University, MS 38677, USA c Department of Chemistry & Biochemistry, University of Mississippi, University, MS 38677, USA |
| Abstract: | A new approach to ketoacid 4, a common C1-C6 fragment used in the total synthesis of epothilones was initiated by direct aldol reaction of acetone with a pivaldehyde-like substance 5, catalyzed with d-proline, leading to a 2,6-diketoalcohol with better than 99% ee. Further intramolecular closure of the diketone 8 followed by oxidation of the silyl protected hydroxycyclohexenone 14 led to the desired product 4. None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available d-proline to construct the chiral center of 4 under very mild reaction conditions provided an economical and practical method for its construction. |
| Keywords: | Epothilone C1-C6 Keto-acid synthon Asymmetric aldol reaction Proline |
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