Total Synthesis and Biological Evaluation of a C(10)/C(12)-Phenylene-Bridged Analog of Epothilone D
Nicole End
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Current address: Dr. Nicole End, Ciba Specialty Chemicals Inc., Group Research, K-420.2.18, CH-4002 Basel.
Search for more papers by this authorPascal Furet
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Search for more papers by this authorNathalie van Campenhout
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Search for more papers by this authorMarkus Wartmann
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Search for more papers by this authorKarl-Heinz Altmann
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH-Hönggerberg, HCI H405, CH-8093 Zürich (tel.: +41 44 633 73 90; fax: +41 44 633 13 60)
Search for more papers by this authorNicole End
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Current address: Dr. Nicole End, Ciba Specialty Chemicals Inc., Group Research, K-420.2.18, CH-4002 Basel.
Search for more papers by this authorPascal Furet
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Search for more papers by this authorNathalie van Campenhout
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Search for more papers by this authorMarkus Wartmann
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel
Search for more papers by this authorKarl-Heinz Altmann
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH-Hönggerberg, HCI H405, CH-8093 Zürich (tel.: +41 44 633 73 90; fax: +41 44 633 13 60)
Search for more papers by this authorAbstract
The total synthesis of compound 8, a conformationally constrained analog of epothilone D (2), has been achieved through a convergent strategy based on three key fragments comprising C(1)C(6) (26), C(7)C(12) (16), and C(13)O(16) (19) of the macrocyclic framework. Construction of the C(12)C(13) bond involved Pd0-mediated B-alkyl Suzuki coupling between aryl bromide 16 and olefin 19, and proceeded in excellent yield, while formation of the C(6)C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low-yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.
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