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Synlett 2004(15): 2709-2712  
DOI: 10.1055/s-2004-835665
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 4-Aza Analogs of Epothilone D

Frédéric Cachoux, Franck Schaal, Antje Teichert, Trixie Wagner, Karl-Heinz Altmann*
Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland
Fax: +41(44)6331360; e-Mail: karl-heinz.altmann@pharma.ethz.ch;
Further Information

Publication History

Received 17 August 2004
Publication Date:
12 November 2004 (online)

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Abstract

An efficient synthesis of epothilone D analogs of type 1 has been developed, which is based on a highly diastereoselective Evans aldol reaction as one of the key steps. A profound difference in the relative stabilities of TBS-protecting groups on C7-O and C15-O was observed between secondary and primary amide groups at C5-N4. Although modeling studies had suggested analogs of type 1 to assume a conformation similar to the NMR-derived conformation of tubulin-bound epothilone A, compounds 1a-d were found to be significantly less active than the parent compound epothilone D.

Key words

epothilones - total synthesis - aldol reaction - microtubule inhibitors - natural products

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1

Current address: ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH-Hönggerberg, HCI 405, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.

6

The target structures are analogs of epothilone D (Figure [1] ), which promotes tubulin polymerization to the same degree as epothilone B. Although less active than epothilone B, epothilone D is also a highly active antiproliferative agent, which inhibits human cancer cell growth in vitro with low nM IC50 values (cf. ref. [3] ).

8

Crystallographic data for 7 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 234369.

14

As the first compound synthesized in this series, 1b was obtained from 12b by removal of both TBS-groups with HF·pyridine, ester saponification, and macrolactonization of the fully deprotected seco-acid. This approach gave pure 1b in only 13% isolated yield (for the cyclization step) after purification by preparative HPLC. Although clearly unsatisfactory, the amount of material obtained through this process was sufficient for complete in vitro biological profiling of 1b and the compound proved to possess only low biological activity. In light of this result resynthesis of 1b from 14b was deemed insensible.

15

The results of the biological evaluations will be published separately.