ChemInform Abstract: Towards the Synthesis of Epothilone A: Enantioselective Preparation of the Thiazole Sidechain and Macrocyclic Ring Closure.

Deaza-epothilone C, which incorporates a thiophene moiety in place of the thiazole heterocycle in the natural epothilone side chain, has been prepared by semisynthesis from epothilone A, in order to assess the contribution of the thiazole nitrogen to microtubule binding. The synthesis was based on the esterification of a known epothilone A-derived carboxylic acid fragment and a fully synthetic alcohol building block incorporating the modified side chain segment and subsequent ring-closure by ring-closing olefin metathesis. The latter proceeded with unfavorable selectivity and in low yield. Distinct differences in chemical behavior were unveiled between the thiophene-derived advanced intermediates and what has been reported for the corresponding thiazole-based congeners. Compared to natural epothilone C, the free energy of binding of deaza-epothilone C to microtubules was reduced by ca. 1 kcal/mol or less, thus indicating a distinct but non-decisive role of the thiazole nitrogen in the interaction of epothilones with the tubulin/microtubule system. In contrast to natural epothilone C, deaza-epothilone C was devoid of antiproliferative activity in vitro up to a concentration of 10 μM, presumably due to an insufficient stability in the cell culture medium.

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A Strategy for Macrocyclic Ring Closure and Functionalization Aimed toward Split-Pool Syntheses

Journal of the American Chemical Society ◽

10.1021/ja992658m ◽

1999 ◽

Vol 121 (45) ◽

pp. 10648-10649 ◽

Cited By ~ 72

Author(s):

Daesung Lee ◽

Jason K. Sello ◽

Stuart L. Schreiber

Keyword(s):

Ring Closure ◽

Macrocyclic Ring

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Macrocyclic Ring Closure of OH-assistedPrins Reaction. A new and efficient synthesis of (R,S)-muscone

Helvetica Chimica Acta ◽

10.1002/hlca.19790620817 ◽

1979 ◽

Vol 62 (8) ◽

pp. 2673-2680 ◽

Cited By ~ 32

Author(s):

Karl H. Schulte-Elte ◽

Arnold Hauser ◽

G�nther Ohloff

Keyword(s):

Ring Closure ◽

Efficient Synthesis ◽

Macrocyclic Ring

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Oxidative macrocyclizations for the vancomycin antibiotics. Unexpected transannular effects in the thallium(III)-mediated M(2–4) macrocyclic ring closure

Tetrahedron Letters ◽

10.1016/s0040-4039(97)00566-2 ◽

1997 ◽

Vol 38 (18) ◽

pp. 3189-3192 ◽

Cited By ~ 16

Author(s):

David A. Evans ◽

Christopher J. Dinsmore ◽

Andrew M. Ratz

Keyword(s):

Ring Closure ◽

Macrocyclic Ring

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New Macrocyclic Ligands. XVI. Synthesis of a Series of N-Benzylated Macrocycles Incorporating N4O2-Donor Set

Australian Journal of Chemistry ◽

10.1071/ch03079 ◽

2003 ◽

Vol 56 (11) ◽

pp. 1141 ◽

Cited By ~ 1

Author(s):

Ronald R. Fenton ◽

Leonard F. Lindoy ◽

Jason R. Price ◽

Brian W. Skelton ◽

Allan H. White

Keyword(s):

Schiff Base ◽

Single Crystal ◽

Metal Ion ◽

Benzyl Chloride ◽

Macrocyclic Ligands ◽

Ring Closure ◽

In Situ Reduction ◽

Macrocyclic Ring ◽

X Ray

The synthesis of five 20-membered, N-benzylated macrocyclic ligands incorporating N4O2-donor sets and from one to three benzyl substituents for use in metal-ion recognition studies is described. The new derivatives were obtained by both benzylation of the pre-formed parent macrocycle using benzyl chloride in acetonitrile in the presence of base or, in one case, by performing macrocyclic ring closure using the appropriate N-benzylated triamine precursor by means of a bis-Schiff base condensation with the corresponding dialdehyde, followed by in situ reduction of the diamine linkages so formed. The single crystal X-ray structure of the symmetrically substituted, di-N-benzylated derivative is reported.

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