Combinatorial synthesis epothilone analogs

Scheme 13.81. Combinatorial Synthesis of Epothilone Analogs Using Microreactors3...

The epothilone synthesis in Scheme 13.59 (p. 1221) has been used as the basis for a combinatorial approach to epothilone analogs.69 The acyclic precursors were... 

The epothilone synthesis in Scheme 13.49 has been used as the basis for a combinatorial approach to epothilone analogs. 167 The acyclic precursors were synthesized and attached to a solid support resin by steps A-E in Scheme 13.58. The cyclization and disconnection from the resin were then done by the olefin metathesis reaction. The aldol condensation in step D is not highly stereoselective. Similarly, olefin metathesis gives a mixture of E- and Z-stereoisomers so that the product of each combinatorial sequence is a mixture of four isomers. These were separated by thin-layer chromatography prior to bioassay. In this project, reactants A (3 variations), B (3 variations), and C (5 variations) were used, generating 45 possible combinations. The stereoisomeric products increase this to 180 (45 x 4). 

In the study of the structure-activity relationships of the epothilones, solid-phase synthesis of combinatorial libraries has been used to probe regions of the molecule important to retention of inq>rovement of activityThe combinatorial approach, using an active natural product as the central scaffold, can also be applied to the generation of large numbers of analogs for structure-activity studies, the so-called parallel synthetic approach. ... 

The sequential reactions in elongating acyl transfers in the synthesis of polyketide natural products and non-ribosomal peptide antibiotics such as erythromycin, rapamycin, epothilone, lovastatin, penicillins, cyclosporin and vancomycin resemble molecular solid-state assembly lines. Such multimodular enzymes may be utilized in combinatorial biosynthesis by way of reprogramming for the manufacture of unnatural analogs of natural products. 

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