Epothilone solid-phase total synthesis

Scheme 25. Solid-phase total synthesis of epothilone A (1).

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

The feasibility of multi-step natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first achieved by Nicolaou and co-workers in epothilone synthesis and in the synthesis... 

This total synthesis is the first of three preparations of macrocycles that will be described (epothilone A, zearalenone, and muscone). All feature cycli-zation/release strategies that involve carbon-carbon bond formation.18 These efforts illustrate how the research on supported syntheses of highly complex structures has inspired the use of creative linker strategies for attachment to a solid phase. 

Scheme 2. Total synthesis of epothilon A on solid-phase by Nicolaou et al.

Of great help in solution chemistry is are presented by solid-phase- bound reagents, which can be removed after reaction by a simple filtration process. The great potential of this approach has recently been demonstrated in a total synthesis of epothilones applying only solid- phase-bound reagents. 

An elegant example of a similar approach was employed toward the total synthesis of epothilone A (52) by Nicolaou et al., utihzing the solid support for the synthesis and elaboration of the natural product core scaffold 50 and cleaving it from the resin via RCM to generate the macrolactone 51 (Scheme 6.13). In case of similar solution-phase reactions (without the solid support), high-dilution conditions were necessary to prevent side reactions and obtain the RCM product in high yield. 

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