Solid-Phase Synthesis of Epothilone

Ai A2A3 Ai A2A3A1A2A3 Ai A1A1 A2A2A2 A3A3 A3 A3A3 A3 A3A3 A3 A3 A3 

---

Scheme 11. Solid-phase synthesis of epothilones. (a) 0.75 equiv of RuCl2(=CHPh)(PCy3)2 (3), CH2C12, 25°C, 48 h, 52% (84a 84b 85a 85b=3 3 l 3) (Nicolaou etal.) [24]...

An especially attractive strategy is simultaneous cyclization/cleavage by RCM [42, 43]. This concept was first introduced by van Maarseveen in the synthesis of seven-membered lactams [44] and subsequently employed by many groups. Recently, this strategy was employed in the solid phase synthesis of epothilone A [45, 46] and dysidiohde analogues [47,48]. 

Scheme 21.2 Solid phase synthesis of epothilone (Nicolaou etal.).

Scheme 18.37 Solid-phase synthesis of epothilone A and stereochemical analogs.

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. ... 

Synthesis of epothilones A and B in solid and solution phase. Nicolaou, K. 

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

In a solid phase bound synthesis of epothilone A and derivatives, Nicolaou et al., in an early stage of the synthesis, connected the vinylic carbon Cl2a cf. 8a) via a linker chain to Merrifield... 

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. 

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

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. 

Nicolaou KC, Winssinger N, Pastor J, Ninkovic S, Sarabia F, He Y, Vourloumis D, Yang Z, Li T, Giannakakou P, Hamel E. Synthesis of epothilones A and B in solid- and solution-phase. Nature 1997 387 268-272. 

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. 

In a novel strategy for the construction of natural product-based libraries by combinatorial chemical synthesis of hybrid structures, chiral building blocks obtained by selective chemical fragmentation and further modification of epothilone A and other myxobacterial natural products (soraphen A, sorangicin A, myxothiazol A and Z, apicularen A), were recombined on solid-phase support via a... 

---