Cyclative Cleavage (Cyclorelease Strategy)

Cyclative cleavage results from intramolecular reaction at the linker which results in a cyclized product. The cleavage can also act as a means of purification if resin-bound side-products are incapable of cyclizing, and thus remain attached to the solid support on release of the desired material [7]. The cyclization-cleavage strategy (cyclative cleavage or cyclorelease strategy) is typically used for synthesis of cyclic structures on a solid support. It uses the characteristics of quasi high-dilution kinetics on solid supports and thus has advantages which are not found in solution-phase chemistry.

In general, the starting material for cyclative cleavage is anchored to the resin via a leaving group (Scheme 6.1.27). An internal nucleophile affords ring closure by displacement of the leaving group either directly or after activation. Apart from nucleophilic attack, cyclative cleavage can be effected, for example, by the Stille (Scheme 6.1.21) or Wittig-Horner reactions [107, 108].

Scheme 6.1.27. General scheme for cyclative cleavage.

Because the intramolecular reaction is much faster than any intermolecular step, this strategy provides an additional purification step, because only the cy-clized products are detached from the bead. Incomplete building blocks will remain attached to the solid support. However, cyclative cleavage must be distinguished from reactions in which the cyclization occurs in solution after cleavage, because unsuccessful cyclization precursors will remain in the liquid phase.

The precursor for cyclization cleavage is usually linked via an ester bond to the solid support whereas the nucleophile is based on amine functionality. Thus the product formed is a cyclic amide or an analog. Indeed, one of the first examples of this type of reaction was the pioneering benzodiazepine synthesis by Camps et al. in 1974 [109]. In this synthesis benzodiazepine ring formation proceeds by simultaneous cleavage from the bead. A vast number of examples has appeared since then and these provide various types of heterocyclic system, as demonstrated by an approach to 3,5-disubstituted 1,3-oxazolidinones 117 via a ring-opening-cyclization-cleavage step [110] (Scheme 6.1.28).

Scheme 6.1.27. General scheme for cyclative cleavage.

0 0

Post a comment