Applications to Combinatorial Reaction Optimization

Warmus et al. (121) recently reported the multivariate optimization of reaction conditions for the synthesis of a known class of ICE (interleukin-ip converting enzyme) inhibitors, represented by compound 9.70. The structure of the compound and the synthetic route, starting from the key bromide intermediate 9.71, are reported in Fig. 9.29 (the acetylvaline moiety of 9.70 was replaced during the optimization with an Fmoc carbamate). 

Coupling of 9.71 with carboxylic acid 9.72 (step a. Fig. 9.29) was performed in a set of 82 reaction conditions (parallel reaction library L18, Fig. 9.30). The base and 

IRP-64 resin, IRC-58 resin, DOWEX 50 resin, Amberlife IR 120 resin. Nation resin used solvents-. DCM, EtOAc, toluene, dioxane, THF, acetone used adjuvants-. PhSMe, Et3SiH, m-cresol, HjO 

TABLE 9.2 Yields and Purity of 9.73 from Parallel Reaction Library L18 Selected Entries 

Entry Base Solvent Adjuvant Reaction Outcome  

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