Strategies for Parallel Synthesis

D.L. Flynn, Phase-trafficking reagents and phase-switching strategies for parallel synthesis, Med Res Rev 19 408-431 1999. 

In a manner paralleling somewhat their strategy for carbaprostaglandin synthesis (Scheme LX), Ikegami, et al., have realized a coriolin total synthesis starting from 1,3-cyclooctadiene. With 701 in hand, they proceeded to elaborate the functionalized... 

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

The split-and-mix strategy appears deceptively similar to parallel synthesis, but can produce libraries of several hundred thousand compounds in one mn. Although it can use the same style of apparatus as for parallel synthesis, there would normally be as many synthesis channels as one has monomers - 20 in the case of natural amino acids (although cysteine is often omitted). However, after the first coupling cycle has been completed, the batches of synthesis beads from each channel would all be combined, mixed well, and re-divided back into the 20 synthesis channels - the step from which the method takes its name. After this, another round of chain extension would commence. In this way all possible sequences are prepared at the same time, but each bead of solid support only contains one sequence. As the number of compounds rises exponentially with each chain extension cycle (hence it is combinatorial), large numbers of monomers limit the number of cycles that can be performed - usually to four rounds (i.e. a tetrapeptide library) with 20 different monomers, = 20" =160 000 compounds. This is because the number of possible sequences should be significantly less than the number of synthesis beads that can be contained in a reasonable volume. 

MCRs have been recognized as valuable tools in the preparation of diversity-oriented synthesis (DOS) and divergent total synthesis (DTS), for the construction of low molecular weight compound libraries through combinatorial strategies and parallel synthesis, and for rapid access to namral product and drug-like small molecules with complex and diverse molecular structures [12], Thus, in 2011, Van der Eycken and coworkers reported a microwave-assisted diastereoselective Ugi-4C-3CR... 

The introduction of fluorine substituents instead of hydrogen may be a useful strategy for the synthesis of metalation-resistant NHCs this has obvious parallels with the use of fluorine in medicinal chemistry to prevent metabolism of drugs by oxidation reactions at that C-H position. Af-Pentafluorophenylmethylene-substituted NHC complexes of iridium and rhodium showed no evidence of the activation of C-H, C-C or C-F bonds.Grubbs and co-workers also prepared a NHC ligand designed to be resistant to ort/ o-metalation by virtue of the presence of ort/ o-fluorine substituents, and the metathesis catalysts prepared from these ligands displayed increased activity when compared to traditional SIMes-based catalysts. 

The following case studies highlight the power of such a strategy in expanding the diversity of monomer collections utilised for parallel synthesis. 

The utility of the stepwise, double-coupling procedure is demonstrated in the parallel synthesis of Tamoxifen derivatives on solid support [127] (Scheme 1-29). 1-Alkenylboronates thus obtained by a diboration-cross coupling sequence are further coupled with p-silyUodobenzene supported on polymer resin. Using this strategy, each position about the ethylene core is modified by the appropriate choice of alkyne, aryl halide, and cleavage conditions for the synthesis of a library of Tamoxifen derivatives. 

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