Lead optimization, catalyst combinatorial

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

The primary use of combinatorial chemistry is for drug discovery and lead optimization. The technique has also significant potential in the fields of material science, catalyst development and studies of molecular recognition. 

Through the synthesis of parallel combinatorial libraries, Jacobsen and coworker discovered a new dass of catalysts for the Strecker reaction [15]. Because of its modular assembly, the new catalyst type was amenable to solid-phase synthesis and fast preparation, screening, and lead optimization were feasible. The best catalyst candidate afforded the Strecker product from N-allylbenzaldimine in 78% yield and 91% ee. Catalyst 21 was prepared as the soluble variant of the optimized candidate and proved to be an effective catalyst for a range of imine derivates 20, affording aromatic amino nitriles 22 in moderate to good yields (65-92%) and high enantioselectivities (70-91% ee) (Scheme 30.4). In addition, aliphatic aldimines 20... 

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