Solid-phase catalysis peptide synthesis

Annis, D. A. Helluin, 0. Jacobsen, E. N. (1998) Stereochemistry as a diversity element solid-phase synthesis of cyclic RGD peptide derivatives via asymmetric Catalysis., Chem., Int. Ed. Engl, 37, 1907-1909. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

An alternative to the synthesis of proteins by classical fragment synthesis in solution or by solid-phase synthesis on a support is the use of enzyme-catalyzed condensation of amino acids or peptides. This possibility was first demonstrated in 1938 91 with the synthesis of poorly soluble benzoyl-leucyl-leucine anilide by papain catalysis. After many years, this approach was extended to the preparation of peptide hormones such as Leu-enkephalin 92 and dynorphin(l -8).[93 This was made possible by the use of highly purified enzymes and by careful control of reaction conditions. The basic principles of protease-catalyzed peptide bond formation have been discussed.194 ... 

Introducing the Tau residue into a peptide according to the first approach demands protection of the amino group, usually in the form of a Z-derivative and turning the sulfonic acid into sulfonyl chloride. Synthesis of (j-su Ifonamidopeptides via an iterative process, both in solution and in the solid phase, has been described.11201 Chiral methylene sulfinamide peptides can be synthesized both in solution and in the solid phase using the sulfonyl chlorides derived from enantiomerically pure 2-substituted taurines under mild coupling conditions (DMAP catalysis and excess methyl trimethylsilyl dimethylketene acetal as a proton trap).11261... 

Since the introduction of sohd-phase peptide synthesis (SPPS) on lightly crosslinked polystyrene (PSty) by Merrifield in 1962,this technique has been optimized in all its aspects and has subsequently found widespread application in many other fields of organic chemistry, e.g. for the synthesis of oligonucleotides, for catalysis, for the immobilization of enzymes in biotechnology, and for the preparation of polymeric reagents. A new but very rapidly growing field of application of this revolutionary method is the use of solid-phase techniques in combinatorial chemistry for the synthesis of hbraries of compounds whose constituents differ widely in their chemical nature. ... 

A PolyHIPE was employed in the form of a disk as support for the immobilization of flavine for further catalysis of the oxidation of benzyldi-hydronicotinamide in a flow system, demonstrating very good results [369]. PolyHIPE polymers also proved to be a usefiil support for solid-phase peptide synthesis [372]. In this case, large cells of the monolith were filled... 

Can an imprinted surface be synthesized in a step-wise fashion, in a manner analogous to solid phase peptide synthesis, such that each functional building brick of the imprint site is positioned in exactly the right place for the chemical task (e.g., binding, catalysis, controlled release) it is designed to do ... 

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