Piperazine 2 carboxylic acid peptides

Scheme 51 Synthesis of piperazine-2-carboxylic acid peptides...

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. 

Reaction of piperazine-2-carboxylic acid (22) with Z-OSu at pH 11 leads to the N4-(benzyloxycarbonyl) monoprotected derivative,12421 which is then converted with 2-(/er/-bu-toxycarbonyloxyimino)-2-phenylacetonitrile at pH 9.5 into the W-/ert-butoxycarbonyl-/V4-benzyloxycarbonyl bis-protected derivative. 242 For further steps in peptide synthesis standard protocols are applied. 

In this development, both amino moieties are differentially protected and thus, incorporation of these amino acids into peptide chains either at the a- or p-position is possible. This procedure has also been applied to the synthesis of piperazine-2-carboxylic acids and derived peptides [135], Scheme 51. For example, the bicyclic a-hydroxy (S-lactam 161, upon ring expansion and subsequent coupling of the resulting NCA 162 with a-amino esters, affords 163 in good yield. 

Protection of the amino group by protonation is of importance only in very special cases. Some activated amino acids and peptides can be obtained only as their salts, since the free compounds form diketo-piperazines or polymers . One amino group in diamino mono-carboxylic acids can be protected in certain cases by protonation (salt formation). In neutral solution the amino acids are present as a Zwitterionic inner salt, therefore reaction of benzyl phenyl carbonate or ethyl trifluorothiolacetate with lysine in neutral solution 23+o.a.o. 

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