N‐Alkoxycarbonylmaleimides 3 have been prepared and used to convert amino acids to maleimido acids (6–8) in aqueous solution. The carboxyl group of maleimido acids can be activated for amide or peptide synthesis (e.g., in the N‐succinimidyl esters 10); t‐butyl‐based protecting groups can be cleaved without damage to the maleimide moiety. Peptides carrying maleimide groups are accessible either from the maleimido acids (e.g., 11b, 15) or by direct maleoylation (e.g., 16b). The maleoyl group can be cleaved off by successive mild alkaline and acid hydrolysis or by hydrazinolysis. The reactivity of maleimides toward thiol groups suggests the use of maleimido acids and maleoylpeptides for preparing a wide range of conjugates of biochemical interest.
Zusammenfassung: Di-tert.-butyldicarbonat eignet sich vorteilhaft zur Einführung der tert.-Butyloxycarbonyl-Schutzgruppe in Aminosäuren und Aminosäurederivaten. Die Umsetzungen verlaufen unter milden und umweltfreundlichen Bedingungen rasch und mit hohen Ausbeuten. Di-tert.-butyl-dicarbonate, a Useful tert.-ButyloxycarbonylatingReagentSummary: Di-tert.-butyl-dicarbonate is an ideal reagent for tert.-butyloxycarbonylating amino acids and their derivatives in regard to both reaction rate and simplicity of the procedure.
tert ‐Butoxycarbonylation of amino acids and their derivatives: N‐tert ‐butoxycarbonyl‐l‐phenylalanine reactant: 223 g (1 mol) of di‐tert‐butyl dicarbonate product: N‐tert‐butoxycarbonyl‐L‐phenylalanine product: Boc‐Ala‐OH product: Boc‐β‐Ala‐OH product: Boc‐Arg‐OH product: Boc‐Arg(NO2)‐OH product: Boc‐Asn‐OH product: Boc‐Asp(OBzl)‐OH product: Boc‐Cys(Bzl)‐OH product: (Boc‐Cys‐OH)2 product: Boc‐Gln‐OH product: Boc‐Glu(OBzl)‐OH product: Boc‐Gly‐OH product: Boc‐His(Boc)‐OH product: Boc‐Ile‐OH product: Boc‐Leu‐OH product: Boc‐Lys(Boc)‐OH product: Boc‐Lys(CBZ)‐OH product: Boc‐Met‐OH product: Boc‐Met‐OH product: Boc‐Pro‐OH product: Boc‐Ser‐OH product: Boc‐Ser(Bzl)‐OH product: Boc‐Thr‐OH product: Boc‐Trp‐OH product: Boc‐Trp‐(FOR)‐OH product: Boc‐Tyr‐OH product: Boc‐Tyr‐OH product: Boc‐Tyr(Bzl)‐OH product: Boc‐Tyr(2,6‐Cl2‐Bzl)‐OH product: Boc‐Val‐OH
Socit?t6 suisse de chimie, BUe -SocietA svizzera di chimica. Basilea Szmzmary. Starting from a selectively protected derivative of a, a'-diaminosuberic acid (3) the linear protected peptide 11 has been obtained. Cyclisation to 12 followed by removal of the protecting groups by hydrogenolysis afforded the 'dicarba' analogue of oxytocin, 1 c, which showed about 5 IU/gmol of uterotonic activity in vitro.The role of the disulfide group in oxytocin (la) was established, in principle, ten years ago by the synthesis of [l, 6-(3-carboxypropylcysteine)]oxytocin ('desamino-lcarba-oxytocin', 2b), an analogue of desamino-oxytocin (2a) in which one of the sulfur atoms of the disulfide bridge is replaced by a methylene group [l]. The finding that this analogue had the biological activities of oxytocin [l-51 proved that the reactivity of the disulfide grouping as such is not required for binding to the biological receptors or for initiation of the response. On the other hand, comparison with the nearly inactive acyclic [l, 6-di-alanineloxytocin ('desthio-oxytocin', 1 d) and [l, 6-diserineloxytocin (1 e) demonstrated the steric importance of the bridge for activity [GI. In the event, 2b and the isomeric '6-carba' analogue 2c turned out to have higher uterotonic activity than desamino-oxytocin [5] which in turn is more potent than oxytocin [7] ; the 'desamino-dicarba' analogue, [1, 6-a-aminosuberic acidloxytocin (2d) [3-51 [8-91 was rather less active. Subsequently several other 'carba' analogues were prepared [lo-111 but in all cases the terminal amino group was omitted, chiefly for reasons of synthetic convenience.Metabolic studies with the intact rat uterus in vitro [12] and in vivo [13] have shown the analogues 2b-d to be more stable than oxytocin; in the isolated uterus, the rate of disposition of these analogues was found to be similar to that of desaminooxytocin [12].To determine the relative contributions to activity and to metabolic stability made by the omission of the amino group on the one hand and by methylene replacements in the disulfide bridge on the other, analogues with the terminal amino group present but with a modified bridge structure were obviously required. We have undertaken the synthesis of two such analogues, [6,l-cystathionine]oxytocin ('1-carba-oxytocin', 1 b) and [l, 6-a, a'-diaminosuberic acidloxytocin ('dicarba-oxytocin', l) From the Doctoral Dissertation to be submitted by 0. KeZZev.
Ausgehend von dem 05,01′ ‐Diaminosuberinsäure‐Derivat (I) wird das lineare geschützte Peptid (II) aufgebaut.
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