Succinimide ring formation

This side reaction is relatively innocuous because the by-product is irreversibly bound to the polymer and only the yield is affected not the purity of the synthetic peptide. More disturbing is the succinimide ring formation at aspartyl residues exposed to HF. Alkylation of the indole ring in tryptophan, the phenolic side chain in tyrosine and the sulfur atom in methionine must be suppressed by the addition of scavengers. The often appUed anisole is less than unequivocal in this role it can be the source of methyl groups which convert the methionine thioether to a tertiary sulfonium derivative. The acid stable thioanisole seems to be a better scavenger. 

The most important degradation mechanism of asparagine and glutamine residues is formation of an intermediate succinimidyl peptide (6.63) without direct backbone cleavage (Fig. 6.29, Pathway e). The reaction, which occurs only in neutral and alkaline media, begins with a nucleophilic attack of the C-neighboring N-atom at the carbonyl C-atom of the Asn side chain (slow step). The succinimide ring epimerizes easily and opens by hydrolysis (fast step), as shown in Fig. 6.27, to yield the iso-aspartyl peptide (6.64) and the aspartyl peptide (6.65) in a ratio of 3 1. 

Fig. 10. Aspartimide formation and succinimide ring reopening in basic medium.

Asp side chain. This results in the formation of a five-membered succinimide ring and the loss of ammonia or water from Asn or Asp, respectively. The succinimide typically hydrolyzes to Asp and iso Asp in a 1 3 ratio. Cleavage of the peptide bond can also occur at Asn residues. 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

Miscellaneous Compounds. A saturated spirocychc pyrrohdine serves as the nucleus for a diamine that has been described as a hypohpemic agent. Treatment of the carbanion of the substituted cylcohexane carboxyhc ester (20-1) with methyl bromoacetate leads to the alkylation and formation of the diester (20-2). Saponification of the ester groups followed by reaction with acetic anhydride leads to ring closure of the succinic anhydride (20-3). Condensation with ammonia leads to the succinimide (20-4). The side chain is then added by alkylation of the anion on nitrogen with l-bromo-4-dimethylaminobutane (20-5). Reaction of this last intermediate with lithium aluminum hydride leads to the reduction of the carbonyl groups to methylene. This affords the pyrrolidine (20-6) atiprimod [22]. 

Bicyclic cyclopropanone aminals with a succinimido moiety as iV-substituent allow displacement of succinimide by hydrogen by heating with triethylammonium formate giving 1. A ratio 3 1 of formate to aminal gave the best results. This reduction could not be applied to bicy-clo[3,1.0]hexane or bicyclo[9.1.0]dodecane systems due to ring-opening reactions under these conditions. ... 

The first remarkable transannulation reaction of humulene involved treatment with jV-bromo-succinimide in aqueous acetone leading to the tricyclic bromohydrin62. Cyclization is induced by attack of a bromonium ion on the trialkylated, electron-rich 1.2-double bond followed by a sequence of 3-exo and 4-exo transannulation reactions. After substitution of bromine by hydroxyl, elimination of water and ring enlargement, caryophyllene (1) is generated stereoselec-tively in 25 % yield. Reaction of humulene in the presence of aqueous sulfuric acid led to a mixture of bi- and tricyclic products although the formation of bicyclo[5.3.0] systems predominates63. 

The formation of imides takes place in the case of dibasic acids which contain a straight chain of four or five carbon atoms. In the resulting compounds the atoms are arranged in what is called a ring. The graphic formula of succinimide may be written in a way which makes this clear —... 

It is possible to prepare ring-compounds of many types as the result of the elimination of atoms or groups from straight-chain compoimds, the formation of rings containing five or six atoms being most easily accomplished. It will be recalled that succinic acid is converted into its anhydride when heated, and that succinamide under similar conditions yields succinimide. The formulas of these compounds are as follows —... 

We must add here that steric hindrance is not necessarily harmful. As mentioned before bulkiness in the activating portion of mixed anhydrides results in more unequivocal acylation reactions. Similarly, in jff-tert.butyl esters of aspartyl residues ring-closure to aminosuccinyl peptides, observed with the corresponding )8-benzyl esters, does not occur. Furthermore, formation of hydantoins and succinimide derivatives is considerably enhanced if glycine is involved in the process, because di-acylation of this unique amino acid without a side chain readily occurs. Accordingly, it is a mistake to use glycine in model experiments designed for the study of side reactions. 

Aminolysis of the intact rings with taurine leads to the formation of poly(2-sulfoethyl aspartamide) silica and the reaction with ethanolamine to the formation of poly(2-hydroxyethyl aspartamide) silica. Poly(succinimide)-based silica phases are manufactured by PolyLC (Columbia, MD, USA) under the trade names of PolyCAT A for poly(aspartic acid) silica, PolySulfoethyl A for poly(2-sulfoethyl aspartamide) silica, and PolyHydroxyethyl A for poly(2-hydroxyethyl aspartamide) silica. All three poly(succinimide)-based columns have a pore size of 200 A and a surface area of 188 m /g. Various poly(succinimide)-based columns have been used for the separation of carbohydrates, phosphorylated and nonphosphorylated amino acids, petides and glycopeptides, oligonucleotides, and various other polar analytes under HILIC conditions, but lately lost some of their momentum due to a lower chromatographic efficiency in comparison to more modern HILIC phases and column bleed [44]. 

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