Succinimide ring

In the following paragraphs, we examine bioactive cyclic imides substituted on the ring and/or on the N-atoms, and begin with N-substituted suc-cinimides. CP-93,393 (4.177, R=R =H) is a selective 5-HT, serotonin autoreceptor agonist developed for the treatment of anxiety and depression. In the rat, hydrolysis of the succinimide bond was observed for the parent drug as well as for metabolites hydroxylated on the succinimide ring (4.177, R=OH,... 

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. 

Incorporation of the pyrrolidine-2,5-dione (succinimide) ring system into a polymeric framework has been accomplished in a variety of ways. The first method involves the addition polymerization of a suitably substituted derivative of succinimide. Several vinyl derivatives, including l-vinylpyrrolidine-2,5-dione (IV-vinylsuccinimide), have been described (B-74MI11100). Several groups have carried out investigations on polymerizable derivatives of A-hydroxysuccinimide, some examples of which are shown in Scheme 2... 

CHClj, and subsequent peptide coupling reaction using TATU, HOAT,188 DIPEA and Boc-(S)-Phe-OH in DMF, and cleavage of the O-benzoyl group using NaCN in MeOH. This reaction sequence shows that the succinimide ring is fully compatible with the mild reaction conditions required for the incorporation of this Asp-Ser- a-chimera into a peptide sequence. CD measurements confirmed the P-turn type II conformation in solution. 

The decomposition of aromatic BMIs follows another pathway involving succinimide ring cleavage followed by carbon monoxide evolution. Moreover it must be pointed out that at temperature as low as 260 °C a depolymerization process can occur probably depending on the chain mobility as was evidenced for model compounds [81]. 

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

The rate of ring closure is a function of the sequence it is fast if R = H, that is in peptides containing the — Asp-Gly — partial sequence and orders of magnitude slower if the aspartyl residue is followed by an amino acid with a bulky side chain, such as valine (R = isopropyl). Opening of the succinimide ring with alkali is not helpful because )8-aspartyl peptides are produced as the preponderant product ... 

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. 

We used a synthetic polypeptide, a,P-poly[N-(2-hydroxyethyl)-D,L-aspartamide], which was prepared by aminolysis with aminoethanol of D,L-poly uccinimide obtained by thermal polycondensation The polysuccinimide is fully racemic and the aminolysis results in random opening of the succinimide rings, as demonstrated by the C-NMR spectrum As enzymes hydrolyze only the peptide bond... 

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. 

The first (and only) detailed DTDA study of parent [4] dendralene (14) was reported by the Sherburn group in 2005 [35]. Upon addition of an excess of NMM, at ambient pressure and temperature, a mixture of five products was obtained in excellent overall yield (Scheme 12.26). The first DA reaction occurred primarily at the terminal diene site to provide l,2-monocyclic[3]dendralene 119, as well as 21% of the internal adduct 120. Triene 119 could not be isolated, and a second cycloaddition, predominately at the internal site, afforded the two endo-DA adducts 121 and 122. The major diastereomer arises via approach of the dienophile anti with respect to the succinimide ring in compound 119. The tris-adducts 123 and 124 originate from reaction at the acyclic diene site of 119, and from the less hindered top face (as drawn). The two intermediates generated... 

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