Aspartimides

An interesting approach to thermosetting acetylene-terminated polyimides via the Michael addition reaction has appeared (38). Acetylene-terminated aspartimides are readily prepared ia high yield via two routes, shown ia Figure 7. 

Fig. 7. Acetylene-terminated aspartimides. (a) Reaction of aromatic diamine with A/-(3-ethynylphenyl)maleimide [105280-01-17 ia a 1 2 molar ratio yields a prepolymer of this general formula, (b) Bismaleimide reacts with 3-ethynylaniline [54060-30-9] ia a 1 2 molar ratio to yield a prepolymer of this general...

Cycloalkyl esters have.been used to protect the /3-CO2H group in aspartyl peptides to minimize aspartimide formation during acidic or basic reactions. Aspartimide foimation is limited to 2-3% in TFA (20 h, 25°), 5-7% with HF at 0°, and 1.5-4% TfOH (thioanisole in TFA). Cycloalkyl esters are also stable to Et3N, whereas use of the benzyl ester leads to 25 % aspartimide formation during Et3N treatment. Cycloalkyl esters are stable to CF3COOH, but are readily cleaved with HF or TfOH. - ... 

This tertiary ester was developed to reduce aspartimide and piperidide formation during the Fmoc-based peptide synthesis by increasing the steric bulk around the carboxyl carbon. A twofold improvement was achieved over the the standard Fbutyl ester. The Mpe ester is prepared from the acid chloride and the alcohol and can be cleaved under conditions similar to those used for the r-butyl ester. ... 

Cleavage is effected with acid. The following table compares the acidolysis rates with Bn and cyclohexyl esters in TFA/phenol at 43°. The Dmp group reduces aspartimide formation during Fmoc-based peptide synthesis. 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

JP Tam, TW Wong, MW Reimen, FS Tjoeng, RB Merrifield. Cyclohexyl ester as a new protecting group for aspartyl peptides to minimize aspartimide formation in acidic and basic treatments. Tetrahedron Lett 4033, 1979. 

A carbodiimide is added to the two reacting species. The urea generated from dicyclohexylcarbodiimide is insoluble and voluminous, so it is often replaced by diisopropylcarbodiimide, which generates a soluble urea. The soluble carbodiimide ethyl-(3-dimethylaminopropyl)-carbodiimide hydrochloride (see Section 1.16) is suitable but expensive. Efficiency of coupling is greater in dichloromethane than in dimethylformamide. There is also the option of adding 1-hydroxybenzotriazole to minimize the side reactions of A-acylurca (see Section 2.12), cyano (see Section 6.15), and aspartimide (see Section 6.13) formation. 

A Karsltrom, A Unden. Design of protecting groups for the P-carboxylic group of aspartic acid that minimize base-catalyzed aspartimide formation, (dimethylpentyl) Int J Pept Prot Res 48, 305, 1996. 

JP Tam, MW Rieman, RB Merrifield. Mechanisms of aspartimide formation the effects of protecting groups, acid, base, temperature and time. Pept Res 1, 6, 1988. 

A Karsltrom, A Unden. A new protecting group for aspartic acid that minimizes piperidine-catalyzed aspartimide formation in Fmoc solid phase peptide synthesis. (3-methylpent-3-yl) Tetrahedron Lett 37, 4234, 1996. 

Piperazine (13) is a base and nucleophile employed (6% in dimethylformamide) in solid-phase synthesis for removal of fluorenylmethyl-based protectors. The reaction is slower (three times) than with piperidine, but it leads to minimal aspartimide or piperazide formation. 

DBU = l,8-diazabicyclo[5.4.0]undec-7-ene (15) is a nonnucleophilic base employed in conjunction with piperidine in dimethylformamide (1 1 48) for removal of fluorenylmethyl-based protectors. The piperidine is necessary as a nucleophile to trap the expelled moiety that does not react with DBU. DBU has no effect on phthalimido [Pth-NH of -Lys(Pht)-], dialky-lphosphoryl [-Tyr(P03R2)-], or Dde-NH [-Lys(Dde)- see Section 6.4], but it promotes aspartimide formation at the pertinent residues of susceptible sequences (see Section 6.13). In dichloromethane, it promotes a reaction between two molecules of urethane-protected amino acid /V-carboxyanhy-dride with release of carbon dioxide (see Section 7.14). 

During Fmoc-based syntheses the aspartyl side chain can undergo intramolecular cyclization during repetitive base treatment, especially Asp-Asn, Asp-Gly, Asp-Gin, and Asp-Ser. Backbone protection prevents aspartimide formation and is introduced wherever prudent. 20 ... 

Scheme 1 Potential Side Reactions of Glycopeptides (A) with Acid, (B) with Base, and (C) by Aspartimide Formation 47-49 ...

Scheme 37 Aspartimide Formation during Convergent /V-Glycopeptide Synthesis 3951...

BMI/amine Michael adduct resins may be further modified and blended with other thermosets or reactive diluents to achieve either specific end-use properties or processability. Epoxy resins are very suitable for the modification of BMI/primary amine adducts, because the secondary amine functionality in the aspartimide structure is a curative for the epoxy group. 

Many side reactions can occur because when BMIs are heated above 200°C, double bonds can also polymerize by a chain polymerization mechanism with the formation of a crosslinked polymer. A typical formulation contains a molar excess of BMI with respect to a diamine. Linear maleimide end-capped aspartimides are formed, which can then be cross-linked by further heating with or without an initiator ( a catalyst ). 

Offer, J., Quibell, M., and Johnson, T. (1996) On-resin solid-phase synthesis of asparagine-AMinked glycopeptides use of /V-(2-accloxy-4-mc(hoxybenzyl) (AcHmb) aspartyl amide-bond protection to prevent unwanted aspartimide formation./. Am. Chem. Soc. Perkin TransI., 175-182. 

The convergent approach to N-glycopeptides was first demonstrated by Peter Lansbury et al. (Scheme 11.4) [52, 53], Condensation of an oligosaccharyl amine with the Asp side chain of a suitably protected peptide was examined in solution phase but can also be carried out in solid phase. However, the drawback of this method is that the Asp unit meant to be coupled to an oligosaccharyl amine is prone to cyclic aspartimide formation with the amide nitrogen atom of the peptide backbone. Samuel Danishefsky and coworkers examined several conditions to overcome... 

Fire resistant polymers were obtained from brominated epoxynovolak resin, BPA/DC prepolymer, BMI, Zn acetate and benzoyl peroxide [103] or from an oligo-aspartimide (BMI-diamine reaction product), BPA/DC, 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane (i.e. Tetrabromo-Bisphenol A) and 2-ethyl-4-methylimi-dazole [104]. A mixture of BPA/DC, BMI and epoxide resin with brominated polycarbonate, copoly[oxy-2,6-dimethylphenylene)-(oxy-2,3,6-trimethylphenylene)] and a catalyst was also suggested [105],... 

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