Hydrolysis 6-substituted amino

Partial hydrolysis of a peptide can be carried out either chemically with aqueous acid or enzymatically. Acidic hydrolysis is unselective and leads to a more or less random mixture of small fragments, but enzymatic hydrolysis is quite specific. The enzyme trypsin, for instance, catalyzes hydrolysis of peptides only at the carboxyl side of the basic amino acids arginine and lysine chymotrypsin cleaves only at the carboxyl side of the aryl-substituted amino acids phenylalanine, tyrosine, and tryptophan. 

Hydrolysis of amino-alkylamino-l,2,5-thiadiazole 1-oxides 55 with concentrated aqueous HC1 gave the amidines 56 (Equation 4) <2001JME1231>. The hydrolysis reactions of 2-alkyl-4-amino-2,3-dihydro-l, 2,5-thiadiazol-3-one 1,1-dioxides 57 in the range 24-73 °C in buffered aqueous solutions gave the corresponding 2-amino-2-[(iV-alkyl-substituted-sulfamoyl)imino]acetic acid salts 58 (Equation 5) <1998JP0489>. 

The cyclization of 285 proceeded similarly as in the synthesis of 278-281. The N,A-dimethyl-substituted amino ester 285 and cyanogen bromide resulted in 286, and subsequent acid hydrolysis led to the urea ester 287, which was cyclized to l-methylperhydro-2,4-quinazolinedione 288 at elevated temperature [69LA(728)64]. 

This enzyme [EC 3.1.1.29], also called peptidyl-tRNA hydrolase, catalyzes the hydrolysis of an A-substituted aminoacyl-tRNA to produce an A-substituted amino acid and tRNA. 

This enzyme [EC 4.1.99.1], also known as L-tryptophan indole-lyase, catalyzes the hydrolysis of L-tryptophan to generate indole, pyruvate, and ammonia. The reaction requires pyridoxal phosphate and potassium ions. The enzyme can also catalyze the synthesis of tryptophan from indole and serine as well as catalyze 2,3-elimination and j8-replacement reactions of some indole-substituted tryptophan analogs of L-cysteine, L-serine, and other 3-substituted amino acids. 

Various diastereomeric di-, tri-, and tetrapeptides that carry the sterically demanding trifluoromethyl group instead of the natural a-proton at different positions within these short peptide sequences have been designed, and their stability towards enzymatic hydrolysis has been investigated. The structures of the a-trifluoromethyl (aTfm)-substituted amino acids are shown in Scheme 1. From these studies we gained valuable information on how a-trifluoromethyl-substi-tuted peptides may interact with proteins. The aTfm amino acids used in this study combine the conformational restrictions [49-52] of C -dialkylation with the unique stereoelectronic properties of the fluorine atom and have shown interesting effects on peptide-enzyme interactions [53,54]. 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

It has been known for many years, however, that the (3-branched amino acids, especially valine and isoleucine, cause problems in synthesis,14,5] and special care and additional reaction time are required when -substituted amino acids are added to a growing peptide chain in synthesis. For example, in the synthesis of [2,4-diisoleucine]oxytocin efforts to couple the isoleucine to isoleucine by the azide method failed and only the rearranged product was obtained 61 Also, it is much more difficult to hydrolyze peptide bonds formed between two or more contiguous -substituted amino adds using standard 6M HC1 conditions. For example, in the hydrolysis of [2,4-diisoleucine]oxytocin (3 isoleucine residues adjacent to each other) complete hydrolysis takes 60 hours. 

Deng and co-workers have also applied the cinchona derivatives to the kinetic resolution of protected a-amino acid N-carboxyanhydrides 51 [48]. A variety of alkyl and aryl-substituted amino acids may be prepared with high se-lectivities (krei=23-170, see Scheme 10). Hydrolysis of the starting material, in the presence of the product and catalyst, followed by extractive workup allows for recovery of ester, carboxylic acid, and catalyst. The catalyst may be recycled with little effect on selectivity (run 1, krei=114 run 2, krei=104). The reaction exhibits first-order dependence on methanol and catalyst and a kinetic isotope effect (A MeOH/ MeOD=l-3). The authors postulate that this is most consistent with a mechanism wherein rate-determining attack of alcohol is facilitated by (DHQD)2AQN acting as a general base. 5-Alkyl 1,3-dioxolanes 52 may also... 

An early structural modification of FA and AP involved alkylation at C-9 and/or N-10. 10-MethylFA (447) [197] was prepared by reaction of 2,4,5-triamino-6-hydroxypyrimidine, 2,3-dibromopropionaldehyde and diethyl p-methylaminobenzoylglutamate (35), followed by alkaline hydrolysis (the Waller condensation). Analogous utilization of 2,2,3-trichlorobutyraldehyde and the requisite p-(JV-substituted amino)benzoylglutamate furnished (448a-c) (Scheme 3.88) [198]. The preparation of (450) by condensation of 2,4,5,6-tetraaminopyrimidine and the a-ketoacetal (449) was reported without details (Scheme 3.89) [199],... 

The opportunity to introduce substituents at C-2 of the pyrrolopyrimidine is afforded by the use of 2-(substituted)amino-3-cyanopyrroles. Treatment of acylaminopyrroles (127), most commonly with R3 = Me, with phosphorus pentoxide, an arylamine hydrochloride, and jV,Ar-dimethyl-cyclohexylamine at elevated temperatures, gives the derivatives (128 X = NH) (Equation (42)) <83LA2066,84CS73, 85CS222,85S101,88CS303,90H(3l)367,93AP(326)303>. In some cases the 4-imino derivative has been converted to the 4-oxo derivative (128 X = O) by hydrolysis. 

O Donnell et al have examined benzophenone-derived glycine acetate (85) as a glycine cation equivalent. Higher order mixed cuprates [R2Cu(CN)Li2] react with (85) to afford alkylated Schiff base (86) in moderate yields. The reaction is sensitive to reaction conditions and reduction competes with or-ganometallic addition. Hydrolysis of (86) provides access to aryl- or alkyl-substituted amino acids (87 Scheme 16). 

Early work" " on the reaction of 2-substituted amino-3-amino-pyridines (54) with alloxan (55) in neutral solution has been corrected. The initial yellow product from the condensation is a ureide of formula 56, which readily rearranges to the colorless spirohydantoin 57 on treatment with acid or base. Tire isomeric pyridine 49 yields a second series of ureides and hydantoins. When 2,3-diaminopyridine itself is used, a mixture of products is obtained in which the 3-oxo compound 56 (R = H) predominates over its 2-oxo isomer. Alkaline hydrolysis followed by decarboxylation and methylation served to confirm the orientation (see Section II2B). If the reaction with alloxan is carried out in alkaline solution, the only product obtained is the 3-oxo-2-carboxylic acid." ... 

A large number of substituted alkyl halides, for instance, chloro ethers,266 chloro sulfides,267 and halo carboxylic esters,268 provide syntheses of phosphonic esters containing also other functional groups. A-(2-Bromoethyl)-phthalimide leads, after hydrolysis, to / -amino phosphonic esters.269... 

Examples of good a correlations are for the alkaline hydrolysis of amino-sulphonate esters (MeNHSOj-OAr) [37], acyloxysilanes (EtjSiOAr) [38] and acyl benzene sulphonates (PhSOj-OAr) [39]. These results indicate that the ArO- bond is being cleaved in the transition state of the rate-limiting step. A typical example is illustrated (Fig. 10) for the alkaline hydrolysis of substituted phenyldimethylphos-phinates [40] where the a dependence is consistent with ArO-P cleavage in the transition state of the rate-limiting step (Eqn. 52). 

When amines are substituted for hydroxide as the base, there is no change in the rate of hydrolysis. This is because amines do not catalyze the hydrolysis of amino acid esters instead they prefer to add directly to the carbonyl carbon to form the corresponding amides. In this reaction the rate-limiting step is not the addition of amine, but rather the deprotonation of the coordinated amine by another base (equations). The p/fa of the tetrahedral intermediate is approximately 7 since almost any nonsterically hindered base with a p/fg above 7 can deprotonate it. ... 

---