Esters, ammonolysis formation

As previously indicated (see pp. 88-91), formation of heterocyclic compounds, mainly pyrazines, was found only in the ammonolysis of some aldose nicotinates33 35 and acetates and benzoates of ketoses.39 37 For ketose esters, whose behavior differed from that of the aldose esters, the formation of imidazole derivatives was also observed these heterocyclic compounds also result from the direct action of ammonia upon the corresponding free sugars, but the presence of the esterifying acyl groups evidently increases their ease of formation and raises their yields. 

From these experiments it would appear that the presence of a free aldehyde group is a necessary but not a sufficient condition for the formation of diamides in the above reactions. Once formed, the aldehyde group must be stabilized long enough to allow it to react with one or more amide molecules, the latter arising from the ammonolysis of the ester groups present in the acylated sugar. 

In the reaction of ammonia with l,3,4,5-tetra-0-benzoyl-/3-n-fructopyranose, a significant proportion of benzoic acid was formed, indicating that the ammonolysis of the sugar ester occurred to a certain extent through acyloxy-group rupture. As neither the formation of imidazole nor of pyrazine derivatives (see Section VI,3, p. 124) re-... 

The presence of alkoxide ion would enhance the rate of ammonolysis, and the formation of bis(amido) derivatives by an ortho-ester mechanism (see Section VI, p. 110) would be partially suppressed in the competitive set of reactions. Thus, ammonolysis of penta-O-benzoyl-D-glucose in the presence of 5 mmolar proportions of sodium meth-oxide showed a decrease of 11% in the yield of the bis(benzamido)-glucitol derivative as compared with the same reaction conducted without added methoxide ion.47... 

Sulphamoyl chloride when reacted with hydroperoxides in the presence of pyridine below — 30 °C leads to the formation of the novel alkyl sulphamoyl peroxides H2NS0200CH2R (R = CH2CH3, CH2CH2CH3) 303 (equation 98)305. Hydrolysis or ammonolysis of these compounds leads to formation of sulphamic acid or sulphamide respectively. 2-Nitrophenylsulphamoyl chloride (304), prepared from the corresponding sulphamic acid by reaction with PC15, has been used to prepare iV-(2-nitrophenyl)-iV -substituted sulphamides (305) and aryl esters (306) (equation 99)306. 

The synthesis of DPP-IV inhibitor Saxagliptin 5 also required (55)-5-amino-carbonyl-4,5-dihydro-lH-pyrrole-l-carboxylic acid, l-(l,l-dimethylethyl)ester 10 (Figure 16.3C). Direct chemical ammonolyses were hindered by the requirement for aggressive reaction conditions, which resulted in unacceptable levels of amide race-mization and side-product formation, while milder two-step hydrolysis-condensation protocols using coupling agents such as 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) [41] were compromised by reduced overall yields. To address this issue, a biocatalytic procedure was developed based on the Candida antartica lipase B (CALB)-mediated ammonolysis of (55)-4,5-dihydro-lH-pyrrole-l,5-dicarboxylic acid, l-(l,l-dimethylethyl)-5-ethyl ester 9 with ammonium carbamate to furnish 10 without racemization and with low levels of side-product formation. 

Several improvements in acylation techniques were announced. Butyllithium wwas determined to be superior to sodium amide in preparation of amide ions for ammonolysis reactions with esters. Phosgene is more reactive than ethyl chloroformate toward eneamines. The intermediate acyl chlorides may then be converted to a variety of products. a-Acetylenic aldehydes are easily prepared by the action of acetylenic Grignard reagents upon ethyl formate. ... 

Ammonia is the smallest noncharged nucleophile for peptide liberation from polymer phase. Cleavage of the benzyl ester link to polystyrene by ammonolysis with the formation of peptide amides, however, liberates on the average only 60—80% of the synthetic product from the support. The best conditions for this detachment yielding directly the important class of peptide amides can be seen in the utilization of dimethylformamide/ methanol 4 1 (v v) saturated with ammonia at 0 °C, in which the peptide-on-polymer is suspended and stored for at least 3 days in a pressure bottle at room temperature. 

Since acetamide, which results from ammonolysis of the ester functions, does not itself condense with free sugars 189) or acetylated aldehydo-sugars 190) the mechanism of formation of the diacetamide derivatives has received considerable study. A possible mechanism 191) is based on intramolecular migration of acetyl groups from oxygen to nitrogen, according to the scheme ... 

When the enzyme is incubated with /J-chloro-L-alanine, the rate of the catalytic reaction declines rapidly as the enzyme becomes irreversibly inhibited. Such inactivation is associated with the binding of close to 1 mole of the 3-carbon chain of the substrate analog per mole of active site. The enzyme, after inactivation by treatment with /8-chloro-L-[ C] alanine, was treated with cyanogen bromide and a C-labeled peptide was then isolated. Treatment of the labeled peptide with mild alkali leads to release of /8-hydroxy-[ CJpyruvate, suggesting an ester linkage. Ammonolysis of the labeled peptide leads to release of the label, and amino acid analyses of enzymic hydrolyzates of the peptide before and after ammonolysis show formation of an equivalent amount of glutamine [Eq. (3)]. The findings indicate that the labeled derivative... 

This result, is apparently, of a more or less general significance for the reactions of nucleophilic substitution at the carbonyl carbon. Thus, quantum chemical calculations predict appreciable acceleration of ammonolysis reactions of esters [93] and carboxylic acids [108] when an additional ammonia molecule takes part in their catalysis. The structure, found by a nonempirical calculation [109], of a transition state in the concerted reaction of formation of formaldehyde XXXVII in the reaction ... 

An enzymatic process was developed using the CAL-B-mediated ammonolysis of (5S)-4,5-dihydro-lH-p3rrrole-l,5-dicarboxylic acid, l-(l,l-dimethylethyl)-5-ethyl ester 77 with ammonium carbamate to furnish 76 without racemization and with very low levels of side-product formation [104]. 

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