Cyanomethyl ester

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

Aminofuran-2-ones (15) (R = COAr, COMe) could be synthesized by Thorpe-Ziegler cyclization of acylmethyl esters 13 and 14 in the presence of NEt3 and NaOEt, respectively. However, the less acidic ethoxycarbonyl-methyl componds 13 and 14 (R = COOEt) or cyanomethyl esters (R = CN) failed to ring close (84LA1702) (Scheme 4). The starting esters could... 

GLYCINE, N-CARBOXY-, N-BENZYL ESTER, CYANOMETHYL ESTER... 

The literature data on the preparation of phosphono-dipeptides from 1-aminoalkanephosphonic acids showed 7-7 that the yields of condensation reactions are usually small or moderate. Moreover,the use of bulky N-blocked amino acids drastically decreased the reaction yield. Thus following Martell s method— we wre unsuccesful in the preparation of dipeptides containing N-terminal valine or leucine,while peptides of phenylalanine were obtained in 5—10% yield.Also the active ester method appeared to give small yields of the desired products. Our studies using p-nitrophenyl- and cyanomethyl esters of N-phtaloyl amino acids confirmed these observations. 

Recognition of the value of active esters for peptide bond formation emerged from work with vinyl esters ly cyanomethyl esters 5-phenyl thioesters 9,P1 piperidino esters 10, 3-pyridyl esters 4-nitrophenyl esters 12 2,4,6-trichlorophenyl esters,and phthalimido esters 17.t l Many activating moieties have surfaced over the years but only a limited number have survived the test of time and are in use today. These include 4-nitrophenyl 12,M 2,4,5-trichlorophenyl pentachlorophenyl pentafluorophenyl succininoido... 

Treatment of diphenylacetonitrile in toluene with sodium amide and 2-chloro-pyrazine gave 2-(C-cyano-C,C-diphenylmethyl)pyrazine (1021), and 2-vinylpyrazine with phenylacetonitrile and sodium heated at 120-130° for 10 minutes gave 2-(3 -cyano-3 -phenylpropyl)pyrazine (731). 2-Amino-5-bromomethyl-3-cyano-pyrazine with sodium hydride and methyl cyanoacetate in tetrahydrofuran formed the dialkylated product (56) (1031). 2-Amino-3-mercapto-5,6-dimethylpyrazine in methanol with potassium hydroxide and chloroacetonitrile gave 2-amino-3-cyanomethyIthio-5,6-dimethylpyrazine (1229), and 2-carboxypyrazine refluxed with chloroacetonitrile and triethylamine in ethyl acetate for 45 minutes gave the cyanomethyl ester (1317). 2-Hydroxy 5-methyl-3-propylpyrazine with cyanogen halides in aqueous sodium hydroxide-dimethylformamide at 0-5° gave l-cyano-5-methyl-2-oxo-3-propyl-l, 2-dihydropyrazine (1123). 

The rate of reaction of carboxylic esters with amines can often be increased by using as acylating agents esters that exchange their alcohol residues with particular ease. With this in mind Schwyzer781 recommends the use of cyano-methyl esters, RCOOCH2CN. The cyanomethyl esters of N-protected amino acids react readily even at room temperature with amino esters and are thus particularly suitable for peptide synthesis. Also, phenyl trifluoroacetate has been recommended for trifluoroacetylation of amino acids and peptides.782 The possibilities offered by such activated esters for peptide synthesis are reviewed in the monograph by Schroder and Liibke.783... 

Thus, the triisopropylsilyl ether of the 4-aminophenol 25 was treated with 2-(4-biphenyl)isopropyl phenyl carbonate in THF followed by addition of excess KH to provide the Bpoc derivative 26. The trimethyltin group was then introduced by directed orf/io-metalation followed by reaction with trimethyltin chloride. Treatment of 27 with BU4NF provided the free phenol, which was then coupled to the cyanomethyl ester of 4-(hydroxymethyl)phenoxyacetic acid under standard Mitsunobu reaction conditions to give the active ester 28 (Scheme 4.1.6). 

Reagents and conditions, i) 2-(4-biphenyl)isopropyl phenyl carbonate, THF, KH ii) tBuLi (2.2 eq), MesSnCI iii) a) BU4NF/THF, b) (4-(hydroxymethyl)phenoxy)acetic acid cyanomethyl ester, PPhj, DEAD, THF... 

The stannane was introduced using the directed ort/io-metalation reaction followed by addition of trimethyltin chloride to give 168. Hydroboration of arylstannane 168 with 9-BBN and oxidative work-up with basic peroxide provided the primary alcohol 169. Mitsunobu reaction of this alcohol with the cyanomethyl ester of 4-hydroxyphenoxyacetic acid afforded preactivated ester derivative 170 in good yield (Scheme 4.2.1). 

A few years after the first publication on acylamino acid thiophenyl esters [4] the peptide research team of the CIBA laboratories in Basel, led by Robert Schwyzer, described a systematic study of the aminolysis of methyl esters substituted with various electron-withdrawing groups [20]. From a series of esters examined with respect to their reaction rates in aminolysis cyanomethyl esters were selected as best suited for peptide synthesis. Cyanomethyl esters were readily prepared through the reaction of acylamino acid salts with chloroaceto-nitrile and they showed satisfactory rates in the acylation of amino acid esters... 

Schwyzer, Robert (pp. 84,205, Plate 39) was born in Zurich, Switzerland, in 1920, but he received his primary and secondary education in the United States. The family later returned to Switzerland and he studied chemistry in Zurich, completing his experimental work for his Ph.D. degree under Paul Karrer. After some years in industry (CIBA), he accepted an invitation to join the faculty of the Federal Institute of Technology (ETH) in Zurich, as professor. Schwyzer first synthesized angiotensin (p. 205), gramicidin S (where he detected cyclodimerization) and, last but not least, the 39-residue sequence of ACTH. He proposed cyanomethyl esters for the formation of the peptide bond. 

Mixed carbonic anhydride N-Carboxyanhydride N-Thiocarboxyamino acid anhydride Benzhydroxamic acid ester Cyanomethyl ester 8-Hydroxyquinoline ester p-Nitrophenyl ester Phenylazophenyl ester Pentachlorophenyl ester Pentafluorophenyl ester Phenyl ester... 

In cyanomethyl derivatization, particularly suited for use with the nitrogen-phosphorus detector, cyanomethyl esters are formed by alkylation of the carboxyl group (R-COO-CH2-CN). The method is rapid, inexpensive, and is resistant to contaminants frequently found during the chromatographic separation of very-long-chain FAs. ... 

Subst. carboxylic acid hydrazides from carboxylic acid cyanomethyl esters... 

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