Amino acid ester isocyanates

Synthesis of Amino Acid Ester Isocyanates Methyl (S)-2-lsocyanato-3-phenylpropanoate. 

SYNTHESIS OF AMINO ACID ESTER ISOCYANATES METHYL [Pg.111]

Amino acid ester isocyanates are produced cleanly by this method and can often be used without purification. If desired, volatile amino acid ester isocyanates, such as the title compound, can be purified to analytical purity by Kugelrohr distillation. The amino acid ester isocyanates generated by this method are formed without detectable racemization (>99.5% ee) the er antiomeric purity of the isocyanates can be checked by trapping with (S)-l-phenylethylamine, followed by 1H NMR analysis of the resulting urea adducts.2 If this method is used to generate isocyanates of peptides, then efficient stirring is necessary to prevent epimerization of the peptide isocyanates.3 4... 

Amino acid ester isocyanates are useful synthetic building blocks, precursors to peptides and azapeptides, 7 8 chiral derivatizing agents,9 13 and reagents for the preparation of chiral chromatographic media.11 12 (S)-2-lsocyanato-3-phenylpropanoate (phenylalanine methyl ester isocyanate) has been used as a... 

SYNTHESIS OF AMINO ACID ESTER ISOCYANATES METHYL (S)-2-ISOCYANATO-3-PHENYLPROPANOATE. 

J.S. Nowick, N.A. Powell, T.M. Ngnyen, G. Noronha, An improved method for the synthesis of enantiomericaUy pnre amino acid ester isocyanates, J. Org. Chem. 57 (1992) 7364-7366. 

A series of various enantiomerically pure amino acid ester isocyanates (for example 452) has been synthesized in yields of 72-95% by carbonylation of the appropriate amino acid ester hydrochlorides (for example 451) with phosgene [311]. The products are based on the amino acids alanine, valine, leucine, isoleucine, phenylalanine, methionine, serine, and glutamic acid. 

General procedure for the preparation of amino acid ester isocyanates [311] A 250-mL, three-necked, round-bottomed flask, fitted with two rubber septa, a nitrogen inlet adapter, and a magnetic stirring bar, was charged with the amino acid ester hydro-... 

An earlier publication [312] described the synthesis of d,l-amino acid ester isocyanates (at that time called dj-carhonyl-amino acid esters) from the corresponding amino acid ester hydrochlorides by carbonylation with phosgene. Ester hydrochlorides of alanine, leucine, phenylalanine 451, aminobutyric add, phenyl glycine, norvaline, norleucine, benzyl cysteine, methionine, aspartic acid, and glutamic acid were used yields of isocyanates were 85-97%. 

Reaction with Phosgene. This reaction of amino acid esters is used for preparing the corresponding isocyanates, especially lysine diisocyanate [4460-02-0] (LDI). LDI is a valuable nonyellowing isocyanate with a functional side group for incorporation in polyurethanes. 

The reaction of immobilized /3-amino acids with isocyanates provides ureas that can be cyclatively cleaved26 to dihydropyrimidinediones, while the analogous reaction27 with anthranilic acids affords 2,4-quinazoline-diones (Fig. 8). A similar process is the cyclization28 of /3-keto esters derived from substituted anthranilates to furnish 4-hydroxyquinolinones, while the hydrazones of immobilized 7-keto esters are cyclatively cleaved29 to dihydropyridazinones. 

Metal chelating amino acid derivatives of cellulose were recently obtained via modification of cellulose with 2,4-toluenediisocyanate, followed by treatment with amino acid ester derivatives [58,59]. Diisocyanates are able to crosslink cellulose chains and/or to yield reactive cellulose isocyanate, depending on the reaction conditions. Sato and his coworkers [60] examined the optimum conditions for the reaction between cellulose and 2,4-toluenediisocyanate and succeeded in introducing 0.30 mol of free isocyanate group per glucose unit. Cellulose isocyanate was further converted into isothiocyanate [61]. This derivative has also been synthesized by condensation of cellulose with 2,4-diisocyanototoluene, followed by hydrolysis and thiophosgene treatment [61]. 

Monosubshtuted hydantoins are a-amino acids cyclically protected at both the carboxyl- and the a-amino group. They can be easily prepared from an aldehyde and isocyanate or by the Bucherer-Bergs synthesis and similar methods. Indeed, the hydantoin synthesis is also a prachcal method for the preparahon of the racemic amino acid. Enzymes belonging to the dihydro-pyrimidinase family hydrolyze hydantoins to the carbamoyl amino acid. The latter can be hydrolyzed in turn to the amino acid by a second enzyme, a carbamoylase. Both enzymes can discriminate between enantiomers and, if their action is cooperative, either the L- or the D-amino acid can be obtained (Scheme 13.10) [36]. What makes the system of special interest is that the proton in the 5-position of the hydantoin ring (it will become the a-hydrogen in the a-amino acid) is considerably more acidic than conventional protons in amino acid esters or amides and much more acidic than the amino acid itself. Thus, the hydantoin can be often racemized in situ at slightly basic pH where the enzymes are stiU stable and active. If these condihons are met. 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

The amino acid ester forms the hydantoin 33 with the isocyanate 41. The free amine 32 attacks the isocyanate carbon and the nucleophilic isocyanate nitrogen in 42 then reacts with the electrophilic ester moiety. The carbonate base prevents protonation of the amine. 

Esters of 2-amino acids, RCH NH j)CO R, do not cyclize, but rather give the corresponding isocyanate, RCH(NCO)CO R (R = PhCHjSCHj, R = CH Ph) [1276]. The treatment of amino acid esters with phosgene has been used as a method for the separation of the parent amino acids the resulting isocyanato esters being readily separated by fractional distillation in vacuo [1062]. In the presence of pyridine, however, COCIj and EtOjCCH(NHj)COjEt give a urea [1264] ... 

Japanese workers have developed a new synthesis of ureas and thioureas through the reaction of carbon dioxide or carbon disulphide with diphenyl phosphite and primary amines. The reaction is thought to take place via an intermediate (85), followed by elimination to give isocyanate or direct displacement by amine. The principles of this new synthesis have also been applied to the preparation of peptides and amino-acid esters. 

The developed solid-phase approach started with the preparation of immobilised ureas 114 obtained via acylation of amino acids linked to acid-labile Sasrin resin 104 with ortho-methoxycarbonyl aryl isocyanates or activated para-nitrophenyl carbamates 113. Alternatively, ureas of type 114 could also be generated by reaction of anthranilic esters 115 with immobilised amino acid-derived isocyanates (easily generated from tethered amino acids with triphosgene or phosgene in toluene in excess of a base such as 2,6-lutidine) or activated carbamates 116 (Scheme 4.1.23). 

A convenient method for the synthesis and derivatization of enantiopure a-iso-cyanato carboxylic acid esters starting from a-amino acid esters has been devised [314], The isocyanates are obtained in enantiomerically pure form (> 99% ee) by a DMAP-catalyzed isocyanation with B0C2O, which proceeds in 10 min at room temperature (for typical procedures employing B0C2O, see the B0C2O Section of the present chapter). In situ derivatization of the isocyanates by reaction with amines and alcohols affords the corresponding enantiopure ureas and carbamates. Methyl esters of various amino acids 472 have been carbonylated by B0C2O at ambient temperature [314]. 

Amino acid esters 523 are readily converted to isocyanates 524 with phosgene [377], and these will react with tert-butyl alcohol to form Boc-amino acids 525. 

Carbonimidodithioates 1080, which can be regarded as thioketals of isocyanates, are easily prepared by reaction of primary amines or amino acid esters with CS2, followed by methylation with Mel. These compounds are converted into S-methyl-thiocarbamates 1081 in good yields upon treatment with ZnCh in MeCN/H20 (3 1) at 60 °C for 6-10 h. S-Methylthiocarbamates 1081 can also be conveniently prepared from 5,S-dimethyldithiocarbonate (DMDTC) 786, as described in Section 4.3.2 Carbamates . 

P-Amino acids — Alkene + isocyanate p-Amino esters... 

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