Amino acids ester synthesis

Further great advances in the field of asymmetric alkylation reactions have been made by several groups working on chiral phase-transfer-catalyzed alkylation of glycinates (see also Section 3.1). A pioneer in this field is the O Donnell group [53, 54] who developed the first a-amino acid ester synthesis using this methodol-... 

T. Sakura and M. Tanaka, Reaction of ketene silyl acetals with diazonium salts A novel a-amino acid ester synthesis, Commun., (1985) 1309-1310. 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

Enzymatic hydrolysis of A/-acylamino acids by amino acylase and amino acid esters by Hpase or carboxy esterase (70) is one kind of kinetic resolution. Kinetic resolution is found in chemical synthesis such as by epoxidation of racemic allyl alcohol and asymmetric hydrogenation (71). New routes for amino acid manufacturing are anticipated. 

Thiophene-2,3-dicarboxylic acid, 4-amino-dimethyl ester synthesis, 4, 924... 

The advantages of the methoxyethyl ester over some of the other water-solubilizing esters are that many of the amino acid esters are crystalline and thus easily purified, are cleaved with a number of readily available lipases, and are useful for the synthesis of A-linked glycopeptides. ... 

CH3.(CH2)2.C(C02.C2H5XC0.N3) mw 198.23 N 21.20% OB to C02 -153.36% ypl oil, expl. Sol in eth and CC14. Prepn is by reacting the K salt, of the half (or mono) ethyl ester of propyl malonic acid with nitrous acid Refs 1) Beil, not found 2) T. Curtius W, Lehmann, Transformation of alkylated malonic acids into a-amino acids. III. Synthesis of cr-aminovaleric acid, propylmalonylazidic acid. . JPraktChem 125, 211-302 (1930) CA 24, 3215(1930)... 

The imidazolide group at the amino end of an amino acid is as reactive toward nucleophiles as the imidazolide group at the carboxylic end of an amino acid. If an N-protected amino acid is selected as nucleophile, this method can also be used for peptide synthesis. The amino-activated amino acids, for example N-( 1 -imidazolylcarbonyl)-amino acid esters, are prepared from a-isocyanatocarboxylic acids and imidazole. 

The reaction conditions for this peptide synthesis are equimolar amounts of the reagents, five to eight hours, and 75-85 °C.[44J Use of a-isothiocyanatocarboxylic acids caused the yields of peptides to be lower. Instead of A-( 1 -imidazolylcarbonyl)amino acid esters, the corresponding triazolides were also utilized in the peptide synthesis. 

Another -activation of amino acids for peptide synthesis is achieved by preparing sulfenamides from sulfenylimidazoles. A sulfenylimidazole is formed in situ from the sulfenyl chloride (prepared from the disulfide and chlorine) and imidazole, which reacts further with an amino acid ester to give a sulfenamide in high yield. Conversion of such sulfenamides with IV-acyl amino acids by means of triphenylphosphine affords dipeptides with racemization of less than 0.5%.[481... 

The other direction concerns the use of immobilized transition metal catalysts in the synthesis of libraries of organic compounds of interest in therapeutic drug discovery. One such strategy uses immobilized catalysts (e.g., scandium complexes), leading to efficient library syntheses of quinolines, amino ketones, and amino acid esters.72,73... 

Alkylation of a-amino esters with 9-bromo-9-phenylf uorene serves as the principal step in the preparation of N-(9-phenylfluoren-9-yl)-a-amino carbonyl compounds which are useful chiral educts for asymmetric synthesis. A discussion of the synthetic utility of N-9-phenylfluoren-9-yl derivatives of amino adds and amino acid esters appears in the procedure following. 

Scheme 7.2 Synthesis of 65 74ACP employing stepwise coupling of amino acid esters.

A-Thiazolyl a-amino acids 56 have been prepared. The preferred route to these compounds would utilise the Hantzsch synthesis, however in this case the in situ formation of the required thiourea derivatives of a-aminoacids 52 failed. A variety of isothiocyanate reagents were tried, with the result being either no reaction, decomposition or the corresponding thiohydantoin 53. A modified version of the Hantzsch synthesis was developed. If the bromoketone 54 is initially treated with sodium thiocyanate an a-thiocyanatoketone 55 is formed, subsequent addition of the amino acid ester 51 yields A-thiazolyl a-amino acids 56 <00T3161>. 

The addition of lithium or magnesium ester enolates to nitrones in THF at 78°C or in Et20 at — 20°C, constitutes a direct synthesis of /V-hydroxy- 3-amino acid esters (Scheme 2.180) (645). 

M. Horikawa, J. Bush-Petersen, E. J. Corey, Enantioselective Synthesis of P-Hydroxy-a-amino Acid Esters by Adol Coupling Using a Chiral Quaternary Ammonium Salt as Catalyst , Tetrahedron Lett. 1999, 40, 3843-3846. 

Co(III)-chelated amino acid ester reactant and/or peptide product (Scheme 1). This basic difficulty was quickly pointed out (5), and has subsequently been examined and commented upon by others (6, 7). Such criticisms are well-founded since epimerization (or racemization) is a common problem, at least to some degree, in all chemical methods of synthesis where acyl-activation is employed. As a result, metal-activation methods have received little attention. However, since 1981 we have refined the Co(III) method such that very fast, clean, couplings can now be carried out using A-[Co(en)2((S)-AAOMe)]3+ reagents, which involve minimal (<2%) epimerization/racemization provided experimental conditions are strictly adhered to. 

FIGURE 7.21 Synthesis of a dipeptide by reaction of an amino-acid A-carboxyanhydride (A) with an amino-acid ester in tetrahydrofuran65 and (B) with an amino acid in aqueous solution.67... 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

X. Song, P. L. Lorenzi, C. P. Landowski, B. S. Vig, J. M. Hilfinger, and G. L. Amidon. Amino acid ester prodrugs of the anticancer agent gemcitabine synthesis, bioconversion, metabolic bioevasion, and hPEPTl-mediated transport. Mol Pharm 2 157-167 (2005). 

N. M. Mahfouz, M. A. Hassan, Synthesis, Chemical and Enzymatic Hydrolysis, and Bioavailabihty Evaluation in Rabbits of Metronidazole Amino Acid Ester Prodrugs with Enhanced Water Solubility , J. Pharm. Pharmacol. 2001, 53, 841-848. 

J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, T. Aoyama, Vitamin K Prodrugs 1. Synthesis of Amino Acid Esters of Menahydroquinone-4 and Enzymatic Reconversion to an Active Form , Pharm. Res. 1995, 12, 18-23 J. Takata, Y. Karube, M. Hanada, K. Matsunaga, Y. Matsushima, T. Sendo, R. Oishi, Vitamin K Prodrugs 2. Water-Soluble Prodrugs of Menahydroquinone-4 for Systemic Site-Specific Delivery , Pharm. Res. 1995, 12, 1973- 1979. 

Dynamic Kinetic Resolution Synthesis of a Fluorinated Amino Acid Ester Amide by a Continuous Process Lipase-mediated Ethanolysis of an Azalactone... 

DKR Synthesis of a FluorinatecI Amino Acid Ester Amide 163... 

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