Amino acids halides

LA Carpino, M Beyermann, H Wenschuh, M Bienert. Peptide Synthesis via amino acid halides. Ace Chem Res 29, 268, 1997. 

L. A. Carpino, M. Beyermann, H. Wenschuh, M. Bienert, Peptide Synthesis via Amino Acid Halides, Acc. Chem. Res. 1996, 29, 268-274. 

Carpino LA, Beyermann M, Wenschuh H, Bienert M. Peptide synthesis via amino acid halides. Acc. Chem. Res. 1996 29 268-274. 

Use of Protected Amino Acid Halides Acid Chlorides... 

Although the first application of acid chlorides in peptide synthesis was reported in the 1930s, the tendency for urethane-protected amino acid halides to convert into oxazol-5(4//)-ones, which are less reactive intermediates, has sometimes negated the benefits from employing this kind of active species. 

Azirine/oxazolone method, a synthetic method for the introduction of sterically highly hindered a,a-disubstituted a-amino acids into peptides. The synthesis of e.g., Aib-rich peptides requires either highly reactive coupling reagents (e.g., amino acid halides) or special derivatives (such as 3-amino-2H-azirines or a-azido carboxylic acid chlorides). The azirine/oxazolone method utilizes an amino component that... 

Nucleophilic substitution by ammonia on a-halo acids (Section 19.16) The a-halo acids obtained by halogenation of carboxylic acids under conditions of the Hell-Volhard-Zelinsky reaction are reactive substrates in nucleophilic substitution processes. A standard method for the preparation of a-amino acids is displacement of halide from a-halo acids by nucleophilic substitution using excess aqueous ammonia. 

The hydrazinolysis is usually conducted in refluxing ethanol, and is a fast process in many cases. Functional groups, that would be affected under hydrolytic conditions, may be stable under hydrazinolysis conditions. The primary amine is often obtained in high yield. The Gabriel synthesis is for example recommended for the synthesis of isotopically labeled amines and amino acids. a-Amino acids 9 can be prepared by the Gabriel route, if a halomalonic ester—e.g. diethyl bromomalonate 7—is employed as the starting material instead of the alkyl halide ... 

The A-phthalimidomalonic ester 8 can be further alkylated at the malonic carbon center with most alkyl halides, or with an o ,/3-unsaturated carbonyl compound thus offering a general route to a-amino acids 9. 

Amino acids can be prepared by reaction of alkyl halides with diethyl acelamidomalonate, followed by heating the initial alkylation product with aqueous 1-ICl. Show how you would prepare alanine, CH3CH(NH2)C02H, one of the twenty amino acids found in proteins, and propose a mechanism for acid-catalyzed conversion of the initial alkylation product to the amino acid. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

Problem 26.6 What alkyl halides would you use to prepare, the following a-amino acids by the amidomalonate method ... 

Amidomalonate synthesis (Section 26.3) A method for preparing a-amino acids by alkylation of diethyl amidomalonate with an alkyl halide. 

Heteroarylphenylalanines could be smoothly obtained via microwave-promoted Suzuki reaction of heteroaryl halides with 2-amino-3-[4-(dihy-droxyboryl)phenyl]propanoic acid (Scheme 28) [46]. Interestingly, the free amino acid could be used without any protection of the amine and carboxylic acid fimctionahty. When 4-(dihydroxyboryl)-L-phenylalanine was used as organometallic partner no racemization was observed. The carboxylate anion and free amino group seem to shield the a-C - H from deprotonation and thus hmit racemization. 

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