Amino esters from carboxylic acids

General. Diphenyl phosphorazidate is a readily available, nonexplosive, and relatively stable azide widely used as a reagent in peptide synthesis, " and as a versatile reagent in a wide array of organic transformations. DPPA has been successfully utilized in the synthesis of a-amino acids and o-aryl carboxylic acids direct preparation of thiol esters from carboxylic acids and thiols the stereospecific preparation of alkyl azides and the phosphorylation of alcohols and amines The application of DPPA in a modified Curtius reaction permits a simple one-step conversion of carboxylic acids to urethanes under mild reaction conditions. DPPA acts as a nitrene source, and can undergo 1,3-dipolar cycloaddition reactions. The Curtius degradation of carboxylic acids in the presence of f-butanol gives the Boc-protected amine directly (eq 1). 

A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc cluster Zn4(0C0CF3)60 as catalyst, essential for condensation and cyclodehydration reactions. For example, the use of (5)-valinol allowed the easy synthesis of oxazolines 125 and 126 in satisfactory yields <06CC2711>. A one-pot direct preparation of various 2-substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent <06TL6497>. 

Procedures A and B illustrate the two current methods for preparation of N-9-phenylfluoren-9-yl derivatives of amino acids and amino acid esters. Free carboxylate (as in alanine in Step A) or free hydroxyl (e.g., serine7) functions can be blocked for the duration of the reaction as trimethylsilyl (TMS) esters or ethers, respectively, by treatment with chlorotrimethylsilane and triethylamine. The TMS group(s) are then removed by methanolysls from carboxylic acids (as in Step A) and mild acidic hydrolysis from hydroxyl groups, both being accomplished during product isolation. In addition to 2, the N-9-phenylfluoren-9-yl derivatives of serine,7 glutamic add y-methyl ester,8 and aspartic acid 3-methyl ester3 9 have been prepared in this manner. 

Carboxylic acid azides are prepared from carboxylic acid halides or from amino acid/peptide esters via hydrazides, followed by nitrosylation with nitrous acid in water or with alkyl nitrites in organic solvents.Also, the aforementioned diphenylphosphorazidate cf. Section 2.3.1.1.2.2.ii.e) is often used in this preparation method starting from carboxylic acids. 

DCC can be used to prepare 5-alkyl and 5-aryl thiocarboxylates (1) from carboxylic acids and thiols according to equation (5). This method has been successfully applied to the synAesis of thiol esters with sensitive substituents, e.g. 5-methyl thioacrylate, a natural product. In particular, N-protected amino acid and peptide 5-phenyl esters, which are useful building blocks in peptide synthesis, are obtained in excellent yields without racemization. N-Hydroxyphthalimide and DMAP have been used as cocatalysts to facilitate the reaction. The preparation of the Wittig reagent (5) by this route is shown in equation (6). 

Many intracellular proteins can be modified after their biosynthesis by the enzymatic addition of a methyl group from S-adenosylmethionine. These posttransla-tional reactions can permanently or temporarily modify the structure and function of the target proteins. Importantly, these modifications can expand the repertoire of the cellular chemistry performed by proteins. Unmodified proteins must function with only the 20 amino acid residues incorporated in ribosomal protein synthesis, while methylation reactions can create a variety of new types of residues for specialized cellular roles. At this point, we understand best the processes that reversibly form methyl esters at carboxylic acid residues. One such reaction in bacteria methylates glutamate residues on several membrane-bound chemorecep-tors whose signaling properties are modulated by the degree of modification at multiple methylation sites. Another methylation system in higher cells leads to C-terminal methyl ester formation on a variety of proteins such as the small and... 

Esters of tertiary alcohols may not be prepared from carboxylic acids containing acidic a-protons using this modified procedure, since deprotonation and subsequent condensation, competes. However, the use of stoichiometric 1,8-Diazabicyclo[5.4.0]-undec-7-ene as base has been shown to provide good yields of i-butyl esters even for acids with acidic a-protons (eq 3). This procedure was unsuccessful for pivaUc acid or for IV-acyl-a-amino acids. 

Amides from Carboxylic Acids Peptide Synthesis. Analogous to ester formation, reaction of equimolar amounts of a carboxylic acid and (1) in THF, DMF, or chloroform, followed by addition of an amine, allows amide bond formation. The method has been applied to peptide synthesis (eq 5). One equivalent of (1) is added to a 1M solution of an acylamino acid in THF, followed after 1 h by the desired amino acid or peptide ester. The amino acid ester hydrochloride may be used directly instead of the free amino acid ester. An aqueous solution of the amino acid salt can even be used, but yields are lower. 

Amides are compounds derived from carboxylic acids and amines, involving elimination of water (similar to ester formation from acids and alcohol). Amide functional groups are quite resistant to hydrolysis, and amide linkages between amino acids and peptides are essential to the stability of proteins. Acetaminophen, a well-known anti-inflammatory drug, is a simple amide formed from 4-hydroxy-phenylamine and acetic acid. 

Tropane alkaloids comprise a large group of bases occurring predominantly in the family of the Solanaceae. Structurally they are esters of carboxylic acids with tropine (3-hydroxy-8-aza-8-methyl-[3.2.1]-bicyclooctane) and are biosynthetically derived from amino acid and acetate precursors. Despite the relative structural simplicity of the alkaloids, their biosynthesis is not well understood from a mechanistic point of view. In this article the available information pertaining to this question is summarized and discussed in context with the information that is available from the analogous pelletierine class of alkaloids. A new proposal for the mechanism of assembly of the acetate derived C, fragment of these alkaloids is introduced. 

Carboxyl Activation Synthesis of Esters and Amides from Carboxylic Acids. 4-(Dimethylamino)pyridinium chlorosulfite chloride is more reactive than either thionyl chloride or thionyl chloride/pyridine for carboxyl activation. Aliphatic and aromatic, as well as amino acids (in racemic form), undergo activation (via the acyl halide) and subsequent esterification by reaction with an alcohol at — 20 °C (eq 1). The esterification step requires the addition of a second equivalent of DMAP and this method has been applied to a range of functionalized carboxylic acids. 

Alcohols from carboxylic acid esters Selective reduction s. 12, 110 2-Amino-l,3-diols from ) -ketocarboxylic acid esters... 

Phthalocyanine sulfonic acids, which can be used as direct cotton dyes (1), are obtained by heating the metal phthalocyanines in oleum. One to four sulfo groups can be introduced in the 4-position by varying concentration, temperature, and reaction time (103). Sulfonyl chlorides, which are important intermediates, can be prepared from chlorosulfonic acid and phthalocyanines (104). The positions of the sulfonyl chloride groups are the same as those of the sulfonic acids (103). Other derivatives, eg, chlormethylphthalocyanines (105—107), / /f-butyl (108—111), amino (112), ethers (109,110,113—116), thioethers (117,118), carboxyl acids (119—122), esters (123), cyanides (112,124—127), and nitrocompounds (126), can be synthesized. 

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