Homologated carboxylic acid derivatives, synthesis

The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines. 

It has long been known that autoxidation of aldehydes leads to carboxylic acids via a radical mechanism which involves the formation and oxidation of acyl radicals, leading to acyl cations via one-electron oxidation processes [68]. However, the recent topic in this field relates to the fact that many new synthetic methods for the synthesis of carboxylic acids derivatives have been developed which rely on the power of one-carbon homologative radical reactions. 

Arndt-Eistert synthesis A procedure for converting a carboxylic acid to its next higher homologue, or to a derivative of a homologous acid, e.g. ester or amide. 

Hi) Carboxylic acids and derivatives. The haloform reaction on thienyl methyl ketones leads to thiophenecarboxylic acids, which can be treated with Raney nickel to produce the open-chain acids. This method has been used for the five-carbon homologation of carboxylic acids and to produce dicarboxylic acids (Scheme 51). Long-chain carboxylic acids may also be prepared by using dicarboxylic acid derivatives for the acylation of thiophenes (Scheme 52). In the synthesis of Queen substance, the precursor (213) has been generated by Raney nickel desulfurization of the appropriate thiophene-2-acetic acid derivative (79T329). 

See also page 403, Section 6, for the synthesis of a,/3-unsaturated nitriles, carboxylic acids and derivatives, and page 1711, Section 4, for the homologation of carbonyl compounds. 

Electrolytic decarboxylative coupling of sodium salts of carboxylic acids takes place during their electrolysis. Carbon dioxide is eliminated, and the free radicals thus generated couple to form hydrocarbons or their derivatives. The reaction is referred to as the Kolbe electrosynthesis and is exemplified by the synthesis of 1,8-difluorooctane from 5-fluorovaleric acid (equation 469) [574]. Yields of homologous halogenated acids range from 31% to 82% [574]. 

Enantiopure l,2-cis-dihydroxycyclohexa-3,5-diene carboxylic acids have considerable synthetic potential as building blocks in chiral synthesis. Such cis-diols can be produced from benzoic acid derivatives by the action of toluate- 1,2-dioxygenase of Pseudomonas putida mt-2125 or homologous enzymes of a different origin (Fig. 16.6-... 

Homologs of pyridine, quinoline, thiophen, and various other heterocycles can be oxidized to carboxylic acids generally without destruction of the hetero ring in the pyrrole series, however, this cannot be done directly but requires intervention of an intermediate (see Fischer et al.A05). More circuitous routes are also sometimes preferable in the quinoline series for instance, in their total synthesis of hydroquinine Rabe et a/.406 obtained the 4-carboxylic acid from 6-methoxy-4-methylquinoline by oxidizing the 4-styryl derivative (obtained by reaction with benzaldehyde) instead of oxidizing the methyl compound directly. Alkyl groups at positions 2 and 4 of pyridine are more easily oxidized than those at position 3. 

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

Since the vast majority of the substrates employed in diastereoselective syntheses are attached via a carboxyl function to the respective auxihary, this chapter deals with the diastereoselective a-fiinctionalization of chiral carboximides and esters, as well as with the homologation and aldolization alternatives of chiral glycinates, glycolates and haloacetates. Also discussed is the use of chiral a,/3-unsaturated representatives in the synthesis of e.p. linear /3- and a,/3-substituted carboxyhc acid derivatives and cyclic analogs (Diels-Alder reactions). Other methods, in which substrates are coupled, for example, via a carbonyl function in order to facilitate the diastereoselective a-aUcylation of aldehydes or... 

D-glucosamine, Tetrahedron Asymm., 5, 2137, 1994 (s) Barton, D. H. R., Chern, C.-Y., and Jas-zberenyi, J. Cs., Homologation of carboxylic acids by improved methods based on radical chain chemistry of acyl derivatives of N-hydroxy-2-thiopyridone, Tetrahedron Lett., 33, 5013, 1992 (t) Barton, D. H. R., Chem, C.-Y., and Jaszberenyi, J. Cs., Two carbon homologation of carboxylic acids via carbon radicals generated from the acyl derivatives of N-hydroxy-2-thiopyridone synthesis of n-l-2 a-keto-acids from Q, acids. (The three carbon problem). Tetrahedron Lett., 33, 5017, 1992. 

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