Homologation of acids

While the direct carbonylation is well accepted by industry, the reductive and oxidative carbonylations are still in the research and development stage. Using Texaco technology (j, 7/ ) the combined synthesis of ethene and ethanol is feasible via homologation of acids according to Figure 3. Ethene can also be obtained from the reductive carbonylation of methyl acetate to ethyl acetate followed by pyrolysis (2 ). Both routes, so far, lack selectivity. 

Reactions based on syngas, in analogy to hydroformylation, have been performed as well. These include aminomethylation [85], amidocarbonylation (see Section 2.1.2.4), homologation of acids [86] and alcohols, (cf. Section 3.2.7) [87] or silyl-formylation (cf. Section 2.6) [88]. All these reactions are far beyond the scope of this chapter and are not discussed further here. 

Homologation of acids (esters). a-Chloro-a-phenylsulfinyl ketones are the condensation products of esters with chloromethyl phenyl sulfoxide. On treatment with t-BuLi-KH these ketones are converted to potassium alkynoxides, which can be transformed into acids through hydration. 

The reduced form of mevalonic acid, compound CXXIX, has been found to be more active than the two dehydrated isomers of this acid, namely, CXXX and CXXXI, respectively [320]. The j8-y-unsaturated acid has been reported to reduce serum and liver concentration of cholesterol in the rat at a dose of 300 mg per kg/day [321]. The homolog of this acid, substance CXXXII, was found to be twice as active when tested under the same conditions [322]. The lower homolog of acid CXXXI, 2-methyl-2-butenecarboxyhc acid (CXXXIII) has been reported not only to decrease serum cholesterol levels but also to prevent the development of atherosclerotic lesions in rats receiving an atherogenic diet [323]. Amides of hydroxy carboxylic acids, e.g. the unsubstituted amide and the iV-phenylethylamide of y-hydroxybutyric acid (CXXXI V), have been reported in the patent literature to be useful hypocholesterolemic agents [324,325]. 

Arndt-Elstert homologation of acids to amides. page 204... 

Stage. Using Texaco technology the combined synthesis of ethene and ethanol is feasible via homologation of acids [10]. 

Figure 7.47 Carbon-14 labeling through CH2N2 mediated homologations of acid chlorides and ring expansions...

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Synthesis of a-Chiral and Homologated Aldehydes, Acids, and P-Chiral Alcohols. 

The lac repressor monomer, a chain of 360 amino acids, associates into a functionally active homotetramer. It is the classic member of a large family of bacterial repressors with homologous amino acid sequences. PurR, which functions as the master regulator of purine biosynthesis, is another member of this family. In contrast to the lac repressor, the functional state of PurR is a dimer. The crystal structures of these two members of the Lac I family, in their complexes with DNA fragments, are known. The structure of the tetrameric lac repressor-DNA complex was determined by the group of Mitchell Lewis, University of Pennsylvania, Philadelphia, and the dimeric PurR-DNA complex by the group of Richard Brennan, Oregon Health Sciences University, Portland. 

The position of the keto group of A-homo-5a-cholestan-3-one (5b) was determined by Nelson and Schut by an unambiguous synthesis of ketone (5b) involving bis-homologation of 2,3-seco-5a-cholestane-2,3-dioic acid (8) using the Arndt-Eistert sequence [(9) (11)]. 

Instead of a-halo esters, related reactants can be used e.g. the a-halo derivatives of ketones, nitriles, sulfones and A,A-disubstituted amides. The Darzens condensation is also of some importance as a synthetic method because a glycidic acid can be converted into the next higher homolog of the original aldehyde, or into a branched aldehyde (e.g. 5) if the original carbonyl substrate was a ketone ... 

The tricyclic antidepressants (as well as, incidentally the antipsychotic drugs) are characterized by a three carbon chain between the ring system and the basic nitrogen. Incorporation of one of those carbon atoms into an additional fused ring is apparently consistent with activity. Preparation of this compound involves first homologation of the side chain. Thus the carboxylic acid 147 is first converted... 

This explanation is probably applicable to the results recorded by Paesy, who found that with the homologous aliphatic acids the strength of the odour—as measured by the reciprocal of the smallest quantity that could be perceived—of formic acid is comparatively small, a maximum is reached with butyric acid and after diminution to the weak oenanthic acid, another maximum is reached with pelargonic acid, thereafter the odour diminishes very rapidly. 

In view of this result, it becomes almost imperative to inquire whether the same method might be given wider application—whether, in discussing the small differences between homologous organic acids, we should pay attention to the possible states of order-disorder in the co-spheres... 

Azetidine-2-carboxylic acid, the lower homolog of proline, has been isolated from Convallaria majalis (lily of the valley) 40,44), Polygonatum officinalis (Solomon s seal) 153), and Polygonatum multiflorum 45). Fowden and Steward 47) surveyed plants from 56 genera for nitrogenous compounds and found azetidine-2 -carboxylic acid to be restricted to members of the Liliaceae. In some species it was identified in leaf, stem, and root but was more commonly found in the seed. In Polygonatum, azetidine-2-carboxylic acid accounted for 75% or more of the total nonprotein nitrogen in the rhizome 45). There was no evidence that it occurred as a constituent of protein. 

In the soil, an imbalance of amino acids, the presence of D-amino acids derived from microbial metabolism, or analogs and homologs of constituent protein amino acids could produce a deviation in the... 

The paraffin wax is oxidized by air in a liquid phase process at 110-130°C. Catalysts for this radical reaction are cobalt or manganese salts [54]. The quality of the obtained mixture of homologous carboxylic acids is impaired by numerous byproducts such as aldehydes, ketones, lactones, esters, dicarboxylic acids, and other compounds. These are formed despite a partial conversion of the paraffin and necessitate an expensive workup of the reaction product [50,55]. 

A two-step procedure was required for the preparation of a diverse set of pyrrole-3-carboxylic acid derivatives. The diketone 15 was prepared using a functional homologation of a 6-ketoester 14 with different aldehydes followed by oxidation with PCC. The Paal-Knorr reaction was carried out in AcOH in a sealed tube under microwave irradiation (180 °C, 5-10 min) to give differently substituted pyrroles with a COOMe group in position 3 (Scheme 5). This group was further transformed to expand the diversity of the products prepared with this method [32]. 

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