7-Keto acids synthesis

A number of aryUead triacetates were synthesised in this section of the PhD project to be utilised in the C-arylation of p-keto aUyl esters. In total, 11 aryUead triacetates were prepared according to the synthetic methods described in Sect. 4.7.1. AU of the aryllead reagents were prepared using Pb(OAc)4, either by direct plumbalion or by transmetallation from the corresponding aryl stannane or aryl boronic acid. The synthesis of all of the aryllead triacetates used in this project has been previously reported, many for the first time by this research group [53, 80, 81, 99]. 

The reaction scheme for enzymatic synthesis of 7-ACA from c halosportn C is shown in Figure 1. The pathway involves the oxidative deamination of cephalosporin C into 7 P (5cephalosporanic acid (keto-AD-7-ACA) by DAO. A portion of the product further reacts nonenzymatically with hydrogen peroxide, which is formed as a by-product in the above reaction, to give GL-7-ACA. GL-7-ACA is hydrolyzed by GL-7-ACA acylase to 7-ACA. C7 side chains of cephalosporin C, keto-AD-7-ACA, and GL-7-ACA ate hydrolyzed by GC acylase to 7-ACA. However, the CC acylase activity for cephalo xirin C is low compared with that for GL-7-ACA. 

Robinson s synthesis of alkaloid tropinone (24), an achiral, wso-structure, represents an elegant application of the Mannich reaction to dialdehyde 21, methyl-amine 22, and C-H acid keto-diester 23 (Scheme 8.9) [42]. 

Ng, E.P.J., Y.-F. Wang, and S. Chiba. 2011. Manganese(III)-catalyzed formal [3-1-2] annulation of vinyl azides and 3-keto acids for synthesis of pyrroles. Synlett 6 783-786. 

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acld in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acrtophenone phenylhydrazone (I) gives 2-phenyllndole (I V). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

The thermal decarboxylation of p keto acids is the last step in a ketone synthesis known as the acetoacetic ester synthesis The acetoacetic ester synthesis is discussed in Section 21 6... 

The carbon-carbon bond forming potential inherent m the Claisen and Dieckmann reac tions has been extensively exploited m organic synthesis Subsequent transformations of the p keto ester products permit the synthesis of other functional groups One of these transformations converts p keto esters to ketones it is based on the fact that p keto acids (not esters ) undergo decarboxylation readily (Section 19 17) Indeed p keto acids and their corresponding carboxylate anions as well lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation... 

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

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