Robinson ester

Glucose 6-phosphate, Robinson ester, the key intermediate in Carbohydrate metabolism (see). 

The substance represented by formula (IV), viz., 4-hydroxy-3-allyl-3 4-dihydroqviinazoline, m.p. 130°, was synthesised by Reynolds and Robinson, and proved to be different from vasicine. Spath and Kuffner established the identity of the degradation product (V), upon which formula (IV) for vasicine was chiefly based by synthesis from isatoic anhydride, which, on treatment with glycine ester hydrochloride and sodium meth-oxide, gave the substituted Wppuric acid (VI), and this, on heating with... 

While mechanistically this reaction is related to the Robinson-Schopf reaction for the generation of the tropinone skeleton, it also has similarities to the Hantzsch reaction. Here the heterocyclic ring 75 is assembled by the condensation of an equivalent of acetonedicarboxylic ester 72 with 2 equivalents of aldehyde 73 in the presence of ammonia or primary amine 74. 

Preparation of the key tropine is achieved by any one of several variations on the method first developed by Robinson, which involves reaction of a primary amine with dihydroxyacetone and glyoxal. Reduction of the carbonyl group in the product (86) followed by acylation affords the aminoester (88). Transesterification with ester aldehyde 89... 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

The condensation of an ester enolate and a ketone can be used as part of a Robinson annulation-like sequence (see 16-38). 

Robinson EC, Hammond BG, Johannsen FR, et al. 1986. Teratogenicity studies of alkylaryl phosphate ester plasticizers in rats. Fundam Appl Toxicol 7 138-143. 

Condensation of 2,4-dihydroxypropiophenone (172) with benzoyl chloride and sodium benzoate goes to afford chromone 174, probably via ester 173. This procedure is known as the Kostanecki-Robinson reaction Methylation (175) of the remaining phenolic function by means of dimethyl sulfate, followed by reaction... 

A similar domino process involving the opening of two epoxide moieties after an enzymatic ester hydrolysis has been described by Robinson and coworkers [16]. Treatment of 8-32 with PLE in an aqueous buffer solution at pH 7.5-8 led to 8-34 in 70% yield after formation of 8-33 (Scheme 8.8). 

The starting point for the 5-fluoropentanecarboxylic esters was cyclohexanone, which was oxidized to 5-hydroxypentane-carboxylic acid by a modification of Robinson and Smith s method.3 This was then converted into the bromo acid by means of hydrogen bromide and sulphuric acid.4... 

D.R. Robinson and W.P. Jencks, The effect of concentrated salt solutions on the activity coefficient of acetyltetraglycine ethyl ester, J. Am. Chem. Soc. 87 (1965) 2470-2479. 

An alternate route to 90 commenced with the Robinson annelation of the aryl pyruvic acid 97 with methylvinyl ketone followed by dehydration and dissolving metal reduction of the resulting mixture of unsaturated acids to provide the cis-keto acid 98 (Scheme 7) (112b). Transformation of 98 to the rrans-ketal ester 99... 

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