Formyl Meldrum’s acid

A special technique starting with formyl-Meldrum s acid has been developed for the synthesis of (9-acetyl-substituted dimenthyl methylenemalonate 8s which is a useful chiral dienophile (Section D.1.6.1.1.1.1,2.). 

Having streamlined the synthesis of acyl chloride 54, the indirect preparation of methyl enol ester 51a was addressed. As previously discussed, attempts to synthesize 53a from formyl Meldrum s acid 58 had proven unsuccessful. However, Cossy and coworkers have reported the preparation of 53a via the ozonolysis of alkene 82 and subsequent use of the crude aldehyde in the total synthesis of octalactin. Thus, methyl vinyl acetate (82) was subjected to ozonolysis at —78 °C, followed by a reductive quench to provide formyl acetate 53a (Scheme 24). The crude methyl formyl acetate was acylated with acyl chloride 54, using the previously optimized conditions, to afford methyl enol ester 51a in 74% yield over two steps. This modification to the synthesis removes a further two reactions from the sequence with a formal synthesis of (—)-7-deoxyloganin (24) now achieved in 10 steps, a length more in keeping with the complexity of this target. 

Condensation of formyl-pyrroles and -indoles with a wide range of other activated methylene compounds has been reported. These include, for example, hydantoin, which provides a useful synthetic route to tryptophane and j8- (pyrrolyl)alanines, thiohydantoin, rhodanine and AT-substituted barbituric acids (B-77MI30505, 79HC(25-3)357). Flash pyrolysis of the condensation product derived from 3-formyl-2,5-dimethylpyrrole with Meldrum s acid produces 6-hydroxy-2-methylindole, (440) — (441) (74AJC2605), whilst the analogous... 

Pyrolysis of Meldrum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione) 362 proceeds by loss of acetone and CO2 to give ketene. Because of the ready availability of the starting material and the ease with which it can be functionalized at the acidic 5-position, pyrolysis of Meldrum s acid derivatives has been widely studied. Pyrolysis of the 5-formyl and 5-acyl derivatives 363 gives formyl or acylketenes 364, which can be trapped in a number of ways170-171. in many cases, loss of acetone and CO2 is accompanied by loss of CO to give a carbene, and this is illustrated by FVP of 365 at 560 °C which affords the Q -diketone 368 by way of ketene 366 and carbene 367172. 

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