3-diketone asymmetrical reduction yeasts

Much the same situation pertains to the asymmetric reduction of diketones and ketoesters. Thus, some years ago, a yeast reduction of the diketone (12) formed a key step in the preparation of important steroids (Scheme 9). Work in... 

Baker s yeast offers the synthetic chemist an enzymatic method for the asymmetric reduction of p-keto esters, a-hydroxyaldehydes and ketones, and p-diketones. Reviews (a) Rene Csuk, R. Glaenzer, B. 1. Chem. Rev. 1991, 91, 49-97. (b) Servi, S. Synthesis, 1990, 1-25. 

Our synthesis started from hydroxy ketone B (Figure 5.31), which was obtained by asymmetric reduction of prochiral diketone A with fermenting baker s yeast.38 The key step in the present synthesis was the ring formation by intramolecular alkylation of C to give D. To obtain C, the enfifo-hydroxy group of B was first epimerized via retro-aldol/aldol by treatment with p-toluenesulfonic acid in carbon tetrachloride. The tricyclic intermediate D was converted to (+)-pinthunamide (146), mp 187-189°C, [a]D215 = +60 (EtOH), which was identical with the natural product. Its absolute configuration was thus determined as depicted in 146.39... 

The first experiments made by Neuberg and Nord with the simplest diketone, diacetyl, showed at once that this substance can be hydrogenated phytochemically with comparitive ease. Acetylmethylcarbinol appears as an intermediate (see below), and the end product of reduction is asymmetric and levorotatory. Reduction was effected by the action of fermenting yeast on diacetyl. The 2,3-butanediol that is formed can be isolated by alcohol-ether extraction of the fermentation mixture after concentration in the Faust-Heim apparatus or by steam distillation in an atmosphere of carbon dioxide under ordinary pressure it is then carefully concentrated with the birectifier and obtained in the pure state by final fractionation. 

Similar reduction of a prochiral diketone C with another yeast, Pichia terricola afforded D, which was converted to JH I,28 JH II,28 JH 029 and 4-methyl JH I.30 In the case of (+)-4-methyl JH I, asymmetric hydrolysis of dimethyl 3-methylglutarate with pig-liver esterase (PLE) was also employed for its... 

The selective enzymatic reduction of 2-substituted / -keto esters or /S-diketones is more interesting than that of unsubstituted compounds since two stereogenic centers can be introduced into the molecule in one step. The observation that baker s yeast reduction of these compounds results in predominantly one of the four possible diastereomeric products has been explained by a keto- enol equilibration of the enantiomeric / -dicarbonyls with the simultaneous removal of one of these substrates by an asymmetric reduction49. 

The methods of condensation and cyclization have recently been considerably improved. It has been found that in the presence of 1 mole of base no condensation takes place at the same time, when the vinyl car-binol (169) is heated with the methylcyclopentanedione in alcoholic solution the yield of (394) increases to 70%. This shows that the base is unnecessary and in this case, apparently, the reaction is an acid-base interaction of a 1,3-diketone and a vinyl carbinol with the intermediate formation of an ion pair. This assumption is confirmed by the fact that the thiouronium salt (392) obtained from (169) and thiourea in acetic acid react with the methylcyclopentanedione in aqueous solution even at room temperature forming (394) with a yield of about 85% on the (169) [497]. It has also been shown that the reaction of the vinyl carbinol (169) with methylcyclopentanedione in a mixture of acetic acid and xylene (1 2) at 120 C enables the estrapentaene (395) to be obtained directly in one stage with a yield of 60-65% [497]. Finally, the microbiological reduction of one of the keto groups of compound (394) using the yeast Saccharomyces uvarum proved to be an asymmetric synthesis in which it was possible to obtain the d-enantiomer of the dihydro derivative with the required configuration of the centers of asymmetry at C13 and C17 with a yield of about 70%. Its subsequent cyclization and further reactions by Scheme 39 led... 

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