Microbial lactone synthesis

Microbial Lactone Synthesis Based on Renewable Resources... 

Macrocyclic lactones as microbial siderophores, synthesis and structure in solution 84CRV587. 

Micafungin (21 Mycamine / Funguard ) FR901379 Macrocyclic lipopeptido- lactone Semi-synthetic NP Microbial Antifungal Inhibits fungal cell wall synthesis 186, 208-210, 248-260... 

The biotechnological synthesis of lactones has reached a high standard. Besides microbial production, lactones can also be enzymatically produced. For instance, a lipase-catalysed intramolecular transesterification of 4-hydroxy-carboxylic esters leads enantioselectively (ee>80%) to (S)-y-lactones the chain length may vary from C5 to Cl 1 [13]. y-Butyrolactone can be produced in that way with lipase from Mucor miehei [30]. 

Figure 12 Synthesis of chiral synthon for thromboxane A2 antagonist (A) stereoselective microbial oxidation of (exo,exo)-7-oxabicyclo[2.2. l]heptane-2,3-dimethanol (36) to the corresponding lactol (33) and lactone (34) (B) asymmetric enzymatic hydrolysis of (exo,exo)-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol, diacetate (37) to the corresponding S-(—)-monoacetate ester (38).

The development of a novel production system for D-pantoyl lactone (which is a lactone compound carrying a chiral hydroxy group and a chiral intermediate for the commercial production of D-pantothenate) by microbial asymmetric reduction has been undertaken. D-pantothenate is mainly used in various pharmaceutical products and as an animal feed additive, the current world production of calcium pantothenate being about 6,000 tons per year. Conventional commercial production of D-pantoyl lactone has depended exclusively on chemical synthesis involving optical resolution of a chemically synthesized racemic pantoyl lactone, which is the most troublesome step of the pantothenate synthesis process. 

Another Important attribute of whole cell/enzyme systems is for the production of optlcally-actlve compounds. As early as the 1950s, the synthesis of optically active gamma- and delta-lactones by microbiological reduction was demonstrated (18). Production of optlcally-pure L-glutamate for use in the flavor enhancer MSG by microbial means is another testimonial to this potential of biotechnology. 

Another example of a highly regio- and enantiospccific microbial Baeyer-Villiger reaction is the transformation of racemic bicyclic ketone 17 by Acinetobacter TD 63433. This leads to chiral lactones 18 and 19 which are of particular interest as synthons for prostaglandin synthesis. Interestingly, each enantiomer of the racemic substrate reacts with a different regioselectivity for the oxygen atom insertion, and the enantioselectivity of the reaction is excellent. 

Azides (175 X = OH) were resolved through microbial reduction of p-keto esters (181) with baker s yeast and provided the azido dienes (182) and (183) in about 70% ee in an approach to enantiocontrolled synthesis of pyrrolizidines (equation 55). In this series extensive racemization toc place prior to or during the vinylaziridine formation. A conversion of chlorobenzenediol (184) to lactone (185) and elaboration of this material to either enantiomer of trihydroxyheliotridane (187) constituted a fully enantiocontrolled approach to both enantiomeric series of highly oxygenated pyrrolizidine alkaloids (Scheme 41).2 ... 

Although reductases play an important role in the in vivo synthesis of many chemicals (see flavour example in Fig. 7.11), little attention has been paid to this type of biocatalyst. In most cases whole microbial or plant cells are used to perform a bioreductive reaction due to the requirement for (expensive) cofactors. Typical examples include the reduction of certain double bonds in terpenes by plant cells [27,41], the reduction of Massoi lactone to R(+)-8-decalactone by Basidiomycetes and S. cerevisiae [28], and the baker s yeast-catalyzed reduction of ketones to (chiral) alcohols [42]. 

One of the key Intermediates in Corey s total synthesis of prostaglandins is the lactone (35) whose optically active form was obtained by resolution of (+) 36. Upon analysis of the sequence of reactions from cy-clopentadiene to 35 one would readily visualize the possibility of carrying out microbial resolution of various Intermediates along the synthetic pathway. One such resolution has been accomplished by microbial reduction of the (+) ketone 37 with Saccharomyces drosophylarum to yield the (+) exo and (-) endo alcohols (38 and 39). These were separated by chromatography and were oxidized to the optically active ketones (37).63 One of these was converted to 36. 4... 

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