Chiral lactone optical resolution

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

D-(-)-Pantoyl lactone 1s a key intermediate for the synthesis of pantothenic acid which is a member of the vitamin B-complex and is an important constituent of Coenzyme A. Although D-(-)-pantoyl lactone has been obtained by classical optical resolution using quinine, ephedrine, and other chiral amines, catalytic asymmetric synthesis appears to be more effective... 

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. 

Many more examples can be found in the recent literature [108]. Another esterase process is described in more detail here. It is the optical resolution of d,l-pantoyl lactone (d,l-PL) by a fungal lactonase. The D-isomer is a key component in the vitamin pantothenic acid and in coenzyme A. d,l-PL is easily produced by adding HCN to the aldol of formaldehyde and isobutanal with subsequent acidic lactonization. For commercial production of D-PL the racemate can be resolved by chiral amines. 

We found in our laboratory, a novel lactonohydrolase that catalyzes reversible hydrolysis of various lactones including aldonate lactones and aromatic lactones. The enzyme was crystallized from Fusarium oxysporum and characterized. It has been shown that the enzyme hydrolyzes only D-pantoyl lactone, a chiral intermediate for the commercial production of D-pantothenate, in a racemic mixture of pantoyl lactone and that the enzyme is very useful for the optical resolution of racemic pantoyl lactone (Fig. 3)7. When F. oxysporum mycelia entrapped in calcium alginate gel were incubated in 30% solution of DL-pantoyl lactone, almost stoichiometric hydrolysis of D-pantoyl lactone was observed. After repeated reactions for 150 times over 150 days, the mycelia retained more than 90% of their initial activity. A 1,000... 

Asymmetric lactonization of prochiral diols has been performed vsdth chiral phosphine complex catalysts (Ru2Cl4((-)-DIOP)3 and [RuCl((S)-BINAP)(QH6)]Cl [17, 18]. Kinetic resolution of racemic secondary alcohol was also carried out with chiral ruthenium complexes 7 and 8 in the presence of a hydrogen acceptor, and optically active secondary alcohols were obtained with >99% e.e. (Eqs. 3.7 and 3.8) [19, 20]. 

Kinetic resolution of chiral acetals has been effected by use of some organoaluminum reagents [84], On treating a chiral acetal 88, derived from (2, 4/ )-(-)-pentanediol, with -Bu3A1 at room temperature, one diastereomer was found to react much faster than the other, and the residu enol ether is transformed into optically pure ketone. The efficiency of this method is demonstrated by a concise synthesis of (5)-(-)-5-hexadecan-l,5-lactone (89), the pheromone of Vespa orientalis, as shown in Sch. 56. 

About 6,0001 of the animal feed additive calcium-D-pantothenate are produced annually via D-pantolactone (d-112) (Scheme 35, left side).D-Pantolactone itself is an important chiral intermediate for chemical synthesis and a chiral resolution agent for optically pure amines. Optically pure d-112 is for instance produced by Fuji Chemical Industries by using the D-specific 1,4-lactone hydroxy-acylhydrolase from Fusarium oxysporum [100-102], an enzyme that catalyzes the stereospecific hydrolysis of various kinds of lactones. Treatment of mc-112 leads to an exclusive hydrolysis of d-112 the hydroxy acid d-113 can be easily separated from the remaining lactone l-1 12 and is subsequently chemically con-... 

Chemical resolution of a meso-elio/. Acylation of the symmetrical meyo-diol ciy-2-cyclopentene-l,4-diol (2) with 1 equiv. of the chiral reagent 1 in pyridine affords a mixture of the monoesters 3 and 4 in 517 yield, together with some of the diester. The mono esters were separated readily by fractional crystallization to give pure, optically active 3 and 4. These esters were converted into the (+ )-and ( —)-5 hydroxy ethers, respectively, and then into the optically active lactones ( + )- and (—)-6 by Claisen rearrangement and lactonization (6, 608-609). These lactones have been converted into both natural and unnatural prostaglandins. See scheme (I) at top of page 321. 

The kinetic resolution should be considerably enhanced if a chiral dicar-boxylic acid capable of ring formation to both 6-hydroxy groups of skyrin would be applied. We selected for this purpose 6,6 -dinitrodiphenic acid dichloride (32) which can easily be obtained in both enantiomeric forms. Reaction of (+)-(R)-binaphthol 31 with racemic 32 afforded the (+)-lactone 33, [a]p +213°, whereas the unreacted acid 34 showed a negative rotation (Scheme 7). Further investigations with the optically pure reagents indicated that (+)-(R)-31 forms only a lactone 33 with (+)-(R)-32 whereas (-)-( )-31 reacts only with (-)-( )-32. The same results were obtained with tetrachlorodiphenic acid dichloride. Similar observations have recently been published by Miyano and co-workers (ref. 20) for 1,1 -binaphthyl-2,2 -dicarboxylic dichloride. 

Lastly, the lactone was formed from the amino acid by Reaction (4). The resolution of the amino ester was done via the formation of diastereo-isomeric salts with (+) or (-)-dibenzoyltartaric acid, as described by Testa et al. The amino ester chiral precursor was shown to have an enantiomeric excess of 80%. It was then assumed that racemizatlon did not occur during the following steps of the monomer synthesis or during the polymerization. This assumption was indirectly verified by the measurements of a melting point of 260 C for the optically active polymer as compared to 11 0 C for the racemic polymer. 

Recently, some chiral Af-oxyls were effective for asymmetric desynunetrization or kinetic resolution to afford optically active lactone or alcohols (Fig. 1) [13-16]. 

In addition to the previously mentioned chirons, albeit with less frequency, a variety of other chiral precursors have been used in the synthesis of natural 5,6-dihydropyrones [3]. Some of them have been prepared with the aid of enzymes. For example, a synthesis of both enantiomers of the natural dihydropyrone rugulactone was based on the enzymatic resolution of the racemic ester 37, obtained in four steps from 1,3-propanediol (Scheme 2.8) [lOh]. Thus, enzymatic hydrolysis of 37 was best catalyzed by a lipase isolated from Candida rugosa and afforded optically enriched (ii)-ester 38 and (S)-alcohol 39. Saponification of 38 was followed by desilylation and selective oxidation of the primary alcohol function to yield aldehyde 40. Still-Gennari olefination of 40 provided Z-a,fl-enoate 41, easily cycUzed to lactone... 

Chiral 6-substituted 5,6-dihydro-2H-p3ran-2-ones (a,p-unsaturated y-lactones) are key structural intermediates of a variety of natural products tiiat exhibit antifungal and antitumor activity [209]. Hasse and Schneider [210] prepared both enantiomeric series of a variety of optically pure 6-alkylated y-lactones via an enzyme-mediated route. The key step in the process was the ring opening of enantiomerically pure alkyloxiranes 117, accessible via the corresponding a-hydroxythioethers 118, which were obtained enantiomerically pure by the lipase-catalyzed kinetic resolutions (Fig. 41). 

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