Hydroxy lactone resolution

Hydroxylation of the sodium enolate of lactone (16) with (+)-( ) gives a-hydroxy lactone in 77% ee (eq 17). Kinetic resolution and asymmetric hydroxylation with (camphor-sulfonyl)oxaziridines has been applied to the synthesis of enantiomerically enriched a-hydroxy carbonyl compounds having multiple stereocenters, which may otherwise be difficult to prepare. Thus hydroxylation of the enolate of racemic 3-methylvalerolactone with substoichiometric amounts of (—)-(l) affords (25,3/J)-verrucarinolactone in 60% ee (eq 18) which on recrystallization is obtained enantiomerically pure. ... 

The key intermediate used for the enzymatic optical resolution was hydroxy lactone ( )-C prepared from citral via ( )-A. Treatment of ( )-C with vinyl acetate in the presence of lipase AK (Amano) effected asymmetric acetylation, and the recovered (-l-)-hydroxy lactone C as well as the acetate (+)-D were obtained. Subsequently, (+)-C was converted to (+)-strigol (51). Three stereoisomers of strigol, 51, 51" and 51 " were also synthesized. 

The same successful procedure applies to other hydroxy compounds such as hydroxy lactones [202], hydroxy amides [203], and hydroxy phosphonic acids [204,205]. The results of these enantioselective resolutions are presented in Scheme 44. 

Scheme 44 Resolution of hydroxy lactones, hydroxy amides, and hydroxy phosphonamides.

A special group of cyclic hydroxy compounds is constituted by 7-hydroxy lactones [214-217] and cyclic semiacetals [218]. For these sensitive and relatively unstable compounds, the experimental conditions of the enzymatic process seem especially attractive and well suited to obtain efficient and enantioselective resolution of racemic substrates (Scheme 47). 

Finally, the more complicated structures of tricyclic compounds that present the hydroxy ketone and hydroxy lactone moieties can be substrates for the enantioselective resolution process and some examples are presented in Scheme 52 [237,238]. 

Enzyme-catalyzed stereoselective hydrolysis allows the preparation of enantio-merically enriched lactones. For instance. Pseudomonas sp. lipase (PSL) was found to be a suitable catalyst for the resolution of 5-undecalactone and 5-dodecalactone (Figure 6.20). Relactonization of the hydroxy acid represents an efficient method for the preparation of both enantiomers of a lactone [67]. 

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

The applications of re-acidic chiral stationary phases include the resolution of a-blockers and /1-blockers, amines, arylacetamine, alkylcarbinols, hydantoins, barbiturates, naphthols, benzodiazapines, carboxylic acids, lactams, lactones, phthaldehydes selenoids, and phosphorus compounds. Hyun et al. [16] achieved a chiral resolution of a homologous series of iV-acyl-x-(l-naphthyl )cthylaminc on AA(3,5-dinitrobenzoyl-(i )-phenylglycine and N-(3,5 - dini tr o ben zoy I)-(,S ) -1 c u c ine CSPs. The authors used hexane-2-propanol (80 20, v/v) as the mobile phase. Similarly, the scope of re-basic CSPs comprises the chiral resolution of / -blockers, amino acids, amines, diamines, amino phosphonates, naphthols, benza-diazapines, carboxylic acids, hydroxy acids, dipeptides, tripeptides, diols,... 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

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. 

In 1965, Raban and Mislow [90] postulated that nuclei placed in an asymmetric magnetic field should show NMR nonequivalence. In 1966, Pirkle [91] first reported the validity of the prediction when it was shown that (5)-l-phenylmethylamine caused F-NMR nonequivalency of 2,2,2-trifluoro-1-phenylethanol in a carbon tetrachloride solution. In later studies, 2,2,2-trifluoro-l-(9-anthryl)ethanol, an NMR shift reagent, was used as a mobile-phase additive to separate 2,4-dinitrophenyl methyl sulfoxide on a silica gel column [92]. Later, one enantiomer of this fluoroalcohol was covalently attached to silica gel and used for resolution of a large number of solutes including sulfoxides, lactones, derivatives of alcohols, amines, amino acids, hydroxy acids, and mercaptans [93]. 

Optically active lactones are also readily available through this classical resolution technique. The racemic lactone is hydrolyzed to the hydroxy acid and resolved with (S)-(-)-NEA (eq 3). After crystallization, the dextro (+)-lactone is regenerated upon acidi-... 

In some cases the resolution of the diastereomeric amides on silica gel is sufficiently large to achieve preparative separation. The preparative separation of diastereomeric hydroxy amides has proved useful in supplying quantities of enantiomerically pure lactones (eq 5). ... 

Jemal, M. Quyang, Z. The Need for Chromatographic and Mass Resolution in Liquid Chromatography/Tandem Mass Spectrometric Methods Used for Quantitation of Lactones and Corresponding Hydroxy Acids in Biological Samples, Rapid Commun. Mass Spectrom. 14, 1757-1765 (2000). 

Racemic hydroxy ester 225 was converted, via a Sharpless kinetic resolution, to the enantiomerically pure epoxide 226. This epoxide was then converted to the diol "/-lactone by intramolecular attack of the ester, assisted by nucleophilic dealkylation with iodide ion. Deprotonation and methylation anti to the alkoxide followed by acetonide formation afforded 227 in 56% yield. Dibal reduction, protection of the resulting aldehyde as the terminal olefin, silylation of the tertiary alcohol, and liberation of the aldehyde via ozonolysis provided a 45% yield of the C-9 to C-15 fragment 228. 

Jemal, M. and Ouyang, Z., The need for chromatographic and mass resolution in liquid chromatography/tandem mass spectrometric methods used for quantitation of lactones and corresponding hydroxy acids in biological samples, Rapid Commun. Mass Spectrom., 14, 1757, 2000. 

The transformation of a series of norbomanone derivatives (Fig. 16.5-34) was studied by Roberts and coworkers who determined that both the MOl complement of NADH dependent BVMOs from Pseudomonas putida ATCC 17453 and the NADPH dependent fraction M02 were successful in the resolution of hydroxy, acetoxy and benzyloxy norbomanones11231. Interestingly 25DKCMO and 36DKCMO when separate, displayed notably different reactivity toward the hydroxy and acetoxy derivative, again emphasizing their complementary nature as potential individual biocatalysts. The benzyloxy lactone is an intermediate in the synthesis of the insect antifeedant azadirachtin. 

With this new approach in mind, the revised retrosynthetic analysis would utilize two different Wittig reactions to homologate the carbon side chains, providing ketoolefm (+)-16 (Scheme 13). Further disconnection revealed hydroxy aldehyde (+)-27 which could arise from a selective DIBALH reaction of lactone (+)-28. Applying Bringmann s method, lactone (+)-28 would be enantiomerically enriched via a kinetic resolution of a racemic lactone mixture. Racemic lactone ( )-28 could arise from a... 

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. 

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