Meso-diols, oxidative lactonization

The latter were transformed into (+)-64, (-)-65 and (+)-66, respectively, in good yields. Lactone (+)-66 was also prepared in 37 % yield by stereospecific Horse Liver Alcohol Dehydrogenase (HLADH) catalyzed oxidation of the meso-diol 67. Lactones (-)-64 and (+)-64 are potentially interesting starting materials for the... 

As for oxidation reactions catalyzed by HLADH, the most frequently reported method is the coupling with FMN [222-224], It has been used for instance for the oxidation of many meso-diols forming lactones [250, 251], or for the oxidation of primary alcohols to obtain chiral aldehydes [252]. Generally, these syntheses were carried out at 12 g scale within a reaction time of a few hours up to 2-3 weeks [247],... 

A thorough study of the use of HLADH for the enantioselective oxidation of meso-diols to lactones has provided a versatile and synthetically useful route to enantiomerically enriched lactones. There are two major advantages of this system in that it appears to accept a fair amount of structural variation and full experimental details are available for preparative scale oxidations. A selection of results obtained with this enzyme system is presented in Scheme 14. 

With a good route to the key meso diol 128 in hand, the authors turned their attention to desymmetrization, using the known asymmetric hydrolysis of meso diacetates by Lipase AK (Scheme 23). The meso diol 128 was first converted to diacetate 140, and then hydrolyzed with Lipase AK to cleave selectively one of the two acetates, producing chiral hydroxyester 141. Oxidation, cleavage of the acetate, and lactonization yielded the (3S,4.R) lactone 129. The corresponding lactol (3S,4 )-130 was found to be the enantiomer of the compound produced in the HLADH synthesis. 

A chiral complex was used in Ru(N0)Cl(salen )/02/UV/CHCl3 for oxidative desymmetrisation of meso-diols to optically active lactols and lactones, e.g. of cis-1,2 -bis(hydroxyhnethyl)-cyclohexane to (1/ , 6S, 7/ 5)-7-hydroxy-8-oxabicyclo[4.3.0] nonane, cf mech. Ch. 1 [363],... 

Other microorganisms and isolated enzymes have been also used for the oxidation of alcohols (Figure 26).27 Horse liver alcohol dehydrogenase was used for the oxidation of meso diols (Figure 26 (d, e)).27e,f When one of the hydroxyl groups was oxidized, cyclization proceeded spontaneously, followed by the enzyme-catalyzed oxidation, giving chiral lactones. 

Horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidoreduction of a variety of compounds [56,57], It has been demonstrated that HLADH catalyzes the stereospecihc oxidation of only one of the enantiotopic hydroxyl groups of acyclic and monocyclic meso-diols [58,59], The authors demonstrated the oxidation of meso exo- and endo-7-oxabicyclo [2.2. l]heptane-2,3-dimethanol to the corresponding enantiomerically pure y-lactones by HLADH. NAD+ and flavin adenine dinucleotide (FAD) at concentrations of 1 and 20 mmol, respectively,... 

PREPARATION OF y-LACTONES BY HLADH-CATALYZED OXIDATIONS OF MESO-DIOLS (YIELDref-). 

J. Bryan Jones and Ignac J. Jakovac 10 PREPARATION OF CHIRAL, NON-RACEMIC Y-LACTONES BY ENZYME-CATALY TED OXIDATION OF MESO-DIOLS (+)-(1R, 6S)-8-0XABICYCL0 [4.3, O]N0NAN-7-0NE... 

Another efficient method is the electrochemical oxidation of NADH at 0.585 V vs Ag/AgCl by means of ABTS2- (2,2,-azinobis(3-ethylbenzothiazoline-6-sulfonate)) as an electron transfer mediator [96]. Due to the unusual stability of the radical cation ABTS, the pair ABTS2 /ABTS is a useful mediator for application in large-scale synthesis even under basic conditions. Basic conditions are favorable for dehydrogenase catalyzed reactions. This electrochemical system for the oxidation of NADH using ABTS2 as mediator was successfully coupled with HLADH to catalyze the oxidation of a meso-diol (ws >-3,4-dihydroxymethylcyclohex-l-ene) to a chiral lactone ((3aA, 7aS )-3a,4,7,7a-tetrahydro-3//-isobenzofurane- l-one) with a yield of 93.5% and ee >99.5% (Fig. 18). 

For the synthesis of optically active 74, we used lipase to achieve asymmetric hydrolysis of meso-diacetate A (Figure 4.7) to optically active monoacetate B. The stereochemical outcome of this asymmetric hydrolysis A B was known to be as depicted through many examples. Acetylation of meso-diol C afforded meso-diacetate D, which was treated with lipase AK provided by Amano Enzyme, Inc. The product was (5R,6S)-E, whose enantiomeric purity was 97% ee as analysed by HPLC of the corresponding 3,5-dinitrobenzoate on Chiralcel-OJ . Oxidation of E furnished F, which was converted to lactone (-)-G. 

Probably the most prominent application of HLADH is the oxidation of meso-diols to homochiral lactones. Both 1,4- and 1,5-diols are accepted as substrates (Table 16.2-4). The overall 4-electron oxidations proceed via two successive steps (tandem oxidation). The enantiomeric excesses often exceed 97%. 

Diols, meso-, enzymic oxidation to y-lactones, 63, 14 DIOLS, VICINAL, EPOXIDES FROM, 63, 140 m-D1oxane, 2-(2-bromoethyD- [33884-43-4], 62, 148... 

Suzuki T, Morita K, Matsuo Y, Hiroi K (2003) Catalytic asymmetric oxidative lactonizations of meso-diols using a chiral iridium complex. Tetrahedron Lett 44 2003-2(X)6... 

As a rule of thumb, oxidation of the (S)- or pro-(S ) hydroxyl group occurs selectively with HLADH (Scheme 2.143). In the case of 1,4- and 1,5-diols, the intermediate y- and 8-hydroxyaldehydes spontaneously cyclize to form the more stable five- and six-membered hemiacetals (lactols). The latter are further oxidized in a subsequent step by HLADH to form y- or 5-lactones following the same (S)-or pro-(5) specificity [1035]. Both steps - desymmetrization of the prochiral or meso-diol and kinetic resolution of the intermediate lactol - are often highly selective. By using this technique, enantiopure lactones were derived from... 

Scheme 2.49 Asymmetric oxidative lactonization of meso diols by lr(l) [88, 94],...

Scheme 28 Enantiospecific preparation of lactones by oxidative lactonization of primary meso-diols. " ...

Unique aqueous electrolysis media have been developed and highly efficient electrochemical oxidations of alcohols were accomplished using these systems. Tanaka s group developed the anodic oxidation of alcohols mediated by N-oxyl in an aqueous silica gel disperse system (Figure 12.6) [18]. The system could be successfully applied to the kinetic resolution of sec-alcohols and the enantioselective oxidation of meso-l,4-diols, affording optically active y-lactones (Scheme 12.3). 

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