Gas chromatographic analysis of ortho esters as a convenient new general method for determining the enantiomeric purities of chiral .delta.-lactones

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The asymmetric synthetic potential of horse liver alcohol dehydrogenase catalyzed oxidations of variously 3-substituted pentane-1,5-diols has been further delineated. The oxidations proceed with enantiotopic selectivity to give the corresponding (3S)-3-substituted valerolactones of up to 78% ee. The reactions occur via initial oxidation of the pro-S hydroxyethyl group, with the initially-formed hydroxyaldehydes undergoing further in situ enzyme-catalyzed oxidation in their hemiacetal forms to give the (3S)-lactones directly. The hemiacetal oxidation step is also stereoselective, with oxidation of the (4S)-enantiomer being much preferred. The size of the substituent at C-3 in the diols (C-4 in the hemiacetals) affects both the enantiotopic and enantiomeric specificity of the enzyme. Both types of stereospecificity are highest when the substituents are smallest, such as methyl or ethyl, and diminish progressively for diol or hemiacetal substrates bearing large aliphatic or aromatic substituents. All reactions were carried out on a preparative (up to 2 g) scale.

Section: Discussionmentioning

confidence: 97%

Enzymes in organic synthesis. 14. Stereoselective horse liver alcohol dehydrogenase catalyzed oxidations of diols containing a prochiral centre and of related hemiacetals

Jones¹,

Lok²

1979

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“…Treatment of 7 and 8 with (+)-(R.R)-2,3-butanediol afforded the orthoesters 12 and 13, whose diastereomeric ratios were determined by glc analysis (10). The orthoesters obtained from (+)-7 and (+)-8 were used as reference standards.…”

Section: Resultsmentioning

confidence: 99%

Enzymes in organic synthesis. 33. Stereoselective pig liver esterase-catalyzed hydrolyses of meso cyclopentyl-, tetrahydrofuranyl-, and tetrahydrothiophenyl-1,3-diesters

Jones¹,

Hinks²,

Hultin³

1985

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Preparative-scale pig liver esterase-catalyzed hydrolyses of five-mcmbercd ring meso-I ,3-diestcrs are enantiotopically selective. While pro-S enantiotopic selectivity is exhibited in cach case, the absolute configuration sense of the hydrolysis in the cyclopentyl series is opposite to that of both the tetrahydrofuranyl and tetrahydrothiophenyl diesters. The enantiomeric excess levels induced are in the 34-46% range.J. BRYAN JONES, R. SCOTT HINKS et PHILIP G. HULTIN. Can. J. Chem. 63, 452 (1985).Les hydrolyses prCparatives, catalysCes par I'esterase du foie de cochon, dc miso-diesters-1.3 incorports dans des cycles i cinq chainons sont tnantiostlectives. MCme si on observe une CnantiosClectivitC pro-S dans chaque cas, le sens de la configuration absolue de I'hydrolyse obtenu en serie cyclopentanique est ['inverse de celui observC avec des dicsters tant tCtrahydrofurannique que tCtrahydrothiophCnique. Les niveaux d'exces CnantionlCriques induits sont de I'ordre de 34 i 46%.[Traduit par le journal]The asymmetric synthetic opportunities provided by the abilities of enzymes to discriminate between enantiotopic groups of symmetrical substrates such as meso compounds are now widely recognized (2). Alcohol dehydrogenases (3) and esterases (4) have already proven particularly valuable in this regard. Of these two enzyme groups, esterases are the more convenient to use because they do not require expensive coenzymes.One of the synthetically most useful hydrolytic enzymes reported so far is pig liver esterase (PLE). PLE is a commercially available enzyme that is capable of effecting stereospecific hydrolyses on a broad structural range of ester substrates (4, 5). Its asymmetric synthetic potential is receiving increasing attention and recently several stereospecific PLEmediated transformations of acyclic and cyclic 1,2-diesters to useful chiral synthons have been documented (4). We now report that PLE-catalyzed hydrolyses of the monocyclic meso-1,3-diesters 1-3 also proceed with considerable enantiotopic stereoselectivity. ResultsThe cis diester substrates 1-3 were prepared by Fischer esterification of the corresponding anhydrides, obtained by literature methods (6, 7a, 8). ln the case of 1 and 2, a methanol esterification procedure was used to give the acid-esters (?)-4 and (+)-5. These were then transformed into 1 and 2 respectively by treatment with diazomethane. For 3, direct Fischer esterification of the anhydride was performed.Each of the cis diesters was a substrate of the enzyme. The rates of PLE-catalyzed hydrolyses were assayed using ethyl butyrate as the reference substrate (9). Diesters 1 and 3 were excellent substrates, with rates of hydrolysis 51% and 35% respectively of that of the ethyl butyrate standard. Although 2 was hydrolyzed more slowly, with a rate of 3% that of the standard, it remained an excellent candidate for a preparativescale reaction.' 'We currently consider that any substrate hydrolyzed at a rate 5 0.02% of that of ethyl butyrate will give good results in preparativescale hydrolyses.Prepara...

“…in benzene (25 mL) containing p-TsOH (10 mg). Following an initial lactonization to (-)-(lS,5R)-3,9-dioxabicyclo[3.3.l]nonan-2-one, the orthoester formed in the usual (8) way and was analyzed by glc (8) using the orthoester from (? )-2 as reference standard.…”

Section: Methodsmentioning

confidence: 99%

“…The alcohol-ester 2 was oxidatively converted to its corresponding lactone, and hence to the (R,R)-butane-2,3-diol orthoester, for e.e. measurement by the standard glc method (8). The e.e.…”

Section: +)-(Ss)-(cis-6-methyltetrahydropyran-2-yl)acetic Acidmentioning

confidence: 99%

“…The dried (MgS04) ether slowly. The mixture was warmed to 20°C during 30 min and then extracts were rotoevaporated to yield the civet constituent (+)-(S,S)-stirred at this temperature for 1 h. The reaction solution was then (cis-6-methyltetrahydropyran-2-y1)acetic acid (8,39 6: 21.93, 23.18, 30.76, 32.75, 41.30, yran (758 mg, 98%);ir (film) v: 3132,2109, 1737, and 164473.96, 74.43, and 175.50ppm. 'Hnmr6:0.96 (t, 3H.…”

Section: Synthesis Of the Civet Constituent (+)-(2s6s)-8mentioning

confidence: 99%

See 1 more Smart Citation

Enzymes in organic synthesis. 36. Synthesis of optically active civet constituent from an enzyme-generated chiral synthon

Jones¹,

Hinks²

1987

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. Can. J. Chem. 65,704 (1987). A synthesis of the civet constituent, (+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic acid, is described, in which the key stereochemistry of the chiral starting material is set by an enantiotopically selective, porcine pancreatic lipase-catalyzed, hydrolysis of a meso diester.J. BRYAN JONES et R. SCOTT HINKS. Can. J. Chem. 65,704 (1987). On dCcrit une synthbse du constituant du civet, I'acide (+)-(methyl-6-cis tktrahydropyrannyl-2) acttique-(S,S), dans laquelle la stkrCochimie clk du produit de dCpart chiral est obtenue par une hydrolyse CnantiosClective d'un diester mkso qui est effectuCe par la catalyse d'une lipase pancrkatique du porc.[Traduit par la revue]The broad spectrum of new asymmetric synthetic opportunities opened up by the exploration of the chiral catalytic properties of enzymes is now well documented (1). Stereospecific transformations on symmetrical substrates are particularly attractive in this regard, with the commercially available porcine pancreatic lipase (PPL) being one of the most widely applied of the enzymes in current use for this purpose (2). In this paper we report a new synthesis of the optically active civet constituent 8 from a PPL-generated chiron.(+)-(S,S)-(cis-6-methyltetrahydropyran-2-yl)acetic acid (8) is a constituent of a glandular secretion of the civet cat (3), whose synthesis, both of the optically active (4) and racemic (5) forms, has attracted considerable attention. Of these syntheses, only the latest one of Keinan et al. (4d), which exploits alcohol dehydrogenase stereospecificity, has been based on an enzymically generated chiron. Our current PPL-based approach is outlined in Scheme 1.The meso diester 1 starting material was readily prepared from 4H-pyran-2,6-dicarboxylic acid (9) (6) in 69% overall yield by the method summarized in Scheme 2.The key stereochemistry of the starting chiron for the synthesis was set by stereoselective PPL-catalyzed hydrolysis of 1 to give the alcohol-ester (-)-2 of 55% e.e. (enantiomeric excess) in 77% isolated yield. Oxidation of 2 + 3 proceeded smoothly in 94% yield. Homologation of 3 was effected in 41% yield by the Arndt-Eistert procedure, a reaction that is known to proceed with retention of configuration at the CY-position of the carboxyl function (7). The remaining steps of transesterification (4 + 5), tosylation (5 + 6), reduction (6 + 7), and oxidation (7 + 8) were achieved in quantitative, 88%, 68%, and 76% yields respectively. The overall yield of the civet constituent 8 from 2 was 18%, with the target product having the same e.e. as the starting chiron 2. The enantiomeric excesses of 2 and 8 were determined directly. The alcohol-ester 2 was oxidatively converted to its corresponding lactone, and hence to the (R,R)-butane-2,3-diol orthoester, for e.e. measurement by the standard glc method (8). The e.e. of 8 was established by its conversion to the methyl ester with diazomethane, followed by 'H nrnr examination of the methoxyl protons in the presence of E u ( h f~)~ (9).Since the stereoisom...