Enzymes in organic synthesis. 32. Stereospecific horse liver alcohol dehydrogenase-catalyzed oxidations of exo- and endo-oxabicyclic meso diols

Abstract

. J. Chem. 62, 2578Chem. 62, (1984.Preparative-scale horse liver alcohol dehydrogenase-catalyzed oxidation of meso exo-and endo-7-oxabicyclo[2.2. llheptane diols provides a direct one-step route to enantiomerically pure chiral y-lactones of the oxabicyclic series.J. BRYAN JONES et CHRISTOPHER J. FRANCIS. Can. J. Chem. 62, 2578Chem. 62, (1984.L'oxydation prkparative, catalysCe par I'alcool dCshydrogCnase du foie de cheval, des oxa-7 bicyclo[2.2.1] heptanediols-exo et -endo miso s'avkre &tre une route directe en une Ctape conduisant aux y-lactones chirales CnantiomCriquement pures de la sCrie oxabicyclique.[Traduit par le journal]The abilities of enzymes to discriminate between enantiotopic groups of compounds that possess prochiral centres or that are meso compounds are being exploited to an everincreasing extent in asymmetric synthesis (2). Horse liver alcohol dehydrogenase (HLADH),l a commercially availableCH(0H) 5 C=O oxidoreductions of a wide range of substrates, is one of the most versatile enzymes in this regard. In its oxidative mode, it has been shown to operate stereospecifically on only one of the enantiotopic hydroxyl groups of acyclic and monocyclic meso-diols (1, 3). In this paper we q LiAtH4* 3 %OMe COOMe report that preparative-scale HLADH-catalyzed oxidations are 4 also enantiotopically specific for meso oxabicyclic diols such as 1 and 2. NaBH41 Lint H4 ResultsThe exo-and endo-diol substrates 1 and 2, the racemic lactones 5 and 6, and racemic diols 7 and 8 required as reference compounds were obtained as shown in Scheme 1.Both 1 and 2 were found to be excellent substrates of the enzyme. Their rates of HLADH-catalyzed oxidations, relative to the usual benchmark of cyclohexanol = 1 .O under equivalent assay conditions, were found to be 0.63 for 1 and 0.2 1 for 2.Such oxidation rates indicate that multi-gram HLADHcatalyzed oxidations will be ~i a b l e .~ The results of the preparative-scale enzyme-mediated oxidations are summarized in Scheme 2.The enantiomeric excesses of the exo-(+)-5 and endo-(+)-6 lactones of Scheme 2 were determined by 'H nmr spectroscopic (&I-8 examination (4) of the dimethyl diols, (+)-7 and (+)-8 respectively, obtained using excess methyllithium as shown for the racemic series in Scheme 1. In the presence of 0.4 equivalents of Eu(hfc),, the protons of the gem-dimethyl groups of the racemic reference diols exo-(*)-7 and endo-(+)-8 were cleanly resolved into two doublets with AA6 values of 0.03 and 0. I I ppm respectively. The spectra of (+)-7 and (+)-8 showed no trace of splitting under the same conditions, thereby demonstrating that their precursor lactones (+)-5 and (+)-6 respectively were enantiomerically pure.' 4The nmr ee (enantiomeric excess) determination method is considered accurate to < r 2%.Can. J. Chem. Downloaded from www.nrcresearchpress.com by 52.41.17.47 on 05/08/18For personal use only.

Transition Metal-Catalyzed Enantioselective Ring-Opening Reactions of Oxabicyclic Alkenes

“…Enzymes have also been used in oxidative and reductive processes. Jones showed that oxabicyclic diol 18 was selectively oxidized by horse liver alcohol dehydrogenase (HLADH) in the presence of nicotine adenine dinucleotide (NAD) and flavin mononucleotide (FMN) to give lactone 19 in 83% yield and >98% ee (eq 2) …”

Diels−Alder Reactions of Hexafluoro-2-butyne with 2-Heterosubstituted Furans: A Facile and General Synthesis of 1,4-Disubstituted 2,3-Di(trifluoromethyl)benzenes

“…Hydrogenation of 3c with 10% palladium on carbon in ethyl acetate afforded only the endo isomer 11 in 94% yield. The exo hydrogen at C-3 was assigned by comparing its coupling constant to the bridge proton H 4 ( J 3,4 = 5.2 Hz) with the structually related literature precedent (∼5 Hz for an exo hydrogen versus ∼0 Hz for an endo hydrogen). − Treatment of 11 with 0.2% HCl in aqueous THF afforded cyclohexanone 12 in 80% yield. No epimerization was detected by 1 H NMR during the hydrolysis.…”

Artificial Biocatalytic Linear Cascades for Preparation of Organic Molecules

“…The double oxidation of alcohols at the expense of molecular oxygen allowed the transformation of primary alcohols to carboxylic acids. In very early work horse liver alcohol dehydrogenase (HLADH) was employed for this type of transformation; thus, a single enzyme was doing two subsequent oxidation steps using FMN for NAD + recycling. , In a related fashion an α-keto acid (α-keto adiapate) was used as oxidant . More recently, engineered variants of galactose oxidase (GalOx) from Fusarium graminearum have been employed in combination with aldehyde oxidases.…”