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Enzymatic Baeyer-Villiger Type Oxidations of Ketones Catalyzed By

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Enzymatic Baeyer-Villiger Type Oxidations of Ketones Catalyzed By BrooRGANrccHEMTSTRY 17, 4l-_52(1989) EnzymaticBaeyer-Villiger Type Oxidations of Ketones Catalyzedby CyclohexanoneOxygenase OssroraNR AnnrL, Cenol C. RyEnsoN,CsRrsropHER Wnr-sH. eNo GEoncE,M. WHrrEsrogsl Department of Chemistry, Haruard Uniuersity, Camhridge, Massac'husetts02138, und Department of Chemistry, Massachusetts Institute of Technologt,, Cumbridge, Mussachusett.s02138 Rec'eiuedFehruury 9, 1988;accepted August 31, 1988 Cyclohexanone oxygenase (EC l l4.l3.-) produced by Acinetobat'ter NCIB 9871 is a flavin-containingNADPH-dependent monooxygenasethat utilizes dioxygen to convert cy- clic ketones into lactones. A variety of ketones were examined in order to determine the substratespecificity. regioselectivity,and enantioselectivityof cyclohexanoneoxygenase. Lactones were synthesizedusing immobilized enzymes.The nicotinamidecotactor required by cyclohexanoneoxygenase was regeneratedin .rilrrr.r,ith glucose 6-phosphate and glucose- 6-phosphatedehydrogenase from Laucono.\to('mesenleroitle.s. i9g9Acactemic press. rnc. INTRODUCTION Microorganisms are capable of effecting a wide range of oxidative transforma- tions of organic compounds (1). Among these transformations, the biological equivalentof the Baeyer-Villigerreactionl (2)-the insertionof an oxygen atom into organic ketones with the production of lactones-has been implicated in microbialdegradations of alkanes.steroids. and cyclic ketones(3-15 ). The ob- jective of this work was to explore the utility of one enzyme-cyclohexanone monooxygenase(EC 1.14.13.-)-capableof catalyzingthis tranformationfor utility in organic synthesis. The microorganismsthat are capableof removing side chains from steroids are alsogenerally able to carry out an additionalBaeyer-Villiger oxidation on the C-17 ketones to give lactones. The microbial double Baeyer-Villiger oxidation of pro- gesteroneby Penicillium c'hrysogenum,for example, gives testololactonein 70Va yield (9). The microbiological Baeyer-Villiger reactionsof steroidsare not limited to C-17 side chains and D-rings. Eburicoic acid undergoescleavage of the A-ring by Glomerella fusarioides and yields 4-hydroxy-3,4-seco-eburica-8,24(28)-diene- 3,2l-dioic acid in l0% vield (10). I To whom correspondence should be addressed. 2 A Baeyer-Villiger rearrangement is defined as an oxygen insertion reaction resulting from the treatment of a ketone with a peracid or other peroxy compound. 4l (x)4-s-2068/u91;3.00 ['opl,right tt 191{9hr Academic Press.lnc, All rights of reproduction in anr lbrm rcservetl. 42 ABRIL ET AL. Analogous microbiological Baeyer-Villiger oxidations of simple cyclic ketones to the correspondinglactones have also been reported (l 1- 15). The oxidation of 2- heptylcyclopentanoneor of 2-pentylcyclopentanoneby Pseudomonasoleouorans gives the corresponding lactones in low yield, with some suggestionthat stereo- chemical selectivity may be involved (11). Microbial oxidation of fenchone with Corynebacterium speciesafford a mixture of 1,2-fencholideand 2,3-fencholidein 42% yield (12). In addition, cell-free enzyme preparations from pseudomonad species catalyze the lactonization of camphor and 2,5-diketo camphane (14, l5). Key enzymes in these microbiological oxidations are the dioxygenases and monooxygenasesthat catalyze the introduction of an oxygen functionality and initiate the carbon-carbon bond cleavage step. Although the most extensively investigatedmonooxygenases are the aromatic hydroxylases,the lactone-forming enzymes are now well establishedas important catalysts in the degradationof a range of organic compounds. These enzymes are flavin dependentand carry out a net four-electron reduction of dioxygen: one atom of oxygen is incorporated into the organic substrate; the second appears as water. Cyclohexanone oxygenaseproduced by Acinetobacter NCIB 9871, belongs to the classof bacterial flavoprotein monooxygenasesthat catalyze lhe conversion of cyclic ketones into the correspondinglactones (16). Specifically.cyclohexanone oxygenase catalyzesthe oxygen insertion and ring expansionof cyclohexanoneto form e-caprolactone, o Cyclohexonone ll Oxygenose ---_-----------> to A + NADPH + O^ / \+ + (t) ' NADP' HZO \, Enz. FAD Mechanistic studies on cyclohexanone oxygenase support the formation of a 4a-hydroperoxyflavinintermediate (17-19). This reactive peroxide acts as a nu- cleophile toward cyclohexanone to form a mixed peroxide, which then decom- poses by a Baeyer-Villiger rearrangementto 4a-hydroxyflavinand e-caprolactone ( 17). We were interestedin the potential synthetic utility of cyclohexanoneoxy- genasefor several reasons. First, cyclohexanoneoxygenase displays a broad substratespecificity for cyclic ketones(201 . Second.work by Schwab(2 1) demon- strates that the lactonization of 2-methylcyclohexanonecatalyzed by cyclohexa- none oxygenase exhibits regioselectivity comparable with that found for the chemical Baeyer-Villiger oxidation; moreover, there is evidencethat the enzyme- catalyzed reaction proceeds with some enantioselectivity(21). Thus, we examined a variety of readily availableketones in order to determine the substratespecificity, regioselectivity, and enantioselectivityof cyclohexanone oxygenase immobilized in a polyacrylamide gel and to ascertain whether this method offered advantages over conventional Baeyer-Villiger procedures. The reduced nicotinamide cofactor NADPH required by cyclohexanone oxygenase was regeneratedin situ with glucose 6-phosphateand glucose-6-phosphatedehy- drogenasefrom Leuconostoc'mesenteroides (Scheme I). ENZYMATIC OXIDATIONS OF CATALYZED KETONES 43 o Cyclohexonone O Oxygenose ll *A*' + o" nAo + Hzo /\l /\R' /i NADPH NADP+ OP HO o HO o HO f-" Hga_Lox''OP HO\\_' \-c02. HO ScHEue I. General scheme for the enzymatic synthesis of lactones catall,zed by cyclohexanone oxygenase with regenerationof NADPH using glucose 6-phosphateand glLrcose-6-phosphatedeh-v- drogenase. RESULTS AND DISCUSSION Determination of Substrate Specfficity of Cyclohexanone Oxygenose and Measurement of Relatiue Rates Table I lists the relative activity of cyclohexanone oxygenasetoward several ketones. These relative rates were measuredby two methods: by following the rate of consumption of NADPH spectrophotometricallyand by following the rate of oxygen uptake with an oxygen electrode.These measurements should be inter- preted cautiously since all compounds were employed at the same nominal con- centration with no regard to differencesin solubility or value of K,,,. These assays were intentionally run under conditions that should saturate the enzyme and therefore approximate Vru^. Cyclohexanone oxygenase was found to catalyze the oxidation of NADPH at the same rate as the reduction of 02, in the presence of the various ketones examined. Addition of catalaseto the assay system had no effect on the rate of oxygen uptake. Substrates and substrate analogs often act as effectors with NADPH-linked monooxygenases(22).Effectors combine with the oxidized en- zyme (F,nz' FAD) and acceleratethe rate of flavin reductionby NADPH. In the presenceof dioxygen, this processwould result in an increasedrate of consump- tion of dioxygen, with some of the dioxygen being reduced to hydrogen peroxide. That is, oxygen insertion into the ketone moiety would be uncoupled from oxida- 44 ABRIL ET AL. TABLE I SubstrateSpecificity of CyclohexanoneOxygenase and Measurementof RelativeRates" Relative Compound rale ( ,'/rI Cyclclhexanone I00 2-Norbornanone ltti o-Fenchone l0 l-Fenchone 60 2-Adamantanone (l ( + )-Dihydrocarvone ')- .rln-7-B enzyI ox y methy I-2-norbone n--5 -one ll0 2-Acetylcyclohexanone 0 2-Cyclohexene-l-one U ( + )-Clamphor 46 Progesterone tl 1.4-Cyclohexanedione 90 I.3-Cycloheranedione 0 4-Phenylc yclohe xanone (, 2-Phenylcyclohexanone l9 4-tt,rl-BuIv lcvclohe xanone llt+ " Rclatil'c nltes were measrrreclspectrophotometri- cally at -140nm and'n,'-diorvgen uptake at 2-5'C.Mea- surementswere perfbrntedin I ml of gly,cine-NaOH buffer ([i0 my. pH fl.0) containing ]-5pr.mol of the indi- cated ketone (initiirlll dissolvedin -s0pl of MeOH). NADPH (0.16 mrr). cyclohexanoneoxygenase (0.6 U). and an equilibrium concentraticlnof iitmospheric diooxygen(0.24 mn). See F,xperimentalfirr details. tion of nicotinamide.In an assaysystem measuring oxygen uptakc. the fbrmation of hydrogen peroxide would appearas activity. Since catalasefailed to alter the rate of dioxygen consumption. we therefore conclude that those ketones that significantlystimulate oxygen uptake are true substratesfbr cyclclhexanoneoxy- genase.This observationis also consistentwith the conclusionof Ryerson et al. (17): direct reactionbetween H:O: and substrateis an unlikely mechanismfor the enzyme-catalyzedconversion of ketonesto lactones. The following conclusionsconcerning the structure-reactivityrelationship can be drawn from the resultspresented in Table l. First, cyclohexanoneoxygenase dispfaysa broad substratespecificity toward alicyc:lic'ketones.Second. the fol- lowing general types of ketones are nol substrates:d,B-unsaturated ketones and 1,3-diketones(acyclic and alicyclic). These observationsare consistentwith the findings of Donoghue er ol. (16). Walsh and Chen (20) have also demonstrated that the enzyme showseven broaderspecificity. working on someacyclic ketones and aryl ketones. The racemic ketone .ryn-7-benzvloxvmethvl-2-norbornen--5-one(Corev's ke- ENZYMATIC OXIDATIONS OF CATALYZED KETONES 45 tone), an intermediatein the synthesisof prostaglandins(23), was a substratewith a relative rate of 110%(relative to cyclohexanone).A total consumption assayrun with a limiting
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