Asymmetric Baeyer-Villiger oxidations of 4-mono- and 4,4-disubstituted cyclohexanones by whole cells of engineered Escherichia coli.

Whole cells of an Escherichia coli strain that overexpresses Acinetobacter sp. NCIB 9871 cyclohexanone monooxygenase have been used for the Baeyer-Villiger oxidations of a variety of 4-mono- and 4,4-disubstituted cyclohexanones. In cases where comparisons were possible, this new biocatalytic reagent provided lactones with chemical yields and optical purities that were comparable to those obtained from the purified enzyme or a strain of bakers' yeast that expresses the same enzyme. The efficient production of cyclohexanone monooxygenase in the E. coli expression system (ca. 30% of total soluble protein) allowed these oxidations to reach completion in approximately half the time required for the engineered bakers' yeast strain. Surprisingly, 4,4-disubstituted cyclohexanones were also accepted by the enzyme, and the enantioselectivities of these oxidations could be rationalized by considering the conformational energies of bound substrates along with the enzyme's intrinsic enantioselectivity. The enzyme expressed in E. coli cells also oxidized several 4-substituted cyclohexanones bearing polar substituents, often with high enantioselectivities. In the case of 4-iodocyclohexanone, the lactone was obtained in > 98% ee and its absolute configuration was assigned by X-ray crystallography. The crystal belongs to the monoclinic P2(1) space group with a = 5.7400(10), b = 6.1650(10), c = 11.377(2) A, b = 99.98(2) degrees, and Z = 2. Taken together, these results demonstrate the utility of an engineered bacterial strain in delivering useful chiral building blocks in an experimentally simple manner.     

Baeyer-Villiger单加氧酶在有机合成中的应用

综述了Baeyer-Villiger单加氧酶在有机合成中的应用.较之传统的化学反应, 氧化酶催化剂反应有较好的选择性、可控性和经济性. 环己酮加氧酶是一种还原型辅酶I (NADPH)依赖型氧化酶, 是最早被报道能够催化Baeyer-Villiger氧化的酶. 这些重要反应产生了合成化学家很感兴趣的扩环产物. 环己酮加氧酶也是有用的生物催化剂, 由于辅酶再生的问题已被工程菌克服了, 所以能像全细胞催化剂那样使用. 对酮包括杂环酮进行Baeyer-Villiger氧化和动态动力学拆分, 放大这种反应作为合成路线是很有前途的.     

Simultaneous biocatalyst production and baeyer-villiger oxidation for bioonversion of cyclohexanone by recombinant Escherichia coli expressing cyclohexanone monooxygenase

Cyclohexanone monooxygenase (CHMO) catalyzing Baeyer-Villiger oxidation converts cyclic ketones into optically pure lactones, which have been used as building blocks in organic synthesis. A recombinant Escherichia coli BL21(DE3)/pMM4 expressing CHMO originated from Acinetobacter sp. NCIB 9871 was used to produce ε-caprolactone through a simultaneous biocatalyst production and Baeyer-Villiger oxidation (SPO) process. Afed-batch process was designed to obtain high cell density for improvin production of ε-caprolactone. The fed-batch SPO process have the best results, 10.2 g/L of ε-caprolactone and 0.34 g/(L·h) of productivity, corresponding to a 10.5- and 3.4-fold enhancement compared with those of the batch SPO, respectively.     

Enzymes in organic synthesis-29 : Preparations of enantiomerically pure cis -2,3- and 2,4-dimethyl lactones via horse liver alcohol dehydrogenase-catalyzed oxidations

Further examples of the broad applicability of horse liver alcohol dehydrogenase-catalyzed oxidations of meso-diols as a route to chiral lactones of asymmetric synthetic value are described. The acyclic meso substrates, cis-2,3-dimethyl- and -diethylbutane-l,4-diols, and cis-2,4-dimethylpentane-l,5diol, are stereospecifically oxidized in good yields to the corresponding enantiomerically pure γ- and δ-lactones. The oxidation of cis-3,4-bis(hydroxymethyl)thiacyclopentane is similarly stereospecific. For each meso-diol the oxidation takes place with a net stereospecificity for the hydroxymethyl groups attached to the S-enters, with the initially formed hydroxyaldehydes undergoing further enzymecatalyzed oxidations via their hemiacetal forms to produce lactone products directly.     

Thiourea-catalyzed enantioselective iso-Pictet-Spengler reactions

A one-pot condensation of isotryptamines and aldehydes that affords enantiomerically enriched 4-substituted tetrahydro-γ-carbolines is reported. The reaction is induced by a chiral thiourea/benzoic acid dual catalyst system. Purification of the N-Boc-protected products by trituration or crystallization provides the optically pure tetrahydro-γ-carboline derivatives in a scalable and highly practical procedure.     

Regiodivergent Baeyer-Villiger oxidation of fused ketone substrates by recombinant whole-cells expressing two monooxygenases from Brevibacterium

Microbial Baeyer-Villiger oxidations of fused bicyclic ketones with a cyclobutanone structural motif were investigated using recombinant Escherichia coli cells expressing two monooxygenases from Brevibacterium. In a kinetic resolution process fused ketones were transformed to regioisomeric lactones: ‘normal’ lactones were generated by migration of the more substituted carbon atom and ‘abnormal’ lactones resulted from migration of the less substituted carbon atom. The two Baeyer-Villigerases demonstrated a significantly different stereoselectivity for the regiodivergent biotransformation.     

Metal-catalyzed asymmetric oxidations mediated by optically pure furyl hydroperoxides

Metal-catalyzed asymmetric oxidations which rely on the use of commercially available t-butyl (TBHP) or cumyl hydroperoxides (CHP) and enantiopure ligands represent the majority of protocols reported to obtain enantiomerically enriched valuable compounds such as epoxides, sulfoxides, diols, etc. Herein, we review our recent results on the complementary and less studied oxidative approach based on the use of optically pure alkyl hydroperoxides as oxygen and chirality source. The synthetic sequence to enantiopure furyl hydroperoxides, easily accessible from ketones of the chiral pool is firstly described. Examples of metal-catalyzed asymmetric oxidations using these compounds for the production of enantiomerically enriched sulfoxides and epoxy alcohols are shown. The entire protocol is made more advantageous by recovering the optically pure alcohols during the purification procedure and recycling them for the one-step synthesis of the hydroperoxides.     

Metal-free catalytic C-Si bond formation in an aqueous medium. Enantioselective NHC-catalyzed silyl conjugate additions to cyclic and acyclic α,β-unsaturated carbonyls

A metal-free method for enantioselective conjugate addition of a dimethylphenylsilyl group to α,β-unsaturated carbonyls is reported. Transformations are catalyzed by a chiral N-heterocyclic carbene (NHC), performed in an aqueous solution (3:1 mixture of water and tetrahydrofuran) and are operationally simpler to perform than the NHC-Cu-catalyzed variant. The chiral catalyst is generated from an enantiomerically pure imidazolinium salt (prepared in three steps) and a common organic amine base (dbu). NHC-catalyzed processes proceed with 5.0-12.5 mol % catalyst loading at 22 °C within 1-12 h, affording the desired β-silyl carbonyls in 85:15 to >98:2 enantiomeric ratio and in 50% to >98% yield. Cyclic enones or lactones and acyclic α,β-unsaturated ketones, esters, and aldehydes can be used as substrates.     

Non-destructive Removal of the Bornanesultam Auxiliary in α-Substituted N-Acylbornane-10,2-sultanis under Mild Conditions: An efficient synthesis of enantiomerically pure ketones and aldehydes

α-Substituted N-acylbornane-10, 2 -sultams 6, 9 , and 10 can be converted into enantiomerically pure ketones 5. 13 , and 14 , respectively, via a two-step procedure involving a known mercaptolysis reaction followed by an [Fe(acac)₃]-mediated coupling of the resulting S-benzyl thioesters with Grignard reagents. Furthermore, enantiomerically pure aldehydes 23 can be obtained from α-substituted N-acylbornane-10,2-sultams 6 via a one-step reduction with (i-Bu)₂AIH. No epimerization at the α-chiral center is observed during the cleavage reaction whereby the chiral auxiliary, bornane-10,2-sultam 1 or ent- l , was recovered. By using this methodology, several natural products or precursors thereof can be prepared.     

Selective and shape-selective Baeyer-Villiger oxidations of aromatic aldehydes and cyclic ketones with Sn-beta zeolites and H2O2

Sn-Beta is used as a heterogeneous catalyst for the Baeyer-Villiger reaction with hydrogen peroxide. Cyclic ketones are transformed into the corresponding lactones, while unsaturated ketones are oxidized to the corresponding unsaturated lactones with very high chemoselectivity. The catalyst is also selective for the oxidation of aromatic aldehydes with H2O2, producing the formate ester or the corresponding hydrolyzed product, that is the alcohol. Shape-selective oxidations are observed for isomeric reactants with different molecular shapes. The catalytic Sn sites have been characterized by 119Sn MAS-NMR spectroscopy, and tetrahedral incorporation into the zeolite framework has been demonstrated. In situ IR spectroscopy and 18O labeling experiments have shown that the oxidation mechanism involves an intermediate of the Criegee type.     

Synthesis of enantiomerically pure tertiary 1,2-aminoalcohols by the highly diastereoselective reductive ring opening of oxazolidines

A number of enantiomerically pure 1,2-aminoalcohols containing tertiary nitrogen atoms bearing chiral substituents have been prepared by highly diastereoselective reductive ring cleavage of oxazolidines derived from ketones and pseudoephedrine or ephedrine. The ring cleavage occurs with retention of configuration.     

Stereoselective synthesis of functionalized gamma-amino esters: azetidinium salts and epoxy esters

Addition of several lithium ester enolates to chiral 1-aminoalkyl chloromethyl ketones 1 affords enantiomerically pure 3-hydroxyazetidinium salts 3 or 3-(1'-aminoalkyl)-3,4-epoxy esters 4, depending on the reaction conditions. [reaction: see text]     

Cyclohydrocarbonylation-based strategy toward poly-substituted piperidines

Convenient accesses to enantiomerically pure 2-, 2,3-, 2,6-, 2,3,6-substituted piperidines and 1,4-substituted indolizine are described. At first, indium-mediated aminoallylation and -crotylation of aldehydes with (R)-phenylglycinol or (1R,2S)-1-amino-2-indanol gave homoallylamines with high stereocontrol. Then, these products, submitted to a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation, afforded perhydrooxazolo[3,2-a]piridines whose oxazolidines are opened with nucleophiles. Finally, the removal of the chiral auxiliaries delivered the enantiomerically pure piperidines.     

A short olefin metathesis-based route to enantiomerically pure arylated dihydropyrans and alpha,beta-unsaturated delta-valero lactones

The synthesis of arylated dihydropyrans and unsaturated lactones starting from enantiomerically pure alpha-hydroxy ketones (prepared by an enzyme-catalyzed benzoin condensation) is described. The key steps are a highly diastereoselective addition of vinyl metal compounds under chelate control and a ruthenium-catalyzed ring-closing olefin metathesis reaction. Elucidation of the relative configuration of the final products was achieved by NOE experiments.     

Towards practical biocatalytic Baeyer-Villiger reactions: applying a thermostable enzyme in the gram-scale synthesis of optically-active lactones in a two-liquid-phase system

Baeyer-Villiger monooxygenases (BVMOs) are extremely promising catalysts useful for enantioselective oxidation reactions of ketones, but organic chemists have not used them widely due to several reasons. These include instability of the enzymes in the case of in vitro and even in vivo systems, reactant/product inhibition, problems with upscaling and the necessity of using specialized equipment. The present study shows that the thermally stable phenylacetone monooxygenase (PAMO) and recently engineered mutants can be used as a practical catalysts for enantioselective Baeyer-Villiger oxidations of several ketones on a preparative scale under in vitro conditions. For this purpose several parameters such as buffer composition, the nature of the solvent system and the co-factor regeneration system were optimized. Overall a fairly versatile and efficient catalytic system for enantioselective laboratory scale BV-oxidations of ketones was developed, which can easily be applied even by those organic chemists who are not well versed in the use of enzymes.     

Chiral enolates for highly stereoselective aldol reactions—Scope and limitations

Enantioselective approaches to the formation of α,β-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure β-substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel synthesis of functionalized β,γ-unsaturated acetals is also described.     

Discrete Metal Catalysts for Stereoselective Ring‐Opening Polymerization of Chiral Racemic β‐Lactones

Poly(β‐hydroxyalkanoate)s (PHAs) are a class of aliphatic polyesters that can be efficiently synthesized by ring‐opening polymerization (ROP) of β‐lactones. The case of chiral racemic β‐substituted β‐lactones is particularly appealing since these monomers open the way to original tacticities and materials different from those biotechnologically produced. In this overview, after briefly surveying general considerations associated to the ROP of β‐lactones and metal‐based catalysts used in stereoselective ROP of racemic β‐butyrolactone, special emphasis is given to discrete rare earth catalysts that have allowed the preparation of highly syndiotactic poly(3‐hydroxybutyrate)s. Recent developments – such as preparation of stereocontrolled PHAs with pendant structural groups via (co)polymerization of functional β‐substituted β‐lactones, and highly alternating copolymers obtained by ROP of mixtures of enantiomerically pure but different monomers – are also discussed.

     

Asymmetric Diels-Alder reactions with 5-menthyloxy-2-(5H)-furanone

A new class of chiral dienophiles, 5-alkoxy-2(5H)-furanones, has been developed. Both enantiomers of 5-menthyloxy-2(5H)-ftiranone are readily available in enantiomerically pure form, starting from furfural and d- or l-menthol. Excellent diastereoselectivities (d.e. β99%) are obtained in thermal Diels-Alder reactions with several cyclic and acyclic dienes. The use of silyl dienol ethers has resulted in new routes to enantiomerically pure cyclohexanones in a highly regioselective manner.     

First asymmetric syntheses of 6-substituted nipecotic acid derivatives

Various nipecotic acid derivatives are known to be potent GABA uptake inhibitors thus being useful in the treatment of a number of neurological and psychological disorders. In this paper, the first asymmetric syntheses of 6-substituted nipecotic acid derivatives are presented. The synthetic strategy was designed to provide access to a large variety of enantiomerically pure 6-substituted nipecotic acid derivatives. The synthesis starts from the chiral N-acyldihydropyridines 15 and 16 obtained via asymmetric electrophilic α-amidoalkylation reaction of a chiral N-acylpyridinium ion. These were utilized for the preparation of enantiomerically pure 6-(4,4-diphenylbutyl)nipecotic acids and 6-(4,4-diphenylbutenyl)nipecotic acids in a multistep synthesis, including the removal of the dimethylphenylsilyl blocking group from the dihydropyridine ring, the reduction of the dihydropyridine heterocycle, a Horner-Wittig reaction and the removal of the chiral auxiliary. The obtained target molecules, however, showed only negligible affinity to the GAT-1- and GAT-3 transport proteins.     

Asymmetric synthesis of chiral N-sulfinyl 3-alkyl- and 3-arylpiperidines by α-alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane

α-Alkylation of N-sulfinyl imidates with 1-chloro-3-iodopropane successfully led to 2-substituted N-tert-butanesulfinyl-5-chloropentanimidates in acceptable diastereomeric ratios (dr 67/33 to 72/28) and good yields (74-86%). Subsequent reduction with NaBH(4) led to the corresponding 2-substituted N-tert-butanesulfinyl-5-chloropentylamines, which could be cyclized to a range of new chiral 3-substituted N-tert-butanesulfinylpiperidines using NaH in DMSO. Finally, the N-tert-butanesulfinylpiperidines could be efficiently deprotected to enantiomerically pure 3-alkyl- and 3-arylpiperidine hydrochlorides.