An efficient chemoenzymatic method to prepare optically active O-methyl-d-serine

Lacosamide is an important anti-epilepsy drug and O-methyl-d-serine is a relevant intermediate in the synthesis of lacosamide. Optically active O-methyl-d-serine was prepared by using a chemoenzymatic method from inexpensive acrylamide. Our method is a four-step reaction sequence: bromination of acrylamide; etherification of dibromopropionamide; ammonolysis of α-bromo-β-methoxy-propionamide; enzymatic racemization and selective hydrolysis. The double-enzyme catalyst system, which consists of α-amino-ε-caprolactam racemase (Locus, E01594) and d-stereospecific amino-acid amidase (Locus, AB026907), was successfully applied to produce enantiopure O-methyl-d-serine (ee >99.8%) in high yield (>98.5%). Optically active O-methyl-d-serine was obtained with a total yield of 81.3%.     

Highly enantioselective enzymatic resolution of cis-fused octalols mediated by Candida antarctica lipase (Novozym 435)

Optically active cis-fused octalin acetates have been prepared by esterification of cis-fused octalols using Candida antarctica lipase (CALB—Novozym 435). The enzyme efficiently resolved the racemic octalols by kinetic resolution, to afford cis-fused octalols and cis-fused octalin acetates with high enantiomeric excesses (up to >99%) and good yields (>40%).     

A practical synthesis of optically active arylglycines via catalytic asymmetric Strecker reaction

A practical procedure for catalytic asymmetric synthesis of optically active arylglycine derivatives via optically active α-aminonitriles has been developed. The N-benzhydryl α-arylaminonitrile intermediates were prepared in excellent yield (89–99%) and enantiomeric purity (96 to >98% ee) by enantioselective cyanation of aldimines with TMSCN/ⁱPrOH in the presence of 2.5 mol % of an easily prepared Ti/chiral amino alcohol complex at 0 °C, without requiring slow addition of the cyanating agent. The easily racemized α-aminonitrile intermediates were efficiently hydrolyzed by an aqueous HCl/TFA mixture to give the arylglycine derivatives in good yield (60–92%) and moderate to excellent enantiomeric purity (85–98% ee).     

Enantioselective formal synthesis of tridemethylisovelleral

A simple and efficient synthetic route to the bicyclic α,β-unsaturated β-keto ester methyl (3aS,7aS)-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-indene-5-carboxylate, a versatile intermediate in the synthesis of biologically active unsaturated 1,4-dialdehydes, is described. The synthesis includes a chirality introducing nonenzymatic asymmetric desymmetrization (ADS) reaction of a cyclic meso-anhydride 4 and a modified Hofmann method for preparing exocyclic dienes. The ester was synthesized in a moderate overall yield (19%) from 6 and with an excellent enantioselectivity (>90%).     

Catalytic asymmetric epoxidation of α,β-unsaturated N-acylpyrroles as monodentate and activated ester equivalent acceptors

Catalytic asymmetric epoxidation of α,β-unsaturated N-acylpyrroles as monodentate and activated ester equivalent acceptors is described. A Sm(O-i-Pr)₃/(R)-H₈-BINOL complex promoted the epoxidation reaction to afford products in high yield (up to quant) and high enantiomeric excess (up to >99.5% ee). Reaction proceeded smoothly using cumene hydroperoxide (CMHP) with low explosive hazard, and completed within 0.2-0.5 h with 5 mol % catalyst. Catalyst loading was successfully reduced to as little as 0.02 mol %. The N-acylpyrrole properties as well as efficient synthesis of α,β-unsaturated N-acylpyrroles are also described.     

Efficient catalytic asymmetric synthesis of α-substituted phenyloxyacetyloxy and aroyloxy phosphonates

Optically active α-substituted phenyloxyacetyloxy and aroyloxy phosphonates have been synthesized via catalytic asymmetric hydrogenation of the corresponding prochiral α,β-unsaturated phosphonates using Rh(I)/(R,R)-Me-DuPhos as the catalyst in methanol at 18 °C. The asymmetric hydrogenation reaction exhibits excellent enantioselectivity with enantiomeric excesses from 91 to 96%.     

Stereocomplementary asymmetric bioreduction of boron-containing ketones mediated by alcohol dehydrogenases

Optically active boron-containing alcohols were prepared via the stereoselective reduction of the corresponding carbonyl compounds by alcohol dehydrogenases. Depending on the substrate, both (R)-alcohols and (S)-alcohols were obtained with excellent enantioselectivity (up to >99% ee) employing either ADH-A or LB-ADH.     

Polymerization and properties of optically active α-(p-substituted benzenesulfonamido)-β-lactones

Optically active α-(p-substituted benzenesulfonamido)-β-lactones having as para substituents OMe, Me, H, and Cl were polymerized in bulk, in ethyl acetate solution with triethylamine or betaine, and in dioxane with butyllithium as initiators. The rate of polymerization was followed by the change of specific rotation with time and was decreasing in following order of para substituents: OMe > Me > H > Cl. The relative reactivity in logarithmic form was plotted against Hammett's σ functions showing a linear relationship with reaction constant ρ = ?0.57.     

Regioselective monohydrolysis of per-O-acetylated-1-substituted-β-glucopyranosides catalyzed by immobilized lipases

The regioselective monohydrolysis of different peracetylated-β-glucopyranosides in aqueous media using immobilized preparations of three different lipases—those from Aspergillus niger (ANL), Candida rugose (CRL) and Candida antarctica B (CAL-B)—has been studied. Three very different immobilization strategies—covalent attachment, anionic exchange and interfacial activation on a hydrophobic support—were employed for each lipase. The role of the immobilization strategy and the effect of the presence of different moieties in the anomeric position of the substrate on the hydrolytic activities, specificities and regioselectivities of the lipases were investigated. For example, the PEI-ANL preparation exhibited 800 times higher activity than the octyl-ANL in the hydrolysis of 2-acetamido-2-deoxy-1-(4-nitrophenyl)-3,4,6-tri-O-acetyl-β-d-glucopyranoside—producing 4-OH derivative in 18% yield—whereas the octyl-ANL was five times more active than the PEI-ANL in the hydrolysis of 1-(4-nitrophenyl)-2,3,4-tri-O-acetyl-β-d-xylopyranoside, producing 4-OH monohydroxy product in >99% yield.The octyl-CRL preparation hydrolyzed regioselectively 3,4,6-tri-O-acetyl-glucal in position 6 in 68% yield while the PEI-CRL produced the 3-OH product in 11% yield, although with moderate specificity. The CNBr-CAL-B hydrolyzed specifically and regioselectively the glucal producing the 3-OH product in >99% yield.     

Chiral,non-racemic α-hydroxyphosphonates and phosphonic acids via stereoselective hydroxylation of diallyl benzylphosphonates

Chiral, non-racemic α-hydroxyphosphonates have been prepared in high enantiomeric excess (96–98% ee), via stereoselective oxaziridine-mediated hydroxylation of diallyl benzylphosphonates. The enantiomeric purity and absolute configuration of the α-hydroxyphosphonates was established from ¹H and ³¹P NMR spectroscopy of the (S)-O-methylmandelate esters. Deprotection of the diallyl α-hydroxyphosphonates under neutral conditions furnished the corresponding free phosphonic acids, retaining a high degree of stereochemical purity (90 to >98% ee).     

One-pot acylation and fractional crystallization: preparation of optically active serinol monobenzoates

Mono-O-acylation of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 4-nitrobenzoyl chloride and DMAP in dichloromethane at room temperature gave crystals of optically active (2S,αR)-3-hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoate hydrochloride [(2S)-2a·HCl] in 33% yield by fractional crystallization. Optically active oxazolidinones, aziridines, and serinol derivatives were synthesized from the benzoate (2S)-2a.     

Highly diastereoselective synthesis of 2-substituted-1,3-diols catalyzed by ketoreductases

The stereoselective reduction of α-substituted-β-hydroxy ketones for the preparation of the corresponding optically pure 2-monosubstituted or 2-disubstituted-1,3-diols is described. These transformations proceed in high optical purities and yields. Ketoreductases were able to catalyze the formation of either the syn or the anti diol, depending on the enzyme. By replacing the α-alkyl substituent for an OAc moiety, in low conversion time (≤24 h), ketoreductases catalyzed the formation of the OAc-protected 1,2,3-triol, in high yield and with high optical purity (>99% de, >99% ee). This is a simple and highly stereoselective method for the synthesis of different diastereomers of chiral diols.     

Hydrogen-transfer polymerization of acrylamide and methacrylamide with optically active basic catalysts

Hydrogen-transfer polymerization of acrylamide and Methacrylamide with an optically active amyl alcoholate or n-amyl alcoholate (sodium, calcium, magnesium, barium, and aluminum) was investigated to 100°C in toluene. The initiation ability of the metal ion of the initiator increased in the order, sodium > barium > calcium > magnesium > aluminum. The optically active polymer was obtained by the polymerization of methacrylamide with an optically active alcoholate (barium or calcium), but was not obtained by the other alcoholates and by the polymerization of acrylamide with the optically active alcoholate. The specific rotation of the optically active polymer obtained was about +1.1° ～ +1.3°. The hydrolyzed product of the optically active polymer was α-methyl β-alanine having optical activity (+1.0°). The initiation mechanisms of the polymerization were thought to be the dehydrogenation of the monomer of the negative ion and the Michael addition reaction with the monomer of the negative ion and the catalyst, and it was confirmed that the optically active polymer was prepared by intermolecular hydrogen transfer mechanism. In the polymerization of MMA with menthol barium and borneol barium as the optically active catalyst, the optically active polymer was obtained.     

The preparation of optically active α-amino 4H-[1,2,4]oxadiazol-5-ones from optically active α-amino acids

Optically active α-amino 4H-[1,2,4]oxadiazol-5-ones (oxadiazolones) were prepared from optically active α-amino acids in five synthetic steps. The oxadiazolone moiety serves as a bioisosteric replacement for the carboxylic acid. Incorporation of an α-amino oxadiazolone into a representative dipeptide mimic is described.     

Development of an efficient method for preparation of 1,3,5-trihydroxyisocyanuric acid (THICA) and its use as aerobic oxidation catalyst

1,3,5-Trihydroxyisocyanuric acid (THICA), which serves as an efficient radical-producing catalyst from hydrocarbons, was successfully prepared by two methods. The reaction of O-benzylhydroxyamine with phenyl chloroformate gave formbenzyloxycarbamic acid phenyl ester of which subsequent treatment with dimethylaminopyridine (DMAP) produced 1,3,5-tribenzyloxyisocyanurate leading to THICA by hydrogenation with H₂ on Pd/C. The other method involved the direct synthesis of 1,3,5-tribenzyloxyisocyanurate from O-benzylhydroxyamine and diphenyl carbonate. The aerobic oxidation of p-methylanisole catalyzed using THICA as a key catalyst afforded p-anisic acid in almost quantitative yield (>99%).     

Phosphoramidite approach for the synthesis of cardiolipin

A phosphoramidite approach was utilized for the first time to synthesize cardiolipin. Optically active 1,2-di-O-acyl-sn-glycerol was coupled with 2-O-protected glycerols utilizing mono- and bifunctional phosphitylating agents to yield, after final removal of protecting groups, the title compound.     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Enantioselective cyanosilylation of aldehydes catalyzed by a novel N,N′-dioxide-Ti(OPr)4 bifunctional catalyst

A novel bifunctional asymmetric catalyst containing N-oxide and titanium(IV) was developed and applied to the asymmetric cyanosilylation of aldehydes. Optically active trimethylsilyl cyanohydrin ethers were obtained up to 99% yield and 80% ee in the presence of 5 mol % catalyst loading at −78 °C. Based on the experimental results, the catalytic cycle was proposed as a pathway in which Lewis acid and Lewis base activated aldehyde and trimethylsilylcyanide (TMSCN), respectively.     

Highly efficient total synthesis of Δ-PGJ2, 15-deoxy-Δ-PGJ2, and their analogues

Palladium-catalyzed reaction of TBS ether of 4-cyclopentene-1,3-diol monoacetate (>95% ee) with an anion derived from methyl malonate and a base such as t-BuOK and LDA proceeded highly efficiently and reproducibly. The product obtained in >90% isolated yield was transformed in five steps into the key cyclopentenone possessing the α-chain at the γ position. Aldol reaction of this enone with the ω-chain aldehyde afforded the aldol adduct, and exposure of the derived mesylate to Al₂O₃ furnished the cross-conjugated dienone of the full structure. Finally, functional group manipulation furnished Δ¹²-PGJ₂ efficiently. Similarly, 15-deoxy-Δ^12,14-PGJ₂, 5,6-acetylene analogues, and a 5,6-dihydro analogue were synthesized.     

The dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat: asymmetric synthesis of α-vinyl-β-hydroxycarboxylic acid derivatives and conversion to α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products)

The synthesis of α-vinyl-β-hydroxyesters and α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) via the dienolate aldol reaction of (E)-N-crotonoyl C(4)-isopropyl SuperQuat is described. High levels of syn-diastereoselectivity (up to >98% de) are observed for the dienolate aldol reaction with boron enolates, generated either directly with Bu₂BOTf or by transmetalation of the potassium enolate with B-bromocatecholborane. Cleavage of the resultant syn-aldol products from the auxiliary gives α-vinyl-β-hydroxyesters in >98% de and >98% ee. Subsequent isomerisation of the double bond into conjugation provides α-ethylidene-β-hydroxyesters (β-substituted Baylis-Hillman products) in high diastereo- and enantiopurity (≥91:9 [(E):(Z)] and >98% ee).