Enantioselective Michael additions on α,β-unsaturated N-acylated oxazolidin-2-ones using mild scandium triflate catalysis

The asymmetric conjugate addition of thiophenol to (E)-3-crotonoyloxazolidin-2-one catalysed by the scandium(III) triflate complex of Ph-PYBOX gave the corresponding adduct in 66% ee. Lanthanoid triflates gave lower enantioselectivities (?28% ee).     

Chemo-enzymatic enantio-convergent asymmetric synthesis of (R)-(+)-Marmin

Asymmetric biohydrolysis of trisubstituted terpenoid oxiranes (rac-1a-rac-3a) was accomplished by employing the epoxide hydrolase activity Rhodococcus and Streptomyces spp. Depending on the biocatalyst, the biohydrolysis proceeded in an enantio-convergent fashion and gave the corresponding vic-diols in up to 97% ee at conversions beyond the 50%-threshold. In order to avoid a depletion of the ee of product by further oxidative metabolism, bioconversions had to be conducted in an inert atmosphere with exclusion of molecular oxygen. The synthetic applicability of this method was demonstrated by the asymmetric total synthesis of the monoterpenoid coumarin (R)-(+)-Marmin in 95% ee.     

Enantioselective aza-Diels-Alder reaction of Brassard’s diene with aldimines catalyzed by chiral N,N′-dioxide-Yb(OTf)3 complex

The chiral N,N′-dioxide-Yb(OTf)₃ complex-catalyzed enantioselective aza-Diels-Alder reaction of Brassard’s diene with aldimines has been developed, giving the corresponding α,β-unsaturated δ-lactam derivatives in moderate yields with good enantioselectivities (up to 81% ee and up to 99% ee by single recrystallization) under mild conditions. Isolation of the reaction intermediate indicates that this asymmetric aza-Diels-Alder reaction proceeds through a stepwise Mannich-type pathway.     

Asymmetric desymmetrization of meso-vic-diols by carbamoylation catalyzed with a chiral Cu(II) complex

Asymmetric desymmetrization of meso-vic-diols was achieved by carbamoylation in the presence of copper triflate and (S,S)-Ph-BOX as a catalyst without any use of bases. The method was successfully applied to asymmetric desymmetrization of five- to eight-membered cyclic meso-vic-diols in high enantioselectivity with up to 93% ee.     

Copper complex catalyzed asymmetric monosulfonylation of meso-vic-diols

Asymmetric desymmetrization of meso-vic-diols was performed by tosylation in the presence of copper(II) triflate and (R,R)-Ph-BOX as a catalyst. The method was successfully applied to asymmetric desymmetrization of cyclic and acyclic meso-vic-diols in high enantioselectivity with up to >99% ee.     

Highly efficient and enantioselective Michael addition of acetylacetone to nitroolefins catalyzed by chiral bifunctional organocatalyst bearing multiple hydrogen-bonding donors

A new efficient catalyst system for the asymmetric addition of acetylacetone to nitroolefins using a chiral bifunctional organocatalyst bearing multiple hydrogen-bonding donors was developed. When using the organocatalyst 2c derived from natural cinchona alkaloid in optimal conditions, up to 98% chemical yield and 98% ee were observed with a variety of aromatic nitroolefins.     

A biomimetic approach to the synthesis of a mycolic acid motif

A new method for the stereoselective synthesis of the (R,R)-β-hydroxy-α-alkyl fatty acid fragment of mycolic acids, via an asymmetric anti-aldol reaction is reported. The ‘mycolic acid motif’ fragment was prepared in three steps and >98% ee.     

Rhodium catalyzed asymmetric 1,4-addition of arylboronic acids to β,γ-unsaturated α-keto ester using chiral tert-butanesulfinylphosphines ligands

Rh-Catalyzed asymmetric 1,4-selective addition of arylboronic acids to β,γ-unsaturated α-keto ester was developed using chiral tert-butanesulfinylphosphine as ligand, good yields (up to 87%), good 1,4-regioselectivities (up to 96:4), and high enantioselectivities (up to 94% ee) were achieved.     

Axially chiral phosphine-oxazoline ligands in silver(I)-catalyzed asymmetric Mannich reaction of N-Boc aldimines with trimethylsiloxyfuran

Axially chiral phosphine-oxazoline ligand L6 was found to be a fairly effective chiral ligand in silver(I)-catalyzed asymmetric Mannich reaction of N-Boc aldimines with trimethylsiloxyfuran to give the corresponding adducts in up to 97% yield, 7:1 dr and 86% ee (major diastereoisomer).     

Synthesis of enantiopure β-amino alcohols via AKR/ARO of epoxides using recyclable macrocyclic Cr(III) salen complexes

A series of chiral macrocyclic Cr(III) salen complexes 1-8 were synthesized and characterized. These complexes were found to be highly active, regio-, diastereo-, and enantioselective catalysts in aminolytic kinetic resolution (AKR) of racemic trans-epoxides as well as asymmetric ring opening (ARO) of prochiral meso-epoxides with various anilines as nucleophiles at room temperature in 18-24 h. Excellent yields (>99% with respect to the nucleophile) with high enantioselectivity (ee, >99%) of chiral anti-β-amino alcohols was achieved with concomitant recovery of corresponding epoxides in high ee (up to >99%). The complex 1 also catalyzed the ARO of meso-epoxides to provide corresponding syn-β-amino alcohols in high yield (99%) and ee (up to 91%). Due to built-in basic sites in the catalyst, no external base (as an additive) was required to promote AKR and ARO reactions. The catalyst 1 was conveniently recycled several times with retention of its performance. The AKR of trans-stilbene oxide with aniline was successfully demonstrated at relatively higher scale (10 mmol) using the catalyst 1.     

A P-chiral bisdiamidophosphite ligand with a 1,4:3,6-dianhydro-d-mannite backbone and its application in asymmetric catalysis

A novel readily available P,P-bidentate diamidophosphite ligand with P^∗-stereocentres is prepared from an inexpensive C₂-symmetric 1,4:3,6-dianhydro-d-mannite. By using this efficient ligand, up to 98% ee is achieved in Pd-catalysed asymmetric allylic alkylation, up to 92% ee in Pd-catalysed asymmetric allylic amination and up to 87% ee in Rh-catalysed asymmetric hydrogenation. The influence of the precatalyst, substrate and solvent on the enantioselectivity is discussed.     

Asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives by organocatalyzed rearrangement of pyranones and enzymatic dynamic kinetic resolution

Dioxygenated cyclopentenones are versatile building blocks for the synthesis of several natural products. Herein we report a direct asymmetric synthesis of trans-4,5-dioxygenated cyclopentenone derivatives through base-catalyzed rearrangement of pyranones followed by dynamic kinetic resolution. Milder conditions than previously reported for this rearrangement have been found regarding amine base catalysis, solvent and temperature effects. All data supports a mechanism involving cyclization of an intermediate formed by electrocyclic ring opening of a pyranone-derived enol. We have developed conditions for asymmetric synthesis of trans-4-tert-butoxy-5-hydroxycyclopent-2-enone, in 81% yield and 95% ee, and analogous dioxygenated cyclopentenones, via a lipase induced dynamic kinetic resolution.     

Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and its application in the synthesis of (S)-Clopidogrel

The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C₆H₂SO₂-DPEN as the catalyst and HCOOH-Et₃N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied.     

Facile one-pot synthesis of BINOL- and H8-BINOL-based aryl phosphites and their use in palladium catalysed asymmetric allylation

Novel P-monodentate aryl phosphite ligands have been synthesised in one step from (R)-BINOL, (R)-H₈-BINOL and (R)-H₈-3,3′-dibromo-BINOL. With the new aryl phosphites, up to 86% ee was observed in the asymmetric Pd-catalysed amination of 1,3-diphenyl-2-propenyl acetate with sodium diformylamide. In the enantioselective alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate, up to 97% enantioselectivity was achieved.     

Asymmetric catalytic aziridination of dihydronaphthalenes for the preparation of substituted 2-aminotetralins

An enantioselective synthesis of substituted 2-aminotetralins from dihydronaphthalenes in four steps is described. The key step is the Jacobsen’s (diimine)copper-catalyzed asymmetric aziridination of dihydronaphthalenes to the respective aziridines in 33-82% yields and 60-87% enantiomeric excess. The enantioselectivity and the yield were dependent on the properties of the nitrene precursor. pTsNIPh appeared in general to give better results than pNsNIPh. Aziridines were ring-opened in the benzylic position by catalytic hydrogenolysis in quantitative yields, and deprotected in two steps to the respective 2-aminotetralins in 66-85% yields. The synthesis of (S)-2-aminotetralin (>98% ee) and (S)-2-amino-7-methoxytetralin (56% ee) were accomplished in 30 and 52% overall yields, respectively.     

Asymmetric autocatalysis of pyrimidyl alkanol and related compounds. Self-replication,amplification of chirality and implication for the origin of biological enantioenriched chirality

We discovered asymmetric autocatalysis in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, where the product 5-pyrimidyl alkanol acts as a highly efficient asymmetric autocatalyst to afford more of itself (Soai reaction). Asymmetric autocatalysis proceeded quantitatively (>99% yield), affording itself as a near enantiomerically pure (>99.5% ee) product. An extremely low enantiomeric excess (ca. 0.00005% ee) can automultiply during three rounds of consecutive asymmetric autocatalysis to >99.5% ee by asymmetric amplification. Circularly polarized light, and inorganic and organic crystals, act as the origin of chirality to trigger asymmetric autocatalysis. Asymmetric autocatalysis has enormous power to recognize and amplify the chirality of hydrogen, carbon, oxygen, and nitrogen isotopomers. Moreover, absolute asymmetric synthesis, i.e., the formation of enantioenriched compounds without the intervention of any chiral factor, is realized by asymmetric autocatalysis. By using designed molecules based on 5-pyrimidyl alkanol, the intramolecular asymmetric control, self-replication, and improvement of chiral multifunctionalized large molecules has been developed by applying asymmetric autocatalysis.     

A new electronically deficient atropisomeric diphosphine ligand (S)-CF3O-BiPhep and its application in asymmetric hydrogenation

A new electronically deficient atropisomeric diphosphine ligand (S)-CF₃O-BiPhep was synthesized from 1-bromo-3-(trifluoromethoxy)benzene in high yield. The key steps included oxidative coupling with anhydrous ferric chloride and optical resolution by (+)-DMTA. The ligand afforded high performance for Ir-catalyzed asymmetric hydrogenation of quinolines with ee up to 92% and TON up to 25,000. It was also successfully applied to the Pd-catalyzed asymmetric hydrogenation of simple indoles with ee up to 87% and Rh-catalyzed asymmetric 1,4-addition of phenylboronic acid to 2-cyclohexenone with 97% ee.     

Iridium-catalyzed asymmetric hydrogenation of 3-substituted unsaturated oxindoles to prepare C3-mono substituted oxindoles

An efficient and enantioselective hydrogenation of 3-substituted unsaturated oxindoles has been developed by an iridium complex of tropos phosphine-oxazoline ligands. It is the first example to prepare chiral C3-mono substituted oxindoles via asymmetric catalysis. And the reaction provides instant access to this kind of compounds with excellent conversion and enantioselectivities (up to 93% ee).     

Preparative asymmetric reduction of ketones in a biphasic medium with an (S)-alcohol dehydrogenase under in situ-cofactor-recycling with a formate dehydrogenase

The substrate range of a novel recombinant (S)-alcohol dehydrogenase from Rhodococcus erythropolis is described. In addition, an enzyme-compatible biphasic reaction medium for the asymmetric biocatalytic reduction of ketones with in situ-cofactor regeneration has been developed. Thus, reductions of poorly water soluble ketones in the presence of the alcohol dehydrogenase from R. erythropolis and a formate dehydrogenase from Candida boidinii can be carried out at higher substrate concentrations of 10-200 mM. The resulting (S)-alcohols were formed with moderate to good conversion rates, and with up to >99% ee.     

Amplification of chirality as a pathway to biological homochirality

Amplification of enantiomeric enrichment is a key feature for the chemical evolution of biological homochirality from the origin of chirality. The aggregations of the enantiomers by diastereomeric interactions enable the modification of their enantiomeric excess during some chemical processes. Fluorine-containing chiral compounds possess large amplification effect via distillation, sublimation and achiral chromatography by self-disproportionation. Asymmetric amplifications in enantioselective catalysis occur by the differential formation and reactivity between homochiral and heterochiral aggregate in solution.We described the amplification of ee in asymmetric autocatalysis of 5-pyrimidyl alkanol in the reaction between diisopropylzinc and pyrimidine-5-carbaldehdye. During the reactions extremely low ee (ca. 0.00005% ee) can be amplified to achieve more than 99.5% ee. Since the proposed origins of chirality such as CPL, quartz, chiral organic crystals of achiral compounds and statistical fluctuation of ee can initiate the asymmetric autocatalysis with amplification of ee, the proposed origin of chirality can be linked with enantiopure organic compound in conjunction with amplification of ee by asymmetric autocatalysis. In addition, we described that the carbon isotopically chiral compound triggers the asymmetric autocatalysis of 5-pyrimiodyl alkanol to afford the enantioenriched product with the absolute configuration correlated with that of carbon isotope chirality, that is, isotope chirality including hydrogen isotopes can control the enantioselectivity of asymmetric addition of alkyl metal reagent to aldehyde.