Rhodium-catalyzed asymmetric 1,4-addition of organoboron reagents to 5,6-dihydro-2(1H)-pyridinones. Asymmetric synthesis of 4-aryl-2-piperidinones

Catalytic asymmetric synthesis of 4-aryl-2-piperidinones was realized for the first time by asymmetric 1,4-addition of arylboron reagents to 5,6-dihydro-2(1H)-pyridinones in the presence of a chiral bisphosphine-rhodium catalyst. In the reaction introducing 4-fluorophenyl group, the use of 4-fluorophenylboroxine and 1 equiv (to boron) of water at 40 degrees C gave the highest yield of the arylation product with high enantioselectivity (98% ee). The (R)-4-(4-fluorophenyl)-2-piperidinone obtained here is a key intermediate for the synthesis of (-)-Paroxetine.     

Chiral epoxides via borane reduction of 2-haloketones catalyzed by spiroborate ester: application to the synthesis of optically pure 1,2-hydroxy ethers and 1,2-azido alcohols

An enantioselective borane-mediated reduction of a variety of 2-haloketones with 10% spiroaminoborate ester 1 as catalyst is described. By a simple basic workup of 2-halohydrins, optically active epoxides are obtained in high yield and with excellent enantiopurity (up to 99% ee). Ring-opening of oxiranes with phenoxides or sodium azide is investigated under different reaction conditions affording nonracemic 1,2-hydroxy ethers and 1,2-azido alcohols with excellent enantioselectivity (99% ee) and in good to high chemical yield.     

Optically active 1,2-bis(1-arylhydroxymethyl) ferrocene: a new, efficient chiral ligand for scandium-catalyzed asymmetric Diels-Alder reaction

[reaction: see text] The Sc(OTf)3/FERRODIOL (2) complex was prepared at -78 degrees C in CH2Cl2 in the presence of 2,6-lutidine and MS 4A. The chiral scandium Lewis acid-catalyzed asymmetric Diels-Alder reaction of cyclopentadiene (3) with 3-acyloxazolidin-2-ones (4) effectively produced the adduct (5) in a high yield with good selectivity, i.e., endo/exo = 90:10 up to 91% ee (endo).     

InBr3-catalyzed Friedel-Crafts addition of indoles to chiral aromatic epoxides: a facile route to enantiopure indolyl derivatives

Aromatic optically active epoxides can be opened in a regioselective and clean way with indoles in the presence of catalytic amount of InBr3 (1 mol %). The reaction takes place with a SN2 pathway affording the 2-aryl-2-(3'-indolyl)ethan-1-ols with excellent enantioselectivity (ee up to 99%).     

Organocatalytic asymmetric direct aldol reactions of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones

The organocatalytic asymmetric direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones in the presence of a catalytic amount of (S)-5-(pyrrolidin-2-yl)-1H-tetrazole in dichloroethane at 40 °C proceeds smoothly to produce (R)-4,4,4-trifluoro-1-aryl-3-hydroxy-1-butanones in high yields with up to 90% ee.     

Stereoselective synthesis of highly enantioenriched (E)-allylsilanes by palladium-catalyzed intramolecular bis-silylation: 1,3-chirality transfer and enantioenrichment via dimer formation

Highly enantioenriched (E)-allylsilanes have been synthesized from optically active allylic alcohols on the basis of Pd-catalyzed intramolecular bis-silylation followed by highly stereospecific Si-O elimination reactions. The method involves three steps: 1) O-disilanylation of the allylic alcohols with chlorodisilanes, 2) intramolecular bis-silylation in the presence of a 1,1,3,3-tetramethylbutyl isocyanide/[Pd(acac)2] (acac = acetylacetonate) catalyst at 110 degrees C, and 3) treatment of the reaction mixture with organolithium reagents. The overall transformation proceeds with nearly complete conservation of the enantiopurity of the starting allyl alcohols by transposition of the C=C bond. For instance, (R)-(E)-3-decen-2-ol (99.6-99.7 % ee) produced (S)-(E)-4-(organosilyl)-2-decene of 98.8-99.4 % ee for a variety of silyl groups, including Me3Si, Me2PhSi, tBuMe2Si, Et3Si, and iPr3Si. In the bis-silylation step, the initially formed trans-1,2-oxasiletanes immediately dimerize to stereoselectively give 1,5-dioxa-2,6-disilacyclooctanes, which are isolated in high yield by carrying out the reaction at 70 degrees C. The eight-membered ring compounds undergo thermal extrusion of (E)-allylsilanes in high yield at 110 degrees C, along with formation of 1,3-dioxa-2,5-disilacyclohexane derivatives. These in turn undergo a Peterson-type elimination by treatment with nucleophiles such as BuLi and PhLi to give the (E)-allylsilanes. All of the steps involved in the sequence proceed with extremely high stereoselectivity and stereospecificity, leading to almost complete 1,3-chirality transfer through the overall transformation. The dimerization step, which forms diastereomeric intermediates, allows the synthesis of a highly enantioenriched allylsilane (99.4 % ee) from an optically active allylic alcohol with lower enantiopurity (79.2 % ee) by enrichment of enantiopurity. A general method for the determination of the enantiomeric excesses of (E)-allylsilanes is also described in detail.     

Direct catalytic asymmetric Mannich-type reaction of beta-keto phosphonate using a dinuclear Ni2-Schiff base complex

Direct catalytic asymmetric Mannich-type reactions of beta-keto phosphonates are described. A homodinuclear Ni 2-Schiff base complex promoted the reaction at 0 degrees C, giving beta-amino phosphonates in up to 90% yield, 20:1 dr, and 99% ee. Control experiments suggested that two Ni metals are important for achieving high yield and stereoselectivity.     

Enantioenriched 1-aryl-2-fluoroethylamines. Efficient lipase-catalysed resolution and limitations to the Mitsunobu inversion protocol

Both enantiomers of eight 1-aryl-2-fluoroethylamines have been synthesised starting with 1-aryl-2-fluoroethanones. Kinetic resolution of the amines using lipase B from Candida antarctica with ethyl methoxyacetate as the acyl donor gave the (R)-amines in 96-99% ee and the (S)-methoxyacetamides in >99.5% ee. The resolution was robust with respect to variation in reaction temperature, acyl donor concentration, water activity and substrate structure. Nine other lipase preparations failed to catalyse the reaction or gave a low enantioselectivity. Secondly, a Mitsunobu inversion protocol starting with enantioenriched 1-aryl-2-fluoroethanols using phthalimide as nucleophile was employed in the synthesis of the (S)-1-aryl-2-fluoroethylamines. Both the inversion efficiency and yield depended on the aromatic substituents. For six of the substrates, clean inversion of the stereochemistry was observed. However, racemisation and low yields were the result when electron-donating substituents were present at the aromatic ring. When substituted with a cyano or a nitro group, an unexpected fluorine elimination occurred, limiting the yield for these transformations. The absolute configuration of the 1-aryl-2-fluoroethylamines was determined using circular dichroism.     

Palladacycle-catalyzed highly efficient kinetic resolution of 1-hydroxy-2-aryl-1,2-dihydronaphthalenes via dehydration reaction

Palladacycles showed their high efficiency in the kinetic resolution of 1-hydroxy-2-aryl-1,2-dihydronaphthalenes via dehydration, providing optically active products in high yields and high ee with an S factor up to 26. The superiority of a benzylic-substituted palladacycle in asymmetric induction was also demonstrated.     

Enantioselective [4+2]-cycloaddition reaction of a photochemically generated o-quinodimethane: mechanistic details, association studies, and pressure effects

1,2,3,4-Tetrahydro-2-oxoquinoline-5-aldehyde (2) was prepared from m-aminobenzoic acid and 3-ethoxyacryloyl chloride (4) in 19 % overall yield. Compound 2 underwent a photochemically induced [4+2]-cycloaddition reaction with various dienophiles upon irradiation in toluene solution. The exo product 10 a was obtained with acrylonitrile (9 a) as the dienophile, whereas methyl acrylate (9 b) and dimethyl fumarate (9 c) furnished the endo products 11 b and 11 c (69-77 % yield). The reactions proceeded at -60 degrees C in the presence of the chiral complexing agent 1 (1.2 equiv) with excellent enantioselectivity (91-94 % ee). The enantiomeric excess increases in the course of the photocycloaddition as a result of the lower product association to 1. The intermediate (E)-dienol 8 was spectroscopically detected at -196 degrees C in an EPA (diethyl ether/isopentane/ethanol) glass matrix. The association of the substrate 2 to the complexing agent 1 was studied by circular dichroism (CD) titration. The measured association constant (K(A)) was 589 M(-1) at room temperature (25 degrees C) and normal pressure (0.1 MPa). An increase in pressure led to an increased association. At 400 MPa the measured value of K(A) was 703 M(-1). Despite the stronger association the enantioselectivity of the reaction decreased with increasing pressure. At 25 degrees C the enantiomeric excess for the enantioselective reaction 2 + 9 a-->10 a decreased from 68 % ee at 0.1 MPa to 58 % ee at 350 MPa. This surprising behavior is explained by different activation volumes for the diastereomeric transition states leading to 10 a and ent-10 a.     

Discovery of a new efficient chiral ligand for copper-catalyzed enantioselective Michael additions by high-throughput screening of a parallel library

A combinatorial library of 125 chiral Schiff base ligands 5 was synthesized with the use of solution-phase parallel synthesis and solid-phase extraction (SPE) techniques to scavenge excess reagents and reaction by-products and avoid chromatography. The synthetic methodology coupled five N-Boc-protected beta-amino sulfonyl chlorides 1a-e with five different amines 2f-j to give 25 N-Boc sulfonamides 3, which were in turn deprotected and coupled with five salicylaldehydes 4p-t to give 125 ligands 5 in good yields and of sufficient purity to be used in ligand-catalyzed reactions. These ligands were tested in the copper-catalyzed conjugate addition of dialkyl zinc to cyclic and acyclic enones. A multisubstrate high-throughput screening of the library was performed with an equimolar mixture of 2-cyclohexenone and 2-cycloheptenone (9 and 10, respectively, 0.2 mmol total), with 5.5 mol% ligand 5 (0.011 mmol) and 5 mol% Cu(OTf)2 (OTf= OSO2CF3) (0.010 mmol) in 1:1 toluene/ hexane at - 20 degrees C. From the screening of the library, 5bhr was identified as the best ligand, which yielded 3-ethylcyclohexanone (12) and 3-ethylcycloheptanone (13) in 82% and 81% ee, respectively, and complete conversions. Under optimized conditions (2.75 mol% 5bhr, 2.5 mol% copper(i) triflate, toluene as reaction solvent), improved results were obtained for 12 (90% ee, 93% yield) and for 13 (91% ee, 95% yield). Selected ligands 5 were also tested in the addition of Me2Zn to 2-cyclohexenone (9, ee up to 79%), of Et2Zn to 2-cyclopentenone (11, ee up to 80%) and to acyclic enones 16 and 17 (ee up to 50%).     

Regio- and enantioselective hydrosilylation of 1-arylalkenes by use of palladium-MOP catalyst

Hydrosilylation of styrenes bearing β-substituents with trichlorosilane was catalyzed by a palladium complex (0.1 mol %) coordinated with (R)- 2-methoxy-2′-diphenylphosphino-1,1′-binaphthyl ((R)-MeO-MOP) to give high yields of optically active 1-aryl-1-silylalkanes (80–85% ee) as single regioisomers. The resulting silanes were readily converted into the corresponding optically active alcohols (80–99% yield).     

Molecular orbital studies on pericyclic reactions of cinnamyl xanthates in beta-cyclodextrin cavities

The solid beta-cyclodextrin (beta-CyD) complex of O-cinnamyl S-methyl dithiocarbonates (xanthate, 1a), upon heating at 45 degrees C, underwent asymmetric [3,31-sigmatropic rearrangement to give the optically S-(1-phenylallyl) S-methyl dithiocarbonate (2a) with 60% ee. Heating the beta-CyD complex of 2a at 120 degrees C caused extrusion of COS to give cinnamyl methyl sulfide (3a) in high yield. The reaction behavior and role of beta-CyD are discussed based on molecular orbital calculation data.     

Optically active nitrile oxides: synthesis and 1,3-dipolar cycloaddition reactions

Baker’s yeast-promoted reduction of the CC bond in 2-aryl-1-nitropropenes gave the corresponding optically active (R)-2-aryl-1-nitropropanes of high enantiomeric purity (ee >90%). They were next converted with the aid of the Mukaiyama and Hoshino method into the optically active nitrile oxides, which were made to react in situ with ethyl propiolate, methylvinyl ketone and (R)-1-phenyl-2-(phenylsulfonyl)ethyl acrylate to yield the appropriate, enantiomerically enriched, isoxazoles or 4,5-dihydroisoxazoles as diastereomeric mixtures, respectively.     

Catalytic asymmetric cyano-ethoxycarbonylation reaction of aldehydes using a YLi3 tris(binaphthoxide) (YLB) complex: mechanism and roles of achiral additives

Full details of a catalytic asymmetric cyano-ethoxycarbonylation reaction promoted by a heterobimetallic YLi3 tris(binaphthoxide) complex (YLB 1), especially mechanistic studies, are described. In the cyanation reaction of aldehydes with ethyl cyanoformate, three achiral additives, H2O, tris(2,6-dimethoxyphenyl)phosphine oxide (3a), and BuLi, were required to achieve high reactivity and enantioselectivity (up to >99% yield and up to 98% ee). The roles of achiral additives and the reaction pathway were investigated in detail. In situ IR analysis revealed that the initiation step to generate LiCN from H2O, BuLi, and ethyl cyanoformate is rather slow. On the basis of mechanistic studies of the initiation step to generate an active nucleophilic species, reaction conditions were optimized by using a catalytic amount of acetone cyanohydrin as an initiator. Under the optimized conditions, the induction period decreased and the reaction completed within 9 min using 5 mol % YLB at -78 degrees C. Catalyst loading was successfully reduced to 1 mol %. Kinetic experiments and evaluation of the substituent effects of phosphine oxide revealed that phosphine oxide had beneficial effects on both the reaction rate and the enantioselectivity. The putative active species as well as the catalytic cycle of the reaction are also discussed.     

Highly Efficient Asymmetric Synthesis of Enantiopure Dihydro-1,2-oxazines: Dual-Organocatalyst-Promoted Asymmetric Cascade Reaction

A one-pot dual-organocatalyst-promoted asymmetric α-aminoxylation/aza-Michael/aldol consendation cascade reaction is presented. The targeted optically active 1,2-oxazine derivatives are synthesized in moderate yields (up to 70%), excellent enantioselectivities (ee >99% in all cases), and excellent diastereoselectivities (dr up to >99:1) under mild conditions. To further elucidate the synthetic utility of the cascade products, cleavage of the N-O bond is demonstrated and an enantiopure syn-1,4-amino alcohol derivative is achieved in excellent yield.     

Hydrovinylation of norbornene. Ligand-dependent selectivity and asymmetric variations

[reaction: see text] Norbornene undergoes Ni-catalyzed (1-2 mol% allylnickel bromide/phosphine/NaBARF or AgSbF(6), 1 bar ethylene, -50 degrees C) hydrovinylation (>97% yield), giving either a 1:1 or a 2:1 (norbornene/ethylene) adduct depending on the size of the phosphine. Use of binaphthol-derived phosphoramidite ligand results in up to 80% ee for the 1:1 adduct. The course of the reaction is highly dependent on the ligand (size and configuration of the appendages) and the counteranion present.     

Photo-Arbuzov rearrangements of 1-arylethyl phosphites: stereochemical studies and the question of radical-pair intermediates.

The direct UV irradiation of the 1-arylethyl phosphites 7, 8, and 9 was carried out in acetonitrile, benzene, and cyclohexane, as was the triphenylene-sensitized reaction of 9. Dimethyl 1-phenylethyl phosphite, 7, gives the photo-Arbuzov rearrangement product, dimethyl 1-phenylethylphosphonate (10), in 67% average yield and minor amounts (2%) of 2,3-diphenylbutane (11a) in quantum yields of 0.32 and 0.02, respectively. The photorearrangement of optically active, predominantly (R)-1-phenylethyl phosphite 7 (R/S = 97/3; 94% ee), at 35-40 degrees C proceeds with a high degree of stereospecificity at the stereogenic migratory carbon to give predominantly (R)-10 (R/S = 86/14, 72 +/- 2% ee). Use of the nitroxide radical trap TEMPO affords phosphonate 10, presumably all cage product, from predominantly (R)-7 (R/S = 97/3; 94% ee) in 64% yield (80% ee, R/S = 90/10). By contrast, the 1-(4-acetylphenyl)-ethyl phosphite, predominantly (S)-8 (S/R = 98/2, 96% ee), on direct irradiation gives the corresponding phosphonate (12) in only 20% yield along with dimer 11b in 40% accountability yield. Phosphonate 12 is nearly racemic (R/S = 52/48). Direct irradiation of predominantly (R)-9 (R/S = 98/2, 96% ee), a 1-(1-naphthyl)ethyl phosphite, results in a product distribution similar to that from predominantly (R)-7, but with a somewhat higher degree of retention of configuration in the product phosphonate 13 (R/S = 93/7, 86 +/- 3 ee). By contrast, the triplet triphenylene-sensitized photorearrangement of largely (R)-9 (R/S = 98/2, 96% ee) leads to product distributions similar to those from direct irradiation of predominantly (S)-8 and is accompanied by almost total loss of stereochemistry in its product phosphonate, 13 (R/S = 51/49). The partial loss of stereochemistry on direct irradiation of 7 and 9 provides evidence for radical pair formation. Furthermore, these stereochemical results are diagnostic of the multiplicity of the initial radical pair formed. Values for kcomb/krot for the proximate free radical pairs from 7 and 9, derived experimentally, are severalfold larger than those for the proximate singlet pair from Ph2C=C=N-CHPhMe, corrected to 35 degrees C. The possibility that kcomb is increased for the pairs from 7 and 9 is proposed.     

Gold-catalyzed highly enantioselective synthesis of axially chiral allenes

Axially chiral allenes are synthesized from chiral propargylamines catalyzed by KAuCl4 in high yields (up to 93% yield) and excellent enantioselectivities (up to 97% ee) in CH3CN at 40 degrees C. The reaction has been applied to the synthesis of novel allene-modified artemisinin derivatives with the delicate endoperoxide moieties remaining intact. A tentative mechanism regarding gold(I)-catalyzed intramolecular hydride transfer was proposed on the basis of deuterium-labeling experiments and ESI-MS analysis of the reaction mixture.     

Chiral phosphine Lewis base catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone and phenyl acrylate

In the aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone (MVK) promoted by chiral phosphine Lewis base: (R)-2'-diphenylphosphanyl-[1,1']binaphthalenyl-2-ol (10 mol%), the aza-Baylis-Hillman adducts 1 were obtained in good yields with high ee (70-94% ee) at -30 degrees C in THF. In CH2Cl2 upon heating at 40 degrees C, the aza-Baylis-Hillman reaction of N-sulfonated imines with phenyl acrylate gave the adducts 2 in high yields (60-97%) with moderate ee (52-77%).