Regio- and enantioselective synthesis of functionalized tetrahydroquinolines by palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic bisacetates

A palladium-catalyzed cyclization of 2-amidophenylmalonates with allylic bisacetates is described. Tetrahydroquinolines having a vinyl group at the 3- or 2-position were produced, in which the regioselectivity of the resulting products was altered depending on the substituent on the amino group. The product was transformed to the azabicyclo[3.3.1]nonene via the ring-closing metathesis. Enantioselective reactions also successfully proceeded in the presence of (S)-BINAP to give the optically active tetrahydroquinoline with high enantioselectivity.     

Phosphine‐Catalyzed Domino Reactions: A Route to Functionalized Bicyclic Skeletons

A novel strategy that involves phosphine‐catalyzed sequential [2+3] and [3+2] annulation reactions was developed. In this domino reaction, γ‐substituted allenoates were used as novel C₄ synthons, and the bicyclic cyclopenta[b]dihydrofuran derivatives were produced in good to excellent diastereoselectivities and yields under mild conditions. Furthermore, preliminary studies on an asymmetric variant of this reaction proceeded with moderate enantioselectivity.     

Gas-phase enantioselectivity of chiral amido[4]resorcinarene receptors

Diastereomeric proton-bound [1(L)HA]+ complexes between selected amino acids (A=phenylglycine (Phg), tryptophan (Trp), tyrosine methyl ester (TyrOMe), threonine (Thr), and allothreonine (AThr)) and a chiral amido[4]resorcinarene receptor (1(L)) display a significant enantioselectivity when undergoing loss of the amino acid guest A by way of the enantiomers of 2-aminobutanes (B) in the gas phase. The enantioselectivity of the B-to-A displacement is ascribed to a combination of thermodynamic and kinetic factors related to the structure and the stability of the diastereomeric [1(L)HA]+ complexes and of the reaction transition states. The results of the present and previous studies allow classification of the [1(L)HA]+ complexes in three main categories wherein: i) guest A does not present any additional functionalities besides the amino acid one (alanine (Ala), Phg, and phenylalanine (Phe)); ii) guest A presents an additional alcohol function (serine (Ser), Thr, and AThr); and iii) guest A contains several additional functionalities on its aromatic ring (tyrosine (Tyr), TyrOMe, Trp, and 3,4-dihydroxyphenylalanine (DOPA)). Each category exhibits a specific enantioselectivity depending upon the predominant [1(L)HA]+ structures and the orientation of the 2-aminobutane reactant in the relevant adducts observed. The results may contribute to the understanding of the exceptional selectivity and catalytic properties of enzyme mimics towards unsolvated biomolecules.     

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.     

Investigation of brush-type chiral stationary phases based on O,O'-diaroyl tartardiamide and O,O'-bis-(arylcarbamoyl) tartardiamide

Four chiral organosilanes based on O,O'-dibenzoyl tartardiamide, O,O'-bis-(3,5-dimethylbenzoyl) tartardiamide, O,O'-bis-(phenylcarbamoyl) tartardiamide and O,O'-bis-[(3,5-dimethylphenyl)carbamoyl] tartardiamide were synthesized and immobilized on silica to afford corresponding brush-type chiral stationary phases (CSPs) with well-defined structures. Using 54 compounds containing a wide variety of structures as analytes, the enantioselectivities of the four CSPs were evaluated under normal-phase modes. 3,5-Dimethyl substituent in the aryl group was found to significantly affect the enantioselectivity of CSPs containing aryl ester moieties. Aryl carbamate moieties in CSPs were observed more beneficial for enantioseparation than aryl ester moieties. The additional hydrogen-bond donors (NH) present in the carbamate groups contributed greatly to the enantioselectivity of CSPs, which is contrary to the results that have been found in network-polymeric CSPs.     

Chiral Induction by Elimination‐Coupled Lithium–Ene Reaction: Synthesis of (+)‐(3R,4R)‐1,2‐Dihydromultifidene

Cyclization of the alkadienyl carbamates 1 to the cis‐divinylcyclopentanes 2 with high enantioselectivity and diastereoselectivity has been successfully achieved by (−)‐sparteine‐induced asymmetric deprotonation. The conversion may be described as a hybrid of a lithium–ene reaction and an S_n ′ reaction.     

Asymmetric Synthesis of Spiroketals with Aminothiourea Catalysts

Chiral spiroketal skeletons are found as core structures in a range of bioactive compounds. These natural compounds and their analogues have attracted much attention in the field of drug discovery. However, methods for their enantioselective construction are limited, and easily available optically active spiroketals are rare. We demonstrate a novel catalytic asymmetric synthesis of spiroketal compounds that proceeds through an intramolecular hemiacetalization/oxy‐Michael addition cascade mediated by a bifunctional aminothiourea catalyst. This results in spiroketal structures through the relay formation of contiguous oxacycles, in which multipoint recognition by the catalyst through hydrogen bonding imparts high enantioselectivity. This method offers facile access to spiroketal frameworks bearing an alkyl group at the 2‐position, which are prevalent in insect pheromones. Optically active (2S,5S)‐chalcogran, a pheromone of the six‐spined spruce bark beetle, and an azide derivative could be readily synthesized from the bicyclic reaction product.     

Asymmetric Organocatalyzed Michael Addition of Nitromethane to a 2‐Oxoindoline‐3‐ylidene Acetaldehyde and the Three One‐Pot Sequential Synthesis of (−)‐Horsfiline and (−)‐Coerulescine

(?)‐Horsfiline and (?)‐coerulescine were synthesized through three one‐pot operations in 33 and 46 % overall yield, respectively. Key to the success was the efficient use of a diarylprolinol silyl ether to catalyze the asymmetric Michael addition of nitromethane to a 2‐oxoindoline‐3‐ylidene acetaldehyde. This allowed the all‐carbon quaternary, spirocyclic carbon stereocenter to be constructed in good yield with excellent enantioselectivity.     

Achiral Pyridine Ligand-Enabled Enantioselective Radical Oxytrifluoromethylation of Alkenes with Alcohols

A conceptually novel strategy with achiral pyridine as the ancillary ligand to stabilize high-valent copper species for the first asymmetric radical oxytrifluoromethylation of alkenes with alcohols under Cu^I/phosphoric acid dual-catalysis has been developed. The transformation features mild reaction conditions, a remarkably broad substrate scope and excellent functional group tolerance, offering an efficient approach to a wide range of trifluoromethyl-substituted tetrahydrofurans bearing an α-tertiary stereocenter with excellent enantioselectivity. Mechanistic studies support the presumed role of the achiral pyridine as a coordinative ligand on copper metal to stabilize the key transient reaction species involved in the asymmetric induction process.     

Photochemical Studies on 5‐Methylbicyclo[1.1.1]pentane Derivatives: p‐Orbital Overlap Controlled Enantioselectivity

The first example of the p‐orbital overlap controlled enantioselectivity of Norrish type II photocyclization reaction was described. Irradiation of 5‐methyl bicyclo[1.1.1]pentanyl ketone with UV in the solid state as well as in the acetonitrile solution afforded the Norrish/Yang photocyclization compound as the sole product. Solid‐state asymmetric photochemical studies using ionic chiral auxiliary technique led to the enantioselectivity as high as 60%. The results were rationalized by X‐ray single crystal structure.     

Enantioselectivity in Ruthenium-Catalyzed Propargylic Substitution Reactions of Propargylic Alcohols with Acetone: A DFT Study

The enantioselectivity in the propargylic substitution reactions of propargylic alcohols with acetone catalyzed by optically active thiolate-bridged diruthenium complexes was examined via ωB97X-D level DFT calculations. Some structures with intramolecular dispersion interactions between ligands were found for the ruthenium-allenylidene complex, which is the key intermediate in the catalytic reaction, and it was determined that the structure corresponding to the X-ray crystal structure, which had provided the transition state model for the enantioselectivity in previous studies, was not the most stable among the obtained structures. Then, a variety of transition-state structures for the nucleophilic attack of prop-1-ene-2-ol, which is the enol isomer of acetone, on the γ-carbon of the ruthenium-allenylidene complex were explored. Among the transition-state structures with lower energies, the number of structures leading to the major (R) product was found to be larger than that of structures leading to the minor (S) product, providing enantioselectivity in terms of probability distributions. The introduction of a phenyl group in the thiolate ligand was suggested to increase the selectivity. Thus, we propose the novel transition state model for the asymmetric catalytic reaction system.     

Enantioselective palladium-catalyzed total synthesis of vitamin e by employing a domino Wacker-Heck reaction

An enantioselective total synthesis of vitamin E in which a novel palladium-catalyzed domino reaction was employed as the key step is described. This reaction allows the formation of the chiral chroman framework and the concurrent introduction of part of the side chain of vitamin E. The sequence comprises an enantioselective Wacker cyclization and a subsequent Heck reaction. Accordingly, reaction of alkenylphenol 12 with methyl vinyl ketone (13) in the presence of catalytic amounts of Pd(OTFA)(2) (TFA = trifluoroacetate), the enantiopure ligand (S,S)-Bn-BOXAX (8 b; Bn = benzyl, BOXAX = 2,2'-bis(oxazolyl)-1,1'-binaphthyl, and p-benzoquinone (9) as an oxidant gives access to chiral chroman 10 with an enantioselectivity of 97 % ee in 84 % yield. Chroman 10 is then converted into 24 by an aldol condensation reaction with (3R)-3,7-dimethyloctanal (11). Subsequent 1,2-addition of methyllithium, elimination of water, and hydrogenation yields vitamin E.     

One‐Pot Tandem Diastereoselective and Enantioselective Synthesis of Functionalized Oxindole‐Fused Spiropyrazolidine Frameworks

A highly efficient palladium(0)‐catalyzed asymmetric [3+2] cycloaddition using 3‐diazooxindoles serving as dipolarophiles affords functionalized pyrazolidine derivatives in an atom‐economical way. In addition, by trapping the pyrazolidine derivatives with maleimides, the corresponding spiropyrazolidine oxindoles containing multiple stereogenic centers have been obtained in high yields along with moderate to good levels of diastereoselectivity and enantioselectivity under mild conditions. Thus, a novel three‐component one‐pot tandem reaction has been developed.     

Highly Enantioselective Ring‐Opening Reactions of Aziridines with Indole and Its Application in the Building of C3‐Halogenated Pyrroloindolines

A magnesium‐catalyzed asymmetric ring‐opening reaction of aziridine with indole has been realized by employing commercially available chiral ligands. Both of the enantiomers of the ring‐opening product could be obtained with good yields and a high level of enantioselectivity. The corresponding ring‐opening product could be further transformed to various types of enantioenriched C₃‐halogenated‐pyrroloindolines.     

Enantioselective nucleophilic addition to N-(2-pyridylsulfonyl)imines by use of dynamically induced chirality

Enantioselective nucleophilic addition of Grignard reagents to N-(2-pyridylsulfonyl)imines in the presence of bis(oxazoline) afforded products with good enantioselectivity. Dynamically induced chirality on the sulfur by coordination of a chiral Lewis acid to a pyridyl nitrogen and one of the sulfonyl oxygens fixes the conformation of the complex and induces enantioselectivity. Since the 2-pyridylsulfonyl group can be easily removed after the addition reaction, it acts not only as a protecting group but also as an efficient stereocontroller.     

Influence of the Tricarbonyl Chromium Complexation of Cyclic Alcohols and of the Planar Chirality on the Kinetic Resolution by Candida Cylindracea Lipase

Tricarbonylchromium complexes of 1-indanol, 1-tetralol, 2-tetralol and the uncomplexed counterparts were kinetically resolved by asymmetric esterification with the Candida cylindracea lipase. We observed a beneficial effect of the tricarbonyl chromium group on the enantioselectivity and we have studied the implication of the relative positions of the tricarbonylchromium group and the alcohol function.     

Effect of microwave heating in the asymmetric addition of dimethylzinc to aldehydes

Microwave-heated enantioselective additions of dimethylzinc to various aldehydes are reported. Dramatically reduced reaction times and lower catalyst loadings (5%), compared with conventionally used conditions, can be achieved, with excellent yields and just small loss of enantioselectivity (up to 83% enantioselectivity is achieved). In the reaction with aliphatic aldehydes the same enantioselectivity has been achieved for microwave-heated and conventional room temperature conditions.     

Recent Advances in Transition Metal‐Catalyzed Asymmetric Radical Reactions

Control of enantioselectivity in radical reactions was a formidable challenge for organic chemists for decades. Thanks to the key role of transition metal complexes both in promoting and highly enantioselectively controlling sophisticated synthetic routes, great improvements in this filed have been achieved by merging transition‐metal asymmetric catalysis with radical chemistry. Herein we provide a perspective of some of the most significant contributions in the field during the past decades. Accordingly, the major advances are classified based on different strategies for controlling stereoselectivity including: (1) chiral metal complex chelation, (2) chiral metal complex combined with radical species and reductive elimination, (3) chiral metal complex outer‐sphere substitution by radical intermediate. Brief discussion of mechanism is presented whenever relevant.     

Lithium Ephedrinate Mediated Aldol Reaction of Arylacetonitriles: Thermodynamic Control of Enantioselectivity

Deracemization , the conversion of a racemic mixture into an enantiomerically enriched material, is achieved with the retro-aldol reaction of rac- 1 in the presence of lithium (−)-ephedrinate [Eq. (1)]. Remarkably, two stereogenic centers are simultaneously deracemized. This reaction shows that efficient thermodynamic control of the enantioselectivity of aldol reactions is possible     

Requirements for the formation of a chiral template

The chemisorptive enantioselectivity of propylene oxide is examined on Pd(111) surfaces templated by chiral 2-methylbutanoate and 2-aminobutanoate species. It has been found previously that chiral propylene oxide is chemisorbed enantiospecifically onto Pd(111) surfaces modified by either (R)- or (S)-2-butoxide. The enantiomeric excess (ee) varied with template coverage, reaching a maximum of approximately 31%. Templating the surface using 2-methylbutanoate, where the chiral center is identical to that in the 2-butoxide species, but is now anchored to the surface by a carboxylate rather than an alkoxide linkage, shows no enantiospecificity. The enantioselectivity is restored when the methyl group is replaced by an amine group, where a maximum ee value of approximately 27% is found. DFT calculations and infrared measurements suggest that the structures of the butyl group on the surface are similar for both 2-butoxide and 2-methylbutanoate species, implying that gross conformational changes are not responsible for differences in chemisorptive enantioselectivity. There is no clear correlation between the location of the chiral center and enantioselectivity, suggesting that differences in the template adsorption site are also not responsible for the lack of enantioselectivity. It is proposed that the 2-butyl group in 2-methylbutanoate species is less rigidly bonded to the surface than that in 2-butoxides, allowing the chiral center to rotate azimuthally. It is postulated that the role of the amino group in 2-aminobutanoate species is to anchor the chiral group to the surface to inhibit azimuthal rotation.