Pyrrole macrocyclic ligands for Cu-catalyzed asymmetric Henry reactions

New chiral perazamacrocycles containing four pyrrole rings have been synthesized by the [2+2] condensation of (R,R)-diaminocyclohexane and 5,5'-(alkane-2,2-diyl)bis(1H-pyrrole-2-carbaldehydes). These macrocycles, differing for the alkyl/aryl meso-substituents, were used as ligands in the copper-catalyzed Henry reactions of aromatic and aliphatic aldehydes with nitroalkanes. In the optimized experimental conditions, the condensations of nitromethane and aromatic and aliphatic aldehydes in the presence of catalytic amounts of copper diacetate and methyl-substituted macrocyclic ligand (2:1 ratio) in ethanol at room temperature provided products often with high enantiomeric excesses (up to 95% ee). The positive influence of the macrocyclic structure on the efficiency/enantioselectivity of the catalytic system was demonstrated by comparison with the outcomes of Henry reactions performed using analogous macrocyclic ligands (trianglamines) and open-chain ligands derived from (R,R)-diaminocyclohexane.     

Synthesis of new planar chiral [2.2]paracyclophane Schiff base ligands and their application in the asymmetric Henry reaction

A series of new planar and central chiral ligands based on [2.2]paracyclophane backbones were designed and prepared from enantiomerically pure 4-amino-13-bromo[2.2]paracyclophane and commercially available chiral amino alcohols. Their application in a copper-catalyzed asymmetric Henry reaction resulted in secondary alcohols with high yield and excellent selectivity for active aldehydes (up to 94% ee). This is a successful example of employing planar chiral [2.2]paracyclophane ligands in copper-catalyzed reaction.     

Synthesis of novel thiophene‐based chiral ligands and their application in asymmetric Henry reaction

Novel chiral thiolated amino alcohols were synthesized from norephedrine and thiophene carbaldehydes (methyl‐ or ethyl‐substituted) and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to provide β‐hydroxy nitroalkanols in high conversion (92%). The reaction was optimized in terms of the metal, solvent, temperature and amount of chiral ligand. The corresponding catalyst with Cu(OTf)₂ and 2‐propanol as the solvent provided the best enantioselectivities (up to 96% ee) of the corresponding nitroalcohols for aliphatic aldehydes. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of chiral 1,3-diamines derived from cis-2-benzamidocyclohexanecarboxylic acid and their application in the Cu-catalyzed enantioselective Henry reaction

In this study, 13 different chiral 1,3-diamines were synthesized from (-)-cis-2-benzamidocyclohexanecarboxylic acid. They were successfully applied as ligands in the Cu-catalyzed asymmetric Henry reaction between benzaldehyde and nitromethane. It was confirmed that the enantioselectivity of the product could be controlled by the substituents on the two amino groups. A time-course study revealed a decrease in product enantioselectivity caused by spontaneous retro-Henry reaction, which was suppressed by conducting the reaction at 0 °C. This versatile reaction afforded various β-nitroalcohols in excellent yields and enantioselectivities (up to 98% yield, 91% enantiomeric excess) under the optimized reaction conditions. The chiral induction mechanism was explained on the basis of a previously proposed transition-state model.     

Synthesis of novel chiral Schiff-base ligands and their application in asymmetric nitro aldol (Henry) reaction

Chiral Schiff-bases prepared from chiral amino alcohols catalyze the enantioselective Henry (nitro aldol) reaction between nitromethane and p-nitrobenzaldehyde in the presence of Cu(OTf)₂ and Zn(OTf)₂. Zn(OTf)₂ promoted the reaction yield, while Cu(OTf)₂ promoted the enantiomeric excess. The highest enantioselectivities were observed with ligand 3 (44% ee) and ligand 5 (47% ee).     

New chiral allylaminosilanes and their use in asymmetric Sakurai reactions

The new allylaminosilanes 2a–c, derived from chiral amines, react with benzaldehyde and pivalaldehyde in the presence of SnCl₄ to give homoallylic alcohols 4a–b with enantiomeric excesses of up to 30%.     

d-Mannitol-derived novel chiral thioureas: Synthesis and application in asymmetric Henry reactions

Five novel thioureas have been obtained through multi-step reactions from d-Mannitol as starting material and applied as catalysts in the asymmetric Henry reaction. Using catalyst 7a, (1S,2R)-2-nitro-1-phenylpropan-1-ol containing two chiral centers was obtained in high yield and with high selectivity (up to 95% yield, 87% ee, 91:9 dr). This catalyst also retained activity in the presence of water, affording a up to 93% yield, 88% ee, and 94:6 dr.     

TARTROL-derived chiral phosphine–phosphite ligands and their performance in enantioselective Cu-catalyzed 1,4-addition reactions

By using (R,R,R,R)-2,3-dimethoxy-2,3-dimethyl-1,4-dioxane-5,6-bis-diphenylmethanol (TARTROL) as a chiral building block, a set of six modular phosphine–phosphite ligands (with a 1,2-phenylene backbone) were synthesized and evaluated in the Cu-catalyzed asymmetric 1,4-addition of Grignard reagents to cyclohexenone. Ligands with bulky substituents at the ortho- and para-positions to the chiral phosphite moiety were found to be the most selective affording the 1,4-addition products with enantioselectivities of up to 84% ee.     

A new class of chiral P,N-ligands and their application in palladium-catalyzed asymmetric allylic substitution reactions

An efficient and modular synthesis of a series of chiral nonracemic P,N-ligands is reported. The P,N-ligands were prepared from 2-chloro-4-methyl-6,7-dihydro-5H-[1]pyrindine-7-one and a series of substituted chiral C(2)-symmetric 1,2-ethanediols (R = Me, i-Pr, and Ph). The ligands were evaluated for use in catalytic asymmetric synthesis in the palladium-catalyzed allylic substitution reactions of a racemic allylic acetate and dimethyl malonate. In the case of the P,N-ligand (R = Ph), the reaction was found to be highly stereoselective (90% ee).     

An efficient synthesis of chiral phosphinyl oxide pyrrolidines and their application to asymmetric direct aldol reactions

Chiral pyrrolidine-based phosphinyl oxides were synthesized and their performance as organocatalysts for asymmetric direct aldol reactions was evaluated. High enantioselectivities and diastereoselectivies were achieved for a range of cyclic ketones and aromatic aldehydes.     

Methods for the synthesis of chiral sulfur heterocycles and their application in the asymmetric Baylis–Hillman reactions

Enantiomerically pure (2S,6S)-2,6-diphenyltetrahydro-2H-thiopyran, (2S)-2-phenyltetrahydro thiophene, and (2S)-2-phenyltetrahydro-2H-thiopyran were prepared in 70–72% yields and with 86–99% ee via cyclization of the corresponding dimesylate in an S_N2 cyclization reaction using sodium sulfide nonahydrate. The results on the application of various chiral sulfides in asymmetric Baylis–Hillman reactions are also described.     

Palladium-catalyzed asymmetric synthesis of axially chiral allenylsilanes and their application to SE2' chirality transfer reactions

Stepwise application of the Pd-catalyzed S(N)2' reaction and the desilylative S(E)2' reaction to the ambivalent 2-bromo-1-silyl-1,3-dienes provides a novel route to the highly enantioselective construction of tertiary and quaternary propargylic stereogenic centers via axially chiral allenylsilanes.     

Design and synthesis of bistereogenic chiral ionic liquids and their use as solvents for asymmetric Baylis-Hillman reactions

Three novel chiral ionic liquids (CILs) containing two chiral centers in the side chain bonded to the 2-position of the imidazolium cation and different anions have been synthesized, characterized and used as chiral solvents for asymmetric Baylis-Hillman (BH) reactions; good yields and fair enantioselectivities were obtained.     

Design and synthesis of chiral 1,10-phenanthroline ligand,and application in palladium catalyzed asymmetric 1,4-addition reactions

Pd-catalyzed asymmetric 1,4-addition of phenylboronic acid to α,β-unsaturated carbonyl compounds was developed using chiral 1,10-phenanthroline derivative as ligand. Good yields (up to 97%), and high enantioselectivities (up to 97% ee) were achieved.     

Nanocrystalline MgO for asymmetric Henry and Michael reactions

Nanomaterials with their three-dimensional structure and defined size and shape are considered to be suitable candidates for proper alignment with prochiral substrates for unidirectional introduction of reacting species to induce an asymmetric center. We herein report the design and development of a truly recyclable heterogeneous catalyst, nanocrystalline magnesium oxide, for the asymmetric Henry reaction (AH) to afford chiral nitro alcohols with excellent yields and good to excellent enantioselectivities (ee's) for the first time. Bronsted hydroxyls are the sole contributors for the ee, while they add on to the activity in AH. It is demonstrated that the hydrogen bond interactions between the -OH groups of (S)-(-)-binol and the -OH groups of MgO are essential for the induction of enantioselectivity. Further, to prove the above hypothesis, we have successfully carried out another reaction, asymmetric Michael reaction (AM) with nanocrystalline MgO. The reusable and suitably aligned nanocrystalline MgO-catalyzed AH and AM reactions afforded chiral products with comparable ee's to that of the homogeneous system.     

Synthesis of novel chiral phosphinocyrhetrenyloxazoline ligands and their application in asymmetric catalysis

Several novel planar chiral phosphinocyrhetrenyloxazolines have been synthesized, and their catalytic activities have been evaluated in a variety of asymmetric catalytic reactions. Preferable effects as compared to their ferrocenyl analogues have been observed in asymmetric allylic amination and asymmetric hydrosilylation, and up to 97% ee and 72% ee were reached, respectively. The Lewis basicity of the phosphorus on the ferrocene and the cyrhetrene, which contributes to their different behavior in catalysis, has been deduced by 31P NMR spectroscopy analysis, as indicated by 1J(77Se-31P) in the corresponding phosphine selenides.     

Design and application of linked-BINOL chiral ligands in bifunctional asymmetric catalysis

The design and application of linked-BINOLs investigated in our group are reviewed. Linked-BINOLs are a kind of semi-crown ether, thus they are flexible and applicable to metals having various ionic radii (Ga3+, Li+, Zn2+, In3+, La3+, and Y3+). The flexible linker segment, containing a coordinative heteroatom, has a crucial role in the construction of a unique and effective chiral environment that is not accessible from BINOL itself. Applications of linked-BINOLs to an epoxide opening reaction, Michael reactions, a direct aldol reaction, direct Michael reactions of a hydroxyketone, and direct Mannich-type reactions of hydroxyketones and N-acylpyrrole are described.     

Second generation levoglucosenone-derived chiral auxiliaries. Scope and application in asymmetric Diels-Alder reactions

Chiral alcohols were designed and easily prepared from levoglucosenone, a biomass-derived valuable synthon. These alcohols were tested as chiral auxiliaries in asymmetric Diels-Alder reactions between the corresponding acrylates with acyclic and cyclic dienes. The regio, stereo, and facial selectivity varied from very good to excellent, depending upon the benzylic substitution of the auxiliary and the diene employed. As a consequence, after removal of the auxiliary, the resulting carboxylic acid derivatives were obtained in 72-99% ee.     

Synthesis of polymer microsphere-supported chiral pyrrolidine catalysts by precipitation polymerization and their application to asymmetric Michael addition reactions

Polymer microsphere-supported chiral pyrrolidine catalysts were successfully synthesized by a precipitation polymerization incorporating a methacrylate monomer bearing chiral N-Boc-pyrrolidine moiety, followed by removal of the N-Boc groups. The resulting polymeric catalysts were applied to the asymmetric Michael addition reactions of aldehydes with alkyl vinyl ketones. The effects of the comonomer, the molar ratios within the catalyst, the catalyst loading, the temperature, and the solvent on the catalytic performance were investigated in detail. The reactions were found to proceed smoothly in the absence of a solvent. A hydrophobic polystyrene-based chiral pyrrolidine catalyst exhibited high reactivity (up to 97% yield) and enantioselectivity (up to 95% ee) during these reactions. The catalyst could also be recovered and reused up to five times without significant loss of activity.     

Synthesis of chiral hydroxyl phospholanes from D-mannitol and their use in asymmetric catalytic reactions

Chiral hydroxyl monophosphane 3 [(2S,3S,4S,5S)-3,4-dihydroxy-2, 5-dimethyl-1-phenylphospholane] and bisphospholanes 5a [1,2-bis[(2S, 3S,4S,5S)-3,4-dihydroxy-2,5-dimethylphospholanyl]benzene] and 5b [1, 2-bis[(2S,3S,4S,5S)-2,5-diethyl-3,4-dihydroxyphospholanyl]benzene] were synthesized from readily available D-mannitol in high yields. Strategies for protection and deprotection of OH-groups in the presence of phosphines have been explored. Rate acceleration in the Baylis-Hillman reaction was observed when a hydroxyl phosphine was used as the catalyst. Rhodium complexes with chiral bisphospholanes are highly enantioselective catalysts for the asymmetric hydrogenation of various kinds of functionalized olefins such as dehydroamino acid derivatives, itaconic acid derivatives, and enamides. An interesting feature of the hydroxyl phospholane system is that hydrogenation of some substrates can be carried out in water with >99% ee and 100% conversion (e.g., itaconic acid).