Chiral zirconium catalysts using multidentate BINOL derivatives for catalytic enantioselective Mannich-type reactions; ligand optimization and approaches to elucidation of the catalyst structure

Catalytic enantioselective Mannich-type reactions of silicon enolates with aldimines were investigated using chiral zirconium catalysts prepared from Zr(O(t)Bu)(4), N-methylimidazole, and newly designed multidentate BINOL derivatives. These new multidentate BINOL ligands were designed on the basis of an assumed transition state structure of a chiral zirconium catalyst derived from two molecules of (R)-6,6'-Br(2)-BINOL. Not only tetradentate BINOL 4 but also tridentate BINOL derivatives were found to be effective, and high enantioselectivities were attained. In a structural study of the most effective zirconium complex prepared from tridentate ligand 6e, several NMR experiments and DFT calculations were carried out. Consequently, the structure of an active catalyst and plausible mechanism of asymmetric induction were elucidated.     

Catalytic, asymmetric trans-selective hetero Diels-Alder reactions using a chiral zirconium complex

[reaction: see text] The first catalytic, asymmetric 2,3-trans-selective hetero Diels-Alder reaction has been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the pyranone derivatives in high yields with high trans-selectivities and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide and (R)-3,3'-diiodobinaphthol or its derivatives, primary alcohol, and a small amount of water. This reaction was applied to the concise synthesis of (+)-prelactone C.     

Chiral hetero Diels-Alder products by enantioselective and diastereoselective zirconium catalysis. Scope,limitation, mechanism,and application to the concise synthesis of (+)-Prelactone C and (+)-9-deoxygoniopypyrone

Catalytic asymmetric hetero Diels-Alder (HDA) reactions using a chiral zirconium complex have been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the corresponding pyranone derivatives in high yields with high diastereo- and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide, (R)-3,3'-diiodobinaphthol or its derivative, a primary alcohol, and a small amount of water. It is noted that 2,3-trans-pyranone derivatives were obtained with remarkably high diastereo- and enantioselectivities in the reaction with 4-methyl Danishefsky's diene. This is the first example of catalytic asymmetric trans-selective hetero Diels-Alder reactions of aldehydes. Furthermore, asymmetric HDA reactions with 4-benzyloxy Danishefsky's dienes were conducted to afford 2,3-cis-pyranone derivatives in high selectivities. Isolation of an intermediate of this asymmetric hetero Diels-Alder reaction indicated that the reaction proceeded in a stepwise cycloaddition pathway. Finally, these catalytic, asymmetric hetero Diels-Alder reactions were successfully applied to concise syntheses of biologically important natural pyranone derivatives, (+)-Prelactone C and (+)-9-deoxygoniopypyrone.     

An air-stable,storable chiral zirconium catalyst for asymmetric aldol reactions

Asymmetric aldol reactions of ketene silyl acetals with aldehydes using an air-stable, storable chiral zirconium catalyst, which could be stored for at least 13 weeks at room temperature, proceeded smoothly to afford the desired adducts in high yields with high selectivity.     

Remarkably stable chiral zirconium complexes for asymmetric Mannich-type reactions

Isolable, air-stable, storable, and highly selective chiral zirconium catalysts for asymmetric Mannich-type reactions have been developed. The reactions of imines with silicon enolates proceeded smoothly using 1-10 mol % of the powdered zirconium catalyst to afford the corresponding adducts in high yields with high stereoselectivities. The catalyst could be recovered and reused without significant loss of activity. On the other hand, zirconium single crystals for X-ray analysis were obtained, and the crystals also showed high performance in the asymmetric Mannich-type reactions. Although NMR analyses of these zirconium catalysts showed different structures in dichloromethane, the formation of the same key intermediate from the different catalysts was indicated.     

Storable, powdered chiral zirconium complex for asymmetric aldol and hetero Diels-Alder reactions

A storable, powdered chiral zirconium catalyst for asymmetric aldol and hetero Diels-Alder reactions has been developed. The catalyst has the same activity as that prepared in situ even after being stored for 3 months. Moreover, this chiral Zr catalyst worked efficiently not only for asymmetric aldol reactions but also for asymmetric hetero Diels-Alder reactions affording the corresponding addition products with high enantioselectivities.     

Chiral catalyst optimization using both solid-phase and liquid-phase methods in asymmetric aza Diels-Alder reactions

[formula: see text] In the presence of 1-5 mol % of a chiral zirconium catalyst, aza Diels-Alder reactions of aldimines with Danishefsky's dienes proceeded smoothly to afford the corresponding piperidine derivatives in high yields with high enantioselectivities. For the catalyst optimization, solid-phase and liquid-phase methods were successfully used. In the solid-phase approach, polymer-supported (R)-1,1'-binaphthols (BINOLs) have been synthesized and rapid optimization using the solid-phase reactions has been achieved. On the other hand, novel chiral zirconium cyanides were developed as excellent catalysts using the liquid-phase approach.     

Catalytic asymmetric aza Diels-Alder reactions of hydrazones using a chiral zirconium catalyst

Catalytic asymmetric aza Diels-Alder reactions of acylhydrazones with Danishefsky’s dienes have been developed. A chiral zirconium complex derived from zirconium propoxide and 3,3′,6,6′-I₄BINOL was found to be effective in this reaction, and the desired optically active 2,3-dihydro-4-pyridone derivatives were obtained with high enantioselectivities. Asymmetric formal synthesis of a natural product, coniine, was conducted using this catalytic asymmetric reaction as a key step.     

Regulated-stereoselective construction of thirteen stereogenic centers necessary for the frame of (+)-discodermolide, based on iterative Lewis acid-promoted aldol reactions

The segments C(1)-C(13) and C(15)-C(21) containing the 13 stereogenic centers required for the frame of (+)-discodermolide were synthesized in good to excellent enantio- and diastereoselectivities from a common racemic aldehyde, derived from 2-methyl-1,3-propanediol. The enantioselective aldol reactions of the racemic aldehyde with a silylketene acetal, derived from ethyl 2-bromopropionate, in the presence of chiral oxazaborolidinones, prepared in situ with N-p-toluenesulfonyl-(R)- and -(S)-valine and BH(3).THF, proceeded under kinetic control to give the stereotriads with a high degree of enantioselectivity. Enantioselective (chiral borane) and diastereoselective (BF(3).OEt(2) and TiCl(4)) aldol reactions with the silylketene acetal, coupled with diastereoselective radical debrominations (Bu(3)SnH, Et(3)B, with or without MgBr(2)), were used iteratively. This aldol reaction strategy for the construction of the polypropionate frame dramatically shortened the steps needed for the construction of the final segments.     

Asymmetric intramolecular [3 + 2] cycloaddition reactions of acylhydrazones/olefins using a chiral zirconium catalyst

Catalytic asymmetric intramolecular [3 + 2] cycloaddition of hydrazone/olefins has been attained. In the presence of a chiral zirconium catalyst prepared from zirconium alkoxide and a BINOL derivative, the desired pyrazolidine derivatives were obtained in high yields with high selectivities. The products were easily converted to 1,3-diamine or beta-aminonitrile derivatives by N-N bond cleavage.     

Development of Asymmetric Reactions Catalyzed by Chiral Organotin‐Alkoxide Reagents

Asymmetric catalysis under almost‐neutral reaction conditions is key for the efficient synthesis of optically active polar molecules. We have developed catalytic enantioselective reactions of acyclic or cyclic alkenyl esters by using an (S)‐BINOL‐derived chiral tin‐dibromide reagent that possesses a bulky aryl group at the 3 or 3′ position as the chiral pre‐catalyst in the presence of a sodium alkoxide and an alcohol, in which a chiral tin alkoxide bromide is generated in situ and recycled with the assistance of an alcohol. In this Personal Account, we describe three types of asymmetric transformation that proceed through a chiral tin enolate: 1) The asymmetric aldol reaction of alkenyl esters or unsaturated lactones with aldehydes or isatins; 2) the asymmetric three‐component Mannich‐type reaction of alkenyl esters and related cycloaddition reactions; and 3) the asymmetric N‐nitroso aldol reaction of unsaturated lactones with nitrosoarenes.     

Highly efficient and reusable dendritic catalysts derived from N-prolylsulfonamide for the asymmetric direct aldol reaction in water

The direct aldol reactions catalyzed by chiral dendritic catalysts derived from N-prolylsulfonamide gave the corresponding products in high isolated yields (up to 99%) with excellent anti diastereoselectivities (up to >99:1) and enantioselectivities (up to >99% ee) in water. In addition, catalyst 1e may be recovered by precipitation and filtration and reused for at least five times without loss of catalytic activity.     

Direct asymmetric aldol reactions inspired by two types of natural aldolases: water-compatible organocatalysts and Zn(II) complexes

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.     

Catalytic enantioselective addition of propionate units to imines: an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives

Optically active anti-alpha-methyl-beta-amino acid derivatives have been prepared based on catalytic enantioselective addition of propionate units to simple and inert imines using a chiral zirconium complex. High reactivity and selectivity with wide substrate scope were attained by using a new chiral ligand, (R)-6,6'-bis(pentafluoroethyl)-1,1'-bi-2-naphthol ((R)-6,6'-C(2)F(5)BINOL). The reactions using geometrically isomeric ketene silyl acetals gave excellent anti-selectivity with high enantiomeric excess in both cases. Synthetic utility of this reaction has been demonstrated by the preparation of various anti-alpha-methyl-beta-amino acid and trans-3,4-disubstituted beta-lactam derivatives.     

Highly enantioselective mukaiyama aldol reaction of alpha,alpha-dichloro ketene silyl acetal: an efficient synthesis of a key intermediate for diltiazem

An efficient synthesis of methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2, a key intermediate for diltiazem (1), has been developed on the basis of the highly enantioselective Mukaiyama aldol reaction of p-anisaldehyde (4a) with alpha,alpha-dichloro ketene silyl acetal 5. Thus, the reaction using a stoichiometric amount of chiral oxazaborolidinone catalyst 12a proceeded to excellent yield (83%) and high enantioselectivity (96% ee), together with the chiral ligand 13a in nearly quantitative recovery. The reaction using a substoichiometric amount of 12e (20 mol %) also proceeded to excellent yield (88%), with somewhat lower enantioselectivity (77% ee). The aldol product 3a thus obtained was easily converted to (-)-2 in excellent yield (80%) and high optical purity (>99% ee). The highly enantioselective Mukaiyama aldol reaction with 5 catalyzed by 12a proved to be applicable to various aldehydes. An efficient preparation of 5 from inexpensive starting materials was also described.     

Organosoluble zirconium phosphonate nanocomposites and their supported chiral ruthenium catalysts: the first example of homogenization of inorganic-supported catalyst in asymmetric hydrogenation

In this article, we report the synthesis, structure, morphologies, and asymmetric catalytic properties of a series of novel organosoluble zirconium phosphonate nanocomposites and their supported chiral ruthenium catalysts, which have a good organosolubility (0.1-0.5 g mL(-1)) in various solvents and mesoporous, filiform, and layered structures. Due to the organosoluble properties in various organic solvents, the first homogenization of zirconium phosphonate-supported catalyst was realized in the field of catalysis. In the asymmetric hydrogenation of substituted α-ketoesters, enantioselectivities (74.3-84.7% ee) and isolated yields (86.7-93.6%) were higher than the corresponding homogeneous Ru(p-cymene)(S-BINAP)Cl(2) due to the confinement effect caused by the remaining mesopores in the backbone of the zirconium phosphonate. After completing the reaction, the supported catalyst can be readily recovered in quantitative yield by adding cyclohexane and centrifugation, and reused for five consecutive runs without significant loss in catalytic activity.     

The development of scalemic multidentate niobium complexes as catalysts for the highly stereoselective ring opening of meso-epoxides and meso-aziridines

The discovery and development of a new Lewis acid system based on a complex formed from niobium(V) methoxide and (R)-3,3'-bis(2-hydroxy-3-isopropylbenzyl)-1,1'-binaphthalene-2,2'-diol, a novel tetradentate BINOL derivative, is presented. The system was shown to be extremely effective in promoting the desymmetrative ring opening of linear and cyclic meso-epoxides using anilines as nucelophiles, delivering the corresponding (R,R) anti-amino alcohols in good to excellent yields (up to quantitative) and excellent enantioselectivity (up to 96% ee). Furthermore, the catalyst system displays a remarkable sensitivity to steric bulk at the beta-carbon of the epoxide, selectively facilitating ring opening of smaller epoxides in the presence of more sterically hindered epoxides. This property was confirmed by a series of competition reactions using a mixture of meso-2-butene oxide and another aliphatic meso-epoxide, with the result that the former, less encumbered epoxide reacted preferentially with up to 98% chemical selectivity. While it was found to be most convenient to conduct the reactions with 10 mol % catalyst loading at 0.16 M, at higher overall concentration the reaction still proceeded efficiently with as little as 0.25 mol % catalyst to give the desired products with no significant reduction in yields or enantioselectivities. In addition, the current catalyst system was also found to mediate the asymmetric ring opening of nonsymmetrical cis-2-alkene oxides with anilines to give preferentially the corresponding (2R,3R)-2-amino-3-ols arising from ring opening at the methyl terminus, in excellent yields (up to quantitative) and good to excellent regio- and enantioselectivities (up to 18:1 and >99% ee, respectively). Intriguingly, it was discovered that the same catalyst system also promoted the ring-opening desymmetrization of aziridines with aniline nucleophiles to give the corresponding (S,S) vicinal diamines in good to excellent yields and enantioselectivity (up to 95% and 84% ee [>99% ee following a single recrystallization]). Catalyst systems that promote closely related reactions with opposite stereochemical outcomes in high selectivity such as the current niobium system are extremely unusual. To the best of our knowledge, this report constitutes not only the first example of the catalytic desymmetrization of both meso-epoxides and meso-aziridines but also a rare example of such complementary stereoselectivity in a catalytic reaction.     

Zirconium-catalyzed enantioselective [3+2] cycloaddition of hydrazones to olefins leading to optically active pyrazolidine, pyrazoline, and 1,3-diamine derivatives

Asymmetric [3+2] cycloaddition of hydrazones to external olefins has been successfully conducted in high yields with high enantioselectivities using a chiral zirconium catalyst. These reactions open ways to synthetically and biologically important pyrazoline, pyrazolidine, and 1,3-diamine derivatives. Further, several experiments suggested that the reactions proceeded via concerted pathways.     

Optimization of catalyst enantioselectivity and activity using achiral and meso ligands

The optimization of asymmetric catalysts for enantioselective synthesis has conventionally revolved around the synthesis and screening of enantiopure ligands. In contrast, we have optimized an asymmetric reaction by modification of a series of achiral ligands. Thus, employing (S)-3,3'-diphenyl BINOL [(S)-Ph(2)-BINOL] and a series of achiral diimine and diamine activators in the asymmetric addition of alkyl groups to benzaldehyde, we have observed enantiomeric excesses between 96% (R) and 75% (S) of 1-phenyl-1-propanol. Some of the ligands examined have low-energy chiral conformations that can contribute to the chiral environment of the catalyst. These include achiral diimine ligands with meso backbones that adopt chiral conformations, achiral diimine ligands with backbones that become axially chiral on coordination to metal centers, achiral diamine ligands that form stereocenters on coordination to metal centers, and achiral diamine ligands with pendant groups that have axially chiral conformations. Additionally, we have structurally characterized (Ph(2)-BINOLate)Zn(diimine) and (Ph(2)-BINOLate)Zn(diamine) complexes and studied their solution behavior.     

Immobilization of BINOL by cross-linking copolymerization of styryl derivatives with styrene, and applications in enantioselective Ti and Al Lewis acid mediated additions of Et2Zn and Me3SiCN to aldehydes and of diphenyl nitrone to enol ethers

The chiral ligand 1,1'-bi-2-naphthol (BINOL) has been succesfully immobilized on polystyrene. Several dendritic and non-dendritic BINOL derivatives (3, and 13-17), bearing at least two polymerizable styryl groups, were prepared and fully characterized. Suspension copolymerization of the MOM- or TIPS-protected cross-linking BINOL ligands (MOM = methyloxymethyl, TIPS = triisopropylsilyl) with styrene, cleavage of the protecting-groups, and loading with a Lewis-acid afforded catalytically active polystyrene-supported BINOLates. The polymer-bound BINOLs p-3, and p-13-p-16 were tested in the Ti-BINOLate-mediated addition of Et2Zn to PhCHO. The enantioselectivities (up to 93%) and conversions obtained with the polymer-bound catalysts were in most cases identical (within experimental error) to those obtained with the unsubstituted 1,1'-bi-2-naphthol and with the non-polymerized BINOL cross-linkers under homogeneous conditions. Special focus was put on the reusability of the supported catalyst: the polymer-beads were used in up to 20 consecutive catalytic runs, with the best polymers showing no or only minor loss of selectivity. BINOL-polymers p-17, obtained by copolymerization of a 3,3'-distyryl-substituted BINOL 17a with styrene, were used in the BINOL. AlMe-mediated cycloaddition of diphenyl nitrone with alkyl vinyl ethers. In all cases the exo/endo selectivity (> or =92:8) and the enantioselectivities with which the exo-cycloadducts were formed (> or =95%) correspond to those observed in the homogeneous reactions. A dendritically cross-linked BINOL-polymer was also employed in the Ti-BINOLate-mediated cyanosilylation of pivalaldehyde. The enantiopurity of the cyanohydrine obtained in the first run was as high as in the homogeneous reaction (72%); surprisingly the catalytic performance of the supported catalyst increased steadily during the first catalytic cycles to reach 83%. Thus, cross-linking BINOLs can be succesfully incorporated into a polystyrene matrix (without racemization!) to give polymer-bound BINOL ligands that give excellent performance over many catalytic cycles with catalytic activities comparable with those of soluble analogues.