Highly enantioselective michael additions of indole to benzylidene malonate using simple bis(oxazoline) ligands: importance of metal/ligand ratio

[Structure: see text] Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyze the copper-catalyzed addition of indoles to benzylidene malonates in up to >99% ee, provided that excess of chiral ligand is avoided. The paradigm followed in many asymmetric catalyses that an excess of chiral ligand with respect to the metal should improve enantioselectivity because a background reaction by free metal is suppressed, is not applicable here, which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalyzed processes known.     

Enantioselective copper-catalysed propargylic substitution: synthetic scope study and application in formal total syntheses of (+)-anisomycin and (-)-cytoxazone

A copper catalyst with a chiral pyridine-2,6-bisoxazoline (pybox) ligand was used to convert a variety of propargylic esters with different side chains (R=Ar, Bn, alkyl) into their amine counterparts in very high yields and with good enantioselectivities (up to 90% enantiomeric excess (ee)). Different amine nucleophiles were applied in the reactions and the highest enantioselectivities were obtained for aniline and its analogues. Interestingly, some carbon nucleophiles could also be used and with indoles excellent ee values were obtained (up to 98% ee). The versatility of the propargylic amines obtained was demonstrated by their further elaboration to formal total syntheses of the antibiotic (+)-anisomycin and the cytokine modulator (-)-cytoxazone.     

A ferrocenyl-DHIPOH/Cu(OAc)2 complex for diastereo- and enantioselective catalysis of the 1,4-addition of glycine derivatives to alkylidene malonates

A planar chiral ferrocene derivative Fc-DHIPOH served as an excellent N,O- chiral ligand for asymmetric copper catalyzed 1,4-addition of glycine derivatives to alkylidene malonates. The corresponding 1,4-adducts were obtained in high yields with excellent enantioselectivities up to 95% ee.     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

Non-metallocene rare earth metal catalysts for the diastereoselective and enantioselective hydroamination of aminoalkenes

In this short review we summarize our work on new cyclopentadienyl-free rare earth metal catalysts for the diastereoselective and enantioselective hydroamination of aminoalkenes. Non-metallocene rare earth metal catalysts based on diamidoamine, biphenolate and binaphtholate ligands are readily available through alkane and amine elimination procedures. Diamidoamine yttrium complexes are efficient catalysts for the highly diastereoselective cyclization of 1-methyl-pent-4-enylamine to yield trans-2,5-dimethyl-pyrroldine with trans to cis ratios of up to 23:1. The X-ray crystal structural analysis of [((2,6-Et₂C₆H₃NCH₂CH₂)₂NMe)Y{N(SiMe₃)₂}] is reported in which yttrium is coordinated in a highly distorted tetrahedral fashion. 3,3′-Di-tert-butyl substituted biphenolate complexes tend to form phenolate-bridged hetero- and homochiral dimers. The low steric demand of the tert-butyl substituents resulted also in low enantioselectivities in hydroamination/cyclization reactions. Binaphtholate complexes with sterically more demanding tris(aryl)silyl substituents were more efficient catalysts; giving enantioselectivities of up to 83% ee. These catalysts could also be applied in kinetic resolution of chiral aminoalkenes giving k_rel values as high as 16. Catalyst activities strongly depend on the reactivity of the leaving group which is protolytically exchanged for the substrate during the initiation step. Complexes with bis(dimethylsilyl)amido ligand initiate rather sluggishly because of the low basicity of this amido ligand and appreciable catalytic activity is only observed at elevated temperatures. Aryl and Alkyl complexes showed significant better rates comparable in magnitude to lanthanocene catalysts.     

A New Modular Phosphite‐Pyridine Ligand Library for Asymmetric Pd‐Catalyzed Allylic Substitution Reactions: A Study of the Key Pd‐π‐Allyl Intermediates

A library of phosphite‐pyridine ligands L1 – L12 a – g has been successfully applied for the first time in the Pd‐catalyzed allylic substitution reactions of several di‐ and trisubstituted substrates by using a wide range of C, N and O nucleophiles, among which are the little studied α‐substituted malonates, β‐diketones, and alkyl alcohols. The highly modular nature of this ligand library enables the substituents/configuration at the ligand backbone, and the substituents/configurations at the biaryl phosphite moiety to be easily and systematically varied. We found that the introduction of an enantiopure biaryl phosphite moiety played an essential role in increasing the versatility of the Pd‐catalytic systems. Enantioselectivities were therefore high for several hindered and unhindered di‐ and trisubstituted substrates by using a wide range of C, N and O nucleophiles. Of particular note were the high enantioselectivities (up to>99 % ee) and high activities obtained for the trisubstituted substrates S6 and S7 , which compare favorably with the best that have been reported in the literature. We have also extended the use of these new catalytic systems in alternative environmentally friendly solvents such as propylene carbonate and ionic liquids. Studies on the Pd‐π‐allyl intermediates provide a deeper understanding of the effect of ligand parameters on the origin of enantioselectivity.     

CuOTf/NNN三齿钳形配体催化不对称Henry反应

以(R)-BINOL为原料合成NNN三齿钳形手性配体,研究了其与各种金属盐形成金属络合物在室温下原位催化芳香醛与硝基甲烷的不对称Henry反应.考察了不同金属盐、溶剂、碱对反应的影响,优化得到最佳反应条件为:CuOTf/NNN三齿配体(1∶1)催化体系,催化剂用量为10 mol%,甲醇作溶剂,室温反应5 d,收率57%,对映选择性80%ee;加入10 mol%有机碱(Me3Si)2MeN后反应速度加快,对映选择性略有降低,室温反应17 h,收率37%,ee值67%.此催化体系适用于大部分的芳香醛,收率中等,对映选择性可达75%ee.     

Chiral rare earth organophosphates as homogeneous Lewis acid catalysts for the highly enantioselective hetero-Diels–Alder reactions

Various trivalent rare earth-chiral phosphate complexes [(R)-1-RE, (R)-3-RE, and (R)-4-Ce] were prepared and evaluated as a Lewis acid catalyst for the asymmetric hetero-Diels–Alder reaction of aldehydes with the Danishefsky's diene. Some of them effectively promoted the reaction at room temperature in the presence or absence of achiral additives under homogeneous conditions to afford the corresponding cycloadducts with high ee's (up to 99% ee). During these reactions, remarkably high asymmetric amplifications (positive nonlinear effects) were observed as the first example in the metal ion–chiral ligand 1:3 catalytic system. A scandium catalyst bearing the H₈-BNP ligand, (R)-3-Sc, could be recovered after the reaction and successfully reused for the next round of reactions. In addition, the hetero-Diels–Alder reaction of -keto esters was effectively catalyzed by the ytterbium complex, (R)-1-Yb, without any additives thus producing the asymmetric quaternary carbon in excellent enantioselectivities (up to >99% ee).     

Novel thiolated amino-alcohols as chiral ligands for copper-catalyzed asymmetric nitro-aldol reactions

Thiolated amino-alcohols have been synthesized and evaluated as a potential new class of chiral ligands for copper-catalyzed nitro-aldol reactions. The model nitro-aldol reaction took place smoothly at ambient temperature in the presence of catalytic amounts (5-15 mol %) of the ligands and copper(II) acetate to afford the nitro-aldol product in good to excellent yield without accompanying dehydration. Amino-alcohol ligands bearing N-(2-alkylthio)benzyl substituents provided only modest enantioselectivities (22-46% ee) while those carrying N-2-thienylmethyl substituents provided better enantioselectivities (up to 75% ee). A range of aromatic aldehydes were acceptable for the nitro-aldol reaction with nitromethane, giving moderate to good enantioselectivities (69-88% ee).     

Novel chiral thioureas for highly enantioselective Michael reactions of malonates to nitroalkenes

Highly efficient Michael addition reactions of malonates to nitroalkenes catalyzed by novel chiral thioureas derived from optically pure BINOL and amino acids are reported. Various trans-nitroalkenes reacted with malonates affording the desired products in up to 95% yield with excellent enantioselectivities (up to 97% ee).     

Palladium-diphosphite catalysts for the asymmetric allylic substitution reactions

[structure: see text] We have designed a series of diphosphite ligands to study the effect of the backbone, the size of the chelate ring, and the substituents of the biphenyl moieties and to determine the scope of this type of ligand in the Pd-catalyzed asymmetric substitution reactions of different types of substrates. Good-to-excellent activities and enantioselectivities have been obtained for disubstituted linear substrate 11 (TOF's up to >2000 mol x (mol x h)(-1), ee values up to 99%) and cyclic substrate 14 (TOF up to 285 mol x (mol x h)(-1), ee values up to 92%). However, these ligands are inadequate for the Pd-catalyzed allylic alkylation of monosubstituted linear substrates because they provide low enantioselectivities.     

Catalytic and highly enantioselective reactions of alpha-sulfonyl carbanions with chiral bis(oxazoline)s

The enantioselective reactions of lithiated benzyl trifluoromethyl sulfones with a substoichiometric amount of a bis(oxazoline) and various aldehydes is disclosed. The products were formed with excellent diastereo- and enantioselectivities. Fluorination of the sulfone with N-fluorobenzenesulfonimide and a stoichiometric amount of a bis(oxazoline) gave products with extremely high enantioselectivities (up to 99% ee; ee=enantiomeric excess). The enantioselective reaction was confirmed to proceed through a dynamic thermodynamic resolution pathway.     

A general organocatalytic enantioselective malonate addition to alpha,beta-unsaturated enones

A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to alpha,beta-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.     

In quest of factors that control the enantioselective catalytic Markovnikov hydroboration/oxidation of vinylarenes

This study attempts to rationalise the unpredictable performance of transition metal catalysed asymmetric hydroboration of vinylarenes on varying the precursor of the catalyst from cationic to neutral species, [M(cod)(L-L)]BF4, [M(mu-Cl)(cod)]2/(L-L), the metal (M=Rh and Ir), and the hydroborating reagent (catecholborane, pinacolborane). The approaches are based on the agreement between experimental data provided by (R)-Binap and (R)-Quinap modified catalytic systems and computational data evidenced by DFT calculations and QM/MM strategies. Unprecedentedly high enantiomeric excesses in the hydroboration/oxidation of vinylarenes with both electron-withdrawing substituents ((R)-(+)-1-p-F-phenylethanol, ee up to 92 %) and electron-releasing substituents ((R)-(+)-1-p-MeO-phenylethanol, ee up to 98 %), can be attributed to a rhodium halide key intermediate.     

手性氨基二醇的合成及其在二乙基锌对醛不对称加成反应中的应用

手性配体催化的烷基锌试剂对醛的不对称加成反应是合成光学活性二级醇的重要方法 [1] ,1 0多年来 ,人们对其进行了深入的研究 ,并取得了很大进展 .其中大部分工作是设计如β-氨基醇等新的手性配体 .此外 ,文献 [2～ 6]还报道了氨基二醇在这类反应中具有手性诱导效果 .为进一步研究手性配体催化的二乙基锌对醛的不对称加成反应 ,我们合成了新的手性氨基二醇配体 ,并将其用于该反应中 .1　结果与讨论1 .1　手性配体的合成　以 L -脯氨酸甲酯盐酸盐 ( 5 )为原料 ,与溴代乙酸乙酯反应生成 ( L ) - N - ( 2 -乙酰乙氧基 )脯氨酸甲酯 ( 6)反应 ,…     

Copper(II)-catalyzed hydrosilylation of ketones using chiral dipyridylphosphane ligands: highly enantioselective synthesis of valuable alcohols

In the presence of PhSiH(3) as the reductant, the combination of enantiomeric dipyridylphosphane ligands and Cu(OAc)(2)·H(2)O, which is an easy-to-handle and inexpensive copper salt, led to a remarkably practical and versatile chiral catalyst system. The stereoselective formation of a selection of synthetically interesting β-, γ- or δ-halo alcohols bearing high degrees of enantiopurity (up to 99.9% enantiomeric excess (ee)) was realized with a substrate-to-ligand molar ratio (S/L) of up to 10,000. The present protocol also allowed the hydrosilylation of a diverse spectrum of alkyl aryl ketones with excellent enantioselectivities (up to 98% ee) and exceedingly high turn-over rates (up to 50,000 S/L molar ratio in 50 min reaction time) in air, under very mild conditions, which offers great opportunities for the preparation of various physiologically active targets. The synthetic utility of the chiral products obtained was highlighted by the efficient conversion of optically enriched β-halo alcohols into the corresponding styrene oxide, β-amino alcohol, and β-azido alcohol, respectively.     

Adaptative Biaryl Phosphite–Oxazole and Phosphite–Thiazole Ligands for Asymmetric Ir‐Catalyzed Hydrogenation of Alkenes

A library of readily available phosphite–oxazole/thiazole ligands ( L1 a – g – L7 a – g ) was applied in the Ir‐catalyzed asymmetric hydrogenation of several largely unfunctionalized E‐ and Z‐trisubstituted and 1,1‐disubstituted terminal alkenes. The ability of the catalysts to transfer chiral information to the product could be tuned by choosing suitable ligand components (bridge length, the substituents in the heterocyclic ring and the alkyl backbone chain, the configuration of the ligand backbone, and the substituents/configurations in the biaryl phosphite moiety), so that enantioselectivities could be maximized for each substrate as required. Enantioselectivities were therefore excellent (enantiomeric excess (ee) values up to >99 %) for a wide range of E‐ and Z‐trisubstituted and 1,1‐disubstituted terminal alkenes. The biaryl phosphite moiety was a very advantageous ligand component in terms of substrate versatility.     

Application of chiral mixed phosphorus/sulfur ligands to enantioselective rhodium-catalyzed dehydroamino acid hydrogenation and ketone hydrosilylation processes

Chiral mixed phosphorus/sulfur ligands 1-3 have been shown to be effective in enantioselective Rh-catalyzed dehydroamino acid hydrogenation and ketone hydrosilylation reactions (eqs 1, 2). After assaying the influence of the substituents at sulfur, the substituents on the ligand backbone, the relative stereochemistry within the ligand backbone, and the substituents at phosphorus, ligands 2c (R = 3,5-dimethylphenyl) and 3 were found to be optimal in the Rh-catalyzed hydrogenation of a variety of alpha-acylaminoacrylates in high enantioselectivity (89-97% ee). A similar optimization of the catalyst for the Rh-catalyzed hydrosilylation of ketones showed that ligand 3 afforded the highest enantioselectivities for a wide variety of aryl alkyl and dialkyl ketones (up to 99% ee). A model for asymmetric induction in the hydrogenation reaction is discussed in the context of existing models, based on the absolute stereochemistry of the products and the X-ray crystal structures of catalyst precursors and intermediates.     

Modular phosphite-oxazoline/oxazine ligand library for asymmetric pd-catalyzed allylic substitution reactions: scope and limitations-origin of enantioselectivity

A library of phosphite-oxazoline/oxazine ligands L1-L15 a-h has been synthesized and screened in the Pd-catalyzed allylic substitution reactions of several substrate types. These series of ligands can be prepared efficiently from easily accessible hydroxyl amino acid derivatives. Their modular nature enables the substituents/configurations in the oxazoline/oxazine moiety, alkyl backbone chain and in the biaryl phosphite moiety to be easily and systematically varied. By carefully selecting the ligand components, therefore, high regio- and enantioselectivities (ee values up to 99 %) and good activities have been achieved in a broad range of mono- and disubstituted linear hindered and unhindered liner and cyclic substrates. The NMR studies on the Pd-pi-allyl intermediates provide a deeper understanding about the effect of the ligand parameters on the origin of enantioselectivity. It also indicates that the nucleophilic attack takes place predominantly at the allylic terminal carbon atom located trans to the phosphite moiety.     

Applications of ruthenium hydride borohydride complexes containing phosphinite and diamine ligands to asymmetric catalytic reactions

[reaction: see text] A series of novel trans-ruthenium hydride borohydride complexes with chiral phosphinite and diamine ligands were synthesized. They can be used in the asymmetric transfer hydrogenation of aryl ketones, including base-sensitive ones, to give chiral alcohols in moderate to good enantioselectivities (up to 94% ee). They are also efficient catalysts for the Michael addition of malonates to enones with enantioselectivities of up to 90%. This kind of catalyst allows a one-pot tandem Michael addition/H(2) hydrogenation protocol to build structures with multiple chiral centers.