Direct Catalytic Asymmetric Mannich‐Type Reaction of α‐N3 Amide

An α‐N₃ 7‐azaindoline amide serves as a latent enolate to directly engage in an asymmetric Mannich‐type reaction with N‐thiophosphinoyl imines by the action of a cooperative catalyst. The thus‐obtained highly enantioenriched anti‐adduct was transformed into β‐amino‐α‐azido acid in high yield by simple acidic treatment.     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N‐monoalkyl cyclohexane‐1,2‐diamines

A number of novel chiral diamines 3 , (1R,2R)‐N‐monoalkylcyclohexane‐1,2‐diamines, were designed and synthesized from trans‐cyclohexane‐1,2‐diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β‐nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)‐N¹‐(4‐methylpentan‐2‐yl)cyclohexane‐1,2‐diamine ( 3g ), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g –Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti‐selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β‐nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition‐state model. Copyright © 2014 John Wiley & Sons, Ltd.     

A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

A concise asymmetric (>99:1 e.r.) total synthesis of (+)‐anti‐ and (?)‐syn‐mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless‐derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)‐anti‐ and (?)‐syn‐mefloquine, respectively. The synthetic (+)‐anti‐ and (?)‐syn‐mefloquine samples were derivatized with (S)‐(+)‐mandelic acid tert‐butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X‐ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)‐anti‐ as well as (?)‐syn‐mefloquine.     

A Highly anti‐Selective Asymmetric Henry Reaction Catalyzed by a Chiral Copper Complex: Applications to the Syntheses of (+)‐Spisulosine and a Pyrroloisoquinoline Derivative

A highly anti‐selective asymmetric Henry reaction has been developed, affording synthetically versatile β‐nitroalcohols in a predominately anti‐selective manner (mostly above 15:1) and excellent ee values (mostly above 95 %). Moreover, the anti‐selective Henry reaction was carried out in the presence of water for the first time with up to 99 % ee. The catalytic mechanism was proposed based on the detection of the intermediates by extractive electrospray ionization mass spectrometry (EESI‐MS). Furthermore, the anti adducts have been successfully transformed into the biochemically important (+)‐spisulosine and a pyrroloisoquinoline derivative.     

Highly Stereoselective Conjugate Addition and α‐Alkynylation Reaction with Electron‐Deficient Alkynes Catalyzed by Chiral Scandium(III) Complexes

The highly Z‐selective asymmetric conjugate addition of 3‐substituted oxindoles to alkynyl carbonyl compounds has been developed by using scandium complexes of chiral N,N′‐dioxides under mild conditions. The thermodynamically unstable Z‐olefin derivatives were obtained in excellent yields and high enantiomeric and geometric control. The catalyst was also found to be effective in the asymmetric acetylenic substitution reaction of 3‐substituted oxindoles, giving excellent enantioselectivities.     

Pyrrolidinyl–Camphor Derivatives as a New Class of Organocatalyst for Direct Asymmetric Michael Addition of Aldehydes and Ketones to β‐Nitroalkenes

Practical and convenient synthetic routes have been developed for the synthesis of a new class of pyrrolidinyl–camphor derivatives ( 7 a–h ). These novel compounds were screened as catalysts for the direct Michael addition of symmetrical α,α‐disubstituted aldehydes to β‐nitroalkenes. When this asymmetric transformation was catalyzed by organocatalyst 7 f , the desired Michael adducts were obtained in high chemical yields, with high to excellent stereoselectivities (up to 98:2 diastereomeric ratio (d.r.) and 99 % enantiomeric excess (ee)). The scope of the catalytic system was expanded to encompass various aldehydes and ketones as the donor sources. The synthetic application was demonstrated by the synthesis of a tetrasubstituted‐cyclohexane derivative from (S)‐citronellal, with high stereoselectivity.     

Enantioselective Alkynylation of Ketones Promoted by β-Sulfonamide Alcohol-Titanium Complexes

A readily available β-sulfonamide alcohol-titanium complex was found to be effective on promoting the asymmetric addition reaction of an alkynylzinc reagent to unactivated simple ketones under very mild conditions. And the corresponding chiral tertiary propargylic alcohols were obtained with enantiomeric excesses of up to 86%, which provided a simple, practical and inexpensive method to generate chiral tertiary propargylic alcohols.     

Catalytic Asymmetric Synthesis of trans‐Configured β‐Lactones: Cooperation of Lewis Acid and Ion Pair Catalysis

The development of the first trans‐selective catalytic asymmetric [2+2] cyclocondensation of acyl halides with aliphatic aldehydes furnishing 3,4‐disubstituted β‐lactones is described. This work made use of a new strategy within the context of asymmetric dual activation catalysis: it combines the concepts of Lewis acid and organic aprotic ion pair catalysis in a single catalyst system. The methodology could also be applied to aromatic aldehydes and offers broad applicability (29 examples). The utility was further demonstrated by nucleophilic ring‐opening reactions that provide highly enantiomerically enriched anti‐aldol products.     

ss‐NMR and single‐crystal X‐ray diffraction in the elucidation of a new polymorph of bischalcone (1E,4E)‐1,5‐bis(4‐fluorophenyl)penta‐1,4‐dien‐3‐one

We report a new polymorph of (1E,4E)‐1,5‐bis(4‐fluorophenyl)penta‐1,4‐dien‐3‐one, C₁₇H₁₂F₂O. Contrary to the precedent literature polymorph with Z′ = 3, our polymorph has one half molecule in the asymmetric unit disordered over two 50% occupancy sites. Each site corresponds to one conformation around the single bond vicinal to the carbonyl group (so‐called anti or syn). The other half of the bischalcone is generated by twofold rotation symmetry, giving rise to two half‐occupied and overlapping molecules presenting both anti and syn conformations in their open chain. Such a disorder allows for distinct patterns of intermolecular C—H…O contacts involving the carbonyl and anti‐oriented β‐C—H groups, which is reflected in three ¹³C NMR chemical shifts for the carbonyl C atom. Here, we have also assessed the cytotoxicity of three symmetric bischalcones through their in vitro antitumour potential against three cancer cell lines. Cytotoxicity assays revealed that this biological property increases as halogen electronegativity increases.     

Catalytic Enantioselective γ‐Selective Additions of 2‐Allylazaarenes to Activated Ketones

Reported herein is the first example of 2‐allylazaarenes in asymmetric catalysis. Highly γ‐selective allylation was demonstrated for activated ketones, including isatins and trifluoromethyl ketones. In the presence of either an amino‐acid‐based tertiary amine or quaternary ammonium salt catalyst, two series of tertiary hydroxy‐containing moieties were installed at the remote δ‐position of azaarenes in good chemical yields, excellent enantioselectivities, and E /Z ratios. The success of current γ‐selective reactions should provide inspiration for expansion to other allylazaarene derivatives and would open up new paradigms for the synthesis of chiral γ‐ and/or δ‐functionalized azaarenes.     

Microwave‐Assisted Convenient Synthesis of α,β‐Unsaturated Esters and Ketones via Aldol‐Adduct Elimination

Various fluorinated 3‐oxo ester/1,3‐diketones were reacted with carbonyl compounds, in presence of piperidine and under microwave irradiation, to afford (E)‐α,β‐unsaturated esters and ketones in good yields. The systematic study reveals that the reaction proceeded through the formation of aldol adduct. The method provides a new and simple way for C,C bond formations.     

L-脯氨酸催化下甲基酮和1-芳基-2,2,2-三氟乙酮的不对称Aldol反应

Direct asymmetric aldol addition of methyl ketones to 2,2,2-trifluoro-1-phenylethanone and its ring-substituted derivatives was achieved using L-proline as a chiral promoter. Various optically active β-trifluoromethyl-β-hydroxy ketones were obtained in almost quantitative yields with moderate enantioselectivities up to 64 % ee.     

Diarylprolinol‐Mediated Asymmetric Direct Cross‐Aldol Reaction of α,β‐Unsaturated Aldehyde as an Electrophilic Aldehyde

The diarylprolinol‐mediated asymmetric direct cross‐aldol reaction of α,β‐unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ‐position of the α,β‐unsaturated aldehyde. Synthetically useful γ,δ‐unsaturated β‐hydroxy aldehydes were obtained with high anti‐selectivity and excellent enantioselectivity.     

Catalytic Asymmetric Michael Reaction of 5H‐Oxazol‐4‐Ones with α,β‐Unsaturated Acyl Imidazoles

The asymmetric Michael reaction between 5H‐oxazol‐4‐ones and α,β‐unsaturated acyl imidazoles is reported. A novel 2‐benzo[b]thiophenyl‐modified chiral ProPhenol species is synthesized and used as a ligand, leading to good enantioselectivities in this asymmetric conjugate addition reaction. Furthermore, the introduction of phenol additives as achiral co‐ligands is found to improve the reaction’s chemical yields, diastereoselectivities, and enantioselectivities.     

Enantioselective Conjugate Addition‐Protonation of 5H‐Oxazol‐4‐ones and 5‐Methylene 1,3‐Oxazolidine‐2,4‐diones: 2,2'‐Biphenol‐Induced Diastereoselectivity Switch

A synthetic strategy for catalytic asymmetric conjugate addition‐protonation and diastereoselective switch between 5H‐oxazol‐4‐ones and 5‐methylene 1,3‐oxazolidine‐2,4‐diones was established. An array of chiral conjugate addition‐protonation products bearing 1,3‐O‐heterotertiary‐O‐heteroquarternary nonadjacent stereocenters were obtained in excellent yields, moderate to good diastereoselectivities, and excellent enantioselectivities (up to 97% yield, 11: 1 dr, and 98% ee). Induction by 2,2’‐biphenol could effectively promote the production of the corresponding diastereoisomers via cycloaddition intermedia.     

Diastereodivergent Asymmetric Michael Addition of Cyclic Azomethine Ylides to Nitroalkenes: Direct Approach for the Synthesis of 1,7‐Diazaspiro[4.4]nonane Diastereoisomers

The first highly diastereoselective and enantioselective catalytic asymmetric Michael addition of cyclic azomethine ylides with nitroalkenes have been developed to diastereodivergently generate either the syn or anti adducts by employing N,O‐ligand/Cu(OAc)₂ and N,P‐ligand/Cu(OAc)₂ catalytic systems. Both catalytic systems exhibit broad substrate applicability to afford the corresponding Michael adducts in good to excellent yields, with excellent levels of diastereo‐ (up to 99:1 diastereomeric ratio) and enantioselectivities (up to >99 % enantiomeric excess). Importantly, the chiral 1,7‐diazaspiro[4.4]nonane diastereomer derivatives can be easily obtained in good yields through facile NaBH₄ reduction of the Michael adducts.     

Exo conformers of N‐(pyridin‐2‐yl)‐ and N‐(pyridin‐3‐yl)norbornene‐5,6‐dicarboximide crystals

Two isomeric pyridine‐substituted norbornenedicarboximide derivatives, namely N‐(pyridin‐2‐yl)‐exo‐norbornene‐5,6‐dicarboximide, (I), and N‐(pyridin‐3‐yl)‐exo‐norbornene‐5,6‐dicarboximide, (II), both C₁₄H₁₂N₂O₄, have been crystallized and their structures unequivocally determined by single‐crystal X‐ray diffraction. The molecules consist of norbornene moieties fused to a dicarboximide ring substituted at the N atom by either pyridin‐2‐yl or pyridin‐3‐yl in an anti configuration with respect to the double bond, thus affording exo isomers. In both compounds, the asymmetric unit consists of two independent molecules (Z′ = 2). In compound (I), the pyridine rings of the two independent molecules adopt different conformations, i.e. syn and anti, with respect to the methylene bridge. The intermolecular contacts of (I) are dominated by C—H...O interactions. In contrast, in compound (II), the pyridine rings of both molecules have an anti conformation and the two independent molecules are linked by carbonyl–carbonyl interactions, as well as by C—H...O and C—H...N contacts.     

Asymmetric Hydrogenation of α-Hydroxy Ketones: A Reaction Sensitive toward Electronic Effect of Substrates

以[RuCl2(benzene)]2 和 SunPhos为原料现场制备的催化剂,催化不对称氢化α-羟基酮类化合物可获得手性1, 2-二醇类化合物,ee值最高达99%。