Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Diastereo‐ and Enantioselective Copper(I)‐Catalyzed Intermolecular [3+2] Cycloaddition of Azomethine Ylides with β‐Trifluoromethyl β,β‐Disubstituted Enones

Reported herein is an asymmetric [3+2] cycloaddition reaction of azomethine ylides with β‐trifluoromethyl β,β‐disubstituted enones, a reaction which is enabled by a Ming‐Phos‐derived copper(I) catalyst (Ming‐Phos=chiral sulfinamide monophosphines, Figure 2 ). This method provides scalable and efficient access to the highly substituted pyrrolidines with a trifluoromethylated, all‐carbon quaternary stereocenter in good yields with up to greater than 20:1 d.r. and 98 % ee. The reaction has a broad substrate scope and tolerates a wide range of functional groups.     

Development of Chiral Spiro P‐N‐S Ligands for Iridium‐Catalyzed Asymmetric Hydrogenation of β‐Alkyl‐β‐Ketoesters

The chiral tridentate spiro P‐N‐S ligands (SpiroSAP) were developed, and their iridium complexes were prepared. Introduction of a 1,3‐dithiane moiety into the ligand resulted in a highly efficient chiral iridium catalyst for asymmetric hydrogenation of β‐alkyl‐β‐ketoesters, producing chiral β‐alkyl‐β‐hydroxyesters with excellent enantioselectivities (95–99.9 % ee) and turnover numbers of up to 355 000.     

Catalytic Asymmetric Epoxidation of α,β‐Unsaturated Esters with Chiral Yttrium–Biaryldiol Complexes

The full details of the asymmetric epoxidation of α,β‐unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium–biphenyldiol catalyst, generated from Y(OiPr)₃–biphenyldiol ligand–triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various α,β‐unsaturated esters. With this catalyst, β‐aryl α,β‐unsaturated esters gave high enantioselectivities and good yields (≤99 % ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5–2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For β‐alkyl α,β‐unsaturated esters, an yttrium–binol catalyst, generated from Y(OiPr)₃–binol ligand–triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (≤97 % ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (?)‐ragaglitazar, a potential antidiabetes agent.     

Iridium‐Catalyzed Intermolecular Asymmetric Dearomatization of β‐Naphthols with Allyl Alcohols or Allyl Ethers

An Ir‐catalyzed intermolecular asymmetric dearomatization reaction of β‐naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]₂ (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β‐naphthalenone compounds bearing an all‐carbon‐substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee . The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.     

Enantioselective Synthesis of Highly Functionalized Dihydrofurans through Copper‐Catalyzed Asymmetric Formal [3+2] Cycloaddition of β‐Ketoesters with Propargylic Esters

An enantioselective synthesis of highly functionalized dihydrofurans through a copper‐catalyzed asymmetric [3+2] cycloaddition of β‐ketoesters with propargylic esters has been developed. With a combination of Cu(OTf)₂ and a chiral tridentate P,N,N ligand as the catalyst, a variety of 2,3‐dihydrofurans bearing an exocyclic double bond at the 2 position were obtained in good chemical yields and with good to high enantioselectivities. The exocyclic double bond can be hydrogenated in a highly diastereoselective fashion to give unusual cis‐2,3‐dihydrofuran derivatives, thus further enhancing the scope of this transformation.     

ZnCl2‐Promoted Asymmetric Hydrogenation of β‐Secondary‐Amino Ketones Catalyzed by a P‐Chiral Rh–Bisphosphine Complex

A new catalytic system has been developed for the asymmetric hydrogenation of β‐secondary‐amino ketones using a highly efficient P‐chiral bisphosphine–rhodium complex in combination with ZnCl₂ as the activator of the catalyst. The chiral γ‐secondary‐amino alcohols were obtained in 90–94 % yields, 90–99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl₂ on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)‐duloxetine, (R)‐fluoxetine, and (R)‐atomoxetine, in high yields and with excellent enantioselectivities.     

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Enantioselective Organocatalytic Reduction of β‐Trifluoromethyl Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral β‐Trifluoromethyl Amines

An efficient organocatalytic stereoselective reduction of β‐trifluoromethyl‐substituted nitroalkenes, mediated by 3,5‐dicarboxylic ester‐dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea‐based (S)‐valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97 % ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched β‐trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal‐free catalytic species were computationally investigated; on the basis of DFT transition‐state (TS) analysis, a model of stereoselection was also proposed.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Catalytic Asymmetric Intramolecular Homologation of Ketones with α‐Diazoesters: Synthesis of Cyclic α‐Aryl/Alkyl β‐Ketoesters

A catalytic asymmetric intramolecular homologation of simple ketones with α‐diazoesters was firstly accomplished with a chiral N,N′‐dioxide–Sc(OTf)₃ complex. This method provides an efficient access to chiral cyclic α‐aryl/alkyl β‐ketoesters containing an all‐carbon quaternary stereocenter. Under mild conditions, a variety of aryl‐ and alkyl‐substituted ketone groups reacted with α‐diazoester groups smoothly through an intramolecular addition/rearrangement process, producing the β‐ketoesters in high yield and enantiomeric excess.     

The Efficient Synthesis of the Optically Active β‐Hydroxyl‐γ‐Butyrolactone Derivatives

The optically active β‐hydroxyl‐γ‐butyrolactones were synthesized from nonchiral starting material by employing reductive cleavage reaction, sharpless asymmetric epoxidation and dihydroxylation, and Lewis acid‐catalysed cyclization as key steps. This strategy can be used to prepare many chiral β‐hydroxyl‐γ‐butyrolactone analogues.     

Rhodium‐catalyzed Asymmetric Hydrogenation of α‐Dehydroamino Ketones: A General Approach to Chiral α‐amino Ketones

Rhodium/DuanPhos‐catalyzed asymmetric hydrogenation of aliphatic α‐dehydroamino ketones has been achieved and afforded chiral α‐amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β‐amino alcohols by LiAlH(tBuO)₃ with good yields_. This protocol provides a readily accessible route for the synthesis of chiral α‐amino ketones and chiral β‐amino alcohols.     

Catalytic Asymmetric Synthesis of Trifluoromethylated γ‐Amino Acids through the Umpolung Addition of Trifluoromethyl Imines to Carboxylic Acid Derivatives

Novel cinchona alkaloid derived chiral phase‐transfer catalysts enabled the highly chemo‐, regio‐, diastereo‐, and enantioselective umpolung addition of trifluoromethyl imines to α,β‐unsaturated N‐acyl pyrroles. With a catalyst loading ranging from 0.2 to 5.0 mol %, this new catalytic asymmetric transformation provides facile and high‐yielding access to highly enantiomerically enriched chiral trifluoromethylated γ‐amino acids and γ‐lactams.     

Asymmetric Conjugate Reduction of α,β‐Unsaturated Ketones and Esters with Chiral Rhodium(2,6‐bisoxazolinylphenyl) Catalysts

New asymmetric conjugate reduction of β,β‐disubstituted α,β‐unsaturated ketones and esters was accomplished with alkoxylhydrosilanes in the presence of chiral rhodium(2,6‐bisoxazolinylphenyl) complexes in high yields and high enantioselectivity. (E)‐4‐Phenyl‐3‐penten‐2‐one and (E)‐4‐phenyl‐4‐isopropyl‐3‐penten‐2‐one were readily reduced at 60 °C in 95 % ee and 98 % ee, respectively, by 1 mol % of catalyst loading. (EtO)₂MeSiH proved to be the best hydrogen donor of choice. tert‐Butyl (E)‐β‐methylcinnamate and β‐isopropylcinnamate could also be reduced to the corresponding dihydrocinnamate derivatives up to 98 % ee.     

Asymmetric Dearomatization of β‐Naphthols through a Bifunctional‐Thiourea‐Catalyzed Michael Reaction

An intermolecular asymmetric dearomatization reaction of β‐naphthols with nitroethylene through a chiral‐thiourea‐catalyzed Michael reaction is described. Enantioenriched functionalized β‐naphthalenones with an all‐carbon quaternary stereogenic center could thus be easily constructed from simple naphthol derivatives in good yields and excellent enantioselectivity (up to 79 % yield, 98 % ee).     

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.     

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.     

Highly Stereoselective β‐Mannopyranosylation via the 1‐α‐Glycosyloxy‐isochromenylium‐4‐gold(I) Intermediates

While the gold(I)‐catalyzed glycosylation reaction with 4,6‐O‐benzylidene tethered mannosyl ortho‐alkynylbenzoates as donors falls squarely into the category of the Crich‐type β‐selective mannosylation when Ph₃PAuOTf is used as the catalyst, in that the mannosyl α‐triflates are invoked, replacement of the ^?OTf in the gold(I) complex with less nucleophilic counter anions (i.e., ^?NTf₂, ^?SbF₆, ^?BF₄, and ^?BAr₄^F) leads to complete loss of β‐selectivity with the mannosyl ortho‐alkynylbenzoate β‐donors. Nevertheless, with the α‐donors, the mannosylation reactions under the catalysis of Ph₃PAuBAr₄^F (BAr₄^F=tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate) are especially highly β‐selective and accommodate a broad scope of substrates; these include glycosylation with mannosyl donors installed with a bulky TBS group at O3, donors bearing 4,6‐di‐O‐benzoyl groups, and acceptors known as sterically unmatched or hindered. For the ortho‐alkynylbenzoate β‐donors, an anomerization and glycosylation sequence can also ensure the highly β‐selective mannosylation. The 1‐α‐mannosyloxy‐isochromenylium‐4‐gold(I) complex ( Cα ), readily generated upon activation of the α‐mannosyl ortho‐alkynylbenzoate ( 1 α ) with Ph₃PAuBAr₄^F at ?35 °C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high β‐selectivity in the present mannosylation.