Copper–Boxmi Complexes as Highly Enantioselective Catalysts for Electrophilic Trifluoromethylthiolations

The enantioselective trifluoromethylthiolation of β‐ketoesters using chiral copper–boxmi complexes as catalysts is reported. A number of α‐SCF₃‐substituted β‐ketoesters have been obtained with up to >99 % enantiomeric excess (ee), and the trifluoromethylthiolated products were then transformed diastereoselectively to α‐SCF₃‐β‐hydroxyesters with two adjacent quaternary stereocenters.     

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.     

Manganese‐Catalyzed anti‐Selective Asymmetric Hydrogenation of α‐Substituted β‐Ketoamides

A Mn‐catalyzed diastereo‐ and enantioselective hydrogenation of α‐substituted β‐ketoamides has been realized for the first time under dynamic kinetic resolution conditions. anti‐α‐Substituted β‐hydroxy amides, which are useful building blocks for the synthesis of bioactive molecules and chiral drugs, were prepared in high yields with excellent selectivity (up to >99 % dr and >99 % ee) and unprecedentedly high activity (TON up to 10000). The origin of the excellent stereoselectivity was clarified by DFT calculations.     

Catalytic Asymmetric Synthesis of 3‐(α‐Hydroxy‐β‐carbonyl) Oxindoles by a ScIII‐Catalyzed Direct Aldol‐Type Reaction

A direct catalytic asymmetric aldol‐type reaction of 3‐substituted‐2‐oxindoles with glyoxal derivatives and ethyl trifluoropyruvate, catalyzed by a chiral N,N′‐dioxide–Sc(OTf)₃ (Tf=trifluoromethanesulfonyl) complex, has been developed that tolerates a wide range of substrates. The reaction proceeds in good yields and excellent enantioselectivities (up to 93 % yield, 99:1 diastereomeric ratio (dr), and >99 % enantiomeric excess (ee)) under mild conditions, to deliver 3‐(α‐hydroxy‐β‐carbonyl) oxindoles with vicinal quaternary–tertiary or quaternary–quaternary stereocenters. Even with 1 mol % catalyst loading or on scaleup (10 mmol of starting material), maintenance of ee was observed, which showed the potential value of the catalyst system. In studies probing the reaction mechanism, a positive nonlinear effect was observed and Sc^III‐based enolate intermediates were detected by using ESIMS. On the basis of the experimental results and previous reports, a possible catalytic cycle was assumed.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

Highly Enantioselective Carbonyl–Ene Reactions of 2,3‐Diketoesters: Efficient and Atom‐Economical Process to Functionalized Chiral α‐Hydroxy‐β‐Ketoesters

Carbonyl–ene reactions of 2,3‐diketoesters catalyzed by [Cu{(S,S)‐tBu‐box}](SbF₆)₂ [box=bis(oxazoline)] generate chiral α‐functionalized α‐hydroxy‐β‐ketoesters in up to 94 % yield and 97 % ee. The 2,3‐diketoesters are conveniently accessed from the corresponding α‐diazo‐β‐ketoester, and a catalyst loading as low as 1.0 mol % can be achieved.     

Highly Enantioselective Conjugate Additions of Phosphites to α,β‐Unsaturated N‐Acylpyrroles and Imines: A Practical Approach to Enantiomerically Enriched Amino Phosphonates

The first highly enantioselective phosphonylation of α,β‐unsaturated N‐acylpyrroles has been developed. Excellent yields (91–99 %) and enantioselectivities (up to >99 % enantiomeric excess (ee)) were observed for a broad spectrum of both phosphites and N‐acylpyrroles under mild conditions. In particular, when diethyl phosphite was employed to test the scope of the N‐acylpyrroles, almost optically pure products (98 to >99 % ee) were obtained for 20 examples of N‐acylpyrroles. Moreover, optically pure α‐substituted β‐ or γ‐amino phosphonates can be obtained by several simple transformations of the pyrrolyl phosphonates. The versatility of the N‐acylpyrrole moiety makes the phosphorus adducts powerful chiral building blocks that enable the synthesis of various phosphonate‐containing compounds. Finally, the present strategy can also be applied to the asymmetric hydrophosphonylation of N‐acylimines with high enantioselectivities (93 to >99 % ee).     

Asymmetric Hetero‐Diels–Alder Reaction of Danishefsky’s Diene with α‐Ketoesters and Isatins Catalyzed by a Chiral N,N′‐Dioxide/Magnesium(II) Complex

A highly enantioselective hetero‐Diels–Alder reaction of Danishefsky’s diene with α‐ketoesters and isatins has been realized by using a chiral N,N′‐dioxide/Mg^II complex. In the presence of only 0.1–0.5 mol % catalyst, a series of substrates were transformed into the corresponding tetrasubstituted 2,3‐dihydropyran‐4‐ones in up to 99 % yield and more than 99 % ee in two hours.     

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

An easily available and efficient chiral N,N′‐dioxide–nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α‐isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98 %) with excellent diastereo‐ (up to >99:1 d.r.) and enantioselectivities (up to >99 % ee). A variety of aromatic, heteroaromatic, α,β‐unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol % L ‐proline‐derived N,N′‐dioxide L5 –nickel(II) complex. This process was air‐tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.     

Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

Highly enantioselective Diels–Alder (DA) and inverse‐electron‐demand hetero‐Diels–Alder (HDA) reactions of β,γ‐unsaturated α‐ketoesters with cyclopentadiene catalyzed by chiral N,N′‐dioxide–Cu(OTf)₂ (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ‐unsaturated α‐ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99 % ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ‐unsaturated α‐ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94 %) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65 %) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1–1.5 mol %). A strong positive nonlinear effect was observed.     

Synthesis of Enantiomerically Pure 1,2,3,4‐Tetrahydro‐β‐carbolines and N‐Acyl‐1‐aryl Ethylamines by Rhodium‐Catalyzed Hydrogenation

The rhodium‐catalyzed asymmetric hydrogenation of different enamides, in particular, dihydro‐β‐carboline derivates, was investigated in the presence of chiral phosphorus ligands. Enantioselectivities of up to 99 % ee were obtained after ligand screening and optimization of the reaction conditions. The scope and limitation of the catalysts were shown in the synthesis of optically active tetrahydro‐β‐carbolines and other benchmark N‐acyl‐1‐aryl ethylamines.     

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.     

Highly Enantioselective Formation of α‐Allyl‐α‐Arylcyclopentanones via Pd‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

A highly enantioselective Pd‐catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α‐aryl‐β‐keto esters employing the (R,R)‐ANDEN‐phenyl Trost ligand has been developed. The product (S)‐α‐allyl‐α‐arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all‐carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)‐tanikolide.     

Nickel(II)‐Catalyzed Asymmetric Propargyl and Allyl Claisen Rearrangements to Allenyl‐ and Allyl‐Substituted β‐Ketoesters

Highly efficient catalytic asymmetric Claisen rearrangements of O‐propargyl β‐ketoesters and O‐allyl β‐ketoesters have been accomplished under mild reaction conditions. In the presence of the chiral N,N′‐dioxide/Ni^II complex, a wide range of allenyl/allyl‐substituted all‐carbon quaternary β‐ketoesters was obtained in generally good yield (up to 99 %) and high diastereoselectivity (up to 99:1 d.r.) with excellent enantioselectivity (up to 99 % ee).     

Asymmetric Synthesis of trans‐β‐Lactams by a Kinugasa Reaction on Water

The asymmetric Kinugasa reaction was performed on pure water for the first time without the need for any organic co‐solvents. In contrast to most asymmetric Kinugasa reactions, trans‐β‐lactams were obtained as the major products in good yields, enantioselectivities, and diastereoselectivities (up to 90 % yield, 98 % ee, and >99:1 d.r.). This reaction is atom‐economical, environmentally friendly, and affords synthetically useful but challenging products.     

Chemoselectivity Control in the Asymmetric Hydrogenation of γ‐ and δ‐Keto Esters into Hydroxy Esters or Diols

The asymmetric hydrogenation of aromatic γ‐ and δ‐keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3‐AMIQ–Ru^II complex was studied. Under the optimized conditions (8 atm H₂ , Ru complex/t‐C₄H₉OK=1:3.5, 25 °C) the γ‐ and δ‐hydroxy esters (including γ‐lactones) were obtained quantitatively with 97–99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H₂ , [t‐C₄H₉OK]=50 mm , 40 °C), the 1,4‐ and 1,5‐diols were obtained predominantly with 95–99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β‐ and ?‐keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ‐?‐diketo diester into a trihydroxy ester.     

Asymmetric Synthesis of Furo[3,4‐b]indoles by Catalytic [3+2] Cycloaddition of Indoles with Epoxides

A highly efficient N,N′‐dioxide–Ni^II catalyst system for the catalytic [3+2] cycloaddition of indoles with epoxides through C?C cleavage of oxiranes was accomplished under mild conditions. It provided a promising approach for chiral furo[3,4‐b]indoles in up to 98 % yield with up to 91 % enantiomeric excess (ee) and >95:5 diastereomeric ratio (d.r.).     

Enzyme‐ and Ruthenium‐Catalyzed Enantioselective Transformation of α‐Allenic Alcohols into 2,3‐Dihydrofurans

An efficient one‐pot method for the enzyme‐ and ruthenium‐catalyzed enantioselective transformation of α‐allenic alcohols into 2,3‐dihydrofurans has been developed. The method involves an enzymatic kinetic resolution and a subsequent ruthenium‐catalyzed cycloisomerization, which provides 2,3‐dihydrofurans with excellent enantioselectivity (up to >99 % ee). A ruthenium carbene species was proposed as a key intermediate in the cycloisomerization.     

Nanosheet‐Enhanced Asymmetric Induction of Chiral α‐Amino Acids in Catalytic Aldol Reaction

An efficient ligand design strategy towards boosting asymmetric induction was proposed, which simply employed inorganic nanosheets to modify α‐amino acids and has been demonstrated to be effective in vanadium‐catalyzed epoxidation of allylic alcohols. Here, the strategy was first extended to zinc‐catalyzed asymmetric aldol reaction, a versatile bottom‐up route to make complex functional compounds. Zinc, the second‐most abundant transition metal in humans, is an environment‐friendly catalytic center. The strategy was then further proved valid for organocatalyzed metal‐free asymmetric catalysis, that is, α‐amino acid catalyzed asymmetric aldol reaction. Visible improvement of enantioselectivity was experimentally achieved irrespective of whether the nanosheet‐attached α‐amino acids were applied as chiral ligands together with catalytic Zn^II centers or as chiral catalysts alone. The layered double hydroxide nanosheet was clearly found by theoretical calculations to boost ee through both steric and H‐bonding effects; this resembles the role of a huge and rigid substituent.     

Cationic Ir/Me‐BIPAM‐Catalyzed Asymmetric Intramolecular Direct Hydroarylation of α‐Ketoamides

Asymmetric intramolecular direct hydroarylation of α‐ketoamides gives various types of optically active 3‐substituted 3‐hydroxy‐2‐oxindoles in high yields with complete regioselectivity and high enantioselectivities (84–98 % ee). This is realized by the use of the cationic iridium complex [Ir(cod)₂](BAr^F₄) and the chiral O‐linked bidentate phosphoramidite (R,R)‐Me‐BIPAM.