Efficient Synthesis of Differentiated syn‐1,2‐Diol Derivatives by Asymmetric Transfer Hydrogenation–Dynamic Kinetic Resolution of α‐Alkoxy‐Substituted β‐Ketoesters

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α‐alkoxy‐β‐ketoesters in the presence of well‐defined, commercially available, chiral catalyst Ru^II–(N‐p‐toluenesulfonyl‐1,2‐diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α‐alkoxy‐β‐hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru^II‐ and Rh^III‐tethered precatalysts extended this process to more‐challenging substrates that bore alkenyl‐, alkynyl‐, and alkyl substituents to provide the corresponding syn α‐alkoxy‐β‐hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)‐2‐ethoxy‐3‐(4‐hydroxyphenyl)‐propanoate, which is an important pharmacophore in a number of peroxisome proliferator‐activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type‐II diabetes.     

Synthesis of Chiral 2‐Aroyl‐1‐tetralols: Asymmetric Transfer Hydrgenation of 2‐Aroyl‐1‐tetralones via Dynamic Kinetic Resolution

The dynamic kinetic resolution of 2‐aroyl‐1‐tetralones was achieved via asymmetric transfer hydrogenation using (S,S)‐RuCl(p‐cymene)TsDPEN (TsDPEN=N‐(tosyl)‐1,2‐diphenylethylenediamine) in formic acid/triethyl‐ amine (5:2, molar ratio), afforded the desired products in good yields (up to 85%) with diastereomeric ratio up to >99:1 and high enantiomeric excesses (up to >99%). The absolute configuration of major the product was confirmed by X‐ray crystal structure analysis.     

Enantioselective Cascade Michael Addition/Cyclization Reactions of 3‐Nitro‐2H‐Chromenes with 3‐Isothiocyanato Oxindoles: Efficient Synthesis of Functionalized Polycyclic Spirooxindoles

An unprecedented Zn(OTf)₂‐catalyzed asymmetric Michael addition/cyclization cascade of 3‐nitro‐2H‐chromenes with 3‐isothiocyanato oxindoles has been disclosed. This transformation provides an efficient access to various synthetically important polycyclic spirooxindoles in a highly stereoselective manner under mild conditions (72–99 % yields, up to >95:5 d.r. and >99 % ee). The reaction leads to the formation of three consecutive stereocenters, including 1,3‐nonadjacent tetrasubstituted carbon stereocenters, in a single operation. A bifunctional activation model of the chiral Zn(OTf)₂/bis(oxazoline) complex was proposed based on control experiments, wherein the Zn^II moiety serves as a Lewis acid and the N atom of the free NH group acts as a Lewis base by a hydrogen‐bonding interaction.     

Highly Stereoselective [3+2] Cycloadditions of Chiral Palladium‐Containing N1‐1,3‐Dipoles: A Divergent Approach to Enantioenriched Spirooxindoles

A catalytic asymmetric [3+2] cycloaddition reaction of chiral palladium‐containing N¹‐1,3‐dipoles with methyleneindolinones has been successfully developed. The reaction allows an efficient construction of 3,3′‐pyrrolinyl spirooxindoles with high yields and excellent stereoselectivities (up to 93 % yield, 19:1 d.r. and >99 % ee). A synthetic application of this methodology is demonstrated and a stereocontrol mechanism is proposed.     

Biocatalytic Conversion of Cyclic Ketones Bearing α‐Quaternary Stereocenters into Lactones in an Enantioselective Radical Approach to Medium‐Sized Carbocycles

Cyclic ketones bearing α‐quaternary stereocenters underwent efficient kinetic resolution using cyclohexanone monooxygenase (CHMO) from Acinetobacter calcoaceticus. Lactones possessing tetrasubstituted stereocenters were obtained with high enantioselectivity (up to >99 % ee) and complete chemoselectivity. Preparative‐scale biotransformations were exploited in conjunction with a SmI₂‐mediated cyclization process to access complex, enantiomerically enriched cycloheptan‐ and cycloctan‐1,4‐diols. In a parallel approach to structurally distinct products, enantiomerically enriched ketones from the resolution with an α‐quaternary stereocenter were used in a SmI₂‐mediated cyclization process to give cyclobutanol products (up to >99 % ee).     

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.     

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.     

Cy‐SaBOX/Copper(II)‐Catalyzed Highly Diastereo‐ and Enantioselective Synthesis of Bicyclic N,O Acetals

Facile and effective access for the asymmetric construction of the useful and important skeleton of the bicyclic N,O‐acetals is described. Cu^II/SaBOX could catalyze the reaction of β,γ‐unsaturated α‐ketoesters with cyclic enamines efficiently, thus affording the desired products in excellent yields with excellent stereoselectivities (21 examples; up to 99 % yields; up to >95:5 d.r.; and 95–99 % ee). This reaction can be well performed on gram scale, even with only 1 mol % catalyst loading. The single‐crystal structures of the copper complexes lead to a good understanding of the stereo‐synergistic effects of the sidearm.     

Construction of Novel Tetrahydro‐β‐carboline‐1‐thione Spirooxindoles by Brønsted Acid Mediated Formal [3+3] Cyclization of 3‐Indolylmethanols with 3‐Isothiocyanato Oxindoles

p‐Toluenesulfonic acid mediated formal [3+3] cyclization of 3‐indolylmethanols with 3‐isothiocyanato oxindoles was realized. This transformation allowed for the synthesis of a series of novel tetrahydro‐β‐carboline‐1‐thione spirooxindoles in moderate to excellent yields (up to 99%) with generally good diastereoselectivities (up to >20:1). The structure of one product was determined by an X‐ray crystal structural analysis.     

Organocatalytic Stereoselective Synthesis of 3‐Alkyl‐3‐hydroxy‐2‐oxindoles Catalyzed by Novel Water‐compatible Axially Unfixed Biaryl‐based Bifunctional Organocatalysts

In this work, six novel axially unfixed biaryl‐based water‐compatible bifunctional organocatalysts were designed and synthesized for the organocatalytic access to a variety of 3‐alkyl‐3‐hydroxy‐2‐oxindole derivatives via aldol reactions in water. Organocatalyzed by 5a , the direct aldol reactions of isatins with enolisable ketones underwent readily in water, furnishing the structurally diverse 3‐alkyl‐3‐hydroxy‐2‐oxindoles in various stereoselectivities (up to>99% dr and >99% ee). Moreover, a plausible transition state of the conducted aldol reactions was hypothesized to shed light on the observed stereoselectivities of the obtained 3‐alkyl‐3‐hydroxy‐2‐oxindoles.     

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

An asymmetric organocatalytic domino oxa‐Michael/1,6‐addition reaction of ortho‐hydroxyphenyl‐substituted para‐quinone methides and isatin‐derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4‐phenyl‐substituted chromans bearing spiro‐connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

Asymmetric Synthesis of Enantioenriched 2‐Aryl‐2,3‐Dihydrobenzofurans by a Lewis Acid Catalyzed Cyclopropanation/Intramolecular Rearrangement Sequence

A cyclopropanation/intramolecular rearrangement initiated by the Michael addition of in situ generated ortho‐quinone methides (o‐QMs) has been developed for the enantioselective synthesis of 2‐aryl‐2,3‐dihydrobenzofurans containing two consecutive stereogenic centers, including a quaternary carbon atom. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in excellent yields (up to 95 %) with excellent stereoselectivity (up to >99 ee, up to >20:1 d.r.).     

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).     

Enantioselective Construction of Functionalized Thiochromans via Squaramide‐Catalyzed Asymmetric Cascade Sulfa‐Michael/Michael Addition

An efficient enantioselective cascade sulfa‐Michael/Michael addition reaction of trans‐3‐(2‐mercaptophenyl)‐2‐propenoic acid ethyl ester with nitroalkenes catalyzed by a chiral squaramide catalyst was disclosed. This cascade reaction afforded thiochroman derivatives with three contiguous stereocenters in high yields (up to 94%), excellent diastereoselectivities (up to >25:1 dr) and enantioselectivities (up to 99% ee).     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C−H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Palladium‐Catalyzed Asymmetric [4+3] Cyclization of Trimethylenemethane: Regio‐, Diastereo‐, and Enantioselective Construction of Benzofuro[3,2‐b]azepine Skeletons

The palladium‐catalyzed asymmetric [4+3] cyclization of trimethylenemethane donors with benzofuran‐derived azadienes furnishes chiral benzofuro[3,2‐b]azepine frameworks in high yields (up to 98 %) with exclusive regioselectivities and excellent stereoselectivities (up to >20:1 d.r., >99 % ee). This catalytic asymmetric [4+3] cyclization of Pd‐trimethylenemethane can enrich the arsenal of Pd‐TMM reactions in organic synthesis. In addition, this strategy provides an alternative approach to chiral azepines by a transition‐metal‐catalyzed asymmetric [4+3] cyclization.     

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.     

Simultaneous Induction of Axial and Planar Chirality in Arene–Chromium Complexes by Molybdenum‐Catalyzed Enantioselective Ring‐Closing Metathesis

The molybdenum‐catalyzed asymmetric ring‐closing metathesis of the various C_s‐symmetric (π‐arene)chromium substrates provides the corresponding bridged planar‐chiral (π‐arene)chromium complexes in excellent yields with up to >99 % ee. With a bulky and unsymmetrical substituent, such as N‐indolyl or 1‐naphthyl, at the 2‐positions of the η⁶‐1,3‐diisopropenylbenzene ligands, both biaryl‐based axial chirality and π‐arene‐based planar chirality are simultaneously induced in the products. The axial chirality is retained even after the removal of the dicarbonylchromium fragment, and the chiral biaryl/heterobiaryl compounds are obtained with complete retention of the enantiopurity.     

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.