Z‐Selective Hydrothiolation of Racemic 1,3‐Disubstituted Allenes: An Atom‐Economic Rhodium‐Catalyzed Dynamic Kinetic Resolution

A Z‐selective rhodium‐catalyzed hydrothiolation of 1,3‐disubstituted allenes and subsequent oxidation towards the corresponding allylic sulfones is described. Using the bidentate 1,4‐bis(diphenylphosphino)butane (dppb) ligand, Z/E‐selectivities up to >99:1 were obtained. The highly atom‐economic desymmetrization reaction tolerates functionalized aromatic and aliphatic thiols. Additionally, a variety of symmetric internal allenes, as well as unsymmetrically disubstituted substrates were well tolerated, thus resulting in high regioselectivities. Starting from chiral but racemic 1,3‐disubstituted allenes a dynamic kinetic resolution (DKR) could be achieved by applying (S,S)‐Me‐DuPhos as the chiral ligand. The desired Z‐allylic sulfones were obtained in high yields and enantioselectivities up to 96 % ee.     

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

The enantioselective tandem reaction of β,γ‐unsaturated α‐ketoesters with β‐alkynyl ketones was realized by a bimetallic catalytic system of achiral Au^ΙΙΙ salt and chiral N,N′‐dioxide‐Mg^ΙΙ complex. The cycloisomerization of β‐alkynyl ketone and asymmetric intermolecular [4+2] cycloaddition with β,γ‐unsaturated α‐ketoesters subsequently occurred, providing an efficient and straightforward access to chiral multifunctional 6,6‐spiroketals in up to 97 % yield, 94 % ee and >19/1 d.r. Besides, a catalytic cycle was proposed based on the results of control experiments.     

Axially Chiral Aryl‐Alkene‐Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

A new class of axially chiral aryl‐alkene‐indole frameworks have been designed, and the first catalytic asymmetric construction of such scaffolds has been established by the strategy of organocatalytic (Z/E)‐selective and enantioselective (4+3) cyclization of 3‐alkynyl‐2‐indolylmethanols with 2‐naphthols or phenols (all >95 : 5 E/Z, up to 98% yield, 97% ee). This reaction also represents the first catalytic asymmetric construction of axially chiral alkene‐heteroaryl scaffolds, which will add a new member to the atropisomeric family. This approach has not only confronted the great challenges in constructing axially chiral alkene‐heteroaryl scaffolds but also provided a powerful strategy for the enantioselective construction of axially chiral aryl‐alkene‐indole frameworks.     

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.     

Chiral N,N′‐Dioxide‐Organocatalyzed Regio‐, Diastereo‐ and Enantioselective Michael Addition–Alkylation Reaction

A highly regio‐, diastereo‐ and enantioselective Michael addition–alkylation reaction between α‐substituted cyano ketones and (Z)‐bromonitrostyrenes has been realized by using a chiral N,N′‐dioxide as organocatalyst. A variety of substrates performed well in this reaction, and the corresponding multifunctionalized chiral 2,3‐dihydrofurans were obtained in up to 95 % yield with 95:5 dr and 93 % ee.     

Novel Asymmetric Formylation of Aromatic Compounds: Enantioselective Synthesis of Formyl 7,8‐Dipropyltetrathia[7]helicenes

Asymmetric formylation of aromatic compounds is virtually unexplored. We report the synthesis and evaluation of a library including 20 new chiral formamides in the kinetic resolution of 7,8‐dipropyltetrathia[7]helicene, affording the corresponding formyl‐ or diformylhelicenes in up to 73 % ee, making enantiopure compounds available by recrystallisation. With the N,N‐disubstituted formamides used in this study, the best enantioselectivity has been achieved with R¹=iPr, R²=Me, R³=H, R⁴=1‐naphthyl or its 1‐pyrenyl equivalent.     

Rhodium‐Catalyzed Parallel Kinetic Resolution of Racemic Internal Allenes Towards Enantiopure Allylic 1,3‐Diketones

A rare case of a parallel kinetic resolution of racemic 1,3‐disubstituted allenes by means of a rhodium‐catalyzed addition to 1,3‐diketones furnishing enantiopure allylic 1,3‐diketones is described. Mechanistic experiments demonstrate that the different allene enantiomers react in parallel to either the diastereomeric E‐ or Z‐allylic 1,3‐diketones with the same absolute configuration of the newly formed stereogenic center. A broad substrate scope demonstrates the synthetic utility of this new method.     

Enantioselective Synthesis of Chiral Cyclopent‐2‐enones by Nickel‐Catalyzed Desymmetrization of Malonate Esters

The enantioselective synthesis of highly functionalized chiral cyclopent‐2‐enones by the reaction of alkynyl malonate esters with arylboronic acids is described. These desymmetrizing arylative cyclizations are catalyzed by a chiral phosphinooxazoline/nickel complex, and cyclization is enabled by the reversible E/Z isomerization of alkenylnickel species. The general methodology is also applicable to the synthesis of 1,6‐dihydropyridin‐3(2H)‐ones.     

Ming‐Phos/Gold(I)‐Catalyzed Stereodivergent Synthesis of Highly Substituted Furo[3,4‐d][1,2]oxazines†

A gold(I)‐catalyzed asymmetric intermolecular tandem [3+3]‐cyclization reaction of 2‐(1‐alkynyl)‐2‐ alken‐1‐ones with nitrones has been developed by using Ming‐Phos as a chiral ligand. This method enables access to the stereodivergent synthesis of highly substituted furo[3,4‐d][1,2]oxazines in excellent efficiency and stereoselectivity (up to 99% yield, 99% ee, >20 : 1 dr).     

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

A flexible approach, applicable on a gram scale, to chiral 2‐endo‐substituted 9‐oxabispidines was developed. The key intermediate, a cis‐configured 6‐aminomethylmorpholine‐2‐carbonitrile, was prepared from (R)‐3‐aminopropane‐1,2‐diol and 2‐chloroacrylonitrile. The 2‐endo substituent was introduced by Grignard addition, cyclization, and exo‐selective reduction, thus furnishing the enantiomerically pure bi‐ and tricyclic 9‐oxabispidines in 19–59 % yield. The CuCl₂ complex of the tricyclic 9‐oxabispidine, which carries an 2‐endo,N‐anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S‐configured β‐nitro alcohols in 91–98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9‐oxabispidines delivered the enantiocomplementary R‐configured products in 33–57 % ee. The respective transition states were discussed.     

Nickel(II)‐Catalyzed Asymmetric Propargyl [2,3] Wittig Rearrangement of Oxindole Derivatives: A Chiral Amplification Effect

A highly enantioselective [2,3] Wittig rearrangement of oxindole derivatives was realized by using a chiral N,N′‐dioxide/Ni^II complex as the catalyst under mild reaction conditions. A strong chiral amplification effect was observed, and allowed access to chiral 3‐hydroxy 3‐substituted oxindoles bearing allenyl groups in high yields and enantioselectivities (up to 92 % ee) by using a ligand with only 15 % ee. A reasonable explanation was given based on the experimental investigations and X‐ray crystal structures of enantiomerically pure and racemic catalysts. Moreover, the first catalytic kinetic resolution of racemic oxindole derivatives by a [2,3] Wittig rearrangement was realized with high efficiency and stereoselectivity.     

Asymmetric Synthesis of 2,3‐Dihydropyrroles by Ring‐Opening/Cyclization of Cyclopropyl Ketones Using Primary Amines

The asymmetric ring‐opening/cyclization of cyclopropyl ketones with primary amine nucleophiles was catalyzed by a chiral N,N′‐dioxide/scandium(III) complex through a kinetic resolution process. A broad range of cyclopropyl ketones and primary amines are suitable substrates of this reaction. The corresponding products were afforded in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield) under mild reaction conditions. This method provides a promising access to chiral 2,3‐dihydropyrroles as well as an effective procedure for the kinetic resolution of 2‐substituted cyclopropyl ketones.     

Rhodium‐Catalyzed Enantioselective [4+2] Cycloadditions of Vinylcarbenes with Dienes

The reaction of 2‐siloxycyclo‐1,3‐dienes with E‐vinyldiazoacetates in the presence of the bulky chiral dirhodium tetracarboxylate catalyst, Rh₂(R‐p‐PhTPCP)₄ results in an enantioselective [4+2] cycloaddition, in which three new stereogenic centers are formed. The [4+2] cycloadducts are generated as single diastereomers with high enantiocontrol (95–98 % ee). When the diene contains an additional stereogenic center, effective kinetic resolution can be achieved.     

Application of a CC Bond‐Forming Conjugate Addition Reaction in Asymmetric Dearomatization of β‐Naphthols

A C? C bond‐forming conjugate reaction was successfully applied to the enantioselective dearomatization of β‐naphthols. A C(sp2)? C(sp3) bond is formed by using propargylic ketones as reactive partners. Good to excellent Z/E ratios and ee values were obtained by employing an in situ generated magnesium catalyst. Further transformations of the Z‐configured C? C double bond in the products were achieved under mild reaction conditions. Moreover, the stereocontrolling element of this magnesium‐catalyzed dearomatization reaction was explored by computational chemistry.     

Zinc(II)‐Catalyzed Intermolecular Hydrative Aldol Reactions of 2‐En‐1‐ynamides with Aldehydes and Water to form Branched Aldol Products Regio‐ and Stereoselectively

This work describes zinc(II)‐catalyzed hydrative aldol reactions of 2‐en‐1‐ynamides with aldehydes and water to afford branched aldol products regio‐ and stereoselectively. The anti and syn selectivity can be modulated by the sizes of sulfonamides to yield E‐ and Z‐configured zinc(II) dienolates selectively. This new reaction leads to enantiopure aldol products by using a cheap chiral sulfonamide. The mechanistic analysis reveals that the sulfonamide amides of the substrates can trap a released proton to generate dual acidic sites to activate a carbonyl allylation reaction.     

Efficient Access to Multifunctional Trifluoromethyl Alcohols through Base‐Free Catalytic Asymmetric C−C Bond Formation with Terminal Ynamides

The asymmetric addition of terminal ynamides to trifluoromethyl ketones with a readily available chiral zinc catalyst gives CF₃‐substituted tertiary propargylic alcohols in up to 99 % yield and 96 % ee. The exclusion of organozinc additives and base as well as the general synthetic utility of the products are key features of this reaction. The value of the β‐hydroxy‐β‐trifluoromethyl ynamides is exemplified by selective transformations to chiral Z‐ and E‐enamides, an amide, and N,O‐ketene acetals. The highly regioselective hydration, stereoselective reduction, and hydroacyloxylation reactions proceed with high yields and without erosion of the ee value of the parent β‐hydroxy ynamides.     

Kinetic Resolution of Racemic Mandelic Acid Esters by N,N′‐Dioxide–Scandium‐Complex‐Catalyzed Enantiomer‐Selective Acylation

A simple and efficient acylative kinetic resolution of racemic mandelic acid esters was accomplished with a chiral N,N’‐dioxide–scandium(III) complex under mild and base‐free reaction conditions. A variety of mandelic acid esters performed well in the reaction, obtaining both acylated products (up to 49% yield, 97% ee) and recovered substrates (up to 49% yield, 95% ee) in high enantioselectivities with perfect selectivity factors (up to 247). The enantioselective recognition and catalytic models were also proposed for the catalytic KR reaction.     

Kinetic Resolution of 1,1′‐Biaryl‐2,2′‐Diols and Amino Alcohols through NHC‐Catalyzed Atroposelective Acylation

We present here a highly efficient NHC‐catalyzed kinetic resolution of a wide range of 1,1′‐biaryl‐2,2′‐diols and amino alcohols to provide them in uniformly ≥99 % ee. This represents the first highly enantioselective catalytic acylation of axially chiral alcohols. The aldehyde backbone that is incorporated into the chiral acyl azolium intermediate was found to have a significant effect on the enantioselectivity of the process.     

Application of a C?C Bond‐Forming Conjugate Addition Reaction in Asymmetric Dearomatization of β‐Naphthols

A C C bond‐forming conjugate reaction was successfully applied to the enantioselective dearomatization of β‐naphthols. A C(sp2) C(sp3) bond is formed by using propargylic ketones as reactive partners. Good to excellent Z/E ratios and ee values were obtained by employing an in situ generated magnesium catalyst. Further transformations of the Z‐configured C C double bond in the products were achieved under mild reaction conditions. Moreover, the stereocontrolling element of this magnesium‐catalyzed dearomatization reaction was explored by computational chemistry.     

Photochemical Deracemization of Allenes and Subsequent Chirality Transfer

Trisubstituted allenes with a 3‐(1′‐alkenylidene)‐pyrrolidin‐2‐one motif were successfully deracemized (13 examples, 86–98 % ee) employing visible light (λ=420 nm) and a chiral triplet sensitizer as the catalyst (2.5 mol %). The photocatalyst likely operates by selective recognition of one allene enantiomer via hydrogen bonds and by a triplet‐sensitized racemization process. Even a tetrasubstituted allene (45 % ee) and a seven‐membered 3‐(1′‐alkenylidene)‐azepan‐2‐one (62 % ee) could be enantiomerically enriched under the chosen conditions. It was shown that the axial chirality of the allenes can be converted into point chirality by a Diels–Alder (94–97 % ee) or a bromination reaction (91 % ee). Ring opening of the five‐membered pyrrolidin‐2‐one was achieved without significantly compromising the integrity of the chirality axis (92 % ee).