Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Asymmetric Synthesis of 3‐Allyloxindoles and 3‐Allenyloxindoles by Scandium(III)‐Catalyzed Claisen Rearrangement Reactions

Scandium‐catalyzed asymmetric Claisen rearrangement reactions of 2‐allyloxyindoles and 2‐propargyloxyindoles provide a novel approach to diverse 3‐allyloxindoles and 3‐allenyloxindoles in excellent yields (up to 99%) and enantioselectivity (up to 99% ee ) under mild reaction conditions. The scandium catalyst was derived from Sc(OTf )₃ and Pybox ligand.     

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.     

Highly Regio‐ and Enantioselective Synthesis of N‐Substituted 2‐Pyridones: Iridium‐Catalyzed Intermolecular Asymmetric Allylic Amination

The first iridium‐catalyzed intermolecular asymmetric allylic amination reaction with 2‐hydroxypyridines has been developed, thus providing a highly efficient synthesis of enantioenriched N‐substituted 2‐pyridone derivatives from readily available starting materials. This protocol features a good tolerance of functional groups in both the allylic carbonates and 2‐hydroxypyridines, thereby delivering multifunctionalized heterocyclic products with up to 98 % yield and 99 % ee.     

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

The asymmetric palladium‐catalyzed decarboxylative allylic alkylation of differentially N‐protected piperazin‐2‐ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine‐2‐ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.     

Regio‐ and Enantioselective Synthesis of N‐Substituted Pyrazoles by Rhodium‐Catalyzed Asymmetric Addition to Allenes

The rhodium‐catalyzed asymmetric N‐selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)‐ruxolitinib.     

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.     

N,N′‐Dioxide/Nickel(II)‐Catalyzed Asymmetric Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction of β,γ‐Unsaturated α‐Ketoesters with Enecarbamates

N,N′‐Dioxide/nickel(II) complexes have been developed to catalyze the inverse‐electron‐demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with acyclic enecarbamates. After detailed screening of the reaction parameters, mild optimized reaction conditions were established, affording 3,4‐dihydro‐2H‐pyranamines in up to 99 % yield, 99 % ee and more than 95:5 d.r. The catalytic system was also efficient for β‐substituted acyclic enecarbamates, affording more challenging 2,3,4‐trisubstituted 3,4‐dihydro‐2H‐pyranamine with three contiguous stereogenic centers in excellent yields, diastereoselectivities, and enantioselectivities. The reaction could be scaled up to a gram scale with no deterioration of either enantioselectivity or yield. Based on these experiments and on previous reports, a possible transition state was proposed.     

Enantioselective Copper(I/II)‐Catalyzed Conjugate Addition of Nitro Esters to β,γ‐Unsaturated α‐Ketoesters

A highly enantioselective Michael addition of nitroacetates to β,γ‐unsaturated α‐ketoesters was developed by using chiral copper catalysts. The Michael addition products can be obtained in high yields with up to 99 % ee. With these densely functionalized products, the chiral cyclic nitrones, which are important synthetic intermediates, can be obtained in one step.     

Bifunctional Ammonium Salt Catalyzed Asymmetric α‐Hydroxylation of β‐Ketoesters by Simultaneous Resolution of Oxaziridines

Chiral bifunctional urea‐containing ammonium salts were found to be very efficient catalysts for asymmetric α‐hydroxylation reactions of β‐ketoesters with oxaziridines under base‐free conditions. The reaction is accompanied by a simultaneous kinetic resolution of the oxaziridine and a plausible and so far unprecedented bifunctional transition‐state model has been obtained by means of DFT calculations.     

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.