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.     

[3,3]‐Sigmatropic Rearrangement/Allylboration/Cyclization Sequence: Enantioenriched Seven‐Membered‐Ring Carbamates and Ring Contraction to Pyrrolidines

The combination of in situ generated α‐isocyanato allylboronic esters and aldehydes afforded seven‐membered‐ring enecarbamates with high levels of diastereo‐ and enantiocontrol. They were easily converted into diversely substituted 1,3‐oxazepan‐2‐ones. An unprecedented rearrangement of 5‐acetoxy‐7‐aryl or styryl derivatives led to tetrasubstituted pyrrolidines. A computational study provides evidence on the feasibility of the proposed mechanism of this unusual ring contraction.     

Palladium‐Catalyzed Oxidative Carbonylation of N‐Allylamines for the Synthesis of β‐Lactams

β‐Lactam scaffolds are considered to be ideal building blocks for the synthesis of nitrogen‐containing compounds. A new palladium‐catalyzed oxidative carbonylation of N‐allylamines for the synthesis of α‐methylene‐β‐lactams is reported. DFT calculations suggest that the formation of β‐lactams via a four‐membered‐ring transition state is favorable.     

Copper‐Catalyzed Cyclization/aza‐Claisen Rearrangement Cascade Initiated by Ketenimine Formation: An Efficient Stereocontrolled Synthesis of α‐Allyl Cyclic Amidines

An efficient and convenient synthesis of α‐allyl cyclic amidines has been achieved by applying a novel cascade reaction. Copper(I)‐mediated in situ N‐sulfonyl ketenimine formation from the reaction of a terminal alkyne with sulfonyl azide is followed by an intramolecular nucleophilic attack on the central carbon atom by an allylic tertiary amine, and then an aza‐Claisen rearrangement takes place through a chair transition state to furnish the titled amidines with complete stereocontrol.     

Double‐Addition Reaction of Aryl Methyl Sulfones with N‐tert‐Butylsulfinyl Imines: Diastereoselective and Concise Synthesis of 2‐Sulfonylated 1,3‐Diamines

We report a double‐addition reaction of methyl phenyl sulfone and methyl 2‐pyridyl sulfone with N‐tert‐butylsulfinyl imines. This method provides concise access to 2‐sulfonylated 1,3‐anti diamines with good to excellent diastereoselectivities. This protocol has the benefit of using readily accessible starting materials and is operationally simple.     

Palladium‐Catalyzed CH Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³)? H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.     

Synthesis of Both Enantiomers of Nine‐Membered CF3‐Substituted Heterocycles Using a Single Chiral Ligand: Palladium‐Catalyzed Decarboxylative Ring Expansion with Kinetic Resolution

The two enantiomers of trifluoromethyl‐benzo[c][1,5]oxazonines, (R)‐ 4 and (S)‐ 4 , can be selectively accessed with high enantiopurity by the Pd‐catalyzed ring‐expansion reaction of trifluoromethyl‐benzo[d][1,3]oxazinones ( 1 ) with vinyl ethylene carbonates ( 3 ) using one antipode of a chiral ligand. Initially, the reaction proceeds by a double decarboxylative ring‐expansion with kinetic resolution of 1 in the presence of a Pd‐catalyst/chiral ligand to provide (R)‐ 4 with high enantiopurity. At the same time, the nonreactive antipode of 1 , (S)‐ 1 , which was recovered with an impeccable s factor of up to 713 and an ideal chemical yield, was transferred into the antipode of the products, (S)‐ 4 , with high enantiopurity by a second run of the Pd‐catalyzed double decarboxylation reaction, but this time without any chiral auxiliary. Thus, both antipodes of the chiral trifluoromethyl heterocycles 4 can be obtained in excellent enantiopurity using only a single antipode of the chiral catalyst.     

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.     

Palladium‐Catalyzed Stereoselective Intramolecular Oxidative Amidation of Alkenes in the Synthesis of 1,3‐ and 1,4‐Amino Alcohols and 1,3‐Diamines

An efficient and practical Pd‐catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3‐ and 1,4‐amino alcohols and 1,3‐diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center     

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.     

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).     

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.     

Ir‐Catalysed Asymmetric Allylic Substitutions with Cyclometalated (Phosphoramidite)Ir Complexes—Resting States,Catalytically Active (π‐Allyl)Ir Complexes and Computational Exploration

Mechanistic aspects of allylic substitutions with iridium catalysts derived from phosphoramidites by cyclometalation were investigated. The determination of resting states by ³¹P NMR spectroscopy led to the conclusion that the cyclometalation process is reversible. A novel, one‐pot procedure for the preparation of (π‐ allyl)Ir complexes was developed, and these complexes were characterised by X‐ray crystal structure analyses and spectral data. They are fully active catalysts of the allylic substitution reaction. DFT calculations on the allyl complexes, transition states of the allylic substitution and product olefin complexes gave further mechanistic insight.     

Asymmetric Synthesis of 2,4,5‐Trisubstituted Δ2‐Thiazolines

Δ²‐Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to 2,4,5‐trisubstituted Δ²‐thiazolines. These Δ²‐thiazolines were synthesized from readily accessible/commercially available α,β‐unsaturated methyl esters through a Sharpless asymmetric dihydroxylation and an O→N acyl migration reaction as key steps. The final products were obtained in good yields with up to 97 % enantiomeric excess.     

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.