Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

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.     

Direct synthesis of γ‐substituted phthalides via ortho‐aryl benzoic acid mediated benzyl radical cyclization

Direct synthesis of γ‐substituted phthalids from related ortho‐aryl benzoic acids with 48–85% yield are covered. The direct oxidation in the presence of peroxydisulphate‐copper (II) chloride in aqueous medium was applied. The reaction is highly regioselective and leads exclusively to γ‐butyrolactone, through very stable benzylic radical intermediate.     

Atom‐Efficient Gold(I)‐Chloride‐Catalyzed Synthesis of α‐Sulfenylated Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate Scope and Experimental and Theoretical Mechanistic Investigation

Gold(I)‐chloride‐catalyzed synthesis of α‐sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohols generated α‐sulfenylated aldehydes and ketones in 60–97 % yield. Secondary aliphatic propargylic alcohols generated α‐sulfenylated ketones in yields of 47–71 %. Different gold sources and ligand effects were studied, and it was shown that gold(I) chloride gave the highest product yields. Experimental and theoretical studies demonstrated that the reaction proceeds in two separate steps. A sulfenylated allylic alcohol, generated by initial regioselective attack of the aryl thiol on the triple bond of the propargylic alcohol, was isolated, evaluated, and found to be an intermediate in the reaction. Deuterium labeling experiments showed that the protons from the propargylic alcohol and aryl thiol were transferred to the 3‐position, and that the hydride from the alcohol was transferred to the 2‐position of the product. Density functional theory (DFT) calculations showed that the observed regioselectivity of the aryl thiol attack towards the 2‐position of propargylic alcohol was determined by a low‐energy, five‐membered cyclic protodeauration transition state instead of the strained, four‐membered cyclic transition state found for attack at the 3‐position. Experimental data and DFT calculations supported that the second step of the reaction is initiated by protonation of the double bond of the sulfenylated allylic alcohol with a proton donor coordinated to gold(I) chloride. This in turn allows for a 1,2‐hydride shift, generating the final product of the reaction.     

Site‐Selective Approach to β‐Fluorination: Photocatalyzed Ring Opening of Cyclopropanols

To expand upon the recent pioneering reports of catalyzed sp³ C?H fluorination methods, the next rational step is to focus on directing “radical‐based fluorination” more effectively. One potential solution entails selective C?C bond activation as a prelude to selective fluorination. Herein, we report the tandem photocatalyzed ring‐opening/fluorination reactions of cyclopropanols by 1,2,4,5‐tetracyanobenzene (TCB) and Selectfluor to afford a process tantamount to site‐selective β‐fluorination of carbonyl‐containing compounds. This new approach provides a synthetically mild and operationally simple route to otherwise difficult‐to‐prepare β‐fluorinated products in good yields and with good‐to‐excellent regioselectivity. Remarkably, substrates that contain other usually reactive (e.g., benzylic) sites undergo ring‐opening fluorination preferably. The versatility of this method to give cyclic β‐fluorides from tertiary cyclopropanols and γ‐fluoro alcohols is also highlighted.     

Direct Catalytic Asymmetric Mannich‐type Reaction of α,β‐Unsaturated γ‐Butyrolactam with Ketimines

We report a direct catalytic asymmetric Mannich‐type addition of α,β‐unsaturated γ‐butyrolactam to α‐ethoxycarbonyl ketimines promoted by a soft Lewis acid/Brønsted base cooperative catalyst. A thiophosphinoyl group on the nitrogen of ketimines was crucial for both electrophilic activation and α‐addition of γ‐butyrolactams. The obtained aza‐Morita–Baylis–Hillman‐type products bear an α‐amino acid architecture with a tetra‐substituted stereogenic center.     

Enantioselective α‐Benzylation of Acyclic Esters Using π‐Extended Electrophiles

The first asymmetric cooperative Lewis base/palladium catalyzed benzylic alkylation of acyclic esters is reported. This reaction proceeds via stereodefined C1‐ammonium enolate nucleophiles. Critical to its success was the identification of benzylic phosphate electrophiles, which were uniquely reactive. Alkylated products were obtained with very high levels of enantioselectivity, and this method has been applied toward the synthesis of the thrombin inhibitor DX‐9065a.     

Synthesis of Polycyclic Indole Skeletons by a Gold(I)‐Catalyzed Cascade Reaction

The conversion of simple, easily available urea‐substituted 3‐phenylpropargyl alcohols catalyzed by a simple IPr–gold(I) catalyst in a gold(I)‐catalyzed cascade reaction composing of a gold‐catalyzed nucleophilic addition and a subsequent gold‐catalyzed substitution reaction delivers 1H‐imidazo[1, 5?a]indol‐3(2 H)‐ones. Other gold(I) catalysts or silver catalysts gave lower yields and often gave other side products. Gold(III) and copper(II) catalysts decomposed the starting material. Twelve examples, including donor and acceptor substituents on the distal nitrogen of the urea substructure, are provided. An X‐ray crystal structure analysis confirmed the structural assignment. The mechanistic investigation including isolation and further conversion of intermediates and reactions with enantiopure starting materials indicated that after the nucleophilic‐addition step, the substrate undergoes an S_N1‐type benzylic substitution reaction at the indolyl alcohol intermediate or an intramolecular hydroamination reaction of the 2‐vinylindole intermediate.     

Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

Reported herein is the distal γ‐C(sp³)?H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp³)?H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp³)?H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp³)?H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp³)?H olefinated products.     

Direct Catalytic Asymmetric Doubly Vinylogous Michael Addition of α,β‐Unsaturated γ‐Butyrolactams to Dienones

An asymmetric doubly vinylogous Michael addition (DVMA) of α,β‐unsaturated γ‐butyrolactams to sterically congested β‐substituted cyclic dienones with high site‐, diastereo‐, and enantioselectivity has been achieved. An unprecedented DVMA/vinylogous Michael addition/isomerization cascade reaction affords chiral fused tricyclic γ‐lactams with four newly formed stereocenters.     

Phosphine‐Catalyzed Enantioselective γ‐Addition of 3‐Substituted Oxindoles to 2,3‐Butadienoates and 2‐Butynoates: Use of Prochiral Nucleophiles

The first phosphine‐catalyzed enantioselective γ‐addition with prochiral nucleophiles and 2,3‐butadienoates as the reaction partners has been developed. Both 3‐alkyl‐ and 3‐aryl‐substituted oxindoles could be employed in this process, which is catalyzed by a chiral phosphine that is derived from an amino acid, thus affording oxindoles that bear an all‐carbon quaternary center at the 3‐position in high yields and excellent enantioselectivity. The synthetic value of these γ‐addition products was demonstrated by the formal total synthesis of two natural products and by the preparation of biologically relevant molecules and structural scaffolds.     

Single‐Flask Multicomponent Palladium‐Catalyzed α,γ‐Coupling of Ketone Enolates: Facile Preparation of Complex Carbon Scaffolds

A three‐component palladium‐catalyzed reaction sequence has been developed in which γ‐substituted α,β‐unsaturated products are obtained in a single flask by an α‐alkenylation with either a subsequent γ‐alkenylation or γ‐arylation of a ketone enolate. Coupling of a variety of electronically and structurally different components was achieved in the presence of a Pd/Q‐Phos catalyst (2 mol %), usually at 22 °C with yields of up to 85 %. Most importantly, access to these products is obtained in one simple operation in place of employing multiple reactions.     

Enantioselective Syntheses of Substituted γ‐Butyrolactones

The previously described chiral 2‐acyloxathianes 5 (Scheme I) are used in two different enantioselective syntheses of γ‐butyrolactones. In one synthesis, Grignard addition, cleavage and reduction to carbinols RR'C(OH)CH₂OH is followed by tosylation, malonate homologation, lactonization, and removal of the carbomethoxy group to give optically active γ‐lactones. A modification of this synthesis (Scheme I) leads to optically active α‐methylene‐γ‐lactones. In the second synthesis, reaction of a bromomagnesium enolate with ketones 5 leads to β‐hydroxyesters, which, by appropriate sequences of reduction and cleavage (Scheme II) are converted to optically active α‐ or β‐hydroxy‐γ‐lactones.     

Nickel(0)‐Catalyzed Enantioselective [3+2] Annulation of Cyclopropenones and α,β‐Unsaturated Ketones/Imines

Ni⁰‐catalyzed chemo‐ and enantioselective [3+2] cycloaddition of cyclopropenones and α,β‐unsaturated ketones/imines is described. This reaction integrates C?C bond cleavage of cyclopropenones and enantioselective functionalization by carbonyl/imine group, offering a mild approach to γ‐alkenyl butenolides and lactams in excellent enantioselectivity (88–98 % ee) through intermolecular C?C activation.     

Oxidative Allene Amination for the Synthesis of Azetidin‐3‐ones

Regioselectivity in the aziridination of silyl‐substituted homoallenic sulfamates is readily diverted to the distal double bond of the allene to yield endocyclic bicyclic methyleneaziridines with excellent stereocontrol. Subsequent reaction with electrophilic oxygen sources initiates facile rearrangement to densely functionalized, fused azetidin‐3‐ones in excellent d.r., effectively transferring the axial chirality of the allene to central chirality in the products. The steric nature of the silyl group dictates which of the two rings of the fused azetidin‐3‐one will undergo further functionalization, providing an additional element of diversity for the preparation of enantioenriched azetidine scaffolds with potential biological activity.     

Ligand‐Enabled PdII‐Catalyzed Iterative γ‐C(sp3)−H Arylation of Free Aliphatic Acid

C?H functionalization of aliphatic carboxylic acids without attaching exogenous auxiliary has been so far limited at the proximal β‐position. In this work, we demonstrate a ligand enabled palladium catalyzed first regioselective distal γ‐C(sp3)?H functionalization of aliphatic carboxylic acids without incorporating an exogenous directing group. Aryl iodides containing versatile functional groups including complex organic molecules are well tolerated with good to excellent yields during the γ‐C(sp3)?H arylation reaction. Interestingly, weak coordination of carboxylate group can be further extended for sequential hetero di‐arylation. Application of the protocol has been showcased by synthesizing substituted α‐tetralone. Mechanistic investigations have been carried out to shed light on the reaction pathway.     

Calcium‐Catalyzed Formal [2+2+2] Cycloaddition

A formal intermolecular [2+2+2] cycloaddition reaction of enynes to aldehydes is presented, which can be realized in the presence of a simple and benign calcium catalyst. The reaction proceeds with excellent chemo, regio‐ and diastereoselectivity and leads to a one‐step assembly of highly interesting bicyclic building blocks containing up to three stereocenters from simple precursors via a new type of skeletal rearrangement of enynes. The observed diastereoselectivity is accounted for by two different mechanistic proposals. The first one engages mechanistic prospects arising from a gold catalyzed reaction in the absence of the stabilizing gold substituent. The second proposal involves an unprecedented cyclization–carbonyl allene ene reaction–hydroalkoxylation cascade.     

Structures and Dynamic Solution Behavior of Cationic,Two‐Coordinate Gold(I)–π‐Allene Complexes

A family of seven cationic gold complexes that contain both an alkyl substituted π‐allene ligand and an electron‐rich, sterically hindered supporting ligand was isolated in >90 % yield and characterized by spectroscopy and, in three cases, by X‐ray crystallography. Solution‐phase and solid‐state analysis of these complexes established preferential binding of gold to the less substituted C?C bond of the allene and to the allene π face trans to the substituent on the uncomplexed allenyl C?C bond. Kinetic analysis of intermolecular allene exchange established two‐term rate laws of the form rate=k₁[complex]+k₂[complex][allene] consistent with allene‐independent and allene‐dependent exchange pathways with energy barriers of ΔG^≠₁=17.4–18.8 and ΔG^≠₂=15.2–17.6 kcal mol^?1, respectively. Variable temperature (VT) NMR analysis revealed fluxional behavior consistent with facile (ΔG^≠=8.9–11.4 kcal mol^?1) intramolecular exchange of the allene π faces through η¹‐allene transition states and/or intermediates that retain a staggered arrangement of the allene substituents. VT NMR/spin saturation transfer analysis of [{P(tBu)₂o‐binaphthyl}Au(η²‐4,5‐nonadiene) ]⁺SbF₆^? ( 5 ), which contains elements of chirality in both the phosphine and allene ligands, revealed no epimerization of the allene ligand below the threshold for intermolecular allene exchange (ΔG^≠_298K=17.4 kcal mol^?1), which ruled out the participation of a η¹‐allylic cation species in the low‐energy π‐face exchange process for this complex.     

Facile Preparation of Spirolactones by an Alkoxycarbonyl Radical Cyclization–Cross‐Coupling Cascade

An alkoxycarbonyl radical cyclization–cross‐coupling cascade has been developed that allows functionalized γ‐butyrolactones to be prepared in one step from simple tertiary alcohol‐derived homoallylic oxalate precursors. The reaction succeeds with aryl and vinyl electrophiles and is compatible with heterocyclic fragments in both coupling partners. This chemistry allows for the rapid construction of spirolactones, which are of interest in drug discovery endeavors.     

Intramolecular CH Activation through Gold(I)‐Catalyzed Reaction of Iodoalkynes

The cycloisomerization reaction of 1‐(iodoethynyl)‐2‐(1‐methoxyalkyl)arenes and related 2‐alkyl‐substituted derivatives gives the corresponding 3‐iodo‐1‐substituted‐1H‐indene under the catalytic influence of IPrAuNTf₂ [IPr=1,3‐bis(2,6‐diisopropyl)phenylimidazol‐2‐ylidene; NTf₂=bis(trifluoromethanesulfonyl)imidate]. The reaction takes place in 1,2‐dichloroethane at 80 °C, and the addition of ttbp (2,4,6‐tri‐tert‐butylpyrimidine) is beneficial to accomplish this new transformation in high yield. The overall reaction implies initial assembly of an intermediate gold vinylidene upon alkyne activation by gold(I) and a 1,2‐iodine‐shift. Deuterium labeling and crossover experiments, the magnitude of the recorded kinetic primary isotopic effect, and the results obtained from the reaction of selected stereochemical probes strongly provide support for concerted insertion of the benzylic C? H bond into gold vinylidene as the step responsible for the formation of the new carbon–carbon bond.