Asymmetric Synthesis of Oxa‐Bridged Oxazocines through a Catalytic RhII/ZnII Relay [4+3] Cycloaddition Reaction

Oxa‐bridged oxazocines bearing three chiral carbon centers were synthesized efficiently through a bimetallic catalytic asymmetric tandem reaction of β,γ‐unsaturated α‐ketoesters with diazoimides. The process contained a rhodium‐promoted in situ generation of isomünchnone from diazoimide decomposition, and a [4+3]‐cycloaddition of β,γ‐unsaturated α‐ketoester catalyzed by a chiral N,N′‐dioxide‐Zn^II complex. Ligand‐accelerated catalysis was found, and a possible transition‐state model was proposed to explain the origin of stereoselectivity.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

Highly enantioselective Diels–Alder (DA) and inverse‐electron‐demand hetero‐Diels–Alder (HDA) reactions of β,γ‐unsaturated α‐ketoesters with cyclopentadiene catalyzed by chiral N,N′‐dioxide–Cu(OTf)₂ (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ‐unsaturated α‐ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99 % ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ‐unsaturated α‐ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94 %) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65 %) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1–1.5 mol %). A strong positive nonlinear effect was observed.     

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.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Stereoselective Synthesis of Highly Functionalized Nitrocyclopropanes through the Organocatalyic Michael‐Addition‐Initiated Cyclization of Bromonitromethane and β,γ‐Unsaturated α‐Ketoesters

A highly diastereo‐ and enantioselective cyclopropanation of β,γ‐unsaturated α‐ketoesters with bromonitromethane has been successfully developed through a domino Michael‐addition/intramolecular‐alkylation strategy. Acceptable yields (up to 89 %) and enantioselectivities (up to 96 % ee) have been obtained.     

Catalytic Enantioselective Inverse Electron Demand Hetero‐Diels–Alder Reaction with Allylsilanes

The first diastereo‐ and enantioselective inverse electron demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the β,γ‐unsaturated α‐ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.     

Chiral Zinc(II)‐Catalyzed Enantioselective Tandem α‐Alkenyl Addition/Proton Shift Reaction of Silyl Enol Ethers with Ketimines

A new catalytic asymmetric tandem α‐alkenyl addition/proton shift reaction of silyl enol ethers with ketimines was serendipitously discovered in the presence of chiral N,N′‐dioxide/Zn^II complexes. The proton shift preferentially proceeded instead of a silyl shift after α‐alkenyl addition of silyl enol ether to the ketimine. A wide range of β‐amino silyl enol ethers were synthesized in high yields with good to excellent ee values. Control experiments suggest that the Mukaiyama–Mannich reaction and tandem α‐alkenyl addition/proton shift reaction are competitive reactions in the current catalytic system. The obtained β‐amino silyl enol ethers were easily transformed into β‐fluoroamines containing two vicinal tetrasubstituted carbon centers.     

Catalytic Asymmetric Intramolecular Homologation of Ketones with α‐Diazoesters: Synthesis of Cyclic α‐Aryl/Alkyl β‐Ketoesters

A catalytic asymmetric intramolecular homologation of simple ketones with α‐diazoesters was firstly accomplished with a chiral N,N′‐dioxide–Sc(OTf)₃ complex. This method provides an efficient access to chiral cyclic α‐aryl/alkyl β‐ketoesters containing an all‐carbon quaternary stereocenter. Under mild conditions, a variety of aryl‐ and alkyl‐substituted ketone groups reacted with α‐diazoester groups smoothly through an intramolecular addition/rearrangement process, producing the β‐ketoesters in high yield and enantiomeric excess.     

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).     

Catalytic Regio‐ and Enantioselective [4+2] Annulation Reactions of Non‐activated Allenes by a Chiral Cationic Indium Complex

Regio‐ and enantioselective [4+2] annulation between β,γ‐unsaturated α‐keto esters and non‐activated allenes was achieved by using a chiral cationic indium(III)/phosphate catalyst. The reaction affords the corresponding C3‐selective dihydropyrans in good yields and with high enantioselectivity (up to 99 % ee ).     

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.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

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.     

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.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.     

Asymmetric Hetero‐Diels–Alder Reaction of Danishefsky’s Diene with α‐Ketoesters and Isatins Catalyzed by a Chiral N,N′‐Dioxide/Magnesium(II) Complex

A highly enantioselective hetero‐Diels–Alder reaction of Danishefsky’s diene with α‐ketoesters and isatins has been realized by using a chiral N,N′‐dioxide/Mg^II complex. In the presence of only 0.1–0.5 mol % catalyst, a series of substrates were transformed into the corresponding tetrasubstituted 2,3‐dihydropyran‐4‐ones in up to 99 % yield and more than 99 % ee in two hours.     

Rhodium‐Catalyzed Asymmetric Arylation of β,γ‐Unsaturated α‐Ketoamides for the Construction of Nonracemic γ,γ‐Diarylcarbonyl Compounds

A highly regio‐ and enantioselective rhodium‐catalyzed 1,4‐addition of arylboronic acids to β,γ‐unsaturated α‐ketoamides using a simple new chiral sulfinylphosphine ligand is described. This transformation provides an attractive approach to construct chiral nonracemic γ,γ‐diarylsubstituted carbonyl compounds, as exemplified in the concise syntheses of sertraline and tetrahydroquinoline‐2‐carboxylamide.