The Catalytic Asymmetric Addition of Diethylzinc to N‐(Diphenylphosphinoyl) Imines Catalyzed by Cu(OTf)2‐Chiral N‐(Binaphthyl‐2‐yl)thiophosphoramide Ligands

Chiral N‐(binaphthyl‐2‐yl)thiophosphoramide L7 [O,O‐diethyl 2′‐(ethylamino)‐1,1′‐binaphthyl‐2‐ylamidothiophosphate] prepared from the reaction of diethyl chlorothiophosphate with (R)‐(+)‐N‐ethyl‐1,1′‐binaphthyl‐2,2′‐diamine was used as a catalytic chiral ligand in the first Cu(OTf)₂‐promoted catalytic asymmetric addition of diethylzinc to N‐(diphenylphosphinoyl) imines in which ~85% ee can be realized.     

tert‐Butanesulfinylphosphines: Simple Chiral Ligands in Rhodium‐Catalyzed Asymmetric Addition of Arylboronic Acids to Electron‐Deficient Olefins

An efficient rhodium complex catalyst system was developed by using a class of simple tert‐butanesulfinylphosphines as bidentate ligands, which solely bear sulfur chirality and combine the advantages of both sulfoxide and phosphine ligands. Excellent activities (in 0.5 hour, up to 99% yield) and enantioselectivities (up to 98% ee) were displayed in Rh‐catalyzed asymmetric 1,4‐additions under mild conditions.     

One Step Synthesis of Chiral Olefins via Asymmetric Diamination and their Applications as Ligands for Rhodium(I)‐Catalyzed 1,4‐Additions

A variety of acyclic chiral dienes were synthesized in a single step via palladium(0)‐catalyzed asymmetric allylic and homoallylic C H diamination of terminal olefins. The applications of such simple dienes as steering ligands for rhodium(I)‐catalyzed asymmetric 1,4‐additions afforded the corresponding adducts in excellent yields and up to 85% ee.     

Palladium‐Catalyzed Asymmetric 1,4‐Addition of Diarylphosphines to Nitroalkenes for the Synthesis of Chiral P,N‐Compounds

A highly stereoselective asymmetric 1,4‐addition of diarylphosphines to nitroalkenes catalyzed by a bis(phosphine) pincer‐palladium complex has been developed for the synthesis of chiral P,N compounds with good to excellent enantioselectivities (up to 94% ee) under mild conditions.     

Enders’ SAMP‐Hydrazone as Traceless Auxiliary in the Asymmetric 1,4‐Addition of Cuprates to Enones

Conjugate additions of Gilman cyanocuprates to (S)‐N‐amino‐2‐(methoxymethyl)pyrrolidine (SAMP)‐hydrazones 4 , 5 derived from cyclic and acyclic α,β‐unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)‐ 1 under the hydrolysis and work‐up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP‐hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP‐hydrazones 5 , however, by the nature of the aryl substituent. Electron‐donating substituents gave poor enantiomeric excesses, whereas electron‐withdrawing groups provided excellent ee values of 98–99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4‐addition/methylation and traceless hydrolytic cleavage of the auxiliary (S)‐ 1 in a one‐pot reaction, resulting in enantiomerically pure methyl ketones 11 – 13 , each of them with>99% ee.     

Spiro‐Pyrrolidine‐Catalyzed Asymmetric Conjugate Addition of Hydroxylamine to Enals and 2,4‐Dienals

A spiro‐pyrrolidine‐catalyzed tandem aza‐1,4‐addition/hemi‐acetalization reaction was developed with excellent enantioselectivity (12 examples of ≥99% ee), and several substrates proceeded with higher ee (up to 10% increase) compared with the literature data. Particularly, an interesting and unusual aza‐1,6‐/oxa‐1,4‐addition for some substrates was also observed.

     

Modification of Chiral Monodentate Phosphine Ligands (MOP) for Palladium‐Catalyzed Asymmetric Hydrosilylation of Cyclic 1,3‐Dienes

Several MOP ligands 5 containing aryl groups at 2′ position of (R)‐2‐(diphenylphosphino)‐1,1′‐binaphthyl skeleton were prepared and used for palladium‐catalyzed asymmetric hydrosilylation of cyclic 1,3‐dienes 6 with trichlorosilane. Highest enantioselectivity was observed in the reaction of 1,3‐cyclopentadiene ( 6a ) catalyzed by a palladium complex (0.25 mol %) coordinated with (R)‐2‐(diphenylphosphino)‐2′‐(3,5‐dimethyl‐4‐methoxyphenyl)‐1,1′‐binaphthyl ( 5f ), which gave (S)‐3‐(trichlorosilyl)cyclopentene of 90% ee.     

Axially Chiral Phosphine‐Oxazoline Ligands in Silver(I)‐ Catalyzed Asymmetric Mannich Reaction of Aldimines with Trimethylsiloxyfuran

A new asymmetric catalytic system for the Mannich reaction of aldimines with trimethylsiloxyfuran is described. The combination of an axially chiral phosphine‐oxazoline ligand (S)‐2‐[(R)‐2′‐(diphenylphosphino)‐1,1′‐binaphthyl‐2‐yl]‐4‐phenyl‐4,5‐dihydrooxazole with silver acetate and 2,2,2‐trifluoroacetic acid is a very effective catalytic system in the asymmetric Mannich reaction of various aldimines with trimethylsiloxyfuran in dichloromethane at −78 °C, affording the corresponding adducts in up to 99% yield, 99:1 (dr) and 99% ee (major diastereoisomer) under mild conditions.     

pseudo Enantiomeric Carbohydrate Olefin Ligands – Case Study and Application in Kinetic Resolution in Rhodium(I)‐Catalysed 1,4‐Addition

In order to investigate significant differences in asymmetric induction for pseudo enantiomeric carbohydrate olefin ligands in rhodium(I)‐catalysed 1,4‐addition reactions, we designed a set of new olefin ligands differing in relative configuration and pyranoside conformation. With these, we have successfully elucidated structural requirements for metal binding and also identified an improved alternative for one pseudo enantiomer. Furthermore, we report the efficient kinetic resolution of a racemic 4‐hydroxycyclopentenone derivative by 1,4‐addition.

     

Chiral Squaramide‐Catalyzed Highly Enantioselective Michael Addition of 2‐Hydroxy‐1,4‐naphthoquinones to Nitroalkenes

A chiral squaramide‐organocatalyzed, highly enantioselective Michael addition of 2‐hydroxy‐1,4‐naphthoquinones to nitroalkenes has been developed. This reaction afforded the chiral naphthoquinones in excellent yields (up to 99%) and excellent enantioselectivity (up to 98% ee) under very low catalyst loading (0.25 mol%). This organocatalytic asymmetric Michael addition provides an efficient alternative route toward the synthesis of chiral functionalized naphthoquinones.     

Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by Chiral Gallium Lewis Acid with Trost‐Type Semi‐Crown Ligands

The combination of Ga(OTf)₃ with chiral semi‐crown ligands ( 1a – e ) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand‐acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p‐phenyl substituent in aromatic silyl enol ether ( 2 h ) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal ( 12 ) with aldehydes in the presence of gallium‐Lewis acid catalysts give the β‐hydroxy thioester with reasonable yields and high diastereo‐ (up to 99 : 1) and enantioselectivities (up to 96% ee).     

Highly Enantioselective Michael Addition Reactions of 3‐Substituted Benzofuran‐2(3H)‐ones to Chalcones Catalyzed by a Chiral Alkyl‐Substituted Thiourea

A highly enantioselective Michael addition of 3‐substituted benzofuran‐2(3H)‐ones to chalcones catalyzed by a chiral bifunctional thiourea was developed. Several chiral 3,3′‐substituted benzofuran‐2(3H)‐ones derivatives, bearing adjacent quaternary‐tertiary stereocenters, were efficiently synthesized with excellent enantioselectivities.     

Construction of Chiral 2‐Substituted Octahydroindoles from Cyclic Ketones and Nitroolefins Bearing only One α‐Substituent

A dual catalytic system has been developed following the screening of a series of chiral primary amine catalysts and chiral phosphoric acid catalysts for the Michael addition of cyclic ketones to nitroolefins bearing only one α‐substituent. The resulting γ‐nitro ketones, which contain a substituent on the carbon connected to the nitro group, were formed in excellent yields (>80%) with high levels of stereoselectivity (up to 94:6 dr and 98% ee) when the reaction was performed in benzene at 0 °C with 10 mol% of the optimal amine/phosphoric acid combination (1:1) as a catalyst. Subsequent reduction of the nitro group followed by intramolecular reductive amination could afford optically active cis‐octahydroindole analogues bearing a non‐functional substituent at their 2‐position.

     

Palladium(II)‐Catalyzed 1,4‐Addition of Arylboronic Acids to β‐Arylenones for Enantioselective Synthesis of 4‐Aryl‐4H‐chromenes

The enantioselective 1,4‐addition of arylboronic acids to β‐arylenones to give β‐diaryl ketones was carried out at 0–25 °C in the presence of a dicationic palladium(II) catalyst, [Pd(S,S‐chiraphos)(PhCN)₂](SbF₆)₂. Addition of a silver salt such as silver tetrafluoroborate [AgBF₄] or silver hexafluoroantimonate [AgSbF₆] (5–10 mol %) was effective to achieve high enantioselectivities at low temperatures (92–99 % ee) and to reduce the catalyst loading to 0.05 mol %. The protocol provided a simple access to 4‐aryl‐4H‐chromenes. Optically active chromenes were synthesized with up to 99 % ee via dehydration of the 1,4‐adducts between arylboronic acids and β‐(2‐hydroxyaryl)‐α,β‐unsaturated ketones.     

Chiral Phosphoric Acid‐Catalyzed Asymmetric Aza‐Friedel–Crafts Reaction of Indoles with Cyclic N‐Acylketimines: Enantioselective Synthesis of Trifluoromethyldihydroquinazolines

An enantioselective aza‐Friedel–Crafts (F‐C) reaction of indoles with cyclic N‐acylketimines has been developed. By using chiral phosphoric acid catalysts, a wide range of enantioenriched trifluoromethyldihydroquinazolines was obtained in excellent yields (up to 98%) with good to high enantioselectivities (up to 99% ee).

     

Evaluation of Palladacycles as a Non‐Rhodium Based Alternative for the Asymmetric Conjugate 1,4‐Addition of Arylboronic Acids to α,β‐Unsaturated Enones

The asymmetric conjugate 1,4‐addition of arylboronic acids to α,β‐unsaturated carbonyl compounds is an extremely versatile and widely used organic transformation. While the rhodium(I)‐catalysed reaction has been thoroughly explored, the asymmetric palladium‐catalysed protocol is far less developed and understood, particularly with acyclic enones as substrates. Herein, we report the systematic evaluation of a series of metallacycles for this reaction and the conjugate addition of arylboronic acids to a wide range of α,β‐unsaturated enones, catalysed by an easily accessible and robust chiral phosphapalladacycle in high yields and enantioselectivities.

     

Cinchona Alkaloid‐Catalyzed Enantioselective Amination of α,β‐Unsaturated Ketones: An Asymmetric Approach to Δ2‐Pyrazolines

Δ²‐Pyrazolines are of significant medicinal and synthetic interest due to their therapeutic properties and utility in the synthesis of 1,3‐diamines, yet few asymmetric methods exist to prepare them. An unprecedented and highly enantioselective organocatalytic synthesis of 2‐pyrazolines was achieved through an asymmetric conjugate addition catalyzed by 9‐epi‐amino Cinchona alkaloids followed by deprotection‐cyclization, which furnished chiral 2‐pyrazolines in 46–78% yield and 59–91% ee. This bifunctional catalytic methodology thus provides easy access to a considerable range of optically active 3,5‐dialkyl 2‐pyrazolines.     

Chiral N,N′‐Dioxide–Yttrium Triflate Complexes‐Catalyzed Asymmetric Aldol Cyclization of α‐Keto Esters with α‐Isothiocyanato Imide

A highly effective aldol cyclization of α‐isothiocyanato imide to both β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters has been developed. A chiral N,N′‐dioxide–yttrium triflate complex was used as the catalyst. A series of cyclic thiocarbamates bearing chiral quaternary stereocenters was synthesized in good to high yields, excellent diastereo‐ (up to 25:1 dr) and enantioselectivities (up to 99 % ee). In addition, the reaction could be carried out on a gram‐scale, and other functionalized derivatives are also conveniently transformed. Interestingly, a discrepancy of diastereoselection was observed between the reactions of β,γ‐unsaturated α‐keto esters and aryl‐substituted α‐keto esters. Moreover, a substrate dependency of non‐linear effects was observed in this reaction. On the basis of the experimental results and the absolute configuration of the products, possible catalytic models have been proposed to explain the origin of the asymmetric process.