Single‐step synthesis of a radically polymerizable 1,1′‐bi‐2‐naphthol derivative for asymmetric catalysis

A new polymerizable 1,1′‐bi‐2‐naphthol derivative for polymer‐supported catalytic asymmetric synthesis is presented. The synthesis is conducted within a single reaction step, which is a major advantage over other approaches presented in the literature. The ligand‐bearing polymer is prepared through copolymerization with N‐isopropylacrylamide. Preliminary experiments on the utility in catalytic asymmetric alkylation reactions reveal the accessibility and activity of the polymer‐attached catalysts. The stereoselectivity of the reaction is found to be somewhat lower than for reactions performed in the presence of free 1,1′‐bi‐2‐naphthol, and thus requires further optimization. The enantiomeric excess of the reaction products was determined via ¹H NMR spectroscopy after chiral derivatization with (R)‐α‐methylbenzyl isocyanate. © 2015 Society of Chemical Industry     

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.     

Asymmetric Aza‐Morita–Baylis–Hillman‐Type Reactions: The Highly Enantioselective Reaction between Unmodified α,β‐ Unsaturated Aldehydes and N‐Acylimines by Organo‐co‐catalysis

The highly enantioselective organo‐co‐catalytic aza‐Morita–Baylis–Hillman (MBH)‐type reaction between N‐carbamate‐protected imines and α,β‐unsaturated aldehydes has been developed. The organic co‐catalytic system of proline and 1,4‐diazabicyclo[2.2.2]octane (DABCO) enables the asymmetric synthesis of the corresponding N‐Boc‐ and N‐Cbz‐protected β‐amino‐α‐alkylidene‐aldehydes in good to high yields and up to 99% ee. In the case of aza‐MBH‐type addition of enals to phenylprop‐2‐ene‐1‐imines, the co‐catalytic reaction exhibits excellent 1,2‐selectivity. The organo‐co‐catalytic aza‐MBH‐type reaction can also be performed by the direct highly enantioselective addition of α,β‐unsaturated aldehydes to bench‐stable N‐carbamate‐protected α‐amidosulfones to give the corresponding β‐amino‐α‐alkylidene‐aldehydes with up to 99% ee. The organo‐co‐catalytic aza‐MBH‐type reaction is also an expeditious entry to nearly enantiomerically pure β‐amino‐α‐alkylidene‐amino acids and β‐amino‐α‐alkylidene‐lactams (99% ee). The mechanism and stereochemistry of the chiral amine and DABCO co‐catalyzed aza‐MBH‐type reaction are also discussed.     

Asymmetric 1,4‐Addition of Diethylzinc to Cyclic Enones Catalyzed by Cu(I)‐Chiral Sulfonamide‐Thiophosphoramide Ligands and Lithium Salts

The chiral sulfonamide‐thiophosphoramide ligand L1 , prepared from the reaction of (1R,2R)‐(−)‐1,2‐cyclohexanediamine with diphenylthiophosphoryl chloride and p‐toluenesulfonyl chloride, was used as a chiral ligand in Cu(MeCN)₄ClO₄‐promoted catalytic asymmetric addition of diethylzinc to cyclic enones using LiCl as an additive in which up to 90% ee can be realized under mild conditions within 0.5 h. This chiral ligand is stable and recoverable after usual work‐up and can be reused in the same catalytic asymmetric reaction. Moreover, it was found that this series of chiral ligands represents a type of S,O‐bidentate ligands on the basis of ¹H NMR, ³¹P NMR and ¹³C NMR spectroscopic investigations. The linear effect of ligand ee and product ee further revealed that the active species is a monomeric Cu(I) complex bearing a single ligand.     

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.     

Organocatalytic Enantioselective Michael‐Addition of Malonic Acid Half‐Thioesters to β‐Nitroolefins: From Mimicry of Polyketide Synthases to Scalable Synthesis of γ‐Amino Acids

Highly enantioselective biomimetic Michael addition reactions of malonic acid half thioesters (MAHTs) to a variety of nitroolefins, affording the optically active γ‐amino acid precursors, were developed by employing the Cinchona‐based squaramides (up to >99% ee). Remarkably, this biomimetic process is enantioconvergent, a highly desirable feature of a catalytic asymmetric reaction, whereby E/Z‐isomers of the nitroolefins afford the same product enantiomer. The synthetic utility of this organocatalytic protocol was also demonstrated in the formal synthesis of pharmaceutically important γ‐amino acids such as baclofen. Moreover, a quantum chemical analysis of the catalyst‐substrate complexes is shown to give a detailed and instrumental insight into the origin of the observed catalytic activity.     

Asymmetric Hydrogenation Catalyzed by (S,S)‐R‐BisPast;‐Rh and (R,R)‐R‐MiniPHOS Complexes: Scope,Limitations, and Mechanism

A new class of chiral C₂‐symmetric bis(trialkyl)phosphine ligands has been prepared and used in Rh(I)‐catalyzed asymmetric hydrogenation reactions. The ligands, 1,2‐bis(alkylmethylphosphino)ethanes 1a‐g (abbreviated as BisP*, alkyl = t‐butyl, 1‐adamantyl, 1‐methylcyclohexyl, 1,1‐diethylpropyl, cyclopentyl, cyclohexyl, isopropyl) and 1,2‐bis(alkylmethylphosphino)methanes 2a‐d (abbreviated as MiniPHOS, alkyl = t‐butyl, cyclohexyl, isopropyl, phenyl) are prepared by a simple synthetic approach based on the air‐stable phosphine–boranes. These new ligands give the corresponding Rh(I) complexes, which are effective catalytic precursors for the asymmetric hydrogenation of a representative series of dehydroamino acids and itaconic acid derivatives. Enantioselectivities observed in these hydrogenations are universally high and in many cases exceed 99%. X‐Ray characterization of four precatalysts, study of the pressure effects, deuteration experiments, and characterization of the wide series of intermediates in the catalytic cycle are used for the discussion of the possible correlation between the structure of the catalysts and the outcome of the catalytic asymmetric hydrogenation.     

Enantioselective Aldol Reaction using Recyclable Montmorillonite‐Entrapped N‐(2‐Thiophenesulfonyl)prolinamide

N‐(2‐Thiophenesulfonyl)prolinamide could be easily introduced into Montmorillonite by a simple ion‐exchange reaction. The asymmetric aldol reactions between various isatins with acetone or acetaldehyde using a heterogeneous Montmorillonite‐entrapped organocatalyst afforded products with high enantioselectivity. The catalyst was readily reusable without significant loss of catalytic activity or enantioselectivity.     

Catalytic Enantioselective Arylative Dearomatization of 3‐Methyl‐2‐vinylindoles Enabled by Reactivity Switch

The first catalytic asymmetric dearomatization of 3‐methyl‐2‐vinylindoles has been established by using quinone monoimides as suitable electrophiles in the presence of chiral phosphoric acid, which afforded chiral indole derivatives bearing a quaternary stereogenic center in a chemospecific and highly enantioselective fashion (up to 81% yield, >99% ee). The success of this reaction was enabled by the reactivity switch of 3‐methyl‐2‐vinylindoles, which has not been reported before. This reaction also represents the first catalytic asymmetric arylative dearomatization of vinylindoles, which will help confront the challenges in catalytic asymmetric arylative dearomatization and dearomatization of vinylindoles.

     

Catalytic Asymmetric β‐Peroxidation of Nitroalkenes

The first example of an asymmetric β‐peroxidation of nitroalkenes is disclosed. The reaction is promoted by catalytic loadings of a commercially available diaryl‐2‐pyrrolidinemethanol derivative and tert‐butyl hydroperoxide as the oxidant. A synthetically useful class of peroxides is obtained in good yield and enantioselectivity (up to 84% ee).     

N,N′‐Dioxide‐Magnesium Ditriflate Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters and β‐Keto Amides

The highly catalytic asymmetric α‐hydroxylation of 1‐tetralone‐derived β‐keto esters and β‐keto amides using tert‐butyl hydroperoxide (TBHP) as the oxidant was realized by a chiral N,N′‐dioxide‐magnesium ditriflate [Mg(OTf)₂] complex. A series of corresponding chiral α‐hydroxy dicarbonyl compounds was obtained in excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The products were easily transformed into useful building blocks and the precursor of daunomycin was achieved in an asymmetric catalytic way for the first time.     

Catalytic Asymmetric Hydrogenation of α‐Arylcyclohexanones and Total Synthesis of (−)‐α‐Lycorane

An efficient catalytic asymmetric hydrogenation of racemic α‐arylcyclohexanones with an ethylene ketal group at the 5‐position of the cyclohexane ring via dynamic kinetic resolution has been developed, giving chiral α‐arylcyclohexanols with two contiguous stereocenters with up to 99% ee and >99:1 cis/trans‐selectivity. Using this highly efficient asymmetric hydrogenation reaction as a key step, (−)‐α‐lycorane was synthesized in 19.6% overall yield over 13 steps from commercially available starting material.     

Preparation of Optically Enriched 3‐Hydroxy‐3,4‐dihydroquinolin‐2(1H)‐ones by Heterogeneous Catalytic Cascade Reaction over Supported Platinum Catalyst

The development of a novel heterogeneous catalytic asymmetric cascade reaction for the synthesis of tetrahydroquinolines from 2‐nitrophenylpyruvates is reported. Optically enriched 3‐hydroxy‐3,4‐dihydroquinolin‐2(1H)‐ones are prepared by enantioselective hydrogenation of the activated keto group over a Cinchona alkaloid‐modified Pt catalyst, reduction of the nitro group and spontaneous cyclization cascade. Acceleration of the enantioselective hydrogenation of the activated keto group over the catalyst modified by Cinchona alkaloids ensured high tetrahydroquinolinone selectivities. The scope of the reaction was checked using twelve substrates. Both yields and enantioselectivities were significantly influenced by the nature and position of the substituents on the phenyl ring. Substituents adjacent to the nitro group considerably increased the product yield, due to their effect on the nitro group′s reduction rate; however, had only a limited effect on 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.     

Highly Efficient Asymmetric Three‐Component Vinylogous Mannich Reaction Catalyzed by a Chiral Scandium(III)‐ N,N′‐Dioxide Complex

The asymmetric three‐component vinylogous Mannich reaction of an acyclic silyl dienol ester, an aldehyde and 2‐aminophenol was accomplished using a chiral N,N′‐dioxide‐scandium(III) complex as the catalyst. A variety of aldehydes were found to be suitable substrates for the reaction and the desired δ‐amino‐α,β‐unsaturated esters were obtained in 90–99% yields with good to excellent enantioselectivities (up to >99% ee) and complete regioselectivities. Moreover, the simple experimental procedures were air‐tolerant and convenient. The present catalytic process provides the potential for large‐scale syntheses of the chiral δ‐amino‐α,β‐unsaturated esters.     

4,4′‐Disubstituted L‐Prolines as Highly Enantioselective Catalysts for Direct Aldol Reactions

A new series of 4,4′‐disubstituted prolines ( 1a–h ) has been developed and tested as organocatalysts in the direct catalytic asymmetric aldol reaction of several aliphatic ketones with aldehydes. Catalyst 1g affords the best enantioselectivities for this transformation. The reaction was carried out in DMF using a catalyst loading of 10 mol % at −10 °C to give the aldol products in up to 97 % ee for acetone. In the cases of cyclohexanone and cyclopentanone, the corresponding anti‐products were obtained in 94 % ee.     

Superparamagnetic Nanoparticle‐Supported (S)‐Diphenyl‐ prolinol Trimethylsilyl Ether as a Recyclable Catalyst for Asymmetric Michael Addition in Water

A new superparamagnetic nanoparticle‐supported (S)‐diphenylprolinol trimethylsilyl ether (Jørgensen–Hayashi catalyst) was synthesized and applied for the asymmetric Michael addition of aldehydes to nitroalkenes in water, which gives products in moderate to good yields (up to 96%), good enantioselectivity (up to 90% ee) and diastereoselectivities (up to 99:1). The immobilized catalyst could be easily separated from the reaction by an external magnet and recycled for four times without significant loss of catalytic efficiency.     

Polyvinylidene chloride supported L‐prolineamide as recoverable catalyst for asymmetric aldol reaction between ketone and aromatic aldehyde

A series of prolineamide modified by polyvinylidene chloride (PVDC) was synthesized and used as green recoverable organocatalysts for the asymmetric Aldol reactions between various ketones and aromatic aldehydes. The effects of solvent and catalyst dosage on the catalytic performances of as‐synthesized organocatalysts were investigated. It was found that as‐synthesized PVDC‐supported L ‐prolineamides possessed good catalytic performance for the asymmetric Aldol reactions between cyclohexanone and a variety of aromatic aldehydes, affording high yields of up to 99%, excellent diastereoselectivities of up to above 8 : 92 d.r. value, and high enantioselectivities of up to above 92.3% e.e. value. In general, the catalytic performance of as‐synthesized organocatalysts closely depended on the catalyst dosage and solvent type as well. Particularly, as‐synthesized organocatalyst 1c, at a dosage of 5 mol % in 10 μL of water, exhibited high catalytic activity and stereoselectivity for the asymmetric Aldol reaction between cyclohexanone and p‐nitrobenzaldehyde at room temperature. In the meantime, it could be easily recovered and recycled, while the activity and enantioselectivity were nearly completely retained even after five cycles of recovery, showing promising application as an efficient green organocatalyst for the aforementioned asymmetric Aldol reactions. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

A Convenient Synthesis of 2,2′,6,6′‐Tetramethoxy‐ 4,4′‐bis(dicyclohexylphosphino)‐3,3′‐bipyridine (Cy‐P‐Phos): Application in Rh‐Catalyzed Asymmetric Hydrogenation of α‐(Acylamino)acrylates

The first example of the synthesis of an axially chiral bis(aryldicyclohexylphosphine) dioxide via catalytic hydrogenation of the optically resolved parent bis(aryldiphenylphosphine) dioxide was reported. The procedure for the synthesis of Cy‐P‐Phos ( 4d ) has thus successfully avoided the need for an otherwise lengthy synthetic route owing to the π‐excessive nature of one of the aryl groups in the latter. The use of Cy‐P‐Phos in the Rh(I)‐catalyzed asymmetric hydrogenation of the derivatives of methyl (Z)‐2‐acetamidocinnamate gave significantly higher rates of reaction as compared to the use of the previously reported optimal ligand Xyl‐P‐Phos ( 4c ) whilst the level of enantioselectivity was essentially maintained.     

Doubly Stereocontrolled Asymmetric Aza‐Henry Reaction with in situ Generation of N‐Boc‐Imines Catalyzed by Novel Rosin‐Derived Amine Thiourea Catalysts

The doubly stereocontrolled organocatalytic aza‐Henry reaction of nitroalkanes to N‐Boc‐imines generated in situ from a variety of substituted α‐amido sulfones was investigated for the first time, in general, affording the corresponding products with high to excellent yields (up to 93% yield) and enantioselectivities (up to 98% ee), and satisfactory diastereoselectivies (anti/syn up to 98:2). Furthermore, these organocatalysts based on rosin have been proved to be the very effective promoters for this catalytic asymmetric process along side the Cinchona alkaloid‐derived catalysts.