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.     

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.     

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     

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.     

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 Ring Opening of meso‐Epoxides with Aromatic Amines Catalyzed by a New Proline‐Based N,N′‐Dioxide‐Indium Tris(triflate) Complex

The catalytic asymmetric ring opening of meso‐epoxides with aromatic amines was achieved using a new proline‐based N,N′‐dioxide‐indium tris(triflate) complex in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee) under mild conditions. The coordination ability of N,N′‐dioxide 1c was investigated by X‐ray and NMR analysis. A plausible seven‐coordinate transition state model was proposed. The chiral N,N′‐dioxides surveyed were synthesized from proline through only three conventional steps. The procedure could be run on a gram‐scale without any loss of enantioselectivity. This protocol provides a highly practical and useful tool for the bulky preparation of optically pure β‐amino alcohols.     

Proline‐Mediated Enantioselective Construction of Tetrahydropyridines via a Cascade Mannich‐Type/Intramolecular Cyclization Reaction

A highly diastereo‐ and enantioselective synthesis of 2,3‐disubstituted tetrahydropyridines was accomplished via a proline‐mediated cascade Mannich‐type/intramolecular cyclization reaction from preformed N‐PMP (p‐methoxyphenyl) aldimines and inexpensive aqueous tetrahydro‐2H‐pyran‐2,6‐diol.     

Highly Diastereo‐ and Enantioselective Vinylogous Mannich Reactions of Fluorinated Aldimines with Siloxyfurans

A highly regio‐ and enantioselective asymmetric vinylogous Mannich reaction of readily available fluorinated aldimines bearing a chiral auxiliary [(S)‐1‐phenylethyl group] with siloxyfurans to afford chiral fluorine‐containing γ‐butenolide or γ‐lactone derivatives has been developed in the presence of silver acetate (10 mol%) and axially chiral phosphine‐oxazoline ligand L1 (11 mol%). In most cases, the corresponding fluorinated adducts were obtained in high yields, good to excellent enantiomeric excesses and up to>20:1 dr.     

Production of (R)‐3′‐fluorophenylethan‐1‐ol by Trichothecium roseum isolate in a laboratory scale bioreactor

BACKGROUND: Enantiomerically pure, fluorinated compounds play an important role in medicinal chemistry. Trichothecium roseum strains were isolated for the production of (R)‐3′‐fluorophenylethan‐1‐ol. Biocatalytic production of optically active (R)‐3′‐fluorophenylethan‐1‐ol was achieved by asymmetric reduction of 3′‐fluoroacetophenone in a batch culture of Trichothecium roseum using ram horn peptone (RHP). The reaction conditions (pH, temperature and agitation) required to improve the conversion of 3′‐fluoroacetophenone and enantiomeric excess (ee) of (R)‐3′‐fluorophenylethan‐1‐ol were studied. RESULTS: The gram scale production of (R)‐3′‐fluorophenylethan‐1‐ol by the most effective biocatalyst, Trichothecium roseum EBK‐11 using RHP was carried out in a fermenter with 1 L working volume. The results showed that the yield with >99% ee of (R)‐3′‐fluorophenylethan‐1‐ol reached 77%. The concentration of (R)‐3′‐fluorophenylethan‐1‐ol at the end of 62 h fermentation was 2.70 g L^?1. CONCLUSION: An important chiral intermediate for the pharmaceutical industry using T. roseum EBK‐11 in submerged culture containing RHP from waste material was produced up to gram scale with excellent ee (99%). In this work, T. roseum fungus was used for the first time as a biocatalyst for efficient production of a chiral alcohol. Copyright © 2009 Society of Chemical Industry     

Enantioselective Synthesis of (−)‐CP‐55940 via Ruthenium‐ Catalyzed Asymmetric Hydrogenation of Ketones

A new and efficient catalytic asymmetric synthesis of the potent cannabinoid receptor agonist (−)‐CP‐55940 has been developed by using ruthenium‐catalyzed asymmetric hydrogenation of racemic α‐aryl ketones via dynamic kinetic resolution (DKR) as a key step. With RuCl₂‐SDPs/diamine [SDPs=7,7′‐bis(diarylphophino)‐1,1′‐spirobiindane] catalysts the asymmetric hydrogenation of racemic α‐arylcyclohexanones via DKR provided the corresponding cis‐β‐arylcyclohexanols in high yields with up to 99.3% ee and >99:1 cis‐selectivities. Both ethylene ketal group at the cyclohexane ring and ortho‐methoxy group at the phenyl ring of the substrates 6 have little effect on the selectivity and reactivity of the hydrogenations. Based on this highly efficient asymmetric ketone hydrogenation, (−)‐CP‐55940 was synthesized in 13 steps (the longest linear steps) in 14.6% overall yield starting from commercially available 3‐methoxybenzaldehyde and 1,4‐cyclohexenedione monoethylene acetal.     

Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives with Iridium‐(P‐Phos) Catalyst

The use of a chiral iridium catalyst generated in situ from the (cyclooctadiene)iridium chloride dimer, [Ir(COD)Cl]₂, the P‐Phos ligand [4,4′‐bis(diphenylphosphino)‐2,2′,6,6′‐tetramethoxy‐3,3′‐bipyridine] and iodine (I₂) for the asymmetric hydrogenation of 2,6‐substituted quinolines and trisubstituted pyridines [2‐substituted 7,8‐dihydroquinolin‐5(6H)‐one derivatives] is reported. The catalyst worked efficiently to hydrogenate a series of quinoline derivatives to provide chiral 1,2,3,4‐tetrahydroquinolines in high yields and up to 96% ee. The hydrogenation was carried out at high S/C (substrate to catalyst) ratios of 2000–50000, reaching up to 4000 h⁻¹ TOF (turnover frequency) and up to 43000 TON (turnover number). The catalytic activity is found to be additive‐controlled. At low catalyst loadings, decreasing the amount of additive I₂ was necessary to maintain the good conversion. The same catalyst system could also enantioselectively hydrogenate trisubstituted pyridines, affording the chiral hexahydroquinolinone derivatives in nearly quantitative yields and up to 99% ee. Interestingly, increasing the amount of I₂ favored high reactivity and enantioselectivity in this case. The high efficacy and enantioselectivity enable the present catalyst system of high practical potential.     

Chiral N,N′‐Dioxide–Scandium(III)‐Catalyzed Asymmetric Epoxidation of 2‐Arylidene‐1,3‐diketones with Hydrogen Peroxide

The catalytic asymmetric epoxidation of 2‐arylidene‐1,3‐diketones using aqueous 30% H₂O₂ as oxidant has been successfully realized by a N,N′‐dioxide–scandium(III) triflate [Sc(OTf)₃] complex, giving the corresponding products in moderate to good yields (up to 85%) with excellent enantioselectivities (up to 99% ee) under mild reaction conditions without extra additives.

     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Copper Complex of Aminoisoborneol Schiff Base Cu2(SBAIB‐d)2: An Efficient Catalyst for Direct Catalytic Asymmetric Nitroaldol (Henry) Reaction

A new bifunctional copper complex of the aminoisoborneol Schiff base – Cu₂(SBAIB‐d)₂ – has been developed for the effective direct catalytic asymmetric Henry reaction. One mol% of this catalyst produces the expected Henry products in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee). The utility of the present catalyst was also extended to the Henry reaction with nitroethane and 1‐nitropropane that furnished the corresponding products in moderate to high yields (up to 99%) with moderate to high enantioselectivities of syn (up to 98% ee) and anti (up to 98% ee) diastereomers. The highlights of this catalytic system are easy manipulation, air and moisture tolerance, the need for 1 mol% of an easily synthesizable catalyst and the high enantioselectivities achieved for a wide range of substrates.     

Vinylogous Mannich‐Type Reaction Catalyzed by an Iodine‐Substituted Chiral Phosphoric Acid

2‐Trimethylsiloxyfuran underwent a vinylogous Mannich‐type reaction with aldimines under the action of a new chiral phosphoric acid, bearing iodine on the 6,6′‐positions of the binaphthyl group, as a chiral Brønsted acid to give γ‐butenolide derivatives bearing an amino functionality with high diastereo‐ and enantioselectivity.     

Highly Enantioselective Friedel–Crafts Reaction of Indole with Alkylidenemalonates Catalyzed by Heteroarylidene Malonate‐Derived Bis(oxazoline) Copper(II) Complexes

A series of cheap and easily accessible heteroarylidenemalonate‐derived bis(oxazoline) ligands 1 and 2 were synthesized and their copper(II) complexes were applied to the catalytic Friedel–Crafts reaction between indoles and diethyl alkylidenemalonates, Excellent asymmetric enantioselectivities were afforded for the S‐enantiomer (up to >99% ee) in isobutyl alcohol, and the R‐enantiomer (up to 96.5% ee) in dichloromethane.     

The Use of an Unusual Rearrangement Sequence for the Syntheses of 3‐(1‐Aminoalkylidene)‐3H‐thiophen‐2‐ones and two Examples of their Surprising Electrophilic‐Induced Dimerization Reactions

The reaction of 2‐amino‐3‐carbomethoxythiophene ( 1a ) and 2‐amino‐3‐carboethoxy‐4,5‐dimethylthiophene ( 1b ) with methyl‐ or ethylmagnesium chloride leads to new 3‐(1‐aminoalkylidene)‐3H‐thiophen‐2‐ones 4a—d in good yields (60—87%). Treatment of the compounds 4a and 4c with catalytic amounts of p‐TsOH in boiling CHCl₃ afforded the (±)‐4,4′‐bis‐(1‐aminoalkylidene)‐3′,4′‐4H,2′H‐[2,3′]bithiophenyl‐5,5′‐diones 9a and 9b as new interesting heterocycles in preparatively useful yields (60/mdash;65%).     

Room Temperature Highly Enantioselective Nickel‐Catalyzed Hydrovinylation

At room temperature, nickel catalysts based on the new phosphoramidite (11bR)‐N‐[(S)‐1‐(naphthalen‐1‐yl)ethyl]‐N‐[(S)‐1‐(naphthalen‐2‐yl)ethyl]dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin‐4‐amine provide excellent selectivities for 3‐arylbut‐1‐enes (93–99%) with high enantioselectivities (90–95% ee) and TOFs (up to 8300 h⁻¹) in the hydrovinylation of electron‐rich and electron‐poor vinylarenes. Within a few minutes, useful chiral building blocks and intermediates can be synthesized using this practical catalytic system.     

Enantioselective Synthesis of Chiral β‐Aryloxy Alcohols by Ruthenium‐Catalyzed Ketone Hydrogenation via Dynamic Kinetic Resolution (DKR)

A highly efficient enantioselective synthesis of chiral β‐aryloxy alcohols by the {RuCl₂[(S)‐SDP][(R,R)‐DPEN]} [(S_a,R,R)‐ 1a ; SDP=7,7′‐bis(diarylphosphino)‐1,1′‐spirobiindane; DPEN=trans‐1,2‐diphenylethylenediamine] complex‐catalyzed asymmetric hydrogenation of racemic α‐aryloxydialkyl ketones via dynamic kinetic resolution (DKR) has been developed. Enantioselectivities of up to 99% ee with good to high cis/anti‐selectivities (up to>99:1) were achieved.     

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.