2-Chlorotetrafluoroethanesulfinamide induced asymmetric vinylogous Mannich reaction

The generality of (S)-2-chlorotetrafluoroethanesulfinamide (CTFSA) induced asymmetric vinylogous Mannich (AVM) addition reaction has been investigated. The reaction of aldimines derived from (S)-CTFSA with 2-(tert-butyldimethylsilyloxy) furan (TBSOF) took place regioselectively at the γ-site at room temperature in DMSO under air atmosphere to give the desired addition products in syn-configuration with high diastereoselectivities (up to 98:2 dr). However, anti-configuration product as major isomer was obtained in the presence of tetra-butyl ammonium fluoride (TBAF) at −78 °C. Facile removal of the auxiliary group without epimerization demonstrated their synthetic potential for piperidone derivatives.     

Synthesis of P-chiral phosphines via chiral metal template promoted asymmetric furan Diels-Alder reaction

The organoplatinum complex containing ortho-metalated (S)-(1-(dimethylamino)ethyl)-naphthalene as the chiral auxiliary has been used to promote the asymmetric [4+2] Diels-Alder reaction between phenyldivinylphosphine and 2-diphenylphosphinofuran. The reaction was complete in 6 days at room temperature, with the formation of four isomeric diphosphino-substituted oxanorbornene metal complexes in the ratio of 4:2:2:1. Only the exo-cycloaddition products were formed. The formation of stereogenic carbon centers within the oxanorbornene skeleton are highly stereoselective, with all four cycloadducts adopting the same absolute configurations. However, the stereocontrol at the external phosphorus stereogenic center is less efficient (S_p:R_p = 2:1 for the template cycloadducts). The chiral naphthylamine auxiliary could be removed chemoselectively by treatment with concentrated hydrochloric acid, and further ligand liberation of the dichloro complexes with aqueous cyanide gave the diphosphino-substituted oxanorbornene ligands. Hydrogenation of the double bonds in the cycloadduct stabilizes the phosphorus stereogenic center of the free diphosphine ligand which otherwise undergoes inversion of absolute configuration.     

Synthesis of Heterocycles via 2-Thioxo-1,2-dihydropyridine-3-carbonitrile Derivative

The present study aimed to investigate the synthetic potentiality and chemical reactivity of 2-thioxo-1,2-dihydropyridine-3-carbonitrile derivative 1. This goal performed via its reaction with each of 1-chloroacetone and iodomethane to afford the corresponding 2-alkylthio derivatives 3 and 9, respectively. Compound 3 underwent intramolecular cyclization to afford the corresponding thieno[2,3-b]pyridine derivative 4 which in turn, reacted with dimethylformamide/dimethylacetal followed by hydrazine hydrate and nitrous acid to afford the corresponding pyridothienopyrimidine and pyridothienopyridazine derivatives 6 and 8, respectively. On the other hand, Compound 9 reacted with hydrazine hydrate to give 3-aminopyrazolo[3,4-b]pyridine derivative 10, which diazotized with nitrous acid to give the corresponding diazonium salt 11. Compound 11 coupled with several active –CH₂-containing reagents to synthesize the corresponding pyridopyrazolo-triazines 15, 24, 29, and 31. The formulas of all newly synthesized heterocyclic compounds were elucidated by considering the data of IR, ¹H NMR, Mass spectral data, as well as data from elemental analyses.     

Synthesis of chiral binaphthalenes using the asymmetric Suzuki reaction

The synthesis of atropisomeric 1,1′-binaphthalenes can be achieved using an asymmetric Suzuki cross-coupling reaction. The Suzuki reaction leading to such hindered compounds is challenging and competing hydrolytic deboronation frequently dominates unless carefully chosen conditions are employed. The simple, standard mechanism is inadequate when describing the Suzuki coupling of hindered partners. Evidence suggests that the key step leading to asymmetry is transmetallation (delivery of the organometallic by the asymmetric ligand) and the reactions operate under kinetic control. Reductive elimination (itself likely to be triggered by oxidative addition of another molecule of halide) is fast compared with equilibration (epimerisation and/or cis-trans isomerisation).     

Asymmetric synthesis of 1,2-bis(diphenylphosphino)-1-phenylethane via a chiral palladium template promoted hydrophosphination reaction

An organopalladium(II) complex derived from (S)-N,N-dimethyl-1-(1-naphthyl)-ethylamine was employed as the chiral auxiliary to promote the asymmetric hydrophosphination reactions between diphenylphosphine and (E) or (Z)-diphenylphosphinostyrene in high regio- and stereoselectivities at low temperature with triethyl amine as external base. Optically active free ligand (R)-1,2-bis(diphenylphosphino)-1-phenylethane was obtained in high yield subsequently. Mechanistic pathways explaining the stereoselectivity of the chiral organopalladium template promoted hydrophosphination reactions are also proposed.     

The highly enantioselective Diels-Alder reaction of 1,2-dihydropyridine using chiral cationic palladium-phosphinooxazolidine catalyst for the synthesis of chiral isoquinuclidines

The enantioselective Diels-Alder reactions of 1-phenoxycarbonyl-1,2-dihydropyridine with 1-alkylated acryloyl-pyrazolidin-3-ones using chiral cationic palladium-phosphinooxazolidine (Pd-POZ) catalyst afforded chiral isoquinuclidines with excellent enantioselectivity (up to 97% ee).     

An efficient synthetic methodology of chiral isoquinuclidines by the enantioselective Diels-Alder reaction of 1,2-dihydropyridines using chiral cationic palladium-phosphinooxazolidine catalyst

High purity chiral isoquinuclidines (97% ee) were obtained from the enantioselective Diels-Alder reaction of 1-phenoxycarbonyl-1,2-dihydropyridine with 1-benzyl-2-acryloylpyrazolidin-3-one using chiral cationic palladium-phosphinooxazolidine (Pd-POZ) catalyst. The obtained DA adduct was easily converted to the chiral piperidine derivative bearing three stereogenetic centers in the structure.     

Highly diastereoselective Henry reaction of nitro compounds with chiral derivatives of glyoxylic acid

N-Glyoxyloyl-(2R)-bornane-10,2-sultam and (1R)-8-phenylmenthyl glyoxylate react stereoselectively with simple nitro compounds giving diastereoisomeric nitroalcohols with high asymmetric induction. N-Glyoxyloyl-(2R)-bornane-10,2-sultam 1a is shown to be a highly efficient chiral inducer, superior to (1R)-8-phenylmenthyl glyoxylate 1b. In all cases, the absolute (2S) configuration at the center bearing the hydroxy group and the relative syn configuration for the major diastereoisomers were determined.     

Synthesis of new enantiomerically pure spirooxindolopyrrolizidines via a three-component asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides derived from isatin

An efficient, one-pot, three-component procedure for the synthesis of a small library of new chiral spirooxindolopyrrolizidines with high regio-, diastereo-, and enantioselectivity, from the 1,3-dipolar cycloaddition of azomethine ylides and optically active cinnamoyl oxazolidinone is described. The process occurs at room temperature in aqueous ethanol as a green solvent and in the absence of any Lewis acids. The oxazolidinone chiral auxiliary is removed in a non-destructive manner. The reaction mechanism is discussed on the basis of the assignment of the absolute configuration of the cycloadducts, and on theoretical calculations.     

Asymmetric ring cleavage reaction with a combination of optically active cycloalkane-1,2-diol and Lewis acid: application to formal synthesis of (−)-alloyohimbane and approach to construction of adjacent chiral quaternary centers

Asymmetric ring cleavage reaction of meso-carbobicyclic ketones by a combination of benzaldehyde, chiral cycloalkane-1,2-diol, and Lewis acid gave optically active styrenyl esters of 26-69% ee in moderate yield. The ring cleavage reaction could be applied to the construction of adjacent chiral quaternary carbons, and also to the formal synthesis of natural alkaloid (−)-alloyohimbane.     

Multicatalytic synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates via a tandem four-component reaction

A tandem four-component reaction of 2-bromobenzaldehyde, alkyne, amine, and diethyl phosphite catalyzed by the combination of palladium and copper salts provides a facile and efficient route to 1,2-dihydroisoquinolin-1-ylphosphonate. A cascade Sonogashira-intramolecular cyclization-nucleophilic addition may be involved in the reaction process.     

An auxiliary induced asymmetric synthesis of functionalized cyclobutanes by means of catalytic (2+2)-cycloaddition reaction

A new entry to optically active hydroxycyclobutanes is described. Treatment of silyl enol ether and (−)-8-phenylmenthyl acrylate in the presence of a catalytic amount of EtAlCl₂ affords enantiomerically enriched multi-substituted cyclobutane compounds in a good yield and diastereofacial selectivity.     

The preparation of novel chiral auxiliaries SAMIQ/RAMIQ and their application in the asymmetric Michael addition

A pair of novel chiral auxiliaries SAMIQ/RAMIQ was synthesized from l- or d-phenylalanine methyl ester hydrochloride over six steps in 45.8% and 44.4% yield, respectively. The SAMIQ-/RAMIQ-hydrazone methodology was applied for the asymmetric Michael addition of ketones to α,β-unsaturated carboxylic acid methyl esters, which afforded 3-substituted-5-oxo-alkanoates in moderate to good yield (65–82%) with excellent enantioselectivity (ee=95.3%∼>99.5%).     

A versatile approach for the asymmetric synthesis of 3-alkyl-2,3-dihydro-1H-isoindolin-1-ones

Based on the use of (R)-p-benzyloxyphenylglycinol (10) as a new oxidatively cleavable chiral auxiliary, a flexible approach to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones via a diastereoselective reductive-alkylation is developed. The oxidative cleavage of the chiral auxiliary by CAN under mild conditions ensured the access to (R)-3-alkyl-2,3-dihydro-1H-isoindolin-1-ones with ee at least 92%.     

Levopimaric acid derived 1,2-diamines and their application in the copper-catalyzed asymmetric Henry reaction

Levopimaric acid, a readily available starting material, was used in efficient syntheses of new enantiopure diamines and Schiff bases with good yields. The synthetic procedure is based on the fumaropimaric acid monomethyl ester conversion into the optically pure trans-1,2-diamine via a Curtius rearrangement. New diamines were studied as ligands in the copper-catalyzed asymmetric Henry reaction.     

Efficient synthesis of 2-imino-1,2-dihydroquinolines and 2-imino-thiochromenes via copper-catalyzed domino reaction

A domino approach to 2-imino-1,2-dihydroquinolines and 2-imino-thiochromenes from sulfonyl azides, alkynes, and 2-acyl anilines or the potassium salt of 2-mercapto-benzaldehyde has been developed. This one-pot method is efficient and versatile.     

Rhodium-catalyzed Reformatsky-type reaction for asymmetric synthesis of difluoro-β-lactams using menthyl group as a chiral auxiliary

We developed a new methodology for the asymmetric Reformatsky-type reaction of (−)-menthyl bromodifluoroacetate (2) with imine in the presence of RhCl(PPh₃)₃. Ester 2 with the cost-effective chiral auxiliary gave (S)-difluoro-β-lactams in moderate to good yields and high diastereoselectivities through spontaneous removal of the auxiliary.     

Synthesis of N2-arylaminopyrimidine-5-carbonitrile derivatives via SNAr amination reaction

An efficient and high-yielding synthesis of N~2-arylaminopyrimidine-5-carbonitrile derivatives starting from arylamines and 2-methylthio-pyrimidine-5-carbonitriIe derivatives has been developed in the presence of cesium carbonate as basic reagent.This new protocol showed high chemical tolerance for a range of functional groups,and only the methylthio substituent on C2 of the pyrimidine ring was replaced with arylamine derivatives under the reaction conditions.     

A novel,C2-symmetric,chiral bis-cyclosulfinamide-olefin tridentate ligand in Rh-catalyzed asymmetric 1,4-additions

A C₂-symmetric, chiral bis-cyclosulfinamide-olefin ligand composed of two 1-oxo-2,3-dihydro-1,2-benzisothiazole moieties with rigid skeletons and a conformationally flexible butenylene chain is disclosed for the first time. HRMS and ¹H NMR analyses verify that the in situ-generated complex of the ligand and [Rh(C₂H₄)₂Cl]₂ possesses a rhodium (I) center coordinated to the tridentate ligand via two sulfinyl moieties and a CdbndC bond. The chiral ligand provided extremely high enantioselectivity (up to >99%ee) in the Rh-catalyzed asymmetric 1,4-additions of arylboronic acids to cyclohexenone and cyclopentenone. The tridentate ligand gave much higher enantioselectivity than the analogous chiral bidentate ligands.     

Synthesis of chiral butenolides using amino-thiocarbamate-catalyzed asymmetric bromolactonization

The asymmetric cyclization of 4,4-disubstituted 3-butenoic acids is studied. Amino-thiocarbamates are used as the catalysts and N-bromosuccinimide is used as the stoichiometric halogen source. The resulting γ-butanolide products are readily converted into the corresponding γ-butenolides (up to 58% ee) derivatives in one-pot.