Enantioselective organocatalytic route to trifluoromethyl-β-amino acids using chiral bases

Herein are studied new aspects of enantioselective (1,3) proton transfer of ethyl-4,4,4-trifluoroacetoacetate (ETFAA) amino derivatives. When catalyzed by an appropriate chiral base, ee's as high as 71% are observed. Special emphasis is given to mechanistic insights of the reaction by use of deuterated derivative. All results converge on a deprotonation as both rate and asymmetric determining step. This study opens a new route to trifluoromethylated chiral building blocks.     

A novel design of a levoglucosenone derived chiral auxiliary

A two-step general approach to a new chiral auxiliary starting from levoglucosenone is reported. The compound is obtained by a [4+2] cycloaddition reaction with anthracene followed by a diastereoselective reduction of the C-2 keto function in high overall yield. The auxiliary has been used as chiral template in an asymmetric Diels-Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene and shown to be efficient for asymmetric induction.     

Enantioselective synthesis induced by chiral organic-inorganic hybrid silsesquioxane in conjunction with asymmetric autocatalysis

5-Pyrimidyl alkanol with up to 96% ee was formed using chiral organic-inorganic hybrid silsesquioxane in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, in conjunction with asymmetric autocatalysis.     

Facile access to chiral 4-substituted chromanes through Rh-catalyzed asymmetric hydrogenation

Rh/ZhaoPhos-catalyzed asymmetric hydrogenation of a series of (E)-2-(chroman-4-ylidene)acetates was successfully developed to prepare various chiral 4-substituted chromanes with high yields and excellent enantioselectivities (up to 99% yield, 98% ee). Moreover, the gram-scale hydrogenation could be performed well in the presence of 0.02 mol% catalyst loading (TON = 5000), the hydrogenation product was easily converted to access other important compounds, which demonstrated the synthetic utility of this asymmetric catalytic methodology.     

Stereoselective synthesis of (S)-dapoxetine: a chiral auxiliary mediated approach

An imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction was explored in the enantioselective synthesis of (S)-dapoxetine (SSRI). The diastereoselective aldol adduct was transformed to highly enantiopure (S)-dapoxetine with overall good yield.     

Resolution of BIPHEP on Rh with a chiral diene auxiliary

Resolution of the atropisomeric chiral BIPHEP ligand on Rh has been achieved with the aid of 2-(4-tert-butyl-phenyl)-8-methoxy-1,8-dimethyl-bicyclo[2.2.2]octa-2,5-diene, a chiral chelating diene ligand. The diene complex 3 containing an (S)-BIPHEP ligand was found to be configurationally stable in CDCl₃ solution at RT. Conversion of the diene complex 3 to a dicarbonyl Rh complex 4 that had a barrier of 25.0 kcal/mol for atropisomerization of the BIPHEP ligand. Preliminary studies of the use of the resolved complex 3 for catalysis are presented.     

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.     

Enantioselective synthesis of (L)-Fmoc-α-Me-Lys(Boc)-OH via diastereoselective alkylation of oxazinone as a chiral auxiliary

Benzyl (2R,3S)-(−)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate (4) was successively alkylated with methyl iodide and 1,4-diiodobutane using a base. In each alkylation step anti-alkylated product formed exclusively. The iodo group was displaced with azide, which served as a precursor for the side-chain amino function. Catalytic hydrogenation with concomitant cleavage of the chiral auxiliary afforded (L)-α-Me-Lys-OH (9) in a total of four steps in good yield. (L)-Fmoc-α-Me-Lys(Boc)-OH (16) was obtained from 9 via regioselective benzyloxycarbonylation. Alternately, (L)-Fmoc-α-Me-Lys(Boc)-OH (16) was obtained via Staudinger reduction of azide (8) in a total of six steps in good yield.     

Synthesis of a simple chiral auxiliary derived from levoglucosenone and its application in a Diels-Alder reaction

The synthesis of a chiral alcohol derived from levoglucosenone has been studied. The alcohol was employed as chiral template in an asymmetric Diels-Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene, and was shown to be an efficient asymmetric inductor. The oxidation reaction detected during the hydrogenation of a secondary allylic alcohol intermediate with Pd/C was also investigated.     

Enantioselective synthesis of martinelline chiral core and its diastereomer using asymmetric tandem Michael-aldol reaction

The martinelline chiral core 3 and its diastereomer were synthesized by using the asymmetric tandem Michael-aldol reaction as the key step from 4-methoxycarbonylanthranilaldehyde and the α,β-unsaturated aldehyde.     

Optical resolution via catalytic generation of chiral auxiliary

A new catalytic method for separating enantiomers of racemic compounds is proposed. Catalytic asymmetric addition of racemic trans-2-substituted cyclohexanols to imines provided diastereomeric mixtures of aminals, and the subsequent separation of the enantiomers by silica-gel column chromatography and the hydrolysis of the aminals produced the alcohols in an optically active form.     

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).     

Acyclic and cyclic aminophosphonic acids: asymmetric syntheses mediated by chiral sulfinyl auxiliary

Aminophosphonic acids have become increasingly important in different fields of chemistry, medicine and agriculture. This account outlines the results obtained in the author’s laboratory on the asymmetric synthesis of acyclic and cyclic aminophosphonic acids mediated by chiral sulfinyl auxiliary. A key reaction in the synthesis of enantiopure α- and β-aminoalkanephosphonic acids involving a highly diastereoselective addition of phosphite anions or α-phosphonate carbanions to enantiopure sulfinimines is discussed. The asymmetric cyclopropanation of enantiopure α-phosphorylvinyl sulfoxides with sulfur ylides is presented as a platform for developing a new approach to optically active β-aminocyclopropanephosphonic acids. It is exemplified by the total synthesis of enantiopure β-amino-γ-phenylcyclopropanephosphonic acid - a constrained analogue of the GABA_B antagonist phaclofen.     

Catalytic asymmetric aza Diels-Alder reactions of hydrazones using a chiral zirconium catalyst

Catalytic asymmetric aza Diels-Alder reactions of acylhydrazones with Danishefsky’s dienes have been developed. A chiral zirconium complex derived from zirconium propoxide and 3,3′,6,6′-I₄BINOL was found to be effective in this reaction, and the desired optically active 2,3-dihydro-4-pyridone derivatives were obtained with high enantioselectivities. Asymmetric formal synthesis of a natural product, coniine, was conducted using this catalytic asymmetric reaction as a key step.     

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.     

Exploiting π-shielding interactions: a highly selective chiral auxiliary derived from a biogenic building block

A chiral auxiliary template, designed on the basis of π-shielding capability has been prepared from readily available L-proline. Cycloaddition to an acrylate derivative gave high endo preference, and diastereoselectivity as high as 99% was attainable. The electronic factors contributing to selectivity were probed, and the technology successfully applied to a polymer supported variant.     

Phase-transfer-catalyzed asymmetric Darzens reaction using a new chiral ammonium salt

Catalytic asymmetric Darzens reaction of haloamides is described. A new and easily-prepared bis-ammonium salt derived from BINOL acts as an effective phase-transfer catalyst and efficiently promotes the reaction to give the desired epoxides under quite mild conditions with up to 70% ee.     

Enantioselective reactions of tert-butyl glycinate-benzophenone Schiff base catalyzed by chiral phase-transfer catalyst in aqueous media without any organic solvent

Chiral phase-transfer catalyzed enantioselective alkylations of tert-butyl glycinate-benzophenone Schiff base were investigated in aqueous media without any organic solvent. Reactions in aqueous media smoothly proceeded to give the desired product in higher yield than under standard liquid-liquid biphasic conditions. In aqueous media the formation of benzophenone, which was caused by in situ hydrolysis of Schiff base, was depressed.     

Enantioselective synthesis of oseltamivir phosphate

The key steps in the enantioselective synthesis of Tamiflu include an asymmetric Diels-Alder reaction, Mitsunobu inversion using Fukuyama modified Weinreb reagent, carbamate directed epoxidation. Epoxide opening with trimethylsilyl azide furnished a 3:1 mixture of regioisomers that converged to afford the same aziridine. Attempted preparation of the unsaturated ester regioselectively using 2-iodoxybenzoic acid (IBX) following Nicolaou’s protocol failed. The unsaturated ester was prepared by phenylselenylation followed by selenoxide elimination.     

Synthesis of a new fluorinated oxazolidinone and its reactivity as a chiral auxiliary in Aldol reactions

A new enantiomerically pure fluorinated oxazolidinone has been prepared from a fluorinated imidoyl chloride and an optically pure sulfoxide. The diastereoselective reduction of the β-iminosulfoxide thus formed followed by elimination of the sulfoxide and cyclization of the created aminoalcohol furnishes the desired product. The fluorinated oxazolidinone was subsequently used as a chiral auxiliary in Aldol reactions. We also found that the selective formation of the syn-Evans and syn-non-Evans diastereoisomer can be controlled by adjusting the Lewis acid/base ratio.