Resolution of 1-arylalkylamines with 3-O-hydrogen phthalate glucofuranose derivatives: role of steric bulk in a family of resolving agents

The development of three new acidic resolving agents which are hydrogen phthalates of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose 1, 1,2:5,6-di-O-cyclohexylidene-α-d-glucofuranose 2 and 1,2-O-cyclohexylidene-5,6-O-diphenylmethylidene-α-d-glucofuranose 3 is shown for the resolution of 1-arylalkylamines 7a–k. The salts between 1, 2 and (RS)-1-arylalkylamines 7a–k selectively crystallize 1·(S) 7a–j and 2·(S) 7a–h salts, allowing us to recover the corresponding bases (S) 7a–j and (S) 7a–h, respectively, in good yield and enantiomeric excess (73–95% ee). Whereas, the salts between 3 and (RS)-1-arylalkylamines 7a–c,g–i,k selectively crystallize 3·(S)-7a–c,g–i salts to recover the corresponding bases (S)-7a–c,g–i in poor enantiomeric excess (4–35% ee). The difference between the resolving ability of 1 and 2 for 1-arylalkylamines 7a–h is very slight, but there is considerable difference compared to ortho-substituted 1-arylalkylamines 7i and 7j. The role of substituents on a family of resolving agents 1, 2 and 3 is also discussed to interpret their resolving ability.     

Preparation of enantiomerically pure (1S,2S)-1-aminocyclopropanephosphonic acid from methylcyclopropanone acetal via spirophosphonate intermediates

An easy and efficient one-pot reaction from readily available methylcyclopropanone acetal (2S)-4b gave the spirophosphonates 8a–b with excellent diastereoselectivity. These phosphonates, after catalytic hydrogenolysis and hydrolysis, furnished the enantiomerically pure (1S,2S)-1-amino-2-methylcyclopropanephosphonic acid 3b (analogue of (1R,2S)-allo-norcoronamic acid).     

Asymmetrical nonbridgehead nitrogen—XXIII: Chiral 3,3-bis(trifluoromethyl)diaziridines

By means of the reaction of O-tosyloxime 1a with propargyl amine, esters of glycine and (S)-α-alanine, β-acetoxyethyl amine and β-dimethylaminoethyl amine functionally substituted 3,3-bis(trifluoromethyl)diaziridines 2a–g have been obtained. In the reactions with more bulky amines, (S)-phenylalanine Et ester, (R, S)-α-phenylethyl amine and t-butyl amine, 1a acts as a tosylating reagent. The ester group in diaziridine 2e is readily saponified by alcoholic alkali, whereas diaziridine 2c is rearranged in these conditions with ring-expansion. Complete asymmetric transformation has been found to take place on the formation of the solid phase of diastereomers 2d and 2j, and a closed cycle of diastereomeric transformations has been accomplished. Diaziridine 2g with chiral centres only at the nitrogen atoms has been obtained with the optical purity of 85.5% by resolution via salt 5c with d-(+)-camphor-3-carboxylic acid. The absolute configuration of (+)-2g and its quaternary salt, (+)-2h, has been determined from CD spectra. Optically active (?)-2h salt (optical purity 2.0%) has been also obtained by asymmetric synthesis on the basis of 1–10-camphorsulphonyl oxime 1b. From the kinetics of 2g, h racemization and 2d, e, i, j, k epimerization the energy parameters of the inversion of N atoms in 3,3-bis (trifluoromethyl)diaziridines have been determined.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.     

Asymmetric catalysis. Part 153: Metal-catalysed enantioselective α-ketol rearrangement

Promoted by catalytic amounts of Ni complexes tertiary α-hydroxyketones 1a, 3a–5a undergo rearrangement, forming chiral isomers 1b, 3b–5b. The best enantioselection was obtained with the model system 1-benzoylcyclopentanol 4a/2-hydroxy-2-phenylcyclohexanone 4b. In a ligand screening 2-[4-(S)-tert-butyloxazolin-2-yl]pyridine gave the highest enantiomeric excess of 46% (S)-4b. The analogous isomerisation reactions of α-hydroxyimines 6a, 7a forming chiral α-aminoketones 6b, 7b were established.     

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

rac-α-Chlorocarboxylic acids, rac-9a–e, were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries (R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- and (S)-4, followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of (S)-α-chloropropanoic acid, a known precursor for the synthesis of (R)-α-aryloxypropanoic acid herbicides such as dichlorprop-P, (R)-3a, or mecoprop-P, (R)-3b, which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (αRS,3S)-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (αRS,3S)-6, by reaction with the corresponding phenoxide followed by mild acid hydrolysis.     

Preparation of (1R,8S)- and (1S,8R)-9-azabicyclo[6.2.0]dec-4-en-10-one: potential starting compounds for the synthesis of anatoxin-a

9-Azabicyclo[6.2.0]dec-4-en-10-one (±)-2, obtained from cyclooctadiene by addition of chlorosulfonyl isocyanate, was N-hydroxymethylated to (±)-3 and then resolved by lipase-catalysed asymmetric acylation of the primary OH group at the (S)-stereogenic centre. High enantioselectivity (E=94) was observed when lipase PS and vinyl butyrate were used in di-iso-propyl ether at −15°C, resulting in the enantiomerically enriched ester 3a and alcohol 3b (e.e. ≥92%). Treatment of 3a and 3b with NH₄OH/MeOH afforded the corresponding β-lactams (1R,8S)-2a and (1S,8R)-2b (e.e. ≥93%), potential starting compounds in anatoxin-a synthesis. The ring opening of lactams (±)-2, (±)-7, 3a and 3b, followed by reduction, resulted in racemic 4–6 and 8 and enantiomeric 4a, 4b, 5a and 5b eight-membered cyclic β-amino acid derivatives.     

Enantiopure erythro- and threo-1-aryl-1-[2-pyrrolidyl]-methanols: synthesis from l-proline

Enantiopure (1R,2S)-erythro- and (1S,2S)-threo-isomers of four new aryl-pyrrolidyl alcohols 5aH, 5aMe, 5bH and 5bMe have been obtained in five steps from (−)-(S)-proline and fully characterized. The oxidation of alcohol 8 into aldehyde 9 was the most difficult step and racemization occurs during Swern oxidation but this difficulty can be overcome by using SO₃/pyridine as oxidant. Diastereomer I of the protected amino alcohol 10a crystallized and was shown to be the (1R,2S)-erythro-isomer (e-10a-I) using X-ray crystallography. Therefore the (1R,2S)-erythro structure was assigned to all compounds obtained from e-10a-I, and, as a consequence, the (1S,2S)-threo structure was assigned to diastereomers II.     

Lipase mediated enantiomer and diastereomer separation of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols

Separation of diastereomeric and enantiomeric mixtures of 2,2′-[1,2- and 1,3-phenylenebis(oxy)]dicyclohexanols rac-3a and meso-3a, and rac-3b and meso-3b—resulting from the reactions of pyrocatechol 1a and resorcinol 1b with cyclohexene oxide 2—were performed using acetylation catalyzed by the highly stereoselective Candida antarctica lipase B (Novozym 435). The absolute configurations of the resulting diols (S,S,S,S)-3a,b, monoacetates (R,R,S,S)-4a,b and diacetates (R,R,R,R)-5a,b were assigned on the basis of the steric analogy to the acetylation of racemic trans-2-phenoxycyclohexanol rac-6 with the same enzyme resulting in the known acetate (−)-(R,R)-7.     

Reactions of β-substituted amines-IV: Kinetics and stereochemistry of the thermal to (r) 3-chloro-1-ethylpiperidine,and the stereo-chemical course of their reactions with nucleophiles

The rate of the thermal rearrangement of (S) 2 chloromethyl-1-ethylpyrrolidine [(S)-1a] to (R)-3-chloro-1-ethylpiperidine [(R) 2a] has been examined at three temperatures in benzene by PMR and polarimetry. The rearrangement was shown to be completely stereospecific and to obey a simple first order rate law. The calculated E_a ΔH3 and ΔS3 were 22 ± 2 $\text{kcal}\text{mole}$ (25°), 21 ± 2.5 $\text{kcal}\text{mole}$ (25°) and - 10 ± 2 e.u. (0°K) respectively. The effect of solvents having differing dielectric constants was also studied. A transition state 9'a and an ion pair intermediate 3a are suggested for the rearrangement. The stereochemical course of the reactions of (S)-1a, (R)-2a and (S)-2a with hydroxide and methoxide ions have been shown to be 100% stereospecific with an uncertainty of about 1%. The absolute configurations of all optically active reactants and products [(S)- and (R)-4a, (S)-4b (R)- and (S)-5a, (R)-5b, (S,S')-6a, (S,R')-7a and (R,R')-8a] were established by chemical correlations with known compounds or by ORD and chemical inference. The ring opening of both the primary and secondary aziridinium ion positions of 1-azonia-1-ethylbicyclo [3.1.0]hexane [(S)-3a] by nucleophiles proceeds entirely by S_N2 processes. The conversion of (R)-1-ethyl-3-hydroxypiperidine [(R)-5a] to (S)-2a. HCl with thionyl chloride in chloroform proceeds by inversion with 4.8% racemization, whereas the thermal rearrangement of (S)-1a to (R)-2a occurs with complete retention of absolute configuration.     

Asymmetric C–C bond forming reactions with chiral crown catalysts derived from d-glucose and d-galactose

New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O-benzylidene-α-d-glucopyranoside 2a, 2e, 2g–i and to methyl-4,6-O-benzylidene-α-d-galactopyranoside 3a, 3e, 3i have been synthesized. These crown ethers showed significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-nitropropane to chalcone (87% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (71% ee) and in the self-condensation of phenacyl chloride (64% ee) to give 14. The absolute configurations of (−)-(2R,3S)-epoxy-3-(4-chlorophenyl)-1-phenyl-1-propanone 12 and (−)-4-chloro-(2R,3S)-epoxy-1,3-diphenyl-1-butanone 14 have also been determined by X-ray diffraction.     

Optically active 1-(benzofuran-2-yl)ethanols and ethane-1,2-diols by enantiotopic selective bioreductions

Enantiotopic selective reduction of 1-(benzofuran-2-yl)ethanones 1a–d, 1-(benzofuran-2-yl)-2-hydroxyethanones 4a–c and 2-acetoxy-1-(benzofuran-2-yl)ethanones 3a–c was performed by baker's yeast for preparation of optically active (benzofuran-2-yl)carbinols [(S)-5a–d, (S)-6a–c and (R)-6a–c, enantiomeric excess from 55 to 93% ee].     

Synthesis of novel β-amino alcohols and their application in the catalytic asymmetric sulfoxidation of sulfides

Novel chiral norephedrine-based β-amino alcohol ligands containing a thiophene ring were prepared from norephedrine and substituted furan carbaldehydes (methyl- or ethyl-substituted) and used in combination with VO(acac)₂ for the asymmetric oxidation of aryl methyl sulfides using H₂O₂ as an oxidant. Amino alcohol derived Schiff bases 4,5a–b gave higher enantiomeric excesses than amino alcohol-derived reduced Schiff based ligands 6,7a–b. Of these chiral ligands, (1S,2R)-5b and (1S,2R)-7b gave high yields (90%) with moderate to high enantioselectivities (78%, 96% ee, respectively). The oxidation of other aryl methyl sulfides with (1S,2R)-5b and (1S,2R)-7b as ligands afforded the corresponding sulfoxides in 60–89% yields and with 92–99% ee.     

Practical and efficient synthesis of chiral 2,4-disubstituted oxazolines from β-phosphonoamides

Herein we report a practical and efficient method for the synthesis of optically active 2,4-disubstituted oxazolines (S)-1a–h in good to excellent yields. The target compounds were prepared in good yield through the Horner–Wadsworth–Emmons reaction of β-phosphonoamide 3 bearing l-phenylalaninol with commercially available aryl aldehydes followed by the cyclodehydration of the corresponding N-(cinnamoyl)-(S)-phenylalaninol derivatives (S)-2a–h. Additionally, the cyclodehydration of β-phosphonoamide (S)-3 followed by the Horner–Wadsworth–Emmons reaction of β-phosphono-oxazoline (S)-4 with aryl aldehydes also gave the 2,4-disubstituted oxazolines (S)-1a–h.     

Enantioselective Michael addition of 2-nitropropane to chalcone analogues catalyzed by chiral azacrown ethers based on α-d-glucose and d-mannitol

The chiral monoaza-15-crown-5 type lariat ethers 1 and 2 derived from α-d-glucose and from d-mannitol, respectively, have been applied as phase transfer catalysts in the enantioselective Michael addition of 2-nitropropane to aromatic 3b–c and heteroaromatic 3d–h chalcone analogues. Among the catalysts, the glucose-based 1c with a phosphinoxidobutyl side arm proved to be the most effective, it inducing 34% e.e. for 4b, 59% e.e. for 4c, 80% e.e. for 4d, 64% e.e. for 4e, 17% e.e. for 4f. Catalyst 1a having 3-hydroxypropyl substituent resulted in 81% e.e. for compound 4g. The formation of the (+)-(S)-enantiomer of 4 was preferred using crown ethers 1a–c, while the (−)-(R)-enantiomer was in excess with catalyst 2. The absolute configuration of the Michael adduct 4d was determined by single-crystal X-ray analysis.     

Synthese von 1-Ary1-4-methylthio-2-azetidinonen

TheN-arylthioformimidates4 a-e, which may be obtained byS-alkylation of the thioformanilides3 a-e, react with chloroacetylchloride/triethylamine to yield the (3R,4S/3S,4R)-1-aryl-3-chloro-4-methylthio-2-azetidinones5 a-e and the formanilides6 a-e. Dehalogenation of5 b-e with tri-n-butyltinhydride yield the title compounds7 b-e. Hydrogenolysis of7 b and7 c yields7 f and7 g.

     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

Complementary kinetic and thermodynamic resolution of a chiral biaryl axis

The condensation of 2′-formylbiphenyl-2-carboxylic acid 4 with (S)-valinol proceeds under kinetic control to give a major product, (4bR,7S,aS)-6,7-dihydro-7-isopropyldibenz[c,e]oxazolo[3,2-a]azepin-9(4bH)-one 6a (84%), in which the biaryl axis has the (S)-configuration. Heating 6a at 140°C with a catalytic amount of acid gives rise to an equilibrium dominated by the diastereoisomeric (4bS,7S)-lactam 6b (6a:6b ratio 27:73), in which the biaryl unit has the (R)-configuration. The structures of both lactams were established by X-ray crystallography; no other diastereoisomers were obtained.     

An efficient substituent dependent synthesis of congested pyridines and pyrimidines

An efficient and versatile synthesis of various congested pyridines 3a-h, 6a,b, 8a-n, 10a-g, and 16a,b, and (pyrimidin-4-yl)acetonitriles 13a-g has been delineated by base catalyzed ring transformation of suitably functionalized 2H-pyran-2-ones 1a-h, 5, 7, and 15 by formamidine acetate 2a, acetamidine hydrochloride 2b, S-methylisothiourea 9a, pyrazol-1-yl-carboxamidine 9b, and arylamidine hydrochloride 12 separately in the presence of powdered KOH in dry DMF.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.