Comparison of chiral NMR solvating agents for the enantiodifferentiation of amines

Chiral, enantiomerically pure organic-soluble acids are often used as NMR chiral solvating agents (CSAs) for analyzing the enantiopurity of amines. However, the reports that describe CSAs for amines provide limited comparisons to other previously reported reagents. As such, it is difficult to know which among the many CSAs to pick when studying a new amine. We report a comparison of thirteen commercially available CSAs for the analysis of primary, secondary and tertiary amines in chloroform-d. (R)-α-methoxyphenylacetic acid, (R)-(-)-O-acetylmandelic acid, (R)-2-methoxy-2-(1-naphthyl)propionic acid and (R)-(-)-1,1′-binaphthyl-2,2′-diylhydrogenphosphate are identified as the best four to use as a starting point for the analysis of a new amine.     

Arthrobacter sp.: a lipase of choice for the kinetic resolution of racemic arylazetidinone precursors of taxanoid side chains

The native strain of Arthrobacter sp. (MTCC 5125) bearing a lipase has been found to be the most effective in the kinetic resolution of racemic arylazetidinones for producing cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-phenyl-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thienyl)-2-azetidinone, and cis-3-acetoxy-4-(t-butyl)-2-azetidinone products. The resolved compounds, which were obtained in high enantiopurity are important intermediates of amino acid side chains of paclitaxel as well as a new generation of taxanoids. The use of co-solvents dramatically improved the resolution efficacy of the lipase.     

Optimisation of a key cross-coupling reaction towards the synthesis of a promising antileishmanial compound

During the course of a research program aimed at identifying novel antileishmanial compounds, a multi-gram synthesis of N-(trans-4-((4-methoxy-3-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)-2-methylpropane-1-sulfonamide ((R)-1) was required. This letter describes optimisation of the reaction conditions and protecting group strategy for a key Buchwald-Hartwig coupling, delivering the required quantities of (R)-1, as well as further compounds in the series.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Solution-processed red iridium complexes based on carbazole-phenylquinoline main ligand: Synthesis, properties and their applications in phosphorescent organic light-emitting diodes

New carbazole-phenylquinoline (CVz-PhQ) based iridium complexes were designed and synthesized for their application in red phosphorescence organic light-emitting diodes (PhOLEDs) and their photophysical, electrochemical and electroluminescence (EL) properties were investigated. The PhOLEDs were fabricated using bis[9-(2-(2-methoxyethoxy)ethyl)-3-(4-phenylquinolin-2-yl)-9H-carbazolato-N,C2′]iridium 2-pyrazinecarboxylic acid (EO-CVz-PhQ)₂Ir(prz) and bis[9-(2-(2-methoxyethoxy)ethyl)-3-(4-phenylquinolin-2-yl)-9H-carbazolato-N,C2′]iridium 5-methyl-2-pyrazinecarboxylic acid (EO-CVz-PhQ)₂Ir(mprz) as the emitter and PVK, co-doped with OXD-7 as the electron transport material and TPD as the hole transport material, as the polymer host. The red emissive PhOLEDs, based on the ITO/poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS)/4,4′,4″-tris(carbazole-9-yl)triphenylamine (TCTA)/poly(N-vinylcarbazole) (PVK):N,N′-diphenyl-N,N′-(bis(3-methylphenyl)-[1,1-biphenyl]-4,4′-diamine (TPD):1,3-bis[5-(4-tert-butylphenyl)-1,3,4-oxadiazole-2-yl]benzene (OXD-7):Ir complex/cathode configuration, exhibited a maximum external quantum efficiency of 3.68% and a maximum luminance efficiency of 6.69 cd/A. Furthermore, by introducing a TCTA interlayer, the PhOLEDs showed only a slight efficiency roll off of 5.4% from a low current density (1.81 mA/cm²) to a high current density (44.59 mA/cm²).     

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

Enantioselective syntheses of tert-butyl ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate and ((S)-2-(3,5-difluorophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate are described. We utilized asymmetric syn- and anti-aldol reactions to set both stereogenic centers. We investigated ester-derived Ti-enolate aldol reactions as well as Evans’ diastereoselective syn-aldol reaction for these syntheses. We have converted optically active ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate to a potent β-secretase inhibitor.     

Stereoselective carbon–carbon bond forming reactions of chiral cyclopent-2-enone and cyclopentene-1-methanol,both spiro-connecting a 1,2:5,6-di-O-isopropylidene-α-d-glucofuranosyl ring

The conjugate additions of a variety of organocopper reagents or dimethyl malonate anion to a spirocyclic cyclopent-2-enone connecting a 1,2:5,6-di-O-isopropylidene-α-d-glucofuranosyl ring as a constituent of the spiro structure, namely (1S,3R,4R,5R)-3,4-(isopropylidenedioxy)-1-[(1R)-1,2-(isopropylidenedioxy)ethyl]-2-oxa-spiro[4.4]non-6-en-8-one, proceeded stereoselectively in some cases affording a variety of β-functionalized cyclopentanone derivatives. The thermal treatment of (1S,3R,4R,5R)-7-(hydroxymethyl)-3,4-(isopropylidenedioxy)-1-[(1R)-1,2-(isopropylidenedioxy)ethyl]-2-oxaspiro[4.4]non-6-ene, another d-glucose-derived spirocyclic substrate, with triethyl orthoacetate in the presence of a catalytic amount of acid afforded the Claisen rearrangement product with a high level of diastereoselectivity.     

Two additional 1,9-diarylnonanoid 3-glucosides from Erica cinerea among which an unusual α-dione in conformational equilibrium

Continuation of the phytochemical analysis of Erica cinerea fresh aerial parts resulted in the isolation of two new compounds with a very close chromatographic behavior. On the basis of spectroscopic evidence (UV, MS and NMR), the structures were established as (−)-(3S,6E)-1,9-bis(p-hydroxyphenyl)-3-hydroxynon-6-en-5-one 3-O-β-d-glucoside named 6,7-anhydroericaone 3-O-β-d-glucoside and (−)-(3S)-1,9-bis(p-hydroxyphenyl)-3-hydroxynonan-5,6-dione 3-O-β-d-glucoside named α-ericadione 3-O-β-d-glucoside. Unanticipated by its α-alkadione type structure —a very unusual feature in the plant kingdom— the latter metabolite was found as a mixture of the minor s-cis and the major s-trans conformers. Moreover, the GC-MS analysis of the aglycone moieties of such glucosides, pointed out the permanent absence of the molecular ion and the constant hydroxybenzylium base peak, as well as the conversion of the α-dione into the major α-keto-enol tautomer.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

Synthesis of a d,d- and l,d-heptose-containing hexasaccharide corresponding to a structure from Haemophilus ducreyi lipopolysaccharides

The synthesis of a linear hexasaccharide, 2-(4-trifluoroacetamidophenyl)ethyl (β-d-galactopyranosyl)-(1→4)-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-(β-d-galactopyranosyl)-(1→4)-(d-glycero-α-d-manno-heptopyranosyl)-(1→6)-(β-d-glucopyranosyl)-(1→4)-l-glycero-α-d-manno-heptopyranoside, corresponding to a structure found in Haemophilus ducreyi LPS, is described. A Barbier reaction between benzyloxymethyl chloride and a properly protected 6-aldo-1-thio-mannopyranoside yielded both the d,d- and the l,d-heptopyranoside (2 and 3, ratio 2:3), which were separated and both used in the synthesis. p-Methoxybenzyl and chloroacetyl groups were employed as temporary protecting groups, selectively removed in the presence of the persistent benzyl, acetyl, benzoyl and isopropylidene groups by treatment with DDQ/H₂O and hydrazine dithiocarbonate, respectively. Thioglycosides were utilised as donors throughout using either NIS/TfOH or DMTST as promoters. The introduction of the spacer into thioglycoside 5 was high-yielding (95%) but with low stereoselectivity (α:β 5:3). All other glycosylations are completely stereoselective. The target hexasaccharide is obtained via a 3+3 block approach with the yield in the final NIS/TfOH-promoted coupling between an N,N-diacetyl-trisaccharide thioglycosyl donor 20 and a 4′′-OH trisaccharide acceptor 13 being 75%.     

Highly enantioselective α-sulfenylation of 5H-oxazol-4-ones to N-(sulfanyl)succinimides

An unprecedented asymmetric α-sulfenylation of 5H-oxazol-4-ones to N-(sulfanyl)succinimides has been established, to access various α-sulfenylated adducts with good to excellent enantioselectivities (86–95% ee) by utilizing a cinchona alkaloid-derived squaramide as catalyst. The conditions of this α-sulfenylation protocol simultaneously satisfy N-(arylthio)succinimides, N-(benzylthio)succinimides, and N-(alkylthio)succinimides by tuning the substituted groups of 5H-oxazol-4-ones on the 2-position as well as additives.     

Asymmetric synthesis of (+)-trachyspic acid

Aldol reaction of di-tert-butyl 4-(4-methoxybenzyloxy)-2-oxobutanoate with pent-4-enal using (S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-ylmethyl)thiourea hydrochloride as a catalyst, followed by Pinnick oxidation and tert-butyl esterification, gave (2S,3S)-di-tert-butyl 2-(2-(4-methoxybenzyloxy)ethyl)-3-allyl-2-hydroxysuccinate in high optical purity (85% ee), from which the total synthesis of (+)-trachyspic acid, a tumor cell heparanase inhibitor, was accomplished.     

Synthesis and conformational and configurational studies of diastereoisomeric O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols

Chiral sulfoximines have applications as transition-state mimicking enzyme inhibitors, as peptide isosteres and as chiral auxiliaries in synthesis. To access the required O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols, 4S,5S-di(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (prepared from diethyl R,R-tartrate) was converted into its monobenzyl ether. Mitsunobu-like coupling with thiophenols gave 4S,5R-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylthiomethyl)-1,3-dioxolanes. Sulfoxidation and S-imination (trifluoroacetamide, iodosobenzene diacetate, rhodium acetate) proceeded without stereoselectivity, giving inseparable diastereomeric mixtures of 4S,5R,S(±)-4-(benzyloxymethyl)-2,2-dimethyl-5-(N-(trifluoroacetyl)arylsulfonimidoylmethyl)-1,3-dioxolanes. Removal of the trifluoroacetyl protection allowed chromatographic separation of the diastereomeric 4S,5R,S(±)-4-(benzyloxymethyl)-2,2-dimethyl-5-(arylsulfonimidoylmethyl)-1,3-dioxolanes. The configurations at sulfur were determined by X-ray crystallography and some analysis of the solution and solid-state conformations was carried out. The resulting O-protected 4-(arylsulfonimidoyl)butane-1,2,3-triols are of use in developing enzyme inhibitors.     

Poly(1,3,4-oxadiazole-imide)s containing dimethylsilane groups

New poly(1,3,4-oxadiazole-imide)s containing dimethylsilane units have been prepared by solution polycondensation reaction of an aromatic dianhydride incorporating dimethylsilane group, namely bis(3,4-dicarboxyphenyl)dimethylsilane dianhydride, with different aromatic diamines having preformed 1,3,4-oxadiazole ring, such as 2,5-bis(p-aminophenyl)-1,3,4-oxadiazole, 2,5-bis[p-(4-aminophenoxy)phenyl]-1,3,4-oxadiazole, 2,5-bis[p-(3-aminophenoxy)phenyl]-1,3,4-oxadiazole, 2-(4-fluorophenyl)-5-(3,5-diaminophenyl)-1,3,4-oxadiazole, and 2-(4-dimethylaminophenyl)-5-(3,5-diaminophenyl)-1,3,4-oxadiazole. The polymers were easily soluble in polar organic solvents, such as N-methylpyrrolidinone, N,N-dimethylformamide, and pyridine, as well as in less polar organic solvents, such as tetrahydrofuran and chloroform. Very thin coatings deposited on silicon wafers exhibited smooth, pinhole-free surface in atomic force microscopy investigations. The polymers showed high thermal stability with decomposition temperature being above 415 °C.They exhibited a glass transition in the temperature range of 202-282 °C, with reasonable interval between glass transition and decomposition temperature. Solutions of the polymers in N,N-dimethylformamide exhibited fluorescence, having maximum emission wavelength in the range of 353-428 nm.     

Measurement and Identification of (R)- and (S)-6-O-Desmethylnaproxen Enantiomers as Diastereomeric O-Ethoxycarbonyl/(R)-(+)-1-Phenylethylamides in Urine by GC and GC-MS

Enantioseparations of (R)- and (S)-6-O-desmethylnaproxens as O-ethoxycarbonyl/(R)-(+)-1-phenylethylamides and (R)- and (S)-naproxens as (R)-(+)-1-phenylethylamides were achieved by achiral gas chromatography in a single run within 11 min. The characteristic mass spectral patterns facilitated easier peak identification. The method for determinations of (R)-naproxen (1.0 to 50 ng) and (S)-naproxen (100 to 2000 ng) was linear with acceptable repeatability and accuracy. The enantiomeric composition ratios between (R)- and (S)-6-O-desmethylnaproxens and between (R)- and (S)-naproxens in urine sample collected six hours after oral administration of (S)-naproxen tablets were measured to be 2.2 (± 0.2):97.8 (± 0.2) and 2.1 (± 0.1):97.9 (± 0.1), respectively.     

An efficient and stereoselective synthesis of (3S,4R)-(−)-trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

An asymmetric conjugate addition reaction between a chiral α,β-unsaturated amido ester and ethyl-N-methylmalonamide has been used as a key step in the synthesis of (3S,4R)-(−)-trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine, a key intermediate for (−)-paroxetine.     

Mn(III) salen complexes-catalyzed enantioselective addition of trimethyl silylcyanide to N-benzylimines in the presence of 4-phenyl pyridine-N-oxide as an additive

Chiral monomeric and dimeric Mn(III) salen complexes viz., [(S,S)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato manganese(III) chloride and 5,5-methylene di-[(S,S)-{N-(3-tert-butyl salicylidine)-N′-(3′,5′-di-tert-butyl salicylidene)}-1,2-cyclohexanediaminato manganese(III) chloride were used as catalysts for the highly enantioselective Strecker reaction of various imines (derived by the condensation of aldehydes and amine) with TMSCN as a source of cyanide in toluene. Excellent yield (95%) of α-amino nitrile with ee >99% was achieved when N-(2-methoxybenzylidine)-1-phenylmethanamine was used as a substrate and 4-phenyl pyridine-N-oxide (4-PPNO) as an additive at ?55 °C in 28 h. The dimeric catalyst was found to be more reactive and enantioselective than the monomeric catalyst. The chiral dimeric catalyst used in the present study was recoverable and recyclable several times with retention of its performance.     

Synthesis of phosphorylated Neisseria meningitidis inner core lipopolysaccharide structures

A phosphoethanolamine-substituted tetrasaccharide structure, 2-aminoethyl 2-acetamido-2-deoxy-α-d-glucopyranosyl-(1→2)-6-O-[2-(tert-butyloxycarbonylaminoethyl)-phosphono]-l-glycero-α-d-manno-heptopyranosyl-(1→3)-[β-d-glucopyranosyl-(1→4)]-l-glycero-α-d-manno-heptopyranoside, corresponding to the non-reducing part of the conserved part of Neisseria meningitidis lipopolysaccharides has been synthesized. Orthogonal protection of the phosphoethanolamino group in combination with the presence of a free amino-containing anomeric spacer allows conjugation to proteins to construct conjugate vaccine candidates. The tetrasaccharide is built up using a linear strategy, where the introduction of the terminal α-GlcNAc moiety is performed using a 2-azido-thioglucoside as a donor and NIS/AgOTf as a promoter. The synthetic pathway includes tetrasaccharide intermediates appropriately designed to permit other phosphorylation patterns as well as elongation at the reducing end.     

Synthesis of (E)-2-(1-ferrocenylmethylidene)malonic acid derivatives by a cobalt-catalyzed domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines

The domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines was investigated in the presence of Co₂(CO)₈ as catalyst. In most cases the main products are 2-(1-ferrocenylmethylidene) malonates formed by an N(1)-C(4) cleavage of the primarily derived β-lactams. The latter compounds could only be isolated when the reaction was carried out at relatively low CO pressure, using an excess of ethyl diazoacetate. trans-N-(tert-Butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam proved to be the most stable one among these compounds and could be isolated in 55% yield. N-alkyl β-lactams were shown to undergo acidic cleavage leading to the E isomers of 2-(1-ferrocenylmethylidene) malonates as the main products. The structures of the two new compounds, (E)-2-ethoxycarbonyl-3-ferrocenyl-N-((R)-1-phenylethyl)-2-propenamide and trans-N-(tert-butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam were confirmed by X-ray crystallography. The relative thermodynamical stability of the products as well as the energetics of the acid-mediated cleavage of the β-lactam ring was elucidated with DFT calculations.     

An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.