Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids

New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,2′-diamino-1,1′-binaphthyl and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with NaBH₄ and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained from (1R, 2R)- or (1S, 2S)-1,2-diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macrocycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were tested as chiral shift reagents (chiral solvating agents) for various α-substituted carboxylic acids, including non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate ¹H NMR signals was observed with ΔΔδ values up to 0.1 ppm.     

Asymmetric allylation of N-benzoylhydrazones promoted by novel C2-symmetric bis-sulfoxide organocatalysts

Novel C₂-symmetric bis-sulfoxide/N-oxide (R,R)-5 was prepared in good yield according to the Andersen protocol with (S)-menthyl p-tolyl sulfinate (2 equiv) and the dilithium derivate of 2,6-dimethylpyridine N-oxide. Reduction of (R,R)-5 to pyridine/bis-sulfoxide (R,R)-6 was accomplished by means of Katritzky’s procedure (Fe⁰/AcOH). Both bis-sulfoxides (R,R)-5 and (R,R)-6 are efficient chiral organocatalysts in the asymmetric allylation of N-benzoyl hydrazones derived from both aldehydes and ketones.     

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%.     

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.     

Synthesis of novel optical isomers of α-methylpolyamines

Earlier unknown (R)- and (S)-α-methylspermidine, (R)- and (S)-α-methylspermine, (R,R)-, (S,S)-, and (R,S)-α,ω-dimethylspermine were synthesized in gram scale from readily available (R)- and (S)-2-aminopropanols in high overall yields.     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

Five novel sensors (R,R)-3–6 and (S, S)-6 were synthesized and developed for enantioselective recognition of chiral compounds. Sensor 6 with two thiourea groups and steric π-conjugation frameworks could discriminate different chiral substrates, including acidic compounds, basic compounds, and neutral compounds. These results disclosed that the outstanding performance of enantioselective discrimination could be attributed to the thiourea group which acted as a hydrogen-bonding donor and the bulky steric moiety of the hosts which provided appropriate chiral environment. This result will be of great practical value in the designation of chiral sensors and high-throughput assay of chiral products.     

Synthesis of oligomers including eight P-chiral centers and the construction of the 12-phosphacrown-4 skeleton

The stepwise oxidative coupling reaction from (S,S)-1 gave optically active oligomers, (S,R,R,S)-2 and (S,R,S,R,R,S,R,S)-3, having four and eight chiral phosphorus atoms, respectively. The behaviors of these oligomers in the solid state and in solution were investigated in detail. The first construction of a 12-phosphacrown-4 skeleton was also reported.     

Synthesis of BINOL-containing oxacalix[4]arenes

Unprecedented chiral oxacalixarenes were obtained from the reaction of (±)-1,1′-binaphthyl-2,2′-diol (BINOL) with 1,5-difluoro-2,4-dinitrobenzene. Structural elucidation of C_2h-symmetric meso (R,S)-oxacalix[4]arene and D₂-symmetric racemic (as well as enantiopure) (R,R)- and (S,S)-oxacalix[4]arene was carried out by means of 1D and 2D NMR spectroscopy, ESI-MS, X-ray diffractometry, and circular dichroism spectroscopy.     

Further monoterpene chromane esters from Peperomia obtusifolia: VCD determination of the absolute configuration of a new diastereomeric mixture

A reinvestigation of the monoterpene chromane ester enriched fraction from Peperomia obtusifolia using chiral chromatography led to the identification of a minor peak, which was elucidated by NMR and HRMS as fenchyl-3,4-dihydro-5-hydroxy-2,7-dimethyl-8-(3″-methyl-2″-butenyl)-2-(4′-methyl-1′,3′-pentadienyl)-2H-1-benzopyran-6-carboxylate, the same structure assigned to two other fenchyl esters described previously, pointing out a stereoisomeric relationship among them. Further NMR analysis revealed that it was actually a mixture of two compounds, whose absolute configurations were determined by VCD measurements. Although, almost no vibrational transitions could be assigned to the chiral chromane, the experimental VCD spectrum was largely opposite to that obtained for the average experimental VCD [(2S,1?R,2?R,4?S + 2R,1?R,2?R,4?S)/2] for fenchol derivatives. These results allowed us to assign the putative compounds as a racemic mixture of the chiral chromane esterified with the monoterpene (1S,2S,4R)-fenchol, which had not been identified in our early work.     

Highly diastereoselective alkylation of vicinal dianions of chiral succinic acid derivatives: a new general strategy to (R)-β-arylmethyl-γ-butyrolactones

The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione react with arylmethyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral α-arylmethylated succinic acid derivatives; the (R)-products are converted into (R)-β-arylmethyl-γ-butyrolactones and (R)-α-arylmethyl-γ-butyrolactones.     

Stereoselective synthesis of 10,14-dimethyloctadec-1-ene, 5,9-dimethyloctadecane, and 5,9-dimethylheptadecane, the sex pheromones of female apple leafminer

The stereoselective synthesis of (10R,14R)-10,14-dimethyloctadec-1-ene (1), (5R,9R)-5,9-dimethyloctadecane (2), and (5R,9R)-5,9-dimethylheptadecane (3) the sex pheromone components of female apple leafminer was accomplished by reductive elimination tosyl and isonitrile groups of dialkylated tosylmethyl isonitrile. The key steps involved were dialkylation of TosMIC with 1-iodo 2-methyl alkanes, which were derived from Evan's alkylation of chiral auxiliary and subsequent reduction.     

Chiral nitrogen-containing calix[4]crown—an excellent receptor for chiral recognition of mandelic acid

A chiral nitrogen-containing calix[4]crown 2 bearing optically pure 1,2-diphenyl-1,2-oxyamino residue at lower rim showed excellent chiral recognition between enantiomers of mandelic acid. Using competitive ¹H NMR titration the ratio of association constants of (S)- and (R)-mandelic acid with the chiral calix[4]crown was determined to be 102, that is 98% de, which is the best result obtained from artificial receptors for the chiral recognition of mandelic acid up to now.     

The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (−)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.     

Lipase immobilized on HOOC-MCF： A highly enantioselective catalyst for transesterification resolution of （R,S）-1-phenylethanol

Pseudomonas cepacia lipase (PSL) immobilized on the carboxyl-functionalized meso-cellular foams (HOOC-MCF) was used for the transesterification resolution of (R,S)-1-phenylethanol in organic solvent.The results showed that the ee value of (S)-1- phenylethanol and (R)-1-phenylethyl acetate reached 99% with 50% conversion of 1-phenylethanol using toluene as solvent. Furthermore,it was found that PSL/HOOC-MCF exhibited high enantioselectivity in organic solvent with log P≤2 such as toluene and hexane.     

Assignment of the relative and absolute configurations of acyclic secondary 1,2-diols

The NMR profiles (¹³C-δ, ¹H-δ, ¹H(OH)-δ, and ³J_H,H) of syn- and anti-diols—3a,b in achiral solvents were found to be very similar to each other. Contrarily, their Δδ (Δδ=δ_(R,R)-2−δ_(S,S)-2) behaviors in chiral bidentate NMR solvent (R,R)- and (S,S)-BMBA-p-Me (2) were found to be significantly different. On the basis of this NMR characteristic, a method has been developed to predict both the relative and absolute configurations of acyclic secondary 1,2-diols.     

Chiral Carbon Nanorings: Synthesis,Properties and Hierarchical Self-assembly of Chiral Ternary Complexes Featuring a Narcissistic Chiral Self-Recognition for Chiral Amines

We report the synthesis and chiroptical properties of novel chiral carbon nanorings S p-/Rp-[12]PCPP containing a planar chiral [2.2]PCP unit, and demonstrate that S p-/Rp-[12]PCPP can not only host crown ether 18-Crown-6 to form ring-in-ring complexes with a binding constant 3.35×10³ M⁻¹, but also accommodate the complexes of 18-Crown-6 and S/R-protonated amines to form homochiral S @Sp -/ R @Rp - and heterochiral S @Rp -/ R @Sp - ternary complexes, displaying significantly larger binding constants of up to 3.31×10⁵ M⁻¹ depending on the chiral guests. Importantly, homochiral S @Sp -/ R @Rp - ternary complexes exhibit an enhanced CD signal, while the heterochiral S @Rp -/ R @Sp - ones have a constant CD signal compared with the chiral carbon nanorings, respectively, which suggests that homochiral S @Sp -/ R @Rp - ternary complexes display a highly narcissistic chiral self-recognition for S/R-protonated chiral amines, respectively. Finally, the chiral ternary complexes can be further applied to determine the ee values of chiral guests. The findings highlight a new application of carbon nanorings in supramolecular sensors, beyond the common recognition of π-conjugated molecules.     

Enantioselective diethylzinc addition to aromatic and aliphatic aldehydes using (3R,5R)-dihydroxypiperidine derivatives catalyst

A series of chiral (3R,5R)-dihydroxypiperidine derivatives 3a-f were conveniently prepared from trans-4-hydroxy-l-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal. Among them, 3d was found to show the best asymmetric induction in promoting the addition of Et₂Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee.     

Highly stereoselective titanium-mediated aldol reactions from chiral α-silyloxy ketones. A reliable tool for the synthesis of natural products

Chiral α-silyloxy ketones participate in highly stereoselective TiCl₄-mediated aldol reactions that afford diastereomerically pure syn-syn adducts in high yield irrespective of the R¹ and R² substituents flanking the carbonyl or the silicon protecting group. Further manipulation of the resulting aldol adducts provide in a straightforward manner highly functionalized fragments that facilitate the synthesis of natural products.     

Analogues of the Quararibea metabolite chiral enolic-γ-lactone from (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids

Reaction of dialkyl (2S,3S)- or (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylates with POCl₃ in pyridine followed by diazomethane resulted in the isolation of dialkyl 2S-4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarboxylates, which are analogues of the Quararibea metabolite chiral enolic-γ-lactone (3-hydroxy-4,5-(R)-dimethyl-2(5H)-furanone). An unusual α-hydroxylation of γ-butyrolactone takes place involving POCl₃ in pyridine. When the dehydration was facilitated with methanesulfonyl chloride in triethylamine, instead of POCl₃, aromatic dialkyl 5-[(methylsulfonyl)oxy]-2,3-furandicarboxylates were obtained.     

A concise and efficient route to the Alzheimer's therapeutic agent (R)-arundic acid

A short and efficient procedure for the preparation of (R)-arundic acid, a therapeutic agent for the treatment of Alzheimer's disease, has been developed. Based on cheap and commercially available (1R)-(+)-camphor as the source of chiral information, (R)-arundic acid is synthesized in a four-step cyclic sequence with 55% overall yield and high optical purity, ≥98% ee. Alkyl halide and acetylene constitute the only consumable carbon sources of this method, which allows obtaining of both enantiomers and recycling of chiral auxiliary.