Hexabromide salt of a tiny octaazacryptand as a receptor for encapsulation of lower homolog halides: structural evidence on halide selectivity inside the tiny cage

Tiny azacryptand 1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane (L) upon reaction with 48% hydrobromic acid (containing <0.05% chloride contamination) forms hexabromide salt (1). Single crystal X-ray crystallographic investigation of the hexaprotonated bromide (1) shows no guest encapsulation inside the tiny cage. This bromide salt 1 with an empty proton cage has been utilized as the receptor for encapsulation of chloride (2) and fluoride (3). Crystallographic results of mixed chloride/bromide (2) and fluoride/bromide (3) complexes of L are examined, which show monotopic recognition of chloride in the case of 2 and fluoride in the case of 3 inside the proton cage with five bromide and three water molecules outside the cavity. Single crystals obtained from an experiment on mixed anionic system (chloride and fluoride), 1 shows selective encapsulation of fluoride, which supports the formation of complex 3 and crystals obtained upon treatment of 2 with tetrabutyl ammonium fluoride also yields complex 3. In a separate reaction between L and 49% hydrobromic acid containing higher chloride contamination (<0.2%) forms chloride/bromide salt (2). ¹H NMR studies of 1 with sodium chloride and fluoride support the encapsulation of the respective anions inside the proton cage.     

Synthesis of ionic liquids functionalized β-cyclodextrin-bonded chiral stationary phases and their applications in high-performance liquid chromatography

Four novel ILs functionalized β-cyclodextrins (β-CDs) were prepared by treating 6-tosyl-β-cyclodextrin with 1,2-dimethylimidazole or 1-amino-1,2,3-triazole, and bonded to silica gel to obtain chiral stationary phases (CSPs) to be used in high-performance liquid chromatography (HPLC). The separation performances of these CSPs were examined with 16 chiral aromatic alcohol derivatives and 2 racemic drugs in acetonitrile-based polar-organic mobile phase. Excellent enantioseparations were achieved for most of the analytes. The highest value of resolution factor calculated is 6.868. Comparison of the performance of 8a, 8b, 8c and 8d suggests that the positively charged imidazole group provides electrostatic interactions probably through strong H-bonding with the analytes, whereas the cationic triazole, which forms a weaker ion pair with its counter ion, is more capable of participating in ion-pairing interactions with acidic analytes. However, for compounds 12 and 13, which have larger molecular volumes than the other analytes, the interactions between analytes and both cationic imidazole and its counter ion of the selectors play an important role in the chiral resolution. Moreover, the high resolutions were found to depend on the properties of the cations and anions on the selectors in combination with the chiral recognition sites on the rim of the CD. The ionic strength in mobile phase affects the relative interactions between analytes and the chiral selector as well as between analytes and solvents.     

Total synthesis of apigenin 7,4′-di-O-β-glucopyranoside, a component of blue flower pigment of Salvia patens, and seven chiral analogues

We have succeeded in the first total synthesis of apigenin 7,4′-di-O-β-d-glucopyranoside (1a), a component of blue pigment, protodelphin, from naringenin (2). Glycosylation of 2 according to Koenigs-Knorr reaction provided a monoglucoside 4a in 80% yield, and this was followed by DDQ oxidation to give apigenin 7-O-glucoside (12a). Further glycosylation of 4′-OH of 12a with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl fluoride (5a) was achieved using a Lewis acid-and-base promotion system (BF₃·Et₂O, 2,6-di-tert-butyl-4-methylpyridine, and 1,1,3,3-tetramethylguanidine) in 70% yield, and subsequent deprotection produced 1a. Synthesis of three other chiral isomers of 1a, with replacement of d-glucose at 7 and/or 4′-OH by l-glucose (1b-d), and four chiral isomers of apigenin 7-O-β-glucosides (6a,b) and 4′-O-β-glucosides (7a,b) also proved possible.     

Reaction of quinidine acetate, epiquinidine and its acetate in superacid: formation of gem-difluoro derivatives with or without rearrangement

In HF-SbF₅, quinidine 1a or its dihydrochloride cyclises previously obtained with usual acids. A similar reaction is observed in the presence of CCl₄. Under similar conditions quinidine acetate 1b and epiquinidine acetate 2b dihydrochlorides both yield 10,10-difluoro derivatives epimeric at C-3, 6 and 7, and 9c and 10b, and a rearranged difluoro derivative 8b and 11b, respectively. Epiquinidine 2a leads to the expected analogues 10a and 11a and to a ketone 9a. Formation of gem-difluoro compounds implies chloro intermediates at C-10, precursors of α-chlorocarbenium ions, which are trapped by a fluoride ion and which lead by halogen exchange to the products.     

Effect of the rigidity and flexibility features of 2-pyridinyl or 8-quinolinyl based N-N chiral ligands on the stereochemical properties of [Pd(N-N)Cl2] complexes

The [Pd(N-N^∗)Cl₂] complexes have been obtained, as yellow solids, in almost quantitative yields; N-N^∗ indicate bidentate chiral ligands (S_a)-1, (S_a)-2, (S,S)-3, (R,R)-4, containing the rigid 2-pyridinyl or 8-quinolinyl building block skeleton and the C₂-symmetric chiral framework trans-2,5-dimethylpyrrolidinyl or (S)-(+)-2,2′-(2-azapropane-1,3-diyl)-1,1′-binaphthalene. The ligands pairs have the same C₂-symmetric chiral framework but different building block skeleton, beyond that for the basicity in the N-donor atoms, for rigidity and flexibility features. The N-N^∗ ligands act as chelating ligands leading a square planar geometry. The compounds [Pd(S,S-3)Cl₂] and [Pd(R,R-4)Cl₂] have been also characterised by X-ray diffraction. The rigidity and flexibility features of (S,S)-3 and (R,R)-4 ligands induce a different orientation of the trans-2,5-dimethylpyrrolidinyl moiety with respect to the pyridinyl and quinolinyl plane. This work shows that intrinsic rigidity and flexibility are not enough to define the ligand properties and to preview the effects that they induce on the reactivity of the metal complex.     

Conformational chirality and chiral crystallization of N-sulfonylpyrimidine derivatives

New N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)uracil (1), 1-(p-toluenesulfonyl)thymine (2), 5-bromo-1-(p-toluenesulfonyl)uracil (3), 1-(methanesulfonyl)uracil (4), 1-(1-naphthylsulfonyl)uracil (5), and 1-(1-naphthylsulfonyl)thymine (6) were prepared by the condensation reaction of silylated pyrimidine derivatives with selected sulfonyl chlorides in acetonitrile. Some members of the series showed unexpected crystal properties as a consequence of their conformational chirality in the solid state. Compounds 1 and 5 exhibited chiral crystallization, which was, in the case of 1, accompanied by the formation of racemically twinned crystals regardless of the solvent used, while 5 gave a conglomerate of enantiomorphous crystals. For 2, 3, and 6, substituents at the C-5 position of the pyrimidine ring prevented chiral crystallization by influencing the crystal packing. Analysis of the crystal structures of 1, 4, and 5, reveals the influence of the arylsulfonyl group on the occurrence or absence of chiral crystallization.     

Chiral β-diketonate ligands of ‘pseudo planar chiral’ topology: enantioselective synthesis and transition metal complexation

A practical enantioselective synthesis of chiral β-diketonate ligands 1a-1d, which are of ‘pseudo planar-chiral’ topology, is described. Additionally, the first chiral bis(diketonates) 2a-2c, ligands of C₂-symmetry that are isoelectronic with respect to related salen ligand systems, have been prepared. Protocols for the metallation of ligands 1a-1d, 2b and 2c are reported.     

Enantioselective total synthesis of pyrroloquinolone as a potent PDE5 inhibitor

A concise enantioselective strategy for the synthesis of key PDE5 inhibitor 2 was developed in 5 and 6 steps using asymmetric hydrogenation and one-pot chiral auxiliary approaches, respectively. The synthesis features the use of imine 6 obtained through Bischler-Napieralsky reaction from amide 5. Absolute R configuration was introduced in (+)-7 by asymmetric transfer-hydrogenation reaction with Ru(II) catalyst followed by establishing the tricyclic pyrroloquinalone core using the Winterfeldt oxidation. Another alternative synthetic approach for the introduction of chirality in the molecule employed imine 6 and chloroformates of different chiral auxiliaries, which achieved N-acyliminium ion intermediates that were reduced in situ using PdCl₂/Et₃SiH protocol. These synthetic routes were applied in the total synthesis of promising male erectile dysfunction (MED) PDE5 inhibitor 1.     

Facile and practical synthesis of a cannabinoid-1 antagonist via regio- and stereoselective ring-opening of an aziridinium ion

A scalable synthetic strategy of a chiral, trisubstituted imidazolidinone (1), a novel cannabinoid-1 antagonist, starting from a commercially available mandelic acid (5) is described. The key step involves a regio- and stereoselective ring-opening of an aziridinium ion by an aniline nucleophile (3). A mechanistic study revealed the insight into rate amplification at a lower temperature for vicinal diamine 12 formation via a aziridinium ion 14. Although most intermediates are not isolable by crystallization due to their intrinsic physical properties (oil or foamy solid), the reported synthesis furnished pure 1 without any chromatography purification throughout the entire synthesis. Employing green chemistry principles, this novel synthesis appears to be highly efficient for the manufacturing of multi-kilogram quantities of an optically-pure active pharmaceutical ingredient.     

Synthesis of the first pseudo-phosphonopeptides derived from (ferrocenyl)aminomethanephosphonous acids

The first example of the condensation of (ferrocene)-N-benzhydrylamino-methanephosphonous acid (1) with α-amino acids 2a-d and several model dipeptides 4a-d and the tripeptide dl-alanyl-dl-leucinyl-glycine (4e) in the presence of DCC resulted in pseudo-phosphono-dipeptides 3a-d and pseudo-phosphono-oligopeptides 5a-d. The probable chiral assistance of the incoming amino acid or peptide in the formation of the new chiral center on phosphorus was also a feature of this method.     

Rhodium complexes with chiral counterions: achiral catalysts in chiral matrices

The neutral complexes [Rh(I)(NBD)((1S)-10-camphorsulfonate)] (2) and [Rh(I)((R)-N-acetylphenylalanate)] (4) reacted with bis-(diphenylphosphino)ethane (dppe) to form the cationic Rh(I)(NBD)(dppe) complexes, 5 and 6, respectively, accompanied by their corresponding chiral counteranions. Analogously, 4 reacted with 4,4^′-dimethylbipyridine to yield complex 7. Complexes 5 and 6 disproportionated in aprotic solvents to form the corresponding bis-diphosphine complexes 8 and 9, respectively. 8 was characterized by an X-ray crystal structure analysis. In order to form achiral Rh(I) complexes bearing chiral countercations new sulfonated monophosphines 13-16 with chiral ammonium cations were synthesized. Tris-triphenylphosphinosulfonic acid (H₃TPPS, 11) was used to protonate chiral amines to yield chiral ammonium phosphines 14-16. Thallium-tris-triphenylphosphinosulfonate (Tl₃TPPS, 12) underwent metathesis with a chiral quartenary ammonium iodide to yield the proton free chiral ammonium phosphine 13. Phosphines 15 and 16 reacted with [Rh(NBD)₂]BF₄ to afford the highly charged chiral zwitterionic complexes [Rh(NBD)(TPPS)₂][(R)-N,N-dimethyl-1-(naphtyl)ethylammonium]₅ (17) and [Rh(NBD)(TPPS)₂][BF₄][(R)-N,N-dimethyl-phenethylammonium]₆ (18), respectively. Complexes 5, 6, and 18 were tested as precatalysts for the hydrogenation of de-hydro-N-acetylphenylalanine (19) and methyl-(Z)-(α)-acetoamidocinnamate (MAC, 20) under homogeneous and heterogeneous (silica-supported and self-supported) conditions. None of the reactions was enantioselective.     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

Novel diaminoaluminum halides and a diaminoaluminum hydride: 1,3,2-Diazaalumina-[3]ferrocenophanes

The dilithiated derivative 2 of 1,1′-bis(trimethylsilylamino)ferrocene (1) reacts with the pyridine adducts of the aluminum trihalides AlX₃ (X = Cl, Br, I) to give the respective 1,3,2-diazaalumina-[3]ferrocenophanes (4b, c, d) as pyridine adducts. The fluoride 4a could not be obtained in this way. The reaction of 1,1′-bis(trimethylsilylamino)ferrocene (1) with the dimethyl(ethyl)amine- or pyridine adduct of aluminium trihydride gave the 1,3,2-diazaalumina-[3]ferrocenophanes (5) and (6) as the amine and pyridine adducts, respectively. Treatment of 5 with trimethyltin fluoride afforded the adduct 7 with an Al–F function. Addition of pyridine converted 7 into the desired pyridine adduct of the fluoride (4a). The molecular structures of the pyridine adducts 4a, 4b, 4c and 6 were determined by X-ray analysis. The pyridine is in the trans-position relative to the N–Si bond vectors, and temperature dependent solution-state NMR spectra prove that prominent structural features are retained in solution.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block

A new, promising chiral building block 9 for the synthesis of 1-deoxy-4,5-trans-oriented azasugars such as 1-deoxynojirimycin (1) was prepared in only four steps from the Garner aldehyde 10 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In practical test, the first synthesis of all four isomers (1 and 6-8) of trans-4,5-orientated 1-deoxyiminosugars using 9 as a common chiral building block was demonstrated.     

Unusual asymmetric oxidation of sulfide; the diastereoselective oxidation of prochiral sulfide-chiral acid salt with hydrogen peroxide without metal

The sulfide 4 was treated with chiral acid in a mixture of toluene and methyl iso-butylketone to precipitate the salt, which reacted with 30% H₂O₂ for 3 weeks at rt. The resulting crystals were collected followed by recrystallization to give the salt of enantiometrically pure sulfoxide and chiral acid 7 in 72% yield and 98.1% de, which was led to chiral sulfoxide S-3 after neutralization. Sulfoxide S-3 was led to S-1a as the candidate for an orally active HIV-1 therapeutic agent.     

Synthesis, crystal structures and triboluminescence of a pair of Eu(III)-based enantiomers

Using the chiral ligands L_SS (+)-4,5-pinene bipyridine and L_RR (−)-4,5-pinene bipyridine (Scheme 1), two novel Eu(III)-based complexes with the formula [Eu(DBM)₃L] (L_SS in 1, L_RR in 2, DBM = dibenzoylmethanate) have been successfully synthesized and characterized by X-ray single crystal determination and spectroscopic methods. The crystal structure analysis of 1 and 2 reveal that they crystallize in the chiral space group P2₁ of the monoclinic system. The central Eu(III) ion is eight-coordinated in a geometrical environment intermediate between a square antiprism and a dodecahedron. The CD spectra reflect that complexes 1 and 2 are enantiomers. When ground in daylight, complexes 1 and 2 exhibit brilliant triboluminescence at room temperature.     

Structural elucidation of the oxidation product of aminoethylcysteine ketimine decarboxylated dimer by peroxynitrite

Aminoethylcysteine ketimine decarboxylated dimer (2) is a natural sulfur compound with antioxidant properties. 2 Inhibits some reactions mediated by peroxynitrite, a strong oxidizing and nitrating agent that reacts with several biomolecules. This work aims to elucidate the structure of the product resulting from the interaction of 2 with peroxynitrite using 1D and 2D NMR experiments and ion trap mass spectrometry. This product is a dimerized form of 2 and is hereafter referred to as 3. During the reactions leading to 2 and during the formation of 3, no chiral selection is operated; all optical isomers are present in D₂O and have been evidenced by ¹H NMR methods in D₂O plus β- or γ-cyclodextrin.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Chiral biomimetic NADH models in the benzo[b]-1,6-naphthyridine series. A novel class of stable, reactive and highly enantioselective NADH mimics

The preparation of a new class of tricyclic models 1 based on a Friedländer reaction between chiral piperidine-2,4-diones 2 and azomethine 3 is reported. Alkylation of the lactam allowed to install various pendant arms on the chiral cyclic inducer. The so-obtained mimics 1a,d,f,g,h,k were involved in the reduction of methyl benzoylformate to furnish methyl mandelate in 4-87% ee (R). The presence of a coordinating pendant arm proved to be essential to reach optimum results in terms of enantioinduction. Asymmetric reduction of 2-benzoylpyridine with mimics 1d,f,g produced α-phenyl-2-pyridinemethanol in 30-84% ee (R).