New efficient synthesis of 1H-imidazo-[4,5-c]quinolines by a sequential Van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization

A new efficient synthesis of multisubstituted 1H-imidazo-[4,5-c]quinoline derivatives via sequential van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization was developed. Azides 4, obtained from Van Leusen reaction of 2-azidobenzaldehyde 1, amine 2 and TosMIC (tosylmethyl isocyanide) 3, reacted with triphenyl phosphine to produce iminophosphorane 5. A tandem aza-Wittig reaction of iminophosphorane 5 with isocyanate generated 1H-imidazo-[4,5-c]quinoline 7 through carbodiimide intermediate 6 in moderate to good yield.     

Kinetic resolution of 1-(benzofuran-2-yl)ethanols by lipase-catalyzed enantiomer selective reactions

Kinetic resolution of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d was performed by lipase-catalyzed enantiomer selective acylation (E≫100) yielding (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d and (1S)-1-(benzofuran-2-yl)ethanols (S)-1a–d in highly enantiopure form. The degree of enantiomer selectivity for enzymatic alcoholysis/hydrolysis processes starting from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2 was also tested under various conditions including supercritical CO₂ medium. Racemization-free lipase-catalyzed ethanolysis of the (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d yielded almost quantitatively the enantiopure (1R)-1-(benzofuran-2-yl)ethanols (R)-1a–d.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: the chiral sulfoxide 1-thiochroman S-oxide

We have determined the absolute configuration of the chiral sulfoxide 1-thiochroman S-oxide 1 using vibrational circular dichroism (VCD) spectroscopy. The VCD spectrum of a CCl₄ solution of 1 was analyzed using density functional theory (DFT), which predicts three stable conformations of 1, separated by <1 kcal/mol. The VCD spectrum predicted using the DFT/GIAO methodology for the equilibrium mixture of the three conformations of (S)-1 is in excellent agreement with the experimental spectrum of (+)-1. The absolute configuration of 1 is therefore (R)-(−)/(S)-(+). (+)-1 and (−)-1 of high enantiomeric excess (e.e.) were synthesized in high yields via asymmetric oxidation of 1-thiochroman 2 using Ti(iso-PrO)₄/(R,R)-1,2-diphenylethane-1,2-diol/H₂O/tert-butyl hydroperoxide and Ti(iso-PrO)₄/l-diethyl tartrate/H₂O/cumene hydroperoxide, respectively.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.     

Characterization of two chimeric sesterterpene synthases from a fungal symbiont isolated from a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum

Two chimeric sesterterpene synthases (AaTPS1 and AaTPS2) were functionally characterized from Alternaria alternata MB-30 isolated from the leaves of a sesterterpenoid-producing Lamiaceae plant Leucosceptrum canum. AaTPS1 generated a 5/8/6/5 tetracyclic sesteraltererol (1) and its absolute stereochemistry was determined by X-ray crystallographic analysis of its derivative 10,11-epoxysesteraltererol (2), which enabled revision of the absolute configuration of C7 of sesterfisherol produced by NfSS and PTTS014 characterized previously and its derivative 10,11-epoxysesterfisherol. AaTPS2 produced a 5/15 bicyclic preterpestacin I (3). Site-directed mutagenesis suggested that F192 in AaTPS1 was likely involved in controlling of the hydroxylation of C12, and eight amino acids were important for the enzyme activity of AaTPS1 and AaTPS2. The engineered Escherichia coli and Saccharomyces cerevisiae strains were constructed for the productions of compounds 1 and 3, and the highest titer of compound 1 reached 62.3 mg/L in shake-flask culture. Both compounds 1 and 2 showed anti-adipogenic activity.     

Generation of chirality in 4,4′-azopyridine by co-crystallization with optically active dicarboxylic acids

The co-crystals of anti-4,4′-azopyridine apy with optically active 9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylic acid 1 and trans-1,2-cyclohexanedicarboxylic acid 2 were prepared and their solid state CD spectra were measured. The positive Cotton effect sign, corresponding to the lowest energy n–π¹ transition, was correlated with the M helicity of the twisted Ar–NN chromophore. The absolute sense of the twist of the guest apy molecule was deduced from the X-ray structures of the (S,S)-1·apy and (S,S)-2·apy complexes.     

Synthesis of amino sugars via isoxazolines DL- and D-lividosamine (2-amino-2,3-dideoxy-ribo-hexose) derivatives from 4-vinyl-1,3-dioxolanes and nitroacetaldehyde acetals

1,3-Dipolar cycloaddition of nitrile oxides, generated from nitroethanol and nitroacetaldehyde derivatives 3, 21 and 22, respectively, and of benzonitrile oxide to 4-vinyldioxolanes 1, 2 gave ca 4:1 erythro/threo mixtures of corresponding isoxazolines. LAH reduction of erytho isoxazolines proceeded with similar (ca 4:1) selectivity to furnish protected ribo-amino-polyols 11, 15,19, DL- and D-lividosamines 31 and 33, respectively, as main products. The DL-lividosamine derivative 33 was obtained pure by crystallization. In the D-series, the corresponding ribo/arabino mixture D-31/D-32 was transformed to the known α-methyl D-lividosaminide D-37.     

Hydrogen-bond-assisted supramolecular 1-D tape-like structures of mesogenic bis-pyrazoles

Two new series of isomeric bis-pyrazoles 1a–b are prepared, characterized, and their mesomorphic properties investigated. These pyrazoyl derivatives were obtained from the condensation of α,β-diketones 2a–b with hydrazine monohydrate in refluxing THF. Two single crystallographic structures of compounds mesogenic 1a (n=14) and nonmesogenic 1b (n=8) were determined by X-ray analysis. Both 1a–14 and 1b–8 crystallize in a triclinic space group P?1 and monoclinic C2/c group, respectively. An extended H-bonded structure was formed in both crystal lattices, giving a pseudo 1D-polymeric tape-like structure. Derivatives 1a exhibited smectic A/C mesophases, in contrast, derivatives 1b were all nonmesogenic. The difference in mesomorphic behavior was attributed to the between linear conformation and the coplanarity of the five rings over than in 1a. The correlation between the molecular structures and the mesomorphic properties is discussed.     

Mycopyranone: A 8,8ˈ-binaphthopyranone with potent anti-MRSA activity from the fungus Phialemoniopsis sp.

A new 8,8?-binaphthopyranone (mycopyranone, 1) was isolated from a solid fermentation of Phialemoniopsis sp. (fungal strain MSX61662), and the structure was elucidated via analysis of the NMR and HRESIMS data. The axial chirality of 1 was determined to be M by ECD. The central chirality at C-4/C-4? was assigned through a modified Mosher’s method, while the absolute configuration at C-3/C-3? was deduced based on analysis of the ³J_H-3-H-4 values and NOESY correlations. Compound 1 was evaluated for its antimicrobial properties against Staphylococcus aureus SA1199 and a clinically relevant methicillin-resistant S. aureus strain (MRSA USA300 LAC strain AH1263). Compound 1 inhibited the growth of both strains in a concentration dependent manner with IC₅₀ values in the low μM range. Molecular docking indicated that compound 1 binds to the FtsZ (tubulin-like) protein in the same pocket as viriditoxin (2), suggesting that 1 targets bacterial cell division.     

Synthesis and chiral recognition ability of O-ethyl (2-naphthyl)phosphonothioic acid

Enantiopure O-ethyl (2-naphthyl)phosphonothioic acid 1 was designed on the model of O-ethyl phenylphosphonothioic acid, based on the fact that the chiral recognition abilities of enantiopure mandelic acid and cis-1-aminoindan-2-ol were improved upon by replacing their phenyl/phenylene groups with naphthyl/naphthylene groups, respectively. Enantiopure 1 was easily obtained by the enantioseparation of racemic 1, which was easily synthesized from commercially available 2-bromonaphthalene and diethoxyphosphonothioic chloride, with enantiopure 1-phenylethylamine. Enantiopure 1 showed an excellent chiral recognition ability for several 1-arylethylamine derivatives during the diastereomeric salt formation. The effect of the enlarged aromatic part of 1 is discussed on the basis of X-ray crystallographic analyses.     

Chiral solvating properties of (S)-1-benzyl-6-methylpiperazine-2,5-dione

In CDCl₃ solution, enantiopure (S)-1-benzyl-6-methylpiperazine-2,5-dione (S)-1a formed diastereomeric CO⋯H–N hydrogen-bonded associates with racemic (RS,Z)-1-benzyl-3-[(dimethylamino)methylidene]piperazine-2,5-diones 2a and 2b, (RS)-tert-butyl pyroglutamate (RS)-2c and (RS)-N-benzoylalanine methyl ester (RS)-2d. This resulted in splitting (doubling) of the characteristic signals in the ¹H NMR and ¹³C spectra of racemic compounds 2a–d in the presence of 1 equiv of (S)-1a. The formation of hydrogen-bonded dimers in CDCl₃ solution was studied by ¹H NMR, ¹³C NMR and 2D NMR and confirmed by the intermolecular NOE observed between the hydrogen-bonded amide protons from each of the monomeric units, (S)-1a and 2a–c. On the other hand, a slightly different binding mode was proposed for association of (S)-1a with alaninamide (RS)-2d. Enantiomer compositions of known (weighed) mixtures of both enantiomers of tert-butyl pyroglutamate 2c were re-determined by ¹H NMR in the presence of (S)-1a in CDCl₃. The experimental values were in good agreement with the theoretical values, thus indicating the potential applicability of (S)-1a and related diketopiperazines as chiral solvating agents in NMR spectroscopy.     

Norcrocrassinone: A novel tetranorditerpenoid possessing a 6/6/5 fused ring system from Croton crassifolius

Norcrocrassinone (1), a novel tetranorditerpenoid possessing a fused 6/6/5 ring system, was isolated from the roots of Croton crassifolius. The structure of 1 was elucidated by extensive spectroscopic methods and confirmed by single crystal X-ray diffraction. The anti-Alzheimer’s disease (AD) activity of 1 was evaluated using humanized Caenorhabditis elegans AD pathological model.     

Verbenanone,an octahydro-5H-chromen-5-one from a Hawaiian-plant associated fungus FT431

Verbenanone (1), a new secondary metabolite with a unique (4aS,8aS)-octahydro-5H-chromen-5-one moiety has been obtained from the endophytic fungus FT431, which was isolated from the native Hawaiian plant Verbena sp. The structure of compound 1 was characterized based on NMR and MS spectroscopic analysis. The absolute configuration (AC) of compound 1 was determined by Mosher acids. Compound 1 was tested against A2780 and A2780cisR, but it was inactive.     

Synthesis and chiral recognition ability of O-phenyl ethylphosphonothioic acid with a conformationally flexible phenoxy group for CH/π interaction

Enantiopure O-phenyl ethylphosphonothioic acid 1 was easily obtained by the enantioseparation of racemic 1, which was prepared from commercially available phosphorothioic trichloride in four steps. Enantiopure 1 was found to show an excellent chiral recognition ability for various 1-arylethylamine derivatives during the diastereomeric salt formation. In particular, enantiopure 1 was able to recognize the chirality of o- and m-substituted 1-arylethylamine derivatives, of which the chirality is generally difficult to establish by conventional resolving agents. X-ray crystallographic analyses of the less-soluble diastereomeric salts revealed that the conformation of the phenoxy group in enantiopure 1 could change in the diastereomeric salt crystals and that the excellent chiral recognition ability of enantiopure 1 resulted from the effective CH/π interaction of the phenoxy phenyl group.     

Lipase-catalyzed synthesis of a tri-substituted cyclopropyl chiral synthon: a practical method for preparation of chiral 1-alkoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane

An efficient method for the preparation of optically active enantiomers of 1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1 has been developed. Treatment of 1 with lipase Amano PS gave (1S,5R)-1-carboxy-2-oxo-3-oxabicyclo[3.1.0]hexane 4a which was converted to (1S,5R)-1-ethoxycarbonyl-2-oxo-3-oxabicyclo[3.1.0]hexane 1a with high enantiomeric purity (98.0% ee, 75% yield), while the (1R,5S)-lactone ester 1b remained intact. A simple procedure for the recovery of 4a from the reaction mixture was also established.     

Solvent- and temperature-controlled inversion of π-facial selectivity in the 1,2-cycloaddition of singlet oxygen to hydroxyphenyl-substituted cyclohexadihydrofurans

Singlet-oxygenation of 3-hydroxyphenyl-substituted dihydrofurans fused with a cyclohexane 1a?c exclusively gave the corresponding syn/anti-stereoisomeric mixtures of dioxetanes 2a?c. The syn/anti-π-facial selectivity in the 1,2-cycloaddition of singlet oxygen (¹O₂) was found to be remarkably sensitive to the solvent as well as the reaction temperature. In fact, the solvent effect was so conspicuous that inversion of the syn/anti-π-facial selectivity was observed in different solvents, such as chloroform and toluene. An LSER (linear solvation energy relationships) analysis suggested that the Lewis-acidity/basicity and HBD (hydrogen-bond donor)/HBA (hydrogen-bond acceptor) ability as well as dipolarity/polarizability of the solvent played an important role in this change in syn/anti-π-facial selectivity. An investigation of the temperature-dependency of the singlet-oxygenation suggested that the syn/anti-π-facial-selective 1,2-cycloaddition of ¹O₂ to 1 was a conformationally-(entropy-) controlled process.     

Naturally-occurring acetylenic compounds and derivatives : Regio- and stereocontrolled chloroformylation of 2-(1-propynyl)thiophene and 2-phenyl-5-(1-propynyl)thiophene

2-Phenyl-5-(1-propynyl)thiophene (1), isolated from Coreopsis grandiflora, and 2-(1-propynyl)thiophene (5), an immediate precursor in the synthesis of junipal (2), were synthesized in high yield by a Pd-catalyzed reaction between propyne and 2-iodo-5-phenylthiophene (4) or 2-iodothiophene (6), respectively. Reaction of 5 with the Vilsmeier reagent derived from POCl₃ and N-methylformanilide (MFA) afforded a mixture from which it was possible to isolate (E)-3-chloro-2-methyl-3-(2-thienyl)acrolein (10) in 37.7% yield. The structure and stereochemistry of 10 was unequivocally established by X-ray diffraction of a single crystal of the 2,4-dinitrophenylhydrazone of 10. GLC analysis showed that 10 was contaminated by ca 7% with an isomer to which, on the basis of ¹H-NMR and mass spectra, the structure of (Z)-3-chloro-2-methyl-3-(2-thienyl)acrolein (11) was attributed.Contrary to what was expected from the literature, junipal (2) represented only a minor component in the reaction mixture obtained by the Vilsmeier reaction on 5.Reaction of 1 with POCl₃ and MFA afforded (44.6% yield) a (E)-3-chloro-2-methylacrolein to which the structure 15 was attributed. Compound 15 was also contaminated by ca 10% of an isomer 16, which very probably corresponded to the (Z)-stereoisomer of 15.     

Inclusion and selectivity of amides by p-terphenyl derivative bearing adamantanecarboxylic acid

Hydrogen-bonding compound (1), which is composed of p-terphenyl and adamantanecarboxylic acid, acted as a host molecule for three amides, respectively, forming crystals. Crystals containing the amides (1a and 1b) were produced from N,N-dimethylformamide (DMF) and N,N-diethylformamide (DEF) in 1:2 host:guest complexation stoichiometry, respectively, whereas guest-free crystals (1c) were generated from N-methylformamide (NMF). In the crystal structures of 1a and 1b, carboxylic acids of 1 interact with oxygen atoms of the amide guests through hydrogen bonds to afford network and layer architectures. Crystals 1a and 1b were given from equimolar binary mixtures of DMF or DEF and NMF, respectively. Further, from a mixture of DMF and DEF, guest-inclusion crystals 1d different from 1a and 1b were formed, where DMF was preferentially accommodated. Competition experiments revealed that the selectivity order of 1 for the amide guests was DMF?>?DEF???NMF.     

Resolution of racemic cis-1-amino-2-indanol by diastereomeric salt formation with (S)-2-phenylpropionic acid

Resolution of racemic cis-1-amino-2-indanol 1, a key intermediate for the synthesis of indinavir, is reported. The conditions were optimized for an industrial-scale resolution of racemic cis-1 using (S)-2-phenylpropionic acid 6 as the resolving agent and ethanol as the solvent. The less-soluble diastereomeric salt, (1R,2S)-1·(S)-6, was obtained in 35% yield with 99% de (E >69%) by crystallization. Resolving agent 6 was efficiently recovered from the salt and the mother liquor.     

Are the absolute configurations of 2-(1-hydroxyethyl)-chromen-4-one and its 6-bromo derivative determined by X-ray crystallography correct? A vibrational circular dichroism study of their acetate derivatives

The vibrational circular dichroism (VCD) spectra of the acetate derivative, 3, of 2-(1-hydroxyethyl)-chromen-4-one, 1, and the acetate derivative, 4, of 6-bromo-2-(1-hydroxyethyl)-chromen-4-one, 2, in the CO stretching region are reported. Density functional theory (DFT) predictions of the VCD spectra of the CO stretching modes of (R)-3 and (R)-4 are in excellent agreement with the experimental spectra for (+)-3 and (+)-4, demonstrating that the absolute configurations of both molecules are (R)-(+)/(S)-(−). Since acetylation of (+)-1 and (+)-2 yields (+)-3 and (+)-4, this in turn leads to (R)-(+)/(S)-(−) for both 1 and 2. The absolute configurations of (−)-1 and (−)-2 were previously determined using X-ray crystallography to be R and S, respectively. Our results lead to the conclusion that the previously reported absolute configuration of 1 is incorrect.This work is the first to apply the ‘conformational rigidification via chemical derivatisation’ methodology to the determination of absolute configuration using VCD spectroscopy and illustrates its utility in determining the absolute configurations of chiral alcohols and, by extension, other classes of chiral molecules containing flexible functional groups.