A DFT study of the origins of the stereoselectivity in the aldol reaction of bicyclic amino ketones in the presence of water

Experimental diastereoselectivities of the direct solvent-less (neat) aldol reactions of tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one) and granatanone (pseudopelletierine, 9-methyl-9-azabicyclo[3.3.1]nonan-3-one) in the presence of catalytic amounts of water are most accurately reproduced by thermodynamic distributions of isomeric products calculated in the gas phase at the B3LYP/6-31g(d) level of theory. Less than 30% systematic errors, on average, exist in the predicted anti/syn-diastereomeric ratio (dr) for the solvent-less reaction of tropinone with several aromatic aldehydes. The CPCM-B3LYP/6-31g(d) method reproduces the anti/syn-diastereomeric ratio of the aqueous aldol reaction of tropinone with several aromatic aldehydes with reasonable deviation (0-88%), excellent (0-10)% agreement was found for the reactions of tropinone and granatanone with benzaldehyde. Qualitatively satisfactory agreement was also found for dr values in different solvents (DMF, THF, and Et₃N). The density functional theory (DFT) results support the notion of the thermodynamic control of the reaction.     

Alkaloids from alkaloids: total synthesis of (±)-7a-epi-hyacinthacine A1 from Z-protected tropenone via Baeyer-Villiger oxidation

Baeyer-Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones 15a-c underwent exclusive epoxidation to 21a-c, the corresponding 6-oxotropane derivative 28 yielded the desired lactone 29. Baeyer-Villiger oxidation was also possible for the O-isopropylidene-protected diols 32a,b. The resulting lactones 33a,b were employed in the total synthesis of (±)-7a-epi-hyacinthacine A₁ (7a-epi-7) via an intramolecular nucleophilic alkyllithium addition to a carbamate as the key lactamization step. The target compound was prepared from tropenone 15b in 10 steps and 14% overall yield. Enzymatic resolution of pyrrolidine (±)-36 provided a formal total synthesis to both enantiomers of 7.     

2-羟基-萘甲醛缩对甲氧基苯甲酰腙的合成与荧光性质研究

合成了2-羟基-萘甲醛缩对甲氧基苯甲酰腙,采用元素分析和红外光谱对该化合物结构进行了表征。详细研究了该化合物在固态、不同溶剂中和有锌离子存在下的荧光光谱,探讨了溶剂极性和锌离子的存在对其荧光光谱的影响。结果表明：该化合物的固体和溶液都有很强的荧光,溶剂对其荧光性质有较大的影响,其DMF溶液在485nm处发光最强。金属锌离子具有荧光增敏性。     

A new tropane alkaloid from the leaves of Erythroxylum subsessile isolated by pH‐zone‐refining counter‐current chromatography

Tropane alkaloids are bioactive metabolites with great importance in the pharmaceutical industry and the most important class of natural products found in the Erythroxylum genus. However, these compounds are usually separated by traditional chromatographic techniques, in which the sample is progressively purified in multiple chromatographic steps, resulting in a time‐ and solvent‐consuming procedure. In this work we present the isolation of a novel alkaloid, 6β,7β‐dibenzoyloxytropan‐3α‐ol, together with the two known 3α‐benzoyloxynortropan‐6β‐ol and 3α,6β‐dibenzoyloxytropane alkaloids, directly from the crude alkaloid fraction from the leaves of Erythroxylum subsessile, by using a single run pH‐zone‐refining counter‐current chromatography method. The ethyl acetate/water (1:1, v/v) biphasic solvent system with triethylamine and HCl as retention and eluter agents, respectively, was used to isolate tropane alkaloids for the first time. The structures of the isolated alkaloids were elucidated by spectroscopic methods.     

Simultaneous determination of atropine,scopolamine, and anisodamine from Hyoscyamus niger L. in rat plasma by high‐performance liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetics study

In order to investigate the pharmacokinetics of tropane alkaloids in Hyoscyamus niger L., a sensitive and specific high‐performance liquid chromatography with tandem mass spectrometry method for the simultaneous determination of atropine, scopolamine, and anisodamine in rat plasma is developed and fully validated, using homatropine as an internal standard. The separation of the four compounds was carried out on a BDS Hypersil? C₁₈ column using a mobile phase consisting of acetonitrile and water (containing 10 mmol ammonium acetate). Calibration curves were linear from 0.2 to 40 ng/mL for atropine, scopolamine, and from 0.08 to 20 ng/mL for anisodamine. The precision of three analytes was <5.89% and the accuracy was between ?1.04 to 2.94%. This method is successfully applied to rat pharmacokinetics analysis of the three tropane alkaloids after oral administration of H. niger extract. The maximum concentration of these three tropane alkaloids was reached within 15 min, and the maximum concentrations were 31.36 ± 7.35 ng/mL for atropine, 49.94 ± 2.67 ng/mL for scopolamine, and 2.83 ± 1.49 ng/mL for anisodamine. The pharmacokinetic parameters revealed areas under the curve of 22.76 ± 5.80, 16.80 ± 3.08, and 4.31 ± 1.21 ng/h mL and mean residence times of 2.08 ± 0.55, 1.19 ± 0.45, and 3.28 ± 0.78 h for atropine, scopolamine, and anisodamine, respectively.     

Synthesis and characterization of metal 2-pyridine carboxaldehyde-N-methyl-N-2-pyridyl hydrazone complexes and their microbiological activity

Complexes of Cu(II), Mn(II), Co(II), Ni(II), Hg(II), Cd(II) and Rh(III) with 2-pyridine carboxaldehyde-N-methyl-N-2-pyridylhydrazone ( pamph) have been prepared and characterized. The new complexes have been characterized by elemental analysis, conductivity and magnetic measurements, IR, UV–vis and ¹H NMR spectroscopic methods. The microbiological activity of the complexes was investigated against bacteria and fungi. Most of the complexes studied appear to be active against bacteria while all are active against fungi. The Cu, Cd and Hg complexes exhibit the highest activity against both bacteria and fungi.     

Synthesis and magnetic,spectral and thermal eukaryotic DNA studies of some 2-acetylpyridine- [N-(3-hydroxy-2-naphthoyl)] hydrazone complexes

Complexes of Ni(II), Co(II), Cu(II), Zn(II), Cd(II), Hg(II) and U(VI)O₂ with 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)] hydrazone (H₂APHNH) have been prepared and characterized by elemental analysis, molar conductance, thermal (TG, DTG), spectral (¹H NMR, IR, UV–Vis, ESR) and magnetic measurements. ¹H NMR spectrum of the ligand suggests the presence of intramolecular hydrogen bonding. IR spectra show that H₂APHNH is a bidentate, tridentate and/or tetradentate ligand. Thermal decomposition of some complexes ended with metal oxide as a final product. ESR spectra gave evidence for the proposed structure and the bonding for some Cu(II) complexes. Biological activity measurements were carried out.     

Cytotoxic Evaluation of Pungencine: A New Tropane Alkaloid from the Roots of Erythroxylum pungens O. E. Schulz

A new tropane alkaloid as well as a new substitution group, (3‐endo,8‐anti)‐8‐methyl‐8‐azabicyclo[3.2.1]oct‐3‐yl 4‐hydroxy‐3,5‐dimethoxybenzoate, called pungencine ( 1 ), was isolated from the roots of Erythroxylum pungens O. E. Schulz . The structure was elucidated by spectral analyses, including ¹H‐ and ¹³C‐NMR and 2D‐NMR techniques (¹H,¹H‐COSY, NOESY, DEPT, HMQC, and HMBC) and HR‐ESI‐MS. Furthermore, compound 1 was tested for cytotoxicity against several cell lines (Jurkat, HL‐60, U937, K562, KG‐1, and U266) and was determined not to inhibit cell viability at 10 μM .     

Enzymatic Resolution of O‐(Methoxymethyl)‐Protected Tropane‐diols

A convenient synthetic route to enantiomerically pure tropane‐diol building blocks is described. The reaction sequence started from tropenone derivatives 1 , which were dihydroxylated to give 6,7‐dihydroxytropanone derivatives 2 . After introduction of the methoxymethyl (MOM) protecting group in diol 2a , a lipase‐mediated resolution of the resulting racemic mono‐MOM ether (±)‐ 5d with vinyl acetate and vinyl trifluoroacetate gave the acetates (?)‐ 6d and (?)‐ 6f , respectively, with 96–99% ee, and MOM ether (+)‐ 5d with up to 89% ee. Deacetylation of (?)‐ 6d afforded quantitatively MOM ether (?)‐ 5d with 99% ee, the absolute configuration of which was assigned via the modified Mosher method to be (R) at C(6). Enzymatic treatment of unprotected diol 2a with vinyl trifluoroacetate or alkoxycarbonylation resulted in the formation of C_s‐symmetrical products 9 and 12 rather than the desired desymmetrized derivatives.     

Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

Synthesis and characterization of several rhenium(I) complexes of 2-acetylpyridine and ferrocenyl carbaldehyde derivatives of 2-hydroxybenzoic acid hydrazide

The rhenium(I) carbonyl halide (X = Cl and Br) complexes, [ReX(CO)₃{H₂(py)L²}] (1a, 1b) and [ReX(CO)₃{H₂(Fc)L²}] (2a, 2b), of the ligands derived from 2-acetylpyridine and ferrocenyl carbaldehyde derivatives of 2-hydroxybenzoic acid hydrazide [H₂(py)L² and H₂(Fc)L², respectively] have been prepared in good yield. The complexes have been characterized by elemental analysis, MS, IR, UV-Vis and ¹H NMR spectroscopic methods and their structures have been elucidated by X-ray diffraction. The ligand forms a five-membered chelate ring but in H₂(py)L² it is N_pyridine,N′-bidentate while it is O,N-bidentate in H₂(Fc)L² complexes.Reaction of complex 1a with copper(II) nitrate yields the unexpected aqua complex [Re{H(py)L²}(H₂O)(CO)₃] (3) where the ligand is monodeprotonated but maintains the coordination mode observed in 1a, as shown by X-ray diffraction. However, reaction of 1b with glycine yields a conformational polymorph of the original compound, 1b′. The X-ray study shows that the orientation of the O-H phenol group against the carbonyl amide group is the main difference.     

Phosphorus-Containing Dendrimers: Synthesis and Properties

Several series of phosphorus-containing dendrimers have been designed to study the variation of their properties, depending on the type, the location (surface, branches, core, and cavities), and the number of functions implied.     

One‐Pot Catalytic Enantioselective Synthesis of 2‐Pyrazolines

A scalable, one‐pot, enantioselective catalytic synthesis of 2‐pyrazolines from beta‐substituted enones and hydrazines is described. Pivoting on a two‐stage catalytic Michael addition/condensation strategy, the use of an aldehyde to generate a suitable hydrazone derivative of the hydrazine was found to be key for curtailing background reactivity and tuning the catalyst‐controlled enantioselectivity. The new synthetic method is easy to perform, uses a new and readily prepared cinchona‐derived bifunctional catalyst, is broad in scope, and tolerates a range of functionalities with high enantioselectivity (up to >99:1 e.r.). The significant scalability of this methodology was demonstrated with the synthesis of more than 80 grams of a pyrazoline product with 89 % catalyst recovery.     

Synthesis of 2′-hydrazine oligonucleotides and their efficient conjugation with aldehydes and 1,3-diketones

Oligodeoxyribonucleotides that contain a novel nucleoside, 2′-O-(2-hydrazinoethyl)uridine, were synthesised by NaBH₃CN reduction of hydrazones formed from 2′-O-(2-oxoethyl)oligonucleotides with FmocNHNH₂, followed by concd aq NH₃ deprotection. The 2′-hydrazine oligonucleotides obtained were then used to synthesise a number of conjugates with aldehydes via hydrazone formation and with1,3-diketones via pyrazole formation. The method was shown to be applicable for the preparation of oligonucleotide-peptide conjugates.     

Synthesis and in vitro antimycobacterial potential of novel hydrazones of eugenol

Fifty one hydrazone derivatives of eugenol were designed and docked with 2NSD and 2X22 (enzymes of H37Rv strain) using Schrodinger v7.4. The selective ten hydrazone derivatives (4, 5, 11, 18, 30, 34, 35, 37, 42, and 45) of eugenol were synthesized via esterification, hydrazination and treatment with different aldehydes. Synthesized compounds were characterized by IR, ¹H NMR, and LCMS data. The compounds were evaluated for their antitubercular potential against H37Rv using microplate alamar blue assay (MABA). The study revealed that all synthesized compounds were significantly active at concentration 50 and 100 μg/ml, whereas compound 11 exhibited activity at 25 μg/ml. Present study showed that antitubercular activity of novel hydrazone derivatives of eugenol is strongly connected with the position of the substituent on aromatic aldehyde or ketones.     

Enantiomeric high‐performance liquid chromatography resolution and absolute configuration of 6β‐benzoyloxy‐3α‐tropanol

The absolute configuration of the naturally occurring isomers of 6β‐benzoyloxy‐3α‐tropanol ( 1 ) has been established by the combined use of chiral high‐performance liquid chromatography with electronic circular dichroism detection and optical rotation detection. For this purpose (±)‐ 1 , prepared in two steps from racemic 6‐hydroxytropinone ( 4 ), was subjected to chiral high‐performance liquid chromatography with electronic circular dichroism and optical rotation detection allowing the online measurement of both chiroptical properties for each enantiomer, which in turn were compared with the corresponding values obtained from density functional theory calculations. In an independent approach, preparative high‐performance liquid chromatography separation using an automatic fraction collector, yielded an enantiopure sample of _OR(+)‐ 1 whose vibrational circular dichroism spectrum allowed its absolute configuration assignment when the bands in the 1100–950 cm^‐1 region were compared with those of the enantiomers of esters derived from 3α,6β‐tropanediol. In addition, an enantiomerically enriched sample of 4 , instead of _OR(±)‐ 4 , was used for the same transformation sequence, whose high‐performance liquid chromatography follow‐up allowed their spectroscopic correlation. All evidences lead to the _OR(+)‐(1S,3R,5S,6R) and _OR(?)‐(1R,3S,5R,6S) absolute configurations, from where it follows that samples of 1 isolated from Knightia strobilina and Erythroxylum zambesiacum have the _OR(+)‐(1S,3R,5S,6R) absolute configuration, while the sample obtained from E. rotundifolium has the _OR(?)‐(1R,3S,5R,6S) absolute configuration.     

Divergent Synthesis of Disulfanes and Benzenesulfonothioates Bearing 2‐Aminofurans From N‐Tosylhydrazone‐Bearing Thiocarbamates

An efficient and convenient synthesis of valuable disulfanes and benzenesulfonothioates, having a 2‐aminofuran framework, has been developed by employing a copper‐catalyzed transformation of readily available N‐tosylhydrazone‐bearing thiocarbamates. This method features an inexpensive metal catalyst, mild reaction conditions, good functional‐group tolerance, short reaction times, and delivers valuable and complex products. A copper carbene generated from an N‐tosylhydrazone‐bearing thiocarbamate is proposed as the key intermediate for the transformation and it triggers the subsequent cascade. Remarkably, the Ts anion released from N‐tosylhydrazone further serves as a nucleophile, thus rendering the formation of benzenesulfonothioates under controlled conditions.     

On-line identification of tropane alkaloids from Erythroxylum vacciniifolium by liquid chromatography-UV detection-multiple mass spectrometry and liquid chromatography-nuclear magnetic resonance spectrometry

The bark of catuaba (Erythroxylum vacciniifolium Martius, Erythroxylaceae), a tree native to the northern part of Brazil, was investigated for its alkaloid content. With the aim of obtaining preliminary structure information on-line, the alkaloid extract was analysed by high-performance liquid chromatography coupled to diode array UV detection, to mass spectrometry and to nuclear magnetic resonance. Interpretation of on-line spectroscopic data obtained from this extract led to structural elucidation of six new alkaloids and partial identification of 18 potentially original alkaloids bearing the same tropane skeleton esterified in positions 3 and 6 by 1-methyl-1H-pyrrol-2-carboxylic acid and/or 4-hydroxy-3,5-dimethoxybenzoic acid.