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Curcumin (CUR) is a natural compound that exhibits anti-inflammatory, anti-bacterial, and other biological properties. However, its application as an effective drug is problematic due to its poor oral bioavailability, solubility in water, and poor absorption from the gastrointestinal tract. The aim of this work is to synthesize monocarbonyl analogs of CUR based on the 9-methyl-9-azabicyclo[3.2.1]nonan-3-one (pseudopelletierine, granatanone) scaffold to improve its bioavailability. Granatane is a homologue of tropane, whose structure is present in numerous naturally occurring alkaloids, e.g., l-cocaine and l-scopolamine. In this study, ten new pseudopelletierine-derived monocarbonyl analogs of CUR were successfully synthesized and characterized by spectral methods and X-ray crystallography. Additionally, in vitro test of the cytotoxicity and anti-inflammatory properties of the synthesized compounds were performed.

Background: Punica granatum (family: Lythraceae) is mainly found in Iran, which is considered to be its primary centre of origin. Studies on pomegranate peel have revealed antioxidant, anti-inflammatory, antiangiogenesis activities, with prevention of premature aging and reducing inflammation. In addition to this it is also useful in treating various diseases like diabetes, maintaining blood pressure and treatment of neoplasms such as prostate and breast cancer. Objectives: In this study we identified anti-cancer targets of active compounds like corilagin (tannins), quercetin (flavonoids) and pseudopelletierine (alkaloids) present in pomegranate peel by employing dual reverse screening and binding analysis. Materials and Methods: The potent targets of the pomegranate peel were annotated by the PharmMapper and ReverseScreen 3D, then compared with targets identified from different Bioassay databases (NPACT and HIT’s). Docking was then further employed using AutoDock pyrx and validated through discovery studio for studying molecular interactions. Results: A number of potent anti-cancerous targets were attained from the PharmMapper server according to their fit score and from ReverseScreen 3D server according to decreasing 3D scores. Conclusion: The identified targets now need to be further validated through in vitro and in vivo studies.

The exo,anti/exo,syn-diastereoselectivity of water promoted direct aldol reactions of tropinone and granatanone (pseudopelletierine) is strongly dependent on the amount of water added and aromatic aldehyde used. DFT methods were applied to calculate the free energies of tropinone and granatanone enols, transition states, and isomeric aldol products. A theoretical model was verified by comparison of results from several DFT methods and functionals with experiments. The 6-31g(d)/CPCM method proved most suited to the problem, although all methods tested predicted similar trends. Explicit inclusion of a water molecule bonded to the amino ketones resulted in increased stability of the enol forms. The dependence of the anti/syn-diastereoselectivity on the amount of water used may be rationalized on the basis of change in the polarity of the reaction medium. The predicted stabilities of competing products agreed with experimental results supporting the notion of thermodynamic control. The isomeric products distributions for the aldol reaction of several aromatic aldehydes in solventless (neat) conditions were accurately calculated from free energies of the aldol addition step in the gas phase using B3LYP/6-31g(d) method and in aqueous conditions using the CPCM-B3LYP/6-31g(d) model. Our methodology can be useful for predicting the outcome of this type of aldol reactions.

A rotational spectroscopy investigation has resolved the conformational equilibrium and structural properties of the alkaloid pseudopelletierine. Two different conformers, which originate from inversion of the N-methyl group from an axial to an equatorial position, have been unambiguously identified in the gas phase, and nine independent isotopologues have been recorded by Fourier-transform microwave spectroscopy in a jet expansion. Both conformers share a chair-chair configuration of the two bridged six-membered rings. The conformational equilibrium is displaced towards the axial form, with a relative population in the supersonic jet of Naxial /Nequatorial ≈2/1. An accurate equilibrium structure has been determined by using the semiexperimental mixed-estimation method and alternatively computed by quantum-chemical methods up to the coupled-cluster level of theory. A comparison with the N-methyl inversion equilibria in related tropanes is also presented.

Direct aldol reactions of tropinone and granatanone (pseudopelletierine) with aromatic aldehydes were promoted by the presence of water. The anti–syn-diastereoselectivity depended on the amount of water used or on the possibility of product precipitation from the reaction mixture. Some of the reactions showed excellent atom economy, a low E factor, and high diastereoselectivity (up to 98%). In several cases ‘seeding’ with the anti isomer, used to induce the deposition of solid products, improved the conversion (up to 1.8 times) and the anti–syn ratio (up to 98:2). The applicability of spontaneous direct aldol reactions in the presence of water was also extended to N-alkyl nortropanones or norgranatanones using an aqueous–organic medium. However, under these conditions only the exo,syn isomers of the N-substituted aldols were obtained. The syn-selectivity for the tropane- and granatane-related aldols is specific for water-promoted reactions and results from thermodynamic control.

TpMo(CO)2(5-oxo-η3-pyranyl) and TpMo(CO)2(5-oxo-η3-pyridinyl) complexes 1 and 2 (Scheme 1, Tp = hydridotrispyrazolylborate) and their progeny have been developed as organometallic enantiomeric scaffolds for the asymmetric construction of a wide variety of heterocyclic systems.1 Readily available and easily synthesized,2 single enantiomers of these simple air-stable organometallic π-complexes function as scaffolds from which widely differing families of complex organic structures can be elaborated in an enantiospecific fashion. The organometallic nature of these enantiomeric scaffolds provides opportunities to implement conceptually unique synthetic design strategies. Herein is described one such strategy: a new molybdenum-mediated semipinacol rearrangement delivering α-quaternary pyranyl and pyridinyl systems that, when coupled sequentially with a molybdenum-mediated intramolecular 1,5-“Michael-like” reaction of 5-oxopyridinyl molybdenum complexes,1m can provide a novel enantiocontrolled entry to heteroatom-bridged [3.3.1]bicyclic systems bearing quaternary centers3,4,5 adjacent to the ring heteroatom (Scheme 1). The concept is highlighted via a synthesis of the azabicyclo[3.3.1]nonane natural product, (-)-adaline.6 Adaline possesses the 9-azabicyclo[3.3.1]nonane skeleton common to several insect- and plant-derived alkaloids, including pseudopelletierine,7 (+)-euphococcinine,8 and porantherine.9 This structure is a higher homolog of the medicinally-important tropane skeleton. A number of racemic10 and enantiospecific syntheses11 of adaline have been reported.

The pKa values of pseudopelletierine (1), 10-methyl-3,10-diazabicyclo[4.3.1]decan-4-one (2), 10-methyl-3, 10-diazabicyclo[4.3.1]decane (3), 6,8-exo-ethanopseudopelloetierine (4), 7,9-exo-ethano derivatives 5 and 6 of 2 and 3 were measured potentiometrically in water-methyl cellosolve (20 : 80 v/v) at 20°C. The conformational problems in the 3,10-diazabicyclo[4.3.1]decane system were discussed based on the observed pKa′ (pKmcs) values. The characteristic conformational behavior of the monocation (7) of 3 was suggested by the higher value of its pKmcs than of 6.

The preparation and characterization of the tropic acid esters of tropan-3β-ol and granatan-3α and 3β-ol are reported. A rapid synthesis of pseudopelletierine is described.