Synthesis and application of chiral beta-amino disulfides as ligands for the enantioselective addition of diethylzinc to aldehydes

A new class of chiral beta-amino disulfides was synthesized from readily available and inexpensive starting materials by a straightforward method and their abilities as ligands were examined in the enantioselective addition of diethylzinc to aldehydes. Enantiomeric excesses of up to 99% have been obtained using 0.5 mol % of the chiral catalysts.

Antinociceptive profile of 2,3,6-trisubstituted piperidine alkaloids: 3-O-acetyl-spectaline and semi-synthetic derivatives of (-)-spectaline

In early studies, we have reported the antinociceptive profile of (-)-spectaline, a piperidine alkaloid from Cassia spectabilis. The present study describes the synthesis, the antinociceptive and anti-inflammatory activities of a series of 2,3,6-trialkyl-piperidine alkaloids: the natural (-)-3-O-acetyl-spectaline (LASSBio-755) and ten semi-synthetic spectaline derivatives. Structure-activity relationship (SARs) studies were performed. The structures of all synthesized derivatives were confirmed by means of nuclear magnetic resonance. Compounds were evaluated for their analgesic (acetic acid-induced mouse abdominal constrictions, hot-plate test, formalin-induced pain test) and some of them for the anti-inflammatory activities (carrageenan-induced rat paw edema test). The pharmacological results showed that several of the new compounds given orally at a dose of 100 mu mol/kg significantly inhibited the acetic acid-induced abdominal constrictions, but they were less active than (-)-spectaline. LASSBio-755 and LASSBio-776 were the most actives with 37% and 31.7% of inhibition. In the formalin-induced pain only LASSBio-776 was able to inhibit by 34.4% the paw licking response of the inflammatory phase, (-)-spectaline and LASSBio-755 did show any activity. In the carrageenan-induced rat paw edema, only (-)-spectaline exhibited an anti-inflammatory profile, showing an ED(50) value of 56.6 mu mol/kg. Our results suggest different mechanisms of action for the analgesic activity observed for LASSBio-776 (3-O-Bocspectaline), LASSBio-755 (3-O-acetyl-spectaline) and (-)-spectaline (LASSBio-754). The antinociceptive profile of some of the semi-synthetic spectaline derivatives extends our research concerning the chemical and pharmacological optimization of isolated natural products in the search of new drug candidates from brazilian biodiversity.

Total synthesis of (-)-indolizidine 167B via an unusual Wolff rearrangement from an alpha,beta-unsaturated diazoketone

A concise synthesis of the (-)-indolizidine alkaloid 167B and two formal syntheses of (-)-indolizidine 209D and (-)-coniceine are described in just three steps from an alpha,beta-unsaturated diazoketone, via an unusual photochemical Wolff rearrangement. Preparation of the unsaturated diazoketone is straightforward from N-Cbz-prolinal and a 3-diazo-2-oxopropylphosphonate, employing a Horner-Wadsworth-Emmons reaction. The strategy should be feasible and easily adaptable to the synthesis of other indolizidine alkaloids and analogues. (C) 2011 Elsevier Ltd. All rights reserved.

Total Synthesis of (+)-trans-Trikentrin A

Several syntheses have already been reported for cis-trikentrins and herbindoles, which are indole alkaloids unsubstituted at the C2 and C3 positions that bear a trans-1,3-dimethylcyclopentyl unit. Herein, we describe the first asymmetric and stereoselective synthesis of the more challenging trans-trikentrin A as its naturally occurring isomer. Different approaches were investigated and the strategy of choice was a combination of an enzymatic kinetic resolution and a thallium(III)-mediated ring contraction. The antiproliferative activities of the natural product and related intermediates have been tested against human tumor cell lines, leading to the discovery of new compounds with potent antitumor activity.

History and Epistemology of Science in the Classroom: The Synthesis of Quinine as a Proposal

The history of the quinine synthesis can be used as a case study to emphasize that science is influenced by social and historical processes. The first efforts toward the synthesis of this substance, which until recently was the only treatment for malaria, were by Perkin in 1856 when, trying to obtain quinine,,. he synthesized mauveine. Since then, the quest for the total synthesis of quinine involved several characters in a web of controversies. A major step in this process was made in 1918 by Rabe and Kindler, who proposed the synthesis of quinine from quinotoxine. Twenty-six years later, after obtaining the total synthesis of quinotoxine, Woodward and Doering announced the total synthesis of quinine. However, the lack of experimental details about Rabe and Kindler's process, associated with Woodward and Doering's failure to reproduce it, raised a series of doubts about the synthesis. Stork and colleagues questioned the veracity of the experimental data and even the scientific reputation of the involved researchers. Doubts remained alive until 2008, when Williams and Smith reported, not without reservations, the reproducibility of Rabe and Kindler's protocol. The scientific knowledge as a social and historical development, its legitimating process, and the absence of neutrality in science constitute aspects that can be discussed from this case study, providing significant contributions to science education, in particular, to the initial or continued training of chemistry teachers.

Stereoselective Catalytic Processes for the Synthesis of Polycyclic Aromatic Compounds

In this PhD-thesis, two methodologies for enantioselective intramolecular ring closing reaction on indole cores are presented. The first methodology represents a highly stereoselective alkylation of the indole N1-nitrogen, leading to 3,4-dihydro-pyrazinoindol-1-ones – a structural class which is known for its activity on the CNS and therefore of high pharmacological interest concerning related diseases. In this approach, N-benzyl cinchona-alkaloids were used for the efficient catalysis of intramolecular aza-Michael reactions. Furthermore, computational studies in collaboration with the research group Prof. Andrea Bottoni (Department of Chemistry “G. Ciamician”, Bologna) were accomplished in order to get insight into the key interactions between catalyst and substrate, leading to enantiomeric excesses up to 91%. The results of the calculations on a model system are in accordance with the experimental results and demonstrate the high sensibility of the system towards structural modifications. The second project deals with a metal catalyzed, intramolecular Friedel-Crafts (FC)-reaction on indolyl substrates, carrying a side chain which on its behalf is furnished with an allylic alcohol unit. Allylic alcohols are part of the structural class of “π-activated alcohols” – alcohols, which are more easily activated due to the proximity to a π-unit (allyl-, propargyl-, benzyl-). The enantioselective intramolecular cyclization event is catalyzed efficiently by employment of a chiral Au(I)-catalyst, leading to 1-vinyl- or 4-vinyl-tetrahydrocarbazoles (THCs) under the formation of water as byproduct. This striking and novel process concerning the direct activation of alcohols in catalytic FC-reactions was subsequently extended to similar precursors, leading to functionalized tetrahydro-β-carbolines. These two methodologies represent highly efficient approaches towards the synthesis of scaffolds, which are of enormous pharmaceutical interest and amplify the spectra of enantioselective catalytic functionalisations of indoles.

Organocatalytic tandem reactions of polyfunctional compounds for the synthesis of enantioenriched heterocycles. Reazioni tandem organocatalitiche di composti polifunzionali per la sintesi di eterocicli enantioarricchiti.

In questo lavoro di tesi sono state sviluppate reazioni domino, tandem e procedure one-pot per ottenere eterocicli enatioarricchiti. Lo sviluppo di queste metodologie sintetiche è molto importante perché permettono di ottenere molecole complesse partendo da prodotti semplici, senza effettuare ripetuti passaggi di purificazione (stop-and-go or step-by-step synthesis). Lo scopo di questo lavoro è di ottenere derivati tetraidrofuranici modificati e derivati ossoazzolinici enantioarrichiti tramite reazioni SN2-Michael o tramite reazioni aldolica-ciclizzazione-Michael usando la catalisi asimmetrica a trasferimento di fase (PTC). Come catalizzatori PTC per imprimere enantioselezione sono stati utilizzati sali di ammonio quaternario derivati dagli alcaloidi della Cinchona. Sono state ottimizzate le condizioni di reazione (base inorganica, temperatura, solvente, tempo di reazione) per i diversi substrati presi in considerazione. I prodotti target sono stati ottenuti con buone rese, ottime diastereoselezioni ma con bassa enantioselezione. I risultati ottenuti richiedono un’ulteriore ottimizzazione e dovranno essere valutate variazioni strutturali dei nucleofili utilizzati. In this thesis were developed domino, tandem reactions and one-pot procedures to obtained enantioenriched heterocycles. The development of these methodologies is very fundamental because they allow to obtain complex molecules starting from raw materials, without carrying out repeated purification steps (stop-and-go or step-by-step synthesis). The purpose of this work is to obtain enantioenriched tetrahydrofuran and oxazoline derivatives through a SN2-Michael reaction or a aldol- cyclization-Michael reaction using the phase-transfer asymmetric catalysis (PTC). For imprint enantioselection we used Cinchona alkaloids quaternary ammonium salts derivatives. The reaction conditions (inorganic base, temperature, solvent, reaction time) were optimised for the different substrates taken into account. The target products were obtained with good yields, excellent diastereoselections but with low enantioselections. The obtained results require further optimization and structural changes in the nucleophiles used must be evaluated.

Beyond simple proton transfer processes: domino reactions between 4-substituted indoles and nitroethene as a new gateway to ergot alkaloids

The multimodal biology activity of ergot alkaloids is known by humankind since middle ages. Synthetically modified ergot alkaloids are used for the treatment of various medical conditions. Despite the great progress in organic syntheses, the total synthesis of ergot alkaloids remains a great challenge due to the complexity of their polycyclic structure with multiple stereogenic centres. This project has developed a new domino reaction between indoles bearing a Michael acceptor at the 4 position and nitroethene, leading to potential ergot alkaloid precursors in highly enantioenriched form. The reaction was optimised and applied to a large variety of substrate with good results. Even if unfortunately all attempts to further modify the obtained polycyclic structure failed, it was found a reaction able to produce the diastereoisomer of the polycyclic product in excellent yields. The compounds synthetized were characterized by NMR and ESIMS analysis confirming the structure and their enantiomeric excess was determined by chiral stationary phase HPLC. The mechanism of the reaction was evaluated by DFT calculations, showing the formation of a key bicoordinated nitronate intermediate, and fully accounting for the results observed with all substrates. The relative and absolute configuration of the adducts were determined by a combination of NMR, ECD and computational methods.

New Indole Alkaloids from the bark of Alstonia scholaris

A new indole alkaloid, akuammiginone (1), and a new glycosidic indole alkaloid, echitamidine-N-oxide 19-O-beta-D-glucopyranoside (2), together with the five known alkaloids, echitaminic acid (3), echitamidine N-oxide (4), N-b-demethylalstogustine N-oxide (5), akuammicine N-oxide (6), and N-b-demethylalstogustine (7), were isolated from the trunk bark of Alstonia scholaris collected in Timor, Indonesia. The structures of all compounds were elucidated by spectroscopic methods. This is the first report of compounds 3-5 and 7 in A. scholaris. Some NMR assignments of the known compounds were revised.

I. Synthetic Studies Toward the Total Synthesis of Polycyclic Natural Products – Communesin F, Perophoramidine and Ineleganolide. II. Nickel Catalyzed Intramolecular C–O Bond Formation

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the o-nitrobenzyl group is disclosed – this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine.

In addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C–P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess.

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.

Finally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group.

Design, Synthesis And Biological Evaluation Of Hybrid Bioisoster Derivatives Of N-acylhydrazone And Furoxan Groups With Potential And Selective Anti-trypanosoma Cruzi Activity.

Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated. The two most active compounds (6, 14) both in the parasite amastigotes and in the enzyme contain the nitro group in para position of the aromatic ring. The permeability screening in Caco-2 cell and cytotoxicity assay in human cells were performed for those most active compounds and both showed to be less cytotoxic than the reference drug, benznidazole. Compound 6 was the most promising, since besides activity it showed good permeability and selectivity index, higher than the reference drug. Thereby the compound 6 was considered as a possible candidate for additional studies.

Synthesis And Antiproliferative Activity Of 8-hydroxyquinoline Derivatives Containing A 1,2,3-triazole Moiety.

Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25 μg mL(-1)); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI50 = 0.43 μg mL(-1)). In structure-activity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the α-glucosidase active site to predict the possible mechanism of action of this series of compounds.

Lawsonia Inermis-mediated Synthesis Of Silver Nanoparticles: Activity Against Human Pathogenic Fungi And Bacteria With Special Reference To Formulation Of An Antimicrobial Nanogel.

Lawsonia inermis mediated synthesis of silver nanoparticles (Ag-NPs) and its efficacy against Candida albicans, Microsporum canis, Propioniabacterium acne and Trichophyton mentagrophytes is reported. A two-step mechanism has been proposed for bioreduction and formation of an intermediate complex leading to the synthesis of capped nanoparticles was developed. In addition, antimicrobial gel for M. canis and T. mentagrophytes was also formulated. Ag-NPs were synthesized by challenging the leaft extract of L. inermis with 1 mM AgNO₃. The Ag-NPs were characterized by Ultraviolet-Visible (UV-Vis) spectrophotometer and Fourier transform infrared spectroscopy (FTIR). Transmission electron microscopy (TEM), nanoparticle tracking and analysis sytem (NTA) and zeta potential was measured to detect the size of Ag-NPs. The antimicrobial activity of Ag-NPs was evaluated by disc diffusion method against the test organisms. Thus these Ag-NPs may prove as a better candidate drug due to their biogenic nature. Moreover, Ag-NPs may be an answer to the drug-resistant microorganisms.

Stereoselective Synthesis Of Aryl Cyclopentene Scaffolds By Heck-matsuda Desymmetrization Of 3-cyclopentenol.

A new enantioselective Heck-Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee's, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cis- arrangement in the formation of the 4-aryl-cyclopentenols.