Asymmetric synthesis of benzylic and heterobenzylic amines

C2-Symmetrical, enantiopure 2,6-di[1-(1-aziridinyl)alkyl]pyridines (DIAZAPs) were prepared by a high-yielding, three-step sequence starting from 2,6-pyridinedicarbaldehyde and (S)-valinol or (S)-phenylglycinol. The new compounds were tested as ligands in palladium-catalyzed allylation of carbanions in different solvents. Almost quantitative yield and up to 99% enantiomeric excess were obtained in the reactions of the enolates derived from malonate, phenyl- and benzylmalonate dimethyl esters with 1,3-diphenyl-2-propenyl ethyl carbonate. Asymmetric synthesis of 2-(2-pyridyl)aziridines from chiral 2-pyridineimines bearing a stereogenic center at the nitrogen atom was development. The envisioned route involves the addition of chloromethyllithium to the imine derived from 2-pyridinealdehyde and (S)-valinol, protected as O-trimethylsilyl ether. The analogous reaction performed on the imine derived from (S)-valine methyl ester gave the product containing the aziridine ring as well as the α-chloro ketone group coming from the attack of chloromethyllithium to the ester function. Other stereogenic alkyl substituents at nitrogen gave less satisfactory results. Moreover, the aziridination protocol did not work on other aromatic imines, e.g. 3-pyridineimine and benzaldimine, which are not capable of bidentate chelation. The N-substituent could not be removed, but aziridine underwent ring-opening by attack of nitrogen, sulfur, and oxygen nucleophiles. Complete or prevalent regioselectivity was obtained using cerium trichloride heptahydrate as a catalyst. In some cases, the N-substituent could be removed by an oxidative protocol. The addition of organometallic (lithium, magnesium, zinc) reagents to 2-pyrroleimines derived from (S)-valinol and (S)-phenylglycinol gave the N-substituted-1-(2-pyrrolyl)alkylamines with high yields and diastereoselectivities. The (S,S)-diastereomers were useful intermediates for the preparation of enantiopure 1-[1-(2-pyrrolyl)alkyl]aziridines by routine cyclization of the β-aminoalcohol moiety and of (S)-N-benzoyl 1-[1-(2-pyrrolyl)alkyl]amines and their N-substituted derivatives by oxidative cleavage of the chiral auxiliary. 1-Allyl-2-pyrroleimines obtained from (S)-phenylglycinol and (S)-valinol underwent highly diastereoselective addition of allylmetal reagents, used in excess amounts, to give the corresponding secondary amines with concomitant allyl to 1-propenyl isomerisation of the 1-pyrrole substituent. Protection of the 2-aminoalcohol moiety as oxazolidinone, amide or Boc derivate followed by ring closing metathesis of the alkene groups gave the unsaturated bicyclic compound, whose hydrogenation afforded the indolizidine derivative as a mixture of separable diastereomers. The absolute configuration of the main diastereomer was assessed by X-ray crystallographic analysis.

Sintesi di molecole biologicamente attive con tecniche chemoenzimatiche:beta-lattami, profeni e alfa-amminoacidi non naturali

Il progetto di ricerca di questa tesi è stato focalizzato sulla sintesi di tre classi di molecole: β-lattami, Profeni e α-amminonitrili, utilizzando moderne tecniche di sintesi organica, metodologie ecosostenibili e strategie biocatalitiche. I profeni sono una categoria di antiinfiammatori molto diffusa e in particolare abbiamo sviluppato e ottimizzato una procedura in due step per ottenere (S)-Profeni da 2-arilpropanali raceme. Il primo step consiste in una bioriduzione delle aldeidi per dare i relativi (S)-2-Aril Propanoli tramite un processo DKR mediato dall’enzima Horse Liver Alcohol Dehydrogenase. Il secondo, l’ossidazione a (S)-Profeni, è promossa da NaClO2 e TEMPO come catalizzatore. Con lo scopo di migliorare il processo, in collaborazione con il gruppo di ricerca di Francesca Paradisi all’University College Dublino abbiamo immobilizzato l’enzima HLADH, ottenendo buone rese e una migliore enantioselettività. Abbiamo inoltre proposto un interessante approccio enzimatico per l’ossidazione degli (S)-2-Aril Propanoli utilizzando una laccasi da Trametes Versicolor. L’anello β-lattamico è un eterociclo molto importante, noto per essere un interessante farmacoforo. Abbiamo sintetizzato nuovi N-metiltio beta-lattami, che hanno mostrato un’attività antibatterica molto interessante contro ceppi resistenti di Staphilococcus Aureus prelevati da pazienti affetti da fibrosis cistica. Abbiamo poi coniugato gruppi polifenolici a questi nuovi β-lattami ottenendo molecule antiossidanti e antibatteriche, cioè con attività duale. Abbiamo poi sintetizzato un nuovo ibrido retinoide-betalattame che ha indotto differenziazione si cellule di neuroblastoma. Abbiamo poi sfruttato la reazione di aperture dell’anello monobattamico tramite enzimi idrolitici, con lo scopo di ottenere β-amminoacidi chirali desimmetrizzati come il monoestere dell’acido β–amminoglutammico. Per quando riguarda gli α-amminonitrili, è stato sviluppato un protocollo di Strecker. Le reazioni sono state molto efficienti utilizzando come fonte di cianuro l’acetone cianidrina in acqua, utilizzando differenti aldeidi e chetoni, ammine primarie e secondarie. Per mettere a punto una versione asimmetrica del protocollo, abbiamo usato ammine chirali con lo scopo di ottenere nuovi α-amminonitrili chirali.

Sintesi e coordinazione di leganti Ciclopentadienilici O-Multifunzionalizzati

The introduction of hydroxyl groups into ligands is able to transfer high hydrophilic features to the related metal systems. The atom-economy synthetic procedure adopted which consists in the one-step Cyclopentene-oxide ring opening, quantitatitatively affords stereoselective formation of the multi-hydroxyl rac-1,2,4- C5H2[CH(CH2)3CHOH]3 Cpººº ligand1. Rh complexation of Cpººº gives rise to a novel class of water-soluble complexes (L,L)RhCpººº (LL=NBD 1, COD 2, CH2CH2 3, CO 4) (Scheme 1) characterized by their spectroscopic features (ESI-MS, IR, 2D NMR, n.O.e.). The X-ray diffraction studies of 1a reveal the occurrence of one couple of enantiomeric pairs in the crystal structure, whilst the crystal packing shows an interesting self-organization in chains of dimeric units of 1a, promoted by strong intermolecular hydroxyl H-bonding. This effect has been exploited by performing VT NMR experiments in different solvents (CDCl3, Py, DMSO). Unpredictably, in the absence of chiral tag, 1 exhibits solvent-dependent chiroptical properties (CD, αD^ 25), which are correlated to UV transitions and DFT calculations. The intra/inter molecular H-binding is crucial in driving the equilibrium between the observed atropisomers 1a and 1b, by varying the planar chirality on the two π-complexes.

Messa a punto di procedure per la semi-sintesi di composti ad attività antitumorale partendo da prodotti naturali. Studi di struttura-attività

Camptothecin, (CPT) is a pentacyclic alkaloid isolated for the first time from the Chinese tree Camptotheca acuminata, and which has soon attracted the attention of medicinal chemists and pharmacologists due to its promising anti-cancer activity against the most aggressive histo-types. So far, most of the synthesized camptothecin analogues are A and B ring modified compounds, which have been prepared via synthetic or semi-synthetic routes. To the best of our knowledge, a very limited number of C, D, or E ring modified analogues of CPT have been reported; moreover, the few derivatives known from the literature showed a reduced or no biological activity. This dissertation presents synthetic studies on camptothecin new derivatives along with the development of a new and general semi-synthetic methodology to obtain a large variety of analogues. We report here the semi-synthesis of a new family of 5-substituted CPT's, along with their biological activity evaluation, which will be compared with reference compounds. The use of carrier-linked prodrugs has emerged as a useful strategy to overcome some of the drawbacks related with the use of the parent drug, such as low solubility, membrane permeability properties, low oral absorption, instability, toxicity, and nontargeting. Herein we report CPT-prodrugs synthesized via ring opening of the lactone moiety as 17-O-acyl camptothecin tripartate conjugates, which bear a polyamine side chain with different architectures, as the carriers. Moreover, we found that the replacement of the oxygen atom with sulphur on the piridone D-ring, dramatically improves the potency of the novel 16a-thio-camptothecin derivatives, opening new possibilities in the modelling of this class of compounds.

Sviluppo di metodi innovativi per la sintesi di nanoparticelle di interesse industriale

Among various nanoparticles, noble metal nanoparticles have attracted considerable attention due to their optical, catalytic and conducting properties. This work has been focused on the development of an innovative method of synthesis for the preparation of metal nanosuspensions of Au, Ag, Cu, in order to achieve stable sols, showing suitable features to allow an industrial scale up of the processes. The research was developed in collaboration with a company interested in the large scale production of the studied nanosuspensions. In order to develop a commercial process, high solid concentration, long time colloidal stability and particle size control, are required. Two synthesis routes, differing by the used solvents, have been implemented: polyol based and water based synthesis. In order to achieve a process intensification the microwave heating has been applied. As a result, colloidal nanosuspensions with suitable dimensions, good optical properties, very high solid content and good stability, have been synthesized by simple and environmental friendly methods. Particularly, due to some interesting results an optimized synthesis process has been patented. Both water and polyol based synthesis, developed in the presence of a reducing agent and of a chelating polymer, allowed to obtain particle size-control and colloidal stability by tuning the different parameters. Furthermore, it has been verified that microwave device, due to its rapid and homogeneous heating, provides some advantages over conventional method. In order to optimize the final suspensions properties, for each synthesis it has been studied the effect of different parameters (temperature, time, precursors concentrations, etc) and throughout a specific optimization action a right control on nucleation and growth processes has been achieved. The achieved nanoparticles were confirmed by XRD analysis to be the desired metal phases, even at the lowest synthesis temperatures. The particles showed a diameter, measured by STEM and dynamic light scattering technique (DLS), ranging from 10 to 60 nm. Surface plasmon resonance (SPR) was monitored by UV-VIS spectroscopy confirming its dependence by nanoparticles size and shape. Moreover the reaction yield has been assessed by ICP analysis performed on the unreacted metal cations. Finally, thermal conductivity and antibacterial activity characterizations of copper and silver sols respectively are now ongoing in order to check their application as nanofluid in heat transfer processes and as antibacterial agent.

Progettazione e sintesi di nuovi derivati azetidinonici biologicamente attivi

In this PhD-thesis new synthetic approaches towards new azetidinone derivatives are described. In particular, 4-alkyliden-β-lactams were used as starting materials for the preparation of new biologically active compounds. The carbapenem Thienamycin has got a broad spectrum of activity as antibiotic. It has got 3 stereocenters and apart of one epimer, all isomers have been synthesized. Using the 4-alkyliden-β-lactam benzilyc ester as precursor, we developed a synthesis for this missing epimer, which is described in chapter II. Biological tests in order to establish its biological activity are under way. The Hunsdiecker-Borodine reaction was extensively studied for the preparation of the mono halogenated and – surprisingly – the dihalogenated derivative from the 4-alkyliden-azetidinone carboxylic acid. The herein described synthetic procedures allowed the preparation of chloro-, bromo- and iodo derivatives in good to excellent yield. Furthermore, the reaction mechanism was investigated by NMR-experiments and is described in detail in chapter III. In chapter IV, synthetic approaches towards new β-lactam derivatives for inhibition of the histone deacetylase enzymes (HDACs) are reported. In collaboration with the company Sigma-Tau (Rome), 14 new β-lactams were synthesized. The new β-lactams were evaluated for the activity showing a promising activityparticulary, 10 of the β-lactams synthesized were evaluated for the in vitro inhibitory activity against the 11 human HDACs isoforms and they showed a selective inhibition of HDAC6 or HDAC8 in micromolar range. Finally, preliminary studies were conducted for the employment of 4-alkyliden-β-lactams as precursors for the synthesis of chiral β-amino acids by an opening of the β-lactam ring. In chapter V is described the ring opening reaction catalyzed by the enzyme lipase Cal-B. Preliminary results have shown that the enzyme not only catalyzes the ring opening of the β-lactam precursor, moreover, it leads to the formation of a cyclic dimer by the reaction of two molecules of β-amino acid obtained.

Sintesi e caratterizzazione di nanopolveri composite allumina-zirconia

Il presente lavoro di tesi riguarda la sintesi di nanopolveri allumina-zirconia, seguendo tre differenti metodologie (sintesi per coprecipitazione, sintesi con il metodo dei citrati, sintesi idrotermale assistita da microonde) e il trattamento termico (calcinazione) delle polveri ottenute, mediante tecniche di riscaldamento convenzionali ed alternative (microonde). Lo scopo del lavoro è consistito nell’individuare, tra le tecniche esaminate, quella più idonea e conveniente, per la preparazione di nanopolveri cristalline 95 mol% Al2O3 – 5 mol% ZrO2 e nell’esaminare gli effetti che la calcinazione condotta con le microonde, ha sulle caratteristiche finali delle polveri, rispetto ai trattamenti termici convenzionali. I risultati ottenuti al termine del lavoro hanno evidenziato che, tra le tecniche di sintesi esaminate, la sintesi idrotermale assistita da microonde, risulta il metodo più indicato e che, il trattamento termico eseguito con le microonde, risulta di gran lunga vantaggioso rispetto a quello convenzionale. La sintesi idrotermale assistita da microonde consente di ottenere polveri nano cristalline poco agglomerate, che possono essere facilmente disaggregate e con caratteristiche microstrutturali del tutto peculiari. L’utilizzo di tale tecnica permette, già dopo la sintesi a 200°C/2ore, di avere ossido di zirconio, mentre per ottenere gli ossidi di alluminio, è sufficiente un ulteriore trattamento termico a basse temperature e di breve durata (400°C/ 5 min). Si è osservato, inoltre, che il trattamento termico condotto con le microonde comporta la formazione delle fasi cristalline desiderate (ossidi di alluminio e zirconio), impiegando (come per la sintesi) tempi e temperature significativamente ridotti. L’esposizione delle polveri per tempi ridotti e a temperature più basse consente di evitare la formazione di aggregati duri nelle nanopolveri finali e di contrastare il manifestarsi di fenomeni di accrescimento di grani, preservando così la “nanostruttura” delle polveri e le sue caratteristiche proprietà.

Nuovi processi catalitici per la sintesi di prodotti ad attività farmacologica

The transition metal-catalyzed allylic alkylation (Tsuji-Trost type reaction) is a powerful tool for C-C, C-N, and C-O bond formation, which has been widely applied to organic chemistry over the last decades. Typical substrates for this transformation are activated allylic compounds such as halides, esters, carbonates, carbamates, phosphates, and so on. However, use of these substrates is associated with the disadvantage of generating a stoichiometric amount of chemical waste. Furthermore, these starting materials have to be prepared in an extra step from the corresponding allylic alcohol. Thus, ideal substrates would be the allylic alcohols themselves, with water being the only byproduct in this case. However, the scarse propensity of the hydroxyl moiety to act as good leaving group has significantly limited their use so far. During the last decade significant efforts have been made in order to develop more atom-economical and environmentally-friendly allylic alkylation protocols by employing allylic alcohols directly. In this PhD dissertation two main projects addressing this topic are presented. “Project 1” deals with the development of new metal-catalyzed intramolecular Friedel-Crafts (FC) allylic alkylations of electron-rich (PAPER A), as well as challenging electron-poor arenes (PAPER B) with alcohols. In “Project 2”, gold(I)-catalyzed intramolecular and stereoselective allylic alkylation reactions are reported. In particular, a FC alkylation of indole-containing allylic alcohols is presented in PAPER C. While, an O-alkylation of aminol-containing allylic alcohols is reported in PAPER D. To the best of knowledge, these reports represent the first example of gold(I)-catalyzed stereoselective alkylations with alcohols.