Research Platform: Chemistry for Life

Asymmetric synthesis of di- and polyaza ligands

admin — 2012-04-02T09:55:00Z

Also involved: Dr. A. Gualandi, L. Cerisoli

Enantiopure 1,2-diamines are useful ligands of organometallic compounds and metal complexes active as stoichiometric or catalytic reagents in a variety of asymmetric transformations. We have been involved for many years in a research directed to the preparation of new ligands containing two or more nitrogen atoms, even in the form of aromatic or saturated cyclic nitrogen heterocycles, especially pyridine and aziridine. To achieve this goal we have principally exploited the diastereoselective organometallic addition to chiral aldimines prepared by condensation of glyoxal and aromatic aldehydes with optically pure amines such as (R)- or (S)-1-phenylethylamine, (S)-valine, (S)-valinol, (S)- or (R)-phenylglycinol and (S,S)- or (R,R)-1,2-diaminocyclohexane.

References

G. Alvaro, D. Savoia: “Addition of organometallic reagents to imines bearing stereogenic N-substituents. Stereochemical models explaining the 1,3-asymmetric induction”; Synlett 2002, 651.
G. Martelli, D. Savoia: “Stereoselective synthesis of 1,2-difunctional compounds through the addition of organometallic reagents to chiral masked forms of glyoxal”; Curr. Org. Chem. 2003, 7, 1049.
V. Bette, A. Mortreux, F. Ferioli, G. Martelli, D. Savoia, J.-F. Carpentier, “New chiral 1,2-diamines and heir use in zinc.catalyzed asymmetric hydrosilylation of acetophenone”; Eur J Org Chem 2004, 3040-3045.
V. Bette, A. Mortreux, D. Savoia, J.-F. Carpentier, “[Zinc-diamine]-catalyzed hydrosilylation of ketones in methanol. New developments and mechanistic insight”, Adv. Synth. Catal. 2005, 347, 289-302.
D. Savoia, G. Alvaro, R. Di Fabio, C. Fiorelli, A. Gualandi, M. Monari, F. Piccinelli: “Highly diastereoselective synthesis of 2,6-di[1-(2-alkylaziridin-1-yl)alkyl]pyridines, useful ligands in palladium-catalyzed asymmetric allylic alkylation”, Adv. Synth. Catal. 2006, 348, 1883-1893.
D. Savoia, G. Alvaro, R. Di Fabio, A. Gualandi: “Asymmetric Route to Pyridines Bearing a Highly Functionalized 2-Alkyl Substituent by Aziridine Ring-Opening Reactions”, J. Org. Chem. 2007, 72, 3859-3862.
A. Gualandi, F. Manoni, M. Monari, D. Savoia: “Stereoselective Synthesis of Substituted 1,2-Ethylenediaziridines and Their Use as Ligands in Palladium-Catalyzed Asymmetric Allylic Alkylation”, Tetrahedron 2010, 66, 715-720.

Cyclic analogues of bioactive peptides

admin — 2012-04-02T09:55:00Z

Also involved: R. De Marco

Cyclic peptides have been widely utilized as templates for the design of different kinds of turn-like structures. In particular, several examples of cyclic, bicyclic or spirocyclic peptidomimetic and non-peptidic scaffolds have been reported in the literature as turn mimicking structures. Our interest is focused on the design, synthesis and conformational analysis of cyclotetrapeptides and partially modified retro-inverso (PMRI)-cyclotetrapeptide models, with a predictable 3D display of the side chains, useful for targeting specific bioactive conformations. As prototypic examples, we studied the models for testing some selected, novel RGD peptidomimetic compounds capable to interfere with integrin receptors and cyclic analogues of the tetrapeptides endomorphin-1 (EM-1, H-Tyr-Pro-Trp-Phe-NH2, and endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2), that have been found to activate μ-opioid receptor (MOR) with high affinity and selectivity.

References

Gentilucci, L.; Cardillo, G.; Spampinato, S.; Tolomelli, A.; Squassabia, F.; De Marco, R.; Bedini, A.; Baiula, M.; Belvisi, L.; Civera, M.. "Antiangiogenic Effect of Dual/Selective α 5β 1/α vβ 3 Integrin Antagonists Designed on Partially Modified Retro-Inverso Cyclotetrapeptide Mimetics" J. Med. Chem. 2010, 53, 106-118.
Gentilucci, L.; Cardillo, G.; Tolomelli, A.; De Marco, R.; Garelli, A.; Spampinato, S.; Sparta, A.; Juaristi, E. "Synthesis and Conformational Analysis of Cyclotetrapeptide Mimetic β-Turn Templates and Validation as 3D Scaffolds" ChemMedChem 2009, 4, 517-523.

Design and Synthesis of New Antimalarial Drugs

admin — 2012-04-02T09:55:00Z

Malaria is an infectious disease causing more than one million deaths per year. Nowadays, the number of active drugs effective against malaria is small and is further narrowing due to the selection of resistant parasite strains. Artemisinin is a natural compound isolated from the plant Artemisia annua, characterized by the presence of an endoperoxide moiety and displaying interesting activities towards resistant strains. Several Artemisinin based drugs have been recently proposed, i.e. Artemether by Novartis, but their complex structure makes these drugs too expensive for a wide use in the less developed countries.
Plakortin is as polyketide metabolite isolated in useful amounts from the Caribbean marine sponge Plakortis simplex that shows a remarkable antimalarial activity against resistant strains. It’s structural simplicity compared to Artemisinin makes Plakortin an interesting model for the rational design of more easily accessible and economic active molecules.

Hyperfine structure investigation: the Lamb-dip technique

admin — 2012-03-29T10:15:00Z

Rotational half-widths can be reduced by one order of magnitude by using the Lamb-dip technique. Therefore, this technique allows us to resolve hyperfine structures due to nuclear quadrupole coupling, and/or spin-rotation and/or spin-spin interactions. Thus, the Lamb-dip technique permits to very accurately determine rotational transition frequencies and parameters. Consequently, it is clear that this technique has a fundamental role in investigating molecular species of astrophysical as well as atmospherical interest.

References

G. Cazzoli & C. Puzzarini, J. Molec. Spectrosc. 226, 161 (2005), (cover picture JMS vol. 226)

Lineshape analysis

admin — 2012-03-29T10:15:00Z

The composition of the atmosphere is indeed very important to understand chemical processes linked to depletion of stratospheric ozone and greenhouse effect. The vertical concentration profiles of atmospheric gases can be provided by remote sensing measurements, but they require the accurate knowledge of the parameters involved: line positions, transition intensities, pressure-broadened half-widths, pressure-induced frequency shifts and their temperature dependence. In particular, the collisional broadening parameters have a crucial influence on the accuracy of spectra calculations and on reduction of remote sensing data.

As concerns astrophysics, for accurately modeling the astronomical observations as well as the energy exchange processes, the collisional rate coefficients related collisional and radiative processes are essential. Among the various experimental data that allow to validate their determination, a relevant role is played by the pressure-broadening coefficients of rotational transitions of the molecules involved, determined at the typical temperatures of the interstellar medium (5-200 K).

References

G. Cazzoli et al., J. Molec. Spectrosc. 229, 158 (2005) [in the frame of: ESA (European Space Agency) Contract N. 16377/02/NL/FF, ESTEC (2004)]

Organocatalyzed synthesis of biologically active compounds

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The cross-aldol addition is one of the most important carbon-carbon bond forming reaction, both as synthetic and as biosynthetic reaction. Among the approaches to control the regio- and stereochemistry of the adducts, organocatalysis is a very promising feature, as it avoids the use of any metal. The regio- and stereochemistry of this reaction has been extensively studied, and very interesting results have been obtained when more then one stereogenic centre is formed. The best results were obtained with 10 mol% of H-D-Pro-L-β³-hPhg-OBn as catalyst. Following this approach, the first total synthesis of (R)-Convolutamydine A has been achieved by the organocatalytic addition of acetone to 4,6-dibromoisatin and the metal free cross-aldol addition of hydroxyacetone (HA) to p-nitro and m-nitrobenzaldehyde catalysed by three di- or tripeptides, all containing D-Pro in the N-terminal position has been studied.
Furthermore the synthesis of imidazolidin-2-one-4-carboxylate and of (tetrahydro)pyrimidin-2-one-5-carboxylate via an efficient modification of the Hofmann rearrangement has been achieved. In our approach, imidazolidin-2-ones-4-carboxylates and (tetrahydro)pyrimidin-2-one-5-carboxylates were obtained in a short time and under very mild conditions by reaction. PhI(OAc)² was the source of iodine (III); this method proved to be quite general because it can be applied to both amino acids in the presence of several protecting groups.

References

Gianluigi Luppi, Magda Monari, Rodrigo J. Corrêa, Flavio de A. Violante, Angelo C. Pinto, Bernard Kaptein, Quirinus B. Broxterman, Simon J. Garden, Claudia Tomasini – “The First Total Synthesis of (R)-Convolutamydine A”, Tetrahedron, 2006, 62, 12017–12024
.Gaetano Angelici, Simone Contaldi, Sarah Lynn Green, Claudia Tomasini – “Synthesis of imidazolidin-2-one-4-carboxylate and of (tetrahydro)pyrimidin-2-one-5-carboxylate via an efficient modification of the Hofmann rearrangement”, Org. & Biomol. Chem., 2008, 6, 1849-1852

Rotational spectroscopy of transient species produced by electric discharge or pyrolysis

admin — 2012-03-29T10:15:00Z

Electric discharges can be used to produce molecular ions, radicals, and unstable neutral molecules in the gas phase. The study of rotational spectra of molecular ions is of particular interest in relation to a possible detection of these species in the interstellar medium by radioastronomers. Gas-phase, high-temperature reactions (above 1000 °C) allow for the production of unstable molecules, which can be detected using high-resolution spectroscopy techniques.

References

G. Cazzoli & C. Puzzarini, J. Chem. Phys. 123, 041101 (2005)

Stereoselective synthesis of diamines

admin — 2012-04-02T09:55:00Z

Also involved: Dr. A. Gualandi, L. Cerisoli

Bis-homoallylic-1,2-diamines can be transformed in different bicyclic compounds exploiting the activation of the alkene double bond(s) by suitable electrofiles. For example, the iodine-mediated cyclization of differently substituted, optically pure 4,5-diamino-1,7-octadienes leads to substituted 2,5-diaza[2.2.1]diazabicyclooctanes. Electrophile-mediated cyclizations of optically pure 1,2-diaminocyclohex-4-ene are currently being investigated as a route to 2-amino-7-azabicyclo[2.2.1]heptane with potential pharmacological activity.

References

G. Alvaro, R. Di Fabio, A. Gualandi, C. Fiorelli, M. Monari, D. Savoia, L. Zoli: “Stereoselective synthesis of substituted 2,5-diazabicyclo[2.2.1]heptanes by iodine-mediated cyclization of optically pure compounds containing the 4,5-diamino-1,7-octadiene and 1,2-diamino-4-alkene moieties”, Tetrahedron 2007, 63, 12446-12453.
S. Grilli, G. Martelli, D. Savoia, C. Zazzetta: “Progress towards the stereoselective synthesis of 3,6-disubstituted 1,2-diamino-4-cyclohexenes by ring closing metathesis reaction”; Adv. Synth. Catal. 2002, 344, 1068.
C. Boga, C. Fiorelli, D. Savoia: “Stereoselective synthesis of 3,6-disubstituted-1,2-diaminocyclohexanes through ring closing metathesis of 4,5-diamino-1,7-octadienes derivatives”, Synthesis 2006, 285-292.

Stereoselective synthesis of natural compounds with pyrrole nucleus

admin — 2012-04-02T09:55:00Z

Also involved: Dr. A. Gualandi, L. Cerisoli

2-Pyrrolecarboxaldehyde has bee used as the starting material for the preparation of the four diastereomers of 8-aminoindolizidine by a short sequence involving as the key steps the allylmetalation of a derived chiral imine, a ring-closing metathesis reaction and hydrogenation of the pyrrole ring. Hydrogenation of calyx[4]pyrrole has been investigated with a variety of catalysts in different conditions in order to optimize the regio- and stereoselective full or half-reduction to the macrocycles containing four pyrrolidine rings or alternating pyrrole and pyrrolidine rings. 2,2’-(dimethylmethyl)dipyrrole-5,5’-dicarboxaldehyde was condensed with an equimolar amount of (R,R)-1,2-diaminocyclohexane to obtain the first example of a chiral octaazamacrocycle containing pyrrole rings, the structure and the coordinating and organocatalytic properties of which are under investigation.

References

V. G. Albano, A. Gualandi, M. Monari, D. Savoia: “Asymmetric synthesis of 8-aminoindolizidine from chiral 2-pyrroleimines”, J. Org. Chem. 2008, 73, 8376-8381.
D. Savoia, A. Gualandi: “Chiral perazamacrocycles: synthesis and applications. Part 1”, Curr. Org. Synth. 2009, 102-118.
D. Savoia,* A. Gualandi: “Chiral perazamacrocycles: synthesis and applications. Part 2”, Curr. Org. Synth. 2009, 119-142.
G. Journot, C. Letondor, R. Neier, H. Stoeckli-Evans, D. Savoia, A. Gualandi: “Catalytic Hydrogenation of meso-Octamethylporphyrinogen (Calix[4]pyrrole)”, submitted.

Synthesis of bioactive compounds using microwaves and microreactors

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Silyloxy azadienes have been shown to be useful and versatile starting compounds for the synthesis of nitrogen heterocycles presenting biological activity as such or by suitable elaborations. These intermediates have the particularity to enable the formation of four important classes of heterocycles: b-lactams, through a direct electrocyclic closure, a pyrrolidin-2.4-dione moiety, a tetrahydrooxazinone, through a hetero Diels-Alder reaction in presence of a carbonyl compound, and a piperidine scaffold with activated dienophiles. We have recently shown that, using this synythetic strategy, important drugs as Prozac, Venlafaxine and Duloxetine have ben obtained. Coupling these new reactions with MAOS (Microwaves Assisted Organic Synthesis) techniques has allowed to obtain such compounds in easier conditions and better yelds.The different cyclization paths are currently under theoretical investigation.

Synthesis, conformational analysis and applications of foldamers

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Short synthetic oligomers that tend to assume an ordered conformation have been defined as “foldamers”. The essential requirement for an oligomer to be included in the foldamer family is to possess a well defined, repetitive secondary structure, imparted by conformational restrictions of the monomeric unit. These simplified artificial systems based on artificial backbones designed to fold in secondary structures may be used for the de novo design of molecules with interesting biological activities. Unnatural foldamers may have homogeneous or heterogeneous (also defined “hybrid”) backbones.
So 4-carboxy oxazolidin-2-ones were designed as new, conformationally restricted building blocks for the construction of pseudopeptide foldamers. The preferred three-dimensional structure of trans-(4S,5R) 4-carboxy oxazolidin-2-one (Oxd) homo-oligomers is a poly-(L-Pro)_n II like helical conformation, stabilized by αC-H···O=C intramolecular hydrogen bonds.
Among the numerous foldamer classes, the study of hybrid foldamers consisting of different constituents is gaining more and more interest, because endless conformational variants can be obtained by simply changing their order and/or their total configuration. These heterogeneous backbones, composed of two or more residue types, can also display well-defined folding behaviour. We have recently introduced some new oligomers, the basic unit of which was constructed by coupling an Oxd unit with different α- or β-amino acids. In any case, in the higher oligomers, there is a stronger tendency to form intramolecular instead of intermolecular hydrogen bonds. The formation of ordered secondary structures increases and seems to be realized generally at the pentamer level.

References

Claudia Tomasini, Gianluigi Luppi, Magda Monari – “Oxazolidin-2-ones-Containing Pseudopeptides that Fold into β-Bend Ribbon Spirals”, J. Am. Chem. Soc., 2006, 128, 2410-2420
Gaetano Angelici, Giuseppe Falini, Hans-Jörg Hofmann, Daniel Huster, Magda Monari, Claudia Tomasini - “Nanofibers from Oxazolidi-2-one Containing Hybrid Foldamers: What is the Right Molecular Size?” Chem. Eur. J., 2009, 15, 8037-8048