Synthesis of chiral compounds - ICB Istituto di Chimica Biomolecolare

Istituto di Chimica Biomolecolare,
UOS DI CATANIA - Via Paolo Gaifami, 18
Chemical modification of natural compounds for phytotherapic/nutraceutical applications, synthesis of intermediates and products with pharmacological interest require the
development of highly efficient and selective methodologies in order to minimize waste and purification steps. Chiral compounds additionally demand high optical purity
since biological activity often resides in only one enantiomer of the molecule. In this context, the research activity is focused on the development of sustainable synthetic
methodologies by means of the use of ecocompatible solvents, biocatalyzed transformations and asymmetric catalytic synthesis.
Nitrilase, nitrile hydratase and amidase:
hydrolytic enzymes capable of transforming
stereoselectively the nitrile group in the carboxyl
group in mild reaction conditions.
Hydrolytic enzymes
are widely employed
in organic synthesis
due to their high
chemo-, regio- and
stereoselectivity, large substrate
acceptance, stability in both
aqueous and organic solvent,
relatively low cost and the
possibility to modulate their
activity by solvent engineering
or the use of suitable additives.
Synthetic applications
b-Glucosidase inhibitor
And Anti-HIV agent
drugs (NSAIDs)
Lipases: in absence of water are able to reverse their physiological
activity and stereoselectively catalyze esterification, alcoholysis,
transacylations and aminolysis reactions in mild conditions.
In organic solvent the direct esterification of a carboxylic acid is
irreversible in the presence of alkyl carbonates and alkyl orthoformates
that remove the formed water
Enzymatic and chemical enantiomeric resolution
Kinetic resolution is a widely used procedure in organic chemistry to separate the enantiomers of
a racemic mixture exploiting the differences of reactivity between the two optical antipodes
towards reagents or chiral catalysts. Enzymatic catalysis is a valuable approach for its versatility,
stereoselectivity, low cost and the “green features” typical of biocatalytic methodologies.
In same instances chemical catalysts have been also employed in racemate resolution through the conversion
of the two enantiomers into a couple of diastereoisomers by generation of new stereogenic centers.
Lipase-catalyzed kinetic resolution of racemic mixtures
Morrone, R.; D'Antona, N.; Biondi, D.; Lambusta, D.; Nicolosi, G. J. Mol. Cat. B: Enzymatic 2012, 84, 173
Morrone, R.; D'Antona, N.; Lambusta, D.; Nicolosi, G. J. Mol. Cat. B: Enzymatic 2010, 65, 49
Synthetic applications
 Lipases are able to transform the
enantiomers of a racemic mixture with
different reaction rate.
Ferrocenyl derivatives
Precursors of biologically
active compounds
D’Antona, N.; Morrone, R.; Bovicelli, P.; Gambera G.; Kubáč, D.; Martínková, L. Tetrahedron: Asymm. 2010, 21, 2448
 Acting on reaction conditions it is
possible to improve the lipase
D’Antona, N.; Morrone, R.; Nicolosi, G.; Pedotti, S. RSC Adv 2013, 3, 11456
Martínková, L; Stolz, A.; Van Rantwijk, F.; D’Antona, N.; Brady, D.; Otten, L.G. Riva, S.; Fessner, W.F; Wiley, 2014, 249
 Lipases are even able to transform
selectively opposite chiral centers
present in the same molecule
(desymmetrization of meso forms)
Synthesis of chiral compounds
Chirality is a fundamental dimension for biological activity and there is a
growing demand for synthetic methods leading to single or enriched
Chemical modification of “chiral pool” can be advantageously exploited for
the synthesis of compounds with multiple stereogenic centres starting from
relatively inexpensive and renewable source of chirality.
Asymmetric catalytic synthesis is a powerful strategy for the generation of stereogenic
centre(s) starting from achiral compounds and the stereoselective construction of molecular
complexity through the intermolecular chirality transfer from a chemical catalyst, which can be
suitable designed to maximize the efficiency of the process.
Zingerol dimer
Zingerol dimer
Sanfilippo, C., Nicolosi, G., Patti, A. Curr. Org. Chem. 2012, 16, 1636
Sanfilippo, C., Patti, A., Dettori, M.A., Fabbri, D., Delogu, G.
J. Mol. Catal. B: Enzym. 2013, 90, 107
unreacted substrates
acylated products
Sanfilippo, C., Nicolosi, G., Patti, A. J. Mol. Catal. B: Enzym. 2014, 104, 82
Resolution of planar chirality via asymmetric reduction
The oxazaborolidine catalyst promoted
the stereoselective reduction of
carbonyl group in the substrate and the
efficiency of the asymmetry induction
was not influenced by the pre-existing
chirality in the substrate.
Synthesis of Glycerophosphoinositol (GPI) Derivatives
parallel kinetic resolution
Glycerophosphoinositols (GPIs) are a class of naturally occurring metabolites
with effects on cell proliferation, motility and invasiveness. They are
catabolised/inactivated by glycerophosphodiester phosphodiesterases (GDEs).
Patti, A.; Pedotti, S. Tetrahedron:Asymmetry 2010, 21, 2631-2637
Sustainable synthesis
GPI analogues stabilised toward the hydrolytic
action of phosphodiesterases
Greco, G.; D’Antona, N.; Gambera, G.;
Nicolosi, G. Synlett. 2014, 25.
a natural
PON 01_00862 :
An integrated technological platform for the
development of new drugs for rare diseases
«on water»
Novel catalysts for asymmetric synthesis
Starting from a variety of functionalized
aldehydes and ketones, tetrahydroquinolines
or quinolines can be selectively obtained by
simple modification of the experimental
conditions (solvent, hydrogen source).
The heteroaromatic scaffold is present in a
variety of biologically active compounds
Lipase-catalyzed green oxidation of C=C double bond
In sustainable synthesis central emphasis need to be
given to waste prevention, reduced energy
requirements and low toxicity for human health and
environment. In this context, multicomponent and
cascade reactions, microwave assisted synthesis and
the use of water as solvent offer valuable contributes.
Chemical step
oxidation of C=C bond
Patti, A.; Pedotti, S. Tetrahedron 2010, 66, 5607-5611
A family of ferrocene-proline conjugates was synthesized and
evaluated for their catalytic activity in the asymmetric aldol the catalyst
(5% mol)
condensation in water. The introduction of the ferrocenyl
moiety led to enhanced efficiency in comparison with the
proline. The reaction proceeded in “on water” conditions and
displayed broad substrate scope and high enantioselectivity
Enzymatic step
Lipase-catalyzed acid oxidation
Tested for antimalarial activity
the product
90-94% ee
Patti, A.; Pedotti, S. Eur. J. Org. Chem. 2014, 624-630
doubled activity compared with the
phenyl analogues
Reductive intramolecular cyclization
Patti, A.; Pedotti, S. T. Grassi, A. Idolo, M. Guido, A.
De Donno J. Organomet. Chem. 2012, 716, 216-221
Patti, A.; Pedotti, S. J. Sep. Sci. 2014, in press, DOI: 10.1002/jssc.201400838
Novel biomimetic oxidant systems based on hydrogen peroxide are
promising alternatives to the current process for their high atom economy
and the production of water as the only by-product
Multivalency is the strategy that nature utilizes to increase avidity, specificity, and selectivity in molecular recognition events. Calix[n]arene macrocycles, which offer
oligomers with different size, shape and conformational flexibility, are promising molecular platforms to be engineered for biomedical applications. The research activity is
focused on the development of large multivalent molecules able to act as ligands of biologically relevant species and assemble in supramolecular nanostructures useful for
nanomedicine applications.
From molecular recognition to biomedical devices
Calixarenes as scaffolds to build
potential anticancer vaccines
Fluorescence (AU)
Calixarene-based Drug Delivery Systems
Monovalent reference
Cell recognition analysis for specific antiMUC1 antibodies tested on MCF7 human
breast cancer cells. No antibody binding was
observed for SK-MEL-28 cell.
Calix[4]arene engineered for
selective tumor cell imaging
Design, synthesis, and drug solubilising properties of the
first folate–calix[4]arene conjugate
Grazia M. L. Consoli, Giuseppe Granata, Corrada Geraci
Org. Biomol. Chem. 2011, 9, 6491–6495
From this result…
…. topical ophtalmic application
First self-adjuvant multicomponent potential vaccine
candidates by tethering of four or eight MUC1 antigenic
immunodominant PDTRP units on a calixarene platform:
synthesis and biological evaluation
Corrada Geraci, Grazia M. L. Consoli, Giuseppe
Granata, Eva Galante, Angelo Palmigiano, Maria
Pappalardo, Salvatore D. Di Puma, Angelo Spadaro
Bioconjugate Chem. 2013, 24, 1710−1720
Sicily Technologic District Micro and Nano Systems
Development of antithrombogenic
materials and blood filters
Development of Micro and Nano-technologies
and Advanced Systems to the Men’s Health
Polycationic calix[8]arene receptors
grafted onto polymeric matrix: smart
material for heparin neutralization
Tommaso Mecca, Francesca Cunsolo,
Polym. Adv. Technol. 2010, 21, 752757
pH-sensitive hydrogel (pH 4.5-5)
Potential drug delivery
systems for…
Physiological pH
Dissolution and drug release
C8-Lysine – Heparin complex
Polycationic calix[8]arenes able to recognize and neutralize heparin
Tommaso Mecca, Grazia M. L. Consoli, Corrada Geraci, Rita La
Spina, Francesca Cunsolo,
Org. Biomol. Chem. 2006, 4, 3763-3768
…….ocular diseases
Selected for Patent
DH  100 nm
DH  200 nm
ASGP-R D-galactose receptor
• Colloidal solution
• High drug loading capacity
• Low corneal cell toxicity
Highly selective tumor cell uptake
Fluorescent labeled
folate–calixarene conjugate
• Antibacterial activity
Biocompatible macroporous
cryogel able to sequester heparin
Chemically modified poly(2-hydroxyethyl methacrylate)
cryogel for the adsorption of heparin
Rita La Spina, Carla Tripisciano, Tommaso Mecca,
Francesca Cunsolo, Viktoria Weber, Bo Mattiasson
J. Biomed. Mat. Res. B 2014, 102, 1207-1216
Development of a Heparin
filter for dialysis applications