COMUNICAZIONI ORALI
O1 – O52
O1
Stereoselective Diels Alder Reactions Catalyzed by Immobilized Chiral
Catalysts in Continuous Flow Systems
Maurizio Benaglia
Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi, 19, Milano, Italy.
[email protected]
Recent progress in flow chemistry techniques using mini and micro flow reactors have
opened a new era in chemical synthesis; the use of reactors in combination with
supported reagents, scavengers and catalysts has found widespread application,
allowing a rapid continuous production of chemicals with minimum purification.
We decided to study the immobilization of chiral imidazolidinones on silica gel, thus
expanding the class of chiral organocatalysts used in reactors under continuous flow
conditions and overcoming the problems inherent to a polymeric support.
Continuous-flow organocatalyzed Diels Alder reactions have been performed with
excellent enantioselectivity for the first time in a chiral “homemade” HPLC column,
packed with silica on which a MacMillan catalyst has been supported by a
straightforward immobilization procedure. The versatility of the system was also proven
by running with the same column continuous-flow stereoselective reactions with three
different substrates, showing that the catalytic reactor may efficiently work in continuo
for more than 150 hours; the regeneration of the HPLC column was also demonstrated,
allowing to further extend the activity of the reactor to more than 300 operating hours.
O2
Efficient Addition of Nitro Compounds to Sulfonyl Azoles: an easy
Route to Functionalized Heteroaromatic Compounds
S. Lancianesi, N. Lucchetti, A. Palmieri, M. Petrini
School of Science and Technology, Chemistry Division, University of Camerino,
Via S. Agostino 1, 62032 Camerino (MC).
[email protected]
Biologically active molecules often embed an heteroaromatic core. In particular,
functionalized azoles represent interesting building blocks in the synthesis of complex
structures of practical importance. For this reason the development of new methods for
the functionalization of nitrogen-containing aromatic rings is of paramount interest.1 In
this context, the chemistry of sulfonylalkylindoles and their analogues has proven to be
a valid alternative to Friedel-Crafts reaction of the indole ring at 3-position, offering a
route to azole compounds not available by direct alkylation.2 Following our ongoing
research in this field,3 we developed a method for the addition of -nitroesters to
sulfonyalkylindoles leading to functionalised indoles 3. On the other hand, addition of
nitrocompounds to sulfonylalkylpyrroles leads to pyrroles 4, hardly achievable by
Friedel-Craft alkylation using nitroalkenes. Nitroalkylpyrroles of type 4 represent
pivotal intermediates for the synthesis of functionalized 6-azaindoles.
(1) a) Faulkner, D. J.; Nat. Prod. Rep. 2002, 1 – 48; b) Saxton, J. E.; The Alkaloids, (Ed.: G. A.
Cordell), Academic Press, New York, 1998; c) Sundberg, R. J.; Indoles, Academic Press, New
York, 1997; d) Saxton, J. E.; Nat. Prod. Rep. 1997, 559 – 590.
(2) a) Bandini, M.; Melloni, A.; Tommasi, S.; Umani Ronchi, A.; Synlett 2005, 1199 – 1222; for
Friedel-Crafts alkylations; b) Palmieri, A.; Petrini, M.; J. Org. Chem. 2007, 72, 1863 – 1866; for
sulfonylalkylindoles.
(3) a) Palmieri, A.; Petrini, M.; Shaikh, R.R. Org. Biomol. Chem. 2010, 8, 1259; b) Martinelli, F.;
Palmieri A.; Petrini, M. Phosphorus Sulfur and Silicon 2011, 186, 1032; c) Palmieri A.; Petrini,
M. Org. Biomol. Chem. 2012, 10, 3486; d) Lancianesi, S.; Palmieri, A.; Petrini, M.; Adv. Synth.
Catal. 2012, 354, 3539-3544.
O3
2,3-Diaryl-β-amino acid Derivatives via Mannich-like Reaction of
Arylacetic Esters: Chirality Switching Induced by an Aryl-substituted
ortho Heteroatom
Andrea Bonetti, Francesca Clerici, Alessandro Contini, Francesca Foschi, Sara
Pellegrino, Michele Penso, Raffaella Soave, Maria Luisa Gelmi.
DIFARM, Sezione di Chimica Generale e Organica "A. Marchesini", Università di
Milano, Via Venezian 21, 20133 Milano, Italy
[email protected]
The structural motif of -amino acid derivatives is recurrent in biologically active
compounds such as -lactam antibiotics1a,b,2 and -peptides1a,3a/d. In this last field, there
is a need of new non proteinogenic-amino acids, and in particular those belonging to
the 2,3 class, since it is known that they could enhance the helical content when inserted
in a peptide sequence as well as the resistance to peptidases.
A very efficient protocol targeted on the synthesis of 2,3-diaryl--amino acid
derivatives was found using a TiCl4/TEA catalyzed Mannich-like reaction. The
presence of an ortho coordinating heteroatom on arylacetic esters is of dramatic
importance to modulate both the reactivity of the ester as well as the diastereoselection
of the reaction. Both NMR and molecular dynamic studies clarified the stereochemical
behavior of the above reaction. The use of phenylmenthyl moiety as chiral auxiliary
allowed preparing the above compounds in high enantiopurity.
1) aMikami, K.; Fustero, S.; Sanchez-Rosello, M.; Acena, J. L.; Soloshonok, V.; Sorochinsky, A.
Synthesis, 2011, 19, 3045-3079. bSzakonyi, Z.; Fulop, F. Amino Acids 2011, 41, 597-608. (a) Seebach,
D.; Beck, A. K.; Capone, S.; Deniau, G.; Grošelj, U.; Zass, E. Synthesis 2009, 1-32 and references cited
therin. (b) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833-2891. x)
You, S.; Zhang, C.; Fischer, W.; Baumann, A.; Spannenberg, D. ; Heller, D. Org. Process Res. Dev.
2003, 7, 355-361.
2) Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89, 1447-1465. (b) Dobrev, A.; Ivanov, C. Chem.
Ber. 1971, 104, 981-985.
3) (a) Balamurugan, D.; Muraleedharan, K. M. Tetrahedron 2009, 65 10074-10082. (b) Goodman, J. L.;
Petersson, E. J.; Daniels, D. S.; Qiu, J. X. Schepartz, A. J. Am. Chem. Soc. 2007, 129, 14746-14751. (c)
Aguilar, M.-I.; Lew, R. A.; Perlmutter, P.; Smith, A. I.; Steer, D. L. Curr. Med. Chem. 2002, 9, 811-822.
(d) Gademann, K.; Hintermann, T.; Schereiber, J. V. Curr. Med. Chem. 1999, 6, 905-925.
O4
Exploring the Boundaries of Vinylogous Mukaiyama Aldol Processes:
Stereoselective Access to Polyunsaturated Homoallylic Alcohols
1
Claudio Curti, 2Gloria Rassu, 1Andrea Sartori, 1Lucia Battistini, 1Franca Zanardi
1
Dipartimento di Farmacia, Università degli Studi di Parma, Via Parco Area delle
Scienze 27A, I-43124 Parma, Italy
2
Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07100 Li Punti
Sassari, Italy
[email protected]
Catalytic enantioselective vinylogous aldol reactions using extended enolates are of
prominent value in synthetic organic chemistry. Such transformations create densely
functionalized adducts whose stereocenters lie in proximity of one of more alkene
moieties, which can be further elaborated to afford a realm of products varied in shape
and complexity.(1) Originally used to forge ,β-unsaturated-δ-hydroxycarbonyls, the
majority of studies in this field have focused on single-vinylogous aldol techniques,
leaving the application of more extended adaptations, giving densely unsaturated
homoallylic alcohols, substantially unexplored.(2) Here, we report our advances in the
development of enantioselective bis-vinylogous and hyper-vinylogous Mukaiyama aldol
reactions between a series of polyenylsilyloxy furans (3) or polyenylsilyoxy indoles and
aromatic aldehydes, realized by use of the enabling catalyst combination of silicon
tetrachloride and Denmark’s chiral bis-phosphoramide base (R,R)-I.(4) Several crucial
issues such as the remote site-, enantio- and geometrical selectivity of the reaction will
be highlighted, ultimately focusing on one main question: how far can we push the
limits of the vinylogous reactivity transmittal?
References
(1) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076
(2) (a) Ratjen, L.; Garcìa-Garcìa, P.; Lay, F.; Beck, M. E.; List, B. Angew. Chem., Int. Ed. 2011, 50,
754. (b) Denmark, S. E.; Kobayashi, T.; Regens, C. S. Tetrahedron 2010, 66, 4745.
(3) Curti, C.; Battistini, L.; Sartori, A.; Lodola, A.; Mor, M.; Rassu, G.; Pelosi, G.; Zanardi, F.;
Casiraghi, G. Org. Lett. 2011, 13, 4738.
(4) Denmark. S. E., Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2000, 100, 1929.
O5
Synthetic Strategies for the Preparation of Bioactive
Glycoglycerolipids
Emiliano Manzo, Dario Pagano and Angelo Fontana.
Istituto di Chimica Biomolecolare (CNR), via campi flegrei 3-80078, Pozzuoli (NaplesItaly)
[email protected]
Complex lipids are cell membrane constituents and are present in all the living
organisms. Some of them have also other functional roles and are recognized markers
for the cellular recognition and communication.1-3 Glycolipids are featured by the
presence of one or more carbohydrates and are structurally divided in different families
including glycoglycerolipids, with acylated glycerol bound to carbohydrate,
glycosphingolipids with an acylated sphingosine (ceramide) and isoprenoid glycosides,
with a terpene alcohol as aglycone. In the last years, members of the family, especially
galactosyldiacylglycerols and ceramides, have attracted the interest of the bio-medical
community for their properties in cancer chemoprevention4 and immunology.5 Here we
discuss a versatile strategy for the synthesis of galactosyldiacylglycerols6 and
sulphoquinovosyldiacylglycerols7 whose availability is hampered by the difficulty in
their isolation and purification from natural sources.
R
R
SO3R
OH
OH
O
O
O
HO
O
HO
O
O
HO
OH
-galactosyl diacylglycerols
O
SO3-
R
O
O
O
O
HO
O
-6-sulphoquinovosyl diacylglycerols
R
O
HO
OH
O
O
R
O
O
OH
-6-sulphoquinovosyl diacylglycerols
:
References
(1) Oshida,Y., Yamada,S., Matsunaga, K., Moriya, T., Ohizumi, Y., J.Nat.Prod. 1994, 57(4), 534-536.
(2) Nakato,K.,Guo,C-T, Matsufuji,M., Yoshimoto, A., Inagaki, M., Higuchi, R., Suzuki, Y., J. Biochem.
2000, 127, 191-198.
(3) Murakami, C., Yamazaki,T., Hanashima,S., Takahashi,S., TAkemura,M., Yoshida,S., Ohta,K.,
Yoshida,H., Sugawara,F., Sakaguchi,K., Mizushina,Y., Biochim. Biophysica Acta 2003, 1645, 7280.
(4) Colombo, D., Scala, A., Taiano, I.M., Toma, L., Roncheti, F., Tokuda, H., Nishino, H., Sakakibara,
J., Bioorg.Med.Chem.Lett. 1996, 6, 1187-1190.
(5) Di Libero, G., Mori, L. Nature Rev. 2005, 5, 485- 496; Di libero, G. Science 2004, 303, 485-486.
(6) Manzo,E.; Ciavatta, M.L.; Pagano, D.; Fontana, A. Tetrahedron Letters 2012, 53, 879-881.
(7) Manzo, E.; Tramice, A.; Pagano, D.; Trincone, A.; Fontana, A. Tetrahedron 2012, 68, 10169-10175.
O
O6
Synthesis of Dihydropyridine and Piperidine Derivatives via an
Unexpected Reaction of Pyridine with Acetyl Chloride
1
1
Alberto Mannu, 1Pietro Spanu, 1Fausta Ulgheri.
Istituto di Chimica Biomolecolare del CNR, trav. La Crucca 3, 07100, Sassari (Italy).
[email protected]
Acetyl chloride reacts with pyridine to give a mixture of N-acetyl-1,4- and 1,2dihydropyridyl acetic acid (1a,b) after water quenching (scheme 1). The reaction
involves the formation of a zwitterionic ketene enolate intermediate which results from
deprotonation of the acetyl moiety of the in situ formed N-acetyl pyridinium ion.
Scheme 1: Synthesis of N-acetyl-1,4- and 1,2-N-acetyl-pyridyl acetic acid by reaction of
pyridine with acetyl chloride.
The effect on the reaction outcome of different parameters as temperature,
pyridine/acetyl chloride molar ratio, and as Lewis acids and triflate counterion presence
has been studied in detail, and a reaction mechanism has been proposed.
The corresponding piperidine derivatives were obtained in quantitative yield by
reduction of 1a and 1b. This procedure represents a new and simple synthetic approach
to analogues of sedum family piperidine alkaloids, an important class of biological
active compounds.1,2
(1) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Smith, A. D.; Tetrahedron 2009, 10192-10213;
(2) Orjales, A.; Mosquera, R.; Toledo, A.; Pumar, M. C.; Garcia, N.; Cortizo, L.; Labeaga, L.;
Innerarity, A.; J. Med. Chem. 2003, 5512-5532.
O7
Multicomponent Reactions and Organocatalysis: a Suitable
Combination for the Stereoselective Synthesis of Tetrahydro-2benzazepines
Lisa Moni, Luca Banfi, Andrea Basso, Martina Spallarossa, Renata Riva.
Dipartimento di Chimica e Chimica Industriale, Università di Genova, via Dodecaneso
31, 16146 GENOVA
[email protected]
The isocyanide-based multicomponent reactions (IMCRs)1 have been recognized as a
very efficient tool to create collections of small organic molecules with great structural
diversity and complexity in a single reaction step. However, a main drawback of these
reactions is the low stereocontrol often achieved in the creation of the new chirality
centre as well as the lack of enantioselective procedures. This hampers the application
of the classical IMCRs in the preparation of chiral collections. Diastereoselective
approaches using chiral components are a possible solution.2 Here we present the
stereoselective synthesis of a family of functionalized seven-membered nitrogen
heterocycles coupling an organocatalytic Mannich reaction with a Staudinger/AzaWittig/Ugi process.
The tetrahydro-2-benzoazepine 1 is prepared exploiting an intramolecular variant of the
Ugi reaction (Ugi-Joullié) involving an isocyanide, a carboxylic acid and the chiral
cyclic imine 2, obtained through a Staudinger aza-Wittig cyclization involving the azido
aldehyde 3. For the synthesis of this chiral building block we planned to use an
organocatalytic Mannich addition of aldehydes to the azido Boc-protected imine 4,
which was synthesized from the azido aldehyde 5.
(1) Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
(2) Banfi, L.; Basso, A.; Guanti, R.; Riva, R. Asymmetric Isocyanide-Based MCRs. In Multicomponent
Reactions; Zhu, J. P.; Bienaymé, H., Eds.; Wiley: Weinheim 2005, 1–32.
O8
1
Design, Synthesis and Preliminary Biological Tests of New ProApoptotic Anticancer Nanoconjugates
Claudio Carrara, 1Luigi Ballabio, 2Daniele Lecis, 1Pierfausto Seneci, 1Emanuela
Licandro
1
University of Milan, Dept. of Chemistry, Via Camillo Golgi 19, I-20133, Milan,
2
IRCCS Foundation – National Cancer Institute, Dept. Of Experimental Oncology, Via
Amadeo 42, I-20133, Milan.
[email protected]
Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are attractive in biomedicine
because of their peculiar chemical-physical properties, in particular their magnetic
behavior.(1) In order to use them in biomedical fields, SPIONs must be coated with
appropriate biomolecules through a stable and easily tunable adsorption. Hence, the
need to develop efficient synthetic strategies for the synthesis of novel bionanoconjugates.(2) In this context, we focused our attention on a new class of
peptidomimetic pro-apoptotic anticancer drugs named SMAC-mimetics. They can
modulate apoptosis, thus promoting the restoration of the physiological process of
programmed cell death in “immortalized” tumor cells through inhibition of antiapoptotic IAP proteins.(3) Our aim was to combine the peculiar properties of SPIONs
with the bioactivity of SMAC-mimetics, opening a possible application of these new
nanoconjugates as theranostics. The potent SMAC-mimic molecule 1, previously
prepared by some of us,(4) contains needed structural parts for its biological activity
(circled regions in 1), and dispensable groups (boxed region in 1). So, we designed new
SMAC-mimetics 2-4 to be coupled with SPIONs (Figure 1).
Figure 1 – SMAC-mimic molecules 1-4 and corresponding SPION-SMAC
nanoconjugates 5-10
Namely, compounds 2-4 have been supported onto the NPs surface by both noncovalent interaction exploiting the carboxylic moieties with naked SPIONs (5, 7 and 8,
Figure 1) and covalent bonding thanks to aminopropylsilane modified nanoparticles
SPION-APTES (6, 9 and 10, Figure 1). Encouraging preliminary cell-free in vitro tests
on nanoconstructs 5, 6, 7 and 9 show strong binding with IAP proteins.
(1) Colombo, M.; Carregal-Romero, S.; Casula, M.F.; Gutiérrez, L.; Morales, M.P.; Böhm, I.B.;
Heverhagen, J.T.; Prosperi, D.; Parak, W.J. Chem. Soc. Rev., 2012, 41, 4306-4334, and references therein.
(2) Prencipe, G.; Maiorana, S.; Verderio, P.; Colombo, M.; Fermo, P.; Caneva, E.; Prosperi, D. and
Licandro, E. Chem Commun., 2009, 6017.
(3) a) Sun, H.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Qian, D.; Lu, J.; Qiu, S.; Bai, L.; Peng, Y.; Cai, Q.;
Wang, S. Acc. Chem. Res., 2008, 41, 1264; b) Gyrd-Hansen, M.; Meier, P. Nat. Rev. Cancer 2010, 10,
561.
(4) Seneci, P.; Bianchi, A.; Battaglia, C.; Belvisi, L. et al. Bioorg. Med. Chem. 2009, 17, 5834.
O9
From Simple and Natural Precursors to Elaborate Biologically Active
Molecules: the Case of (L)-erythro ceramide C6
1
1
Matteo Di Nicola, 1Marco Glucini, 1Roberta Properzi, 2Aurora Sganappa, 1Federico
Sorana, 1Mara Tomassetti, 1Enrico Marcantoni
School of Science and Technology, Chemistry Division, University of Camerino, via S.
Agostino 1, 62032 Camerino (MC).
2
CMCE Department, Chemistry Section, Politecnico di Milano, Via L. Mancinelli 7,
20131 Milano.
[email protected]
Chiral compounds are challenging and fundamental targets for synthetic organic
chemists due to their ubiquitous presence in chemistry, biochemistry, and medicine.1
One powerful tool that chemists have at their disposal to get hold of these compounds is
total synthesis. Total synthesis is the art of making complex and usually biologically
important molecules from simple and inexpensive precursor. This is the principle at the
base of our work: the first stereoselective total synthesis of the unnatural (L)-erythroceramide C6 from the natural aminoacid (L)-serine. Sphingolipids are common small
molecules extensively widespread in the human body, and ceramides are a category
within this major family of lipids.2 They exert structural functions and deeply influence
cell regulation and signal transductions pathways, which mediates the effect of agents,
as tumor necrosis factor-alpha, on cell growth and differentiation.3,4 Our chiral pool
synthesis uses a natural aminoacids as a precursor and claims excellent overall yield and
stereoselectivity. We focused our efforts on the synthesis of the (L)-erythro enantiomer
(Scheme 1), exploting the reactivity of a Garner’s type aldehyde, which undergoes the
addition of an organocerium reagent.4 We definitely provided a simple and efficient
total synthesis of the unnatural enantiomer of ceramide C6, enriching the selection of
this class of lipids for biological evaluations.
Scheme 1: Structure of target compound
(1)
(2)
(3)
(4)
(5)
Koskinen, A. M. P. Pure Appl. Chem. 2011, 83, 435-443.
Ait-Youcef, R.; Moreau, X.; Greck, C. J. Org. Chem. 2010, 75, 5312-5315.
Hannun, Y. A. Science 1996, 274, 1855-1859.
Obeid, L.M.; Linardic, C.M.; Karolak, L.A.; Hannun, Y.A. Science 1993, 259, 1769-1771.
Bartoli, G.; Marcantoni, E.; Di Antonio, G.; Fiocchi, R.; Giuli, S.; Marcolini, M. Synthesis 2009,
951-956.
O10
Synthesis and Bioactivity of Enantiopure 1,2-Dihydroxyindolizidines
Franca M. Cordero, Bhushan B. Khairnar, Carolina Vurchio, Alberto Brandi
Dipartimento di Chimica“Ugo Schiff”, Università di Firenze,
50019 Sesto Fiorentino (FI), ITALY
[email protected]
(+)-Lentiginosine, a hydroxyindolizidine alkaloid found in the leaves of Astragalus
lentiginosus, is a selective inhibitor of amyloglucosidases and a potent inhibitor of Heat
shock protein 90 (Hsp90) a therapeutic target for some diseases including cancer.1
Non-natural (–)-lentiginosine is a caspase-dependent apoptosis inducer on different
strains of human cancer cells, but with very low cytotoxicity.2
The interesting biological profile of lentiginosine in both its enantiomeric forms
encourages the collection of variously functionalised derivatives to modulate bioactivity
and study the interaction of 1,2-dihydroxyindolizidines with bioreceptors.
In this communication, some aspects of the stereoselective synthesis of 7- and/or 8substituted and benzo-fused lentiginosine derivatives such as 1-3 and the effect of the
structural modifications on bioactivity will be presented.
(1) Dal Piaz, F.; Vassallo, A.; Chini, M. G.; Cordero, F. M.; Cardona, F.; Pisano, C.; Bifulco, G.; De
Tommasi, N.; Brandi, A. PLoS One 2012, 7, e43316.
(2) (a) Macchi, B.; Minutolo, A.; Grelli, S.; Cardona, F.; Cordero, F. M.; Mastino, A.; Brandi A.
Glycobiology 2010, 20, 500-506. (b) Minutolo, A.; Grelli, S.; Marino-Merlo, F.; Cordero, F. M.;
Brandi, A.; Macchi, B.; Mastino, A. Cell Death. Dis. 2012, 3, e358.
O11
Deoxycolic acid Derived Biarylphosphites as Highly Enantioselective
Ligands in the Rh-catalyzed Conjugate Addition of Arylboronic acids
to Nitroalkenes
Anna Iuliano and Varsha R. Jumde
Università di Pisa - Dipartimento di Chimica e Chimica Industriale, via Risorgimento
35, 56125 Pisa
[email protected]
Nitroalkenes are among the most interesting electrophilic acceptors for the Rh-catalyzed
asymmetric conjugate addition of arylboronic acids, as their addition products are
versatile substrates for various transformations and useful precursors in the synthesis of
pharmaceuticals and natural products. However, despite the synthetic importance of
optically active nitro compounds, there are few reports on the Rh-catalyzed asymmetric
conjugate addition of arylboronic acids to nitroalkenes,(1) due to the hard control of the
reaction stereoselectivity. Quite recently we have developed bile acid derived tropos
and atropoisomeric biaryl phosphites as chiral ligands in the Rh-catalyzed asymmetric
conjugate additions of arylboronic acids to cyclic enones(2) and other Rh-catalyzed
asymmetric reactions.(3) The good results obtained prompted us to check their use in the
asymmetric conjugate addition of arylboronic acids to nitroalkenes having different
structures (Scheme 1).
O
+
Ar
O
B
OH
OH
R
NO2
*
NO2
NO2
[Rh(C2H4)2Cl]2, L* (1.5%, P/Rh=2)
Ar
P
COOMe
O
L* =
Toluene/H2O (10:1), KOH (0.5mol) Ar
R
NO2
AcO
Ar = Ph, 3-OMeC6H4, 4-OMeC6H4, 4-CF3C6H4, 2-Np, 3-ClC6H4, 4-MeC6H4
R = Ph, 4-OMeC6H4, 4-FC6H4, 2-Np, 4-MeC6H4, 2-thienyl, Pr, iPr, c-C6H11
O
*P
O
Biphenyl, 1
5,5'-Diphenyl= biphenyl, 2
(S)-Binaphthyl, 3
(R)-Binaphthyl, 4
Scheme 1
A strong dependence of the ligand effectiveness on the substrate structure was observed:
the atropoisomeric phosphite 3, having a (S)-binaphthyl moiety gave higher yields and
ees (up to 96%) in the arylation of nitrocyclohexene, a very challenging substrate,
whereas with acyclic substrates the most active and enantioselective Rh-catalyst was
obtained starting from the diastereomeric ligand 4. The reaction of acyclic nitroalkenes
was fast and highly enantioselective, giving almost quantitative yields of products with
ee values ranging from 96 to 99%, independently of alkene as well as boronic acid
structure. Substrate dependent asymmetric activation of tropos ligands was observed,
which allowed to obtain high yield and ees of the conjugate addition products also using
phosphites 1 and 2, possessing flexible biphenyl moieties.
(1) Wang, Z.-Q.;. Feng, C.-G; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q. Angew. Chem. Int. Ed. 2010, 49,
5780-5783; Lang, F.; Chen, G.; Xing, J.; Han, F.; Cun, L.; Liao, J. Chemistry –A European Journal
2011, 17, 5242-5245; Xue, F.; Wang, D.; Li, X.; Wan, B. J. Org. Chem. 2012, 77, 3071-3081.
(2) Iuliano, A.; Facchetti, S.; Funaioli, T. Chem. Commun. 2009, 457-459; Facchetti, S.; Cavallini, I.;
Funaioli, T.; Marchetti, F.; Iuliano, A. Organometallics 2009, 28, 4150-4158.
(3) Iuliano, A.; Losi, D.; Facchetti, S. J. Org. Chem. 2007, 72, 8472-8477; Jumde, V. R.; Facchetti, S.;
Iuliano, A. Tetrahedron: Asymmetry 2010, 21, 2775-2781.
O12
Monocyclic β-Lactams and Cystic Fibrosis: Facing Antioxidant and
Antimicrobial Activity of N-thiomethyl-azetidinones
1
Daria Giacomini, 1Paola Galleti, 1Matteo Pori, 1Soldati Roberto, 1Rinaldo Cervellati,
2
Clementina Cocuzza, 2Rosario Musumeci
1
Department of Chemistry “G. Ciamician”, University of Bologna, Italy
2
Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Italy
[email protected]
Beta-Lactam antibiotics are still the main class of agents used to treat bacterial
infections. However, the treatment of bacterial infections became tangled because of the
increasing emergence of multidrug-resistant microorganisms. Many staphylococcal
infections are in fact associated with multiple recurrences and developed resistance to
beta-lactam antibiotics. This concern appeared particularly important in case of the
cystic fibrosis (CF) disease, where a persistent colonization of pathogen bacteria
occurred and a constant use of antibacterial agents selected methicillin resistant S.
Aureus strains (MRSA).
We have actively contributed to this field with the design and synthesis of new
monocyclic beta-lactams1 as interesting scaffolds for antibiotics against resistant
bacteria2 and as effective enzymatic inhibitors.3
Very recently a series of N-thiomethyl-azetidinones were evaluated in vitro against
Gram-positive and Gram-negative clinical isolates and in particular on MRSA and
MSSA strains from clinical isolates of CF patients.4 The combination of a N-SMe group
and a benzyl ester on the 4-alkylidene-side chain or electron-withdrawing groups, such
as OAc, on the C-4 position of the beta-lactam ring strengthened the potency against
Gram-positive bacteria. We also evaluated antioxidant activity and redox potentials of
the new beta-lactams,5 with the aim to develop new promising molecules which
associated antibacterial and antioxidant activities able to contrast the adverse conditions
in CF due to colonization by MRSA and extensive epithelial damage by chronic
pulmonary oxidative stress.
We are now developing a library of dual-active compounds, with various polyphenolic
antioxidant moieties and a beta-lactam ring both N-thiomethylated and not, varying the
substituent groups on the C-4 in order to achieve the best antibacterial activity.
(1) Galletti, P.; Giacomini, D. Curr. Med. Chem. 2011, 18, 4265-4283.
(2) Broccolo, F.; Cainelli, G.; Caltabiano, G.; Cocuzza, C.E.A.; Fortuna, C.G.; Galletti, P.; Giacomini, D.;
Musumarra, G.; Musumeci, R.; Quintavalla, A. J. Med. Chem. 2006, 49, 2804–2811
(3) Cainelli, G.; Galletti, P.; Garbisa, S.; Giacomini, D.; Sartor, L.; Quintavalla, A. Bioorg. Med. Chem.
2005, 13, 6120–6132. Dell’Aica, I.; Sartor, L.; Galletti, P.; Giacomini, D.; Quintavalla, A.; Calabrese,
F.; Giacometti, C.; Brunetta, E.; Piazza, F.; Agostini, C.; Garbisa, S, J. Pharmacol. Exp. Ther. 2006,
316, 539–546. Galletti, P.; Quintavalla, A.; Ventrici, C.; Giannini, G.; Cabri, W.; Penco, S.; Gallo, G.;
Vincenti, S.; Giacomini, D. ChemMedChem 2009, 4, 1991-2001.
(4) Galletti, P.; Cocuzza, C.; Pori, M.; Quintavalla, A.; Musumeci, R.; Giacomini, D. ChemMedChem
2011, 6, 1919-1927.
(5) Cervellati, R.; Galletti, P.; Greco, E.; Cocuzza, C.E.A.;Musumeci, R.; Bardini, L.; Paolucci, F.; Pori,
M.; Soldati, R.; Giacomini, D. Eu. J. Med. Chem. 2013, 60, 340-349.
O13
Macromolecular Non-Releasing Additives for Safer Food Packaging
1
Federica Ceccherini, 1Stefano Menichetti, 1Caterina Viglianisi, 2Simona Losio, 2Maria
Carmela Sacchi, 3Giorgio Mancini, 3Paola Stagnaro, 4Alessandro Adobati, 4Sara Limbo
1
Department of Chemistry ‘U. Schiff’, University of Florence, via della Lastruccia 3-13,
I-50019 Sesto Fiorentino (FI), Italy
2
ISMAC-CNR, via Bassini 15, 20133 Milano, Italy
3
ISMAC-CNR, via De Marini 6, 16149 Genova, Italy
4
DeFENS, University of Milan, via Celoria 2, 20133, Milano, Italy
[email protected]
Due to their peculiar sealing properties, their low cost and low reactivity, polyolefins
are the plastics most frequently used as food contact materials. The principal limit of
their use is the easy degradation due to thermo- and/or photo-oxidation at all stages of
their life cycle, i.e. during processing, storage, and use. In fact, polyolefins are usually
stabilized by melt blending with additives, such as free radical scavengers and anti-UV
filters, to inhibit or retard degradation. Commonly used stabilizers are relatively low
molecular weight polar compounds (i.e. BHA, BHT and HALS) very different from the
apolar polyolefinic matrix. This causes several disadvantages such as: i) poor
stabilizer/polyolefin compatibility; ii) stabilizers physical loss by migration and iii) food
contamination.
We propose the design and synthesis of monomers bearing stabilizing functionalities,
inspired to BHT, BHA or HALS, and their copolymerization with ethylene or propylene
to obtain non-releasing polymeric additives (1-3). These macromolecular additives will
be used as stabilizers for the preparation of polyolefinic materials required in food,
pharmaceutical and biomedical packaging with low risk of degradation and
contamination.
(1) Stagnaro, P.; Mancini, G.; Piccinini, A.; Losio, S.; Sacchi, M. C.; Viglianisi, C.; Menichetti, S.;
Adobati, A.; Limbo, S. Journal of Polymer Science, Part B: Polymer Physics, 2013, 51, 10071016.
(2) Sacchi, M. C.; Losio, S.; Stagnaro, P.; Menichetti, S.; Viglianisi, C. Macromolecular Reaction
Engineering, 2013, 7, 84-90.
(3) Viglianisi, C.; Menichetti, S; Assanelli, G.; Sacchi, M. C.; Tritto, I.; Losio, S. Journal of
Polymer Science, Part A: Polymer Chemistry, 2012, 50, 4647-4655.
O14
Engineering of Bio-Interfaces by Grafting-from and Grafting-to
Approaches: from
Poly(ethylene glycol)s to Poly(oxazoline)s
1
Michel Klein Gunnewiek, 2Andrea Di Luca, 3Michele Maggini, 2Lorenzo Moroni,
4
Nicholas D. Spencer and 1G. Julius Vancso and 1,4Edmondo M. Benetti
1
Materials Science and Technology of Polymers (MTP), Mesa+ Institute for
Nanotechnology, University of Twente, email: [email protected], P.O. Box 217,
7500AE Enschede, The Netherlands.
2
Department of Tissue Regeneration MIRA Institute for Biomedical Techonology and
Technical Medicine, University of Twente, PO Box 217, 7500AE Enschede, The
Netherlands.
3
University of Padova, Department of Chemical Sciences, via Marzolo 1, 35131
Padova, Italy.
4
Laboratory for Surface Science and Technology (LSST), Department of Materials,
ETH Zürich, email: [email protected], Wolfgang-Pauli-Strasse 10, 8093
Zürich, Switzerland
Modification of surfaces with polymer grafts has been increasingly applied during the
last two decades as an effective technique to determine the integration of bulk materials
into a biological medium. Chemistry and macromolecular architecture of surface
modifiers thus have been tailored to assess the required interfacial properties by the
subsequently formed films (1). On the one hand controlled surface-initiated
polymerization methods (CSIP) have been applied to produce structured films featuring
variable thicknesses, denities and compositions. On the other hand "grafting-to"
approaches involving bio-degradable copolymers as adsorbants gained substantial
interest due to their broad applicability on a variety of target substrates (2,3). In all cases
nowadays efforts in the fabrication of grafted polymer films has been dedicated to
answer the fundamental requirements of bio-compatibility and inertness against an
unspecific biological response.
(1) Benetti, E.M.; Zpotoczny, S.; Vancso, G.J. Adv. Mater. 2007, 19, 268-271.
(2) Pidhatika, B.; Möller, J.; Benetti, E.M.; Konradi, R.; Rakhmatullina, E.; Mühlebach, A.;
Zimmermann, R.; Werner, C.; Vogel, V.; Textor, M. Biomaterials 2010, 31, 9462-9472.
(3) Gillich, T.; Benetti, E.M.; Rakhmatullina, E.; Konradi, R.; Li, W.; Zhang, A.; Schlüter, D.; Textor,
M. J. Am. Chem. Soc. 2011,133, 10940-10950.
O15
Synergic Strategies against Gram-positive Multiresistant Pathogens
1
Cosimo G. Fortuna, 2Andrea Pace, 3Rosario Musumeci
1
Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, 95125
Catania, Italy.
2
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari, Università degli
Studi di Palermo, Viale delle Scienze Ed.17, 90128 Palermo, Italy.
3
Dipartimento di Medicina Clinica e Prevenzione d. U , Università degli Studi di
Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy
[email protected]
Multi-drug resistant (MDR) bacteria, informally known as “Superbugs”, are the results
of decades of use and misuse of antibacterial agents, which triggered the development
of resistance to all antibiotics in clinical use independently from the biological target of
the drug.(1) One of the promising strategy to contrast this phenomenon is the synergy
between on-field clinical research, in silico, and wet-lab chemistry. This approach
allows to timely respond to the rise of resistance through a series of steps including: i)
clinical isolation, ii) genomic characterization, iii) resistance mechanism identification,
iv) new target definition, v) drug optimization.
In this communication, preliminary results from a recent project on drug development
against MDR bacteria, are reported. (2-4)
These include the setup and validation of a chemoinformatic strategy based on a
molecular interaction field (MIF). Modeling studies included a recently developed
algorithm called Fingerprints for Ligands and Proteins (FLAP)(5) and were performed
to evaluate possible differences, with respect to Linezolid, in the interaction of the most
active compounds in the series with the ribosomal subunit 50S.
The validation of this approach has been achieved through the synthesis and bioactivity
testing of two series of Linezolid-like 1,2,4-oxadiazoles.
References
(1) Gootz, T. Crit. Rev. Immunol. 2010, 30, 79-93.
(2) Financial support from Italian MIUR within the “FIRB-Futuro in Ricerca 200 ” Program - Project
RBFR08A9V1 – is gratefully acknowledged.
(3) Palumbo Piccionello, A.; Musumeci, R.; Cocuzza, C.; Fortuna, C.G.; Guarcello, A.; Pierro, P.; Pace,
A. Eur. J. Med. Chem, 2012, 50, 441-448.
(4) Fortuna, C.G.; Bonaccorso, C.; Bulbarelli, A.; Cocuzza, C.; Goracci, L.; Musumarra, G.; Pace, A.;
Palumbo Piccionello, A.; Guarcello, A.; Pierro, P.; Torsello, A.; Musumeci, R. Eur. J. Med. Chem. 2013,
http://dx.doi.org/10.1016/j.ejmech.2013.03.069
(5) Baroni, M.; Cruciani, G.; Sciabola, S.; Perruccio, F.; Mason, J. S. J. Chem. Inf. Model. 2007, 47, 279–
294.
O16
Synthesis and Characterization of New Derivatives of Natural
Bioactive Polyphenols to Improve Oral Bioavailability
1,2
1
Andrea Mattarei, 3 Michele Azzolini, 1,3 Lucia Biasutto, 2 Matteo Romio, 1,3 Mario
Zoratti and 2 Cristina Paradisi
CNR Institute of Neuroscience, 2 Department of Chemical Sciences, University of
Padova, 3 Department of Biomedical Sciences, University of Padova
[email protected]
Plant polyphenols, a vast family of over 8000 natural substances, are credited with
beneficial effects for human health(1). In vitro experiments have shown that some can
prevent the onset and inhibit the growth of several types of cancer, protect the
cardiovascular system and slow-down senescence and the course of neurodegenerative
diseases. A major issue concerning the efficient use in vivo of natural polyphenols is
their low bioavailability, since only low concentrations are found in plasma and lymph
even after a polyphenol-rich meal, and mostly in the form of metabolites. We are thus
developing polyphenol prodrugs(2,3), with the goals of increasing absorption from the
gastrointestinal tract, and of providing temporary protection from Phase II metabolism.
We report here the synthesis, stability tests and pharmacokinetic studies of new
derivatives of resveratrol and pterostilbene - two major natural phenols belonging to the
family of stilbenoids - based on protection of the hydroxyl groups via acetal and
carbamate ester-type bonds.
Amino deoxy sugars, amino acids, and oligoethylene glycol capping groups R were
tested in order to modulate the chemico-physical properties of the resulting prodrugs.
(1) Quideau, S.; Deffieux, D; Douat-Casassus, C.; Pouységu. Angew. Chemie Int. Ed.. 2011, 50, 586621.
(2) Biasutto, L.; Marotta, E.; Bradaschia, A.; Fallica, M.; Mattarei, A.; Garbisa, S.; Zoratti, M.; Paradisi,
C. Bioorg. Med. Chem. Lett. 2009, 19, 6721-6724.
(3) Biasutto, L.; Marotta, E.; De Marchi, U.; Zoratti, M.; Paradisi, C.; J. Med. Chem. 2007, 50, 241-253.
O17
A novel Efficient Olefination Reaction for the Preparation of
Cinnamonitriles
Matteo Alonzi, Ferdinando Pizzo, Luigi Vaccaro
CEMIN – Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica,
Università di Perugia I-06123 Perugia
[email protected]
Our research is devoted to the definition of new synthetic methodologies able to
minimize waste in the production fine chemicals1. Key features of our approach are the
combined use of immobilized catalysts, safer reaction media such as water or solventfree conditions and flow procedures1.
We have recently devoted our attention to a new synthetic process (Peterson-type
olefination) for the preparation of double bond starting from aldehydes. In this
communication we present the first mild and high yielding fluoride catalysed olefination
reaction for the synthesis of cinnamonitriles starting from aromatic aldehydes and
acetonitrile in the presence of a silazane base. Coherently with our research, this new
approach to olefination offers several advantages including the use of an easily
recoverable polymer-supported catalyst, avoiding the need for a superbase or any
organometallic reagents.
Scheme 1. Preparation of cinnamonitriles from aromatic aldehydes
(1) a) Strappaveccia, G.; Lanari, D.; Gelman, D.; Pizzo, F.; Rosati, O.; Curini, M.; Vaccaro, L. Green
Chem. 2013, 15, 199. b) Bonollo, S.; Lanari, D.; Longo, J.; Vaccaro, L. Green Chem, 2012, 12, 164169. c) Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Org. Lett., 2011, 13, 2150; d) Bonollo, S.;
Lanari, D.; Marrocchi, A.; Vaccaro, L. Curr. Org. Synth., 2011, 8, 319; e) Bonollo, S.; Lanari, D.;
Angelini, T.; Pizzo, F.; Marrocchi, A.; Vaccaro, L. J. Catal. 2012, 285, 216. f) Zvagulis, A.;
Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Adv.Synth. Catal. 2010, 352, 2489. g) Angelini, T.;
Lanari, D.; Maggi, R.; Pizzo, F.; Sartori, G.; Vaccaro, L. Adv. Synth. Catal., 2012, 354, 908 – 916.
h) Angelini, T.; Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Org. Lett., 2012, 14, 4610-4613.
O18
Catalyst-free Tosylation of Lipophilic Alcohols in Water
1
Manuela Oliverio, 1 Paola Costanzo, 1Rosina Paonessa, 2Monica Nardi, 1Antonio
Procopio
1
Dipartimento di Scienze della Salute, Università degli Studi Magna Græcia, Viale
Europa – Località Germaneto-88100, Catanzaro,
2
Dipartimento di Chimica, Università della Calabria, Cubo 12c-Ponte Bucci-87030,
Arcavacata di Rende (CS), Italy
[email protected]
Tosylation of alcohols is one of the most useful methods in organic synthesis to
transform a hydroxyl group into a good leaving group.(1) Tosylation of lipophilic
alcohols in particular, is pivotal for the scalable synthesis of pharmaceuticals and
bioactive molecules. Alcohols characterized by high logP (2) values often represent
intermediates for large-scale pharmaceutical processes passing through tosylation.
Several attempts to improve the eco-compatibility of the tosylation reaction have been
recently published (3), in order to avoid the use of large amount of organic bases, such
as pyridine.
In this work, we present the first catalyst-free and on water method for the tosylation of
lipophilic alcohols.
Tosylation can be realized in a few minutes under microwave-assistance, exploiting the
water insolubility of reagents and products as the driving force of the reaction. A
biodegradable water solution of p-toluenesulfonic acid is the only waste produced, with
optimization in terms of atom economy and E-factor. Also, we checked the ability to
scale-up the method from a small laboratory scale to a higher laboratory scale.(4)
(1) lAROCK, R. C., Comprehensive Organic Transformation, VCH, Weinheim, 1989.
(2) LEO, A.; HANSCH. C.; ELKINS, D., Chem. Rev., 1971, 71, 525–616
(3) (a)DAS, B.;REDDY, V. S.; REDDY, M. R.; Tetrahedron Lett., 2004, 45, 6717-6719 (b)
COMAGIC, S.; SCHIRRMACHER, R.; Synthesis, 2004, 885-888
(4) OLIVERIO, M.; COSTANZO, P.; PAONESSA, R.; NARDI, M.; PROCOPIO, A., RSC Advances,
2013, 3, 2548-2552
O19
Computational Studies on Organic Reactivity in Ionic Liquids
1
1
Cinzia Chiappe, 1Christian Silvio Pomelli.
Dipartimento di Farmacia – Università di Pisa Via Bonanno 33, 56126 Pisa.
[email protected]
Computational studies on organic reactions in ionic liquids (ILs) are analyzed from
different points of view. Important information about reaction mechanisms in ILs has
been obtained from these studies although the theoretical approaches are still not able to
give an exhaustive picture of the chemical processes occurring in ionic media.
Challenges and perspectives of this investigation field are discussed and the
fundamental role played by experimental results in the development of this intriguing
sector is pointed out.
O20
Marine Microalgae between Energy and Functional Products
A. Fontana,1 A. Cutignano,1 R. De Palma,2 G. d’Ippolito,1 E. Manzo,1 G. Nuzzo1
1
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche Via Campi
Flegrei 34, 80078 Pozzuoli, Napoli, Italy;
2
Department of Clinical and Experimental Medicine, Second University of Naples, Via
S. Pansini 5 (Edif. 3), 80131 Napoli, Italy
[email protected]
Microalgae have long been recognized as potentially important source of lipids for
preparation of functional health products (chemicals, drugs, vitamins, etc.) 1. In the last
years, the attention for microalgal lipids has been further increasing as consequence of
the consideration that they can be suitable source of third generation biofuels. Diatoms
(Bacillariophycea) form a group of unicellular algae that colonize oceans and
freshwater basins all over the world. The more than 100’000 species that compose the
class are of extreme importance for the biogeochemical cycling of minerals such as
silica and for global primary productivity. For more than one decade, together with an
interdisciplinary group of colleagues, I have focused my interest on the physiological
factors that promote growth of diatoms in marine environments2. We also took
advantage of these studies to explore the technological aspects concerning diatom
culturing and the biotechnological potential of these protists by massive cultivation in
closed systems. In 2011, with the financial support of public institutions and industrial
partners, we started the research program SIBAFEQ that aims to define the use of
diatom biomass for the production of energy by exploitation of the algal lipids as oil and
algal carbohydrates as substrates of fermentative processes to yield bio-hydrogen3. Here
I discuss the progress of the project and the state of the art about biofuel production and
valorization of side-products as novel antitumor leads and immunomodulatory agents.
(1) Spolaore P, Joannis-Cassan C, Duran E, Isambert A. J. Biosc Bioeng; 2006, 101, 87–96.
(2) Cutignano A, Lamari N, d’Ippolito G, Manzo , Cimino G, Fontana A. J. Phycol, 2011, 47, 233243
(3) Dipasquale L, d’Ippolito G, Gallo C, Vella FM, Gambacorta A, Picariello G, Fontana A. Int. J.
Hydr. Ener., 2012, 17, 12250–1225
O21
NIR Squaraines as Sensitizers for DSSC.
1
Nadia Barbero, 1Claudia Barolo, 1Roberto Buscaino, 2Michael Grätzel, 1Claudio
Magistris, 1Jinhyung Park, 1Pierluigi Quagliotto, 1Guido Viscardi, 2Iun-Ho Yum.
1
Dipartimento di Chimica, Centro di Eccellenza NIS, Università di Torino,
Via P. Giuria, 7 I-10125, Torino, Italy.
2
Laboratoire de Photonique et Interfaces, Institut des Sciences et Ingénierie Chimiques,
EPFL, Station 6, CH-1015, Lausanne, Switzerland.
[email protected]
The strong request for renewable energy sources has recently boosted the interest in
photovoltaic devices. Among all the organic and hybrid organic-inorganic solar cells,
Dye Sensitized Solar Cells (DSC) have demonstrated the highest conversion
efficiencies and a mature research and development plan. Compared to traditional
photovoltaics, DSSC have several advantages, such as improved performances at low
light intensities and diffuse light, color tunability, and transparency, which make DSC
very appealing for building-integrated photovoltaics (BIPV).
When a visible photon is absorbed by the sensitizer (S) in its ground state, anchored to a
TiO2 anatase nanoparticle, an electron is first promoted to an excited state and then
injected into the conduction band of the TiO2 semiconductor. The oxidized sensitizer
(S+) needs to be regenerated by a mediator, typically an iodide ion. The most successful
charge-transfer sensitizers employed are Ru(II) complexes but Zn porphyrin derivatives
yielded 12% solar-to-electric power conversion efficiencies (1).
The majority of these metal complexes show: i) not ideal matching of the absorption
spectra to the solar radiation; ii) high costs; iii) tedious purification. Metal-free organic
sensitizers are accessible by simple synthetical approaches and well established
purification approaches. They can be simply modified structurally and functionalised in
order to obtain the desired spectroscopic properties between 400–700 nm.
Squaraines have been investigated for their
sensitization properties as highly stable dyes with
intense absorption in the NIR regions. In general, these
dyes are prepared by direct condensation reaction of
electron rich aromatic heterocyclic compounds or
heterocyclic quaternized salts with squaric acid. Since
a number of heterocyclic systems with varying πframework are available, there are miscellaneous
possibilities to design tunable squaraine dyes and
absorption in the far red to near infrared domain (2).
We present synthesis and photovoltaic properties of squaraines, to obtain a
panchromatic response (3).
(1) YELLA, A.; LEE, H.W.; TSAO, H.N.; YI, C.; CHANDIRAN, A.K.; NAZEERUDDIN, M.K.; DIAU,
E.W.G.; YEH, C.Y.; ZAKEERUDDIN, S.M.; GRÄTZEL, M. Science., 2011, 334, 629-634.
(2) MCEWEN, J.J.; WALLACE, K.J. Chem. Comm., 2009, 6339-6351.
(3) PARK, J.; BAROLO, C.; SUVAGE, F.; BARBERO, N.; BENZI, C.; QUAGLIOTTO, P.;
COLUCCIA, S.; DI CENSO, D.; GRÄTZEL, M.; NAZEERUDDIN, M.K.; VISCARDI, G. Chem.
Comm., 2012, 2782-2784.
O22
Design and Synthesis of Organic Chromophores for DSSC with New
Ligands for TiO2
1
1
Irene Murgia, 1Maurizio Taddei, 1Elena Cini, 1Riccardo Basosi, 1Maria Laura Parisi,
1
Adalgisa Sinicropi, 2Massimo Calamante, 2Alessandro Mordini, 2Gianna
Reginato,2Lorenzo Zani
Università degli Studi di Siena, Dipartimento di Biotecnologie Chimica e Farmacia, via
A. Moro 2, 53100 Siena, Italy.
2
ICCOM CNR, via Madonna del Piano 10, 50019 Sesto Fiorentino (Fi), Italy.
[email protected]
Dye-sensitized solar cells (DSSCs) are a smart alternative to silicon-based photovoltaic
devices for light harvesting and electricity production. In DSSCs a molecular
photosensitizer is adsorbed on a thin layer of a mesoporous semiconductor (usually
TiO2) and, after photoexcitation, one elctron is transferred to the semiconductor. The
cycle is closed by an electrochemical process that restores the electronic configuration
of the sensitizer with passage of an electric current between the electrodes. The core of
the system is the molecualr sentizers and, amongst different kind of dyes, organic
chromophores has found several applications.1 Such compounds are usually
characterized by a D-π-A architecture, in which a donor group (D) is connected to an
acceptor/anchoring group (A) through a conjugated bridge (π). Upon irradiation, such
an arrangement facilitates the generation of photoinduced intramolecular charge-transfer
states, thus promoting electron injection.
We have explored the possibility to modify the ligand in order to introduce different
functional groups with potential high affinity with TiO2 and verify the influence of the
diverse nature of the A-group on the cell features. Starting from a preliminary
computational analysis, an homologous class of organic cromophores carrying different
anchoring groups was selected and further synthesized exploiting a new general
convergent approach based on a chemoselective Horner–Wadsworth–Emmons reaction.
(1) a) Y. Ooyama, Y. Harima, Eur. J. Org. Chem. 2009, 2903; b) A. Mishra, M. K. R. Fischer, P.
Bäuerle, Angew. Chem. Int. Ed. 2009, 48, 2474.
O23
Synthesis and Characterization of Luminescent Ionic Liquids
1
Giulia Fiorani, 2Francesco Enrichi, 1Alvise Benedetti, 1Maurizio Selva
1
Dipartimento di Scienze Molecolari e Nanosistemi, Centre for Sustainable
Technologies, Università Ca’ Foscari Venezia,
Calle Larga Santa Marta – Dorsoduro 2137, 30123 Venezia (Italy)
2
CIVEN, Coordinamento Interuniversitario Veneto per le Nanotecnologie, Via delle
Industrie 5, 30175 Marghera (Venezia), Italy
[email protected]
The preparation of metal-free luminescent Ionic Liquids (ILs) is a challenging topic
from both synthetic and physical organic chemistry standpoints. Nevertheless, the
combination of ILs characterized by fully tunable properties, with luminescent moieties
opens a wide range of potential applications in material science (1). This concept has
been exploited by us to develop a protocol based on the use of methylcarbonate ILs and
luminescent species derived from amino acids (2). The following strategy was
implemented: a) methylphosphonium and methylammonium methylcarbonate salts
([Pxxx1][MeOCO2] and [N1114][MeOCO2]; X=8, 4, respectively) were prepared by a
straightforward, halide-free methodology; b) methylcarbonate salts were then subjected
to a metathesis reaction with aminoacids bearing luminescent fragments (LAA)
(Scheme 1). At the same time, the preparation of LAA was optimized with a focus on
increasing the sustainability of preparative steps.
Both the synthesis and the preliminary characterization of the new luminescent ILs will
be discussed. The luminescence properties as well as the thermal analysis (TGA and
DSC) of such compounds will be described.
Cations
Q=P, R1=-CH3; R2=R3=R4=-C8H17
Q=P, R1=-CH3; R2=R3=R4=-C4H9
Q=N, R1=R2=R3=-CH3; R4=-C8H17
Anions (R5)
Scheme 1. Anionic and cationic moietiessynthesized.
(1) a) Soo Joa, T.; McCurdya, W. L.;Tanthmanathama, O.; Kima, T. K.; Hana, H.; Bhowmika, P. K.;
Heinrichb, B.; Donniob, B.J. Mol. Struct. 2012, 1019, 174-182; b) Tanabe, K.; Suzui, Y.; Hasegawa,
M.; Kato, T. J. Am. Chem. Soc.2012, 134, 5652-5661; c) Olivier, J.-H.; Camerel, F.; Barberá, J.;
Retailleau, P.; Ziessel, R. Chem. Eur. J.2009, 15, 8163-8174.
(2) Fabris, M.; Lucchini, V.; Noè, M.; Perosa, A.; Selva, M.Chem. Eur. J.2009, 15, 12273-12282.
O24
Activating Small Abundant Molecules such CO2, H2O2 and O2. Efforts
to Create “Green” Catalytic Chemical Processes
Blerina Gjoka, Elena Badetti, Cristiano Zonta, Giulia Licini.
Dipartimento di Scienze Chimiche, Università di Padova, via Marzolo 1, 35131 Padova.
[email protected]
The development of effective catalytic activation of abundand and usually inert
molecules and their use for transformations of nonfood-based renewable feedstock in
useful chemical compounds and fuels represents a challenge for both academia and
industry. For example, carbon dioxide can be activated as an ideal C1 synthon to afford
carbonates, polycarbonates, carbamates (1) or lignin, a potential source of aromatic
compounds (2), largely available, benignity, low cost could be selectively transformed
under oxidative conditions into valuable organic, substituted phenols or alkenes.
Herein, we will report our recent results on the catalytic properties of mononuclear
amino triphenolate metal complexes on H2O2, CO2 and O2 activation and their
applications as homogeneous catalysts for chloro and bromohaloperoxidation(3),
CO2/epoxides cycloaddition for the synthesis of cyclic carbonates (4) and aerobic
oxidative cleavage of diols.
Acknowledgments: Cost Action CM1003 'Biological Oxidation Reactions - Mechanisms
and Design of new Catalysts (STSM B.G.)
(1) M. Aresta, Carbon Dioxide as a Chemical Feedstock, Wiley-VCH, 2010;
(2) Collinson, S. R.; Thielemans, W. Coord. Chem. Rev. 2010, 254, 1854; Zakzeski, J.; Bruijnincx, P.
C. A.; Jongerius, A. L.; Weckhuysen, B. M. Chem. Rev. 2010, 110; 1514;
(3) F. Romano, A. Linden, M. Mba, C. Zonta, G. Licini Adv. Synth. Catal. 2010, 352, 2937; C. Zonta,
G. Licini Chem. Eur. J. 2013, 19, in press;
(4) C. J. Whiteoak, B. Gjoka,E. Martin, M. Martinez Belmonte, E. C. Escudero Adan, C. Zonta, G.
Licini, A. W. Kleij Inorg. Chem. 2012, 51, 10639.
O25
Green Flow Approaches for the Definition of Waste-Minimized
Reduction Protocols
Eleonora Ballerini, Ferdinando Pizzo, Luigi Vaccaro
CEMIN – Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica,
Università di Perugia I-06123 Perugia
[email protected]
We are developing novel green synthetic methodologies based on the use of tailor-made
immobilized catalysts specifically designed for their use in safer reaction media (1).
We have also exploited the use of flow chemistry to minimize waste in the synthesis of
fine chemicals (2). At this concern, our flow approach based on the adoption of solventfree conditions (SolFC) or highly concentrated conditions (HiCC) able to operate on a
multigram scale, has allowed to successfully reduce the E-factor (Kg waste/Kg product)
(2). Highlights of these protocols are the recovery of the product with a minimal amount
of an appropriately sustainable organic solvent, as well as the recovery and reuse of the
solid catalyst without compromising its efficiency.
In this contribution, we report our recent results in the definition of flow procedures for
the reduction of β-azido ketones to β-amino ketones and to γ-amino alcohols and of βazido acids to β-amino acids.
A representative schematic example of our approach is represented by the β-azidation of
α,β-unsaturated ketones and the definition of a novel reduction system operating in flow
conditions for the multistep preparation of N-Boc-β-amino ketones (2a and unpublished
results) (Scheme 1).
O
O
R1
PS-DABCOF2 (10 mol%) Pd/Al2O3, (5 mol%)
R2
HCOOH (1 eq)
Boc2O (1 eq)
TMSN3 (1.1 eq)
R1
R2
NHBoc
flow
Scheme 1. One-pot synthesis of N-Boc-β-amino ketones from α,β-unsaturated ketones.
This approach has allowed to minimize the use of the organic solvent needed for the
complete recovery of product and leave the catalyst efficient and reusable.
References
(1) As representative examples see: a) Angelini, T.; Bonollo, S.; Lanari, D.; Pizzo, F.; Vaccaro, L. Org.
Lett., 2012, 14, 4610-4613. b) Bonollo, S.; Lanari, D.; Angelini, T.; Pizzo, F.; Marrocchi, A.; Vaccaro, L.
J. Catal. 2012, 285, 216-222.
(2) a) Angelini, T.; Lanari, D.; Maggi, R.; Pizzo, F.; Sartori, G.; Vaccaro, L. Adv. Synth. Catal., 2012,
354, 908 – 916. b) Bonollo, S.; Lanari, D.; Longo, J.; Vaccaro, L. Green Chem, 2012, 12, 164-169. c)
Strappaveccia, G.; Lanari, D.; Gelman, D.; Pizzo, F.; Rosati, O.; Curini, M.; Vaccaro, L. Green Chem.
2013, 15, 199-204.
This work has been partially supported by FIRB -Futuro in ricerca and by the Israel-Italy Joint Innovation
Program for Scientific and Technological Cooperation in R&D 2012-2014
O26
Design and Characterization of Photo- and Thermo-crosslinkable
Materials for Photovolatic Applications
1
1
Luca Beverina, 1Mauro Sassi, 1Riccardo Turrisi, 1Alessandro Sanguineti, 2Antonio
Facchetti
Università di Milano-Bicocca, Dipartimento di Sceinza dei Materiali, Via R. Cozzi 53
Milano.
2
Polyera Corporation, 8045 Lamon Avenue, Skokie, IL 60077 (USA)
[email protected]
Organic π-conjugated materials are the core components of a large number of modern
technologies having an increasing impact on everyday life. The development of
performing materials for technological applications requires in the first place the
capability to design molecules and/or polymers with suitable solution performances.
Assembly of solid state devices also requires the capability to control the aggregation
process while transferring the molecules/polymers from the solution to the solid state.
The degree of control over the solid-state morphology is at least as important as the
capability to control the molecular optoelectronic properties.
In this contribution we discuss our recent results in the development of photo- and
thermo-crosslinkable conjugated materials1 to be employed as donor and acceptors in
organic photodiodes and solar cells. We will particularly focus on squaraine,2
diketopyrrolopyrroles3 and perylene immide4 derivatives that are amongst the most
performing materials so far described for OPV applications.
Figure 1. AFM images of pristine (left) and photocrosslinked (right) fullerene and acrylic
squaraine mixture.
(1) Nielsen, C. B.; Angerhofer, A.; Abboud, K. A.; Reynolds, J. R. J. Am. Chem. Soc. 2008, 130, 9734–
9746.
(2) Beverina, L.; Drees, M.; Facchetti, A.; Salamone, M.; Ruffo, R.; Pagani, G. A. Eur. J. Org. Chem.
2011, 2011, 5555–5563.
(3) Sassi, M.; Crippa, M.; Ruffo, R.; Turrisi, R.; Drees, M.; Pandey, U. K.; Termine, R.; Golemme, A.;
Facchetti, A.; Beverina, L. J. Mater. Chem. A 2013, 1, 2631.
(4) Sanguineti, A.; Sassi, M.; Turrisi, R.; Ruffo, R.; Vaccaro, G.; Meinardi, F.; Beverina, L. Chem.
Commun. 2013, 49, 1618–1620.
O27
Controlled Chemical Functionalization of Carbon Nanostructures for
Organic Photovoltaics and Functional Materials
1
Patrizio Salice, 2Camillo Sartorio, 1Alessandro Burlini, 1Daniele Gragnato, 2Sebastiano
Cataldo, 1Simone Silvestrini, 1Michele Maggini, 2Bruno Pignataro, 1Enzo Menna
1
2
Dipartimento di Scienze Chimiche, Università di Padova, Italy.
Dipartimento di Chimica “S. Cannizzaro”, Università di Palermo.
[email protected]
The covalent chemistry of carbon nanostructures (CNSs) has put forth a wide variety of
interesting derivatives that widen the potential of carbon allotropes in functional
materials including BHJ solar cells, (1) polymer membranes, and biocompatible
scaffolds. However, the functionalization protocols often require long reaction times
and frequently harsh conditions. Under this prospective, we have anticipated the
employment of flow apparatuses as fast and reliable tools that allow a precise reaction
control through efficient heat and mass transfer. (2) Indeed, we have demonstrated that
many reactions can be translated from the usual batch conditions to a flow chemistry
protocol, not only retaining the properties of the products (solubility, conversion) but,
more importantly, requiring shorter times with the potential advantage of a quick
response when new functional groups or wider scope investigations are involved. (3)
These results were validated by merging a collection of different characterization
techniques in a consistent protocol (UV-vis, TGA, ATR-IR, XPS, AFM, DLS, Raman)
that provided the key parameters for the design and controlled processing of novel
decorated carbon nanostructures. (4)
Moreover, to prove the robustness of our approach, we provide evidence that the
interaction between CNSs and poly-3-hexylthiophene (P3HT) in solution and in a blend
is strongly dependent on the way the CNSs are functionalized.
(1) Salice, P.; Maity, P.; Rossi, E.; Carofiglio, T.; Menna, E.; Maggini, M., Chemical Communications
2011, 47 (32), 9092-9094.
(2) Cataldo, S.; Salice, P.; Menna, E.; Pignataro, B., Energy & Environmental Science 2012, 5 (3), 59195940.
(3) Maggini, M.; Menna, E.; Carofiglio, T.; Rossi, E.; Pace, A.; Salice, P., WO Patent 2,012,156,297:
2012.
(4) Salice, P.; Fenaroli, D.; De Filippo, C. C.; Menna, E.; Gasparini, G.; Maggini, M., Chimica Oggi /
Chemistry Today 2012, 30 (6), 37-39.
O28
Applications of KuQuinones as Sensitive Material on
Photelectrochemical Devices
Pierluca Galloni, Sara Lentini, Federica Sabuzi, Barbara Floris, Emanuela Gatto,
Mariano Venanzi and Valeria Conte.
Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata.
[email protected]
Recently we discovered a new class of diquinoid compounds,1 called KuQuinones,
that shows very interesting photo- and electrochemical properties such as a broad
absorption spectra in visible region and a very low reduction potential. For these
reasons we used such diquinoid molecules in photoelectrochemical devices using
different deposition methods on ITO surface.2
The characterization of redox and spectrophotometric properties of films and the IPCE
values (incident photon to current conversion efficiency) of cell will be reported; the
results in terms of photocurrent generation and film stability are promising and they will
be discussed as a function of deposition techniques used.
References.
(1) Coletti, A.; Lentini, S.; Conte, V.; Floris, B.; Bortolini, O.; Sforza, F.; Grepioni, F.; Galloni, P. J. Org.
Chem. 2012, 77, 6873.
(2) a) Kim, H.; Gilmore, C. M.; Piqué, A.; Horwitz, J. S.; Mattoussi, H.; Murata, H.; Kafafi, Z. H.;
Chrisey, D. B. J. Appl. Phys. 1999, 86, 6451. b) Donley,C.; Dunphy, D.; Paine, D.; Carter, C.; Nebesny,
K.; Lee,P.; Alloway, D.; Armstrong, N. R. Langmuir 2002, 18, 450. c) Armstrong, N. R.; Veneman, P.
A.; Ratcliff, E.; Placencia, D.; Brunbach, M. Acc. Chem. Res. 2009, 42, 1748.
O29
Solvent- and Light-Controlled Unidirectional Transit of a
Nonsymmetric Molecular Axle Through a Nonsymmetric Molecular
Wheel
Arturo Arduini,1 Rocco Bussolati,1 Andrea Secchi,1 Alberto Credi,2 Simone Monaco,2
Serena Silvi,2 Margherita Venturi2
1
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/a, I-43124
Parma (Italy).
2
Dipartimento di Chimica “G. Ciamician”, Università di Bologna, Via Selmi 2, I-40126
Bologna (Italy).
[email protected]
The principles and methods of supramolecular chemistry applied to the construction of
working devices and molecular machines represent a powerful strategy for the
development of nanoscience and nanotechnology as well as for the comprehension of
the several biological processes in which natural motors and machines operate (1). The
development of a pseudorotaxane motif capable of performing unidirectional threading
and dethreading processes under control of external stimuli is particularly important for
the construction of processive linear motors based on rotaxanes and, at least in
principle, it discloses the possibility to access to rotary motors based on catenanes.
Here we report a strategy to obtain the solvent-controlled unidirectional transit of a
molecular axle through a molecular wheel. It is based on the use of appropriately
designed molecular components, the essential feature of which is their non-symmetric
structure. Specifically they are an axle containing a central electron-acceptor 4,4′bipyridinium core functionalized with an hexanol chain at one side, and a stilbene unit
connected through a C6 chain at the other side, and a heteroditopic tris(phenylureido)calix[6]arene wheel (2).
(1) R. A. L. Jones, Soft Machines, Nanotechnology and Life; Oxford University Press: New York,
USA, 2004; D. S. Goodsell, Bionanotechnology – Lessons from Nature; Wiley-Liss: Hoboken
(NJ), USA, 2004. S. Mann, Angew. Chem. Int. Ed. 2008, 47, 5306-5320.
(2) See also: S. Silvi, A. Arduini, A. Pochini, A. Secchi, M. Tomasulo, F. M. Raymo, M. Baroncini,
A. Credi, J. Am. Chem. Soc. 2007, 129, 13378-13379; A. Arduini, F. Calzavacca, A. Pochini, A.
Secchi, Chem. Eur. J. 2003, 9, 793-799.
O30
Calixarene Hosts and Ammonium Guests: from endo-cavity
Complexes to Interpenetrated Systems with Self-sorting Abilities
Carmen Talotta, Carmine Gaeta, Gerardo Concilio, Roberta Ciao and Placido Neri
Dipartimento di Chimica e Biologia, Università degli Studi di Salerno, Via Giovanni
Paolo II n. 132, 84084, Fisciano (Salerno), Italy
[email protected]
Recently (1,2a) we have reported the first examples of endo-cavity complexation and
through-the-annulus-threading of scarcely efficient calix[6-8]arene hosts 1a−c
exploiting the inducing effect of the "superweak" TFPB anion (Figure). We have also
established that 18-membered dihomooxacalix[4]arene derivatives 2a-b are currently
the smallest calixarenes able to host linear and branched alkylammonium guests inside
their aromatic cavity (2b). xploiting the threading of dialkylammonium∙TFPB− axles
through the calixarene wheels (1) we have obtained the first examples of rotaxane (3a,b)
and catenane architectures 4+ (3c). Interestingly, these studies have evidenced that the
"threading of a directional alkylbenzylammonium axle through calix[6]arene wheels
occurs with an endo-alkyl preference" (endo-alkyl rule). On the basis of this endo-alkyl
rule, specific stereosequences, exemplified by pseudo[3]rotaxanes (H,H)-52+ and (H,T)62+, were obtained with rationally designed bis(alkylbenzylammonium) axles (3d).
Successively, we have found that such pseudo[3]rotaxane architectures have intriguing
self-sorting capabilities, which allowed to define an integrative self-sorting system able
to discriminate simultaneously at the sequence and stereochemical level (4).
(1) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett, 2010, 12, 2092−2095.
(2) (a) Gaeta, C.; Talotta, C.; Farina, F.; Camalli, M.; Campi, G.; Neri, P. Chem. Eur. J. 2012, 18,
1219−1230. (b) Gaeta, C.; Talotta, C.; Farina, F.; Teixeira, F. A.; Marcos, P. A.; Ascenso, J. R.;
Neri, P. J. Org. Chem. 2012, 77, 10285−10293
(3) (a) Pierro, T.; Gaeta, C.; Talotta, C.; Casapullo, A.; Neri, P. Org. Lett. 2011, 13, 2650–2653. (b)
Talotta, C.; Gaeta, C.; Neri, P. Org. Lett. 2012, 14, 3104–3107. (c) Gaeta, C.; Talotta, C.; Mirra,
S.; Margarucci, L.; Casapullo, A.; Neri, P. Org. Lett. 2013, 15, 116−119. (d) Talotta, C.; Gaeta,
C.; Pierro, T.; Neri, P. Org. Lett. 2011, 13, 2098–2101
(4) Talotta, C.; Gaeta, C.; Qi, Z.; Schalley, C. A.; Neri, P. Angew. Chem. Int. Ed. Engl. 2013, DOI:
10.1002/ange.201301570.
O31
Synthesis and Self-assembly of Diphenylalanine-chromophore
Conjugates
Ilaria Morbioli, Miriam Mba
Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova
(Italy).
[email protected]
Supramolecular self-organisation is a fundamental tool in the bottom-up approach
towards new soft functional nanomaterials. Supramolecular architectures incorporating
functional chromophores are getting an increasing attention as new materials for organic
electronics.1 In this case, precise control over chromophore’s spatial disposition may
enhance energy and electron transfer processes.
Diphenylalanine is a self-assembling building block able to self-organize in ordered
structures spanning from nanotubes to spheres and therefore is an appealing candidate
for the construction of soft functional materials.2 We have synthesized a series of
chromophore-diphenylalanine conjugates containing
pyrene and ferrocene
chromophores and studied the self-assembly of this new compounds in solution.
Organogel formation was observed in different organic solvents. The organogels are
responsive to external stimuli such as temperature or sonication, moreover, in the case
of ferrocene-diphenylalanine conjugate the organogel showed a response to redox
stimuli.
(1) Hirst, A. R.; Escuder, B.; Miravet, J. F.; Smith, D. K. Angew. Chem.-Int. Edit. 2008, 47, 8002-8018..
(2) Yan, X.; Zhu, P.; Li, J. Chem. Soc. Rev. 2010, 39, 1877-1890
Acknowledgements:PRAT CPDA119117/11 from the University of Padova and COST Action CM1005
for financial support.
O32
Dynamic Multi-Component Assemblies for Amino Acids Recognition
Elena Badetti, Francesca A. Scaramuzzo, Giulia Licini, Cristiano Zonta
Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Via Marzolo 1,
35131 Padova, Italy
[email protected]
The study of dynamic multi-component assemblies created from reversible covalent
bonds is at the forefront of recent supramolecular chemistry efforts, with the ultimate
goals of creating molecular machines, complex nanoarchitectures, dynamic
combinatorial libraries (DCLs) and sensors (1). One of the most widely explored
reversible associations in this field is imine or hemiaminal formation from carbonyls
and primary amines (2) while secondary amines, being more sterically bulky and
thereby often less nucleophilic, have not been as extensively studied (3). The
communication shows an approach to generate in situ five-component assemblies based
on the combination of the tris(2-pyridylmethyl)amine scaffold and amino acids (Figure
1). Their use in as receptors for amino acids will be discussed.
Figure 1. Synthesis of a five-component assembly using reversible covalent chemistry.
Acknowledgments: Università di Padova. Grant Number: PRAT-CPDA099121, MIUR
PRIN-2010-11 2010CX2TLM_002
(1) (a) Jin, Y.; Yu, C.; Denman, R. J.; Zhang, W. Chem. Soc. Rev. 2013, Advance Article. (b) Canary, J.
W.; Mortezaei, S; Liang, J. Coord. Chem. Rev. 2010, 254, 2249–2266.
(2) (a) Osowska, K.; Miljanic, O.S. J. Am. Chem. Soc. 2011, 133, 724-727. (b) Drahonovsky, D.; Lehn,
J. M. J. Org. Chem. 2009, 74, 8428-8432. (c) Meyer, C.D.; Joiner, C.S.; Stoddart, J. F. Chem. Soc.
Rev. 2007, 36, 1705-1723.
(3) (a) You, L.; Pescitelli, G.; Anslyn, E. V.; Di Bari, L. J. Am. Chem. Soc. 2012, 134, 7117-7125. (b)
You, L.; Long, S. R.; Lynch, V. M.; Anslyn, E. V. Chem. Eur. J. 2011, 17, 11017-11023.
O33
Hydrogen Atom Transfer from Activated Phenols to Short-Lived
Aminoxyl Radicals. The Role of Charge Transfer Contribution from Stacking Interactions
1
Osvaldo Lanzalunga, 1Claudio D’Alfonso,1Marco Mazzonna,
2
Massimo Bietti, 2Michela Salamone
1
Dipartimento di Chimica, Università di Roma “La Sapienza” and Istituto CNR di
Metodologie Chimiche (IMC-CNR), P.le A. Moro, 5 00185 Rome, Italy
2
Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata", Via della
Ricerca Scientifica, 1 00133 Rome, Italy.
[email protected]
A kinetic study of the hydrogen transfer process from activated phenols to a series of
short-lived aminoxyl radicals has been carried out by laser flash photolysis in CH3CN
(Scheme 1) as an extension of our previous study of the reactions promoted by the
phthalimide-N-oxyl radical (1).
Scheme 1
A significant effect of the aminoxyl radical structure on the rate constants for the
hydrogen transfer process (kH) was observed with kH values that regularly increase by
increasing the NO-H bond dissociation energy values (BDENO-H) of the parent Nhydroxylamines. On the basis of the results of kinetic analysis and theoretical
calculations we suggest that these reactions proceed by a hydrogen atom transfer (HAT)
mechanism characterized by a significant degree of charge transfer resulting from a stacked conformation between the aminoxyl radicals and the phenolic aromatic ring.
The use of HAT reactivity studies of short-lived aminoxyl radicals as a tool for
evaluating the radical scavenging ability of phenolic antioxidants will be critically
discussed on the basis of the comparison of our results with the reactivity data for the
hydrogen abstraction from activated phenols promoted by peroxyl radicals.
(1) D’Alfonso, C.; Bietti, M.; DiLabio, G. A.; Lanzalunga, O.; Salamone, M. J. Org. Chem. 2013, 78,
1026-1037.
O34
Synthesis of Metal Complexes based on N-aminoethylpiperazine-Ndiazeniumdiolate with Controlled NO Release
1,2
Aurora Pacini, 1,2Luca Pasotti, 1Silvia Pizzocaro, 1,2Enrico Monzani, and 1,2Luigi
Casella
1
Dipartimento di Chimica, Università di Pavia, Viale Taramelli 12, 27100 Pavia
2
Noxamet Srl, Sede Operativa di Pavia, Viale Taramelli 12, 27100 Pavia
[email protected]
We report on a series of metal complexes characterized by the property of controlled
NO release, in which the chemical structure and composition are based on Naminoethylpiperazine-N-diazeniumdiolate residue and are termed "metal-nonoates".(1)
Simple metal-nonoate complexes have already demonstrated their potential in
pharmacology as powerful vasodilators even at very low doses.(1) Here we report on
the preparation and spectroscopic characterization of second-generation metal-nonoates,
in which the primary amino group of N-aminoethylpiperazine-N-diazeniumdiolate is
conjugated with an amino acid, a short peptide or other residues. We will also show
how the introduction of new chelating groups can modulate the NO release by the
resulting complexes. An important objective of the extended ligand modification is the
thermodynamic and kinetic stabilization of the metal-nonoates, through the increase of
denticity of the polydentate ligands. The metal ion itself has an important role in the
control of the kinetics of NO release, as it has been shown in our previous studies.(1) In
the present context, we will consider metal-nonoates containing Ni(II), Cu(II) and
Zn(II).
Another motivation for introducing peptide residues into the "nonoate" ligand of these
complexes is linked to different reasons: (i) using peptides as biomimetic portions, (ii)
taking advantage of receptors for penetration through biological membranes, and (iii)
having useful building-blocks to synthesize molecules with different chemical and
physical characteristics.
(1) Ziche, M.; Donnini, S.; Morbidelli, L.; Monzani, E.; Roncone, R.; Gabbini, R.; Casella, L. Chem
Med Chem. 2008, 3, 1039-47.
O35
Phytotoxic Metabolites Produced by Botryosphaeriaceae Involved in
Grapevine Trunk Diseases
1
Sara Basso, 1Anna Andolfi, 2Lucia Maddau, 2Benedetto T. Linaldeddu, 2Antonio
Deidda, 1Salva Serra, 1Alessio Cimmino, 1Antonio Evidente
1
Dipartimento di Scienze Chimiche, Università degli Studi di Napoli Federico II via
Cintia 4, 80126 Napoli, Italy.
2
Dipartimento di Agraria, sez. di Patologia vegetale ed Entomologia, Università di
Sassari, via E. De Nicola 1, 07100 Sassari, Italy.
[email protected]
Fungi belonging to the Botryosphaeriaceae family are well known as cosmopolitan
pathogens, saprophytes and endophytes and occur on a wide range of hosts including
grapevine. Grapevine disease symptoms caused by members of this family include leaf
spots, fruit rots, shoot dieback, bud necrosis, vascular discoloration of the wood, and
perennial cankers (1). The nature and appearance of wood symptoms caused by these
pathogens suggest that phytotoxic metabolites could be involved in the host–pathogen
interaction. For example phytotoxins such as (3R,4R)-(-) and (3R,4S)-(-)-4hydroxymelleins, isosclerone and tyrosol has been isolated and identified from a strain
of Neofusicoccum parvum isolated from symptomatic grapevines in Catalogna (2).
Another species, N. australe involved in the aetiology of grapevine cordon dieback in
Italy, showed to produce in vitro structurally different secondary metabolites. The main
phytotoxin, named cyclobotryoxide, was characterized as a new cyclohexenone oxide
(1). It was produced together with 3-methylcatechol and tyrosol (3).
OH
CH3
O
OCH3
O
1
In addition, the species Diplodia seriata showed to produce already known melleins as
(3S,4R)-4-hydroxymellein, (3S)-7-hydroxymellein and a new one characterized as
(3S,4R)-4,7-dihydroxymellein (4).
More recently, a new species of Lasiodiplodia was isolated from declining grapevines
in Sardinia (Italy). This still undescribed species showed to produce in liquid culture
several phytotoxic secondary metabolites. In this communication the chemical and
biological characterization of these bioactive secondary metabolites is discussed
together with their role in the pathogenesis process.
(1) ÚRBEZ-TORRES, J.R. Phytopathol. Mediterr. 2011, 50, S5-S45.
(2) EVIDENTE, A.; PUNZO, B.; ANDOLFI, A.; CIMMINO, A.; MELCK, D.; LUQUE, J.
Phytopathol. Mediterr. 2010, 49, 74-79.
(3) ANDOLFI, A.; MADDAU, L.; CIMMINO, A.; LINALDEDDU, B.T.; FRANCESCHINI, A.;
SERRA, S.; BASSO, S.; MELCK, D.; EVIDENTE, A. J. Nat. Prod. 2012, 75, 1785-1791.
(4) ANDOLFI, A.; MUGNAI, L.; LUQUE, J.; SURICO, G.; CIMMINO, A.; EVIDENTE, A. Toxins
2011, 3, 1569-1605.
O36
Alkylation of G-quadruplex DNA by Functionalized NDIs
1
Luca Germani,1Filippo Doria, 2Matteo Nadai, 1Mariella Mella, 4Daniele Fabris, 2Sara
N. Richter,* and 1Mauro Freccero*
1
Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia (Italy)
2
Dip. di Medicina Molecolare, Università di Padova, via Gabelli 63, 35121 Padua
(Italy)
3
The RNA Institute, University at Albany,1400 Washington Ave., Albany, NY 12222,
USA
[email protected]
In the last decade there was a growing interest in G-quadruplex structures (G4) due to
the important biological role that they exhibit both in vitro and in vivo (1). The selective
targeting of these structures by small molecules is a “hot topic” in cancer therapy. In
fact, G4 alkylation and cross-linking as been suggested to be an efficient strategy for
probing specific G4 structures and targeting oncogenes containing G4.
G4 are supramolecular DNA and RNA secondary structures stabilized by Hoogsteen
hydrogen that nucleic acid guanine-rich strand are capable to form under particular
conditions (Na+ and K+ rich buffer).
The recent literature shows a great number of selective ligands for G4 structures, but
most of them are reversible ones. The addiction of a strong energetic contribution, for
example a covalent bond, can improve the ability of the ligand.
This is the strategy that my research group has pursued for the last five years (2,3).
Therefore in addition to the non-covalent interactions we have introduced an additional
moiety that can target covalently the G4. To achieve this feature we use a naphthalene
diimides (NDIs) core as G4 recognising planar moiety and a side arm carring the
alkylating portion. This one could be an activable electrophilic precursor (such as
quinone methide, QM) or a intrinsically reactive oxirane.
(1) (a) Biffi, G.; Tannahill, D., McCafferty, J., Balasubramanian, S. Nature Chem. 2013, 5, 182-186; (b)
Balasubramanian, S.; Hurley, L. H.; Neidle, S. Nat. Rev. Drug. Discover. 2011, 10, 261-275.
(2) (a)Nadai,M.; Doria, F.; Di Antonio, M.; Sattin, G..; Germani, L.; Percivalle, C.; Palumbo,M.; Richter,
S.N.; Freccero, M.; Biochimie 2011, 93, 1328-40; (b)Di Antonio, M.; Doria, F.; Richter, S. N.;
Bertipaglia, C.; Mella, M.; Sissi, C.; Palumbo, M.; Freccero, M. J. Am. Chem. Soc. 2009, 131, 13132-41.
(3) (a) Doria, F.; Nadai, M.; Folini, M.; Di Antonio, M.; Germani, L.; Percivalle, C.; Sissi, C.; Zaffaroni,
N.; Alcaro, S.; Artese, A.; Richter, SN.; Freccero, M. Org Biomol Chem. 2012, 10, 2798-2806; (b) Doria,
F.; Nadai, M.; Folini, M.; Scalabrin, M.; Germani, L.; Sattin, G.; Mella, M.; Palumbo, M.; Zaffaroni, N.;
Fabbris, D.; Freccero, M.; Richter, SN. Chemistry Eur. J. 2013, 19, 78-81.
O37
Industrial Development of Generic APIs
From Problems to Opportunity - Case Study
Claudio G. Pozzoli, Valentina Canevari, Marco Brusasca
Farmabios SpA (Zellbios Group) – via Pavia 1- 27027-Gropello Cairoli (PV)- Italy
[email protected]
Identification, development and the subsequent implementation of an industrial
production route for the manufacture of a generic API (Active Pharmaceutical
Ingredient) starts with a thorough literature and patent search of the target molecule.
The aim of this research is to provide the technicians of a generic company all the
necessary information and direction regarding the R&D activities, the patent rights and
importantly the safety aspects. The patent rights may cover the molecule itself, its
possible synthesis, use of particular technologies, etc..
The basic drug-patent, i.e. the first patent filed by the originator company usually claims
the molecule itself, its preparation and pharmacological application(s). However, rarely
the reported synthetic procedure is practical on a commercial scale. This happens
because quite often the procedural details are missing or because the reported yields are
not satisfactory or are missing altogether.
Many a times years after the publication of the basic patent or the commercial launch of
the product the same originator companies file new patents claiming different synthetic
routes or improvement to the original one, in an attempt to hamper the activities of the
generic companies.
However, if properly studied and solved, the problems encountered in the basic patent
become opportunities for generic companies to file new patent applications (as process
patent) thereby granting their own synthesis and the ability to market the generic API at
the expiration of the basic patent.
In some cases the scale-up problems, though not mentioned in the patent, are evident to
experts in this field while reviewing a patent. In such cases when the synthetic route
described in the original patent is not deemed feasible, or when the internal know-how
suggests alternative ‘smarter’ synthetic route, the generic companies develop brand new
manufacturing routes that are significantly different than the ones described by the
originators.
This communication presents some of the above mentioned situations encountered in
our laboratories during the development of novel synthetic routes for some highly active
molecules; specifically -. Mivacurium chloride (muscle relaxant), Exemestane (steroidal
aromatase inhibitor) and Azacitidine (cytotoxic).
During the presentation a brief description of different patent types and their constraints
as well as containment issues of high potent compounds at industrial level will be also
presented.
O38
Improved Industrial Synthesis of Varenicline
Emanuele Attolino, Roberto Rossi, Pietro Allegrini
Dipharma Francis s.r.l. via Bissone 5, 20021 Baranzate (MI), Italy.
[email protected]
7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine, namely
Varenicline, is a nicotinic receptorpartial agonist. It stimulates nicotine receptors more
weakly than nicotine itself does and for this reason is used to treat smoking addiction.As
a partial agonist it both reduces cravings for and decreases the pleasurable effects of
cigarettes and other tobacco products. It has been developed by Pfizer and is
commercialized as tartrate saltunder the trade name Champix®.
Researcher from Pfizer, reported1several processes for the preparation of
Varenicline, all of them characterized by the use of protected amine 2 as key
intermediate. After double nitration of 2, hydrogenation of nitro derivative 3,
condensation with glyoxal and deprotection,Varenicline1 could be easily obtained.
Three main problems can be encountered in this approach:the key intermediate 2
preparation, the use of protections and the regioselectivity of the nitration reaction.
With the aim of producingVarenicline efficiently in a cost effective way, and
making use of safe procedures, we developed a modified sustainable synthetic
approach.2
N
O2N
2
NH
NP
NP
N
O2N
3
1
Scheme 1
In this communicationan overview on the implementation of the aforementioned
process to develop an industrial process of the key intermediate 2, and its conversion to
Varenicline, will be given. In particular we will discuss the selection criteria that led to
the definition of a new, safe and environmentally friendly synthetic industrial process.
(1) a) O’Donnell, C.J.; Singer, R.A.; Brubaker, J.D.; McKinley, J.D. J. Org. Chem. 2004, 69, 57565759. b) Brooks, P.R.; Caron, S; Coe, J.W.; Ng, K.K.; Singer, R.A.; Vazquez, E.; Vetelino, M.G.;
Watson, H.H.; Whritenour, D.C.; Wirtz, M.C. Synthesis2004, 1755-1758. c) Singer, R.A.;
McKinley, J.D.; Barbe, G;Farlow, R.A. Org. Lett. 2004, 6, 2357-2360.
(2) Attolino, E.; Rossi, R.; Allegrini, P., US 2013/030179
O39
PAT in the Large Scale Synthesis of Fosfomycin Key Intermediate
Alfonso Melloni, Alberto Guidi, Roberto Brescello, Massimo Verzini, Livius Cotarca
ZaCh System S.p.A. (via Dovaro, 2 – 36045 Almisano di Lonigo, VI).
[email protected]
(-) (1R,2S)-(Z)-1,2-Epoxypropylphosphonic acid (EPPA) also called Fosfomycin, is a
low molecular weight cell-wall active antibiotic indicated in the treatment of urinary
tract infections (Figure 1). It was discovered by Hendlin et al. in 1969 in a fermentation
broth of Streptomyces fradiae and since then several syntheses have been published.
Figure 1
On large scale Fosfomycin is prepared as its (R)-phenyl ethyl amine (PEA) salt starting
from phosphorous trichloride, t-butanol and propargyl alcohol (Figure 2).
Figure 2
This first step requires careful control of the addition rate and stoichiometry of the
reagents in order to optimise the formation of di-tert-butyl prop-2-ynyl phosphate 1.
Accordingly, we have developed an elegant in-process control method (Process
Analytical Technology), by monitoring on-line the formation of phosphorylated
intermediates by means of an FT-IR probe. Consequently, it is possible to estimate and
fine-tune the required amounts of the reagents in order to minimise the formation of
undesired by-products.
O40
Hydrogen-Bonding Brønsted Acid Tetrazole Catalysed Chemoselective
Oxidation of Sulfides
Francesco Secci, Angelo Frongia, Pier Paolo Piras
Dipartimento di Scienze Chimiche, Università degli studi di Cagliari, Complesso
Universitario di Monserrato, S.S. 554, Bivio per Sestu,
I-09042, Monserrato, Cagliari, Italy. e-mail: phone number (+39)0706754402
[email protected]
The oxidation of organosulfides1 with tBuOOH or H2O2 catalyzed by hydrogen
bonding-Brønsted acids aminotetrazole derivatives, and/or ammonium salts have been
fully studied. The catalytic oxidation reaction has been performed in organic solvents
and in water as a versatile eco-friendly2 new approach to sulfoxides as an efficient and
chemoselective oxidation process.
2.5-5 mol. % catalyst loading afforded organosulfoxides with complete conversion and
high isolated yields around 90-95%. Tetrazoleamide derivatives can be easily recovered
by simple filtration and reused several times.
Reactions were scaled up from mg to multigram scale in order to test the robustness and
the diastereoselection of the process. 1H-NMR, potentiometric studies and
computational calculations were performed with the aim to disclose the role of tetrazole
amide-tBuOOH and tetrazole amide-H2O2 complexes in the the catalytic oxidation of
organosulfide derivatives as new performing and useful oxidation catalysts.
R
S
cat. (5 mol %.)
R'
Ox. 1.1 eq.
solvent, rt
R
O
S
O
R'
+
R
O
S
R'
20 examples
chemoselectivity >99:<1
Yields >90%
N N
N
N
Ha
O
N
Hb
O O
Hc
R''
R'' = tBu, H
(1) For selected examples see: a) F. Di Furia, G. Modena, R. Seraglia, Synthesis. 1984, 325; b) P. Pitchen,
E. Dunach, M.N. Desmukh, H.B. Kagan J. Am. Chem. Soc. 1984, 106, 8188; c) M. Palucki, P.
Hanson, E. N: Jacobsen Tetrahedron Lett. 1992, 33, 7111; d) N. Komatsu, M. Hashizume, T. Sugita,
S. Uemura J. Org. Chem. 1993, 58, 4529; e) C. Bolm, F. Bienewald, Angew. Chem. 1995, 107, 2883;
Angew. Chem. Int. Ed. Engl. 1995, 34, 2640; f) C. Kokubo, T. Katsuki, Tetrahedron 1996, 52, 13895;
g) M. Mba, L. J. Prins, G. Licini Org. Lett. 2007, 9, 21.
(2) For metal-free sulfoxidation procedures see: a) F. Shi, M. K. Tse, H. M. Kaiser, M. Beller Adv. Synth.
Catal. 2007, 349, 2425. b) R. E. del Rio, B. Wang, S. Achab, L. Bohè Org. Lett. 2007, 9, 2265. c) H.
Golchoubia, F. Hosseinpoor Molecules 2007, 12, 304. d) Z.-G. Xiong, J. Zhang, X.-M. Hu Appl.
Catal., A 2008, 334, 44. e) A. Russo, A. Lattanzi, Adv. Synth. Catal. 2009, 351, 521; f) S. Wei, K. A.
Stingl, K. M. Weiss, S. B. Tsogoeva, Synlett 2010, 5, 707. g) K. A. Stingl, S. B. Tsogoeva
Tetrahedron: Asymmetry 2010, 21, 1055.
O41
Synthesis of 3-Hydroxyisoquinolines by Coupling an Ugi
Multicomponent Reaction with a Reductive Heck Cyclization
1
1
Renata Riva, 1Luca Banfi, 1Lisa Moni, 2Thomas J. J. Müller, 1Gianluca Valentini
Dipartimento di Chimica e Chimica Industriale, Università di Genova, Via Dodecaneso
31, 16146 GENOVA
2
Institut für Organische Chemie und Makromolekulare Chemie, Heinrich Heine
Universität Düsseldorf, D-40225 Düsseldorf.
[email protected]
In order to broaden the scope of a previously reported synthesis of 2,4-diarylpyrano[2,3b]indoles through an insertion-coupling-cycloisomerization domino synthesis mediated
by Pd-Cu catalytic system,1 we planned to apply a similar strategy for preparing
heterocycle 2 by the transition metal mediated cyclization of Ugi product 3 in the
presence of a terminal alkyne.
R3
R1
OH
R1
N
O
1
R3
one-pot
N
R2
R2
N
H
O
R5 ≠ H
4
R4
X
R4
X
O
Pd-Cu
R1
N
R2
N
H
O
R1
H
N
R2
2
N
H
O
R1
R3
Ugi
R5 = H
O
3
R2
R3
CHO
NC
CO2H
R5 NH2
Unexpectedly R4–CCH was not incorporated during the planned Heck-Sonogashira
cycloisomerization, giving 3-hydroxyisoquinolines 4 instead, as the result of a reductive
6-exo-dig Heck cyclization in which only the Pd-catalyst is involved.
3-Hydroxyisoquinolines are rather unexplored compounds having nevertheless a
remarkable biological activity.2 Moreover, scaffold 4 displays very interesting
photophysical properties, which makes its application in the field of material sciences
very attractive. For this reason we prepared a small library of compounds 4 with three
diversity points, using either ammonia or an ammonia surrogate. In this latter case we
were also able to obtain 4 through an efficient one-pot procedure starting from the
appropriate ortho-halo benzaldehyde as carbonyl input and a propiolic acid.
(1) Schönhaber, J.; Frank, W.; Müller, T. J. J. Org. Lett. 2010, 12, 4122-4125.
(2) Kanojia, R. M.; Press, J. B.; Lever, O. W.; Williams, L.; McNally, J. J.; Tobia, A. J.; Falotico, R.;
Moore, J. B. J. Med. Chem. 1988, 31, 1363-1368.
O42
A Novel and Concise Synthesis of (±)-Clavicipitic Acid by a Rh(I)Catalyzed Intramolecular Imine Hydroarylation Reaction
Michele Mari, Mariangela Casoli, Francesca Bartoccini and Giovanni Piersanti
Department of Biomolecular Sciences, University of Urbino,
P.zza del Rinascimento 6, 61029 Urbino (PU), Italy
[email protected]
Clavicipitic acid (Fig. 1), an ergot alkaloid isolated from SD58 and Claviceps
fusiformis, is a unique member of the 3,4-disubstituted indole alkaloids characterized by
a tricyclic azepinoindole skeleton. This unusual ergot alkaloid biosynthesis derailment
product occurs in nature as a mixture of cis and trans diastereoisomers, the proportions
of which depend on the specific microorganism from which it is isolated (1).
Clavicipitic acid has been the target of several multistep total syntheses both racemic
and optical avtive (2). These gave the desired product as mixtures of cis and trans
isomers in low overall yield and involved many classical synthetic procedures,
including extensive protection, deprotection, and functional group modification.
We envisioned a concise and efficient synthesis of (±)-cis and (±)-trans-clavicipitic acid
using a Friedel-Craft alkylation of 4-boronic ester indole with dehydroalanine (3) and
an unprecedented Rh(I)-catalyzed intramolecular 1,2-addition of boronic ester into an
unactivated imine group as the keys carbon-carbon forming steps. Preliminary results
for an enantioselective variant of this synthesis, using chiral diene ligands in Rhcatalyzed arylation, will be also disclosed.
Ph
H
N
N
COOH
CHO
Rh(I)-catalyzed imine
hydroarylation
NH2
BPin
Friedel-Crafts alkylation
with dehydroalanine
COOMe
N
H
(±)-Clavicipitic Acid
N
H
Ph
COOMe
BPin
N
H
Figure 1. Outline of the synthsesis of (±)-Clavicipitic acid
(1) (a) Robbers, J. E.; Floss, H.G. Tetrahedron Lett. 1969, 10, 1857-1858. (b) King, G. S.; Mantle, P. G.;
Szczyrbak, C. A.; Waight, E. S. Tetrahedron Lett. 1973, 14, 215-218. (c) King, G. S.; Waight, E. S.;
Mantle, P. G.; Szczyrbak, C. A. J. Chem. Soc., Perkin Trans. 1 1977, 2099-2103. (d) Robbers, J. E.;
Otsuka, H.; Floss, H. G.; Arnold, E. V.; Clardy, J. J. Org. Chem. 1980, 45, 1117-1121.
(2) (a) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486-1487. (b) Yokoyama,
Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Murakami, Y. Tetrahedron Lett. 1999, 40, 7803-7806. (c)
Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem.
2004, 1244-1253. (d) Shinohara, H.; Fukuda, T.; Iwao, M. Tetrahedron 1999, 55, 10989-11000. (e) Ku,
J.-M.; Jeong, B.-S.; Jew, S.-s.; Park, H.-g. J. Org. Chem. 2007, 72, 8115-8118. (f ) Xu, Z.; Li, Q.; Zhang,
L.; Jia, Y. J. Org. Chem. 2009, 74, 6859-6862. (g) Xu, Z.; Li, Q.; Zhang, L.; Jia, Y. J. Org. Chem. 2010,
75, 6316. h) Xu, Z.; Hu, W.; Liu, Q.; Zhang, L.; Jia, Y. J. Org. Chem. 2010, 75, 7626-7635.
(3) (a) Angelini, E.; Balsamini, C.; Bartoccini, F.; Lucarini, S.; Piersanti, G. J. Org. Chem. 2008, 73,
5654-5657. (b) Lucarini, S.; Bartoccini, F.; Battistoni, F.; Diamantini, G.; Piersanti, G.; Righi, M.;
Spadoni, G. Org. Lett. 2010, 12, 3844-3847. (c) Silvia, B.; Bartoccini, F.; Righi, M.; Piersanti, G. Org.
Lett. 2012, 14, 600-603.
O43
Imidazole Analogues of Resveratrol:
Synthesis and Cancer Cell Growth Evaluation
Fabio Bellina, Nicola Guazzelli, Marco Lessi, Chiara Manzini
Dipartimento di Chimica e Chimica Industriale, Via Risorgimento 35, 56126 Pisa (Italy)
[email protected]
Stilbenes are naturally occurring phytoalexins that generally exist as their more stable E
isomers. The most well known natural stilbene is resveratrol (Res), firstly isolated in
1939 from roots of Veratrum grandiflorum (white hellebore) (1) and since then found in
various edible plants, notably in Vitis vinifera L. (Vitaceae) (2). The therapeutic
potential of Res covers a wide range of diseases, and multiple beneficial effects on
human health such as antioxidant, anti-inflammatory and anti-cancer activities have
been suggested based on several in vitro and animal studies (3). In particular, Res has
been reported to be an inhibitor of carcinogenesis at multiple stages via its ability to
inhibit cyclooxygenase, and is an anticancer agent with a role in antiangiogenesis (4).
Moreover, both in vitro and in vivo studies showed that Res induces cell cycle arrest
and apoptosis in tumor cells (4). However, clinical studies in humans evidenced that
Res is rapidly absorbed after oral intake, and that the low level observed in the blood
stream is caused by a fast conversion into metabolites that are readily excreted from the
body (5). Thus, considerable efforts have gone in the design and synthesis of Res
analogues with enhanced metabolic stability. Considering that reduced Res (dihydroresveratrol, D-Res) conjugates may account for as much as 50% of an oral Res dose (5),
and that D-Res has a strong proliferative effect on hormone-sensitive cancer cell lines
such as breast cancer cell line MCF7 (6), we recently devoted our synthetic efforts to
the preparation of trans-restricted analogues of Res in which the E carbon-carbon
double bond is embedded into an imidazole nucleus. To keep the trans geometry, the
two aryl rings were linked to the heteroaromatic core in a 1,3 fashion. Based on this
design, we successfully prepared a variety of 1,4-, 2,4- and 2,5-diaryl substituted
imidazoles including Res analogues 1, 2 and 3, respectively, by procedures that involve
transition metal-catalyzed Suzuki-Miyaura cross-coupling reactions and highly selective
N-H or C-H direct arylation reactions as key synthetic steps.
The anticancer activity of compounds 1–3 was evaluated against the 60 human cancer
cell lines panel of the National Cancer Institute (NCI, USA). The obtained results, that
will be showed and discussed along with the protocols developed for the preparation of
imidazoles 1–3, confirmed that a structural optimization of Res may provide analogues
with improved potency in inhibiting the growth of human cancer cell lines in vitro when
compared to their natural lead.
(1)
(2)
(3)
(4)
(5)
(6)
Takaoka, M. J. Chem. Soc. Jpn. 1939, 60, 1090-1100.
Langcake, P.; Pryce, R. J. Physiological. Plant Patology 1976, 9, 77-86.
Vang, O.; et al. PLoS ONE 2011, 6, e19881. doi:10.1371/journal.pone.0019881
Kraft, T. E.; et al. Critical Reviews in Food Science and Nutrition 2009, 49, 782-799.
Walle, T. Ann. N.Y. Acad. Sci. 2011, 1215, 9-15. doi: 10.1111/j.1749-6632.2010.05842.x
Gakh, A. A.; et al. Bioorg. Med. Chem. Lett. 2010, 20, 6149-6151.
O44
Organocatalytic Asymmetric Strategies for the Synthesis of
Functionalized Indole Derivatives
Luca Bernardi, Lorenzo Caruana, Mariafrancesca Fochi
Department of Industrial Chemistry, “Toso Montanari”, University of Bologna. V.
Risorgimento 4, 40136. Bologna, Italy.
[email protected]
The indole scaffold has long been of great interest to chemists and biologists owing to
its ubiquity in a large number of biologically active alkaloids and pharmaceutical
agents.(1) Accordingly, it is not surprising that indoles behave as lead compounds and
are key building blocks in numerous pharmaceuticals. Indole derivatives constitute an
important class of therapeutic agents in medicinal chemistry including antihypertensive,
antiproliferative, antiviral, antitumor, analgesic, anti-inflammatory, antimicrobial,
antifungal activities, etc. This structural motif has been the object of numerous research
from the first preparation of indoles dated from 1866 (2).
With the development of catalytic asymmetric methodologies directed to the synthesis
of biologically active molecules during the last years, organocatalysis has emerged as a
powerful tool and a number of organocatalyzed syntheses of indolyl substrates have
been developed in recent years (3).
Following our interest in asymmetric syntheses, we have recently developed various
organocatalyzed procedures in order to achieve indolyl substrates using various
activation mode such as hydrogen bonding, Brønsted acid catalysis, enamine and
iminium catalysis. The obtained results will be presented.
(1) Kaushik, N. K; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H.
Molecules 2013, 18, 6620–6662.
(2) Baeyer, A. Justus Liebigs Ann. Chem. 1866, 140, 295–313.
(3) (a) Bartoli, G.; Becivenni, G.; Dalpozzo R. Chem. Soc. Rev. 2010, 39, 4449 – 4465; (b) Bandini,
M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608 – 9644.
O45
Photoresponsiveness and Outstanding Self-assembly Ability Combined
in a Single Amino Acid
Miriam Mba, Daniela Mazzier, Claudio Toniolo, Alessandro Moretto
Department of Chemical Sciences, University of Padova
[email protected]
Self-assembly has emerged as a powerful process for the production of well-ordered
supramolecular structures at the nanometric scale. Among them, spherical (micellar and
vesicle-like) architectures are attracting much attention due to their promising
applications in biomedicine and nanotechnology.1 Peptides offer important advantages
as building blocks for the construction of self-assembled nanostructures because of their
biocompatibility and structural/functional diversity. In the literature there are many
examples of supramolecular vesicles and micelles formed by block copolymers
containing at least one high-molecular-weight polypeptide domain as well as small or
medium-size peptides conjugated with molecules of non-peptidic nature. In comparison,
spherical nanostructures based exclusively on low-molecular-weight peptides are much
less common. The chemical diversity of peptides may be further expanded with the use
of non-proteinogenic amino acid residues. We have already described a symmetrically
,-disubstituted glycine, bis[p-(phenylazo)benzyl]glycine (pazoDbg), that contains
two side-chain azobenzene moieties and undergoes reversible cis-trans isomerization
upon exposure to light of the appropriate wavelength.2 In the present work, we explored
the self-assembly properties of this photoswitchable amino acid tris-covalently linked to
the C3-simmetrical 1,3,5-triazine template (Figure 1).
Figure 1: Chemical structure and isomerization process of a pazoDbg-containing building blocks
conjugate to the triazine template and TEM analysis on the light-driven, reversible, microstructure
morphological transition of this systems generated from a DMSO/H 2O suspension.
(1) Fuks, G.; Talom R. M.; Gauffre, F. Chem. Soc. Rev., 2011, 40, 2475-2493.
(2) Fatás, P.; Longo, E.; . Rastrelli, F.; Crisma, M.; Toniolo, C.; Jiménez, A. I.; Cativiela, C.; Moretto,
A. Chem. Eur. J. 2011, 17, 12606-12611.
O46
Self-Organized Silica Nanoparticles for Therapy and Sensing.
F. Mancin, P. Scrimin., E. Lubian
Department of Chemical Science, University of Padova, Padova, Italy
e-mail: [email protected]
Silica nanoparticles have shown a great potential for nanomedicine applications because
of their high versatility and the new therapeutic modalities they could make possible.
The one-pot synthetic procedure of organically modified silica nanoparticles
(ORMOSIL)1 recently proposed in our group (Scheme 1), allow the preparation of dyedoped, PEGylated and targeted nanoparticles that can be exploited for different
applications. In particular, the possibility to tailor the chemical properties of the external
shell, for example by introducing NH2-terminated group, allows the easy conjugation of
nanoparticles with preactivated molecules capable to act as targeting agents. In this
view, we investigated, using the Plasmon Surface Resonance (SPR) technique, the
binding properties of nanoparticles, functionalized with the anti-inflammatory drug
Naproxen, with the HSA (Human Serum Albumin) protein, as a model for
nanoparticles-protein interaction. The results obtained show that the Naproxencontaining nanoparticles maintain a good affinity towards albumin notwithstanding the
potential interference of the PEG coating.
Other than drugs, the versatile synthetic procedure permits to introduce also
fluorophores, as modified quinolinium derivatives, for the realization of a chemosensing
nanosystems. Here, we focused our attention to halogen anions2 and in particular to
chlorine, that is wellknown
to
be
responsable of the
activation of many
biological processes.
Preliminary
results
demonstrate that in the
presence
of
an
halogen,
the
fluorescence emission
of the quinoline is
quenched, and the
sensitivity
increase
with the increasing
dimensions of the
anion (I- > Br- > Cl-).
References
[1]. Rio-Echevarria, I.; Selvestrel, F.; Segat, D.; Guarino, G.; Tavano, R.; Causin, V.; Reddi, E.; Papini,
E.; Mancin, F., J. Mat. Chem. 2010, 20, 2780–2787. [2]. Bau, L.; Selvestrel, F.; Arduini, M.; Zamparo, I.;
Lodovichi, C.; Mancin, F., Org. Lett. 2012, 14, 2984–2987.
Acknowledgements: This work was funded by the FIRB 2011 project “RINAM ”.
O47
Medium Effects on Hydrogen Atom Abstraction from Aliphatic CH
Bonds by Alkoxyl Radicals. Control Over Reactivity and Selectivity
through Acid-base Interactions
Michela Salamone, Ilaria Giammarioli, Massimo Bietti
Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata", Via della
Ricerca Scientifica, 1 00133 Roma
[email protected]
Hydrogen atom abstractions by radical and radical-like species attract considerable
interest as these reactions play a key role in a variety of chemical and biological
processes of great importance such as lipid peroxidation, the oxidative damage to
biomolecules and polymers, the antioxidant activity of vitamin E and of other natural
and synthetic antioxidants, the degradation of volatile organic compounds, as well as in
a large number of synthetically useful procedures. Among the abstracting radicals,
alkoxyl radicals (RO) have received considerable attention.
Solvent effects on hydrogen abstraction reactions from aliphatic CH bonds by alkoxyl
radicals have been studied in detail, providing a general mechanistic description that
highlights the important role of solvent/substrate and solvent/radical hydrogen bond
interactions in these processes.1 For substrates such as alkylamines and ethers a
decrease in the rate constant for α-C−H abstraction (kH) by increasing solvent hydrogen
bond donor ability has been observed. This behavior has been explained on the basis of
a hydrogen bonding interaction between the solvent and the substrate heteroatom that
decreases the degree of overlap between the α-C−H bond and the heteroatom lone-pair
resulting in an increase in the strength of this bond and in a destabilization of the carbon
centered radical formed after abstraction.
On the basis of this mechanistic description it is reasonable to expect that similar effects
may be observed in the presence of Lewis and Brønsted acids, that by interacting with a
basic site in proximity of an abstractable hydrogen atom, are expected to influence the
hydrogen abstraction reactivity and selectivity. Along these lines, in order to probe this
issue and to develop an understanding of the role of acid-base interactions on hydrogen
abstraction reactions by alkoxyl radicals, we have carried out detailed time-resolved
kinetic studies in acetonitrile solution and in the presence of Lewis and Brønsted acids
of different strength on the hydrogen abstraction reactions from a variety of basic
hydrogen atom donors by the cumyloxyl radical.2 The results of these studies will be
discussed.
(1) Bietti, M.; Martella, R.; Salamone, M. Org. Lett. 2011, 13, 6110-6113. Salamone, M.; Giammarioli,
I.; Bietti, M. J. Org. Chem. 2011, 76, 4645-4651. Bietti, M.; Salamone, M. Org. Lett. 2010, 12, 36543657.
(2) Salamone, M.; Mangiacapra, L.; DiLabio, G. A.; Bietti, M. J. Am. Chem. Soc. 2013, 135, 415-423.
Salamone, M.; Giammarioli, I.; Bietti, M. Chem. Sci. 2013, Advance Article DOI: 10.1039/C3SC51058A
O48
Revisiting Nucleophilic Oxidations: Electrophilic Addition to C=X (X =
C, N, O) Double Bonds
Giulia Licini, Cristiano Zonta
Dipartimento di Scienze Chimiche, Università di Padova, via Marzolo 1, 35131 Padova.
[email protected]
The explanation of an oxidation reaction that has been discussed for more than 50 years
gave the unprecedented opportunity to elucidate the chemistry behind the reaction of an
“electrostatically positive nucleophile” and an “electrostatically negative electrophile”
(1). In this reaction the inversion of the Hammett ρ value is not representative of a
change in mechanism. The new description redefines and extends some of the concept
associated to nucleophilic substitution and in particular the concept of nucleophilic
oxidation (Figure 1).
This presentation deals to the observation arising to a more general theoretical
revisitation of the nucleophilic oxidation mechanism, with particular emphasis to the
oxidations of double bonds.
Figure 1. Example of reactions explained using a nucleophilic oxidations mechanism.
(1) Licini, G.; Zonta, C. Angew. Chem. Int. Ed., 2013, 52, 2911-2914.
O49
Identification of a New Binding Site for Blood Group Antigens in
Cholera Toxin by NMR Studies
1
1
Donatella Potenza, Francesca Vasile, Anna Bernardi
Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19 20133
Milano.
[email protected]
Diseases caused by Vibrio cholera and enterotoxigenic E. Coli lead to millions of
deaths each year. In particular, the severity of cholera caused by the El Tor biotype of V.
Cholera is known to be blood dependent, but there is no clear blood-group dependence
for the Classical Cholera Toxin (CT). Indeed, several reports state that CT does not bind
to blood group oligosaccharides
Here we report a comprehensive study, performed by STD-NMR and tr-NOESY
experiments, of the interaction between Classical Cholera Toxin (CT) with blood
groups H-tetra, A-penta and B-penta saccharides (compounds 1, 2 and 3 respectively,
Figure 1). This work shows for the first time that all ABH antigens bind to the toxin.
The research highlights the differences in the interaction due to the presence of an
additional monosaccharide (Galattosamine in compound 2 and Galattose in 3 respect to
the H-antigen 1) and offers a comprehensive frame for interpretation of the
epidemiological analysis linking CT infection and blood group type.
The three ABH blood group antigens 1-3 were screened in the presence of CT, in order
to identify the binding epitope, the bound conformations and their affinity for the
protein.
The same compounds have also been studied in the presence of El Tor CT in order to
identify any differences of interaction with the two different biotypes. In particular, Htetra was analysed in the presence of the two protein (CT and El Tor CT) showing the
same binding epitope, that includes the two Fucose and the Glucose residues
Additionally, we have shown, by competition experiments, that the blood group Htetrasaccharide 1 and the GM1 oligosaccharide (GM1os) bind to classical CT in a
different receptor site.
[1] Heggelund, J. E.; Haugen, E.; Lygren, B.; Mackenzie, A.; Holmner, Å.; Vasile, F.; Reina, J. J.;
Bernardi, A.; Krengel, U. Biochem Biophys Res Commun. 2012, 418(4), 731-735
O50
Glucose Oxidase from Penicillium Amagasakiense: Insight on the
Thermally-induced Structural Modification from Molecular Dynamics
Simulations
1
1
2
Guido Todde, 1Sven Hovmöller, 1,2Aatto Laaksonen, 1,2Francesca Mocci
Department of Material and Environmental Chemistry, Stockholm University, Sweden
Dipartimento di Scienze Chimiche e Geologiche, Cagliari University, Italy.
[email protected]
Glucose Oxidase (GOx) is a flavoenzyme catalyzing the oxidation of β-D-glucose to βgluconolactone and has important non-biological applications in food and medical
industries. Concerning the latter, prototypes have been already synthesized to be used as
a catalyst in miniature enzymatic fuel cells, which in the future might provide electricity
to disease monitoring nano-devices (1). Unfortunately, GOx suffers from relatively
short lifetime.
Recently a few studies on smaller proteins have shown that understanding how the
breakdown process starts and proceeds might be of great help to artificially improve the
stability of the protein. To rationally establish which amino acid should be substituted,
some research groups have used Molecular Dynamics (MD) simulations, which allow to
identify at the atomic level the possible pathways to unfolding and denaturation and to
identify which amino acids substitutions could increase the stability.
Here we present an investigation aimed to verify whether the MD approach to study
denaturation, used so far for smaller proteins or protein portions, can be used to study
proteins of GOx size (ca. 1200 amino acids) and whether weak points in the protein can
be identified by this approach. This is a fundamental condition to use MD simulations to
rationally design mutations. In computer
simulations the denaturation can be induced
and speeded up by increasing the
temperature (2). We performed a set of MD
simulations at different temperatures (300,
400, 500 and 600 K) and repeated a few
times the simulations at the two higher
temperatures to assure that the obtained
results were statistically relevant. The exit
from the native state could be successfully
identified with the clustering approach (3).
The analysis revealed that common set of
amino acids is always involved in the initial Cartoon representation of GOx. In red
phase of the denaturation, and therefore a and orange are highlighted the regions
strategy for the enzyme modification could involved in the initial phase of
denaturation.
be proposed (3).
(1)
(2)
(3)
(4)
Heller, A.; Phys. Chem. Chem. Phys., 2004, 6, 209 ;
Daggett, V; Chem. Rev, 2006, 106, 1898–916
Levitt, M; J. Mol. Biol., 1983, 168, 621-657
Todde, G; Hovmöller, S; Laaksonen, A; Mocci, F.; 2013, submitted
O51
Comparing and Taming the Reactivity of Lithiated Oxetanes and
Tetrahydrofurans: Concepts and Applications
Vito Capriati
Dipartimento di Farmacia – Scienze del Farmaco, Università di Bari “Aldo Moro”,
Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125 Bari, Italy
[email protected]
Among saturated oxygen heterocycles, both oxetane and tetrahydrofuran derivatives are
important scaffolds in a broad array of biologically active natural compounds (1).
However, while increasing attention has recently been paid to the regio- and
stereoselective construction of these ring motifs and new reactivity discover, direct
functionalization processes remain extremely rare (2). In addition, conventional strong
organolithium bases are long-lasting known to promote, in the case of oxetanes, both
nucleophilic substitution reactions at C-2 in competition with -lithiation, and reverse
[3+2] cycloadditions for tetrahydrofurans. The occurrence of such competing reaction
pathways and fragmentation reactions has most likely discouraged the use of these
heterocycles as starting materials in organic synthesis for many years.
In this communication, we report and compare the protocols found for a direct
regioselective lithiation-electrophile interception of both aryloxetanes (3) and
aryltetrahydrofurans. The role played by aggregation, the nature of the solvent, and the
presence of co-solvents in coaxing -lithiated intermediates to react as nucleophiles
(thereby suppressing their intrinsic carbene-like character) while keeping their
cycloanionic structure intact, will be discussed. The ability to effect ortho metallation
reactions together with mechanistic, stereochemical aspects, and synthetic applications
will be tackled as well.
(1) (a) Hailes, H. C.; Behrendt, J. M. In Comprehensive Heterocyclic Chemistry III. Oxetanes and
Oxetenes: Monocyclic, Katritzky, A. R. Ed., Pergamon, Oxford, 2008, vol. 2, ch. 2.05, p. 321. (b)
Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261-290.
(2) (a) Bukhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Carreira, E. M. Angew. Chem. Int.
Ed. 2010, 49, 9052-9067; (b) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem. Int. Ed. 2013, 52, 44534456 and references therein.
(3) (a) Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Chem. Comm. 2011, 47, 9918-9920. (b)
Coppi, D. I.; Salomone, A.; Perna, F. M.; Capriati, V. Angew. Chem. Int. Ed. 2012, 51, 7532-7536.
Acknoledgements: This work was financially supported by MIUR–FIRB (Code: CINECA RBF
12083M5N) and by the German-Italian Vigoni project for the year 2011.
O52
Structural Effects on the Reactions of Alkoxyl Radicals with Amides.
Hydrogen Abstraction Selectivity and the Role of Specific
Substrate-radical Interactions
Michela Salamone, Federica Basili, Massimo Bietti
Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata", Via della
Ricerca Scientifica, 1 00133 Roma
[email protected]
Hydrogen atom abstraction is one of the most fundamental chemical reactions and plays
a major role in a variety of important chemical and biological processes. Among the
abstracting radicals, alkoxyl radicals (RO) have received most attention, and several
aspects of the hydrogen abstraction reactions of these radicals have been investigated in
detail. One aspect that is attracting considerable interest is the possible role of specific
substrate-radical interactions. In this context we have recently shown by time resolved
kinetic and computational studies, that in the presence of substrates characterized by
high hydrogen bond acceptor (HBA) abilities, such as alkylamines, DMSO and HMPA,
large increases in reactivity were observed on going from the cumyloxyl radical
(PhC(CH3)2O, CumO) to the benzyloxyl radical (PhCH2O, BnO).1 This behavior has
been explained on the basis of two different mechanisms: the reactions of CumO have
been described as direct hydrogen abstractions; with BnO, the kinetic data have been
rationalized in terms of a mechanism that proceeds through the formation of a hydrogen
bonded substrate/radical pre-reaction complex followed by intramolecular hydrogen
abstraction.
Amides are characterized by relatively high HBA abilities, that are very close to those
of alkylamines. Quite surprisingly, little information is presently available on the
hydrogen abstraction reactions from amides, despite of the great importance of this class
of compounds. Along these lines, in order to provide quantitative information on the
role of structural effects on the reactivity and selectivity in the hydrogen abstraction
from amides, we have carried out a detailed time-resolved kinetic study on the reactions
of CumO and BnO with a series of secondary and tertiary alkanamides.2 Particular
attention has been devoted to the contribution of substrate-radical hydrogen bond in
these reactions. The results of this study will be presented.
(1) Salamone, M.; DiLabio G. A.; Bietti M. J. Org. Chem 2012, 77, 10479-10487; Salamone, M.;
DiLabio G. A.; Bietti M. J. Am. Chem. Soc. 2011, 133, 16625-16634
(2) Salamone, M.; Milan M.; DiLabio G. A.; Bietti M. J. Org. Chem. 2013, ASAP,
DOI 10.1021/jo400535u