Plenary Lectures

SYNTHESIS OF PHARMACOLOGICALLY RELEVANT RING SYSTEMS BY NEW ONE POT CYCLIZATIONS

Peter Langera,b

a Department of Chemistry, University of Rostock, peter.langer@uni-rostock.de, Albert-Einstein-Str. 3a, 18059 Rostock, Germany

b Leibniz Institute of Catalysis at the University of Rostock e. V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany

In recent years, a number of one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes, 1,3-bis(silyl enol ethers), have been developed [1]. This includes cyclizations with oxalyl chloride [2], 3-silyloxy- and 3-alkoxy-2-en-1-ones [3], benzopyrylium triflates [4], iminium salts [5], and various other electrophiles [6] which provide a convenient access to highly functionalized alkylidenebutenolides, salicylates and phenols, carba- and heterocycles, bridged and nonbridged N-heterocycles, and wide range of arenes and heteroarenes, respectively. The synthesis of fluorinated arenes based on one-pot cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes and its fluorinated analogues with corresponding fluorinated, trifluoromethyl-substituted, and perfluoroalkyl-substituted enones have also been reported [7]. In addition, organosulfur compounds can be readily prepared either starting from thio-substituted dienes or from sulphur containing dielectrophiles [8].

OEt

OO 2 Li+_ _

OO

HOOEt

O

OSiMe3Me3SiO

OEt

OO

EtOO

HO

O

MeO O

OEt

O

O

OEt

O

OR

O

OEt

OHO

OOEt

O

OH

O

OSO2Ph

HR

O N

O

O

OEt

HN

MeO

OOEt

HN

OOEt

O

O

OEt

RN

OR

O

OEt

O

CO2Et

NO

HOOEt

O

R

References [1] For a review of 1,3-bis(silyl enol ethers) in general, see: Langer, P. Synthesis 2002, 441. [2] Review: Langer, P. Synlett 2006, 3369. [3] Review: Feist, H.; Langer, P. Synthesis 2007, 327. [4] Review: Langer, P. Synlett 2007, 1016. [5] Review: Langer, P. Eur. J. Org. Chem. 2007, 2233. [6] Review: Bellur, E.; Feist, H.; Langer, P. Tetrahedron 2007, 63, 10865. [7] Review: Langer, P. Synlett 2009, 2205. [8] Review: Nawaz, M.; Sher, M.; Langer, P. Synlett 2010, 2383.

PL1

TRANSFORMATIONS OF PORPHYRINOIDS TRIGGERED BY COORDINATION

Lechosław Latos-Grażyński

Department of Chemistry, University of Wrocław, llg@wchuwr.pl, 50-383 Wrocław, Poland

Insertion of boron(III), silicon(IV) or phosphorus(V) into N-confused porphyrin triggers the N-confused pyrrole inversion followed by a fusion step affording an 18 π-electron aromatic porphyrinoid with a fused tri-pentacyclic ring confined in the macrocyclic core: N-fused porphyrin. A template factor has been recognized as a driving force of fusion which allows a specific mode of the coordination core adjustment to the given small sizes of coordinated

cations. In fact N-fused porphyrin and related porphyrinoids are geometri-cally adjusted to create a suitable coordinating center for phosphorus(V) 1 or silicon(IV) 2. The structural changes of the investigated complexes are easily triggered by two-electron reduction of N-fused porphyrin to yield N-fused isophlorin. Remarkably, the coordination allowed to identify new constitutional isomers of porphyrins which preserve the basic skeleton of

maternal N-fused porphyrin. The template effect of phosphorous forcing contraction operates also for other porphyrinoids including tetraaryl-21-telluraporphyrin which converts to the complex of phosphorous(V) N-fused dihydrotelluraporphyrin containing an inverted tellurophene ring 3. A cycle of direct transformations affords an elegant triangle of three mutually convertible N-fused porphyrinoids, with distinct spectroscopic features: antiaromatic, nonaromatic and aromatic. Alternatively to insertion, the silicon atom has been introduced into the porphyrin-like structure replacing one of pyrroles with silole to form 21-silaphlorin 4. An effort to trap 21-silaporphyrin resulted in the serendipitous discovery of a unique transformation of 21-silaphlorin 4 into a non aromatic isomer of 2,3-diphenyl-5,10,15,21-tetra(p-tolyl)-carbacorrole (iso-carbacorrole) 5 which contains a cyclopentadiene ring embedded in the tripyrrolic framework. Coordination of silver(III) or copper(III) affords organometallic complexes of “true” carbacorrole 6 in which the metal(III) ions are bound by three pyrrolic nitrogens and a tetrahedrally hybridized C(21) atom of the cyclopentadiene moiety. The inner-core reactivity of carbaporphyrinoids and metallocarbaporphyrinoids has been also explored affording appropriate hybrid ligands. The created coordination center provides a suitable environment allowing stabilization of organocopper(II) complexes.

PL2

A STEREOCONTROLLED AND FLEXIBLE ROUTE TO OPTICALLY-ENRICHED OXABISPIDINES

Heloise Brice,a Duncan M. Gill,a* Laura Goldie,b Philip Keegan,a and William J. Kerrb*

aPharmaceutical Development, AstraZeneca R&D Charnwood bDepartment of Pure and Applied Chemistry, University of Strathclyde

Over recent years, molecules possessing both the bispidine (1; X = CH2) and oxabispidine (1; X = O) unit have been shown to display a range of biological properties that have made them attractive targets for the pharmaceutical industry.1 The lupine alkaloid, (-)-sparteine 2, also has the bispidine structure (1; X = CH2) at its core, with this optically-enriched natural product having been employed as the key chiral ligand in an extensive array of enantioselective transformations.2 The imperfect stereoselectivity observed in some of these processes, together with the lack of a naturally occurring antipode has driven efforts to prepare and study analogous chiral bispidines, in particular those which may serve as surrogates for (+)-2.3 In contrast, chiral oxabispidines (1; X = O) have been the focus of significantly less attention as ligands for use in enantioselective organic reactions, despite the potentially similar chiral environment. Although some stereoselective routes to oxabispidines have emerged recently, the available methods tend to be limited by (i) the requirement for more than one pre-formed chiral substrate, (ii) relatively lengthy synthetic pathways, and (iii) a lack of flexibility relating to the substituent groups that can be introduced around the oxabispidine core.4 Accordingly, pharmaceutical applications have been restricted to compounds containing the simplest core structure lacking substitution on the carbon skeleton.

1RN

XNR

(-)-2N

NH

H

A BC D

We have developed a flexible and stereocontrolled route to oxabispidine acetals 5 proceeding from oxazine 4, which in turn is prepared in a short and efficient synthetic sequence from commercially available (S)-(-)-2,3-epoxypropylphthalimide 3. The key reaction is an intramolecular Mannich cyclization of an imine (formed upon condensation of 4 with the appropriate aldehyde) and represents an attractively late point at which diversity is incorporated. The inherent flexibility imparted by the differentiated nitrogens of 5 has been exploited in the synthesis of a range of oxabispidines 6, exemplifying all combinations of R1 and R2 = H or Me.

1 Bispidines: Mazurov, A.; et al. PCT Int. Appl., 2008, WO 2008-057938. Oxabispidines: Melvin, M. S. PCT Int. Appl., 2008, WO 2008-057938; Bjoere, A.; et al. PCT Int. Appl., 2006, WO 2006-SE688 20060612; Zask, A.; et al. U.S. Pat. Appl. Publ., 2009, US 2008-251712 20081015; Furber, M.; et al. J. Med. Chem., 2007, 50, 5882; Chan, C.; et al. PCT Int. Appl., 2002, WO 2002-GB2586 20020606. 2 Stoichiometric processes: Hoppe, D.; Hense, T., Angew. Chem., Int. Ed., 1997, 36, 2282; catalytic processes: Chuzel, O.; Riant, O., Top. Organomet. Chem., 2005, 15, 59. 3 O’Brien, P., Chem. Commun., 2008, 655. 4 Breuning, M.; Steiner, M. Synthesis, 2007, 1702; Breuning, M.; Steiner, M., Tetrahedron Asymmetry, 2008, 19, 1978; Breuning, M., et al. J. Org. Chem., 2008, 74, 1407.

PL3

EXPEDITIOUS ACCESS TO HETEROCYCLIC DIVERSITY

Viktor Krchnak

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN,

vkrchnak@nd.edu, 46556, USA

To cover a diverse set of heterocyclic frameworks and at the same time to make syntheses

efficient and expeditious, we assembled diverse and structurally unrelated heterocycles from

common solid-supported intermediates. This strategy allows to efficiently prepare compounds

with different frameworks and skeletal disimilarity. Our approach will be documented on

transformation of polymer-supported α-acylamino ketones. Syntheses involved known as well

as novel chemical routes and comprised variety of chemistries (C-C, C=C, C-N, C=N, C-O

bond formations). Different sizes of heterocycles (4-, 5-, 6-, and 7-membered rings) were

prepared including dihydro-pyrrol-2-ones, pyrazin-2-ones, dihydro-triazepin-6-ones,

morpholin-3-ones, imidazoles, β-lactams, and isoquinolin-1-ones [1]. Further elaboration to

fused ring systems was also documented. In addition several unexpected synthetic routes

leading to efficient syntheses of heterocycles will be presented [2].

NR1

N

O

R1R2

O

R1N

OR2

NN

R2R1

OR3

N

NR2

R1

R

N

O

R1

O R2

R3

R3

R1

O

NO

R2

R3

L

H

H

H

H

N

NN

R2

O

R1H

R3 R4

NH

XR3

X = H or NH2

PPh3

R3

Br

R3

NNH2

R3

R4R2 = OEt

O

R2

OR O

R =

R =R =

R =

R =H

HBr

R3

R =

NH

R1L

R2

O

XR1

ON

N+

O

O- XR1

O

N

N

O

R2R2

R3R3

References

[1] Pudelova, N., Krchnak, V.: J. Comb. Chem. 2009, 11, 851-859.

[2] Krupkova, S., Slough, G.A., V. Krchnak, V.: J. Org. Chem. 2010, 75, 4562-4566,

PL4

Multicomponent reaction design in the quest for

molecular complexity and diversity

Romano V.A. Orru

Synthetic & Bioorganic Chemistry, Dept of Chemistry & pharmaceutical Sciences, VU University, Amsterdam, The Netherlands (r.v.a.orru@vu.nl)

The main research interest of the Synthetic & Bio-organic Chemistry group focuses on sustainable (atom and step economy) synthetic method development employing domino (or tandem) processes. The methodology is applied to the diversity-oriented synthesis of small focused libraries of fine-chemicals with a high added value, like building blocks for medicines or ligands for catalysis. A powerful strategy involves the use of multicomponent reactions (MCRs), which combine at least three different simple reagents in a well-defined manner to form a single product. Smart design of our synthetic strategies based on the concepts of Diversity Oriented Synthesis (DOS) and Biology Oriented Synthesis (BIOS) take advantage of the potential of MCRs allowing molecular complexity and diversity to be created by facile formation of several covalent bonds in one-pot transformations. At the same time our reactions proceed with high atom economy and low E factors thus minimizing the number of functional group manipulations towards a given complex molecular target and avoiding the use of protective groups. This lecture focuses on the design, of novel MCRs for atom- and step efficient syntheses and discusses some asymmetric methodology for stereoselective MCRs employing biocatalysis. Both mechanistic aspects, stereochemistry using biocatalysis, optimization towards robust procedures and synthetic utility are discussed e.g. in the synthesis of potentially biologically active molecules (antitumor, antibiotics, hepatitis C) as well as ligands relevant to catalysis (N-heterocyclic carbene complexes, organocatalysts).

PL5

THE DOMINO APPROACH TO MOLECULAR COMPLEXITY: MODULAR CONSTRUCTION OF SYNTHETICALLY USEFUL

HETEROCYCLIC FRAMEWORKS

Simeon Arseniyadis

Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette Cedex (France)

Unsaturated bicyclic vicinal diols can react with Pb(OAc)4 or PhI(OAc)2 acting as domino promoters in several ways, depending on the reaction conditions. When the angular position bears a functional substituent, such as an alkoxy, an ester or a carbonyl group, more than one domino reaction paths could be put in competition. Structurally different products can be reached selectively in a single synthetic operation, in spite of the similarities in the starting compounds, which differ only by the substitution pattern at the angular position (C11). The nature of substituent at C11 is responsible for the modular aspect of the domino process as well as the extent of the generated complexity, and therefore determines the regiochemical course leading to original scaffolds. Thus, it is possible to select either a ring-expanding [1], a hetero[4 + 2 + 2]cycloaddition [2], a hetero[4 + 3 +2]cycloaddition [3], an oxonium path [4] or simply to interrupt the process half the way through at the [4π + 2π] stage [5], by varying the functional group at C11.

"Hetero[4+3+2]"

A

Plastic Surgery by Careful Planning of Incisions at the Angular Position (C11):

O

O

O

H

12

HO

HO

O

H

HO

HO

O

HO

HO

ROR

O

O

OMe

"Hetero[4!+2!+2!]"

O O

O

Me Me

Me

O

O

AcO

O

O OO

AcO

OAc1112

11(S*)

11(R*)

"Ring Expansion" "Hetero[4!+2!]" "Oxonium"

Reshaping of the Molecule by Strategic Combination of Reactive Groups

11

11

11

11 11

1111

"Oxonium"

HO

HO

R

HO

HO

MOMOH

O O

O

H

H

O

O

AcO

O

H

11

12

"Hetero[4!+2!]/Friedel-Crafts"

12

11

11

"Oxonium"

MeO

OMe

OMe

11(R*)

11(S*)

O

AcO

AcO

OH

O

O

n = 1

n = 0

O O

AcO

O

OOAc

H

11

11

HO

HO

O

O n11

"Ring Expansion"

"Oxonium"

R = Ester

R = Ether

R = Mesityl

R = Methyl

11

O

AcO OAcO

H

PivO

n

n = 1

n

n = 1, 2

nPb(OAc)4 and/or PhI(OAc)2 Mediated "One-Pot" Multistage Transformations

The Probe

12

The substrate-based modulation is derived from the mechanistic role of each functional

group installed at the angular position; by inserting diverse reactivity, the ensuing domino

PL6

probe can be oriented to a different outcome. The presentation will focus on probing this class of domino reactions in an effort to define the origins of orienting factors and to develop a prognostic model for general use. A “where from to where” and a “what for” aspect will be discussed. Within the time limits, some applications to the construction of key building blocks for bioactive natural products which are likely to be major synthetic targets will be presented in reasonable detail. References [1] Corbu A., Gauron G., Castro J., Dakir M., Arseniyadis S.: Org. Lett. 2007, 9, 4745.

Elkhayat Z., Safir I. Aquino M., Perez M., Gandara Z., Retailleau P., Arseniyadis S.: Eur. J. Org. Chem. 2009, 2687.

[2] Elkhayat Z., Safir I., Retailleau P., Arseniyadis S.: Org. Lett. 2007, 9, 4841. [3] Aquino M., Safir I., Elkhayat Z., Gandara Z., Perez M., Retailleau P., Arseniyadis S.: Org.

Lett. 2009, 11, 3610. [4] Safir I., Castellote I., Porcel S., Kaoudi T., Birlirakis N., Toupet L., Arseniyadis S.: Chem.

–Eur. J. 2006, 12, 7337. [5] Chanu A., Safir I., Basak R., Chiaroni A., Arseniyadis S.: Org. Lett. 2007, 9, 1351. Chanu

A., Castellote I., Commeureuc A., Safir I. Arseniyadis S.: Tetrahedron Asymmetry 2006, 17, 2565.

PL6

CHEMO-ENZYMATIC SYNTHESIS OF NITROGEN HETEROCYCLES

Maurice C.R. Franssen

Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, the Netherlands

The use of enzymes in organic chemistry is well established nowadays, even in industry, because of their selectivity, high yields and mild reaction conditions. This presentation describes two applications of enzymes in the synthesis of nitrogen heterocycles.

The first example focuses on the use of Sulfolobus KDG aldolases as stereoselective catalysts for carbon-carbon bond formation. The enzyme couples two substrates, the natural ‘donor’ is pyruvate and the natural ‘acceptor’ is glyceraldehyde. The donor specificity is very strict, but the acceptor can be easily replaced by a wide range of aldehydes. We found that azido-aldehydes are surprisingly good substrates, giving rise to azido-functionalized products. In order to determine the stereoselectivity of the enzyme we reduced the azide group, leading (after ring closure and further reduction) to chiral hydroxyprolines and carboxyhydroxy-piperidines.

The second case relates to the biobased economy. Nitrogen heterocycles are important compounds in chemical and pharmaceutical industry, but they are all synthesized from fossil materials and ammonia. Since fossil materials will be scarce in the future, and because the production of ammonia is highly energy-intensive, we studied the use of natural compounds as feedstocks for nitrogen containing chemicals. In nature, nitrogen is fixed enzymatically by nitrogenase; the resulting ammonia mostly ends up in proteins and amino acids. We investigated the use of glutamic acid, the most abundant amino acid, as a starting material for the preparation of a number of nitrogen containing compounds, like the industrial solvent N-methylpyrrolidone and the monomer N-vinylpyrrolidone [1,2].

References [1] Lammens T. M., de Biase D., Franssen M. C. R., Scott E. L., Sanders J.P.M.: Green

Chem. 2009, 11, 1562. [2] Lammens T. M., Scott E. L., Franssen M. C. R., Sanders J. P. M.: Green Chem. 2010, 12,

1430.

PL7

CROSS-COUPLINGS AND C-H ACTIVATIONS OF PYRIMIDINES, PURINES AND

PYRROLO[2,3-d]PYRIMIDINES. FROM NEW NUCLEOSIDE CYTOSTATICS TO

BASE-FUNCTIONALIZED DNA

Michal Hocek Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead

Sciences & IOCB Research Center, Flemingovo nám. 2, CZ-16610 Prague 6, Czech Republic,

hocek@uochb.cas.cz; http://www.uochb.cas.cz/hocekgroup

Novel methodologies of synthesis of modified nucleobases, nucleosides, nucleotides and

oligonucleotides have been developed largely using modern organometal-catalyzed reactions

(cross-couplings, C-H activations,1 etc.). An efficient two-step methodology of construction

of functionalized nucleic acids was developed by a novel chemo-enzymatic approach using

aqueous-phase cross-coupling reactions of nucleotides followed by incorporation by DNA

polymerase.2 The methods are applied in the synthesis of derivatives for biological activity

screening (two novel types of nucleoside cytostatics3 will be presented) and the use of

functionalized oligonucleotide probes for electrochemical detection of DNA hybridization or

for DNA bioconjugation.4

This work was supported by ASCR (Z4 055 0506), Ministry of Education (LC512, 1M0508), Grant Agency of the ASCR (IAA400040901), Czech Science Foundation (203/09/0317) and Gilead Sciences, Inc..

References:

1. Čerňa, I.; Pohl, R.; Klepetářová, B.; Hocek, M. J. Org. Chem. 2010, 75, 2302-2308.

2. Hocek, M.; Fojta, M. Org. Biomol. Chem. 2008, 6, 2233-2241.

3. Nauš, P.; Pohl, R.; Votruba, I.; Džubák, P.; Hajdúch, M.; Ameral, R.; Birkus, G.;

Wang, T.; Ray, A.S.; Mackman, R.; Cihlar, T.; Hocek, M. J. Med. Chem. 2010, 53,

460-470.

4. Raindlová, V.; Pohl, R.; Šanda, M.; Hocek, M. Angew. Chem. Int. Ed. 2010, 49, 1064-

1066.

PL8

HETEROCYCLIC SYNTHESIS FOR CHEMICAL INTERVENTION IN

CELLULAR AGEING

Mark C. Bagley

Department of Chemistry, Cardiff University,

e-mail Bagleymc@cardiff.ac.uk, Cardiff, CF83 3AW, UK

Accelerated cellular ageing and the phenotypic changes associated with cell senescence may

have a dramatic role to play in the onset of age-related diseases. This presentation describes

how new rapid methods for the synthesis of heterocycles, in combination with the use of an

extremely rare autosomal recessive genetic disorder, can help us to understand the age-related

biochemical triggers for cell senescence and how this process can be rescued using inhibitors

of MAPK signal transduction [1-3]. The use of microwave heating has delivered a library of

complementary mitogen-activated protein kinase (MAPK) inhibitors to understand the role of

cell signalling in the pathology of WS. In particular, a range of different inhibitors of p38

MAPK and the downstream target (MK2) of this signal transduction cascade have been

prepared and tested in Werner syndrome cells to understand their biochemical role and

compare their effectiveness in Werner syndrome cells. Microwave irradiation was found to

improve routes to the Vertex compound VX–745, Boehringer-Ingelheim’s BIRB 796, a

library of pyrazolyl ketones related to Roche compound RO3201195, and Palau Pharma

compound UR-13756 (Figure 1), amongst others. Furthermore, when some of these chemical

inhibitors were added to Werner syndrome fibroblasts, their growth rate and cell morphology

was restored. This opens the opportunity for using chemotherapeutic treatments for

inflammatory conditions to combat rapid ageing in Werner syndrome patients, with relevance

to the relationship between inflammation, ageing and disease progression in normal

individuals.

Figure 1. Preparation of MAPK inhibitors for biological evaluation in WS cells.

References

[1] An international effort to cure premature ageing (news article). Faragher R., Goto M.:

Bioscience Trends. 2007, 1, 66–67.

[2] Promoting research at the interface between chemistry and biology (news article). Bagley

M.: RSC Chemical Biology Forum News 2005, (8), 5.

[3] Use of p38 MAPK inhibitors for the treatment of Werner syndrome. Bagley M. C., Davis

T., Murziani P. G. S., Widdowson C. S., Kipling D.: Pharmaceuticals 2010, 3, 1842-1872.

PL9

DISCOVERY AND PRECLINICAL PROFILING OF NEW PYRAZOLO[1,5-a]PYRIMIDINE-BASED INHIBITORS OF CDK2 AND

CHK1 KINASES

Kamil Paruch

Department of Chemistry, Masaryk University, Kamenice 5, Brno, 62500, Czech Republic

e-mail: paruch@chemi.muni.cz

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. The lecture will describe the synthesis, in vitro and in vivo profiling of numerous structurally diverse pyrazolo[1,5-a]pyrimidine-based CDK inhibitors, which resulted in the identification of SCH 727965 (dinaciclib), a potent and selective CDK inhibitor that is currently undergoing clinical evaluation [1].

N

N N

N

NH

OH

NO dinaciclib

N

N N

NHN

Cl

Cl

CDK2 IC50 = 500 nM

N

N N

NH

Br

NO

O

CDK2 IC50 = 18 nM CDK2 IC50 = 1 nM

Checkpoint kinase 1 (CHK1) is a serine/threonine kinase that controls the cellular response to DNA damage. Inhibition of CHK1 abrogates cell-cycle arrest resulting in genomic instability and ultimately progression into mitosis and cell death. Systematical variation of substituents on the pyrazolo[1,5-a]pyrimidine core combined with high-content cell-based screening lead to the discovery of the clinical candidate SCH 900776, which interacts synergistically with DNA antimetabolite agents to selectively induce cell death in tumor cell backgrounds [2].

N

N N

HN

NH2

Br

CDK2 IC50 = 80 nMCHK1 IC50 = 1080 nM

N

N N

HN

NH2

CDK2 IC50 = 6100 nMCHK1 IC50 = 60 nM

NN

N

N N

HN

NH2

CDK2 IC50 = 22 000 nMCHK1 IC50 = 100 nM

NN

NN

References [1] Paruch, K; Dwyer, M. P. et al. ACS Med. Chem. Lett. 2010, 1, 204. [2] Guzi, T.; Paruch, K. et al. Mol. Cancer Ther. 2011, 10, 591.

PL10

A MULTIPLY CONVERGENT SYNTHETIC ROUTE TO TRIOXACARCINS

Jakub Švendaa,b, Nicholas Hilla, and Andrew G. Myersa

aDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA

bPresent affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Dortmund

44227, Germany

Presented in this lecture will be the development of a highly convergent synthetic route to the trioxacarcins, a class of densely oxygenated, structurally complex natural products with potent antiproliferative effects in various human cancer cell lines. To address the chemical synthesis of natural and unnatural trioxacarcins broadly, a differentially protected trioxacarcin precursor was targeted. The trioxacarcin precursor was assembled in six steps from three components of similar structural complexity and was converted, in two additional steps, to the natural trioxacarcin DC-45-A2 [1]. The highly convergent nature of the sequence, based on the plan in which strategic bond-pair constructions are staged at or near the end of the synthetic route, allows for rapid structural modifications of the trioxacarcin scaffold in order to explore the potential of the trioxacarcins for the development of small-molecule probes and drugs.

X-ray crystal structure of DC-45-A2 References [1] Švenda, J.; Hill, N.; Myers, A. G. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6709−6714.

PL11

Short Lectures

-HALOGENATED N-(1-ACETHOXYETHYL)- AND N-(1-TOSYLETHYL)UREAS IN HETEROCYCLIC SYNTHESES

Pavel A. Solovyev, Anastasia A. Fesenko, Nikolay N. Kurochkin, and Anatoly D. Shutalev

Department of Organic Chemistry, Moscow State Academy of Fine Chemical Technology, paulnighti@gmail.com, 119571 Moscow, Russian Federation

In continuation of our work on synthesis of hydrogenated nitrogen-containing heterocycles using ureidoalkylation we report here application of readily available -halogenated N-(1-acetoxyethyl)- and N-(1-tosylethyl)ureas (e.g., 1) to the preparation of functionalized 1,2,3,4-tetrahydropyrimidin-2-ones, hexahydropyrimidin-2-ones, 1,2-dihydropyrimidin-2-ones, 2,3-dihydro-1H-1,3-diazepin-2-ones, and dihydrofurans.

Starting compounds, ureas 1, were obtained in 12 steps from corresponding -halogenated aldehydes and urea. Reaction of 1 with sodium enolates of -oxoesters or 1,3-diketones 2 in acetonitrile at room temperature yielded the corresponding oxoalkylureas 3 (X = Cl) or hydroxypyrimidines 4 (X = F) in high yields. In the case of chloromethyl-substituted ureas 3 (n = 1), spontaneous cyclization of the obtained 3 was observed to give 5-ureido-4,5-dihydro-furans 5. Treatment of dichloromethyl- and trichloromethyl-substituted ureas 3 (X = Cl, n = 23) or trifluoromethyl-substituted pyrimidines 4 (X = F, n = 3) with TsOH in refluxing MeCN led to formation of the corresponding 4-dihalomethyl- and 4-trihalomethyl-substituted 1,2,3,4-tetrahydropyrimidin-2-ones 6.

HN NH

O

RCH3-mXm

N NH

O

R

R

OHN NH

O

RCH3-nXn

OHHN NH2

O

RCH3-nXn

O+ NaH

Base

2 3 4

5

6

X = Cl

NH2HN

O

LGCH3-nXn

ONH

H2N

OCOOEt

R

n = 1X = Cl

HN NH

O

COOEt

MeNC

O R1O R1 O R1

O R1O R1

TsOH

m = 2

X = Cl

NaCN

m = 3

n = 2-3

R = Me, Ph; R1 = OEt, Me

1

7 8

TsOHn = 2-3

LG = OAc, Ts

X = Cl, F

n = 1-3, m = 2-3 We have shown that trichloromethyl-substituted pyrimidines 6 (X = Cl, m = 3) in the presence of bases (NaH, DBU) transform into previously hardly available 5-functionalized 1,2-dihydropyrimidin-2-ones 7 through elimination of chloroform. Treatment of dichloromethyl-substituted pyrimidines 6 (X = Cl, m = 2) with NaCN in DMF gave 2,3-dihydro-1H-1,3-diazepine-2-one (8) as a result of cascade reaction proceeding with ring expansion. Mechanisms of all above transformations will be discussed.

SL1

SYNTHESIS OF 2-SUBSTITUTED TETRAHYDROQUINOLINE ALKALOIDS

Yoshihiro NODA and Keita ISHII

Department of Chemical Biology and Applied Chemistry, College of Engineering, Nihon University, Tamura-machi, Koriyama, Fukushima, 963-8642, Japan

A novel 2-substituted tetrahydroquinoline alkaloids, angustureine, galipinine, cuspareine, and galipeine were isolated from Galipea officinalis Hancock in 1999 [1]. Their tetrahydroquinoline alkaloids have been reported to exhibit anti-malarial and cytotoxic activities.

Total synthesis of (-)-(R)-angustureine was achieved using 1,3-dithiane derivative, N-Ts aziridine as electrophile and intramolecular SNAr reaction as key steps as shown in Scheme 1.

In this report, we are trying to modify above reaction for synthesis of racemic angustureine, galipinine and cuspareine.

Further synthetic study of optically active angustureine and other related 2-substituted tetrahydroquinoline alkaloids is currently underway. References [1] Jacquemond-Collet, I et. al. Phytochemistry 1999, 51, 1167. [2] Theeraladanon, C, et. al. Tetrahedron Asymmetry 2005, 16, 827

N

CH3

N

CH3 O

O N

CH3

OCH3

OCH3

N

CH3

OH

OCH3Angustureine Galipinine Cuspareine Galipeine

Structures of 2-substituted tetrahydroquinoline alkaliods with anti-malarial activity isolated from Galipea officinalis .

BnO O

TsN

F

SS+

SS

HNTs

F N

SS

C5H10Ts

N C5H10H

(-)-(R)-angustureine1) 2) 3) 4)

Scheme 1. Reagents and conditions:1) n-BuLi,THF. 2) NaH, DNF. 3) Li,NH3. 4) MeI, K2CO3, THF

F

SS+TsN OBn

SS

OBn

TsF N

SS

Ts

OBnHN

NH

CHO

angustureine

galipinine

cuspareine

1) 2) 3),4),5)6)

Scheme 2. Reagents and conditions:1) n-BuLi,THF. 2) NaH, DNF.3) NaBH4, NiCl2. 4) Mg, MeOH.5) H2/ Pd-C, then Swern oxid. 6) Wittig reaction; H2/Pd-C; MeI. K2CO3, THF

SL2

MICROWAVE-ASSISTED SYNTHESIS IN ORGANOPHOSPHORUS CHEMISTRY INCLUDING P-HETEROCYCLIC CHEMISTRY

György Keglevich

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, gkeglevich@mail.bme.hu, 1521 Budapest, Hungary

A variety of reactions including esterifications, alkylations, additions, cycloadditions, fragmentations and condensations were carried out under microwave MW-assisted and solventless conditions, occasionally in ionic liquids (ILs).

Esterifications of phosphinic acids (1) and inverse-Wittig reactions (2) do not take place on traditional thermal heating, but maybe realized under MW conditions that is the consequence of a specific MW effect.

PAr O

+

CO2Me

CO2Me

150 °C

no solvent

MW

PAr

COOMe

O COOMeMeMe

=

MeCl

, ,

Ar = 2,4,6-trialkylphenyl

(2)P

O OH

+ ROH~200 °C

− H2O

MW

MeMe

=

Me

, ,

R = alkyl

(1)

R' R'

PO OR

Diels–Alder cycloadditions (3) and fragmentation-related phosphorylations (4) became much faster and more efficient on MW irradiation.

N

Me

Ph

H

HO

O

PPhO

Cl

N

O

Ph

O

110 °CMW

no solvent P

ClMe

PhO

MePPhO

Cl

CO2Me

CO2Me

110 °CMW

no solvent

CO2Me

CO2Me(3)

MeCO2MeCl

CO2Me

ILArOH200 °CMW

P MePh

O

OAr

Ar = Ph, 4-MePh, 4-ClPh

IL = [bmim][BF4] or [bmim][PF6]

MePPhO

Cl CO2Me

CO2Me−

(4)

The MW irradiation is an excellent tool to promote three-component condensations, like the Kabachnik–Fields reaction. We found that exotic and expensive catalysts suggested in the literature may be omitted if the condensation of simple oxo-compounds, primary amines and diethyl phosphite is carried out under MW conditions (5).

In a novel extension, the primary amines were reacted with two equivalents of formaldehyde and the >P(O)H species to provide bis(phosphonomethyl)- or bis(phosphinoxido) products (6) that, after double deoxygenation, may be used as bidentate P-ligands in ring Pt complexes.

RNH2 + 2 HCHO PO

H2 Y2 no solvent

100 °CMW

RNCH2

CH2

PY2

PY2

O

O+

R = nPr, nBu Y = EtO, MeO, Ph

− H2O

(6)YNH2

O

R2R1+ P

O

H(EtO)2+

no solvent

~115 °CMW

C

R1

R2YNH P(OEt)2

O

Y = Ph, Bn R1

R2

H Me

Ph Ph

− H2OH

H

(5)

SL3

SYNTHESIS OF FERROCENYL-1,2,3-TRIAZOLE-SUBSTITUTED CISPENTACIN STEREOISOMERS

Loránd Kissa, and Ferenc Fülöpa,b

aInstitute of Pharmaceutical Chemistry bStereochemistry Research Group of the Hungarian Academy of Sciences, University of

Szeged, H-6720 Szeged, Eötvös u. 6, Hungary

Cyclic β-amino acids are key elements of many natural products, precursors of bioactive β-lactams. Several β-amino acid derivatives such as cispentacin, icofungipen, oryzoxymicin, or oxetin possess strong antifungal or antibacterial properties. The alicyclic, O- and N-heterocyclic conformationally rigid β-amino acids are building blocks in the synthesis of novel peptides. The enantiomerically pure β-amino acids and their derivatives are efficient chiral auxiliaries in asymmetric syntheses [1]. Recently the triazole-modified analogues of a series of antiviral compounds such as of zanamivir or oseltamivir have been described as important derivatives with high pharmaceutical potential. The triazole skeleton is key component of the antiviral agent ribavirin, carbocyclic ribavirin, and of the biologically active modified nucleosides e.g. triazole-modified neplanocines [2]. During our present research work the synthesis of ferrocenyl-1,2,3-triazole-substituted aminocyclopentanecarboxylate stereo- and regioisomers has been accomplished from bicyclic lactams in 5 steps. The synthetic method was based on diastereoselective epoxidation, regioselective azidolysis and azide-ethynylferrocene dipolar cycloaddition reactions.

NH

O

FeNN

N

CO2Et

NHBoc

HO

FeNN

N

CO2Et

NHBoc

HO

CO2Et

NNHBoc

HO

N NFe

FeNN

N

CO2Et

NHBoc

HO

HNO

CO2Et

NOH

BocHN

N NFe

Fe

CO2Et

OH

NBocHNN N

5 steps

References [1] a) Kiss, L.; Forró, E.; Fülöp, F: Synthesis of carbocyclic β-amino acids. Amino Acids, Peptides and Proteins in Organic Chemistry. Vol. 1, Ed. A. B. Hughes, Wiley, Weinheim, 2009, 367. b) Fülöp, F. Chem. Rev. 2001, 101, 2181. c) Kazi, B.; Kiss, L.; Forró, E.; Fülöp, F. Tetrahedron Lett. 2010, 51, 82. d) Kiss, L.; Fülöp, F. Synlett 2010, 1302. [2] a) Kiss, L.; Forró, E.; Sillanpää, R.; Fülöp, F. Tetrahedron 2010, 66, 3599. b) Kiss, L.; Forró, E.; Sillanpää, R.; Fülöp, F. Tetrahedron Asymm. 2008, 19, 2856.

SL4

DOMINO RADICAL REACTIONS TOWARDS INDOLE-HETEROCYCLES OF BIOLOGICAL INTEREST

Janos Sapi, Ingrid Simon, Marc Pudlo, Stéphane Gérard

ICMR CNRS UMR 6229, Université de Reims-Champagne-Ardenne, Faculté de Pharmacie 51 rue Cognacq-Jay, 51096 Reims, cedex, France

janos.sapi@univ-reims.fr

Polycyclic (dihydro)indole derivatives are attractive synthetic targets due to their varying biological activities. The 1,3-dihydroindol-2-one (oxindole) ring is a key structural unit of numerous natural products[1] (horsfiline, spirotryprostatines, alstonisine…) and synthetic analogs of biological interest. Among the various powerful methods for the construction of such heterocyclic systems domino radical cyclization excelled in efficiency[2]. Herein we disclose a simple aryl radical induced 5-exo-trig/5-exo-trig type domino cyclization approach for the synthesis of 3-pyrrolidinone substituted oxindoles (2).

N OR

O N

I

R1

R2

N

NO

R1

O

R

R2

N

NO

R1

R

R2

1

3 4

5domino radical cyclization

2

( )

(dihydro)indole-heterocycles

FG transformations

In a second series of experiments the same type of domino radical cyclization was combined for the first time with Smiles-rearrangement[3] affording 3-(2-arylacetamido)-substituted oxindoles (4) by a very efficient manner.

N OR

O N

ISO2

R1

R3

SO2

N

NHO

R1

O

R

R3N

R

NH-R1

O

R3

3

domino radical cyclization- Smiles rearrangement 3

4 (dihydro)indole-heterocycles

FG transformations

( )

Both 3-substituted oxindoles (2, 4) could be considered as valuable intermediates for the synthesis of more complex indole derivatives by simple functional group transformations. References [1] (a) Bindra J.S. Oxindole Alkaloids in Alkaloids Ed. Academic Press, 1973, Vol. 14, p 83. (b) Marti C., Carreira E. Eur. J. Org. Chem. 2003, 2209. [2] Albert M., Fensterbank L., Lacôte E., Malacria M. “Tandem Radical Reactions” in Radicals in Synthesis II, Topics in Current Chemistry; Gansäuer, A. Ed. Springer Verl, Berlin, Heidelberg, NewYork 2006; p 1. [3] DaMatta M.L.E.N., Motherwell W.B., Ujjainwalla F. Tetrahedron Lett. 1997, 38, 141.

SL5

SYNTHESIS OF NATURALLY OCCURRING CHROMONE

DERIVATIVES BY PALLADIUM-CATALYZED CROSS-COUPLING

REACTIONS

Tamás Patonaya, Anita Ábraháma,b, Attila Vasasa,c, and Gergı Zoltán Nagya

aDepartment of Organic Chemistry, University of Debrecen, patonay.tamas@science.unideb.hu, H-4032 Debrecen, Hungary

bResearch Group of Homogeneous Catalysis, HAS-UD, H-4032 Debrecen, Hungary cChinoin Private Co. Ltd - member of sanofi-aventis group, H-1045 Budapest, Hungary

Chromonoids and flavonoids are well known naturally occurring derivatives often having remarkable biological effects. Many of them have C-alkenyl units on their resacetophenone- or phloroacetophenone-type Ring A or a tricyclic furochromone or pyranochromone ring system which can be achieved by the ring-closure of these intermediates. Some representative examples are shown below.

OHO

OH O

HOOC

OMe

OH

O

O

O

OMe

O

O

O

OH

O

O

O

OH

OH

O

OOMe

O O

OOH

O

A

B

C

O

O

HO

OH

OH

OH

We presumed that the key step, i.e. the formation of the C-C bond can be performed by using the Heck or Sonogashira reactions which can provide a new approach to these important target molecules. Recently, we have presented the applicability of the Heck reaction in field of simple bromochromones [1] and 6-bromo-7-hydroxychromones [2]. In our contribution we will present our new results on the use of palladium-catalyzed cross-coupling reactions in the synthesis of alkenylated and alkynylated mono and dihydroxylated heterocycles and the also the ring closure of these products. Applications in the synthesis of naturally occurring structures and related systems will also be demonstrated. References [1] Patonay, T.; Vasas, A.; Kiss-Szikszai, A.; Silva, A.M.S.; Cavaleiro, J.A.S.: Austr. J. Chem. 2010, 63, 1592. [2] Vasas, A.; Patonay, T.; Kónya, K.; Silva, A.M.S.; Cavaleiro, J.A.S.: Austr. J. Chem. 2011, 64, 647.

SL6

SYNTHESIS OF A LIBRARY OF OLIGOTHIOPHENES AND THEIR UTILIZATION AS AMYLOID LIGANDS

Therése Klingstedt, Andreas Åslund, Rozalyn A. Simon, Leif B. G. Johansson, Jeffrey J. Mason, Sofie Nyström, Per Hammarström and K. Peter R. Nilsson.a

aLinköpings Universitet, Department of Physics, Chemistry and Biology, jefma@ifm.liu.se, SE-58183, SWEDEN

Herein we report the synthesis of a novel set of anionic LCO ligands and provide some insight of the basic molecular requirements for optimal performance of these dyes in the detection of amyloid protein aggregates.

The development of molecular dyes for the detection of proteinaceous deposits is of great importance, as the formation of extra- or intracellular protein aggregates, amyloid, is a common pathological hallmark associated with many diseases, including; Alzheimer’s; Parkinson’s; Huntington’s; and the infectious prion diseases.[1] These molecular probes are important to advance the understanding of molecular pathogenesis underlying amyloid diseases.

Luminescent conjugated polythiophenes (LCPs) have recently been introduced as a novel class of amyloid-binding fluorescent probes. In 2009, Åslund et al. improved on the concept, presenting defined structures termed luminescent conjugated oligothiophenes (LCOs) which could be utilized for in vivo imaging of protein aggregates.[2] LCPs and LCOs are comprised of a conjugated thiophene backbone, giving a combination of flexibility and rigidity, which results in conformation-sensitive spectral signatures when in contact with amyloid proteins.

An investigation of various length and arrangements of the thiophene backbone to influence the spectral difference between Aβ plaques and NFTs when binding to LCOs was undertaken. Furthermore, examination of the capacity to detect pre-fibrillar Aβ assemblies, as reported for the LCO p-FTAA, affected when changing the length of the thiophene backbone or the amount of anionic substituents.

References [1] Chiti, F.; Dobson, C. M.: Annu. Rev. Biochem.2006, 75, 333-366. [2] Åslund,A.; Sigrudson, C. J.; Kilngstedt, T.; Grathwohl, S.;Bolmont, T.; Dickstein, D. L.; Glimsdal, E.; Prokop, S.; Lindgren, M.; Konradsson, P.; Holtzman, D. M.; Hof, P. R.; Heppner, F. L.; Grandy, S.; Jucker, M.; Aguzzi, A.; Hammarström, P.; Nilsson, K. P. R.: ACS Chem. Biol. 2009.

SL7

NEW RING FUSED IMIDAZO[5,4-f]BENZIMIDAZOLEQUINONES:SYNTHESIS and ANTI-CANCER STUDIES

Vincent Fagana, Sarah Bonhama, Michael P. Cartyb, and Fawaz Aldabbagha,*

aSchool of Chemistry, National University of Ireland Galway, IrelandbSchool of Natural Sciences, National University of Ireland Galway, Ireland

Fawaz.Aldabbagh@nuigalway.ie

This group has recently reported several classes of benzimidazolequinone anti-tumouragents.[1-4] Highly potent five to seven-membered alicyclic [1,2-a] ring fusedbenzimidazolequinones have been prepared via alkyl radical cyclizations.[4] The pyrido[1,2-a]benzimidazolequinone 1 was the most potent compound prepared being more than 300times more cytotoxic than the clinically used drug mitomycin C (MMC) towards humanhypoxic (low pO2) cells. One-pot double radical cyclizations allowed the synthesis ofalicyclic ring fused imidazo[4,5-f]benzimidazoles and imidazo[5,4-f]benzimidazoles.[5]

Dipyridoimidazo[5,4-f]benzimidazolequinone 2b, and iminoquinone precursor 2a showedselective toxicity towards cancer cell lines expressing high levels of the quinone reductaseenzyme, NAD(P)H:quinone oxidoreductase (NQO1, also known as DT-diphorase). Synthesisof the new heterocyclic system: [1,4]oxazino ring fused imidazo[5,4-f]benzimidazoles 3a-3bis now presented. The mechanism for cyclization via amine N-oxide intermediates, and anti-cancer activity of a library of imidazo[5,4-f]benzimidazolequinones is described.[6]

N

N YO

N

NYX

NHN

O

ONH2

Me

OCONH2

N

N

O

O

2a; X = NH, Y, Y = CH22b; X = O, Y, Y = CH23a: X, Y, Y = O3b: X = O, Y = CH2, Y = O

MMC 1

[1] (a) O’Shaughnessy J., Cunningham D., Kavanagh P., Leech D., McArdle P.,Aldabbagh F.: Synlett 2004, 2382. (b) O’Shaughnessy J., Aldabbagh F.: Synthesis2005, 1069. (c) Hehir S., O’Donovan L., Carty M. P., Aldabbagh F.: Tetrahedron2008, 64, 4196.

[2] (a) O’Donovan L., Carty M. P., Aldabbagh F.: Chem. Commun. 2008, 5592. (b)Fahey K., O’Donovan L., Carr M., Carty M. P., Aldabbagh F.: Eur. J. Med. Chem.2010, 45, 1873.

[3] Moriarty E., Carr M., Bonham S., Carty M. P., Aldabbagh F.: Eur. J. Med. Chem.2010, 45, 3762.

[4] Lynch M., Hehir S., Kavanagh P., Leech D., O’Shaughnessy J., Carty M. P.,Aldabbagh F.: Chem. Eur. J. 2007, 13, 3218.

[5] Fagan V., Bonham S., Carty M. P., Aldabbagh F.: Org. Biomol. Chem. 2010, 8, 3149.[6] Fagan V., Bonham S., Carty M. P., Aldabbagh F.: unpublished results.

SL8

INTERACTIONS OF ANTIVIRAL INDOLO[2,3-b]QUINOXALINE

DERIVATIVES WITH DNA

Marcus Wilhelmssona, Ngarita Kingi

b and Jan Bergman

c

aDepartment of Chemistry and Bioscience, Chalmers University of Technology, SE-41296,

Gothenburg, Sweden b Drug Development, Vironova AB, ngarita.kingi@vironova.com

Gävlegatan 22, SE-11330, Stockholm, Sweden cUnit for Organic Chemistry, Department of

Biosciences and Nutrition, Karolinska Institute, SE-14157, Huddinge, Sweden

The novel indoloquinoxaline derivatives (1 and 2) have, in preliminary studies, been

demonstrated to have excellent inhibitory effects against Human cytomegalovirus (HCMV),

Herpes simplex virus (HSV) and Varicella zoster virus (VZV) as compared with B-220 (3)

and already established antiviral agents Cymevene® (Roche) and Foscavir® (AstraZeneca).

The mechanism of anti-viral action is somewhat unclear but it appears to involve reversible

non-covalent binding by intercalation into the DNA helix and, thus, disturbing the processes

those are vital for viral uncoating [1]. We have performed extensive spectroscopic studies to

investigate the interaction between a series of novel indoloquinoxaline derivatives and DNA

by determining the binding constant, the binding geometry and the AT-specificity. The

variation in structure, such as, the linker length, permanent/non-permanent nitrogen salt and

introduction of substituents on the indoloquinoxaline moiety, are shown to have an immediate

significant influence on the interaction between the ligands and DNA [2].

NN

N

N

N

NN

N

+

+

NN

N

N

NN

N

N

-Br

+

+

N N

N

N

1 2 3

-Br

-Br

-Br

Additional studies for compounds 1 and 2 and similar derivatives are currently being tested in

the EU funded project I-CARE: Integrative nano-Composites And Regeneration of the Eye.

The objective of this project is to develop a regenerative-based treatment for Corneal Herpes

Keratitis (HSK) [3].

References

[1] Homman M., Engqvist R., Soederberg-Naucler C., Bergman J., PCT Int. Appl. 2007,

WO2007084073A1.

[2] Wilhelmsson M., Kingi N., Bergman J.: J. Med. Chem. 2008, 51, 7744-7750

[3] www.euronanomed.net

SL9

DNA ADDUCTS DERIVED FROM BENZENE: THEIR SYNTHESIS, METABOLIC TRANSFORMATION, AND EXCRETION

Igor Linharta, Petr Mikešb, Kateřina Míčováa, Jan Krouželkaa, Václav Šístekb, Antonín Králíka, Emil Frantíkc, and Jaroslav Mrázc

aDepartment of Organic Chemistry, Institute of Chemical Technology, Prague, Technická 5, Prague, linharti@vscht.cz, 166 28 Czech Republic

bApigenex, Ltd., Poděbradská 186, Prague, 180 66 Czech Republic cNational Institute of public Health, Šrobárova 48, Prague 100 42 Czech Republic

Benzene is a proven human and animal carcinogen present almost ubiquitously in the environment. However, the mechanism by which it exerts the carcinogenic effect is not well understood. Three reactive intermediates in the metabolism of benzene, benzene oxide (BO), o-benzoquinone (o-BQ), and p-benzoquinone (p-BQ) react with nucleosides, nucleotides and the DNA yielding numerous adducts described in the literature. Surprisingly, only one of them, N2-(4-hydroxyphenyl)-2'-deoxyguanosine-5'-phosphate (N2HPDGP), was found in living cells whereas none has been detected in vivo.

We synthesised a complete series of known nucleobase and nucleoside adducts derived from BO, o- and p-BQ for use as analytical standards. Urine of mice exposed to benzene vapours at the concentration levels of 900 and 1800 mg/m3, 6 h daily for 14 days, were analysed by LC-ESI-MSMS for DNA adducts, namely, 7-phenylguanine (7-PhG), 3-phenyladenine (3-PhA), N2-(4-hydroxyphenyl)guanine (N2HPG), 3-hydroxy-3,N4-benzethenocytosine (CBQ), 7-hydroxy-1,N2-benzethenoguanine (GBQ), 7-(3,4-dihydroxy-phenyl)guanine (DHPG) and 3-(3,4-dihydroxyphenyl)adenine (DHPA). Detection limits ranged from 50 to 400 pg/mL. Only DHPA, an adenine adduct derived from o-BQ, could be identified in the urine of mice exposed to the higher level of benzene. However, DHPA belongs to rapidly depurinating adenine adducts, which can reflect only a short time exposure. Its applicability in biological monitoring is therefore very limited. Absence of BO adducts (7-PhG, 3-PhA) in urine is consistent with the observed very low reactivity of BO with DNA. In vitro, conversion to these adducts at physiological pH was about 0.001 % and 0.003 % for the DNA adenine and guanine adducts, respectively.

To explain the discrepancy observed between reported DNA adduct formation in vitro and their absence in the urine, we hypothesised that they could undergo efficient biotransformation in vivo. Indeed, after administration of N2HPG or benzetheno adducts to rats, extensive biotransformation was observed, indicating that only minor fractions of the administered dose could be recovered unchanged from urine.

Acknowledgement: Supported by Ministry of Education, Youth and Sports, grants No. 2B08051 and MSM 604 613 73 01.

SL10

BIOLOGICAL ACTIVITY OF PYRAZOLONES AND THEIR

PRECURSORS SYNTHESISED VIA DIAZENES

Martin Gazvoda, Bojan Burja, Marijan Kočevar, Slovenko Polanc

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, SI-1000 Ljubljana, Slovenia, e-mail: martin.gazvoda@fkkt.uni-lj.si

Pyrazoles are small heterocyclic molecules which can be found in many natural products and biologically active compounds [1]. Our research group recently disclosed simple and general route to pyrazol-3-ones, also typical pyrazole derivatives [2]. Starting from commercially available aldehydes and acetic acids the synthesis pathway enables the isolation of acrylic acids 1, hydrazides 2 and pyrazolones 3, 4 where diazenes 5 act as key intermediates.

We explored the application of pyrazol-3-ons 4 and their precursors 1, 2, 3 as an attractive gateway for the synthesis of different types of biologically active compounds.

In past years there has been an intense effort to develop anti-cancer drugs that damage the tumor vasculature, obstruct blood flow and ultimately kill the tumor while leaving normal cells intact [3]. Combretastatins have proven to be exceptional for such an approach,

especially combretastatin A-4 (6) [4]. In recent publication we described synthesis and biological activity of pyrazolone-fused combretastatins and their precursors with some excellent anti-cancer activity [5]. The pyrazolone-fused combretastatin A-4 analogue (7) and the hydrazide 8 are highly

cytotoxic against various tumor cell lines including cisplatin resistant cells. Details and some recent efforts to increase biological activity will be presented.

References [1] Qi X., Ready J. M.: Angew. Chem., Int. Ed. 2007, 46, 3242. [2] Burja B., Kočevar M., Polanc, S.: Tetrahedron 2009, 65, 8690. [3] Jordan M. A., Wilson L.: Nature 2004, 4, 253. [4] Nam N.-H.: Curr. Med. Chem. 2003, 10, 1697. [5] Burja, B., Čimbora-Zovko T., Tomić S., Jelušić T., Kočevar M., Polanc S., Osmak M.: Bioorg. Med. Chem. 2010, 18, 2375.

R1

R2

O

OH

R1

R2

O

N

N

COOMeR1

R2

NH

HN

O

R1

R2

O

NH

HN

COOMeR1

R2

NH

N

O

COOMe

1 2 53 4

MeO

OH

OMe

MeO

MeO

O

NH

OMe

MeO

MeO

HN

CO2Me

6 8

MeO

OH

OMe

MeO

MeONH

HN

O

7

SL11

Posters

MICROWAVE-ASSISTED REACTIONS OF SOME P- AND N-HETEROCYCLES

Erika Bálint, Erzsébet Jablonkai, Judit Takács and György Keglevich

Department of Organic Chemistry and Technology, BUTE, ebalint@mail.bme.hu, 1111, Hungary

These days, the utilization of the microwave (MW) technique in organic synthesis has become widespread [1,2]. There is already some application in industrial scale, however, the real breakthrough is expected in next years. Phase transfer catalyst (PTC) is also a good tool in enviormentally friendly chemistry. The combination of MW with solventless conditions and PTC offers also attractive possibilities [3]. During of our research work, first we have studied the alkylating esterification of cyclic phosphinic acids and then the N-alkylation of 5-membered N-heterocycles by alkyl halogenides under MW conditions. Our aim was to examine what will happen if the PTC and the MW techniques are combined. Control experiments were carried out under conventional heating. Besides, our aim was to find the optimum conditions of these reactions and to identify the products. We proved the efficiency of the MW irradiation in case of the model reactions studied, and we found that in most cases the PTC enhanced the reaction. We have also explored the optimum reaction conditions.

+ R'X

∆ or MW

R = H, Me or Me, MeR'X = EtI, nPrBr, iPrBr, nBuBr, BnBr

K2CO3

PTC

POHO

RR

=

Me

, ,

R R

POR'O

NH

NR

carbazole, imidazole, benzimidazole,indole-3-carbaldehyde

no solvent

M = Cs, K

BnBr+

∆ or MW

M2CO3

PTC

Finally, we have studied the phospha-Michael addition of >P(O)H species to maleimide derivatives under MW conditions. We have succeed in carrying out these reactions in good yields without the use of any solvents and catalysts.

N

O

O

Y + N

O

O

Y(RO)2P

O

R1 = Et, Me, Et, PhR2 = Et, Me, Ph, Ph

no solvent

Y = Me, Ph

MWP(O)H

R1

R2

References [1] Microwaves in Organic Synthesis; Loupy, A. Ed., Wiley-VCH, Weinheim, 2002. [2] Green Chemistry and Catalysis; Sheldon, R. A., Arends, I., Hanefeld, U., Wiley-VCH, Weinheim, 2007. [3] Keglevich, G.; Bálint, E.; Karsai, É.; Grün, A.; Bálint, M.; Greiner, I. Tetrahedron Lett., 2008, 49, 5039.

P1

THE SYNTHESIS AND GLYCOSIDASE INHIBITORY EVALUATION OF CHIRAL POLYHYDROXYCYCLOPENTA[c]ISOXAZOLIDINES

Attila Bokros, Petra Pádár, János Szolomájer, Zoltán Kupihár, Annamária Bánfi, Nemere Varga, and Lajos Kovács*

Department of Medicinal Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary,

*E-mail: kovacs@ovrisc.mdche.u-szeged.hu

The chiral pool is a valuable renewable source of starting materials, with carbohydrates being the most abundant representatives. The use of carbohydrates has its pros and cons and the chemical industry mostly refrained from its widespread use. There are, however, some distinct classes of compounds where the application of these substances is beneficial. One example is the synthesis of highly functionalized chiral carbocycles. The ω-unsaturated D-glucose-derived oxime (1) can be transformed into single diastereomer (3) according to Dransfield et al. Bicycles (3) can be easily cleaved into cyclopentanes (4). We have elaborated a stereoselective route to single diastereoisomers of polyhydroxylated chiral 9-oxa-1-azabicyclo[4.2.1]nonanes (5) through an intramolecular 1,3-dipolar cycloaddition involving nitrone (2). The core structures served as starting points for the generation of combinatorial libraries with the objective to obtain glycosidase inhibitors. To this end, carbocycles 3-5 have been derivatized in (a) acylation, (b) uretane and (c) urea formation reactions. The resulting compounds have been deprotected and their yeast α-glucosidase inhibitory activity has been assessed. Some of these compounds had inhibitory effect comparable with that of acarbose, an antidiabetes drug.

References P. Pádár, P. Forgó, Z. Kele, N. M. Howarth, L. Kovács, Nucleosides Nucleotides Nucleic Acids, 2005, 24, 743-745. P. Pádár, M. Hornyák, P. Forgó, Z. Kele, G. Paragi, N. M. Howarth, L. Kovács, Tetrahedron, 2005, 61, 6816-6823. P. Pádár, A. Bokros, P. Forgó, Z. Kele, N. M. Howarth, L. Kovács, J. Org. Chem, 2006, 71, 8669-8672.

P2

MODULAR APPROACH TO DIVERSE HETARYL C-NUCLEOSIDES

Jan Bártaa, Tomáš Kubelkaa, Matin Štefkoa, and Michal Hoceka

aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, barta@uochb.cas.cz, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic

C-Nucleosides are an important class of compounds which are characterized by replacement of the labile C-N bond by a chemically and enzymatically more stable C-C bond, thus they exhibit in vivo stability against nucleosidase enzymes. These artificial aryl C-nucleosides could serve as new building blocks in chemical biology due to their capability of π-stacking and self pairing within DNA duplex. C-Nucleosides also have applications in medicinal chemistry, as the inhibitors of purine nucleosides phosphorylase or IMP dehydrogenase. There are several approaches for the synthesis of C-nucleosides, but all suffer from poor yields and/or insufficient anomeric selectivity.[1] We are currently involved in the development of modular methodologies based on the synthesis of various key intermediate C-nucleosides and their further use for a generation of series of diverse derivatives. In our novel modular approach we have synthesized several new types of various hetaryl C-nucleosides in two key steps.[2] The first step was the preparation of haloaryl-C-nucleoside intermediate which was subsequently submitted to palladium-catalyzed reactions to introduce the various types of substituents.

This work is part of a research project from the Academy of Sciences of the Czech Republic Z4 055 0506. It was supported by the Ministry of Education, Youth and Sports (LC512), by Grant Agency of the ASCR (IAA400550902) and by Gilead Sciences, Inc.

References [1] Štambaský J.; Hocek M.; Kočovský P. Chem. Rev. 2009, 109, 6729. [2] (a) Hocek M., Pohl R.; Klepetářová B. Eur. J. Org. Chem. 2005, 4525. (b) Joubert N.;

Pohl R.; Klepetářová B.; Hocek M. J. Org. Chem. 2007, 72, 6797. (c) Bárta J.; Pohl R.; Klepetářová B.; Hocek M. J. Org. Chem. 2008, 73, 3798. (d) Kubelka T.; Slavětínská L.; Klepetářová B.; Hocek M. Eur. J. Org. Chem. 2010, 2666. (d) Štefko M.; Slavětínská L.; Klepetářová B.; Hocek M. J. Org. Chem. 2010, 75, 442.

P3

ISOCYANIDE-BASED MULTICOMPONENT SYNTHESIS OF

BIOLOGICALLY INTERRESTING HETEROCYCLES

Ayoob Bazgir

Department of Chemistry, Shahid Beheshti University, General Campus., Email: a_bazgir@sbu.ac.ir, Tehran 1983963113, Iran

Isocyanide-based multicomponent reactions (IMCRs) are particularly interesting as they are more versatile and diverse than other MCRs [1]. The great potential of isocyanides for the development of multicomponent reactions lies in the diversity of bond forming processes available, functional group tolerance, and the high levels of chemo-, regio-, and stereoselectivity often observed. Moreover, there is virtually no restriction on the nature of the nucleophiles and electrophiles in IMCRs. MCRs involving isocyanides have emerged as valuable tools for the preparation of structurally diverse chemical libraries of drug-like heterocyclic compounds [2]. In this context, N-heterocyclic molecules show interesting features that make them attractive for use in IMCRs. Heterocyclic compounds occur widely in Nature and are essential to life. N-heterocyclic molecules constitute the largest portion of chemical entities, which are part of many natural products, fine chemicals, and biologically active pharmaceuticals vital for enhancing the quality of life [3]. Herein, we report novel isocyanide-based multicomponent methods for the preparation of new N-heterocycles.

NH2

NH2

O O

OOHN NH

OO

Ar

HN

RO

+ RNC

ArCHO

ArCHON

N

O

Ar

NHR

O

O

OH

C C R'R'N

N

O

R'

R'

NHR

[1] Domling A.: Chem. Rev. 2006, 106, 17. [2] Ugi I., Werner B., D?mling A.: Molecules 2003, 8, 53. [3] Craig P. N.: In Comprehensive Medicinal Chemistry; Drayton C. J., Eds.; Pergamon Press: New York, 1991, Vol 8.

P4

SYNTHESIS OF ARYLOXY-ALKYLAMINES WITH SODIUM CHANNEL BLOCKING ACTIVITY

Hedvig Bölcskeia, Pál Kocsisb, István Tarnawab, Anikó Gereb, Sándor Kolokb and

György Dománya

aDepartment of Medicinal Chemistry I, Gedeon Richter Plc., e-mail: h.bolcskei@richter.hu,

bFarmacology and Drug Safety Research, Gedeon Richter Plc., H-1475, Budapest, 10, POB: 27, Hungary

Company Gedeon Richter is very active in the field of voltage gated sodium channel blockers. The centrally acting muscle relaxant tolperisone (Mydeton) and the neuroprotective agent vinpocetine (Cavinton) have long been used as drugs. Their action on sodium channels may contribute to their pharmacological effect. Searching the follow-up compound of tolperisone several aryloxy-alkylamines were synthesized. Modifying the aromatic (heteroaromatic) moiety, the spacer, the amine function we could establish structure-activity relationships. The sodium channel blocking activity of our new compounds was tested by BTX binding and/or fluorometric membrane potential measurement.

X

N()n

YR1

R2X = Br, Cl, F, CN, Ph, Me, etc.Y = O, SR = alkyl, substituted alkyl, cycloalkyl, etc.

HNNH

NHNH

HN

HN

NH

NH

NHHN

CONEt2

[1] Bölcskei H., Tarnawa I., Kocsis P.: Med. Chem. Res. 2008 17, 356.

P5

NEW N-YLIDES AND THEIR METAL COMPLEXES AS POTENTIAL INHIBITORS FOR GLUTAMATE RACEMASE

Ramona Danaca, Rodica Postolachia and Aurel Puia

aDepartment of Chemistry, Alexandru Ioan Cuza University of Iasi, rdanac@uaic.ro, Iasi 700506, Romania

Ylides are bipolar organic compounds in which the carbanion is covalently bound to a positively charged heteroatom [1]. Nitrogen ylides can coordinate metal ions forming complexes [2]. Glutamate racemase (GR) is a source of D-glutamate in bacteria [3] which is an essential component of the peptidoglycan layer of bacterial cell walls and it is a target for antibacterial drug development since many clinically used antibiotics act on this pathway [4-5].

We report here the synthesis and complexation properties of new stable disubstituted 4-(4-pyridyl)pyridinium ylides with the general formula shown in the figure below:

N N

OAr

XNHC6H4R(p)

X= O, S

Physical methods (NMR, IR, UV-VIS, MS, XRD) were used for establishing the structures of the new ylides and their complexes with cobalt, nickel, copper. Interaction of some ylides and some metal complexes with the RacEa peptide (the catalytic site from Glutamate racemase) was studied using Affinity-MS, and some of the tested compound showed to bind to the synthetic RacEa peptide. The peptide (LGCTHY) from Glutamate Racemase RacEa was synthesized by solid phase peptide synthesis (Fmoc-SPPS). This peptide is part of the catalitic site of the enzyme, therefore our preliminary Affinity-MS study is of interest for development of N-ylides-based Racemase inhibitors. References [1] Zugrăvescu I., Petrovanu M.: N-Ylid Chemistry, McGraw-Hill International Company, Bucharest, 1976. [2] Chauvin R., Canac Y.: Topics in organometalic chemistry, Springer-Verlag, Berlin Heidelberg, 2010. [3] Stewart L.: Microbial Biotechnology 2008, 1, 345–360. [4] Lundqvist, T., Fisher, S. L., Kern, G.: Nature 2007, 447, 817–822. [5] Whalen K. L., Pankow K. L., Blanke S. R., Spies M.A.: ACS Med. Chem. Lett. 2010, 1, 9–13.

P6

EFFICIENT METHODS FOR THE SYNTHESIS OF PYRAZOLES AND

OXAZEPINES

Mohammad Ghaffarzadeh,* Ebrahim Saeedian Moghadam, Fereshteh Faraji

Chemistry and Chemical Engineering Research centre of Iran (CCERCI), Email: faraji@ccerci.ac.ir, PO Box 14335-186 Tehran, Iran.

Heterocyclic compounds are highly ranked among pharmaceutically important natural and synthetic materials. The remarkable ability of heterocyclic nuclei to serve both as biomimetics and active pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs. Heterocyclic derivatives such as pyrazoles and oxazepines are just a few examples from various pharmaceuticals featuring a heterocyclic component. Heterocycles containing the pyrazole ring are important targets in synthetic and medicinal chemistry because this fragment is a key moiety in numerous biologically active compounds [1], among them such prominent drug molecules as Celecoxib, Pyrazofurine, and many others. Herein, we report a novel one-pot method for the preparation of biologically important amino pyrazoles.

R R

O O

AcOH

NaNO2 R R

O O

NOH

NH2NH2

N

NH

R

R

NH2

The modification of the oxazepine nucleus synthesis is a versatile research area due to its presence in some natural products and biologically active substances [2]. There are many methods for the synthesis of oxazepine ring systems. However, new, simple, and efficient ways for constructing oxazepine rings are still in great demand [3]. Therefore, due to the biological importance of oxazepines, we report a simple synthesis of dibenz[b,f]-1,4-oxazepines by intramolecular nucleophilic displacement of chloro group under microwave irradiation.

O

NNH2

OHX

+

OHC

Cl XY

Y

MW, 5 min.

DMF/KOH

[1] Elguero J.: In Comprehensive Heterocyclic Chemistry II; Katritzky A. R., Rees C. W., Scriven E. F., Eds, Elsevier: Oxford, 1996; Vol 3, pp 1-75. [2] Serrano-Wu M. H. Laurent D. R. S., Chen, Y.: Bioorg. Med. Chem. Lett. 2002, 12, 2757. [3] Ouyang X., Tamayo N., Kiselyov A. S.: Tetrahedron 1999, 55, 2827.

P7

SYNTHESIS OF SOME NOVEL NEW S- AND N,S-SUBSTITUTED

NITRODIENES

F.Serpil GÖKSEL, Cemil İBİŞ, and Elif AYDIN

Istanbul University, Faculty of Engineering, Department of Chemistry,

segoksel@istanbul.edu.tr

Avcılar 34320, Istanbul, Turkey

As a part of our consecutive studies, we now report the some new S- and N,S-substituted

nitrodienes. Nitro-substituted polyhalogeno-1,3-butadienes can react with nucleophiles such

as amines, alcohols, and thiolalcohols. The synthesis of some thiosubstituted 2-nitrodiene

compounds has been reported [1-3].

It is known some mono- and di-substituted piperazine derivatives are significant for clinical

chemistry, gen transfer studies and posses high biological activity for multidrug resistance in

cancer. In this study, the mono(thio) substituted nitrodiene compound was synthesized from

nitrodiene and thiol. In the following step, reactions of piperazine derivatives with the

mono(thio) substituted nitrodiene compound were studied.

Reaction products were purified by column chromatography. Structures of these novel

products were determined by microanalysis and spectroscopic methods (IR, 1H-NMR,

13C-

NMR, UV and MS).

R1: -(CH2)6-CH3

R2: , , ,

References

[1] Kaberdin R. V., Potkin V. I. and Zapol’skii V. A.: Russian Chemical Reviews. 1997,

66(10), 827-842.

[2] Potkin V. I., Izv.Akad. Nauk Bel., Ser.Khim.Nauk., 1991,(1)65.

[3] Ibiş C. Göksel F. S. and Aydınlı G.,Phosphorus, Sulfur and Silicon, 2003, 178, 777.

F

F

Br

Cl

O2N

ClS R1

ClBr

Cl

O2N

Cl

N N

S R1

R2

P8

INTRAMOLECULAR CYCLYSATION OFO6-HYDROXYALKOXYPURINES

Michal Himla, Kateřina Zacharovováa, and Igor Linharta

aDepartment of Organic Chemistry, Institute of Chemical Technology Prague,himlm@vscht.cz, Technická 5, 166 28 Prague 6, Czech Republic

2-Amino-6-chloropurine activated in the 6 position with DABCO is known to readilyundergoes reactions with divers nucleophiles. Thus, its reaction with primary or secondaryalcohols in the presence of a base leads to O6-alkylated guanines [1,2,3]. With ethyleneglycol, propan-1,3-diol and butan-1,4-diol the reaction performed in dry DMF with NaH as abase gave smoothly corresponding O6-hydroxyalkyl guanines. After transformation of thehydroxy group to a suitable leaving group (halogen or activate ester) O6-hydroxyalkylpurinesunderwent intramolecular cyclisation yielding corresponding tricyclic products. Best resultswere achieved with PPh3/CBr4 as a reagent for transformation the OH group. The ring closurereaction proceeded exclusively at N1 nitrogen of guanine. The same reaction sequenceperformed with 6-chloropurine as the starting material yielded corresponding series oftricyclic purine derivatives. No ring closure reaction at N7 was observed. A regio-selectiveand efficient synthetic method for tricyclic purine derivatives was developed. The productsmay find applications as biologically active compounds [4,5]. Reaction conditions and othersynthetic approaches to tricyclic purines will be discussed.

N

N NH

N

X

Cl

N

N NH

N

X

OOH

n

N

N N

N

X

OnDABCO

DMF

OHOH

n

base

n=1,2 or 3

PPh3

CBr4

X = NH2 or H

N

N NH

N

X

N

N

-Cl+

Acknowledgement: Financial support by grants MSM 604 613 73 01, LC06070 and 2B08051from the Ministry of Education, Youth and Sports is gratefully acknowledged.

References[1] Balsinger R. W., Montgomery J. A.: J. Org. Chem. 1960, 25, 1573.[2] Linn J. A., McLean E. D., Kelley J. L.: J. Chem. Soc., Chem. Commun. 1994, 913.[3] Lembitz N. K., Grant S., Clegg W., Griffin R. J., Heath S. L., Golding B. T.: J. Chem.

Soc., Perkin Trans. 1 1997, 185.[4] Holý A.: Principy biorganické chemie ve vývoji antivirotik a cytostatik. Univerzita

Palackého v Olomouci, 2004.[5] Hakimelahi G. H., Ly T. W., Moosavi-Movahedi A. A., Jain M. L., Zakerinia M., Davari

H., Mei H.-C., Sambaiah T., Moshfegh A. A., Hakimelahi S.: J. Med. Chem. 2001, 44,3710.

P9

THE SYNTHESIS and CHARACTERIZATION OF NOVEL CYCLIC

HALOQUINONE DERIVATIVES

Cemil IBIS, Sibel SAHINLER AYLA, and Kadriye CAKAN

University of Istanbul, Faculty of Engineering, Department of Chemistry, 34320, Avcilar,

Istanbul, TURKEY

E-mail: ibiscml@istanbul.edu.tr

Quinones are well known in biologic systems. The synthesis of benzo- and naphthoquinone

compounds as a new biologically active agents in medicinal chemistry have received a

considerable attention [1-3]. The aim of this study is the synthesis of the novel oxygen

containing benzoquinone compounds as a potential biologic active agents and characterize

them with spectral methods.

In this study the novel crown ethers with haloquinone group were synthesized. The structures

of novel compounds were characterized by using Micro analyses, 1H-NMR,

13C-NMR, FT IR,

MS, UV-vis.

O

OCl

Cl

O

O

Cl

ClO

O

O

O

O

O

O

OCl

Cl

O

O

O

References

[1] Huang, ST., Kuo, HS., Hsiao, CL., Lin, YL.: Bioorganic&Medicinal Chemistry 2002, 10,

1947.

[2] Ibis, C., O. Gunes, Z.: Heteroatom, 2010, 21 (6), 446.

[3] Ibis, C., O. Gunes, Z.: Dyes and Pigments, 2008, 77, 39.

P10

NEW HETEROCYCLIC DERIVATIVES OF BENZIMIDAZOLE WITH

ANTICANCER ACTIVITY

Luba Ignatovich, Olga Starkova, Vitalijs Romanovs, and Irina Shestakova

Latvian Institute of Organic Synthesis, Laboratory of Organometallic Chemistry

e-mail: ign@osi.lv Riga LV 1006, Latvia

Benzimidazoles and their derivatives are well documented in the literature to exhibit a wide

range of biological activities [1]. The position and type of substituents in the benzimidazole

are responsible for the variety of their biological activities. Taking into consideration the

information gained from the literature analysis of known anticancer drugs and the fact that

silylation (germylation) increases lypophilicity of the compounds and can change their

metabolism [2], we decided to synthesize silicon- and germanium-containing

benzimidazoles 1 and their N-substituted derivatives 2, and to test the cytotoxicity against

cancer cell lines HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) and normal

mouse fibroblasts NIH 3T3.

NH2

NH2

R

X

CHOR'3M

X

NH

N

R'3M

R

X

N

N

R'3M

R

+NaHSO3

DMF, 80 oC

R"

1

2

M = Si, Ge; X = O, S; R = H, Me, Cl, Br;R' = alkyl, phenyl; R'3M = 1-methyl-1-silacyclopentyl-,

1-methyl-1-silacyclohexyl-; R" = alkyl, allyl, propargyl

R"Br/18-Crown-6/C6H6

A preliminary analysis of the structure –activity relationship for the benzimidazole derivatives

clearly indicates that the introduction of silyl(germyl) substituents into furan or thiophene ring

of 2-furyl(thienyl)benzimidazoles 1 significantly increases the cytotoxicity of the compounds.

IC50 for the most active benzimidazoles 1 are in the range 0.08-1.0 g/ml (for R’3M = H, IC50

= 8–100 g/ml). Introduction of the certain silyl group (1-methyl-1-silacyclopentyl- or 1-

methyl-1-silacyclohexyl-) at the furan rings improves the cytotoxicity against cancer cells

MG-22A (IC50 = 1 g/ml) and suitably decrease cytotoxicity to normal cells NIH 3T3 (IC50 =

100–427 g/ml). Furthermore, these groups greatly reduce the toxicity of new furyl-

benzimidazoles (LC50 = 763–1452 mg/kg). Alkylation of benzimidazoles 1 leads to new

compounds 2, they also possess a high cytotoxic effect on cancer cells (IC50 = 1–3 g/ml).

References [1] Kleemann A., Engel J., Kutscher B., Reichert D. Pharmaceutical Substances, Thieme, Stuttgart-

New York, 2009.

[2] E. Lukevics, L. Ignatovich, In: Metallotherapeutic Drugs and Metal-Based Diagnostic Agents. The

Use of Metals in Medicine, (Eds.: M. Gielen, E. R. T. Tiekink), John Wiley & Sons, 2005, Ch.5, p. 83.

P11

Synthesis of a Functionalized Multifunctional Amyloid Ligand

Leif B.G. Johansson and K. Peter R. Nilsson

Linköpings Universitet, Department of Physics, Chemistry and Biology leffe@ifm.liu.se, SE-58183 Linköping, Sweden

The formation and accumulation of protein aggregates, amyloid, give rise to distinct pathological conditions known as amyloidoses. Alzheimer’s disease and Parkinson’s disease are both examples of neurodegenerative conditions resolving on local amyloid accumulation in the brain. To be able to study these diseases, molecular probes that selectively identify the amyloid are needed as a research tool. Luminescent conjugated oligothiophenes (LCOs) have been proven to be utilized for in vivo imaging of protein aggregates by using fluorescence microscopy.[1] Herein we report the synthesis of an asymmetric functionalized thiophene tetramer. This will provide the possibility to use other techniques than fluorescence, such as SPR, MRI and PET for detecting the interaction between the LCO and amyloid fibrils. Additionally, the functionalized LCO might also be implemented as an amyloid capturing reagent in novel sensitive assays for detection of amyloid and serve as a molecular scaffold for novel therapeutical inventions towards protein misfolding diseases. References [1] Åslund A, Sigurdson C.J, Klingstedt T, Grathwohl S, Bolmont T, Dickstein D.L, Glimsdal E, Prokop S, Lindgren M, Konradsson P, Holtzman D.M, Hof P.R, Heppner F.L, Gandy S, Jucker M, Aguzzi A, Hammarström P and Nilsson K.P.R.: ACS Chem. Biol., 2009, 4 (8), pp 673–684.

P12

DIELS−ALDER REACTION OF ELECTRON DEFICIENT 2H−PYRAN-2-

ONES WITH ELECTRON RICH VINYL MOIETY CONTAINING

DIENOPHILES AND CHARACTERIZATION OF THE INTERMEDIATE

PRODUCTS

Amadej Juranovič, Krištof Kranjc, Franc Perdih, Slovenko Polanc and Marijan Kočevar

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5,

amadej.juranovic@fkkt.uni-lj.si, SI-1000 Ljubljana, Slovenia

Diels−Alder reaction is still one of the most intensively studied reactions in organic synthesis [1].

2H-Pyran-2-ones 1 are, because of their intrinsic cisoid conformation, potent dienes for variety of

dienophiles. In the past we showed that cycloaddition between ethyl vinyl ether (2, R4 = Et) and

2H-pyran-2-on 1 led to the substituted anilines 6 [2]. It was also established that an appropriate

base (DABCO) tremendously affects the formation of the aromatic product 6. Our main goal was

to isolate both intermediate products 4 and 5 and to determine the role of acidic (Dowex) or basic

(DABCO) catalyst on the outcome of the reaction [3]. When the reaction was conducted

thermally or under microwave assisted heating not even traces of 2-oxabicyclo[2.2.2]oct-5-enes 4

were detected. On the other hand, we were able to prepare them under high pressure (13−15

kbar), which is widely known to accelerate the reactions with the negative activation volume. We

also found out that regioselectivity of high pressure promoted cycloadditions was the same in all

cases studied, but their stereoselectivity (ratio endo/exo stereoisomers 4) was highly affected by

the type of dienophile. Semiempirical calculations (methods AM1 and PM3) were in agreement

with experimental results. Dihydrobenzene derivatives 5 could be synthesized thermally without

addition of any catalyst that usually affects the elimination step toward final aromatic product 6.

It is worth to mention, that this type of compound is impossible to obtain in pure form as the

aromatization proceeds spontaneously even in pure crystalline state.

[1] Afarinkia, K., Vinader, V., Nelson, T. D., Posner, G. H.: Tetrahedron 1992, 48, 9111−9171.

[2] Kranjc, K., Kočevar, M.: Synlett 2008, 2613−2616.

[3] Juranovič, A., Kranjc, K., Perdih, F., Polanc, S., Kočevar, M.: Tetrahedron 2011, 67,

3490−3500.

O O

NHCOR3R1

R2

NHCOR3

NHCOR1

OR4OR4

R2

R3

R1

R2

1

2

5

6

- CO2

O

R3CONHOR4

H

R2O

R1

endo-4

O

R1CONHH

N

R2O

R1

( )n

Oexo-4

NHCOR3

N

R1

R2

5

( )nO

N

3

n = 1, 3

( )n

O

- CO2

- R4OH

-

( )n

HN O

O

R3CONHN

H

R2O

R1

( )n

O+

endo-4

R3 = Ph, Me, 2-chloro-3-pyridyl, 2-furyl, 3,4,5-(MeO)3-C6H2, 4-NO2-C6H4, 6-chloro-3-pyridyl, cyclobutyl, cyclopropyl;

R1 = CO2Me, CO2Et, COMe, COPh; R2 = Me; R4 = Et, COMe, COEt, cyclohexyl; n = 1, 3

P13

SOME 3-AMINOINDOLE-2-CARBONITRILE CHEMISTRY

Andrey Berezina, Panayiotis A. Koutentisa and Sophia S. Michaelidoua

aDepartment of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus e-mail: koutenti@ucy.ac.cy

Treatment of 2-(4-chloro-5H-1,2,3-dithiazolylideneamino)benzonitrile 1 with Ph3P gave unexpectedly 3-aminoindole-2-carbonitrile 3 [1]. The reaction was shown to proceed via the 2-cyano cyanothioformanilide 2 [2][3]. Although of mechanistic interest this route was not suitable for the synthesis and isolation of 3-aminoindole-2-carbonitrile 3 on a gram scale that would allow a study of its chemistry. As such a Thorpe-Zeigler cyclization was pursued and optimized that gave the desired indole in high yield without the need of chromatography [4][5]. Subsequent Friedländer cyclizations of 3-aminoindole-2-carbonitrile 3 with various cyclic ketones gave a range of interesting new fused carbazoline scaffolds 4.

SS

N

N Cl

N

Ph3P

NH

N

S

N

Ph3PDBU

1

2

NH

NH2

N

3

4

NH

N

NH2

O

n

n

Scheme 1 References [1] Michaelidou S. S., Koutentis, P. A.: Tetrahedron 2009, 65, 8428. [2] Michaelidou S. S., Koutentis P. A.: Synthesis 2009, 4167. [3] Koutentis P. A., Michaelidou S. S.: Tetrahedron 2010, 66, 6032. [4] Michaelidou S. S., Koutentis P. A.: Tetrahedron 2010, 66, 685. [5] Michaelidou S. S., Koutentis P. A.: Tetrahedron, 2010, 66, 3016.

P14

Carbocyclic analogs of pseudoisocytidine

Lukáš Maiera, Kamil Paruch

a

aDepartment of Chemistry, Masaryk University, Kamenice 5/A8, Brno,

lmaier@mail.muni.cz, paruch@chemi.muni.cz , 623 00, Czech Republic

C-linked nucleosides analog pseudoisocytidine (1), shows activity against cytarabine-resistant

leukemia and is stable toward deamination by cytidine deaminase [1]. Unfortunately,

hepatoxicity of unknown origin in humans led to discontinuation of its clinical trials [2].

We have developed synthesis of carbocyclic analogs of 1 that are represented by general

formula 2. The compounds are envisioned to possess greater chemical and metabolic stability

toward degradation in the cell. Namely, the cyclopentane analogs should not undergo ring

opening and anomerization processes. As their tetrahydrofuran counterparts, properly

functionalized carbocyclic compounds 2 may inhibit important enzymes (e.g. DNA

polymerases, ribonucleotide reductase [3] etc.) while their biological and toxicological

profiles may be superior.

Starting from methyl propiolate and cyclopentadiene, we prepared key cyclopentane

intermediate 3 (Scheme 1), which was subsequently converted into the target molecules 2a-c

with differently substituted pyrimidine base.

Scheme 1

Furthermore, intermediate 3 is to be used for preparation of other analogs with different

heterocyclic systems and carbocyclic variants.

References

[1] Burchenal, J. H.; Fox, J. J. Cancer Res. 1976, 36, 1520.

[2] Woodcock, T. M.; Burchenal, J. H. Cancer Res. 1980, 40, 4243.

[3] Lutz, S.; Benner, S. A. Nucleic Acids Res. 1999, 27, 2792.

P15

α,β-UNSATURATED ACIDS AS STARTING MATERIALS FOR THE

SYNTHESIS OF FUMARAMIDES AND QUINOXALINONES

Vita Majce, Marijan Kočevar, and Slovenko Polanc

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5,

SI-1000 Ljubljana, Slovenia, vita.majce@fkkt.uni-lj.si

Diazenes are an interesting group of compounds and a longtime interest of our research group

[1]. Diazenedicarboxamides in particular have been shown to inhibit an essential bacterial

enzyme D-alanine:D-alanine ligase [2]. Due to their reactive nature, we wanted to synthesize

structurally similar compounds by replacing the reactive N=N moiety with a C=C double

bond, resulting in fumaramides 5. The synthetic route involves the synthesis of monoamides

of maleic acid 1 by opening of maleic anhydride with an appropriate amine (R1R

2NH) and

consequent coupling with EDC·HCl to give the corresponding maleamides 4. We optimized

the isomerization of maleamides 4 under focused microwave irradiation in the presence of

different bases. A catalytic amount (8 mol%) of a heterocyclic amine – piperidine, has shown

the best results, giving 5 in high yields and purity [3]. The starting monoamides of maleic acid

1 were also used for the synthesis of N-substituted 2-(3-oxo-1,2,3,4-tetrahydroquinoxalin-2-

yl)acetamides 2. The reaction directly from 1 proceeds poorly (MW, CH3CN), but the yields

are increased by utilizing methyl esters of 1 and/or catalyzing the reaction with a base in polar

solvents. Since 2 and benzodiazepines 3 are indistinguishable by NMR techniques it remains

to be confirmed by X-ray crystallography which isomer is formed by this reaction.

[1] Košmrlj J., Kočevar M., Polanc S.: Synlett 2009, 14, 2217.

[2] Kovač A., Majce V., Lenaršič R., Bombek S., Bostock J. M., Chopra I., Polanc S., Gobec

S.: Bioorg. Med. Chem. Lett. 2007, 17, 2047.

[3] Majce V., Kočevar M., Polanc S.: Tetrahedron Lett. 2011, 52, 3287.

P16

SYNTHESIS OF (–)-HYPEROLACTONE C FROM (S)-STYRENE OXIDE

David M. Hodgson and Stanislav Man

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom, david.hodgson@chem.ox.ac.uk

Hyperolactone C was originally isolated from the leaves and stems of Hypericum chinese L. (1995)[1] as a part of a small family of related lactones. Hyperolactone C and ent-zingiberene are precursors of biyouyanagin A (3),[2] a new anti-HIV agent.[3] Quite recently, Xie and co-workers reported a new 6-step catalytic asymmetric synthesis of (–)-hyperolactone C.[4]

Our current work was based on the 7-step rac-hyperolactone C synthesis from ethyl acetoacetate.[5] We developed new asymmetric route starting from (S)-styrene oxide (1).[6] The key step of the synthesis was Rh2(OAc)4 catalyzed oxonium ylide formation–rearrangement of silylated diazoalcohol 2 followed by acid work-up to give, as a major diastereomer, lactone 3. Lactone 3 was successfully oxidized to give (–)-hyperolactone C.

AcknowledgmentWe thank the European Union for a Marie Curie Fellowship (PIEF-GA-2009-237270 to S.M.)

References[1] Aramaki Y., Chiba K., Tada M., Phytochemistry 1995, 38, 1419.[2] Nicolaou K. C., Sarlah D., Shaw D. M., Angew. Chem. Int. Ed. 2007, 46, 4708.[3] Tanaka N., Okasaka M., Ishimaru Y., Takaishi Y., Sato M., Okamoto M., Oshikawa T.,

Ahmed S. U., Consentino L. M., Lee K.-H., Org. Lett. 2005, 7, 2997.[4] Du C., Li L., Li Y., Xie Z., Angew. Chem. Int. Ed. 2009, 48, 7853.[5] Hodgson D. M., Angrish D., Erickson S. P., Kloesges J., Lee C. H., Org. Lett. 2008, 10,

5553.[6] D. M. Hodgson, S. Man, Chem. Eur. J. 2011, DOI: 10.1002/chem.201101082.

Zn / trace MeSO3H

Ph OH

CN

Ph O

CN

Et3N, THF Ph O

OCO2Et

THF, refluxthen aq. HCl

Me2CCNOH Br

Br CO2Et

PhO

91%68% 81%

Ph O

OCO2Et

N2

p-ABSA

92%reflux

Ag2OCH2Cl2 Et3N

S-1

then Ph3PPh O

OCO2R

N2CH2Cl2, rt

OCO2R

N2OPhO O

Ph3POO3

CH2Cl2, − 78 °C

− 78 °C to rt 75%

+ −O

CO2R

N2OPh

OCO2R

N2OPh

EtOAc, 50 °C

CH2Cl2, rt

OH

OSiMe3

TMSCN 2. MeSO3H

NaBH(OAc)3

1. cat. Rh2(OAc)4 OO

OPh

O

CH2Cl2, rt

2. DDQ1. TMSOTf / Et3N

CH2Cl2, rt

O O

OPh

O

(–)-Hyperolactone C

CH2Cl2

2 3

88%

63% over 3 steps 81%

P17

REACTIONS OF BENZENE OXIDE WITH DNA AND MODEL

NUCLEOPHILES

Kateřina Míčová and Igor Linhart

Department of Organic Chemistry, Institute of Chemical Technology Prague,

Technická 1905, Prague,

micovak@vscht.cz, 166 28 Czech Republic

Benzene oxide (BO) is a reactive metabolic intermediate of benzene. Its capability of binding

to biologically important thiols, such as glutathione and cysteine units in proteins and to

nucleophilic centres in the DNA was studied in model reactions with N-acetylcysteine, purine

nucleosides (2´deoxyadenosine, dA and 2’-deoxyguanosine, dG), nucleotides (2’-

deoxyadenosine-5’-monophosphate, dAMP and 2'-deoxyguanosine-5’-monophosphate,

dGMP) and with the DNA itself. Reactions were performed in aqueous TRIS buffer solutions

(pH 7.4) at 37°C. Reaction products were analysed by LC/MS. Primary 6-hydroxycyclohexa-

2,4-dien-1-yl derivatives were converted to corresponding phenylguanines and

phenyladenines by acidic hydrolysis and these products were identified and quantified using

authentic standards. Reaction of BO with N-acetylcysteine yielded 0.3, 1.0 and 10.7 % of the

adduct at pH 5.5, 7.4 and 11.4, respectively. The primary adduct formed, N-Acetyl-S-(6-

hydroxy-2,4-cyclohexadien-1-yl)cysteine was completely converted to N-acetyl-S-

phenylcysteine (phenylmercapturic acid) after standing 1 h at pH 2 at room temperature. On

the other hand, reactions benzene oxide with dA or dG afforded only traces (not more than

0.006 %) of corresponding adducts. So, 2’-deoxyadenosine gave two products before acidic

hydrolysis (6-hydroxycyclohexa-2,4-dien-1-yl)-2’-deoxyadenosines and major deribosylated

adducts (6-hydroxycyclohexa-2,4-dien-1-yl)adenines. After acidic treatment (pH 1, 100°C, 1

h) these peaks disappeared and two other peaks co-eluting with authentic 3-phenyladenine (3-

PhA) and N6-phenyladenine (6-PhA) were detected, the latter being the predominating one.

Similarly, dG gave only 7-(6-hydroxycyclohexa-2,4-dien-1-yl)guanine, which under the same

acidic conditions gave 7-phenylguanine (7-PhG).

Reactions of BO with the DNA afforded only traces (not more that 0,7 %) of adenine and

guanine adducts. They were identified after complete acidic hydrolysis of DNA as 7-PhG, 6-

PhA and 3-PhA. Surprisingly, their yields increase with the reaction time even after 4.5 h, i.e.,

after BO had disappeared from the reaction mixture its half life in neutral aqueous solution

being about 30 min. Similarly, a significant increase in the adduct yields with reaction time

was observed in model reactions with dGMP and dAMP.

Very low reactivity of BO with the DNA as well as with purine nucleosides and nucleotides

was observed indicating that BO can hardly be responsible for the DNA damage caused by

benzene. Low DNA reactivity of BO also explains negative findings of corresponding DNA

adducts in experimental animals or humans exposed to benzene.

Acknowledgement. Financial support by grants 2B08051 and MSM 604 613 73 01from the

Ministry of Education, Youth and Sports is gratefully acknowledged.

P18

NEw FOUR-COMPONENT SYNTHESIS OF FERROCENYL AMODODIESTERS AND FERROCENYL TERIAMIDES

Peiman Mirzaei

Department of Chemistry, Shahid Beheshti University, General Campus., Tehran, Email: p_mirzaei@sbu.ac.ir 1983963113, Iran,

Within the past decade, the resurgence of interest in multicomponent reactions (MCRs) has been driven, not only due to their convergent nature, superior atom economy, and straightforward experimental procedures but also because of their value to the pharmaceutical industry for construction of low molecular weight compound libraries through combinatorial strategies and parallel synthesis [1]. Ferrocene derivatives find an ever growing application in many fields, from chiral catalysis to material science, to medicinal chemistry [2]. A number of reasons may be enumerated to explain the success of ferrocenes, among which, its unusual stability for an organometallic species: ferrocenes can be handled in the air when solid and often in solution also. Ferrocenes are reactive aromatic compounds, but they are sensitive to oxidizing agents – as most electrophilic reagents are – as well as to acids [3]. Thus, formation of ferrocenyl amidoesters or ferrocenyl triamides via MCRs is useful in functionalizing ferrocenes, because oxidation can be easily avoided, reaction conditions are mild, and ester or amide groups may be transformed into a variety of functional groups. Herein, we describe an efficient synthetic approach to ferrocenyl amidodiesters and ferrocenyl triamides by an isocyanide-based four-component reaction.

Fe

CHO

+ RNCr.t.

Fe

O O

O O

CH2Cl2

OR'R'O

O O

HN

O

R

+

R'OH

Fe

NHArArHN

O O

HN

O

RArNH2

[1] Tietze, L. F., Modi, A.: Med. Res. Rev. 2000, 20, 304-322 [2] Argyropoulos, N., Argyropoulou, E. C.: J. Organomet. Chem. 2002, 654, 117-122. [3] Uno, M., Dixneuf, P. H.: Angew. Chem. Int. Ed. Engl. 1998, 37, 1714-1717.

P19

SYNTHESIS AND IN VITRO ANTIBACTERIAL ACTIVITEIS OF NOVEL3-(PHENYL AMINO) QUINAZOLIN-4(3H)-ONES

Department of Chemistry, Sabzevar Branch, Islamic Azad University, Sabzevar, Iran Email:

Ali Asghar Mohammadi

Aliamohammadi@iaus.ac.ir Quinazolinone derivatives have drawn much attention due to their broad range of pharmacological activities such as antibiotic, antidefibrillatory, antispermatogenic, vasodilatory, and analgesic ability [1]. Several methods have been reported for the synthesis of quinazolinones [2]. As per our ongoing work to synthesize privileged-class bioactive nitrogen-containing heterocyclic compounds [3], and in view of our interest in the KAl(SO4)2.12H2O catalyzed reaction [4], We have designed the three-component one-pot synthesis of novel 3-(phenyl amino) quinazolin-4(3H)-one 4 from isatoic anhydride 1, ortoester 2, and phenylhydrazine 3 using non-toxic and easily available KAl(SO4)2.12H2O (Alum) as a heterogeneous catalyst (Scheme 1).

NH

O

O

O1

R1NHNH2

2

3

+

N

N

O

4

Alum

HN R1

R2R2C(OR3)3

Scheme 1

[1] a) Russel H. E., Alaimo R. J.: J. Med. Chem. 1972, 15, 335. (b) Levin J. I., Chan P. S., Bailey T., Katocs A. S., Venkatesan A. M.: Bioorg. Med. Chem. Lett. 1994, 4, 1141.

[2] a) Su W. : Yang B.: Aust. J. Chem. 2002, 55, 695. (b) Shi D., Rong L., Wang J., Zhuang Q., Wang X., Hu H.: Tetrahedron Lett. 2003, 44, 3199. (c) Mohammadi A. A., Dabiri M., Qaraat H.: Tetrahedron 2009, 65, 3804.

[3] a) Mohammadi A. A., Mivechi M., Kefayati H.: Monatsh. Chem. 2008, 139, 935-937. (b) Azizian J., Mohammadi A. A., Karimi N., Karimi A. R., Mohammadizadeh M. R.: Catal. Commun. 2006, 7, 752.

[4] a) Azizian J., Mohammadi A. A., Karimi A. R., Mohammadizadeh M. R. : Appl. Catal. A: Gen., 2006, 300, 85. (b) Azizian J., Mohammadi A. A., Karimi A. R., Mohammadizadeh M. R.: J. Org. Chem., 2005, 70, 350.

.

P20

TOWARDS N2,8-DISUBSTITUTED GUANINES, HAPTENS FOR

IMMUNOCHEMICAL ANALYSES OF DNA ADDUCTS WITH

ARYLAMINES AND NITROARENES

Alena Moulisováa and Igor Linhart

a

aDepartment of Organic Chemistry, Institute of Chemical Technology Prague, Technická

1905, Prague, Alena.Moulisova@vscht.cz, 166 28 Czech Republic

Modified purines often show significant biological activity because of structural similarity

with important endogenous compounds. They are also formed by reactions of electrophiles or

free radicals with DNA. These lesions of DNA can be detected in biological fluids or tissues

using sensitive analytical methods including immunochemical methods [1, 2].

Our aim was to develop synthetic methods for 8-arylamino guanines bearing an ω-

carboxyalkyl link at the N2 position. These compounds could be used as haptens for the

development of immunochemical methods to analyse 8-arylamino adducts formed from

numerous carcinogenic arylamines and nitroarenes.

Esters of N2-(ω-carboxyalkyl)guanines, namely, N

2-carboxymethyl-, N

2-(2-carboxyethyl)- and

N2-(3-carboxypropyl)guanine were prepared by reactions of 2-bromhypoxanthine with

corresponding amino acid esters to give N2-substituted guanines. Reactions were performed in

anhydrous DMF with pyridine as a base. Three N2-substituted guanines were obtained in 90,

55, and 57 % yields for ethyl 2-aminoacetate, ethyl 3-aminopropanoate and ethyl 4-

aminobutyrate, respectively. However, our attempts to brominate these unprotected

derivatives by N-bromosuccinimide at C-8 position were unsuccessful.

Therefore, another approach to C8-substituted purines was tested based on the condensation

of vicinal diaminopyrimidine with N-arylcarbamates followed by appropriate modification of

the C2 position. 4,5,6-Triaminopyrimidine was chosen as a model compound for

condensation with N-arylcarbamates. When melted with methyl N-phenylcarbamate at 180°C

4,5,6-triaminopyrimidine gave N,N´-diphenylurea and 8-oxoadenine but not the expected

product. Nevertheless, addition of N,N'-dicyclohexylcarbodiimide (DCCI) as a coupling

reagent to the reaction mixture changed the course of reaction so that the requested product,

8-phenylaminoadenine. Two intermediate phenylcarbamoylated derivatives of 4,5,6-

triaminopyrimidine were identified by LC/MS analysis. The condensation reaction will be

optimised using other carbodiimides as coupling reagents.

Acknowledgement: Financial support by grants LC06070 and MSM 604 613 73 01 from the

Ministry of Education, Youth and Sports is gratefully acknowledged.

References

[1] Linhart I., Novák J.: Chem. Listy, 2002, 96, 276.

[2] Glüsenkamp K.-H., Krüger K., Eberle G., Drosdziok, W., Jähde E., Gründel O., Neuhaus

A., Boese R., Rajewsky M.F.: Angew. Chem. Int. Ed. Engl. 1993, 32, 1640.

P21

SYNTHESIS OF NATURALLY OCCURRING 6- OR 8-ALKENYLATED

HYDROXYFLAVONES

Gergő Zoltán Nagya, and Tamás Patonay

a

aDepartment of Organic Chemistry, University of Debrecen,

nagy.gergo@science.unideb.hu, H-4032 Debrecen, Hungary

Chromonoids and flavonoids are well-known naturally occurring derivatives often having

remarkable biological effects. In the last decades the palladium-catalyzed arylation and

vinylation of alkenes (Heck reaction) has become a versatile tool in organic chemistry. Since

only sporadic reports were found in the literature, our research group initiated a systematic

survey on the use of palladium-catalyzed cross-coupling reactions of chromones, flavones and

coumarins. The usefulness of this methodology was demonstrated in the case of

bromochromones1 and 6-bromo-7-hydroxychromones

2.

Iodination of phloroacetophenone derivatives was studied and optimized followed by their

transformation to iodinated chromones. These substrates were submitted to Heck reactions to

give the expected alkenes in moderate to good yields. The investigations were extended to

various iodinated 5,7-dimethoxy- and 5-hydroxy-7-methoxyflavones.

OH

O

MeO

OMe

MeO

OMe

O

O

R1

R2

R2O

OR2

O

O

MeO

OH

O

OI

Heck reactionMeO

OH

O

OHO

MeO

OMe

O

O

R1

R2

R3

IodinationHeck reaction

Iodination

Protecting

Claisen-Schmidtcondensation

Cyclization

R1 = H, OMe, OBn, R2 = H, OMe R3 = OCOOEt, C(CH3)2OH

R2 = H, OMe

Our results proved the synthetic value of this approach in the field of alkenylated

polyhydroxyflavones. Two natural products such as trans-tephrostachin and trans-

anhydrotephrostachin were synthetized. Studies on the deprotection and ring-closure of the

obtained products into tricyclic systems are in progress.

References

1. Patonay, T.; Vasas, A.; Kiss-Szikszai, A.; Silva, A.M.S.; Cavaleiro, J.A.S.: Austr. J. Chem.

2010, 63, 1592-1593

2. Vasas, A.; Patonay, T.; Kónya, K.; Silva, A.M.S.; Cavaleiro, J.A.S.: Austr. J. Chem. 2011,

64, 647-657

P22

SELECTIVE NITRILE-OXIDE DIPOLAR CYCLOADDITION TOWARD THE SYNTHESIS OF HIGHLY FUNCTIONALIZED -

AMINOCYCLOHEXANECARBOXYLATE STEREOISOMERS

Melinda Nonna, Loránd Kissa, Reijo Sillanpääc and Ferenc Fülöpa,b

aInstitute of Pharmaceutical Chemistry, bStereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary cDepartment of Chemistry, University of Jyväskylä, FIN-40351, Jyväskylä, Finland

Highly functionalized cyclic amino acids as important bioactive derivatives have been the focus of the organic and medicinal chemistry over the past ten years. The multifunctionalized cyclohexane amino acids such as the antibiotic oryzoxymycin [1], the antiviral agents tamiflu [2], zanamivir and 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) [3] are important derivatives with high pharmacological potential. Also their modified derivatives [4] exhibit strong antiviral, antifungal or antibacterial activities. The synthesis of highly functionalized β-aminocyclohexanecarboxylate regio- and stereiosomers from bicyclic β-lactam has been developed by regioselective iodolactonization, stereo- and regioselective nitril oxide cycloaddition followed by lactone and isoxazoline ring opening reactions.

CO2Et

NHBoc

CO2Et

NHBoc

HO

OH

HO

OH

BocHN

BocHN

CO2Et

NHBoc

HO

OH

BocHN

NH

O

CO2Et

NHBoc

HO

CO2Et

NHBoc

HO

CO2Et

NHBoc

HO

N O

N O

N O References [1] a) Kiss, L.; Fülöp, F. Synlett 2010, 1302. b) Kiss, L.; Forró, E.; Fülöp, F. Synthesis of carbocyclic β-amino acids. Amino Acids, Peptides and Proteins in Organic Chemistry. Vol. 1, Ed. A. B. Hughes, Wiley, Weinheim, 2009, 367. [2] a) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.; Hayashi, Y. Chem. Eur. J. 2010, 16, 12616. b) Zhu, S.; Yu, S.; Wang, Y.; Ma, D. Angew. Chem. Int. Ed. 2010, 49, 4656. [3] a) Wena, W-H.; Wang, S-Y.; Tsai, K-C.; Cheng, Y-S. E.; Yang, A-S.; Fang, J-M.; Wong, C-H. Bioorg. Med. Chem. 2010, 18, 4074. b) Xu, G.; Kiefel, M. J.; Wilson, J. C.; Andrew, P. W.; Oggioni, M. R.; Taylor, G.L. J. Am. Chem. Soc. 2011, 133, 1718. [4] a) Wen, W-H.; Wang, S-Y.; Tsai, K-C.; Cheng, Y-S. E.; Yang, A-S.; Fang, J-M.; Wong, C-H. Bioorg. Med. Chem. 2010, 18, 4074. b) Lu, W. J.; Chen, Y. L.; Ma, W. P.; Zhang, X. Y.; Luan, F.; Liu, M. C.; Chen, X. G.; Hu, Z. D. Eur. J. Med. Chem. 2008, 43, 569.

P23

SYNTHESIS AND TRANSFORMATIONS OF ALICYCLIC 2-AMINO- AND 2-HYDROXYSULFONIC ACIDS

Márta Palkó, and Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary

E-mail: palko@pharm.u-szeged.hu

2-Aminoalkanesulfonic acids, especially taurine and substituted taurines, are not only very important sulfur analogues of naturally occurring aminocarboxylic acids, but also one class of important naturally occurring amino acids, which have been found in many mammalian tissues and in marine algae, fish [1]. They play an important role in several essential biological processes, such as development of the central nervous system and the retina, calcium modulation, membrane stabilization, reproduction, and immunity [2]. As part of our program to synthesize structurally diverse β-amino acids our aim was to prepare alicyclic 2-aminosulfonic acid. Our present aim was also to examine the transformation of newly prepared taurine analgues, and to develop the synthesis of alicyclic 2-hydroxysulfonic acids.

SO3.DMF/ CH3CN

CF3SO3H NH

SO3H

NH2

SO3Ha: HCl, H2O/∆

b: MW

CH3O

1a: cyclopentene 1b: cyclohexene, 1c: cycloheptene, 1d: cyclooctene 1e: 1,3-cyclohexadiene, 1f: 1,4-cyclohexadiene, 1g: 1,5-cyclooctadiene 1h: norbornene, 1i: norbornadiene

1a-i

2

3

Na2SO3O

SO3H

OHn n

n = 1,2,3H2O

4-6 7-9

We now report some examples of a practical two-step conversion of cycloalkenes 1a-i into 2-aminocycloalkanesulfonic acids 3, based on the use of the commercially available, solid, and easily handled SO3/DMF complex [3]. A stoichiometric amount of trifluoromethanesulfonic acid was added to the aminosulfonation mixture (cycloalkene, SO3/DMF complex, acetonitrile) to accelerate the reaction and prevent the competitive formation of by-products. After deprotection of the N-acetyl-aminosulfonic acid 2, microwave irradiation in water or heating in aqueous HCl, resulted in the corresponding 2-aminocycloalkanesulfonic acids 3 in good yields. 2-Hydroxysulfonic acids 7-9 were synthesized by the ring opening of epoxides 4-6 with aqueous Na2SO3. Amino- and hydroxysulfonic acids are useful synthons providing possibilities for further transformations, which will also be discussed. References [1] Huxtablae, R. J: Physiol. Rev. 1992, 72, 101. [2] Schuller-Lewis G. B.; Park, E. FEMS Microbiol. Lett. 2003, 226, 195. [3] Cordero, F. M.; Cacciarini, M.; Machetti, F.; De Sarlo, F. Eur J Org. Chem. 2002, 1407.

P24

THE SYNTHESIS OF NOVEL CYCLIC NAPHTHOQUINONE

DERIVATIVES

Sibel SAHINLER AYLA, Cemil IBIS

University of Istanbul, Faculty of Engineering, Department of Chemistry, 34320, Avcilar,

Istanbul, TURKEY

E-mail: sibelsah@istanbul.edu.tr

1,4-naphthoquinone derivatives have been found to possess high biologic activity profile such

as antimycobacterial, anti-imflammatory, antiallergic and antimalarial. The incorporation of

sulfur atom in 1,4-naphthoquinone derivatives has led to antifungal, anticancer and antiviral

activities.[1]. Some of the sulfur containing 1,4-naphthoquinone derivatives have been

synthesized in literature before. [2-3] The aim of this study is the synthesis of the novel 1,4-

naphthoquinone derivatives containing sulfur atom and characterize them with spectral

methods.

The structures of novel compounds were characterized by using Micro analyses, 1H-NMR,

13C-NMR, FT IR, MS, UV-vis.

O

O

S

S

CO

O

C

O

O

O

O

S

S

S

O

OS

CH3

CH3

References

[1]. Tandon, V. K.; Singh, R. V.; Yadav, D. B. Bioorg. Med. Chem, Lett. 2004, 14, 2901

[2]. Sayil, C.; Ibis, C. Bull. Korean Chem. Soc. 2010, 31(5), 1233-1236.

[3]. Ibis, C.; Deniz, NG. Phosphorus, Sulfur Silicon and Relat. Elem., 2010, 185(11), 2324-

2332.

P25

SYNTHESIS OF MAYOTLIDE

Svetlana Savinaa,b

, Pau Ruiz-Sanchisa,d

, Gerardo Acostaa,b

,

Fernando Albericioa,b,c

and Mercedes Álvareza,b,d

aInstitute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain.

bCIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park,

Baldiri Reixac 10, 08028-Barcelona, Spain. cDepartment of Organic Chemistry,University of Barcelona, 08028-

Barcelona, Spain. dLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-

Barcelona, Spain

ssavina@pcb.ub.es, mercedes.alvarez@irbbarcelona.org

Mayotlide is a heterocyclic peptide isolated recently by PharmaMar from a sample of Spongia

sp with cytotoxyc activity in three human cancer cell lines (MDA-MB-231, A549, HT29) at

micromolar concentration. The first key feature present in its intriguing structure is the

tricyclic unit, 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylate (HPIC), formed by

internal cyclization of a Trp residue. The structure of this natural product was determined by

mass spectroscopic techniques, nuclear magnetic resonance, and degradation [1].

In the literature are described few natural products with related structures, whose members

exhibit numerous bioactivities, including antitumor, antimicrobial, antinematodal and

cytotoxicity. Notable members include the chetomin, chaetocochins A, B and C; all isolated

from the solid-state fermented rice culture of the fungus Chaetomium cochliodes [2].

Natural products with HPI or HPIC unit bound through C3a

to the N of a tryptamine or Trp.

An extra degree of complexity is shown in kapakahines C and D, which are macrocyclic

peptides formed through a bond between the N8 of an HPIC located at the N-terminal of the

linear structure and the C4a

of a -carboline unit, located close to the C-terminal [3]. Synthetic

approximations to this Trp-Trp system have been studied by several groups and only few total

synthesis of natural compounds with that feature have been described [4].

The synthetic results in the preparation of mayotlide will be presented.

References [1] Bhushan, R.; Brückner H. Aminoacids 2004, 27, 231.

[2] a) Waksman S.A., Bugie E., J. Bacteriol. 1944, 48, 527. b) Geiger W.B., Conn J.E., Waksman S.A., J.

Bacteriol. 1944, 48, 531. c) Geiger W.B., Arch. Biochem. 1949, 21, 125. d) Safe S., Taylor A., J. Chem. Soc.

Perkin Trans. 1 1972, 472. e) McInnes A.G., Taylor A., Walter J.A., J. Am. Chem. Soc. 1976, 98, 6741. f)

Kikuchi T., Kadota S., Nakamura K., Nishi A., Taga T., Kaji T., Osaki K., Tubaki K., Chem. Pharm. Bull. 1982,

30, 3846. g) Li G.-Y., Li B.-G., Yang T., Yan J.-F., Liu G.-Y., Zhang G.-L., J. Nat. Prod. 2006, 69, 1374. [3] Yeung B.K.S., Nakao Y., Kinnel R.B., Carney J.R., Yoshida W.Y., Scheuer P.J., Kelly-Borges M., J. Org.

Chem. 1996, 61, 7168.

[4] a) Matsuda, Y.; Kitajima, M.; Takayama, H., Org. Lett., 2008, 10, 125. b) Espejo, V. R.; Rainier, J. D., J.

Am. Chem. Soc., 2008, 130, 12894.

P26

TARGETED CONJUGATES OF PREDNISOLONE BASED ON α-

CYCLODEXTRIN-PEG-POLYPSEUDOROTAXANES

Miloš Sedlák, Eliška Bílková, and Aleš Imramovský

Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice , Czech Republic

E-mail: milos.sedlak@upce.cz

The reaction of α-amino-ω-methoxypoly(ethylene glycol) [M = 5 kDa] or star α-amino-poly(ethyleneglycol) [M = 20 kDa] with hemiesters of prednisolone dicarboxylic acids (succinic, glutaric, adipic, phthalic acid) has been used to prepare the corresponding conjugates. The synthesized conjugates form polypseudorotaxanes with α-cyclodextrins which were characterized by 2D NOESY NMR spectra, powder X-ray diffraction patterns and in one case also by STM microscopy. The rate of prednisolone release from the carrier can be controlled by three factors: character of the linker between the polymeric carrier and prednisolone, the molecular mass of PEG and complex formation with α-cyclodextrin [1].

Principle of release of prednisolone from polypseudorotaxanes. We also prepared and characterized pH-sensitive conjugates and their polypseudorotaxanes [2]. Another methods of achieving goal-directed anti-inflammatory drug action is based on the fact that a number of pathogen processes induce lowering of pH value (≈ 5). For the pH-sensitive bond between prednisolone and PEG-carboxylic acid hydrazide, we have selected imino group, which is stable at pH values 7.4–7.6. On the other hand, the bond should be very easily hydrolyzed at lowered pH value. The synthesized polypseudorotaxanes represent new promising transport systems intended for targeted release of prednisolone in transplanted liver a) [1] or in the inflammatory tissues b) [2].

The authors acknowledge the financial support from the MSM 002 162 7501 and GAČR P106/11/058. References [1] Bílková E., Sedlák M., Dvořák B.,Ventura K., Knotek P., Beneš L.: Org. Biomol. Chem. 2010, 8, 5423-5430. [2] Bílková E., Sedlák M., Chárová P., Knotek P., Beneš L.: Int. J. Pharm. DOI.

10.1016/j.ijpharm.2011.04.060

P27

SYNTHESIS AND SOME APPLICATIONS OF PHENACYLFURANS

Olga Serdyuka, Alexander Butinb, and Vladimir Abaevc

aDepartment of Chemistry, Southern Federal University, oserduke@mail.ru, Rostov-on-Don, 344090, Russian Federation

bKuban State Technological University, Krasnodar, 350072, Russian Federation cNorth-Ossetian State University, Vladikavkaz, 362025, Russian Federation

Recently we have shown that the reaction of xanthates 1 with 2-methylfuran under Fenton conditions leads to phenacylfurans 2 [1]. The transformation proceeds at very mild conditions and represents a new convenient method of the phenacylfuran synthesis.

R2

S

S

O

R3

OEtR1

O

H2O2

DMSOFeSO4

R2

O

R3

R1

O+

1 2 (24-65%)

(a) R1=H, R2=Br, R3=H(b) R1=H, R2=OMe, R3=H(c) R1=H, R2=NO2, R

3=H(d) R1=R2=OMe, R3=H(e) R1,R2=OCH2CH2O, R3=H(f) R1=H, R2=R3=Cl

The obtained phenacylfurans can be used as starting compounds for the preparation of new carbo- and heterocycles. Thus, stirring of the compounds 2 in the mixture of acetic acid/ hydrochloric acid gives isomeric cyclopentanone derivatives 3 and 4 in good yields [2].

R2

O

R1

O AcOH, HCl

R2

O

R1

O

O

O OMeO

MeO

O

O

O

O2d,e

r.t., 20h

3 (67%)

4 (62%)

Authors thank the program of the state supporting for young scientists (grant МК-2367.2011.3). Financial support was also provided by Russian Foundation of Basic Research (grant 10-03-00254-a). References [1] Abaev V.T., Bosikova K.V., Serdyuk O.V., Butin A.V.: Chem. Heterocyclic Comp., 2009, 45 (5), 611. [2] Serdyuk O.V., Abaev V.T., Butin A.V.: Chem. Heterocyclic Comp., 2011, (7), in press.

P28

Total synthesis of crispine A enantiomers through a Burkholderia cepacia lipase-catalysed kinetic resolution

László Schönsteina, Enikı Forróa and Ferenc Fülöpa

aInstitute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary

slaszlo@pharm.u-szeged.hu

The plant Carduus crispus has been used for a long time in Chinese folk medicine for the treatment of colds, stomach problems and rheumatism. 8,9-Bis(methyloxy)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (crispine A) [1] was isolated in 2002 by Zhao from this plant. In recent years extensive investigations have been carried out on the chemistry of tetrahydroisoquinoline alkaloids [2] in view of their potential pharmaceutical activity. We developed a new total synthesis of both enantiomers of the antitumour-active alkaloid crispine A. This alkaloid was synthesized through a Burkholderi cepacia lipase-catalysed acylation of the primary hydroxy group of N-Boc-protected 1-(3-hydroxypropyl)-6,7-bis(methyloxy)-1,2,3,4-tetrahydroisoquinoline [(±)-1] and enantioselective hydrolysis of the corresponding O-decanoate [(±)-2, R = (CH2)8Me] with a remote, four-atom distant stereogenic centre. High enantioselectivities were observed for S-selective O-acylation with vinyl decanoate in the presence of Et3N and Na2SO4 in t-BuOMe at 45 °C (E = 68), and for S-selective hydrolysis with H2O in t-BuOMe at 45 °C (E = 52).

(-)-1 or (+)-1

S

(± )-1: R = H

(± )-2: R = CO(CH2)8CH3

NBoc

MeO

MeO

OR

enzymaticacylationor hydrolysis

NBoc

MeO

MeO

OR(-)-crispine A

N

MeO

MeO or

(+)-crispine A

N

MeO

MeOR

The enzymatic resolutions performed in two steps, afforded the key alcohol and ester enantiomers with high enantiomeric excesses (ee ≥ 94%). Ester enantiomers (+)-2 and (-)-2 [R = (CH2)8Me] were hydrolysed to the corresponding alcohols (+)-1 and (-)-1 in K2CO3/MeOH without loss of enantiopurity. Ring-closure reactions of alcohol enantiomers (+)-1 and (-)-1 with thionyl chloride afforded the desired crispine A enantiomers (ee ≥ 95%).

References [1] Zhang Q., Tu G., Zhao Y., Cheng T. Tetrahedron, 2002, 58, 6795-6798. [2] Miyazaki M., Ando N., Sugai K., Seito Y., Fukuoka H., Kanemitsu T., Nagata K., Odanaka Y., Nakamura K. T., Itoh T. J. Org. Chem., 2011, 76, 534-542.

P29

SYNTHESIS AND CONFORMATIONAL ANALYSIS OF NEW NAPHTH[1,2-e][1,3]OXAZINO[3,4-c]QUINAZOLINE DERIVATIVES

István Szatmária, Renáta Csütörtökia, Andreas Kochb, Matthias Heydenreichb, Erich Kleinpeterb, and Ferenc Fülöpa

aInstitute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary,

E-mail: szatmari.istvan@pharm.u-szeged.hu bDepartment of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476

Potsdam (Golm), Germany

The Betti reaction is a convenient method for the preparation of α-aminobenzylnaphthol derivatives. In previous studies, the synthesis and conformational analysis of naphth[1,2-e] [1,3]oxazino[3,4-c][1,3]benzoxazine1 and 8-substituted 10,11-dihydro-8H,15bH-naphth [1,2-e][1,3]oxazino[4,3-a]isoquinoline2 derivatives have been achieved. Since quinazoline and quinazolinone derivatives exhibit a wide range of biological activities and in order to extend the series of naphthoxazino-fused heterocyclic ring systems our primary present aim was to synthesize naphthoxazinoquinazolines. A further aim was the conformational analysis of these polycyclic compounds by NMR spectroscopy and accompanying molecular modelling.

X = p-NO2; m-Cl; p-Cl; H; p-Me; p-OMe; p-NMe2

OH

NOH

NH

HN

OH

NH

HN

O

HN

NH2

O

HN

NH2

NH2CHO

X

XX

X

X XOH

NH2

NH2

O

N

HN R1

R2

OH

NH

HN O

R1 = H; =OR2 = H; Ph; =O

For the synthesis of the proposed naphthoxazinoquinazoline derivatives, the preparation of 1-(amino(2-aminophenyl)methyl)-2-naphthol as starting material was achieved by the reaction of 2-naphthol, 2-nitrobenzaldehyde and tert-butyl carbamate or benzyl carbamate, followed by reduction and/or removal of the protecting group. The aminonaphthol derivative thus obtained was converted in ring-closure reactions with formaldehyde, benzaldehyde and/or phosgene to the corresponding naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives. The conformational analysis of some derivatives by NMR spectroscopy and accompanying molecular modelling were also done.

References [1] Heydenreich M., Koch A., Klod S., Szatmári I., Fülöp F., Kleinpeter E. : Tetrahedron 2006, 62, 11081. [2] Heydenreich M., Koch A., Szatmári I., Fülöp F., Kleinpeter E. : Tetrahedron 2008, 64, 7378.

P30

Formation of aromatic amidoximes with hydoxilamine and scale-up in

microreactor

Attila Vörösa,b, Katalin Molnárb, Zoltán Baána, István Hermecza, Péter Mizseyb, Zoltán Fintaa

aSanofi-aventis/Chinoin R&D, 1045 Budapest, Tó u. 1-5. bBudapest University of Technology and Economics Department of Chemical and

Environmental Process Engineering, Hungary, 1111 Budapest, Budafoki út 8.

Application of microreactors is new trend in chemistry. Microreactors have several advantages compared to batch technology. Small volumes (few ml or µl) and high surface/volume ratio enable their safe application for highly toxic or explosive reactants and for dangerous reactions, too. Quick, and efficient optimization is a valuable advantage of a microreactor for process chemists in early development phase, while low amounts of materials are being used. Nowadays, more and more reactions are accomplished in microreactor in the fine-, and pharmaceutical industry [1, 2, 3].

Amidoximes are commonly used for synthesis of heterocycles in pharmaceutical chemistry, such as oxadiazoles. Amidoximes can be prepared from the corresponding nitriles in reaction with hydroxylamine. Hydroxylamine is considered as a toxic and a dangerous reagent, since even metal traces at ppm level can catalyze its decomposition [4]. Temperature of process has to be lower than decomposition temperature of hydroxylamine, and it can be higher through precise temperature control and high pressure in microreactor than in batch.

Batch mode preparation of this molecule was not robust and safe during development, therefore continuous mode synthesis of amidoximes was targeted as an alternative technology to reach the desired reproducibility and process safety. Replacing hydroxylamine hydrochloride 50% water solution of hydroxylamine was used in microreactor to ensure the homogeneity of the reaction mixture. During the formation of various aromatic amidoximes, microreactor and continuous process technologies were screened and applied to have considerable benefit on safety aspects of the process. References [1] Braune, S.; Poechlauer, P.; Reintjens, R.; Steinhofer, S.; Winter, M.; Lobet, O.; Guidat, R.; Woehl, P.; Guermeur, C.: Chimica Oggi 2009, 27(1), 26. [2] Schwalbe, T.; Kadzimirsz, D.; Jas, G.: QSAR Comb. Sci. 2005, 24, 758. [3] Bogdan, A. R.; Poe, S. L.; Kubis, D. C.; Broadwater, S. J.; McQuade, D. T.: Angew. Chem. Int. Ed. 2009, 48, 8547. [4] Iwata, Y., Koseki, H.: Journal of Hazardous Materials, 2003, 39.

P31