AFM, SPM
CH 2 W 2 NaH, THF
E. Salamci 1 K. Ecer 1
M. Senturk2 esalamci@atauni.edu.tr
Cyclitol is a generic term used to describe polyhydroxycycloalkanes. Many biologically important molecules and natural products contain polyhydroxylated carbocycles [1,2].
Cyclooctanetetrols and aminocyclooctanetriol analogues form a class of polyhydroxylated cyclooctanoids. Several cyclitols have been used as sweeteners, antibiotics, antiviral, antidiabetes, and anticancer agents. Cyclooctanetetrol and derivatives are generally important intermediates in the synthesis of supramolecules and natural products. Diaminocyclooctandiols are core units in various bioactive compounds, e.g. aminoglycoside antibiotics and antiviral nucleosides [3,4].
O
R= OH, Cyclooctanetetrol
R= NH2, 3-Aminocyclooctanetriol
Epoxycyclooctane-3,4-diol R= Cl, 3-Chlorocyclooctanetriol
R HO
HO
HO
HO HO
The aim of this research is to develop new synthetic methodologies for cyclooctanetetrols and their derivatives. Starting from cis,cis-1,3-cyclooctadiene and cyclooctene epoxide, the corresponding endoperoxide and azido alcohol were synthesized. Then, these compounds would be used for the synthesis of various new cyclooctanetetrols and their derivatives such as two isomeric cyclooctanetetrols, 3-aminocyclooctanetriol, 3-chlorocyclooctanetriol and epoxycyclooctane-3,4- diol. All of the synthesized cyclitols exhibited strong enzyme-specific inhibition against α- glycosidase.
References:
1) Salamci, E., Tetrahedron, 2010, 66(23), 4010-4015.
2) (a) Gultekin, M. S., Celik, M., Balci, M. Curr. Org. Chem. 2004, 8, 1159-1186. (b) Salamci, E., Seçen, H., Sütbeyaz, Y., Balci, M., J. Org. Chem. 1997, 62, 2453-2457.
3) Grabowski, S., Armbruster, J., Prinzbach, H. Tetrahedron Let. 1997, 38, 5485-5488.
4) Gypser, A., Michel, D., Nirschi, D. S., Sharpless, K. B. J. J. Org. Chem. 1998, 63, 7322-7327.
Acknowledgment: The authors are indebted to TUBITAK (Scientific and Technological Research Council of Turkey) for their financial support of this work (Grant No: 110T208 and 106T647).
3. Advanced Methods of Organic Synthesis: Poster presentation P-78 REDUCTION OF 4,6,10-TRIHYDROXY-1,4,6,10- TETRAAZAADAMANTANES. FIRST SYNTHESIS OF
ISOMER OF UROTROPIN N.D. Zelinsky IOC RAS, Laboratory 42, Moskow, Russia A.N. Semakin
A.Yu. Sukhorukov S.L. Ioffe
V.A. Tartakovsky artyomsemakin@mail.ru
Azaadamantanes are supposed as perspective compounds for application in different areas such as medicinal chemistry and design of energetic compositions.
Recently we have discovered an unusual heterocyclotrimerization of oximino groups in tris(β-oximinoalkyl)amines leading to 4,6,10-trihydroxy-1,4,6,10-tetraazaadamantanes (Scheme 1). Since 1,4,6,10-tetraazaadamantanes are a novel type of heterocage compounds a detail investigation of their chemistry is reasonable.
Scheme 1
N
N N
R1 R3
HO N OH
OH
R2 N NN
N R3
R1 R2 HO OH
OH
2 MeOHAcOH
1 R4
R4
The present report deals with reduction of hydroxylamino groups in 4,6,10- trihydroxy-1,4,6,10-tetraazaadamantanes and their quaternary ammonium salts into secondary amino groups. A number of 4,6,10-NH adamantanes has been synthesized including isomer of urotropin – unsubstituted 1,4,6,10-tetraazaadamantane 4a (Scheme 2).
Scheme 2
N NN N R3
R1 R2 HO OH
OH
2
N NN N R3
R1 R2 HO OH
OH
3 R'
X
N NN N R3
R1 R2 H H
H
4
N NN N R3
R1 R2 H H
H
5 R'
X [ H ]
[ H ]
N NN N
H H
H
4a
References:
1. A. N. Semakin, A. Yu. Sukhorukov, A. V. Lesiv, S. L. Ioffe, K. A. Lyssenko, Yu. V. Nelyubina, V. A.
Tartakovsky Organic Letters 2009, 11(18), 4072.
We are grateful for the financial support from RFBR (grant 09-03- 00676-a).
3. Advanced Methods of Organic Synthesis: Poster presentation P-79 NEW PHOSPHORYLATED PHENOLS,
POLYPHENOLS, CONTAINING STERICALLY HINDERED FRAGMENTS
1 - A.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Laboratory of Organoelemental Synthesis, Kazan, Russia
2 - A.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Laboratory of Diffraction Research Methods, Kazan, Russia
3 - A.E. Arbuzov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Laboratory of Physical-Chemical Analysis, Kazan, Russia
T.R. Shaekhov1 E.M. Gibadullina1
D.B. Krivolapov2 J.K. Voronina2 D.R. Sharafutdinova3
A.R. Burilov1 shaekhov@iopc.ru
Important property of the polyphenolic compounds that define use in vivo and synthetic materials is high antioxidant activity and ability to form stable radicals. This property is most full shown in sterically hindered phenols many of which are used in industry for production of polymeric materials and also in synthesis of drugs. We developed methods of synthesis of a wide range phosphorylated polyphenolic compounds containing sterically hindered fragments with use dimethyl(diphenyl)(3,5-di-tert-butyl-4-oxocyclohexa- 2,5-dienylidene)-methylphosphonates.
O
PO R
R
OH
P O R
R
OH OH
HO
OH OH
P
P R
O R O
RR
OCH3 H3CO
OH OH
P
P R
O R O
R R
OH OH
P
P R
O R O
RR
OH HO
OH
HO OH
OCH3 H3CO
OH HO
H+
H+
H+ 1a,b
R = OCH3(a) ; OPh(b)
2a,b H+
5a,b
4a,b 3a,b
OH O
OH
HO R
R
R R
P OH O R
OH O
P
O P
P O
R O OH
O R R
O
OH OH
OH HO
OH
OH
OH HO
OH
OH
R1 R1
R1 R1
O
O P RR
H+ + 4
R1 = C2H5(c) ; C5H11(d) ; C7H15(e) 6 c-e 1a,b
7 c-e 6 h, reflux
R = OCH3(a) ; OPh(b)
The structure of synthesized compounds was proved by NMR 1H, 13С, IR spectroscopy, mass-spectrometry (MALDI) and element analysis.
Acknowledgement. This work was supported by the Russian Foundation for Basic Research (grant no. 11-03-00416-а), аnd as part of the Federal Program State contract № П837.
3. Advanced Methods of Organic Synthesis: Poster presentation P-80 N-CHLOROSULFONYLTRICHLOROACETIMIDOYL CHLORIDE: NOVEL CONVENIENT REAGENT FOR
HETEROCYCLIZATION
Institute of Organic Chemistry, NAS of Ukraine, Kyiv-94, Ukraine A.A. Shalimov
С.V. Lobanov P.P. Onysko
A.D. Sinitsa ashal@ukr.net
Synthetic approach for N-chlorosulfonyltrichloroacetimidoyl chloride (1) was developed and potentialities of this novel 1,3-CNS-bielectrophilic reagent in construction of biologically promising six- and seven-membered heterocyclic systems were disclosed.
It was shown that (1) reacts regioselectively with phenols, thiophenols or aromatic amines to give 4,2,1-benzoxathiazines, 1,2,4-benzodithiazines and 1,2,4-benzothiadiazines (3) (X= O, S, NR′), respectively. The reaction involves initial nucleophilic substitution of imidoyl chlorine atom followed by intramolecular Friedel-Krafts cyclization of intermediates (2).
Cl
CCl3 N
SO2Cl
X = O, S, NR', R' = H, Alk R= H, Alk, OAlk, Cl
X CCl3
S N
O O
R
Ar XH
R CH3
N SO2Cl
CCl3 Cl
R CH3
S N N
O O
CCl3 R R'
R= H, CH3 (1)
(2) (6)
R= H; R'= H, CH3, Pr-i R= CH3; R'= H, R=R'= CH3
PhCH(R)NHR'
AlCl3
CCl3 N
SO2Cl Ph N
R R' CCl3 N
SO2Cl X
Ar
AlCl3
(3) (4)
(5)
N R
CH3
(7) H+ Et3N
Et3N
CCl3
The reaction of (1) with benzylamines represents a novel convenient approach to difficultly accessible 1,2,4-benzothiadiazepines (5) by cyclization of amidines (4).
N-Chlorosulfonyltrichloroacetimidoyl chloride (1) reveals itself as reactive dienophile in the reactions with dienes. It was shown that [2+4] cycloaddition with substituted butadienes proceeds regiospecifically and leads to tetrahydropyridines (6) which are readily transformed into 2-trichloromethylpyridines (7) under acidic conditions.
The structure of heterocycles synthesized was confirmed by 1Н, 13С NMR, IR spectra and X-ray analysis.
3. Advanced Methods of Organic Synthesis: Poster presentation P-81 SYNTHESIS OF 4-HYDROXY-4-ALKYL-4,7-
DIHYDROTETRAZOLO[5,1-c][1,2,4]TRIAZINES AND THEIR TRANSFORMATIONS
Institute of Organic Synthesis UD RAS, Ekaterinburg, Russia E.V. Schegolkov
Ya.V. Burgart
V.I. Saloutin schegolkov@ios.uran.ru
The interaction of both non-fluorinated and polyfluoroalkyl-containing 1,3-dicarbonyl compounds 1 with tetrazolyldiazonium salts yields the stable 4-hydroxy-4- (polyfluoro)alkyl-1,4-dihydrotetrazolo[5,1-c][1,2,4]triazines 2. It is typical for azo coupling reactions of polyfluoroalkyl-containing 1,3-dicarbonyl compounds with hetaryldiazonium salts having the NH group in their α-position,1-3 while such reactions of non-fluorinated 1,3-dicarbonyl compounds are revealed for the first time.
O O
R1 R2
H
N N H
N N N
N
R1 O O
R2
H N
NH N
N N N
N N N
R1 O R2 N
H2 1) PPh3, AcOH, T
2) 25% NH4OH +
1 2, 55-75% 3, 44-58%
R1 = Me, AlkF; R2 = Alk, Ar, OAlk
We have failed to achieve the dehydration effect of the fluoroalkyl-containing heterocycles 2. However, we have found that the destruction of tetrazole ring occurs in boiling acetic acid in the presence of triphenylphosphine to result in the aromatized 3-amino-5-(polyfluoro)alkyl-6-acyl(benzoyl)-1,2,4-triazines 3.
References:
1. Shchegol’kov, E.V.; Sadchikova, E.V.; Burgart, Ya.V.; Saloutin, V.I. Russ. Chem. Bull., Int. Ed.
2008, 57, 612.
2. Shchegol’kov, E.V.; Sadchikova, E.V.; Burgart, Ya.V.; Saloutin, V.I. Russ. J. Org. Chem. 2009, 45, 572.
3. Shchegol’kov, E.V.; Khudina, O.G.; Anikina, L.V.; Burgart, Ya.V.; Saloutin, V.I. Pharmaceut.
Chem. J. 2006, 40, 373.
This work was financed by the Russian Foundation for Basic Research (Project No. 09-03-00274a), the Ministry Education and Science of the Russian Federation (State Contract No. 02.740.11.260), the Project of the Program of UB RAS 09-P-3-2001, and the State Program for Support of Leading Scientific School (No. 65261.2010.3).
3. Advanced Methods of Organic Synthesis: Poster presentation P-82 SYNTHESIS AND CHEMICAL TRANSFORMATION
OF DERIVATIVES 2(3)-THIENYLIMINO-2(3)Н- FURAN-3(2)-ONES
Perm State University, Natural and Biological Active Compounds, Perm, Russia
S.A. Shipilovskikh A.O. Panchenko
A.E. Rubtsov Shipilovskikh@psu.ru
2(3)-Imino-2(3)Н-furan-3(2)-ones are a class of highly reactive compounds, on the basis of which it is possible to obtain various heterocyclic and acyclic compounds [1]. From literature it is known, that derivatives of 2-aminothiophenes have a large range of biological activity [2].
With this information we have great interest in synthesis of derivatives 2(3)-iminofuran-3(2)-ons with thiophene substituent. For this purpose we have synthesized compounds 2,4.
R2 R3
S NH2 R1
R2 R3
S N
R1
PPh3
S O
Ar1 O N
R3 R2
R1
O R2
R3 S
R1
N O
Ar2 Ar2
R2
R3 S
R1
N O
O H
O H
(MeO)2O
Ar1
OH
O O
O
H Ar1 O
O
O (MeO)2O
1
2
3
4
Ar1=Ph, 4-MeC6H4; 4-MeOC6H4; 4,2-(MeO)2C6H4; 4-BrC6H4; 4-ClC6H4; 4-EtOC6H4; 4-C5H5O;
4-FC6H4. R1=COOEt; CN.R2+R3=(CH2)4; (CH2)3; CH3, CH3; CH3, Ph; Ph, CH3; H, Ph; Ph,H; Ph, Ph; Ph, PhCH2.
References:
1. Sabnis, R. W. Sulfur Reports, 16 (1), 1-17 (1994).
2. Zalesov, V.V., Rubtsov, A.E. Chem. of Heterocyclic Compounds, 40(2), 133-153 (2004).
This study was performed under financial support by the Russian Foundation for Basic Research (project no. 11-03-00882)
3. Advanced Methods of Organic Synthesis: Poster presentation P-83 SYNTHESIS AND BIOLOGICAL EVALUATION OF
INDOLE-CONTAINING ALLOCOLCHICINOIDS 1 - N.I. Lobachevsky Nizhny Novgorod State University, Organic Chemistry Department, Nizhny Novgorod, Russia
2 - University of Cologne, Organic Chemistry Department, Cologne, Germany
3 - Children’s Hospital Cologne, Department of Paediatric Oncology, Cologne, Germany
N.S. Sitnikov1 J. Velder2 A. Prokop3 A.Yu. Fedorov1
H.-G. Schmalz2 nikolaj-sitnikov@ya.ru
(-)-Colchicine [1], the major alkaloid from Colchicum autumnale, is known for decades as an efficient antimitotic agent able to inhibit microtubule formation (tubulin polymerization) in living cells, thus causing mitosis arrest in the metaphase. While high toxicity has prevented its use as an antitumor agent, colchicine still represents an important lead structure for drug discovery [2]. Allocolchicine (1) [1] is a constitutional isomer of colchicine bearing a six membered aromatic C-ring instead of the tropolone moiety.
Allocolchicine itself as well as its analogues show promising biological activities similar to colchicines. Herein we report the synthesis of a series of novel allocolchicine analogs 2-4 containing 1-methyl-1H-indolyl fragment.
MeO MeO MeO
N
MeO MeO MeO
N
MeO MeO MeO
N
2 3 4
X X X
X = O; OH; N3; NHAc MeO
MeO MeO
NHAc
COOMe 1
(-)-(aR, 7S) Allocolchicine
The fused four-membered carbocyclic skeleton in compounds 2, 3 was constructed via Suzuki – Miyaura cross-coupling reaction and subsequent Friedel – Crafts annulation. In turn, Weinreb ketone synthesis and subsequent direct intramolecular C-H arylation reaction gave access to compounds of type 4.
OH O
MeO MeO
OMe OMe N
MeO MeO
Br
OMe O
N PinB
2 + 3 I
Br
+
N +
N O
MeO MeO
OMe I
O O
MeO MeO
OMe I
N
4
Preliminary biological screening of compounds 2, 3 on BJAB tumor cell line revealed high antimitotic and apoptose-inducing activity (nanomolar or subnanomolar concentration range) along with particularly low unspecific cytotoxicity as determined by LDH-release assay.
colchicine 2
(X = O) 3 (X = O)
2 (X = OH)
3 (X = OH)
2 (X = NHAc)
3 (X = NHAc)
IC50 [µM] 0.02 0.0025 < 0.001 0.03 0.008 0.08 0.03
AC50
[µM] 0.03 0.005 < 0.001 0.1 0.01 0.5 0.05
References:
[1] O. Boye, A. Brossi in The Alkaloids (Eds.: A. Brossi, J. A.Cordell), Academic Press, New York, 1992, 41, 125.
[2] G A. Dorlans, B.Gigant, R. B. G. Ravelli et al., Proc. Natl. Acad.Sci. USA, 2009, 106, 13775
Acknowledgements - this work was supported by Russian Foundation for Basic Research (09-03- 00647-а), German Academic Exchange Service (DAAD № A/08/79551), Council for grants under the President of Russia (МД-5606.2010.3).
3. Advanced Methods of Organic Synthesis: Poster presentation P-84 SYNTHESIS OF 5-FUNCTIONALIZED
4-TRIHALOMETHYL-1,2,3,4-TETRAHYDRO- PYRIMIDIN-2-ONES
Moscow State Academy of Fine Chemical Technology, Department of Organic Chemistry, Moscow, Russia
P.A. Solovyev A.A. Fesenko
A.D. Shutalev paulnighti@gmail.com
4-Trihalomethyl-1,2,3,4-tetrahydropyrimidin-2-ones are of great interest as potentially biologically active compounds and starting materials for the synthesis of various heterocycles. However no methods for the preparations of the above-mentioned compounds exist so far. In continuation of our studies on synthesis of hydrogenated nitrogen-containing heterocycles we report here a general approach to 4-trichloromethyl- and 4-trifluoromethyl- 1,2,3,4-tetrahydropyrimidin-2-ones.
N-[(1-Acetoxy-2,2,2-trihalo)ethyl]ureas 1 obtained in two steps from chloral hydrate or fluoral hydrate and urea were used as starting materials. Reaction of 1 with sodium enolates of β-oxoesters, 1,3-diketones or arylsulfonylketones 2 in MeCN or THF at room temperature gave the corresponding oxoalkylureas 3 in high yields.
HN NH O EWG
R1 Hal3C
N NH O EWG
R1
R1 EWG
O
HN NH O EWG
R1 Hal3C
OH HN NHR
O EWG
R1 Hal3C
NHR O HN
O OAc Hal3C
+ NaH
Base
TsOH
-H2O
Hal = Cl, F; EWG = COOEt, Ac, Bz, SO2Ph, Ts; R = H, Ac; R1= Me, Ph, CF3
1 2 3
4 5
6
(Hal = Cl)
Treatment of 3 (R = H) with TsOH in refluxing MeCN or EtOH led to heterocyclization of 3 into hydroxypyrimidines 4 followed by dehydration of the latter. As a result, target 4-trichloromethyl- and 4-trifluoromethyl-substituted pyrimidinones 5 were formed in good yields. These compounds can also be obtained by refluxing of 3 (R = Ac) in EtOH in the presence of TsOH.
We have shown that trichloromethyl-substituted pyrimidines 5 in the presence of bases (NaH, DBU) transform into previously hardly available 5-functionalized 1,2- dihydropyrimidin-2-ones 6 via elimination of chloroform.
3. Advanced Methods of Organic Synthesis: Poster presentation P-85 SYNTHESIS AND TRANSFORMATIONS OF HEXAAZAISOWURTZITANE DERIVATIVES Institute for Problems of Chemical and Energetic Technologies, Siberian Branch of the Russian Academy of Sciences (IPCET SB RAS)
S.V. Sysolyatin admin@ipcet.ru
The interest in 2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane (hexaazaisowurtzitane) derivatives, which were previously synthesized exclusively to obtain high-energy compounds [1], has been attracted by their unusual structure. These species are caged nitrogen heterocycles, which implies them to have biologically active properties. In vivo studies with mice have corroborated their biological activity and revealed their low toxicity (LD50 >1000 mg/kg), which allows hexaazaisowurtzitane derivatives to be classified as Toxicity Class III materials (slightly toxic) [2].
Hexaazaisowurtzitane derivatives are prepared by condensation of glyoxal with primary amines.
+
O O
H H N
H2 R
N
N N
N N
N R
R
R
R R
R
The use of amines with substituents at α-position as well as amides does not result in the formation of the isowurtzitane structure. When benzylamine is condensed with glyoxal, there is formed hexabenzylhexaazaisowurtzitane in 80% yield, which can readily be transformed into other derivatives:
N
N N
N N
N PhCH2
PhCH2
O RR O
O R
O R N
N N
N N
N PhCH2
PhCH2
CH2Ph CH2Ph
CH2Ph CH2Ph
H2, Pd/C
Ac2O, ДМФА, PhBr
N
N N
N N
N R'
R'
O RR O
O R
O R
Synthesis methods and transformations of different hexaazaisowurtzitane derivatives are considered.
References:
1. S.V. Sysolyatin, A.A. Lobanova, Yu.T. Chernikova, G.V. Sakovich, Synthesis methods and properties of hexanitrohexaazaisowurtzitane, Uspekhi khimii, 2005, Vol. 74, No. 8, pp. 830-838.
2. T.G. Tolstikova, E.A. Morozova, S.V. Sysolyatin, Yu.I. Zhukova, A.I. Kalashnikov, V.N. Surmachev, Synthesis and biological activity of 2,4,6,8,10,12-hexaazatetracyclo [5,5,0,03,11,05,9] dodecane derivatives, Chemistry for Sustainable Development, 2010, Vol. 18, No. 4, pp. 511-516.
3. Advanced Methods of Organic Synthesis: Poster presentation P-86 NEW THREE-COMPONENT REACTION OF ISOCYANIDES WITH THIOCARBAMATES AND
ISOTHIOCYANATES
Urals Federal University, Chemical Technology Department, Ekaterinburg, Russia