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CHEMICAL PROBLEMS 2018 № 2 (16) ISSN 2221-8688
UDC 547.852.2
SYNTHESIS OF 1 -AZAFAGOMINE BASED ON RASEMIC DIETHYL-3-(HYDROXYMETHYL)-3,6-DIHYDROPYRIDAZINE- 1,2-DICARBOXYLATE
F.A. Akhundova*, M.J. Alves**, E.Z. Huseynov,* M.M. Kurbanova*
*Baku State University1 Z.Khalilov 23 str., Baku, Azerbaijan **University of Minho, Campus deGualtar4710-057 Braga, Portugal E-mail: _fidan. axundova. 88@mail. ru
Received 21.03.2018
Rasemic diethyl-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate was synthesized following Diels-Alder reaction in the presence of achiral (2E)-penta-2,4-dien-1-ol and diethylazodicarboxylate. Dienophile 4-phenyl-1,2,4-triazole-3,5-dione (PTAD)) was substituted for diethylazodicarboxylate. Achiral (2E)-penta-2,4-dien-1-ol was obtained by repeating the literature procedure.Due to the two bulky groups in the diethyl-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate, the duplication of peaks in the 1H and 13C NMR spectrum was typical for some regions. C=C double bond of the diethyl-3-(hydroxymethyl)-3,6 dihydropyridazine-1,2-dicarboxylate was oxidized in the presence of OsO4 and N-methylmorpholineN-oxide. It revealed that diethyl-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate subjected tocis-dihydroxylated, not trans-dihydroxylated. Duplication of signals in the 1H and 13C IMR spectrums was observed in triol intermediate as well. Based on a modified Bols's protocol, 5-epi-1-azafagomine synthesized by cleavage of groups attached to six-membered ring nitrogen atoms. The target compounds were obtained in good yields. Structures of synthesized compounds approved by NMR, Mass, Infrared spectroscopies. Keywords: 1-Azafagomine, Diels-Alder reaction , azasugar, Bols protocol
INTRODUCTION
1-Azasugars are a series of synthetic nitrogen-containing sugar analogues consisting of a monosaccharide structure where the anomeric carbon was replaced by a nitrogen atom.The name 1-azasugar is used here rather than the name iminosugar in accordance with IUPAC nomenclature that recommends that carbohydrates in which the ring-oxygen was substituted with N be called iminosugars, and those where a carbon was substituted with N be called azasugars[1].
Interest in these compounds is based on the discovery that many of them are potent glycosidase inhibitors [2,3]. So far glycosidase inhibitors were investigated as antidiabetic, antiviral or antimetastatic agents, work which resulted in the antidiabetes drug acarbose[4] and the new antiinfluenza drug Zanamivir[5].
At present, the field of azafagomine is a very exciting area of research because of biological activity.
RESULTS AND DISCUSSION
The synthesis of homochiral 1- coworkers through a synthetic sequence based azafagomine was accomplished by Bols and on the Diels-Alder cycloaddition to 4-phenyl-
1,2,4-triazole-3,5-dione (PTAD) to achiral dienes: 2,4-pentadienoic acid, methyl 2,4-pentadienoate and 2,4-pentadienol [2]. In this article we report on new synthesis of 5-epi-1-azafagomine through the modification [6] of Bols protocol. 2,4-Pentadienol was obtained by
following the literature procedure [7]. Rasemic cycloadduct (I) was obtained in a good yield by a modification of this protocol, by changing the dienophile/diethyl- azodicarboxylate instead of 4-phenyl-1,2,4-triazole-3,5-dione (PTAD).
.OH
DEAD
HO
2,4-Pentadienol
HO
O
XOFt HO,/#
OFt NMO,OsO4 '
OFt -,
Y HO\^
I
O
U
N^OFt OFt
II
□ H6N2O
100„
0C
HO
HO'/„.
HO^'
NH
Nh
III
Synthesis of 5-epi-1-azafagomine (III).
1H NMR spectrum of compound (I) showed 1:1ofrotamers A and B. In some regions of the 1H NMR spectrum there is the duplication of peaks.13C NMR spectrum shows either broad peaks or duplication of signals for all carbons. These phenomena are probably related to the difficulty of nitrogen's inversion due to the two bulky groups attached thereto. It found that diethyl-3-(hydroxymethyl)-3,6-dihydro-pyridazine-1,2-dicarboxylate (I)cis-dihydro-xylated with OsO4 in good yield and total
selectivity, but not trans-dihydroxylated; in this case the selectivity dropped to zero. cis-Dihydroxylation of diethyl-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate (I) with OsO4 leads to triol (II). Duplication of signalswere observed for triol intermediate in13C and 1H NMR spectrum. Hydrazinolysis of the urethane group furnished 5-epi-1-azafagomine (III) in 81% yield.The structure of the obtained compounds was confirmed on the basis of IR, 1H NMR, 13C NMR and HRMS (ESI) spectra.
EXPERIMENTAL PART
Solvents were distilled under anhydrous conditions. All reagents were purchased and used without further purification. Glassware was dried prior to use. TLC plates (silica gel 60 F254) were visualized either at a UV lamp or in I2. 1H NMR and 13C NMR were run on a Bruker Avance III 400 spectrometers. (Measuring frequency: 1H NMR= 400 MHz, 13C NMR= 100.6 MHz) Infrared spectra were recorded on a Bomem MB 104. Samples were run as oils of thin films. Mass spectra were recorded on a VG Autopsic Mass spectrometer.
I. Diethyl-3-(hydroxymethyl)-3,6-dihydro-pyridazine-1,2-dicarboxylate
To a solution of 2,4-pentadienol 1.33 g (16.0 mmol) in dry toluene (10 ml) was added diethyldiazodicarboxylate 7.30 ml (40% in toluene, 16.0 mmol) under magnetic stirring at rt. The stirring was continued for 24 h and the solvent removed to give cycloadduct (I) as an orange oil (4.32 g; 99%).
II. cis-Dihydroxylationofdiethyl-3- (hydroxyl-methyl)-3,6-dihydropyridazine-1,2dicarboxylate
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SYNTHESIS OF 1 -AZAGOFAMINE BASED ON
Cycloadduct (I) 1.85 g (7.17 mmol) was dissolved in acetone (18.4 mL) and water (2.05 mL), N-methylmorpholineN-oxide (1.25 g; 9.30 mmol) was added followed by a solution of OsO4 in water (4%; 0.76 mL; 0.12 mmol). The mixture was stirred for 1 day at rt. The reaction was quenched by addition of 5% aqsoln Na2S2O3 (10 mL). The acetone was removed by evaporation and the residue redissolved in AcOEt, filtered through a pad of silica, washed
with AcOEt, and concentrated to give a yellow oil (II) ( 2.00 g; 96%).
III. Synthesis of 5-epi-1-azafagomine
Triol (II) (1.40 g; 4.80 mmol) was dissolved in hydrazine hydrate (82 mL) and heated at 100 0C for 18 h. The solution was concentrated and the crude product subjected to dry-flash chromatography in EtOH/NH4OH (25%) 99:1 giving pure (III) (0.57 g; 81%).
Table 1. Spectral analysis of I-III compounds
IR spectra (Vmax) (I) 3483, 1707 cm-1
1H NMRSh (400 MHz, CDCl3) (I) 1.23-1.30 (12H, m, 4CH3, A+B), 2.58 (1H, br s, OH), 3.35 (1H, dd, J 12.3, 9.5 Hz, H-30, A), 3.45 (1H, dd, J 12.0, 9.8 Hz, H-30, B), 3.56-3.69 (2H, m, 2H-3', A+B), 3.77 (1H, dd, J 13.5, 4.3 Hz, H-6, A), 3.91 (1H, br s, H-6, B), 4.11-4.26 (8H, m, 4CH2, A+B), 4.30 (1H, tdd, J 6.0, 3.9, 2.2 Hz, H-6, B), 4.34-4.44 (1H, m, H-6, A), 4.72 (2H, br s, H-3, A+B), 5.66-5.88 (4H, m, H-4+H-5, A+B) ppm.
13C NMRSc (100 MHz, CDCl3)(I) 14.3 (CH3, A), 14.4 (CH3, B), 42.2 (C-6, A), 43.6 (C-6, B), 55.9 (C-3, A), 56.9 (C-3, B), 61.9 (C-30, A+B), 62.6, 62.7, 62.8, 62.9 (CH2, A+B), 123.4, 124.2, 124,6, 125.2 (C-4 or C-5, A+B), 154.9, 155.7, 156.2, 156.3 (C=O, A+B) ppm.
HRMS (ESI) (I) Calculated : CnH1sN2NaO5, 281.1108; found: 281.1109.
IR spectra (Vmax) (II) 3419, 2983, 2937, 1698 cm-1
1HNMR Sh (400 MHz, CDCl3) (II) 1.23-1.32 (12H, m, 4CH3, A+B), 3.12 (1H, br d, J 10.8 Hz, H-6, A), 3.21 (1H, br d, J 10.8 Hz, H-6, B), 3.50 (2H, t, J 11.6 Hz, H-30, A), 3.62 (1H, d, J 8.0 Hz, H-30, B), 3.65-3.95 (4H, br s, H-4+H-5, A+B), 4.01 (2H, dd, J 13.2, 5.6 Hz, H-6, A), 4.10-4.25 (9H, m, H-6, B+4CH2, A+B), 4.52-4.64 (2H, br s, H-3, A+B) ppm.
13C NMRSc (100 MHz, CDCl3)(II) 14.3, 14.4 (CH3, A,B), 44.0, 45.7 (C-6, A,B), 58.4, 59.0 (C-3, A,B), 61.9, 62.8 (C-30, A,B), 63.0, 63.1 (2CH2, A or B), 63.2, 63.3 (2CH2, A or B), 64.0, 64.3 (C-4 or C-5, A,B), 66.4, 66.7 (C-4 or C-5, A,B), 155.2, 156.5 (C=O, A,B), 157.1, 157.3 (C=O, A,B) ppm.
HRMS (ESI) (II) Calculated: Cn^NNaOy 315.1163; found: 315.1163
1H NMRSh (300 MHz, D2O) (III) 3.00 (1H, d, J 14.4 Hz, H-6), 3.07 (1H, ddd, J 9.6, 6.4 e 3.2 Hz, H-3), 3.10 (1H, d, J 14.4 e 2.8 Hz, H-6), 3.64 (1H, dd, J 12.0 e 3.2 Hz, H-30), 3.67 (1H, d, J 6.4 Hz, H-4), 3.84 (1H, dd, J 12.0 e 2.8 Hz, H-30), 4.00 (1H, d, J 1.6 Hz, H-5) ppm.
1. McNaught A.D. carbohydrates. Pure &Appl. Chem. 1996, vol. 68, no.10. pp.1919-2008.
2. Bols M., Hazell R.G., Thomsen IB. 1-Azafagomine: A Hydroxyhexahydro-pyridazine That Potently Inhibits Enzymatic Glycoside Cleavage. Chem. Eur. J.1997, vol. 3, no.6. pp. 940-947.
3. Lopez O.L, Bols M. Anomer-Selective Glycosidase Inhibition by 2-#-Alkylated 1 -Azafagomines. ChemBioChem. 2007, vol. 8, no.1, pp. 657-661.
4. Truscheit E., Frommer W., Junge B., Müller L., Schmidt D. Chemistry and Biochemistry of Microbial a-Glucosidase Inhibitors. Angew. Chem. Int. Ed. Engl. 1981, vol. 20, no. 8, pp.744-761.
Willard Lew, Huiwei Wu, Dirk B. Mendel, Paul A.Escarpe, Xiaowu Chen, W. Graeme Laver, Bradford J. Graves, Choung U. Kim. A new series of C3-aza carbocyclic influenza neuraminidase inhibitors: synthesis and inhibitory activity. Bioorg. Med. Chem. Lett. 1998, vol. 8, no. 23, pp. 3321 -3324.
6. Gurbanova M.M., Huseynov E.Z., Rahimova F.A., Maharramov A.M. Application of a-amino acids as chiral organic catalysts in the asymmetric Hantzsch reaction. Kimya Problemleri -Chemical Problem. 2014, no. 2, pp. 210-213. (In Azerbaijan).
7. Jessup P.J. Petty, C.B. Roos, J. Overman, L.E. Adamantanone . [Tricyclo[3.3.1.13,7] decanone]. Organic Syntheses, Coll. 1988, vol. 6, p. 95.
REFERENCES
Nomenclature of 5.
DiETiL-3-(HiDROKSiMETiL)-3,6-DiHiDROPiRiDAZiN-1,2-DiKARBOKSiLAT dSASINDA 1-
AZAFAQOMiNiN SiNTEZi
F.N. Axundova*, M.J. Alves**, E.Z. Huseynov*, M.M. Qurbanova*
*Baki Dovldt Universiteti AZ1148 Baki, Z.Xdlilov kug., 23; e-mail: [email protected] **Minyu Universiteti, Braqa, Portuqaliya
Rasemik dietil-3-(hidroksimetil)-3,6-dihidropiridazin-1,2-dikarboksilat Dils-Alder reaksiyasi dsasinda axiral (2E)-penta-2,4-dien-1-ol vd dietilazodikarboksilat dsasinda sintez edilmi§dir. Axiral(2E)-penta-2,4-dien-1-ol dddbiyyata uygun olaraq sintez edilmi§dir. Dietil-3-(hidroksimetil)-3,6-dihidropiridazin-1,2-dikarboksilata birld§mi§ iki agir qrup sdbdbinddn 1H and 13C NMR spektrindd pikldrin ikild§mdsi mu§ahidd olunmu§dur. N-metilmorfolin N-oksid vd OsO4 i§tirakinda dietil-3-(hidroksimetil)-3,6-dihidropiridazin-1,2-dikarboksilat birld§mdsindd ikiqat rabitd C=C oksidld§dirilmi§dir. Bu zaman mudyydn edilmi§dir ki, OsO4 addukt ild trans deyil, cis-dihidroksilld§ir. 1H and 13C NMR spektrindd pikldrin ikild§mdsi triol intermediati ugun dd qeydd alinir.Modifikasiya olunmu§ Bols reaksiyasi dsasinda azota birld§mi§ qruplar kdnarla§dirilaraq 5-epi-1-azafaqomin sintez olunmu§dur. Sintez edilmi§ birld§mdldrin qurulu§lari kutld spektrometri, iQ vd NMR analiz metodlari ild tdsdiq olunmu§dur.
Agar sozldr: 1-azafaqomin,Dils-Alder reaksiyasi, dietilazodikarboksilat
190
8УЭТИЕ818 ОЕ 1-AZAFAGOMINE ВА8ЕБ ON
СИНТЕЗ 1-АЗАФАГОМИНА НА ОСНОВЕ ДИЕТИЛ-3-(ГИДРОКСИМЕТИЛ)-3,6-ДИГИДРОПИРИДАЗИН-1,2-ДИКАРБОКСИЛАТА
Ф.Н. Ахундова ', М.Дж. Алвес**, Э.З.Гусейнов*, М.М. Курбанова*
* Бакинский Государственный Университет **Университет Минью, Брага, Португалия
Рацемат диэтил-3-(гидроксиметил)-3,6-дигидропиридазин-1,2-дикарбоксилата был синтезирован по реакции Дильса-Альдера в присутствии ахирального (2Е)-пента-2,4-диен-1-ола и
диэтилазодикарбоксилата. Диенофил 4-фенил-1,2,4-триазол-3,5-дион (ФТАД) был заменен на диэтилазодикарбоксилат (ДЭАД)). Ахиральный (2Е)-пента-2,4-диен-1-ол был получен повторением литературной методики. Из-за наличия двух объемных групп в диэтил-3-(гидроксиметил)-3,6-дигидропиридазин-1,2-дикарбоксилате в некоторых областях 1Н и 13С ЯМР спектров наблюдалось удвоение пиков. Кратная С=С связь диэтил-3-(гидроксиметил)-3,6-дигидропиридазин-1,2-дикарбоксилата была окислена в присутствии OsO4 и Ы-метилморфолинЫ-оксида. Было установлено, что в присутствии OsO4 диэтил-3-(гидроксиметил)-3,6-дигидропиридазин-1,2-дикарбоксилат подвергся не транс, а цис-дигидроксилированию. Удвоение сигналов 1Н и 13С ЯМР спектров также наблюдалось и для триол интермедиата. Основанный на модифицированном протоколе Болса, 5-эпи-1-азафагомин был синтезирован отщеплением групп, которые присоединены к атому азота шестичленного цикла. Целевые продукты были получены в хороших выходах. Структуры синтезированных соединений были доказаны ЯМР, масс и ИК спектроскопиями. Ключевые слова: азафагомин,диэтилазодикарбоксилат, реакция Дильса-Альдера, ахиральный (2Е)-пента-2,4-диен-1 -ол
