Synthesis of optically active diethyl (s)-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate Текст научной статьи по специальности «Химические науки»

AZ9RBAYCAN KIMYA JURNALI № 4 2017

27

UDC 547.852.2

SYNTHESIS OF OPTICALLY ACTIVE DIETHYL (S)-3-(HYDROXYMETHYL)-3,6-DIHYDROPYRIDAZINE-1,2-DICARBOXYLATE

F.N.Akhundova, M.J.Alves*, M.M.Qurbanova

Baku State University *Universidade do Minho

[email protected]

Received 02.11.2016

The optically active diethyl (S)-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate were synthesized based on asymmetric Diels-Alder reaction in the presence of (S)-BINOL chiral catalyst, the structure was approved by NMR, Mass, Infrared spectroscopies, and specific rotation was determined by AUTOPOL III polarimeter.

Keywords: Diels-Alder reaction, (S)-BINOL chiral catalyst, glycosidase, optical purity.

Introduction

Diels-Alder cycloaddition of 2,4-penta-dienol to diethyl azodicarboxylate (DEAD) leading to (±)-1-azafagomine [1]. 1-Azafagomine and its derivatives are very good as a- and P-glucosi-dase inhibitors [2]. Glycosidases and related enzymes are crucial in many biological processses. Potent and selective inhibitors of these enzymes are important, because they can be used to interfere with such processes. Thus, glycosidase inhibitors are potential agents against diabetes [3], cancer, AIDS [4], hepatitis, Gaucher's disease [5] and influenza. An important class of glycosidase inhibitors is made up of the hydroxylated piperidines and pyrrolidines that occur in plants and microorganism and have been dubbed the "sugarshaped alkaloids from plants". They are reversible competitive inhibitors of glycosidases. One example of these compounds is l-deoxynojirimycin [6], which closely resembles glucose: the ring oxygen has been exchanged for a nitrogen atom. Nowaday the field of azafagomine is a very exciting area of research because of biological activity.

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

13

and 13C NMR were run on a Bruker Avance III 400 spectrometers (measuring frequency: 1H

13

red spectra were recorded on a Bomem MB 104. Samples were run as oils as thin films. Mass spectra were recorded on a VG Autopsic Mass spectrometer.

Synthesis of 2,4-pentadienic acid (I). 1 L three neck flask equipped with an ice con-densator then pirimidine was added (84 ml) and putted under magnet stirrer bar. Then malonic acid (83.2 g) was added in small portion. During 30 min it was finished. After that acrolein was added for 30 min drop by drop by dropping funnel. The mixture stayed under magnet stirring bar till end of CO2 formation. The mixture transferred to an 1000 ml Erlenmeyer flask under stirring and ice was placed (400 ml) inside of flask and was carefully acidified with H2SO4 (52 ml). The mixture was extracted with DCM (5^100 ml) after combining the organic phase it was dried over Mg2SO4 and was filtrated and concentrated to give yellow solid.

Synthesis of 2,4-pentadienol (II). 250 ml necked bottom flask with magnet stir bar was placed in ice bath, 5.09 g 2,4-pentadienic acid was dissolved in dried THF (77 ml), then NEt3 8.9 ml was added, 5 ml ethylchloroformate was dissolved in 13 ml THF and placed in dropping funnel then was connected with 250 ml three bottom flask and left it to pour drop by drop after that left it to stir for 30 min (-5°^ -00)C. After 30 min reaction was stopped and filtrated under the vacuum then was washed thoroughly THF (3*50 ml) (solution a). 1 l three necked bottom flask was pla-

NMR=400 MHz, 13C NMR= 100.6 MHz), Infra- ced in ice bath (70C) 515 ml by H2O, 4.804 g

28 SYNTHESIS OF OPTICALLY ACTIVE DIETHYL (S)-3-(HYDROXYMETHYL)

NaBH4 were added and was stirred [temperature (15-17)0C]. Solution a was added drop by drop for 30 min, in meanwhile ice bath was removed then left it to stir for 3.5 h. In the next step after 3.5 h 1 L flask was placed nine bath 20 ml 37% HCl was added (under N balloon) with dropping funnel drop by drop. The mixture was extracted firstly with diethyl ether (200 ml+ 2^100 ml) organic layer was combined, washed with 10% NaOH (50 ml)+H2O (50 ml)+brine (50 ml), then MgSO4 was added and filtrated under the vacuum. Using Buchi-580 under 750C temperature diethyl ether and THF were distillated in order to obtain 2,4-pentadienol.

Synthesis of diethyl (S)-3-(hydroxylme-thyl)-3,6-dihydropyridazine-1,2-dicarboxylate (III). Solution a. To a solution of 2,4-pentadie-nol (0.1 g, 1.19 mmol) in dry toluene (6 ml) was added dimethylzinc (0.991 ml, 1.19 mmol) under magnetic stirring at the 00C for 5 min.

Solution b. To a solution of (S)-BINOL (0.340 g, 1.19 mmol) in dry toluene (6 ml) was added methyl magnesium bromide (0.849 ml, 1.19 mmol) under magnetic stirring at the 00C for 5 min. Then solution a was added to solution b and 10 ml toluene was added as well, then left it to stir for 5 min at 00C. After 5 min temperature was decreased -780C, DEAD (0.543 ml, 1.19 mmol) was added, then 10 ml toluene was added too after that left it the temperature to become room temperature. The reaction was stirred for 18 h. The reaction was quenched with saturated solution of NaHCO3 (1 ml), filtered through a pad

of celite, and the celite washed with EtOAc (3 x20 ml). The filtrates were combined and concentrated under reduced pressure giving a yellow oil. The crude oil was purified by "dry-flash" chromatography (silica, petroleum ether/diethyl ether). (S)-BINOL was recovered with petroleum ether and product with diethyl ether as a yellow oil.

Results and discussion

The synthesis of homochiral (-)-1-azafa-gomine was accomplished by Bols and cowor-kers through a synthetic sequence based on the Diels-Alder cycloaddition to 4-phenyl-1,2,4-tri-azole-3,5-dione (PTAD) to achiral dienes: 2,4-pentadienoic acid, methyl 2,4-pentadienoate and 2,4-pentadienol [1]. The racemic cycloadduct obtained from 2,4-pentadienol and PTAD. The racemic cycloadduct obtained from 2,4-pen-tadienol and PTAD then was resolved by lipase-mediated transesterification. 1-Azafagomine was then isolated in 37% overall yield from this intermediate [7, 8].

In this paper, we report a new synthesis of optically active cycloadduct (III) in the presence of chiral catalyst (S)-BINOL. We discovered that, instead of using PTAD it is better to use DEAD due to its lower price and yield for cycloadduct was obtained 73%.

Synthesis of optically active diethyl (S)-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-di-carboxylate can be represented below by the following scheme:

-CO2H O

U

V. H piridine 1) NEt3, Cl O ^ ,THF

Y + HO2C COH-►

O ^ 2) NaBH4 H2O

I '

HO

OH O

1) Me2Zn 00C

2) (S)-BINOL, MeMgBr, 00C 4

\з' O

к к

N 2 OEt

I

N1 .OEt

0 5

3) DEAD, -780C

II "II III

O III

Y

O

Synthesis of diethyl (S)-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate (III).

АЗЕРБАЙДЖАНСКИЙ ХИМИЧЕСКИЙ ЖУРНАЛ № 4 2017

F.N.AKHUNDOVA et al. 29

The spectral analysis of the (S)-3-(hydroxymethyl)-3,6-dihydropyndazine-1,2-dicarboxylat

Specific rotation [а]в2и = - 23.40 (concentration - 1.25% in CHCI3)

IR spectra (Vmax) 3483, 1707 cm-1

'H NMR 5H (400 MHz, CDCls) 1.23-1.30 (12H, m, 4CH3, A+B), 2.58 (1H, s, OH), 3.35 (1H, d.d, J =12.3, 9.5 Hz, H-3', A), 3.45 (1H, d.d, J= 12.0, 9.8 Hz, H-3', B), 3.56-3.69 (2H, m, 2H-3', A+B), 3.77 (1H, d.d, J= 13.5, 4.3 Hz, H-6, A), 3.91 (1H, s, H-6, B), 4.11-4.26 (8H, m, 4CH2, A+B), 4.30 (1H, t.d.d, J = 6.0, 3.9, 2.2 Hz, H-6, B), 4.34-4.44 (1H, m, H-6, A), 4.72 (2H, s, H-3, A+B), 5.66-5.88 (4H, m, H-4 + H-5, A+B) ppm

13C NMR, 5C (100 MHz, CDCls) 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-3', 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) calculated for CnH^NNaOs: 281.1108; found: 281.1109.

The presence of (S)-BINOL (1,1'-bi-2-naftol) as a chiral catalyst plays an important role synthesis of asymmetric cycloadduct. In the end of the reaction purification of (S)-BINOL by dry-flash chromatography gives a chance to use catalyst constantly without losing activity. Recycling method of catalyst brings economic and ecological benefits.

The structure of optically active diethyl (S)-3-(hydroxymethyl)-3,6-dihydropyridazine-1,2-dicarboxylate was proved by IR, 1H NMR, 13C NMR and HRMS (ESI). 1H NMR analysis showed a 1:1 mixture of rotamers, due to inversion of the nitrogen atoms lone pair within the six membered ring. 13C NMR also showed peak duplication.

References

1. Bols M., Hazell R.G., Thomsen I.B. 1-Azafago-mine: A Hydroxyhexahydropyridazine that Potently Inhibits Enzymatic Glycoside Cleavage // Chem. Eur. J. 1997. No 6. P. 940-947.

2. Lopez O.L., Bols M. Anomer-selective glycosidase inhibition of 2-N-alkylated 1-azafagomines // Chem. Bio. Chem. 2007. V. 8. Issue 6. P. 657-661.

3. Dwek R.A., Fellows L.E., Tyins A.S., Petursson S., Namgoong S.K., Ramsden N.G., Jacob G.S., Rade-nincher T.W. Aminosugar derivatives as potential anti-human immunodeficiency virus agents // Proceedings of the National Academy of Sciences USA. 1988. No 85. P. 9229-9233.

4. Jacob G.S., Scudder P., Butters T.D., Jones I., Tiemeiereds D.C., Chu C.K., Cutler H.G. Aminosugar attenuation of HIV infection, in Natural Products as Antiviral Agents. Plenum Press, New York. 1992. No 32. P. 137-151.

5. Alper J. Carbohydrate Chemistry // Sci. 2001. No 291. P. 2338.

6. Evans S.V., Fellows L.E., Arthur E. Bell Glucosi-dase and trehalase inhibition by 1,5-dideoxy-1,5-imino-D-mannitol, a cyclic amino alditol from Lon-chocarpus sericeus // Phytochemistry. 1983. No 22. P. 768 -770.

7. Alves M.J., Costa F., Duarte V., Fortes G., Martins A., Micaelo Nuno. Advances in the Synthesis of Ho-mochiral (-)-1-Azafagomine and (+)-5-epi-1-Aza-fagomine. 1-^-Phenyl Carboxamide Derivatives of both Enantiomers of 1-Azafagomine: Leads for the Synthesis of Active a-Glycosidase Inhibitors // J. Org. Chem. 2011. No 76. P. 9584-9592.

8. Fleet G.W.J., Nicholas S.J., Smith P.W., Evans S.V., Fellows L.E., Nash R.J. Regioselective hydration of alkynones by palladium catalysis // Tetrahedron Lett. 1985. No 26. P. 3127-3130.

OPTiKi AKTtV DiETiL (S)-3-(HiDROKSiMETiL)-3,6-DiHiDROPiRiDAZiN-1,2-

DiKARBOKSiLATIN SiNTEZi

F.N.Axundova, M.J.Alves, M.M.Qurbanova

Asimmetrik Dils-Alder reaksiyasi asasinda (S)-BINOL xiral katalizatoru i§tirakinda optiki aktiv dietil (S)-3-(hidroksimetil)-3,6-dihidropiridazin-1,2-dikarboksilat sintez olunmu§, qurulu§u kütla, lQ, NMR-spektroskopiya metod-lari ila tasdiq olunmu§ va alinan enantiomerin xüsusi dönma bucagi AUTOPOL III polyarimetrinda tayin edilmi§dir.

Agar sözlar: asimmetrik Dils-Alder reaksiyasi, (S)-BINOL xiral katalizatoru, qlukoksidaza, optiki tamizlik.

СИНТЕЗ ОПТИЧЕСКИ АКТИВНОГО ДИЕтЩ)-3-(ГИДРОКСИМЕТИЛ)-3,6-ДИГИДРОПИРИДАЗИН-1,2-ДИКАРБОКСИЛАТА

Ф,Н,Ахундова, М.Дж.Алвес, М.М.Курбанова

На основе асимметрической реакции Дильса-Альдера в присутствии хирального катализатора (S)-BINOL синтезировано оптически активное соединение диетил(8)-3-(гадроксиметил)-3,6-дигидропиридазин-1,2-дикар-боксилат. Структура синтезированного энантиомера доказана методами ЯМР, масс-, инфракрасной спектроскопии. Определен также удельный угол вращения на поляриметре AUTOPOL III.

Ключевые слова: Асимметрическая реакция Дильсa-Альдерa, хиральный катализатор (S)-BINOL, глюкоксидаза, оптическая чистота.