Synthesis of new 2-aminocarbohydrate-1,4-naphthoquinone derivatives promoted by ultrasonic irradiation

Abstracts

In this report we describe the ultrasound-accelerated synthesis of new naphthoquinone derivatives 6a-f and 7a-c, which possess an aminocarbohydrate chain at the C-2 position of the quinone ring. This novel type of 1,4-naphthoquinone derivative has been synthesized under mild conditions by the reaction of 1,4-naphthoquinone (8a) or methoxylapachol (8b) with different aminocarbohydrates 9a-d. Characterization of all substances was confirmed by one- and two-dimensional nuclear magnetic resonance (NMR) techniques (¹H, 13C-APT, cosy-¹H vs. ¹H and HETCOR ¹J CH) and by high-resolution electrospray ionization mass spectrometry (HR ESI MS).

naphthoquinones; aminocarbohydrates; sonochemistry

Neste trabalho nós descrevemos o uso do ultrassom na síntese de novas naftoquinonas, 6a-f e 7a-c, contendo na posição 2 do anel quinonoídico substituintes do tipo aminocarboidratos. Estas substâncias foram preparadas, em condições brandas, através da reação da 1,4-naftoquinona (8a) ou do metoxi-lapachol (8b) com diferentes aminocarboidratos 9a-d. As estruturas das substâncias foram confirmadas através das técnicas de RMN de ¹H e de 13C-APT, uni- e bi-dimensionais (COSY-¹H vs. ¹H e HETCOR ¹J CH), e por espectrometria de massas de alta resolução com ionização por electrospray (ESI MS).

SHORT REPORT

Synthesis of new 2-aminocarbohydrate-1,4-naphthoquinone derivatives promoted by ultrasonic irradiation

Caroline F. J. Franco^I; Alessandro K. Jordão^I; Vitor F. Ferreira^I; Angelo C. Pinto^III; Maria C. B. V. de Souza^I; Jackson A. L. C. Resende^II; Anna C. CunhaI, ^*

^IDepartamento de Química Orgânica, Instituto de Química

^IIDepartamento de Química Inorgânica, Laboratório Regional de Difração de Raios X (LDRX), Outeiro de São João Batista, Universidade Federal Fluminense, 24020-141 Niterói-RJ, Brazil

^IIIDepartamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21941-590 Rio de Janeiro-RJ, Brazil

ABSTRACT

In this report we describe the ultrasound-accelerated synthesis of new naphthoquinone derivatives 6a-f and 7a-c, which possess an aminocarbohydrate chain at the C-2 position of the quinone ring. This novel type of 1,4-naphthoquinone derivative has been synthesized under mild conditions by the reaction of 1,4-naphthoquinone (8a) or methoxylapachol (8b) with different aminocarbohydrates 9a-d. Characterization of all substances was confirmed by one- and two-dimensional nuclear magnetic resonance (NMR) techniques (¹H, ¹³C-APT, cosy-¹H vs. ¹H and HETCOR ¹J_CH) and by high-resolution electrospray ionization mass spectrometry (HR ESI MS).

Keywords: naphthoquinones, aminocarbohydrates, sonochemistry

RESUMO

Neste trabalho nós descrevemos o uso do ultrassom na síntese de novas naftoquinonas, 6a-f e 7a-c, contendo na posição 2 do anel quinonoídico substituintes do tipo aminocarboidratos. Estas substâncias foram preparadas, em condições brandas, através da reação da 1,4-naftoquinona (8a) ou do metoxi-lapachol (8b) com diferentes aminocarboidratos 9a-d. As estruturas das substâncias foram confirmadas através das técnicas de RMN de ¹H e de ¹³C-APT, uni- e bi-dimensionais (COSY-¹H vs. ¹H e HETCOR ¹J_CH), e por espectrometria de massas de alta resolução com ionização por electrospray (ESI MS).

Introduction

The naphthoquinones are important natural substances that are widely distributed in different families of plants, fungi and some animals;¹ many of them play integral roles in vital biochemical processes. For example, vitamins K₁ and K₂ are natural naphthoquinones that are responsible for the human blood coagulation mechanism.² Due to this involvement in metabolism, this class of substances has been extensively studied concerning their various biological properties. Many of them have ceased to be mere curiosities and have become very useful drugs for mankind.³

Recent reports in the literature^2,4-8 point out that their mechanisms of action normally involve the generation of active oxygen species (e.g., superoxide radical anions, hydrogen peroxide and hydroxyl radicals) by redox cycling, intercalation in the DNA double helix or alkylation of biomolecules. In all of these cases, the biological activity requires bioreduction of the quinone nucleus as the first activating step.^6,8 As the bioreduction of the quinones is influenced by their redox properties, the electron-accepting capacity of these compounds can be modified by adding electron-attracting or donating substituents to the quinone system.^4,5,9-12 The introduction of vicinal oxidizable groups, such as amino substituents, onto the quinone nucleus can exert influence on its redox properties, inducing oxidative stress in cells, and alkylation of cellular macromolecules, including lipids, proteins and DNA.^2,4 Indeed, the literature to date clearly shows that aminoquinone frameworks are present in several important bioactive compounds that exhibit antitumor³1, antimalarial¹³2, antithrombotic¹⁴3, antifungal⁹4 and molluscicidal¹⁵ activities 5 (Figure 1).

Several methods for the conversion of quinones into their amino derivatives have been reported in the literature: a) reduction of nitroso-quinone compounds¹⁶ with sodium dithionate; b) reaction of hydrazoic acid with quinones,^17,18 c) nucleophilic substitution reactions of 2-methoxy-quinone^{4,10,15,19,20} or halo-derivatives^21-23 with amines; d) direct 1,4-type addition of amines to the quinones with²⁴ or without^25,26 Lewis acid catalysis (e.g., CeCl₃.H₂O); e) Lewis acid catalyzed addition (e.g., CeCl₃, CAN, FeCl₃ and I₂) under ultrasonic irradiation;²⁷ f) nuclear amination of p-hydroquinones with primary aromatic amines catalyzed by fungal laccases;²⁸ and g) Michael-type addition of 2,3-dichloronaphthoquinone with potassium cyanate.²⁹

Sugar-containing quinones^30,31 (O-glycoside derivatives) or N-heterocyclic moiety³² have been found in many compounds possessing significant antitumor activity.

Although these methods previously described have been used for the synthesis of aminoquinones, there is a lack of synthetic studies for the preparation of sugar-aminonaphthoquinones. Additionally, the development of a versatile method for their preparation in mild conditions is of great importance since it is possible that these new substances can constitute a new class of bioactive naphthoquinone derivatives.

As part of an ongoing research program on the synthesis of new biologically active naphthoquinones and on the basis of our experience in the field of the use of readily available carbohydrates^33,34 in organic reactions, herein we report the ultrasound-accelerated synthesis of new naphthoquinone derivatives 6a-d and 7a-c (Schemes 1 and 2) possessing an aminocarbohydrate chain at C-2 position of the quinone moiety.

Results and Discussion

Methyl 5-amino-5-deoxy-1,2-O-isopropylidene-β-D- ribofuranoside 9a, 6-amino-1,2:3,4-di-O-isopropylidene-α-D- galactopyranose 9b and 5-amino-5-deoxy-1,2-O-isopropylidene-α-D- xilofuranose 9c were prepared from their corresponding commercially reagents D-ribose, D-xylose and D-galactose by using known methods of carbohydrate protection and derivatization.^35-37 The ultrasound-accelerated 1,4-addition of aminocarbohydrates 9a-c to 1,4-naphthoquinone (8a) was first carried out in the presence of iodine at room temperature, following the procedure described in the literature²⁷ (Scheme 1, method A). The novel aminonaphthoquinones 6a-c were purified by flash column chromatography using 50% n-hexane/ethyl acetate as eluent. The yields of these reactions are listed in Table 1. The reaction of D-glucosamine hydrochloride 9d using method A failed to produce the compound 6d. Thus, the reaction under ultrasound irradiation was also investigated in the absence of iodine (Scheme 1, method B). This method led to better yields of the aminonaphthoquinones 6a-c, as shown in the Table 1. In this case, the 1,4-addition reaction between naphthoquinone 8a and D-glucosamine hydrochloride 9d resulted in the compound 6d, as a mixture of two diastereoisomers, α:β (1:1) in 40% yield. The treatment of this mixture with acetic anhydride in pyridine in excess produced the desired tetraacetate derivative in 60% yield as a mixture of anomers (3:1), being 6e the major isomer. The yields of the quinones 6a-d were dependent on the structure of the aminocarbohydrates 9a-d in question. The reactions worked very well with primary amines 9a-c, affording the corresponding coupling products in good yields, while more hindered amine, e.g., 9d, led to the product 6d in moderate yield.

The characterization of the aminonaphthoquinone structures 6a-c and 6e was performed by using one- and two-dimensional NMR techniques and by HR ESI MS. The preferential conformations of the carbohydrates were assigned based upon the proton coupling constants (J) of furan or pyran ring, and by chemical shift comparison with previous data reported in the literature for analogous carbohydrates.^38-41

The ¹H NMR spectrum of compound 6a showed the anomeric proton (H-1') as a singlet at δ 4.98. The protons H-2' and H-3' appeared as doublets at δ 4.59 (J_{H-2', H-3'} = 6.1 Hz) and δ 4.57 (J_{H-3', H-2'} = 6.1 Hz), respectively. The protons H-4' and H-5' were identified as multiplets at δ 4.41-4.45 and 3.16-3.29, respectively. The absence of vicinal coupling indicates a trans relationship between protons H-1' and H-2' and the β-anomeric configuration for the carbohydrate.⁴¹ The envelope conformations ºE and ⁴E for compounds 6a and 6c, respectively, were established on the basis of X-ray crystallographic data of 5-modified analogous of methyl 2,3-O-isopropylidene-β-ribofuranoside⁴² and 5-deoxy-1,2-O-isopropylidene-α-D-xylofuranose.⁴³

The twist-boat conformation of the D-galactose ring in 6b was confirmed by the 1H-1H vicinal coupling constants values J_H-1',H-2', J_H-2',H-3', J_H-3',H-4' and J_H-4',H-5' (5.0, 2.4, 8.0 and 1.5 Hz, respectively) of the ring protons.³⁸

The α:β ratio of D-glucosamine derivatives 6e and 6f was determined by the areas of the H-1' peaks of the respective anomers in the ¹H NMR spectra. The α-configuration at position C-1' of the major isomer 6e is supported by the small coupling constant between H-1' and H-2' (d, J_{H-1', H-2'} = 4.0 Hz). The structures of the two possible chair conformations (⁴C-1 and ¹C-4) of the α-pyranose form are shown in Figure 2. The large vicinal coupling constants for the protons ³J_{H-2', H-3'} and ³J_{H-3', H-4'} (10.0 and 9.5 Hz, respectively) are in agreement with trans-diaxial arrangements for the protons H2'-H3' and H3'-H4', suggesting a ⁴C-1 conformation for the pyran ring.

The use of 2-methoxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone (8b) (2-methoxylapachol ) in ultrasound-accelerated reaction (Scheme 2) with aminocarbohydrates 9a-c was also studied. The novel sugar-lapachol derivatives 7a-c were prepared in moderated yields by nucleophilic substitution reaction of 8b with amines 9a-c (Table 1).

For comparison purposes, the reactions of amine 9a with naphthoquinone 8a or methoxylapachol 8b were carried out under conventional heating. In both cases, no conversion into products was observed after a 2 h reaction, indicating that the ultrasound irradiation is essential for the activation and performing of these coupling reactions. The effects of sonication on reactions can be related to high temperature and pressure resulting from acoustic cavitation.⁴⁴

The structures proposed for compounds 7a, 7b and 7c are supported by their HR ESI MS and NMR spectroscopic data (¹H, APT, HETCOR ¹J_CH and ⁿJ_CH, n = 2,3).

Experimental

Chemical reagents and all solvents used in this study were purchased from Merck AG (Darmstadt, Germany) and VETEC LTDA. The synthesis of new aminonaphthoquinones 6a-d and 7a-c was performed in an ultrasonic bath (40 KHz) model USC 1400, ultrasonic cleaner, UNIQUE. Melting points were determined with a Fisher-Johns instrument and are uncorrected. Infrared (IR) spectra were recorded on Perkin-Elmer FT-IR model 1600 spectrophotometer, in KBr pellets. NMR spectra, unless otherwise stated, were obtained in deuterated CDCl₃ using a Varian Unity Plus 300 MHz spectrometer. Chemical shifts (δ) are expressed in ppm and the coupling constants (J) in Hertz. High-resolution electrospray ionization mass spectrometry (HR ESI MS) was performed in positive ion mode on a Waters-Micromass Q-Tof Micro instrument. The progress of all reactions was monitored by TLC performed on 2.0 cm × 6.0 cm aluminum sheets precoated with silica gel 60 (HF-254, E. Merck) to a thickness of 0.25 mm. The developed chromatograms were viewed under ultraviolet light at 254 nm. Merck silica gel (60-200 mesh) was used for column chromatography.

Synthesis

General procedure for the preparation of the novel aminonaphthoquinones 6a-d and 7a-c

A solution of naphthoquinone 8a or 8b (0.5 mmol) and aminocarbohydrate 9 (0.5 mmol) in methanol (MeOH) (2 mL) was sonicated for 2 h at r.t.. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (gradient elution, 10-30% AcOEt in hexane) to afford the desired compounds 6a-c and 7a-c.

2-(Methyl-5'-deoxy-2',3'-O-isopropylidene- β-D-ribofuranosid-5'-yl)-amino-1,4- naphthoquinone, 6a

The reaction between naphthoquinone 8a (158 mg, 1 mmol) and aminocarbohydrate 9a (101 mg, 0.5 mmol) yielded 6a (74 mg, 0.2 mmol, 73%) as a brown solid: mp 140-142 ºC; IR (KBr) ν_max/cm^-1 3244 (N-H); 1683 and 1601 (C=O), 1567 (C=C); ¹H NMR (300 MHz, CDCl₃) δ 1.25 (s, 3H, C(CH₃)₂), 1.42 (s, 3H, C(CH₃)₂), 3.16-3.29 (m, 2H, H-5' and H-5''), 3.34 (s, 3H, OCH₃), 4.41-4.45 (m, 1H, H-4'), 4.57 (d, 1H, J 6.1, H-3'), 4.59 (d, 1H, J 6.1 Hz, H-2'), 4.98 (s, 1H, H-1'), 5.67 (s, 1H, H-3), 6.40 (dd, 1H, J 4.4 Hz, N-H), 7.54 (td, J 7.5 and 1.5 Hz, H-7), 7.65 (td, J 7.5 and 1.5 Hz, H-6), 7.98 (dd, J 7.9 and 1.5 Hz, H-8 ), 8.03 (dd, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (75.0 MHz, DMSO-d₆) δ 24.8 [C(CH₃)₂], 26.3 [C(CH₃)₂], 45.3 (C-5' and C-5''), 55.3 (OCH₃), 82.1 (C-3'), 84.3 (C-4'), 85.2 (C-2'), 101.3 (C-3), 109.5 (C-1'), 112.7 [C(CH₃)₂], 126.1 (C-5), 126.2 (C-8), 130.4 (C-8a), 132.0 (C-7), 133.4 (C-4a), 134.6 (C-6), 148.0 (C-2), 182.9 (C-1), 198.9 (C-4); HRMS (ESI) [M⁺Na]⁺ Found: 382.1256. Calc. for C₁₉H₂₁NO₆Na: 382.1261.

2-(6'-Deoxy-1',2':3',4'-di-O-isopropylidene-D- galactopyranos-6'-yl)-amino-1,4- naphthoquinone, 6b

The reaction of naphthoquinone 8a (158 mg, 1 mmol) and aminocarbohydrate 9b (128 mg, 0.5 mmol) formed 6b (90 mg, 0.22 mmol, 70%) as a brown solid: mp 60-62 ºC; IR ν_max/cm^-1 1609 and 1678 (C=O), 1572 (C=C), 3379 (N-H); ¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (s, 3H, C(CH₃)₂), 1.42 (s, 3H, C(CH₃)₂), 1.45 (s, 3H, C(CH₃)₂), 1.52 (s, 3H, C(CH₃)₂), 3.40-3.51 (m, 2H, H-6' and H-6''), 4.01-4.10 (m, 1H, H-5'), 4.25 (dd, 1H, J 8.0 and 1.5 Hz, H-4'), 4.34 (dd, 1H, J 5.0 and 2.4 Hz, H-2'), 4.73 (dd, 1H, J 8.0 and 2.4 Hz, H-3'), 5.56 (d, 1H, J 5.0 Hz, H-1'), 5.80 (s, 1H, H-3), 7.58 (dd, 1H, J 6.2 Hz, N-H), 7.61 (td, 1H, J 7.5 and 1.5 Hz, H-7), 7.72 (td, 1H, J 7.5 and 1.5 Hz, H-6), 8.04 (dd, 1H, J 7.5 and 1.5 Hz, H-8), 8.10 (dd, 1H, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (75.0 MHz, DMSO-d₆) δ 24.5 [C(CH₃)₂], 25.0 [C(CH₃)₂], 25.9 [C(CH₃)₂], 26.2 [C(CH₃)₂], 42.5 (C-6' and C-6''), 64.7 (C-5'), 70.1 (C-2'), 70.5 (C-3'), 71.0 (C-4'), 95.9 (C-1'), 100.2 (C-3), 108.3 [C(CH₃)₂], 108.9 [C(CH₃)₂], 125.6 (C-5), 126.2 (C-8), 130.5 (C-8a), 132.6 (C-7), 133.2 (C-4a), 135.2 (C-6), 148.7 (C-2), 181.7 (C-1 or C-4), 181.8 (C-1 or C-4); HRMS (ESI) [M⁺Na]⁺ Found: 438.1541. Calc. for C₂₂H₂₅NO₇Na: 438.1523.

2-(5'-Deoxy-1',2'-O-isopropylidene-D-xylofuranos-5'-yl)-amino-1,4- naphthoquinone, 6c

The reaction of naphthoquinone 8a (158 mg, 1 mmol) and aminocarbohydrate 9c (95 mg, 0.5 mmol) led to formation of 6c (72 mg, 0.2 mmol, 75%) as a brown solid: mp 160-163 ºC; IR ν_max/cm^-1 1608 and 1679 (C=O), 1566 (C=C), 3390 (N-H); ¹H NMR (300 MHz, DMSO-d₆) δ 1.33 (s, 3H, C(CH₃)₂), 1.51 (s, 3H, C(CH₃)₂), 3.43-3.61 (m, 2H, H-5' and H-5''), 4.16 (dd, 1H, J 4.8 and 2.9 Hz, H-3'), 4.36-4.42 (m, 1H, H-4'), 4.56 (d, 1H, J 4.0 Hz, H-2'), 5.62 (d, 1 H, J 4.0 Hz, OH), 5.89 (s, 1H, H-3), 5.97 (d, 1 H, J 4.0 Hz, H-1'), 7.60 (dd, 1H, J 6.0 and 6.2 Hz, N-H), 7.85 (td, 1H, J 7.5 and 1.5 Hz, H-7), 7.95 (td, 1H, J 7.5 and 1.5 Hz, H-6), 8.06 (dd, 1H, J 7.5 and 1.5 Hz, H-8), 8.10 (dd, 1H, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (75.0 MHz, DMSO-d₆) δ 26.1 [C(CH₃)₂], 26.7 [C(CH₃)₂], 41.1 (C-5' and C-5"), 73.9 (C-3'), 77.8 (C-4'), 85.0 (C-2'), 99.7 (C-3), 104.4 (C-1'), 110.8 [C(CH₃)₂], 125.5 (C-5), 126.0 (C-8), 130.4 (C-8a), 132.4 (C-7), 133.0 (C-4a), 135.0 (C-6), 148.8 (C-2), 181.6 (C-1 or C-4), 181.7 (C-1 or C-4); HRMS (ESI) [M⁺Na]⁺ Found: 368.1112. Calc. for C₁₈H₁₉NO₆Na: 368.1104.

2-(Methyl-5''-deoxy-2'',3''-O-isopropylidene- β-D-ribofuranosid-5''-yl)-amino- 3-(3'-methyl-buten-2'-yl)-1,4- naphthoquinone, 7a

The reaction of naphthoquinone 8b (158 mg, 1 mmol) and aminocarbohydrate 9a (101 mg, 0.5 mmol) formed 7a (43 mg, 0.1 mmol, 20%) as a brown oil; IR ν_max/cm^-1 1670 and 1732 (C=O), 1600 (C=C), 3343 (N-H); ¹H NMR (500 MHz, DMSO-d₆) δ 1.35 (s, 3H, C(CH₃)₂), 1.48 (s, 3H, C(CH₃)₂), 1.75 (s, 3H, H-1'), 1.82 (s, 3H, H-5'), 3.35 (s, 3H, OCH₃), 3.37 (d, 1H, J 6.0 Hz, H-4'), 3.69-3.72 (m, 2H, H-5'' and H-5'''), 4.42 (dd, 1H, J 7.0 and 6.5 Hz, H-4''), 4.68 (d, 1H, J 6.0 Hz, H-3''), 4.86 (d, 1H, J 6.0 Hz, H-2''), 5.10 (s, 1H, H-1''), 5.14 (t, 1H, J 6.0 Hz, H-3'), 6.63 (dd, 1H, J 6.5 and 6.0 Hz, N-H), 7.83 (td, 1H, J 7.5 and 1.5 Hz, H-7), 7.91 (td, 1H, J 7.5 and 1.5 Hz, H-6), 8.04 (dd, 1H, J 7.5 and 1.5 Hz, H-8), 8.10 (dd, 1H, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (125.0 MHz, DMSO-d₆) δ 15.4 (C-5'), 20.3 (C-4'), 22.1 [C(CH₃)₂], 22.9 (C-1'), 23.7 [C(CH₃)₂], 44.6 (C-5''), 51.9 (OCH₃), 78.9 (C-2''), 82.1 (C-3''), 82.5 (C-4''), 106.4 (C-1''), 109.1 [C(CH₃)₂], 112.9 (C-3), 119.9 (C-3'), 123.0 (C-5) or (C-8), 123.2 (C-5) or (C-8), 127.7 (C-4a), 129.3 (C-8a), 130.0 (C-2'), 132.0 (C-6), 143.4 (C-2), 179.1 (C-4), 180.0 (C-1); HRMS (ESI) [M⁺Na]⁺ Found: 450.1915. Calc. for C₂₄H₂₉NO₆Na: 450.1818.

2-(6''-Deoxy-1'',2'':3'',4''-di-O-isopropylidene- D-galacto-pyranos-6''-yl)-amino-3-(3'-methyl-buten-2'-yl)-1,4- naphthoquinone, 7b

The reaction of naphthoquinone 8b (158 mg, 1 mmol) and aminocarbohydrate 9b (128 mg, 0.5 mmol) formed 7b (77 mg, 0.16 mmol, 32%) as brown oil; IR ν_max/cm^-1 1600 and 1668 (C=O), 1570 (C=C), 3347 (N-H); ¹H NMR (500 MHz, DMSO-d₆) δ 1.21 (s, 3H, C(CH₃)₂), 1.23 (s, 3H, C(CH₃)₂), 1.30 (s, 3H, C(CH₃)₂), 1.34 (s, 3H, C(CH₃)₂), 1.62 (H-1'), 1.69 (H-5'), 3.27 (dd, 1H, J 7.0 Hz, H-4'), 3.60 (dd, 1H, J 14.0 and 8.0 Hz, H-6''), 3.72 (dd, 1H, J 14.0 and 4.0 Hz, H-6'''), 3.84-3.85 (m, 1H, H-5"), 4.19 (dd, 1H, J 8.0 and 1.5 Hz, H-4''), 4.30 (dd, 1H, J 4.5 and 2.5 Hz, H-2''), 4.58 (dd, 1H, J 8.0 and 2.5 Hz, H-3''), 5.02-5.04 (m, 1H, H-3'), 5.42 (d, 1H, J 5.0 Hz, H-1''), 6.36 (dd, 1H, J 6.5 and 6.0 Hz, N-H), 7.69 (td, 1H, J 7.7 and 1.5 Hz, H-7), 7.77 (td, 1H, J 7.5 and 1.5 Hz, H-6), 7.90 (dd, 1H, J 7.8 and 1.5 Hz, H-8), 7.91 (dd, 1H, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (125.0 MHz, DMSO-d₆) δ 18.20 (C-5'), 23.0 (C-4'), 24.4 [C(CH₃)₂], 25.0 [C(CH₃)₂], 25.6 (C-1'), 25.8 [C(CH₃)₂], 26.1 [C(CH₃)₂], 44.9 (C-6'' and C-6'"), 66.9 (C-5''), 70.1 (C-2''), 70.5 (C-3''), 71.0 (C-4''), 95.9 (C-1''), 108.2 [C(CH₃)₂], 108.9 [C(CH₃)₂], 115.8 (C-3), 122.5 (C-3'), 125.6 (C-8), 125.9 (C-5), 130.6 (C-4a), 131.5 (C-8a), 132.7 (C-7), 134.7 (C-6), 146.9 (C-2), 181.8 (C-4), 182.8 (C-1).

2-(5'''-Deoxy-1''',2'''-O-isopropylidene-D-xylofuranos-5'''yl)-amino-3-(3'-methyl-buten-2'-yl)-1,4- naphtho-quinone, 7c

The reaction of naphthoquinone 8b (158 mg, 1 mmol) of aminocarbohydrate 9c (95 mg, 0.5 mmol) led to formation of 7c (74 mg, 0.18 mmol, 37%) as a brown oil; IR ν_max/cm^-1 1600 and 1670 (C=O), 1600 (C=C), 3343 (N-H), 3400-3500 (OH); ¹H NMR (500 MHz, DMSO-d₆) δ 1.33 (s, 3H, C(CH₃)₂), 1.47 (s, 3H, C(CH₃)₂), 1.75 (H-1'), 1.82 (H-5'), 3.38 (dd, 1H, J 15.5 and 6.0 Hz, H-4'), 3.43 (dd, 1H, J 15.5 and 6.5 Hz, H-4''), 3.82-3.90 (m, 2H, H-5''' and H-5''''), 4.11 (d, 1H, J 3.0 Hz, H-3'''), 4.31 (td, 1H, J 6.0 and 3.0 Hz, H-4'''), 4.54 (d, 1H, J 3.5 Hz, H-2'''), 5.13 (dd, 1H, J 6.5 and 6.0 Hz, H-3'), 5.58 (d, 1H, J 5.0 Hz, OH), 5.96 (d, 1H, J 3.5 Hz, H-1'''), 6.53 (dd, 1H, J 6.5 and 6.0 Hz, N-H), 7.81 (td, 1H, J 7.5 and 1.5 Hz, H-7), 7.90 (td, 1H, J 7.5 and 1.5 Hz, H-6), 8.04 (dd, 1H, J 7.5 and 1.5 Hz, H-8), 8.05 (dd, 1H, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (125.0 MHz, DMSO-d₆) δ 15.4 (C-5'), 20.3 (C-4'), 22.2 (C-1'), 22.9 [C(CH₃)₂], 23.7 [C(CH₃)₂], 43.2 (C-5''' and C-5''''), 78.9 (C-3'''), 82.1(C-4'''), 82.5 (C-2'''), 106.4 (C-1'''), 109.1 [C(CH₃)₂], 112.9 (C-4), 119.9 (C-3'), 123.0 (C-8), 123.2 (C-5), 129.3 (C-4a), 129.8 (C-7), 130.0 (C-8a), 132.1 (C-6), 143.4 (C-2), 181.9 (C-4), 183.0 (C-1); HRMS (ESI) [M⁺Na]⁺ Found: 436.1750. Calc. for C₂₃H₂₇NO₆Na: 436.1730.

2-(2'-Deoxy-D-glucopyranos-2'-yl)-amino-1,4- naphtho-quinone, 6d

The reaction of naphthoquinone 7a (316 mg, 2 mmol) and aminocarbohydrate 8d (384 mg, 1 mmol) led to formation of 2-(2'-deoxy-D-glucopyranos-2'-yl) amino-1,4-naphthoquinone 6d, as mixture of two diastereoisomers, α:β (1:1), in 40% yield.

2-(2'-Deoxy-1,3,4,6-tetra-O-acetyl-α-D-glucopyranos-2'-yl)-amino-1,4- naphthoquinone, 6e

Cold acetic anhydride (3.0 mL) was added to a stirred suspension of brown oil 6d (1,120 mg, 3.36 mmol) in anhydrous pyridine (5.4 mL) at 0 ºC. The mixture was stirred at this temperature until dissolution was complete; it was then kept at room temperature for 12 h. The solution was poured into cold water (15 mL) and cooled for 1 h. The resulting solid was separated by filtration, washed with water, and dried over phosphorous pentoxide. The product was chromatographed on a silica gel column, using 50% n-hexane/ethyl acetate as mixture eluent, giving a brown solid in 60% yield as a mixture of anomers (3:1), 6e being the predominant isomer. IR ν_max/cm^-1 1610 (C=O), 1677 (C=O), 1750 (C=O), 1576 (C=C), 1221 (C-O), 3365 (N-H); ¹H NMR (500 MHz, DMSO-d₆) δ 1.37 (s, 3H, CH₃C=O), 1.48 (s, 3H, CH₃C=O), 1.77 (s, 3H, CH₃C=O), 1.84 (s, 3H, CH₃C=O); 4.13-4.17 (m, 1H, H-5'), 4.26-4.30 (m, 1H, H-6' and H-6''), 4.33 (dd, 1H, J 12.5 and 4.0 Hz, H-6''), 4.52 (td, 1 H, J 10.0 and 3.5 Hz, H-2'), 5.29 (dd, 1 H, J 9.5 and 9.5 Hz, H-4'), 5.53 (dd, 1H, J 10.0 and 9.5 Hz, H-3'), 6.23 (d, 1H, J 4.0 Hz, H-1'), 6.33 (s, 1H, H-3), 6.56 (d, 1H, J 9.5 Hz, N-H), 7.87 (td, 1H, J 7.5 and 1.5 Hz, H-7), 7.96 (td, 1H, J 7.5 and 1.5 Hz, H-6), 8.06 (dd, 1H, J 7.5 and 1.5 Hz, H-8), 8.09 (dd, 1H, J 7.5 and 1.5 Hz, H-5); ¹³C NMR (125.0 MHz, DMSO-d₆) δ 20.0 (CH₃C=O), 20.5 (CH₃C=O), 20.6 (CH₃C=O), 20.7 (CH₃C=O), 52.7 (C-2'), 61.5 (C-6' and C-6"), 67.7 (C-4'), 69.4 (C-5'), 71.2 (C-3'), 89.1 (C-1'), 102.2 (C-3), 125.6 (C-8), 126.2 (C-5), 130.3 (C-8a), 132.7 (C-4a), 132.9 (C-7), 135.2 (C-6), 148.5 (C-2), 169.3 (CH₃C=O), 169.5 (CH₃C=O), 170.3 (CH₃C=O), 170.5 (CH₃C=O), 181.3 (C-1), 182.6 (C-4); HRMS (ESI) [M⁺Na]⁺ Found: 526.1317. Calcd for C₂₄H₂₅NO₁₁Na: 526.1319.

Conclusions

We have developed a method for the synthesis of new series of substituted-2-aminonaphthoquinones 6a-d and 7a-c by the reaction of 1,4-naphtoquinone (8a) or 2-methoxylapachol (8b) with different aminocarbohydrates 9a-d, under ultrasonic irradiation, which accelerate the 1,4-addition, in the absence of iodine (method B) being a faster and cleaner direct access for the synthesis of new sugar-based quinone compounds. Further efforts are being dedicated towards the evaluation of the biological profiles of this novel type of 1,4-naphthoquinone derivatives.

Acknowledgments

This work was supported by the Brazilian agency FAPERJ-PRONEX. Fellowship granted to UFF, by FAPERJ (E-26/171.512/2006) is gratefully acknowledged. We would like to thank the Universidade Federal do Rio de Janeiro, Departamento de Química Orgânica, LABEM - Laboratório Multiusuário de Espectrometria de Massas for the mass spectra.

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Submitted: March 3, 2010

Published online: August 24, 2010

Publication Dates

• Publication in this collection
  24 Jan 2011
• Date of issue
  Jan 2011

History

• Received
  03 Mar 2010