C -Glycosylation of naphthols using glucosyl donors

Attempts to effect direct C -glycosylation of naphthols 6 , 7 , and 8 using glucosyl donors 9 and 10 were unsuccessful. O -Glycosides 11 , 12 and 15 were obtained under Mitsunobu conditions, however, these failed to undergo rearrangement to the C -glycosides 13 , 14 and 16, respectively. Successful C glycosylation of naphthols 7 and 8 was realized using the more reactive 2-deoxyglucosyl acetate donor 18 with trimethylsilyl triflate and silver perchlorate as the Lewis acid promoters. Use of acetonitrile as solvent formed the C -glycosides 20 and 22 in preference to the corresponding O -glycosides 19 and 21 , respectively.


Introduction
The pyranonaphthoquinone family of antibiotics have attracted considerable synthetic interest 1 due to their proposed ability to act as bioreductive alkylating agents via quinone methide intermediates.Our approach to the synthesis of several of the simpler members of the pyranonaphthoquinone antibiotics has focused on the addition of a silyloxyfuran to a naphthoquinone followed by oxidative rearrangement of the resultant furonaphthofuran adduct. 2 Recently our attention has been directed towards the synthesis of some of the more complex pyranonaphthoquinone antibiotics which contain C-glycoside moieties as typified by medermycin 1 3 and mederrhodin 2. 4 To date only one lengthy synthesis of medermycin 1 has been reported 5 in which the pyranonaphthalene skeleton was assembled by addition of a Cglycosyl-sulfonylphthalide to an enone.
Given the significant biological activity exhibited by Cglycosylpyranonaphthoquinone antibiotics such as medermycin 1, we embarked on a flexible synthetic programme that would provide access to a range of C-glycosidic pyranonaphthoquinones for biological evaluation.Our initial attention focused on the synthesis of a glucosyl analogue of medermycin 3 and a 2deoxyglucosyl analogue of medermycin 4 using a furofuran annulation -oxidative rearrangement strategy as previously used for the synthesis of kalafungin 5 and related aglycones. 6,7ilst the syntheses of aryl C-glycosides have been well documented, 8 the synthesis of Cglycosidic members of the pyranonaphthoquinone group of antibiotics has received little attention to date.Given that the naphthoquinone functionality is installed via oxidation of an oxygenated naphthalene precursor, a crucial step for the synthesis of glucosyl pyranonaphthoquinones 3 and 4 is a successful method to effect C-glycosylation of appropriate naphthol precursors.We therefore herein report our model studies on the C-glycosylation of naphthols 6,7 and 8 using glucosyl donors 9,10 and 2-deoxyglucosyl donors 17,18.

Discussion
Our initial task was to establish conditions for effecting C-glycosylation of naphthols 6,7 and 8. Pyranose 9 and glucosyl fluoride 10 were selected as the glucosyl donors as they are both readily available from D-glucose.Pyranose 9 was prepared from methyl-2,3,4,6-tetra-O-benzyl-α-Dglucopyranoside following the procedure of Glaudemans et al. 9 Pyranose 9 was then converted to glucosyl fluoride 10 using diethylaminosulfur trifluoride using the conditions reported by Posner and Haines 10 and later by Kovac et al. 11 The acetate protected 2-deoxypyranoside 18 was prepared by acetylation of 2deoxyglucose following the procedure reported by Overend et al. 12 affording glycosyl acetate 18 (α:β, 10:1) in 73% yield.Alternatively, the procedure of Mioskowski et al. 13 required treatment of tri-O-acetyl-D-glucal with triphenylphosphine hydrobromide and acetic acid, affording the desired acetate 18 (α:β, 9:1) in 72% yield.The benzyl protected 2-deoxypyranoside 17 was also prepared from tri-O-benzyl-D-glucal according to the procedure of Mioskowski et al. 13 affording glycosyl acetate 17 (α:β, 9:1) in 86% yield.Attempts to prepare 2-deoxyglucosyl fluorides met with little success due to their apparent instability. 14 common method to effect C-glycosylation involves initial formation of an O-glycoside followed by effecting rearrangement to a C-glycoside.Suzuki et al. 15 favour the use of anomeric fluorides as the glycosyl donors with hafnocene dichloride and silver perclorate as the promoters to effect the O-to C-glycoside rearrangement.A mixture of glucosyl fluoride 10, the appropriate naphthol 6, 7, or 8 and 4Å molecular sieves in dry dichloromethane was cooled to -78 °C.The Lewis acid (hafnocene dichloride) and promoter (silver perchlorate) were then added.The solution was allowed to warm to -20 °C and stirred for 1 hour, however, the desired C-glycosides 13, 14, 16 were not observed (Scheme 1).Longer reaction times did not result in the formation of the desired product, even when the reaction was allowed to warm to room temperature.Use of an alternative Lewis acid, zirconocene dichloride, was also unsuccessful.
Disappointed by the lack of success in effecting C-glycosylation using Suzuki's methodology, attention turned to use of a two step procedure reported by Kometani et al. 16 for effecting C-glycosylation.This methodology involves the formation of an O-glycoside under Mitsunobu conditions followed by rearrangement to a β-C-glycoside after activation by boron trifluoride diethyletherate.Accordingly, a solution of glucopyranose 9 and the appropriate naphthol 6, 7 or 8 in tetrahydrofuran at 0 °C was treated with diethyl azodicarboxylate and triphenylphospine to form the corresponding β-O-glycosides 11, 12, 15 in reasonable yields (Scheme 1).

Scheme 1
O-Glycoside 11 was obtained as colourless needles in 43% yield.In the 1 H nmr spectrum the anomeric proton 1'-H resonated as a doublet at δ 5.23 with the coupling constant, J1',2' 7.7 Hz, confirming the β-stereochemistry about the glycosidic bond.In the 13 C nmr spectrum C-1' resonated downfield of the other glycosyl carbons at δ 101.5 consistent with formation of β-Oglycoside 11.O-Glycoside 12 was isolated as tan platelets in 63% yield.In the 1 H nmr spectrum the anomeric proton, 1'-H, resonated as a doublet at δ 5.21, J1',2' 7.7 Hz and C-1' resonated at δ 101.6 in the 13 C nmr spectrum.
O-Glycoside 15 was obtained as colourless needles in 56% yield.In the 1 H nmr spectrum the anomeric proton 1'-H resonated as a doublet at δ 5.08, J1',2' 7.1 Hz and C1' resonated at δ 102.6 in the 13 C nmr spectrum.The synthesis of the O-glycoside 15 (α:β, 5:1) has recently been reported by Larsen and Andrews 17 with their data supporting the assignment of βstereochemistry at the glycosidic linkage for our compound.For comparison, in the α-anomer 1'-H resonated as a doublet at δ 5.62 with coupling constant, J 1',2' 3.5 Hz and C-1' resonated at δ 95.5 in the 13 C nmr spectrum. 17reatment of the O-glycosides 11, 12, 15 in dichloromethane at room temperature with boron trifluoride diethyl etherate failed to effect rearrangement to the desired C-glycosides 13, 14, 16.The glycosidic linkage was eventually cleaved instead, liberating the starting naphthols 6, 7, 8. Given the lack of success at forming C-glycosides of the simple naphthols 6, 7, 8 when using glycosyl donors derived from D-glucose, it was decided to investigate the use of more reactive 2deoxyglucosyl donors.It was felt that the bulky benzyloxy group at C2 might be preventing the O-to C-glycoside rearrangement from occurring.
Given the difficulties experienced with the preparation and storage of the unstable 1-fluoro derivatives of 2-deoxysugars, our attention turned to the use of the more stable 1-O-acetyl-2deoxyglucosyl donors 17 and 18. 2-Deoxyglucosyl acetates 17 and 18 were reacted with naphthols 6, 7 and 8 in dichloromethane using dicyclopentadienylhafnocenedichloride and silver perchlorate in the presence of 4Å molecular sieves (Scheme 2).In none of these reactions was Cglycoside formation observed.
It was next decided to investigate a different method for effecting C-glycosylation as reported by Toshima et al. 18 using trimethylsilyl triflate and silver perchlorate (1:1) as the Lewis acid promoters.Naphthols 7 and 8 were reacted with acetate protected 2deoxyglucosyl acetate 18 in dichloromethane at 0 °C using the trimethylsilyl triflatesilver perchlorate promoter system, the reaction then being warmed to room temperature over 1 h.For both naphthols 7 and 8 mixtures of the O-glycosides 19 and 21 and the desired β-C-glycosides 20 and 22 were obtained, even after prolonged stirring.
In contrast, using the more coordinating solvent, acetonitrile, β-C-glycosides 20 and 22 were formed exclusively, in yields of 82% and 97% respectively.A similar effect on changing the solvent to acetonitrile, when using boron trifluoride diethyletherate as the Lewis acid in analogous C-glycosylation reactions, has been reported by Larsen et al. 19 and by Allevi et al. 20 The α-O-glycoside 19 was isolated in 34% yield and β-C-glycoside 20 was isolated in 29% yield from the reaction of naphthol 7 with 2-deoxylglucosyl donor 18 using dichloromethane as solvent with trimethylsilyl triflate and silver perchlorate as the promoters.The infra-red spectrum for α-O-glycoside 19 lacked a hydroxyl stretch and high resolution mass spectrometry confirmed the molecular formula as C 23 H 26 O 9 .In the 1 H nmr spectrum the anomeric proton 1'-H resonated as a doublet at δ 5.85, with the coupling constant, J 1',2' 2.

Scheme 2
The α-O-glycoside 21 was isolated in 39% yield and the β-C-glycoside 22 in 31% yield from the reaction of naphthol 8 with 2-deoxyglucosyl acetate 18 using the trimethylsilyl triflate-silver perchlorate promoter system in dichloromethane.The anomeric proton 1'-H of the α-Oglycoside 21 resonated at δ 5.83 as a broad doublet, with the coupling constant, J 1',2' 2.6 Hz establishing the α-stereochemistry at the anomeric position.The anomeric carbon C-1' resonated at δ 95.3 in the the 13 C nmr spectrum also consistent with formation of the α-O-glycoside 21.
In the 1 H nmr spectrum of the β-C-glycoside 22, the anomeric proton 1'-H resonated at δ 5.62 as a doublet of doublets, with the coupling constants, J 1',2'ax 11.9 and J 1',2'eq 2. 1 Hz, allowing assignment of the β-stereochemistry of the C-glycoside bond.In the 13 C nmr spectrum, the anomeric carbon C-1' resonated at δ 76.6.During the course of this work compounds 21 and 22 were synthesized by Larsen et al. 19 and the spectroscopic data obtained in the present work agreed well with their data. 19n conclusion, it was found that use of the more reactive 2-deoxyglucosyl donors rather than glucosyl donors was necessary to effect successful C-glycosylation of naphthols 6, 7, and 8.The best conditions found for the C-glycosylation involved the use of trimethylsilyl triflate and silver perchlorate as the Lewis Acid promoters using acetonitrile as solvent.Having established an effective method for C-glycosylation of these model naphthols with 2-deoxyglycosyl donors, our attention can then focus on extension of this C-glycosylation to the use of a naphthol that has appropriate functionality for further elaboration to analogues of the Cglycosylpyranonaphthoquinone antibiotic medermycin 1.

Experimental Section
General Procedures.Petroleum ether refers to the fraction with bp 40-60 o C and was redistilled before use.Dichloromethane and acetonitrile were distilled from calcium hydride immediately before use.Flash column chromatography was performed on Merck silica gel 60 (230-400 mesh) using the eluent specified under medium pressure.All reagents were purchased from commercial suppliers and were used without further purification.Melting points are uncorrected.Optical rotations were measured using a PolAAR 2001 polarimeter in various solvents at the temperature and concentration (g.100 mL -1 ) indicated.Specific rotations are given in 10 - 1 deg.cm 2 .g - .Readings were taken using the 589.3 nm sodium line in a 0.5 dm cell.Infrared spectra were recorded using a Perkin Elmer 1600 Series FTIR spectrometer as a thin film on a single sodium chloride plate seated in the apparatus on a custom made perch. 1 H NMR spectra were recorded on a Bruker AC200B spectrometer (200.13MHz) or a Bruker AM400 (400.12MHz) spectrometer.Data is expressed as parts per million downfield shift from tetramethylsilane as an internal standard, and reported as a position (δH), relative integral, multiplicity (s = singlet, br.s = broad singlet, d = doublet, dd = double doublet, ddd = double double doublet, t = triplet, q = quartet or m = multiplet), coupling constant (J Hz) and assignment. 13C NMR spectra were recorded on a Bruker AC200 (50.3 MHz) spectrometer at ambient temperatures with complete decoupling and were interpreted with the aid of DEPT 135 and DEPT 90 experiments.Elemental analyses were carried out by Dr R. G. Cunninghame and associates at the Campbell Microanalytical Laboratory, University of Otago, Dunedin, New Zealand.Low resolution mas spectra were recorded on a VG70-250S, a VG70-SD or an AEI model MS902 double focusing magnetic sector mass spectrometer operating with an ionisation potential of 70eV (EI, CI).High resolution mass spectra were recorded at nominal resolution of 5000 or 10000 as appropriate.Major fragments are given as percentages relative to the base peak and are assigned where possible.Ionisation methods employed were (i) electron impact (EI), (ii) chemical ionisation with ammonia as reagent gas (CI), (iii) fast atom bombardment (FAB), (iv) liquid secondary ion mass spectrometry (LSIMS) using a 4nitrobenzylalcohol (NBA) matrix.) in dry tetrahydrofuran (10 mL) was added diethylaminosulfur trifluoride (DAST) (0.3 mL, 2.4 mmol).The mixture was allowed to warm to room temperature and after 30 min.the reaction had proceeded to completion.After cooling to -20 °C, methanol (1 mL) was added and the mixture concentrated at reduced pressure.