First and short syntheses of biologically active, naturally occurring brominated mono-and dibenzyl phenols

First and short syntheses of biologically active, naturally occurring 3,4,6-tribromo-5-(2,3-dibromo-4,5-dihydroxybenzyl)benzene-1,2-diol 3 , 3,4,6-tribromo-5-(2,3,6-tribromo-4,5-dihydroxybenzyl)benzene-1,2-diol 4 and 3,4-dibromo-5-[3-bromo-2-(2,3-dibromo-4,5-dihydroxybenzyl)-4,5-dihydroxybenzyl]benzene-1,2-diol 5 from the red alga were carried out.


Results and Discussion
Bromophenols 3, 4 and 5 as biologically active natural products are highly brominated monoand dibenzyl phenols (Figure 1).One ring of 3 and two rings of 5 are dibrominated pyrocatechol derivatives while both rings of 4, a symmetric molecule, are tri-brominated pyrocatechol derivatives.One ring of 3 and 4 is a tri-brominated pyrocatechol derivative and these rings are the same.For the synthesis of these compounds, our method is based on the preparation of aromatic rings with Br, followed by their connection.For these purposes, acetylation of (3,4dimethoxyphenyl)methanol 6 with Ac 2 O 5,6 (acetic anhydride)/pyridine was performed to give 3,4-dimethoxybenzyl acetate 7 in in high yield.From this acetate 7, bromoalcohol 9 was synthesized via 8 (Scheme 1). 6On the other hand, tribromoveratrole 13 7 was also obtained via 10-12 (Scheme 1) for the preparation of the other ring of 4. Methyl protection of starting materials is necessary to prevent side reactions and purification-characterization difficulties.Therefore, phenolic reagents were methylated or purchased as methylated.Bromoalcohol 9 was reacted with both 13 to give 16, and 14 8 to give 15 in the PPA 9 (polyphosphoric acid) at 80°C (Scheme 2).Monobenzyl phenol derivatives 15 and 16 were obtained in high yields in their reactions as a sole product.According to their NMR data, 15 is unsymmetrical while 16 is symmetric.Protons of 15 resonate at 6.48, 4.49, 3.96, 3.93 and 3.89 ppm as singlet (s) with relative intensities of 1:2:3:6:3, while protons of 16 resonate at 4.91, 3.90 and 3.87 ppm with relative intensities of 1:3:3 as s.NMR data of 15 and 16 are consistent with the proposed structures.They are precursor compounds of natural products 3 and 4, respectively.
Their formations should be a sequential disubstitution to 18. Monosubstituted product(s) may provide information about these disubstituted isomeric products.To this end, reaction of 17 with 18 in equimolar (1:1) was performed, and a monosubstituted product was obtained from this reaction as the sole product.The presence of an AB system in the 1 H-NMR spectrum of this product shows that substitution may occur at C-4 or C-6 in 18.To be sure of the place of the monosubstitution in 18, bromination of 18 was performed and dibromoveratrole was obtained as the sole product.Dibromoveratrole should be 22 because other dibromides such as 14 do not give an AB-system in the aromatic region of their 1 H-NMR spectra.Therefore, the monosubstitution product should be 21.
Substitution at C-5 or C-6 atoms in 21 may give two isomeric products.They will be disubstituted isomeric products obtained from the reaction of 17 with 18.According to the NMR spectra of disubstituted isomeric products, it is not easy to establish their exact configurations.Therefore, the exact structure of one of them was determined by X-ray crystallographic analysis (Figure 2). 13This isomer is pentabromide 19 which is a precursor compound for the natural compound 5.The other disubstituted product should be 20.NMR data of 19-22 are also consistent with the proposed structures.
The molecular structure of the pentabromide 19 was successfully determined using singlecrystal X-ray diffraction analysis.The unit cell of pentabromide 19 comprises two centrosymmetric molecules (C 26 H 24 Br 5 O 6 ) which, however, in spite of the considerable structural similarity, are structurally inequivalent to each other (see Figure 2).Therefore, X-ray structure determination of pentabromide 19 revealed that the asymmetric unit contains two independent conformational isomers, which are (conformers in 3-D) due to rotations about σ-bonds (the different rotation of methoxy about the C phenyl -O2 and C phenyl -O2' bonds).Moreover, in both conformers edge phenyl rings are considerably folded on each other.(distance between C5/C10 and C15/C20 phenyl ring centroid is 3.777(6) Å; C5'/C10' and C15'/C20' ring centroid is 3.781(6) Å) (Figure 3).

Conclusions
The first and short synthesis of brominated natural products 3 and 4 from the red alga Symphyocladia latiuscula as monobenzylphenol derivatives and 5 from the red alga Rhodomela confervoides as dibenzylphenol derivative were carried out.

Experimental Section
General.All chemicals and solvents are commercially available and were used after distillation or treatment with drying agents.Melting points were determined on a capillary melting apparatus (Buchi530) and are uncorrected.IR spectra were obtained from solutions in 0. Synthesis of 3,4-dimethoxybenzylacetate (7).3,4-Dimethoxybenzyl alcohol (6) (10.0 g, 60 mmol) was allowed to react at room temperature for 1 day with pyridine (15 mL) and Ac 2 O (10 mL) by applying a known method. 5,6The reaction mixture was poured into dilute aqueous HCl (700 mL) with ice and checked with pH paper.It was extracted with CH 2 Cl 2 (2 × 50 mL), the extract was washed with cold NaOH (0.5 %, 100 mL) and water (200 mL), and dried over CaCl 2 .
The solvent was evaporated and the 3,4-dimethoxybenzylacetate (7) (11.97 g, 97%) was obtained as colourless liquid.(13). 7To a solution of 1,2dihydroxybenzene 10 (5.0 g, 45.4 mmol) in acetic acid (HOAc, 100 mL) bromine (58.0 g, 363.2 mmol, 8 equivalent) was added at room temperature.After the reaction mixture was heated and refluxed for 18 h, the solvent and excess bromine were removed.Tetrabromocatechol 11 was obtained in quantitative yield.To a mixture of glacial HOAc (15 ml), water (5 ml) and tetrabromocatechol 11 (5.0 g, 11.74 mmol) zinc dust were added and the mixture was refluxed for 4 minutes.The filtered liquid was precipitated in water as solid and then tribromocatechol 12 was crystallized from boiling water as thin needles (0.82 g, 20%).

X-Ray structure determination
For the crystal structure determination, the single crystal of the compound pentabromide 19 was used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-dimensional area IP detector).The graphite-monochromatized Mo K α radiation (λ=0.71073Å) and oscillation scans technique with ∆ω=5 o or one image were used for data collection.The lattice parameters were determined by the least-squares methods on the basis of all reflections with F 2 >2σ(F 2 ).Integration of the intensities, correction for Lorentz and polarization effects and cell refinement were performed using CrystalClear (Rigaku/MSC Inc., 2005) software. 13The structures were solved by direct methods using SHELXS-97 14 and refined by a full-matrix least-squares procedure using the program SHELXL-97. 14

Scheme 3 .
Scheme 3. Synthesis of biologically active natural product 5 and its derivative 23.

Figure 2 .
Figure 2. The molecular structure of pentabromide 19.The asymmetric unit contains half of the molecule.Displacement ellipsoids are shown at the 50% probability level.