Synthesis of o -brominated diaryl ethers using symmetrical iodonium salts: application to the synthesis of Bastadin precursors

The coupling of o -brominated phenols with symmetrical iodonium salts for the construction of the corresponding diaryl ethers was studied. Bis-(2-benzyloxy-5-formyl-phenyl)-iodonium bromide 6b , only once mentioned in the literature, was fully characterized and tested for the synthesis of Bastadin related diaryl ethers.


Introduction
Diaryl ether is the common structural feature of many natural products with significant biological activity.Vancomycin is the most prominent example, since it is a very potent antibiotic and constitutes the last defense of science against the penicillin resistant Staphylococcus aureus. 1 Bastadins, a family of linear or macrocyclic bis-diaryl ether tetrapeptides possessing brominated aryl units and unique α-oximinino amide bonds, are yet another example. 2espite recent advances in the synthesis of diaryl ethers, 3 the efficient preparation of ohalogenated derivatives continues to constitute a synthetic challenge with which we were faced in the course of ongoing research towards the synthesis of Bastadins.We would like to report herein results related to our studies on the construction of the o-brominated diaryl ether moiety of these natural products, based on the coupling of phenols with triazenes or iodonium salts.

Results and Discussion
According to the first method, the triazene functionality of an appropriately substituted aryl can be used to facilitate its coupling to phenols. 4 Subsequent to diaryl ether formation, this directing group could be reductively or hydrolytically removed.
In order to investigate the utility of this method for the construction of diaryl ethers related to Bastadins, we opted to use as models triazenes of aniline, p-toluidine and its o-brominated analogs.These substrates were conveniently obtained from the corresponding diazonium salts by treatment with pyrrolidine (Scheme 1).Although their coupling with simple phenols proceeded in good yields (Scheme 2) subsequent hydrolysis of the triazene group proved to be problematic (Scheme 3).Although the non-halogenated triazenes were easily converted to the corresponding phenols under acidic conditions (Scheme 3; entries 1,2), substituted substrates required more vigorous conditions or failed all together to provide the desired products (Scheme 3; entries 3-6).Even the reported alternative indirect hydrolysis procedure, 5 through the intermediacy of the corresponding aryl iodides or bromides, was unsuccessful in our hands resulting mainly to competing reduction byproducts (Scheme 3, entries 7-9).Finally, we tested the conversion of triazenes to protected phenols, which also proved to be low yielding or totally unsuccessful (Scheme 3, entries 10-12).Scheme 4. Synthesis of diaryl ethers utilizing iodonium salts.
On the contrary, the iodonium salt method for the construction of diaryl ethers proved to be more fruitful. 6Coupling of the known symmetrical iodonium salt 6a (R 1 = Me) with obrominated phenols proceeds in good to fair yields (Scheme 4) and allowed us to develop an efficient and general synthetic strategy towards Bastadins.
Employing this strategy we were able to construct for the first time an unsymetrically brominated member of this class of natural products, Bastadin 12, albeit in fully protected form. 7ttempts to achieve its final deprotection failed, presumably due to the methyl ether protected phenol groups originating from the iodonium salt used.
Thus, we were forced to investigate alternatively protected iodonium salts.Although the most straightforward method for their construction requires cheap and either commercially available or easily prepared p-benzaldehyde derivatives, the conditions employed are harsh and seriously limit the repertoire of compatible protective groups for the phenol moiety.Thus, from the derivatives tested only the benzyloxy and o-nitrobenzyloxy p-benzaldehydes furnished the corresponding iodonium salts and only the former in synthetically useful yield (Scheme 5).
It is noteworthy that, although the benzyl-protected iodonium salt (6b) has been previously utilized, no detailed experimental procedure for its preparation has been reported. 8Considerable experimentation was required to optimize the reaction conditions and yields reported herein.Gratifyingly, coupling of this iodonium salt with phenols was equally effective as its methyl protected counterpart (Scheme 4, entries 4, 6, 8 -11).

Conclusions
In conclusion, the coupling of phenols with symmetrical iodonium salts provides an efficient method for the construction of densely functionalized diaryl ethers, even ortho-brominated ones.Indeed, elaboration of the diaryl ethers thus obtained to free Bastadin 12 has been successful and its total synthesis as well as that of other members of this family of natural products will be soon reported elsewhere.

Experimental Section
General Procedures.All reactions were carried out under a dry argon atmosphere with anhydrous, freshly distilled solvents under anhydrous conditions unless otherwise noted.All reactions were magnetically stirred with Teflon stir bars, and temperatures were measured externally.Reactions requiring anhydrous conditions were carried out in oven dried (120 °C, 24 h) or flame dried (vacuum < 0.5 Torr) glassware.Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous materials.All reagents were obtained from Aldrich Chemical Co. Inc. and used without further purification.All reactions were monitored by thin layer chromatography (TLC) carried out on 0.25-mm E.Merck silica gel plates (60F-254).E.Merck silica gel (60, particle size 0.040-0.063mm) was used for flash column chromatography.Infrared spectra (IR) were recorded on Nicolet, Magna FT-IR 550, mass spectra were recorded using a VG ZAB ZSE instrument, optical rotations were recorded using a Perkin-Elmer 241 polarimeter.Samples were analysed as neat films on sodium chloride plates.Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AM-250 instrument.Chemical shifts are measured in parts per million (δ) relative to the deuterated solvent used in the experiment.Multiplicities are designated as singlet (s), doublet (d), triplet (t), or multiplet (m).

3-[2-Bromo-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-4-methoxy-benzaldehyde (8e).
A stirred solution of the appropriate bromophenol (6.0 g, 21 mmol) in 115 mL DMF was cooled at 0 °C.Sodium hydride (550 mg, 23 mmol) was added in small portions followed by a catalytic amount of imidazole.The mixture was allowed to warm to ambient temperature and was stirred at this temperature for 30 min.Subsequently iodonium salt 6a 6a (11.0 g, 23 mmol) was added and the mixture was heated at 90 °C for 3 h.Upon completion of the reaction the mixture was partitioned between water and ethyl acetate.The organic layer was washed with water and brine, dried (MgSO 4 ), concentrated and purified by flash column chromatography (20% ethyl acetate in hexane) to give 6.7 g (76%) of diaryl ether 8e as white amorphous solid; ν max /cm

Bis-(2-benzyloxy-5-formyl-phenyl)-iodonium bromide (6b).
To a 250 mL round bottom flask equipped with an efficient mechanical stirrer were added successively KIO 3 (6.74g, 31.5 mmol), AcOH (10 mL) and Ac 2 O (15 mL).The reaction was placed in an ice bath and concentrated H 2 SO 4 (6.74 mL) was added dropwise.p-Benzyloxybenzaldehyde (20 g, 94.3 mmol) was dissolved with gentle heating and stirring in 30 mL AcOH.This solution was allowed to cool to ambient temperature and added dropwise to the reaction mixture.During the addition, when the aldehyde was crystallizing out of the added solution it was redissolved with gentle heating and stirring and the solution was allowed to cool to ambient temperature before resuming its addition to the reaction mixure.The vessel containing the aldehyde was washed with AcOH (10 mL) and the washings were added to the reaction mixture.The reaction mixture was protected from light and stirring was continued for 2 h at 0 °C and then for 24 h at ambient temperature.During the course of the reaction the initially formed thick light orange suspension turned to a dark brown solution.This solution was poured into a vigorously stirred solution of KBr (4.