No abstract

Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug development. Alcohols and phenols are generally converted into the corresponding primary sulfamates (ROSO(2)NH(2) and ArOSO(2)NH(2), respectively) by reaction with sulfamoyl chloride (H(2)NSO(2)Cl). The lability of the O-sulfamate group, especially to basic conditions, usually restricts this method to a later stage of a synthesis. To enable a more flexible approach to the synthesis of phenolic O-sulfamates, a protecting group strategy for sulfamates has been developed. Both sulfamate NH protons were replaced with either 4-methoxybenzyl or 2,4-dimethoxybenzyl. These N-protected sulfamates were stable to oxidising and reducing agents, as well as bases and nucleophiles, thus rendering such masked sulfamates suitable for multi-step synthesis. The protected sulfamates were synthesised by microwave heating of 1,1'-sulfonylbis(2-methyl-1H-imidazole) with a substituted phenol to give an aryl 2-methyl-1H-imidazole-1-sulfonate. This imidazole-sulfonate was N-methylated by reaction with trimethyloxonium tetrafluoroborate, which enabled subsequent displacement of 1,2-dimethylimidazole by a dibenzylamine (e.g. bis-2,4-dimethoxybenzylamine). The resulting N-diprotected, ring-substituted phenol O-sulfamates were further manipulated through reactions at the aryl substituent and finally deprotected with trifluoroacetic acid to afford a phenol O-sulfamate. The use of 2,4-dimethoxybenzyl was particularly attractive because deprotection occurred quantitatively within 2 h at room temperature with 10% trifluoroacetic acid in dichloromethane. The four key steps in the protocol described [reaction of 1,1'-sulfonylbis(2-methyl-1H-imidazole) with a phenol, methylation, displacement with a dibenzylamine and deprotection] all proceeded in very high yields.

Two series of inhibitors of sulfatase 2, ARSA and ARSB were designed based on biphenyl and biphenyl ether scaffolds substituted with e.g. sulfamate and carboxylate groups.

Groups. -The protection-deprotection strategy comprises reaction of phenols (I) with sulfonylbis(methylimidazole) (II) to provide aryl imidazole sulfonates (III), which are activated by reaction with trimethyloxonium tetrafluoroborate, before further reaction with the methoxy-substituted dibenzylamine (IV) or (VII). Deprotection of the nitrogen atom and release of the phenol O-sulfamates (VI) is accomplished with the use of dilute trifluoroacetic acid. The sulfamate protecting groups are stable to common reaction conditions, affording useful orthogonality with other protecting groups. Especially useful is the application of dimethoxybenzyl as the N-protecting group that is stable to bases, nucleophiles, and other reagents. -(REUILLON, T.; BERTOLI, A.; GRIFFIN, R. J.; MILLER, D. C.; GOLDING*, B. T.; Org. Biomol. Chem. 10 (2012) 37, 7610-7617, http://dx.doi.org/10.1039/c2ob26057c ; Inst. Cancer Res., Sch. Chem., Univ. Newcastle, Newcastle upon Tyne NE1 7RU, UK; Eng.) -H. Hoennerscheid 08-083