Halogenation cyclic ethers

Isol. from L. okamurai. Possible precursor of a wide range of Cis-halogenated cyclic ethers found in marine red algae. 

Bioactive halogenated cyclic ethers fall into one of the most representative classes of organohalogens (Figure 43.1). These compounds have a common molecular architecture the halogenated stereocenter adjacent to ethereal oxygen. 

SCHEME 43.7. Stereoselective bromoallenylation in total syntheses of halogenated cyclic ethers. 

Martiriol and a few other non-halogenated cyclic ethers have also been identified in several species of Laurenda. The first to have been isolated is teurilene, a tricyclic squalenoid from a Japanese variety of Laurenda obtusa (Suzuki et al., 1985).It is a meso compotmd, optically inactive by internal symmetry, and strongly cytotoxic with an ED50 of 0.18 pgml against leukemia P-388. A compound very similar to the latter, emylene, was discovered later in a plant of the family Simaroubaceae, Eurycoma longifolia (Morita et al., 1993). 

Aplysia 260 Terpenes and halogenated terpenes, halogenated cyclic ethers, peptides and cyclic depsipeptides, macrolactones, alkaloids... 

Halogens are frequently used as oxidation agents and, under two-phase conditions, they can either be employed as ammonium complex halide salts [3], or in the molecular state with or without an added quaternary ammonium catalyst [4]. Stoichiometric amounts of tetra-n-butylammonium tribromide under pH controlled conditions oxidize primary alcohols and low-molecular-weight alkyl ethers to esters, a,cyclic ethers produce lactones [3], and secondary alcohols yield ketones. Benzoins are oxidized to the corresponding benzils (80-90%) by the tribromide salts in acetonitrile in the presence of benzoyl peroxide [5]. 

The reaction that takes place is hydrogen halide-promoted ether cleavage. In such a reaction with excess hydrogen halide, the C—O—C unit is cleaved and two carbon-halogen bonds are formed. This suggests that cineole is a cyclic ether because the product contains both newly formed carbon-halogen bonds. A reasonable structure consistent with these facts is... 

Ethers, particularly cyclic ethers, are another group of nucleophilic solvents engaged in cohalogenations. Halogenation of olefins in presence of epoxides leads to the formation of / ,/ -dihaloethers (equation 52)432. 

A second synthesis of epoxides and other cyclic ethers involves a variation of the Williamson ether synthesis. If an alkoxide ion and a halogen atom are located in the same molecule, the alkoxide may displace a halide ion and form a ring. Treatment of a halohydrin with base leads to an epoxide through this internal SN2 attack. 

Alcohols with a hydrogen in the 8 position can be cychzed with lead tetraace-tate. ° The reaction is usually carried out at 80°C (most often in refluxing benzene), but can also be done at room temperature if the reaction mixture is irradiated with uv light. Tetrahydrofurans are formed in high yields. Little or no four- and six-membered cyclic ethers (oxetanes and tetrahydropyrans, respectively) are obtained even when y and s hydrogens are present. The reaction has also been carried out with a mixture of halogen (Br2 or I2) and a salt or oxide of silver or mercury (espe-cially HgO or AgOAc), with iodosobenzene diacetate and I2, and with ceric... 

Gimstone, F.D., and B.S. Perera, The Halogenation of Some Long-Chain Hydroxy Alkenes with Special Reference to the Possibility of Neighbouring Group Participation Leading to Cyclic Ethers and Lactones, Chem. Phys. Lipids 11 43-65 (1973). 

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