Synthesis of 2-Cyanomethyl-3-hydroxy-5-iodomethyltetrahydrofuran from Various Isoxazolines: Effects of 3-Substituents in the Diastereoselective Iodoetheration Reactions of Isoxazolines

Abstract

Highly substituted tetrahydrofuran derivatives were prepared from isoxazolines by electrophilic iodoetheration using iodine or iodine monochloride. In the mechanism of the iodoetheration reaction, the cationic stabilities of the 3substituents (R1) in the isoxazolines (1) were very important because the 3-substituents should detach from the isoxazoline ring as cations to form 2-cyanomethyl-3hydroxy-5-iodomethyltetrahydrofurans (3) as shown in Scheme 1. In general, trityl group or α-silyloxylbenzyl group was applied as R1 groups and both of them afforded good results in the iodoetheration. However, we found these groups were not convenient to be prepared. The triphenylacetonitrile oxide (trityl group) was prepared through silver fulminate that was a very explosive intermediate, and was too dangerous for us to prepare. 2-t-Butyldimethylsilyloxy-2-phenylacetohydroximoyl chloride, a precursor of 2-t-butyldimethylsilyloxy-2-phenylacetonitrile oxide (α-silyloxylbenzyl group) was prepared from mandelic acid in several steps. The compound was not stable enough to store even in a refrigerator, moreover the chiral center in mandelic acid only made the reaction to be complicated and was not necessary in the iodoetheration reaction. In order to find a better group for R1, we examined diphenylmethyl and 4-methoxybenzyl groups. Diphenylacetohydroximoyl chloride was prepared from commercially available diphenylacetaldehyde and could be easily converted to diphenylacetonitrile oxide by triethylamine or ethylmagnesium bromide. 4-Methoxyphenylacetohydroximoyl chloride could not be prepared from 4-methoxyphenylacetaldehyde because the oxidation of 4-methoxyphenethyl alcohol afforded only 4-methoxybenzaldehyde. Thus, 4-methoxyphenylacetohydroximoyl chloride was prepared from 4methoxy-β-nitrostyrene by titanium tetrachloride and triethylsilane in low yield, and the purification of 4-methoxyphenylacetohydroximoyl chloride was a very hard job because of its instability. Interestingly, diphenylacetohydroximoyl chloride had low solubility in organic solvents such as hexane and dichloromethane and we could easily isolate it as a white solid by washing the crude compound with solvent (hexane/dichloromethane = 1/1). Moreover diphenylacetohydroximoyl chloride was so stable enough to store several month at room temperature, while 4-methoxyphenylacetohydroximoyl chloride was unstable and had to be used immediately. Four kinds of nitrile oxides were examined in the cycloaddition reactions and the results were summarized in Table 1. Triphenylacetonitrile oxide and diphenylacetonitrile oxide were used as isolated forms (Entry 1 and 2), and 2-tbutyldimethylsilyloxy-2-phenylacetonitrile oxide and 4methoxyphenylacetonitrile oxide were generated from (2-t-