An efficient two-step method for the differential functionalization of 1,2and 1,3-diols, involving regioselective cleavage of five-and six-membered cyclic formals with acetyl chloride followed by conversion of the resulting chloromethyl ether acetate 1 to an alkoxymethyl ether acetate (21, has been developed. When applied to unsymmetrically substituted cyclic formals, the differential functionalization sequence is highly selective and produces an alkoxymethyl ether acetate having the acetate a t the less hindered center and the acetal moiety a t the more hindered center. Removal of either protecting group affords a selectively monoprotected diol: for the case of a n unsymmetrical diol, removal of the acetate gives a product selectively protected with a n acetal group at the more hindered hydroxyl.The development of efficient methodology for the selective, differential protection of diols is a perennial challenge in organic chemistry.' A generally useful method should allow for monoprotection of symmetrical diols as well as permit differentiation of the chemically distinct hydroxyl groups of unsymmetrical substrates. While a variety of techniques are available for the monoprotection of symmetrical there are few methods that allow for chemoselective functionalization of the more hindered hydroxyl group in a n unsymmetrically substituted diol.la A potentially attractive approach to the differential functionalization of 1,2and l,&diols was suggested by the results of our previous study of the acylative ring-opening of cyclic formal^.^ As shown below, the acid-catalyzed cleavage of unsymmetrically substituted cyclic formals with acetic anhydride occurs via preferential rupture of the less congested C(2)-0 bond to give products having a n acetate at the primary site and an acetoxymethyl ether moiety a t the secondary p~s i t i o n .~ Such highly selective acylative cleavage, which results from a rate-limiting electrophilic attack that is acutely sensitive to steric effect^,^ was also observed in the Lewis-acid catalyzed reaction of a limited @
The reaction of alkyllithiums with cis-4-methyl-2-vinyl-1,3-dioxane proceeds in virtually quantitative yield via a formal S(N)2' ring opening that proceeds in a regioselective manner to give preferential cleavage of the C(2)-O(l) bond remote from the 4-methyl substituent, affording the E-enol ether as the major stereoisomer. A two-step mechanism, involving addition of the alkyllithium followed by syn-elimination of lithium alkoxide, is suggested to account for the stereochemical outcome.
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