Anti-1,3-diols by Addition of Dialkylzinc Reagents to 4-Acetoxy-1,3-dioxanes

Dialkylzincs couple with 4-acetoxy-6-alkyl-1,3-dioxanes in the presence of trimethylsilyl triflate (TMSOTf) to form trans-4,6-dialkyl-1,3-dioxanes with excellent diastereoselectivities. These dioxanes could be deprotected to yield anti-1,3-diols. A variety of functional groups are tolerated in the dialkylzinc, although silyl and benzyl ethers led to diminished diastereoselectivities. Substituents at the C5-position of the dioxane ring have little effect on the selectivity, while small C2 (acetal) substituents led to slightly reduced diastereoselectivity. These couplings work best with cyclic acetals, which can be difficult to hydrolyze. The 4-(benzyloxy)butanal (BOB) acetal has been developed as a new cyclic acetal protecting group that is compatible with dialkylzinc coupling reactions. BOB protecting groups are easily removed by catalytic hydrogenation followed by mild acid hydrolysis.