Complementary Synthesis of Anti- and Syn-Hydroxymethyl 1,3-Diols via Regioselective Ring Opening of TIPS-Protected 2,3-Epoxy Alcohols: Toward Polypropionate Fragments

Hydroxymethyl 1,3-diol motifs are common structural motifs in natural products, particularly in polypropionates with important therapeutic potential. However, general and complementary methods for their regio- and diastereoselective synthesis remain limited. In this study, we expanded a second-generation epoxide-based methodology involving the regioselective cleavage of TIPS-monoprotected cis- and trans-2,3-epoxy alcohols using alkenyl Grignard reagents. Regioselective ring opening of cis-epoxides provided anti-1,3-diols, while trans-epoxides afforded the corresponding syn-1,3-diols. The use of cis-propenylmagnesium bromide and vinyl Grignard reagents enabled direct access to cis- and terminal homoallylic 1,3-diols, respectively, with moderate to good yields (46–88%) and excellent regioselectivities (95:5). In contrast, reactions with trans-propenyl Grignard reagent led to partial alkene isomerization, limiting their synthetic utility. To address this, a complementary two-step approach employing propynyl alanate addition followed by sodium/ammonia reduction was incorporated, providing access to trans-homoallylic 1,3-diols with high diastereoselectivity. All 1,3-diols were characterized by NMR spectroscopy, confirming regioselective epoxide opening. These combined strategies offer a practical and modular platform for the synthesis of syn- and anti-hydroxymethylated 1,3-diols and their application to the construction of polypropionate-type fragments, supporting future efforts in the total synthesis of polyketide natural products.