As published in JACS, researchers in the Johnson Group have developed a highly diastereoselective synthesis of 2,6-cis-disubstituted tetrahydropyrans (THPs) via Lewis acid-catalyzed formal [4 + 2] cycloaddition of donor−acceptor cyclobutanes and aldehydes. THP products are formed in up to 96% yield and 99:1 diastereoselectivity.
Aromatic, cinnamyl, and aliphatic aldehydes are competent dipolarophiles in this system. This methodology was extended to a [[2 + 2] + 2] cycloaddition of 4-methoxystyrene, dimethyl methylidene malonate, and an aldehyde to furnish THPs directly without prior isolation of the cyclobutane.
Research from the Johnson Group, as published in JACS, present a concise and convergent route to (+)-polyanthellin A. This synthesis features a diastereoselective cyclopropane/aldehyde [3+2] cycloaddition to install the hydroisobenzofuran core.
The use of MADNTf2 as a potent, bulky Lewis acid was essential to allow a labile β-silyloxy aldehyde to be used in the cycloaddition. Other key steps include a ring-closing metathesis and a selective olefin oxidation.