Sequential Methods for Di- and Tetrahydro-Pyranone Synthesis Enable Concise Access to Tuscolid δ-Lactone.

Two novel tandem sequences for stereoselective synthesis of elaborate hydropyranones are reported. The first one relies on an aldol-lactonization procedure of a chiral enolate with an unprotected aldehyde, while the second one is based on a challenging dienolate ketone addition with concomitant cyclization and substrate controlled reduction. Both approaches proceed with high efficiency and stereoselectivity and enable very short accesses to the authentic pyranone subunit of the complex polyketide tuscolid and will be important to develop a first total synthesis of this structurally unique macrolide and to evaluate the tuscolid-tuscoron rearrangement.