Efficient Synthesis of an Indinavir Precursor from Biomass-Derived (-)-Levoglucosenone

Lignocellulosic biomass pyrolysis with acid catalysis selectively produces the useful chiral synthon 6,8-dioxabicyclo[3.2.1]oct-2-ene-4-one ((-)-levoglucosenone,LGO). In this report, LGO was used to prepare (3R,5S)-3-benzyl-5-(hydroxymethyl)-4,5-dihydrofuran-2(3H)-one, which is an intermediate used in the construction of antivirals including the protease inhibitor indinavir. To achieve the synthesis, the hydrogenated derivative of LGO was functionalised using aldol chemistry and various aromatic aldehydes were used to show the scope of the reaction. Choice of base affected reaction times and the best yields were obtained using 1,1,3,3-tetramethylguanidine. Hydrogenation of the α-benzylidene-substituted bicyclic system afforded a 4:3 equatorial/axial mixture of isomers, which was equilibrated to a 97:3 mixture under basic conditions. Subsequent Baeyer-Villiger reaction afforded the target lactone in 57 % overall yield for four steps,a route that avoids the protection and strong base required in the traditional approach. The aldol route is contrasted with the α-alkylation and a Baylis-Hillman approach that also both start with LGO.