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

Abstract

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.

Oxygenated commodity chemicals from chemo‐catalytic conversion of biomass derived heterocycles

“…Burseran and Isostegane) while 2H‐HBO is an intermediate to C 7–12 5‐alk(en)yl‐γ‐lactones, which is known as Laiscent TM , a dairy flavor. LGO is a promising precursor for pharmaceuticals, with many applications having been reported in the 1980s–1990s, and with more recent examples being synthetic routes to the antiviral indinavir and a range of pharmaceutically active cyclopropylesters …”

Synthesis of a Chiral Auxiliary Family from Levoglucosenone and Evaluation in the Diels–Alder Reaction

“…(1S,5R)-3-((E)-Benzylidene)-6,8-dioxabicyclo[3.2.1]octan-4-one (9). 2 As per the literature procedure, a mixture of benzaldehyde (2.20 g, 1.2 equiv, 20.7 mmol) and TMG (2.20 mL, 1.0 equiv, 17.2 mmol) were heated to 100 °C. Dihydrolevoglucosenone 8 (2.20 g, 1.76 mL, 1.0 equiv, 17.2 mmol) was added and the reaction mixture was stirred at 100 °C for 1 h then the mixture was directly applied to a column of silica, eluting with EtOAc/hexanes 3:17.…”

Bio‐available Solvent Cyrene: Synthesis, Derivatization, and Applications

“…Tagirov et al reported that the acetal of Cyrene could be cleaved in ar eaction with chlorotrimethylsilane and sodium iodide to give dihydropyran-3-one derivative 3 in moderate yield (Scheme 1a). [34] In addition, they showedt hat Cyrene was a competent nucleophile for direct alkylation with benzylbromide, although ac omplexm ixture of products was obtained. [32] The Beckmann rearrangemento fC yrened erivatives can give av ariety of products depending on the specific conditions that are employed.…”

“…[33] Owing to the facile enolization of Cyrene( 2)i nt he presence of as trongb ase, several groups have subjected the bicycle to aldol condensation protocols to form enones.F or example, Greatrex and co-workersreported that in the presence of tetramethylguanidine that Cyrene reactedw ith av ariety of aldehydes 10 to afford enones 11 in moderate to good yields (Scheme 3a). [34] In addition, they showedt hat Cyrene was a competent nucleophile for direct alkylation with benzylbromide, although ac omplexm ixture of products was obtained. Witczak et al reported ar elateds tudy in which they used piperidine as the base and heterocyclic aldehydes 12 in an aldol condensation reaction to afford enones 13 (Scheme 3b).…”