Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science
RESEARCH ARTICLE

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

Edward T. Ledingham A , Kieran P. Stockton A and Ben W. Greatrex A B
+ Author Affiliations
- Author Affiliations

A School of Science and Technology, University of New England, Armidale, NSW 2351, Australia.

B Corresponding author. Email: ben.greatrex@une.edu.au

Australian Journal of Chemistry 70(10) 1146-1150 https://doi.org/10.1071/CH17227
Submitted: 26 April 2017  Accepted: 13 June 2017   Published: 7 July 2017

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.


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