Synthesis of Bioorthogonal Mycolic Acids: Chemoselective Reduction of β-Ketoesters Containing a Terminal Alkyne Using the Noyori Catalyst

The asymmetric reduction of β-ketoester using the Noyori catalyst is a highly effective synthetic methodology, offering excellent stereocontrol for the preparation of enantiopure -hydroxyesters from prochiral substrates in high yields. This reaction has been used in a total synthesis of mycolic acids, which are α-alkyl, β-hydroxy fatty acids forming the main part of the mycobacterial cell outer membrane. Recently, the metabolism of mycobacteria has been explored using the chemical reporter strategy with bioorthogonal analogues or precursors of mycolic acids. Introducing a bioorthogonal alkyne into these compounds is a challenging task and particularly valuable for subsequent probe attachment via click chemistry. This work presents approaches for the synthesis of several alkyne-containing mycolic acids featuring the native structure of natural mycolic acids. The chemoselectivity of the enantioselective reduction of several β-ketoesters using the Noyori catalyst in the presence of a terminal alkyne group was investigated. Conditions have been optimized to ensure that the alkyne remains intact during the reduction process. This study provides valuable tools for further mycomembrane studies using the CuAAC reaction and the optimized conditions extends the possibilities in the synthesis of β-ketoesters with an alkyne function.