Total Synthesis of Mycobacterium tuberculosis Dideoxymycobactin‐838 and Stereoisomers: Diverse CD1a‐Restricted T Cells Display a Common Hierarchy of Lipopeptide Recognition

Mycobacterium tuberculosis produces dideoxymycobactin‐838 (DDM‐838), a lipopeptide that potently activates T cells upon binding to the MHC‐like antigen‐presenting molecule CD1a. M. tuberculosis produces DDM‐838 in only trace amounts and a previous solid‐phase synthesis provided sub‐milligram quantities. We describe a high‐yielding solution‐phase synthesis of DDM‐838 that features a Mitsunobu substitution that avoids yield‐limiting epimerization at lysine during esterification, and amidation conditions that prevent double‐bond isomerization of the Z‐C20:1 acyl chain, and provides material with equivalent antigenicity to natural DDM‐838. Isomers of DDM‐838 that varied in stereochemistry at the central lysine and the C20:1 acyl chain were compared for their ability to be recognised by CD1a‐restricted T cell receptors (TCRs). These TCRs, derived from unrelated human donors, exhibited a similar spectrum of reactivity towards the panel of DDM‐838 isomers, highlighting the exquisite sensitivity of lipopeptide‐reactive T cells for the natural DDM stereochemistry. Sensing stereochemistry: M. tuberculosis dideoxymycobactin‐838 (DDM‐838) is an antigen involved in cell‐mediated immunity. DDM‐838 and stereoisomers epimeric in the depsipeptide backbone and isomeric in the C20:1 acyl‐chain were synthesized. T cell receptors derived from unrelated human donors preferentially bind natural DDM‐838 in complex with the antigen presenting molecule CD1a and display similar patterns of discrimination for DDM‐838 stereoisomers.