Total synthesis of methyl-lysophosphatidic acid and analogues: confirmation of the proposed structure of a phospholipid antigen for CD1c-restricted T cells

CD1c-restricted T cells play a crucial role in immune surveillance and anti-tumor immunity. Recently, a novel methyl-lysophosphatidic acid (mLPA), which bears a rare methyl phosphate headgroup, was identified as a potential antigen for these T cells, selectively accumulating in leukemia cells. However, uncertainties surrounding the structure of this natural product prompted us to pursue its chemical synthesis. Herein, we report the first total synthesis of mLPA, along with its desmethyl and dimethyl analogues. Our synthetic mLPA exhibits spectral characteristics consistent with the reported data for the natural product, confirming the proposed structure and the presence of a mixture of diastereomers. Synthetic mLPA and the two analogues will be valuable tools for investigating the anti-leukemic potential of CD1c-restricted T cell responses.