An efficient asymmetric synthesis of the LTB 4 inhibitor Ontazolast is described. Commercially available (S)-r-pinene, which contains a 93.5% enantiomeric excess (ee) of the desired isomer, can be oxidized using phase-transfer conditions to the corresponding (R)-hydroxy ketone. Condensation of this keto alcohol with 2-(aminomethyl)pyridine provides an intermediate imine that can be alkylated with cyclohexylmethyl bromide or iodide. The alkylation proceeds with nearly complete transfer of chirality under mild conditions. Cleavage of the chiral auxiliary and isolation of the resulting (S)-pyridylamine by crystallization with L-tartaric acid furnishes the key amine building block in >99% ee and in excellent overall yield. The tartrate salt is then directly converted to the final product. The reaction sequence is described on a multigram scale.
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