A concise synthesis of tubuphenylalanine and epi-tubuphenylalanine via a diastereoselective Mukaiyama aldol reaction of silyl ketene acetal

Abstract

We have developed a straightforward and auxiliary-free synthetic route towards tBu-tubuphenylalanine (tBu-Tup) and tBu-epi-tubuphenylalanine (tBu-epi-Tup), which are the key components of tubulysins and their analogs. A Lewis acid-mediated diastereoselective Mukaiyama aldol reaction using silyl ketene acetal and N-Boc-L-phenylalaninal provided γ-amino-β-hydroxyl-α-methyl esters, which were deoxygenated to γ-amino-α-methyl esters under Barton–McCombie deoxygenation conditions. Notably, the desired tBu-Tup and tBu-epi-Tup were obtained in good overall yields in four steps.