Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.