Flow chemistry tames allenyllithium

When chemists at Pfizer were looking to make a chiral homopropargyl β-amino alcohol en route to one of their clinical candidates, they wanted to improve their six-step route. Teaming up with researchers at continuous-flow research firm Snapdragon Chemistry, led by Yuan-Qing Fang and Matthew M. Bio, they made the desired compound in just two steps from commercially available starting materials (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201704882). The synthetic route (shown) begins with lithiation of allene gas to produce allenyllithium, a compound so reactive that it’s usually made and used only at -78 °C. Such cryogenic conditions typically limit the use of allenyllithium. By using a continuous-flow process for the reaction, the chemists controlled the allene lithiation reaction so that they could use allenyllithium at about 0 °C. After lithiation, the compound undergoes transmetalation with zinc. The resulting intermediate is then used with a chiral (1S,2R)-N-pyrrolidinyl-norephedrine ligand to asymmetrically propargylate a β-amino aldehyde, producing the desired chiral homopropargyl β-amino alcohol.