Scalable Enantioselective Synthesis of Fmoc‐β2‐Serine and Fmoc‐β2‐Threonine by an Organocatalytic Mannich Reaction

Abstract

AbstractThe diastereoselective Mannich reaction of functionalized aldehydes, using a phenethylamine‐derived iminium precursor, by activation with prolines and prolinol derivatives have been studied. Optimized reaction conditions have been developed, allowing for scale‐up and preparation of γ‐amino alcohol derivatives on multi‐gram scale from β‐hydroxypropanal and ‐butanal, with diastereoselectivites of typically >73:27 and yields of >60 %. After chromatographic diastereoisomer separation, hydrogenolytic debenzylation, enantiomerically pure Fmoc‐β2‐Ser(tBu)‐OH and Fmoc‐β2‐Thr(tBu)‐OH were thus prepared on multi‐gram scale in 6 steps and with overall yields of 24 % and 10 %, respectively, starting from commercially available starting compounds.