Reductive Amination Without the Aldehyde: Use of a Ketolactol as an Aldehyde Surrogate Alan M. AllgeierDenise AndersenMichael D. BartbergerEmilio E. Bunel • Robert D. LarsenPingli LiuThomas StorzJason S. Tedrow

To overcome stability issues associated with the use of an aldehyde in a catalytic reductive amination reaction, a cyclic ketolactol (x-hydroxylactone) was employed as an aldehyde surrogate to form a c-aminoacid. The reaction proceeded most favorably over a Pt/C cata- lyst. The thermodynamics of each step were evaluated using density functional theory calculations, which cor- rectly predicted the dominance of the ring-closed lactol reactant, yet suggested a preference for a ring-opened iminium intermediate upon the initial, slightly endoergic addition of amine substrate. Exoergic hydrogenation of this intermediate provided the thermodynamic driving force for the overall transformation. During development, the reac- tion was observed to depend significantly on the volumetric gas to liquid mass transfer coefficient (kLa) and this parameter was optimized to ensure successful scale up in a 400 L stirred tank reactor.