Reductive Amination Without the Aldehyde: Use of a Ketolactol as an Aldehyde Surrogate

To overcome stability issues associated with the use of an aldehyde in a catalytic reductive amination reaction, a cyclic ketolactol (ω-hydroxylactone) was employed as an aldehyde surrogate to form a γ-aminoacid. The reaction proceeded most favorably over a Pt/C catalyst. The thermodynamics of each step were evaluated using density functional theory calculations, which correctly 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 reaction was observed to depend significantly on the volumetric gas to liquid mass transfer coefficient (k_La) and this parameter was optimized to ensure successful scale up in a 400 L stirred tank reactor.