All C-F stereocenters generated by HpcH are (3S)-configured, with no detection of (3R)-products, as we had previously established with NMR studies of fluoropyruvate adducts. The origins of this exquisite stereoselectivity, alongside with the kinetic resolution phenomenon and the beneficial nature of Phe-170 and Leu-212 mutations, can altogether be rationalized by two factors: (1) the electronicsdetermined requirement for cis-geometry of the metal-bound fluoroenolate intermediate, and (2) the enzyme-determined Si-facial consistency (relative to C-3 of the fluoroenolate) for proton abstraction and attack onto an aldehyde. For the racemic fluoro-donors, only one substrate enantiomer has an acidic proton orientable such that H-abstraction leads to a cis-fluoroenolate. The alkyl group is thus forced into the trans position of the fluoroenolate and directed towards the space occupied by Phe-170 and Leu-212 (Figure ). During the course of our studies, the Clapés group reported that reduction of Trp-19 to a small residue (W19V or W19A) was the key change that unlocked activity with bulky non-fluorinated α-ketoacids. The product stereochemistry with these donors indicates that the C-3 bulk occupied the cis position of the enolate, which is directed towards Trp-19. In contrast, the W19A mutation was ineffective with our fluorodonors, corroborating our theory that fluorine defeats an alkyl group in the competition of both groups for the cis position. To rule out an electronic explanation of reactivity differences between fluoro-donors, we note that in the hypothetical absence of steric factors, the inductively releasing effect of an alkyl group would increase the nucleophilicity of the fluoroenolate, and thus accelerate the rate-determining step of C-C bond formation. However, the experimental addition rates of alkyl-substituted FKB (2a) and FKV (2b) were slower, not faster than FP (1) itself. Inhibition of the aldolase by our bulky fluoro-donors is also unlikely, as their co-presence had no effect on the conversion of FP. These findings overall reinforce that the fluorodonor scope of HpcH is dominated by steric factors that appear to be different from those of non-fluorinated donors.