Finally, the optimization of the VL parameters were performed (Figure ). The objective function (F) was set to be the sum of the branch selectivity (bs) and enantiomeric excess (ee) corrected by the range confining penalty function (P). The parameter set which reproduce (S)-quinoxt Bu3 were used as the initial guess, and eight steric parameters (a1- 1, b1-1, a1-2, b1-2, a1-3, b1-3, a1-4 and b1-4) were optimized. The ranges were set to be 1.0-6.0 Å for all parameters. The results are summarized in Figure , in which the objective function (F), the branch selectivity (bs) and the enantiomeric excess (ee) are plotted with dots, crosses and open circles, respectively. As expected from the derivative values at the initial step (Figure ), bulk of the ovoids corresponding to R and and) increased significantly, while the parameters for R 4 remained almost constant. On the other hand, despite the negative derivative values at the initial step (Figure ), bulk of the ovoid corresponding to R 1 (a1-1 and b1-1) converged at slightly bigger values than those for Me group. This is probably because, as optimization proceeds, R 1 became no longer the only substituent which breaks symmetry of the ligand unlike it was at the first step of the optimization (see above), allowing R 1 to be a larger substituent. Overall, the optimization terminated after 13 iterations, where the branch selectivity and the enantiomeric excess were estimated to be extremely high (99.9% and 99.4%, respectively). As the optimized VL parameters demand substituents R 1 -R 4 to have different size and shape to each other, real ligand molecules which meet these criteria would be out of the current synthetic scope. However, we believe that the VLAO method can accelerate discovery of useful ligands by motivating chemists to explore such untapped chemical spaces.