Synthesis of Both Enantiomers of a P-Chirogenic 1,2-Bisphospholanoethane Ligand via Convergent Routes and Application to Rhodium-Catalyzed Asymmetric Hydrogenation of CI-1008 (Pregabalin)

Both enantiomers of a P-chirogenic 1,2-bisphospholanoethane ligand are synthesized via two
convergent methods. The first method relies on the chiral alkylation of 1-((−)-menthoxy)phospholaneborane
using a s-BuLi/(−)-sparteine derived chiral base. Only one enantiomer of the catalyst could be synthesized
via this method because only one antipode of sparteine is available in nature. The second route relies on
the combination of methylphosphine borane and a chiral 1,4-diol. Either enantiomer of the ligand can be
synthesized via the second route from the appropriate enantiomer of the 1,4-diol. Asymmetric hydrogenation
using catalyst precursor 36 on acetamidoacrylic acid derivatives provided modest to good enantioselectivity
(77−95% ee) under low H2 pressure (30 psi). Asymmetric hydrogenation of CI-1008 (pregabalin) precursors,
39 and 40, provided good enantioselectivities (92%) at high catalyst loading (1 mol %) and low pressure
(30 psi). Enantiomeric excesses dropped sharply with catalyst loading at this pressure. Increasing the
pressure of H2 caused a significant increase in enantiomeric excess for low catalyst loading reactions.
Several studies were undertaken to further investigate the enantioselectivity dependence on both pressure
and catalyst loading.