Quinine-Derived Thiourea and Squaramide Catalyzed Conjugate Addition of α‑Nitrophosphonates to Enones: Asymmetric Synthesis of Quaternary α‑Aminophosphonates

Conjugate
addition of α-nitrophosphonates to enones was carried
out in the presence of two sets of organocatalysts, viz. a quinine-thiourea
and a quinine-squaramide. The quinine-thiourea provided the products
possessing an α-quaternary chiral center in high enantioselectivities
only in the case of electron rich enones. On the other hand, the quinine-squaramide
was more efficient in that a wide variety of electron rich and electron
poor enones underwent Michael addition of nitrophosphonates to afford
the quaternary α-nitrophosphonates in excellent yields and enantioselectivities.
The hydrogen bonding donor ability of the bifunctional catalyst, as
shown in the proposed transition states, appears primarily responsible
for the observed selectivity. However, a favorable π-stacking
between the aryl groups of thiourea/squaramide and aryl vinyl ketone
also appeared favorable. The reaction was amenable to scale up, and
the enantioenriched quaternary α-nitrophosphonates could be
easily transformed to synthetically and biologically useful quaternary α-aminophosphonates
and other multifunctional molecules.