Development of bifunctional salen catalysts with modular ligand motifs for asymmetric synthesis

This dissertation describes the development of bifunctional Lewis acid/base complexes for use in asymmetric catalysis. Metal complexes of ortho -functionalized chiral salen ligands were designed to incorporate the desired functionality within a rigid scaffold. These complexes contain a Lewis acidic metal for activation of a carbonyl electrophile (enone, aldehyde or α-ketoester), and a tethered base for activation of a carbon-nucleophile (malonate or organozinc reagent). This design is novel in that it presents a modular framework with electronically separate and distinct sites for the individual activation of the two reaction partners.* The work began with the synthesis and complexation studies of a chiral quinoline functionalized salen. The addition of diethylzinc to benzaldehyde was catalyzed by quinoline salen complex Zn-28b. The quinoline nitrogens are presumed to act as Lewis base promoters, by coordinating to the diethylzinc and increasing its nucleophilicity.* While the quinoline salen complexes did show promise as Lewis acid/Lewis base catalysts, they were not useful in reactions that require activation by a Brønsted base catalyst. A unique class of modular, heterobimetallic, BINOL salen complexes were synthesized for this purpose. Ni·Cs-BINOL salen 74 was shown to catalyze the Michael reaction of malonates and cyclic enones with moderate yields and enantioselectivity up to 90% ee.* Since the quinoline salen showed promise as a Lewis acid/Lewis base catalyst, we sought to examine other amine functionalized salen ligands in the addition of organozinc reagents to carbonyl electrophiles. Simple and divergent synthetic routes allowed access to a variety of amino salens in 3 to 5 steps. These crystalline, storable salens were then used to create a library of highly modular complexes (M-salen). Zn-salens catalyze the addition of diethylzinc to aldehydes with exceptional reaction rates at 5–10 mol% catalyst. Ti(Oi-Pr)2-salens were identified as the first highly efficient catalysts for the addition of dialkylzincs to α-ketoesters.* Mechanistic evaluation of the successful catalysts has provided data in support of a bifunctional activation pathway. This project has culminated in the identification of over 100 potential bifunctional salen catalysts in which it is possible to independently adjust the activation of nucleophile and electrophile. *Please refer to dissertation for diagrams