Side Arm Strategy for Catalyst Design: Modifying Bisoxazolines for Remote Control of Enantioselection and Related

Abstract

In asymmetric catalysis, the remote control of enantioselection is usually difficult due to the long distance communication between the chiral center of the catalyst and the reactive site of the substrate. The development of efficient and highly enantioselective catalysts for such reactions is of great importance and highly desirable. The stereocontrol over an asymmetric reaction is a delicate process (ca. 3.0 kcal/mol difference in transition states can lead to >99/1 enantiomeric selectivity at room temperature), it therefore requires fine-tuning on the electronic nature of the central metal together with a precisely created cavity to accommodate the substrates and reagents. We envision that a solution is the design of new catalysts by finding an easy and efficient way to tune the electronic properties, the chiral space, and the shape of the catalytic site. Since an extra coordination group in the organometallic complex could not only alter the microenvironment around the metal center in a three-dimensional manner but also tune the electronic properties of the metal center, about 10 years ago, we introduced a side arm strategy for ligand/catalyst design. This Account describes our efforts toward this goal. Based on this side arm strategy, we have developed two series of ligands based on the bisoxazoline framework; namely, trisoxazoline (TOX) ligands and side armed bisoxazoline (SaBOX). The "side arms" are shown to play multiple roles in different cases, for example, as a ligating group, a steric group, or a directing group, which are dependent on the metal and the functionality at the side arm. Metal catalysts based on these ligands have proven to be highly efficient for a number of asymmetric transformations, including Friedel-Crafts reaction, Kinugasa reaction, Nazarov reaction, 1,2-Stevens rearrangement, Cannizzaro reaction, and cyclopropanation. In comparison with the parent BOX ligands, the metal catalysts based on these TOX and SaBOX ligands usually exhibit higher efficiency and diastereo- and enantioselectivity with better impurity tolerance and stability. Moreover, in several TOX-metal complex catalyzed reactions such as Friedel-Crafts reaction and [3 + 2] cycloaddition, stereoselectivity could be switched based on reaction conditions. These ligands were particularly prominent in the remote controls of enantioselection such as the conjugate additions to alkylidene malonates and ring-opening/cyclization cascades of cyclopropanes, for which high stereoselectivity is usually difficult to achieve due to the poor chiral communication. The works by us and other groups have demonstrated that the side arm strategy can be employed as a general principle for ligand and catalyst design and should not be limited to the BOX scaffolds and the reactions described in this Account. Wide application of the new strategy in organometallic homogeneous catalysis can be anticipated.