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.

Cyclopentadienyl-bis(oxazoline) Magnesium and Zirconium Complexes in Aminoalkene Hydroaminations

“…Exhaustive evaporation to remove residual dioxane and diethyl ether gives broad spectra. Data given here contain residual ethers, the 2C and magnesium methyl signals were not detected in the 13 C{ 1 H} NMR spectrum or through 2D correlation spectroscopy, and C analyses were systematically lower than calculated values. Mp: 145−147°C (dec).…”

“…Thus, the low-temperature structure is C 1 symmetric. The magnesium methyl and 2-C of the oxazoline were difficult to observe in the 13 C{ 1 H} NMR spectra of these compounds, either generated in situ or of isolated materials. However, with small amounts of dioxane, the MgMe resonance was observed at −11 ppm.…”

“…11 The reaction of deprotonated bis(oxazoline) and organic electrophiles has been very useful to obtain tris(oxazolinyl)ethane (tris-ox) ligands 12 or side-armcontaining bis(oxazolines) that show improved enantioselectivity in a host of catalytic conversions. 13 Recently, we reported the synthesis of the tetramethylcyclopentadienyl ligand MeC-(Ox…”

Ring Opening of Donor–Acceptor Cyclopropanes with N-Nucleo­philes

“…82 The Tang group has developed an asymmetric catalytically induced version for the nucleophilic ring opening of activated cyclopropanes with amines. [84][85][86] Conditions analogous to those suggested in Charette's method 80 facilitated ring opening for cyclopropane-1,1-diesters 57a-n by secondary amines yielding 58а-w. Notably, the most convenient yield/enantiomeric excess relationship for products 58 was achieved upon employing tris-indaneoxazoline 59 as a ligand for asymmetric induction (Scheme 26).…”

Highly Enantioselective [3+2] Annulation of Indoles with Quinones to Access Structurally Diverse Benzofuroindolines

“…[5j] In view of the potent antitumor activity of molecules containing such scaffolds,t he development of efficient and enantioselective methods to allow the synthesis of structurally diverse benzofuroindolines,e specially those without 3-substituents that are susceptible to rearomatization and are thus challenging, [7] is of particular importance for small-molecule libraries. [10,11] To address the aforementioned challenge in the catalytic enantioselective synthesis of 3nonsubstituted benzofuroindolines,a ne ster group was accordingly installed on the quinone ring, which may also enhance the electrophilicity of quinones ( Figure 1). [10,11] To address the aforementioned challenge in the catalytic enantioselective synthesis of 3nonsubstituted benzofuroindolines,a ne ster group was accordingly installed on the quinone ring, which may also enhance the electrophilicity of quinones ( Figure 1).…”