Modular Synthesis of Chiral Homo- and Heterotrisoxazolines. Improving the Enantioselectivity in the Asymmetric Michael Addition of Indole to Benzylidene Malonate

Abstract

A simple approach to a diverse set of chiral trisoxazolines is described. Deprotonation of bisoxazolines 2, followed by treatment of 2-chloromethyloxazolines 3, affords chiral trisoxazolines, including chiral homo- and hetero-trisoxazolines in good to high yields. These trisoxazolines are successfully applied in the asymmetric reaction of indole with benzylidene malonate, and ee's up to 93% were obtained.

Exploiting Threefold Symmetry in Asymmetric Catalysis: The Case of Tris(oxazolinyl)ethanes (“Trisox”)

“…In all cases polyolefins with M w /M n values of between 1.58 and 2.08 were obtained and isotacticities of 80-95 % determined by 13 C NMR spectroscopy ( Figure 6). …”

“…Tang and co-workers have found that such potentially tricoordinating ligands may provide Cu-based Lewis acid catalysts that display a significantly improved performance in comparison to the bisoxazoline reference system. [13] However, the role of the "sidearm" is not always clear, [13,14] and a separation of the influence of the BOX-unit and the third "ligand arm" is only meaningful if the metalligand bonding of these components differs significantly. On the other hand, upon going to C 3 -chiral tripods, all three possible ligating units become equivalent, effectively giving up the sidearm notion as discussed above.…”

“…However, the class of non-C 3 -symmetrical trisoxazolines developed by Tangs group (5) do in principle offer the possibility of this type of coordination, [13] although there is to date no crystallographically characterised complex to firmly establish facial binding. These trisoxazoline ligands have been successfully employed in a range of highly enantioselective catalytic transformations.…”

“…[13] This would lead to products having the absolute stereochemistry, as observed in the Mannich addition. However, the substitutional lability of the copper(II) complexes, and thus the possibility of rapid equilibria, sets limits to interpretations based on Xray structural data.…”

Functionalization of Indole and Pyrrole Cores via Michael-Type Additions

“…The C3-symmetric trisoxazoline 121a-copper(ClO 4 ) 2 · 6H 2 O complex, as a catalyst, is an air-and water-stable compound (Scheme 34) [108][109][110].…”