Stereochemical Consequences of Threefold Symmetry in Asymmetric Catalysis: Distorting C₃ Chiral 1,1,1‐Tris(oxazolinyl)ethanes (“Trisox”) in Cu^II Lewis Acid Catalysts

Abstract

The underlying conceptual differences in exploiting two- and threefold rotational symmetry in the design of chiral ligands for asymmetric catalysis have been addressed in a comparative study of the catalytic performance of bisoxazoline (BOX) and tris(oxazolinyl)ethanes (trisox) containing copper(II) Lewis acid catalysts. The differences become apparent in constructing new catalysts by systematically "deforming" the stereodirecting ligand by inverting chiral centres or replacing chiral by achiral oxazolines. The catalytic alpha-amination of ethyl 2-methylacetoacetate with dibenzyl azodicaboxylate, which occurs with high enantioselectivity for both Ph(2)-BOX and Ph(3)-trisox copper catalysts, has been employed as the test reaction. In the trisox-copper complex [Cu(II)(iPr(3)-trisox)(kappa(2)-O,O'-MeCOCHCOOEt)](+)[BF(4)](-) (1), which was characterised by X-ray diffraction, two of the oxazoline groups are coordinated to the central copper atom, whilst the third oxazoline unit is dangling with the N-donor pointing away from the metal centre. A similar arrangement is found for the stereochemically "mixed" C(1)-trisox complex [Cu(II){(Ph(3)-trisox(R,S,S)}(kappa(2)-O,O'-MeCOCHCOOEt)(H(2)O)](+)[ClO(4)](-) (2), in which the phenyl substituents adopt a first coordination sphere meso arrangement. The almost identical selectivity of the Ph(3)-trisox(R,R,R)- and Ph(2)-BOX(R,R)-derived catalysts is as expected from the proposed model of the active catalyst based on a partially decoordinated podand. The behaviour of the "desymmetrised" trisox-Cu catalysts may be rationalised in terms of a general steady-state kinetic model for the three possible active bisoxazoline-copper species, which are expected to be in rapid exchange with each other in solution. This applies to both the trisox derivatives with stereochemically inverted and achiral oxazoline rings. The study underscores previous observations of superior performance of the catalysts bearing C(3)-chiral stereodirecting ligands as compared to systems of lower symmetry.

The Role of Symmetry in Asymmetric Catalysis

“…Mannich reactions using homochiral phenyl‐substituted trisoxazoline and box ligands as well as a tripodal ligand with one stereocenter inverted were studied. The homochiral C 3 ‐( R , R , R ) and C 2 ‐symmetric ( R , R ) ligands led to similar results in Cu(II)‐catalyzed α‐aminations of an α‐substituted β‐ketoester with dibensyl azodicarboxylate, whereas the heterochiral C 1 ‐symmetric ( R , S , S ) ligand gave the product with opposite absolute configuration with inferior selectivity (Table 4) 27…”

“…The synthetic method employed for the preparation of the ligands is based on a [2+1] coupling procedure,19 and therefore allows the preparation of trisoxazolines where one of the rings carries a substituent with different structure or different absolute configuration (Figure 5). 27 In contrast to C 2 ‐symmetric ligands, those with threefold symmetry remain chiral (with C 1 symmetry) upon inversion of one of the stereocenters…”

“…The symmetry of the tripodal ligand may also be reduced by replacing one or two of the oxazoline rings with achiral units 27. This was accomplished by the introduction of 4,4‐dimethyl‐oxazolin‐2‐yl groups.…”

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

“…As another test reaction we investigated the direct a-amination of a-substituted b-ketoesters with azodicarboxylates, [40] for which an efficient copper(II)-bisoxazoline-catalysed version had previously been reported by Jørgensen and co-workers. [41] Here again, the trisox systems proved to be superior to the corresponding BOX-Cu II catalysts.…”

A New Class of Modular Oxazoline‐NHC Ligands and Their Coordination Chemistry with Platinum Metals

“…[3] Indeed, such chiral enantiopure units are not only easily accessible, but being rigid, quasi-planar five-membered rings they also provide a good control of the first coordination sphere of the transition metal upon N-coordination. [4] N-Heterocyclic carbenes [5] are excellent "anchor" units for late transition metals which form strong metal-carbon bonds [6] and have thus been widely used in homogeneous catalysis. [7] They may be combined with other ligating units by the appropriate functionalization of the N-atoms in their heterocyclic structures.…”