Control of Diastereo- and Enantioselectivity in Metal-Catalyzed 1,3-Dipolar Cycloaddition Reactions of Nitrones with Alkenes. Experimental and Theoretical Investigations

Abstract

The scopes and limitations of the catalytic effects of achiral and chiral Mg(II) and Cu(II) complexes on the stereochemistry of the 1,3-dipolar cycloaddition reaction of nitrones with alkenes have been investigated. A remarkably high degree of endo-selectivity (endo/exo > 20) is induced in the 1,3-dipolar cycloaddition reaction by the presence of a catalytic amount of, especially, a Mg(II)−phenanthroline complex. The diastereochemical assignment of the product is confirmed by an X-ray crystallographic determination of the structure of the exo-isoxazolidine. By the reaction of an alkene bearing a chiral auxiliary, with different nitrones and a catalytic amount of the Mg(II)−phenanthroline complex, one of four possible diastereomers of the isoxazolidines is exclusively formed. The absolute stereochemistry of this product is also assigned by an X-ray crystallographic investigation. The presence of a catalytic amount of a chiral Mg(II)−bisoxazoline complex in the 1,3-dipolar cycloaddition reaction leads to high endo-selectivity and occasionally with an ee > 80%. The reaction mechanism of the Mg(II)-catalyzed reaction is discussed on the basis of the experimental results and semiempirical quantum chemical calculations. The calculations are used to account for the catalytic effect of the Mg(II)−ligand complexes and to determine transition state energies for both the uncatalyzed and Mg(II)−ligand-catalyzed reactions.

Enantioselective magnesium-catalyzed transformations

“…The first example of enantioselective magnesium-catalyzed 1,3-dipolar cycloaddition was described by Jørgensen et al in 1996. 22 It occurred between nitrones and alkenes in the presence of a chiral bis(oxazoline) magnesium(II) catalyst with enantioselectivities of up to 82% ee. Ever since, other chiral magnesium complexes have been successfully applied to this type of reaction.…”

Asymmetric 1,3-dipolar cycloadditions of acrylamides

“…Application of 10 mol% of the achiral MgI 2 -phenanthroline complex 63 led to the attainment of high endo selectivity (endo:exo 95:5) (entries 6-9, Table 3). 147 When the chiral magnesium-bisoxazoline complex 64 was employed in cycloadditions with C,N-diphenylnitrone 78, high endo selectivity was observed (ratio of endo:exo >95:5) and enantiomeric excesses of up to 82% were achieved for the endo-isomer (entries 10 and 11, Table 3). 147 The diastereofacial discrimination in favour of the endo-diastereomer is due to the preferred endo attack of the nitrone 78 on the -Re face of the alkene 75 from below the plane of the alkene (Figure 27).…”

Asymmetric Syntheses of Analogs of Kainic Acid

“…Figure 12. Exo/Endo selectivity using oxazolidinone alkene dipolarophiles A study by Gothelf, K. V. et al [Gothelf, K. V. et al 1996] established that the octahedral Ti(O-iPr) 2 Cl 2 Lewis acid catalyst favored the exo pathway and tetrahedral metal complex catalysts favored the endo pathway.…”

“…It should be noted that the assignment of exo and endo isomers were based on the coupling constants between H3 and H4 in the isoxazolidine rings [Huisgen, R. et al 1969] [Gothelf, K. et al 1996]. The exo adduct with a cis relative configuration between H3 and H4, has a larger H3-H4 coupling constant than the endo isomer which has a trans relative configuration between H3 and H4.…”

“…Preparation of MgI 2 -Phenanthroline (0.1M in CH 2 Cl 2 ) [Gothelf, K. V. et al 1996] Magnesium (103.5 g, 4.6 mmol), I 2 (448.6 mg,1.8 mmol) and diethyl ether (10 ml) were placed in a 25 ml flask with a magnetic stirring bar under N 2 . The mixture was stirred at room temperature 3h in which the iodine color disappeared.…”