Asymmetric metal-catalyzed [3+2] cycloadditions of azomethine ylides (2006)

Cycloadditions of azomethine ylides with olefins provide a short, attractive route to pyrrolidine units with the\npotential to control the relative and absolute configuration by means of a chiral catalyst. Grigg and co-workers\nhave pioneered the use of chiral transition metal complexes to induce enantioselective cycloadditions of this\ntype. However, stoichiometric amounts of metal complexes were employed in this work.\nPaying regard to Griggs investigations it was intended to develop a system which gives asymmetric induction\nusing catalytic amounts of chiral transition metal complexes. A first screening of different transition metal\nsources showed promising results for Cu(I) and Ag(I) species. The application of their complexes with several\nmembers of different ligand classes to the 1,3-dipolar cycloaddition reaction directed the interest towards\nphosphinooxazoline (PHOX) ligands. The catalysts derived from the two different metals and PHOX ligand 39\ninduced enantioselectivity in both cases. Subsequent investigations demonstrated that\nalso the use of the analogous Au(I) catalyst led to the formation of enantioenriched pyrrolidines.\n\nAlthough the Cu(I)-PHOX catalyst generated the five-membered heterocycle 38a with higher enantiomeric\nexcess than the other two catalysts (Table 28, compare entries 1 with 2 and 3) the focus was directed to the\nAg(I) system. Firstly, because a further screening with differently substituted PHOX ligands indicated only for\nthe Ag(I) system the chance of substantial improvement of the enantioselectivity. Secondly, much higher\nendo:exo selectivity could be observed than for the other two systems. Optimization of the substitution pattern of\nthe PHOX ligand showed that particularly the variation of the substituents at the phosphorous atom\nand the C5 position of the oxazoline moiety had a positive effect on asymmetric induction.\n\nScheme 47 shows the most selective PHOX ligand (79) found to date which resulted in formation of the\npyrrolidine product 38a with 84% enantiomeric excess.\n\nAlthough Ag(I)-PHOX complexes gave only moderate to good asymmetric induction in intermolecular\n[3+2] cycloadditions, they demonstrated to be efficient catalysts for intramolecular [3+2] cycloadditions of\nazomethine ylides, giving access to tricylic products with almost complete diastereocontrol and enantiomeric\nexcesses of up to 99%..\n\nAdditionally the C5-substituted PHOX ligands, originally synthesized for the [3+2] cycloaddition reaction, were\napplied to the Ir(I)-catalyzed asymmetric hydrogenation of an imine as well as tri- and tetrasubstituted olefins.\nThey induced similar or superior enantioselectivity than the best PHOX ligand (bis(ortho-tolyl)phosphino-tertbutyloxazoline).\nThis confirmed the preliminary assumption that the steric bulk caused by the substituents at the\nC5 position of the oxazoline ring might direct the methyl groups of the isopropyl substituent at the C4 position to\nthe coordination center creating a “tertiary butyl substitute“. Thus, this ligand type represents a less expensive\nsubstitute of the tert-leucine-derived PHOX ligand.