Enantioselective Copper-Catalyzed Conjugate Addition of Dimethylzinc to 5-(1-Arylalkylidene) Meldrum’s Acids

Abstract

The asymmetric formation of all-carbon quaternary benzylic stereocenters containing a methyl substituent was realized by the enantioselective copper-catalyzed 1,4-addition of dimethylzinc to alkylidene Meldrum’s acids in the presence of a chiral phosphoramidite. Copper source and ligand optimization studies are presented, as well as the scope and limitations of dimethylzinc addition to various alkylidene Meldrum’s acids. Good to excellent yields and enantioselectivities were obtained.

Key words

Meldrum’s acid - all-carbon quaternary stereocenters - enantioselective conjugate addition - copper catalysis - organozinc reagents - phosphoramidite ligand

References

• For reviews, see:
• 1a Trost BM. Jiang C. Synthesis  2006,  369 
• 1b Christoffers J. Baro A. Adv. Synth. Catal.  2005,  347:  1473 
• 1c Douglas CJ. Overman LE. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5363 
• For reviews, see:
• 2a Thaler T. Knochel P. Angew. Chem. Int. Ed.  2009,  48:  645 
• 2b Alexakis A. Vuagnoux-d’Augustin M. Martin D. Kehrli S. Palais L. Hénon H. Hawner C. Chimia  2008,  62:  461 
• 2c Cozzi PG. Hilgraf R. Zimmermann N. Eur. J. Org. Chem.  2007,  5969 
• 2d Christoffers J. Koripelly G. Rosiak A. Rössle M. Synthesis  2007,  1279 
• Alexakis’ group:
• 3a Henon H. Mauduit M. Alexakis A. Angew. Chem. Int. Ed.  2008,  47:  9122 
• 3b Hawner C. Li K. Cirriez V. Alexakis A. Angew. Chem. Int. Ed.  2008,  47:  8211 
• 3c Palais L. Mikhel IS. Bournaud C. Micouin L. Falciola CA. Vuagnoux-d’Augustin M. Rosset S. Bernardinelli G. Alexakis A. Angew. Chem. Int. Ed.  2007,  46:  7462 
• 3d Vuagnoux-d’Augustin M. Kehrli S. Alexakis A. Synlett  2007,  2057 
• 3e Vuagnoux-d’Augustin M. Alexakis A. Chem. Eur. J.  2007,  13:  9647 
• 3f Martin D. Kehrli S. d’Augustin M. Clavier H. Mauduit M. Alexakis A. J. Am. Chem. Soc.  2006,  128:  8416 
• 3g Fuchs N. d’Augustin M. Humam M. Alexakis A. Taras R. Gladiali S. Tetrahedron: Asymmetry  2005,  16:  3143 
• 3h d’Augustin M. Palais L. Alexakis A. Angew. Chem. Int. Ed.  2005,  44:  1376 
• Hoveyda’s group:
• 3i May TL. Brown MK. Hoveyda AH. Angew. Chem. Int. Ed.  2008,  47:  7358 
• 3j Brown MK. Hoveyda AH. J. Am. Chem. Soc.  2008,  130:  12904 
• 3k Brown MK. May TL. Baxter CA. Hoveyda AH. Angew. Chem. Int. Ed.  2007,  46:  1097 
• 3l Lee K. Brown MK. Hird AW. Hoveyda AH. J. Am. Chem. Soc.  2006,  128:  7182 
• 3m Hird AW. Hoveyda AH. J. Am. Chem. Soc.  2005,  127:  14988 
• 3n Wu J. Mampreian DM. Hoveyda AH. J. Am. Chem. Soc.  2005,  127:  4584 
• Tomioka’s group:
• 3o Matsumoto Y. Yamada K. Tomioka K. J. Org. Chem.  2008,  73:  4578 
• 4a Wilsily A. Fillion E. Org. Lett.  2008,  10:  2801 
• 4b Fillion E. Wilsily A. Liao E-T. Tetrahedron: Asymmetry  2006,  17:  2957 
• 4c Fillion E. Wilsily A. J. Am. Chem. Soc.  2006,  128:  2774 
• 5a Shintani R. Duan W.-L. Hayashi T. J. Am. Chem. Soc.  2006,  128:  5628 
• 5b Mauleón P. Carretero JC. Chem. Commun.  2005,  4961 
• For enantioselective conjugate additions to alkylidene Meldrum’s acid acceptors leading to tertiary stereocenters, see:
• 6a Knöpfel TF. Zarotti P. Ichikawa T. Carreira EM. J. Am. Chem. Soc.  2005,  127:  9682 
• 6b Watanabe T. Knöpfel TF. Carreira EM. Org. Lett.  2003,  5:  4557 
• 7a Feringa BL. Acc. Chem. Res.  2000,  33:  346 
• 7b Feringa BL. Pineschi M. Arnold LA. Imbos R.
  de Vries AHM. Angew. Chem., Int. Ed. Engl.  1997,  36:  2620 
• 8 Alexakis A. Benhaim C. Rosset S. Humam M. J. Am. Chem. Soc.  2002,  124:  5262 
• 10 Rimkus A. Sewald N. Org. Lett.  2003,  5:  79 
• 11a Brown RFC. Coulston KJ. Eastwood FW. Gatehouse BM. Guddatt LW. Pfenninger M. Rainbow I. Aust. J. Chem.  1985,  37:  2509 
• 11b Baxter GJ. Brown RFC. Aust. J. Chem.  1975,  28:  1551 

9

The absolute stereochemistry of 2 was opposite to the one observed for the addition of Et₂Zn to 2,2-dimethyl-5-(1-arylethylidene)-1,3-dioxane-4,6-dione, see reference 4c.