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.

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 

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.

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