Controlling Diastereoselectivity in the Tandem Microwave-Assisted Aza-Cope Rearrangement-Mannich Cyclization

Abstract

The first microwave-assisted version of the tandem aza-Cope rearrangement-Mannich cyclization was developed. This sequence provides acylpyrrolidines in a single synthetic step while significantly reducing reaction times as compared to analogous reactions using conventional heating. Diastereoselectivity in these reactions may be improved by increasing the size of the amine-protecting group, an observation which has not been reported previously for aza-Cope-Mannich reactions leading to monosubstituted acylpyrrolidines. Finally, in some cases, diastereoselectivity could be improved by lowering the reaction temperature.

Key words

tandem reactions - diastereoselectivity - rearrangements - cyclizations - amino alcohols

References and Notes

• For reviews of tandem or domino reactions, see:
• 1a Pellissier H. Tetrahedron  2006,  62:  1619 
• 1b Pellissier H. Tetrahedron  2006,  61:  2143 
• 1c Nicolaou KC. Montagnon T. Snyder S. Chem. Commun.  2003,  551 
• 1d Parsons PJ. Penkett CS. Shell AJ. Chem. Rev.  1996,  96:  195 
• 1e Bunce RA. Tetrahedron  1995,  51:  13103 
• 2 Overman LE. Kakimoto M.-A. J. Am. Chem. Soc.  1979,  101:  1310 
• For reviews of the aza-Cope rearrangement-Mannich cyclization and related reactions, see:
• 3a Bonin M. Micouin L. Chem. Rev.  2004,  104:  2311 
• 3b Overman LE. Aldrichimica Acta  1995,  28:  107 
• 3c Overman L. Acc. Chem. Res.  1992,  25:  352 
• 3d Overman L. Ricca D. In Comprehensive Organic Synthesis   Vol. 8:  Trost BM. Pergamon; New York: 1991.  p.1007-1046  
• 4a Overman LE. Jacobsen EJ. Doedens RJ. J. Org. Chem.  1983,  48:  3393 
• 4b Overman LE. Kakimoto M.-A. Okazaki ME. Meier GP. J. Am. Chem. Soc.  1983,  105:  6622 
• 4c Jacobson J. Levin J. Overman L. J. Am. Chem. Soc.  1988,  110:  4329 
• 4d Doedens R. Meier G. Overman L. J. Org. Chem.  1988,  53:  685 
• 4e Deng W. Overman LE. J. Am. Chem. Soc.  1994,  116:  11241 
• 4f Overman L. Trenkle W. Isr. J. Chem.  1997,  37:  23 
• Aza-Cope-Mannich reactions have also been initiated by elimination of a leaving group to form the iminium cation. See, for example:
• 5a Overman LE. Jacobsen EJ. Tetrahedron Lett.  1982,  23:  2741 
• 5b Sakurai O. Horikawa J. Iwasaki T. J. Chem. Soc., Chem. Commun.  1995,  2527 ; and ref. 4e
• For recent applications of the aza-Cope rearrangement-Mannich cyclization in the synthesis of natural products, see:
• 6a Earley WG. Jacobsen JE. Madlin A. Meier GP. O’Donnell CJ. Oh T. Old DW. Overman LE. Sharp MJ. J. Am. Chem. Soc.  2005,  127:  18046 
• 6b Brummond KM. Hong S.-P. J. Org. Chem.  2005,  70:  907 
• 6c Brüggemann M. McDonald AI. Overman LE. Rosen MD. Schwink L. Scott JP. J. Am. Chem. Soc.  2003,  125:  15284 
• For reviews, see:
• 7a O’Hagan D. Nat. Prod. Rep.  2000,  17:  435 
• 7b Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 
• 7c Bellina F. Rossi R. Tetrahedron  2006,  7213 
• 8a Cooke A. Bennett J. McDaid E. Tetrahedron Lett.  2002,  43:  903 
• 8b Agami C. Cases M. Couty F. J. Org. Chem.  1994,  59:  7937 
• For books, see:
• 9a Microwave Assisted Organic Synthesis   Tierney JP. Lidstrom P. Blackwell; Oxford: 2005. 
• 9b Kappe O. Stadler A. Microwaves in Organic and Medicinal Chemistry   Wiley-VCH; Weinheim: 2005. 
• 9c Microwaves in Organic Synthesis   Loupy A. Wiley-VCH; Weinheim: 2006. 
• For reviews, see:
• 10a Varma RS. Pure Appl. Chem.  2001,  73:  193 
• 10b Perreux L. Loupy A. Tetrahedron  2001,  57:  9199 
• 10c Lidstrom P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 
• 10d Kuhnert N. Angew. Chem. Int. Ed.  2002,  41:  1863 
• 10e Nuchter M. Ondruschka B. Bonrath W. Gum A. Green Chem.  2004,  6:  128 
• 10f Kappe O. Angew. Chem. Int. Ed.  2004,  43:  6250 
• For examples of imine or iminium cation formation using microwave-assisted methods, see:
• 11a Shi L. Tu Y.-Q. Wang M. Zhang F.-M. Fan C.-A. Org. Lett.  2004,  6:  1001 
• 11b Kalbalka GW. Wang L. Pagni RM. Tetrahedron Lett.  2001,  42:  6049 
• 11c Gadhwal S. Baruah M. Prajapati DS. Sandhu JS. Synlett  2000,  341 
• 11d Varma RS. Dahiya R. Kumar S. Tetrahedron Lett.  1997,  38:  2039 
• 12 Desai H. D’Souza BR. Foether D. Johnson BF. Lindsay HA. Synthesis  2007,  902 
• For reviews of allylic strain-directed reactions, see:
• 15a Hoveyda AH. Evans DA. Fu GC. Chem. Rev.  1993,  93:  1307 
• 15b Hoffman RW. Chem. Rev.  1989,  89:  1841 

13

Relative stereochemistry was confirmed by NOE analysis of 10b. MeMgBr addition to 9a and 9b followed by benzyl or benzhydryl deprotection yielded the same pyrrolidine.

14

For an excellent discussion of the possible pathways for erosion of stereoselectivity in the aza-Cope-Mannich reaction, see ref. 4d