Asymmetric 1,3-Dipolar Cycloaddition Reactions of Metal Stabilized Azomethine Ylides

Jenn Carman

University of North Carolina – Chapel Hill

January 30, 2009

Outline

• Introduction

• Achiral N-metalated azomethine ylides and chiral dipolarophiles

• Chiral N-metalated azomethine ylides and achiral dipolarophiles

• Chiral catalysis

• Conclusion

Formation of Azomethine Ylides

I. Deprotonation by a base

II. Ring opening

III. Carbene Chemistry

Potential Applications to Natural Product Synthesis

Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225.Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006, 8, 1073.

I. Pyrrolidines

II. Imidazolidines

Use in Total Synthesis

Obst, U.; Betschmann, P.; Lerner, C.; Seiler, P.; Diederich, F. Helv. Chim. Act. 2000, 83, 855.Sebahar, P. R. and Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666.

Overman, L. E. and Tellew, J. E. J. Org. Chem. 1996, 61, 8338.

Ylide Conformation

Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.Ardill, H.; Grigg, R.; Sridharan, V.; Surendrakumar, S. Tetrahedron, 1988, 44, 4953.

Galliford, C. V.; Martenson, J. S.; Stern, C.; Scheidt, K. A. Chem. Commun. 2007, 631.

I. Steric interactions

II. Rate of isomerization

Role of Molecular Orbitals

Fukui, K. Acc. Chem. Res. 1971, 4, 57.Houk, K. N. Acc. Chem. Res. 1975, 8, 361.

Houk, K. N. J. Am. Chem. Soc. 1973, 95, 7287.Houk, K. N. J. Am. Chem. Soc. 1973, 94, 8953.

Exo and Endo Transition States

Oderaotoshi, Y.; Cheng, Wenji, C.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043.

Concerted or Stepwise?

Tatsukawa, A.; Kawatake, K.; Kanemasa, S.; Rudzinski, J. M. J. Chem Soc. Perkin Trans. 2 1994, 2525.Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321.

Experimental Determination

Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321.

Proposed Catalytic Cycle

Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321.

Achiral N-Metalated Azomethine Ylides and Chiral Dipolarophiles

Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido, K. Bull.Chem. Soc. Jpn. 1990, 63, 2857.

Increased Steric Bulk on the Auxiliary

Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido, K. Bull.Chem. Soc. Jpn. 1990, 63, 2857.Kanemasa, S.; Hayashi, T.; Tanaka, J.; Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56, 4473.

Menthyl Auxiliary

Grigg, R.; Thornton;-Pett, M.; Yoganathan, G. Tetrahedron 1999, 55, 1763.Barr, D. A.; Dorrity, M. J.; Grigg, R.; Hargreaves, S.; Malone, J. F.; Montgomery, J.; Redpath, J.; Stevenson, P.;

Thronton-Pett, M. Tetrahedron 1995, 51, 273.Barr, D. A.; Dorrity, M. J.; Grigg, R.; Malone, J. F.; Montgomery, J.; Rajviroongit, S.; Stevenson, P.; Thronton-Pett,

M. Tetrahedron 1990, 31, 6569.

endo transition state:

Enone Dipolarophiles

Galley, G.; Lienscher, J.; Patzel, M. J. Org. Chem. 1995, 60, 5005.

R Group Yield (%) 1:2

A 90 95:5

B 96 92:8

C 78 >95:5

D 88 >95:5

E 94 >95:5

Chiral Amines as Auxiliaries

Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles, S. J.; Hursthouse, M. B.; Groundwater, P. W.; Meth-Cohn, O. Tetrahedron 2005, 61, 3745.

Vinyl Sulfoxides

Ruano, J. L. G.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2002, 67, 981.Ruano, J. L. G.; Tito, A.; Peromingo, M. T. J. Org. Chem. 2003, 68, 10013.

R’ Solvent Temp Yield (%) A:B

Me THF RT 52 90:10

Et MeCN RT 61 20:80

Et MeCN Reflux 53 94:6

Chiral Sulfinimines

Viso, S.; Fernandez de la Pradilla, R.; Guerrero-Strachan, C.; Alonso, M.; Martinez-Ripoll, M.; Andre, I. J. Org. Chem. 1997, 62, 2316.

Recent Application to the Synthesis of Biologically Active Molecules

Najera, C.; de Gracia Retamosa, M.; Sansano, J. M. Tetrahedron: Asymmetry 2006, 17, 1985.Najera, C.; de Gracia Retamosa, M.; Sansano, J. M.; de Cozar, A.; Cossio, F. P. Eur. J. Org. Chem. 2007, 5038.

Nitroalkenes as Dipolarophiles

Ayerbe, M.; Arrieta, A.; Cossio, F. P. J. Org. Chem. 1998, 63, 1795.Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.; Carrascal, T.; Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-

Vanaclocha, F.; Cossio, F. P. Angew. Chem., Int Ed. 2005, 44, 2903.

R1 Metal Salt Yield (%) endo:exo

PhenylorPhenol AgOAc 29‐69 2:98

Phenyl LiClO4 47‐66 83:17

Phenol LiClO4 24‐45 2:98

Chiral Lactones: Exo Selective Cycloaddition

Pyne, S. G.; Safaei, G. J.; Koller, F. Tetrahedron Lett. 1995, 36, 2511.Pyne, S. G.; Safaei, G. J.; Javidan, A.; Skelton, B. W.; White, A. H. Aust. J. Chem. 1998, 51, 137.

R Metal Salt Base Temp. Yield (%) A:B

Me LiBr DBU ‐78oC 52 82:18

Me AgOAc DBU RT 83 58:42

Ph LiBr NEt3 0oC 59 93:7

Chiral N-Metalated Azomethine Ylides and Achiral Dipolarophiles

Grigg, R.; Thornton, P. M.; Xu, J.; Xu, L.-H. Tetrahedron 1999, 55, 13841.

Methyl Acrylate as Dipolarophile

Grigg, R.; Thornton, P. M.; Xu, J.; Xu, L.-H. Tetrahedron 1999, 55, 13841.Alcaide, B.; Almendros, P.; Alonso, J. M.; Redondo, M. C. J. Org. Chem. 2003, 68, 1426.

Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F. Chem Commun. 2000, 485.

Synthesis of Indolizidinone Amino Esters

Alcaide, B.; Almendros, P.; Redondo, M. C.; Ruiz, M. P. J. Org.Chem. 2005, 70, 8890.

Synthesis and Deprotection of Pyrroloimidazoles

Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett. 1996, 37, 1707.Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett. 1996, 37, 1711.

Saturated Oxazin-2-ones

Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkin, D. Tetrahedron: Asymmetry 1991, 2, 997.Anslow, A. S.; Harwood, L. M.; Phillips, H.; Lilley I. A. Tetrahedron: Asymmetry 1995, 6, 2465.

Improved Selectivity

Chinchilla, R.; Falvello, L. R.; Galindo, N.; Najera, C. Eur. J. Org. Chem. 2001, 3133.

Intramolecular Cycloaddition

Bobbeck, D. R.; Warner, D. L.; Vedejs, E. J. Org. Chem. 2007, 72, 8506.Warner, D. L.; Hibberd, A. M.; Kalman, M.; Klapars, A.; Vedejs, E. J. Org. Chem. 2007, 72, 8519.

Chiral Ylide Cycloaddition Using Catalytic Copper

Garner, P.; Hu, J.; Parker, C. G.; Youngs, W. J.; Medvetz, D. Tet. Lett. 2007, 48, 3867.

Importance of Ylide Conformation

Galliford, C. V.; Martenson, J. S.; Stern, C.; Scheidt, K. A. Chem. Commun. 2007, 631.

Azalactone as an Ylide Precursor

Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638.

Aryl Substitution Yield (%) ee (%)

p‐MeO 77 95

p‐Br 75 93

p‐NO2 98 91

o-Me 73 86

Catalytic Cycle

Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. 2007, 129, 12638.

Iron Ligand Provides Different Selectivities

Martin-Matute, B.; Pereira, S. I.; Pena-Cabrera, E.; Adrio, J. Silva, A. M. S.; Carretero, J. C.; Adv. Synth. Catal. 2007, 349, 1714.

Lopez-Perez, A.; Adrio, J. Carretero, J. C.; J. Am. Chem. Soc. 2008, 130, 10084.

Copper Catalyst Tolerant of Substituents

Wang, C.-H.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250.

R1 R2 R3 R4 R5 Yield (%)

ee (%)

Ph H Me Me CO2Me 95 >99

p‐Cl‐Ph H Me Me CO2Me 92 >99

Ph Ph H Me CO2Me 75 97

Ph H H t‐Bu H 94 97

Copper Transition State: Endo

Shi, M. and Shi, J.-W. Tetrahedron: Asymmetry 2007, 18, 645.

Nickel Catalyst Gives Endo Transition State

Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J. Org. Chem. 2008, 73, 305.

Phosphoramidite Catalysts

Najera, C.; de Gracia Retamosa, M. Sansano, J. M. Angew. Chem. Int. Ed. 2008, 47, 6055.

Phosphoric Acid

Liu, W.-J.; Chen, Z.-H.; Gong, L.-Z. Org. Lett. 2008, 10, 5357.

Zinc Catalyst and Ferrocenyl Ligand

Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8, 4687.

Catalytic Silver and Ferrocenyl Ligand

Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400.

Hydrogen Bonding Capabilities Control Enantioselectivity

Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 750.

R R1 Yield (%) ee (%)

NH2 Ph 95 90

NH2 4‐naphthyl 98 91

NMe2 Ph 96 ‐85

NMe2 2‐naphthyl 91 ‐87

Calculated Transition State Structures

Conclusions

• Azomethine ylide cycloadditions are an effective way to make substituted pyrrolidine rings,

pyrrolizidines.

• By varying the reaction conditions (metal salt, ligand, solvent, temperature), the product with the

desired stereochemistry can be obtained

• Starting materials are often easily made from compounds such as amino acids

Acknowledgements

• Johnson group

• Jeff Johnson

Chiral Centers from Achiral Starting Materials

Grigg, R. and Sarker, M. A. B. Tetrahedron 2006, 62, 10332.

Stereochemistry and Regioselectivity

Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484.Fukui, K. Acc. Chem. Res. 1971, 4, 57.