A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.

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CONTENTS  INTRODUCTION  REACTION  MECHANISM  APPLICATION  SCOPE  CONCLUSION  REFERENCE.

CONTENTS  INTRODUCTION  REACTION  MECHANISM  APPLICATION  SCOPE  CONCLUSION  REFERENCE.

Presentation transcript:

A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005

Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

Cyclopropane Strain and Reactivity  Cyclopropane has significant ring strain.  Cyclopropanes have pi character.

Alkenes and Cyclopropanes  “Virtually every reaction that an alkene undergoes has its counterpart in the repertoire of transformations possible with cyclopropanes.” Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 901.

Alkenes and Cyclopropanes  Carreira’s approach to spirotryprostatin B  Cossy’s approach to zincophorin Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, ASAP. Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem. Int. Ed. 2002, 41, 2144.

Alkenes and Cyclopropanes

Oxocarbenium-Based Heterocycle Syntheses

Zimmerman-Traxler Cyclization

The Kulinkovich Cyclopropanation Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.

Cyclopropanation Yields Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2,

Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

Initial Attempts at Oxepane Formation

Softer Lewis acids (CuSO 4, ZnCl 2, SnCl 2 ) stop at acetal

Mechanism of Oxepane Formation

Stereochemistry of Oxepane Formation

Zimmerman-Traxler Cyclization

Initial Limitations of Oxepane Formation

Two-Lewis Acid System No problems associated with coexistence of two Lewis acids

Yields and Scope of Oxepane Formation O'Neil, K. E.; Kingree, S. V.; Minbiole, K. P. C. Org. Lett. 2005, 7,

Appearance of Trans Oxepane

Inclusion of Sidechain Functionality

Certain chelating groups are tolerated…

Inclusion of Sidechain Functionality Certain chelating groups are tolerated… but others fail to rearrange to oxepane

Reaction Optimization  Alternate Lewis acids Zirconium tetrachloride  Alternate drying agents Molecular sieves  Alternate solvent systems More or less polar solvents

Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

Nitrogen Analogs: Azepines  Analogous reaction in nitrogenous heterocycles?

Nature of Protecting Group on Nitrogen

Assembly of Azepine Precursor

Cyclization attempts

Cyclization Attempts with Free Amine Amino alcohol not yet isolated

Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

Radical Cyclization

Heterolysis is known for cyclopropanols with mild single electron oxidants (e.g., Mn 3+ and Fe 3+ ).

Radical Cyclization Utilizing Azide Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116,

Radical Cyclization Towards Heterocycles

Radical Cyclization Towards Functionalized Heterocycle

Progress Towards Piperidine

Recourse for Piperidine

Towards the Pyrrolidine Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,

Outline  I. Introduction to Cyclopropanes and Heterocycle Formation Strategies  II. Proof of Concept: Oxepane Synthesis  III. Progress Towards Nitrogenous Heterocycles  IV. Radical Strategies  V. Future Directions

Alternative Ring Size

Sites of Functionalization on Oxepane Ring

Cyclopropane Functionalization via Cyclopropene Doyle, M. P.; Protopopova, M.; Müller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, Müller, P.; Granicher, C. Helv. Chim. Acta 1995, 78, 129. Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719.

Natural Product Total Synthesis

Conclusions  Cyclopropanes can be utilized as homo-alkenes to prepare heterocycles  A facile two-step procedure has been developed to prepare oxepanes with excellent stereoselectivity  Further substitution and alternate heterocycles are being explored  Radical cyclization promises another method to deliver heterocycles from cyclopropanols

Epilogue on Undergraduate Teaching and Research  Quality of Life  Opportunities for Funding  Satisfaction Direction of research Students

The Group Kerry O’Neil, JMU ’05Seth Kingree, JMU ’06Cambria Baylor, JMU ’06 Andrew Blanchard, JMU ’07Steve Andrews, JMU ’07Erik Stang, JMU ’06

Where’s James Madison University?

Funding

Acknowledgements  NMR: Tom Gallaher and Jeff Molloy  Nebraska Center for Mass Spectrometry  Drs. Kevin Caran and Scott Lewis  James Madison University

Future Direction: Cyclopropane Functionalization

Other Backups: Discrete Homoenolate

Other Backups: Radical

Aza Cope Possibility

Modified Point of Attachment

Precedent For Acyliminium Formation  Hsung Precedent