Catalytic Asymmetric Electrocyclizations : Early Investigations in an Emerging Field

1. Catalytic Asymmetric Electrocyclizations: Early Investigations in an Emerging Field R. David Grigg Schomaker Group Organic Student Seminar University of Wisconsin-Madison October 14, 2010

2. Background Woodward, R.B. and Hoffmann, R. The Conservation of Orbital Symmetry. Verlag Chemie, Weinheim, 1970. • Electrocyclic reactions • Stereospecific cyclization • Several drawbacks limit practical use of these reactions

3. A Powerful Synthetic Tool Nicolaou, K.C.; Petasis, N.A.; Zipkin, R.E. J. Am. Chem. Soc. 1982, 104, 5560-5562. • Biomimetic syntheses of endiandric acids • 8π-6π cascades • Natural products isolated as racemates

4. Asymmetric Electrocyclization In Nature Korman, T.P.; Hill, J.A.; Vu, T.N.; Tsai, S. Biochemistry2004, 43, 14529-14538. Miller, A.K.; Trauner, D. Angew. Chem. Int. Ed. 2005, 44, 4602-4606. Díaz-Marrero, A.R.; Cueto, M.; D’Croz, L.; Darias, J. Org. Lett.2008, 10, 3057-3060. • Enzyme provides chiral environment for cyclization

5. Nazarov Cyclization Nazarov, I.N.; Zaretskaya, I.I. Bull. Acad. Sci. U.R.S.S., Classe sci. chim. 1942, 200-209. Frontier, A.J.; Collison, C. Tetrahedron2005, 61, 7577-7606. • Earliest catalytic asymmetric examples with Nazarovcyclization • 4πelectrocyclization: controtatory

6. Substrate-Controlled Torquoselectivity Frontier, A.J.; Collison, C. Tetrahedron2005, 61, 7577-7606 Denmark, S.E.; Wallace, M.A.; Walker, C.B. J. Org. Chem. 1990, 55, 5543-5545 • Favoring direction of orbital rotation (torquoselectivity) • Torquoselectivity can be controlled by a stereocenter

7. Lewis Acid-Mediated Asymmetric Nazarov Evans, D.A.; Rovis, T.; Kozlowski, M.C.; Downey, C.W.; Tedrow, J.S. J. Am. Chem. Soc. 2000, 122, 9134-9142. Aggarwal, V.K.; Belfield, A.J. Org. Lett. 2003, 5, 5075-5078. • Chiral ligand (bisoxazoline) on Lewis acid could control torquoselectivity

8. Lewis Acid-Mediated Asymmetric Nazarov Aggarwal, V.K.; Belfield, A.J. Org. Lett. 2003, 5, 5075-5078. Evans, D.A.; Burgey, C.S.; Kozlowski, M.C.; Tregay, S.W. J. Am. Chem. Soc.1999, 121, 686-699. • Bulky substituents critical to achieving high enantioselectivity

9. Cu-tris(oxazoline) Catalyst He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2003, 125, 14278-14279. Hargaden, G.C.; Guiry, P.J. Chem. Rev. 2009, 109, 2505-2550. Cao, P.; Deng, C.; Zhou, Y.; Sun, X.; Zheng, J.; Xie, A.; Tang, Y. Angew. Chem. Int. Ed. 2010, 49, 4463-4466. • Polarized divinylketonescyclize with poor enantioselectivity using Cu(II)-PyBOX Lewis acids • Desired less planar chiral ligand • tris-oxazolinePendant group on box ligand Pendant Group

10. Catalyst Design and Scope Cao, P.; Deng, C.; Zhou, Y.; Sun, X.; Zheng, J.; Xie, Z.; Tang, Y. Angew. Chem. Int. Ed. 2010, 49, 4463-4466. • Only minor improvement in selectivity with pendant group • 10 mol% catalyst loading: Ionizing additive improved turnover R = Ph for Catalyst Screening

11. Stereochemical Model Cao, P.; Deng, C.; Zhou, Y.; Sun, X.; Zheng, J.; Xie, Z.; Tang, Y. Angew. Chem. Int. Ed. 2010, 49, 4463-4466. He, W.; Sun, X.; Frontier, A. J. Am. Chem. Soc. 2008, 130, 1003-1011. ? • Double-bond isomerization prior to cyclization • Steric effect identified for disfavored rotation (3.94 kJ mol-1) • Role of sidearm not defined

12. Enantioselective Protonation in the Nazarov Mohr, J.T.; Hong, A.Y.; Stoltz, B.M. Nature Chem.2009, 359-369. Liang, G.; Gradl, S.N.; Trauner, D. Org. Lett.2003, 5, 4931-4934. • Cyclization of 2-alkoxy divinylketone with Sc-PyBOX catalyst • Other substrates produced mixtures with low enantioselectivities • Suspected poor control of torquoselectivity • Protonation of enolate proposed to occur asymmetrically

13. Enantioselective Protonation in the Nazarov Liang, G. and Trauner, D. J. Am. Chem. Soc.2004, 126, 9544-9545. Evans, D.A.; Masse, C.E.; Wu, J. Org. Lett. 2002, 4, 3375-3378. • Simplified system improved enantioselectivity • Direction of conrotatoryelectrocyclization did not affect stereochemical outcome

14. Summary:Lewis Acid-Promoted NazarovCyclizations • Demonstrated viability of the transformation • Control of torquoselectivity achieved • Viable alternative: enantioselectiveprotonation • High catalyst loadings common

15. Brønsted Acid-Promoted Nazarov Cyclizations Terada, M. Synthesis 2010, 1929-1982. Rueping, M.; Ieawsuwan, W.; Antonchick, A.P.; Nachtsheim, B.J. Angew. Chem.Int. Ed.2007, 46, 2097-2100. • Precedent:Enantioselective transformations of imines with chiralBrønsted acids • Carbonyl activation could allow asymmetric Nazarovcyclization • Control of torquoselectivity or enantioselectiveprotonation

16. First EnantioselectiveOrganocatalyticElectrocyclization Rueping, M.; Ieawsuwan, W.; Antonchick, A.P.; Nachtsheim, B.J. Angew. Chem.Int. Ed.2007, 46, 2097-2100. • Chiral BINOL phosphates • N-triflyl phosphoramide improved reactivity • Low diastereoselectivity

17. Organocatalytic Enantioselective Protonation Rueping, M.; Ieawsuwan, W. Adv. Synth. Catal. 2009, 351, 78-84. • Octahydro-BINOL derivative improved selectivity for asymmetric enolateprotonation • No stereochemical model for either system

18. Bifunctional Organocatalyst Approach Bow, W.F.; Basak, A.K.; Jolit, A.; Vicic, D.A.; Tius, M.A. Org. Lett.2010, 12, 440-443. Basak, A.K.; Shimada, N.; Bow, W.F.; Vicic, D.A.; Tius. M.A. J. Am. Chem. Soc.2010, 132, 8266-8267. Shimada, N.; Ashburn, B.O.; Basak, A.K.; Bow, W.F.; Vicic, D.A.; Tius, M.A Chem. Commun.2010, 46, 3774-3775. • Asymmetric Nazarov for α-ketoenones • Well-designed for interaction with a bifunctionalorganocatalyst

19. Thiourea Catalysts for Asymmetric Nazarov Basak, A.K.; Shimada, N.; Bow, W.F.; Vicic, D.A.; Tius, M.A. J. Am. Chem. Soc.2010, 132, 8266-8267. • Bifunctional nature of catalyst crucial to enantioselectivity • Product could inhibit turnover • No well-defined stereochemical model

20. Summary:Organocatalytic Asymmetric Nazarov • Organocatalytic methods compare well to techniques utilizing Lewis acidic metals • Alternative approaches have achieved lower catalyst loadings • Attempts made to broaden substrate scope • Mechanisms of stereoinduction not well-understood at present

21. 6πElectrocyclizations: Beginnings Guner, V.A.; Houk, K.N.; Davies, I.W. J. Org. Chem.2004, 69, 8024. Bishop, L.M.; Barbarow, J.E.; Bergman, R.G.; Trauner, D. Angew. Chem. Int. Ed. 2008, 47, 8100-8103 • Rate of thermal 6πelectrocyclizations strongly dependant upon substrate electronics • Lewis acid interaction with EWG could catalyze the reaction • DFT calculations identified significant activation barrier lowering for ester at position 2

22. Catalytic Carba – 6πElectrocyclization Bishop, L.M.; Barbarow, J.E.; Bergman, R.G.; Trauner, D. Angew. Chem. Int. Ed. 2008, 47, 8100-8103. Bishop, L.M.; Roberson, R.E.; Bergman, R.G.; Trauner, D. Synthesis2010, 2233-2244. • t1/2 = 4 h at 50 °C without Me2AlCl • t1/2 = 21 min at 50 °C with 1 equiv Me2AlCl Uncatalyzed 1 equiv LA 0.43 equiv LA • Cyclization& stereocontrol feasible with Sc(III) & Cu(II) Lewis acids

23. 6 π Electrocyclization: Indoline Synthesis Speckamp, W.N.; Veenstra, S.J.; Dijkink, J.; Fortgens, R. J. Am. Chem. Soc.1981, 103, 4643-4645. Maciver, E.E.; Thompson, S.; Smith, M.D. Angew. Chem. Int. Ed. 2009, 48, 9979-9982. • 2-aza-pentadienyl anions found to be excellent substrates for facile electrocyclization • Asymmetric phase transfer catalysis proposed as a route to asymmetric indoline synthesis

24. Cyclization via Phase-Transfer Catalysis Maciver, E.E.; Thompson, S.; Smith, M.D. Angew. Chem. Int. Ed. 2009, 48, 9979-9982.

25. Electrocyclization or Mannich? Maciver, E.E.; Thompson, S.; Smith, M.D. Angew. Chem. Int. Ed. 2009, 48, 9979-9982. Corey, E.J.; Xu, F.; Noe, M.C. J. Am. Chem. Soc. 1997, 119, 12414-12415. • Possibility for an intramolecularMannich-type reaction • No cyclization with a substrate that could control enolate geometry

26. Chiral Brønsted Acid Catalysis: 6π Huisgen, R. Angew. Chem. Int. Ed. 1980, 92, 979. Müller, S.; List, B. Angew. Chem. Int. Ed.2009, 48, 9975-9978. • α,β-unsaturated hydrazone rearrangement to give 2-pyrazoline is isoelectronic to a pentadienyl anion 6πelectrocyclization • Acid-promoted: might occur asymmetrically with chiralBrønsted acid

27. 2-Pyrazoline Synthesis via Electrocyclization Müller, S.; List, B. Angew. Chem. Int. Ed.2009, 48, 9975-9978. • Chiral phosphoric acids found to give optically active products with good yield and enantioselectivity • Could form hydrazone intermediate in situ

28. Mechanistic Questions Müller, S.; List, B. Synthesis2010, 2171-2179. • Two mechanistic scenarios • Intramolecular Michael addition would be a disfavored 5-endo-trig • Stereochemical model not proposed at present

29. 6πElectrocyclization Summary • High activation barrier limits scope to substrates with compatible electronics, though encouraging results have been obtained • Methods have worked well for heterocycle formation • Approaches include phase-transfer catalysis & chiralBrønsted acid catalysis • Mild conditions • Exact cyclization mechanisms not well understood

30. Conclusions & Future Directions • Catalytic asymmetric electrocyclizations have the potential for becoming key synthetic transformations • Enantioselective reactions can be approached with Lewis acidic metals and organocatalysts • Selectivity can be accomplished by control of torquoselectivity and through enantioselectiveprotonation • Future efforts will seek to cyclize more diverse polyene structures in both the Nazarov reaction and 6π systems • Improving understanding of stereoinduction mechanism will be a key goal in future efforts

31. Acknowledgements • Jennifer Schomaker • Kat Myhre • Practice Talk attendees • Alex Clemens • James Gerken • Jonathan Hudon • Michael Ischay • Liz Tyson • Dan Wherritt • Kevin Williamson • Gene Wong Schomaker Group Members • Luke Boralsky • Rachel Dao • Ally Esch • John Hershberger • Dagmara Marston • Alan Meis • Simon Pearce • Jared Rigoli • VitaliyTimokhin