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Enantioselective Radical Reactions

Enantioselective Radical Reactions. Justin Potnick March 12, 2004. Outline. Introduction to Radical Reactions Atom Transfers Reductive Alkylations Fragmentations Tandem Addition-Trapping Reactions Oxidations Summary. Introduction. Typical radical reactions go through 3 steps

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Enantioselective Radical Reactions

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  1. Enantioselective Radical Reactions Justin Potnick March 12, 2004

  2. Outline • Introduction to Radical Reactions • Atom Transfers • Reductive Alkylations • Fragmentations • Tandem Addition-Trapping Reactions • Oxidations • Summary

  3. Introduction • Typical radical reactions go through 3 steps • Generation of radical from non-radical species • Propagation/Chain transfer process • Termination Initiation Propagation Termination Precursor Radical-1 Radical-2 Neutral Product Chain transfer

  4. Radical Properties x • Short lived, highly reactive species; difficult to use • Proceed under mild, neutral conditions • Radical reactions have been performed in aqueous media • Compatible with many functional groups, inert toward -OH or -NH • Early, reactant-like TS‡ allows for prediction of product stereochemistry from ground state structure C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem Rev.1991, 91, 1237

  5. Creating Selectivity • Chiral source must be present during reaction • Chiral source bound to achiral substrate (complex-controlled) • Chiral source bound to the reagent (reagent-controlled) • •

  6. Outline • Introduction to Radical Reactions • Atom Transfers • Reductive Alkylations • Fragmentations • Tandem Addition-Trapping Reactions • Oxidations • Summary

  7. Atom Transfer Reactions • • • Typically involve transfer of a hydrogen or halogen atom • Transfer of atom from a chain-transfer agent to a radical species to generate another radical • Chiral Lewis Acid • Chiral Reagent •

  8. Enantioselective Atom Transfer • Lewis acids have been used to enhance and catalyze radical reactions • Conjugate addition followed by selective H-atom transfer • Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, F. J. Org. Chem.1995, 60, 3576

  9. Radical Initiator • Trialkylboranes give free alkyl radicals upon treatment with oxygen • Et3B/O2 works as a radical initiator even at -78 C • Advantageous for stereoselective reactions: improved selectivities at lower temperatures • Alternate methods of radical generation typically involve high temperatures Et3B/O2 • • • • Ollivier, C.; Renaud, P. Chem. Rev.2001,101, 3415-3434

  10. Enantioselective Atom Transfer • Selectivity was dependent on concentration of reactants • Low ee at low concentration • Suggests uncomplexed radical reacting to give racemic product in competing background reaction Murakata, M.; Tsutsui, H.; Takeuchi, N.; Hoshino, O. Tetrahedron1999, 55, 10295

  11. Acyclic Systems • With previous cyclic system, selectivity is easier to control • Acyclic systems require more control • The complexing chiral group must be fixed relative to the prochiral center • The chiral group must shield one face of the radical or alkene • Reactivity of the complex must exceed reactivity of the free substrate • • • Murakata, M.; Tsutsui, H.; Takeuchi, N.; Hoshino, O. Tetrahedron1999, 55, 10295

  12. Rotamer Control • Rotamer control in radical transformations is important for selectivity • Achiral auxiliaries can provide a handle to control rotamers of acyclic substrates • Oxazolidinone templates were chosen based on success of chiral auxiliaries in Lewis acid promoted free radical transformations • S-cis favored due to A1,3 strain No rotamer control Rotamer control • • • • • • • Sibi, M. P.; Porter, N. A. Acc. Chem. Res.1999, 32, 163

  13. Acyclic Rotamer Control Sibi, M. P.; Asano, Y.; Sausker, J.B. Agnew. Chem., Int. Ed.2001, 40, 1293

  14. Conjugate Additions to -Methacrylates • • • • Sibi, M. P.; Sausker, J. B., J. Am. Chem. Soc. 2002,124, 984-991.

  15. Achiral Napthosultam Template • aPh3SnH was used as H-atom donor Sibi, M. P.; Sausker, J. B., J. Am. Chem. Soc. 2002,124, 984-991.

  16. Predicted Transition State to Account for Selectivity • Attack from re face Attack occurs before any rotamer interconversion: precursor geometry imparts on product stereochemistry S-trans rotamer Sibi, M. P.; Sausker, J. B., J. Am. Chem. Soc. 2002,124, 984-991.

  17. -Substituted β-Amino Acids Sibi, M. P.; Patil, K. Agnew. Chem., Int. Ed.2004, 43, 1235

  18. Reasons for selectivity • Radical reactions proceed through an early transition state → resembles starting complex • H-atom transfer occurs rapidly on rotamer conformation timescale • Atom transfer or radical addition to a neutral molecule proceed at high rates: approximately 104-108 dm3M-1s-1 • Geometry of starting material affects product stereochemistry • Exploitation of relatively slow conformation changes is possible Sibi, M. P.; Manyem, S.; Zimmerman, J., Chemical Reviews 2003,103, 3263-3295.

  19. Memory of Chirality • Atom transfer occurs at a high rate • Dependent on temperature and concentration of H-atom donor • • Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D., J. Am. Chem. Soc. 2000,122, 9386-9390.

  20. Chiral Reagents Reduction of -bromoketones Reduction of -bromoesters Hydrometallation of methyl methacrylate Nanni, D.; Curran, D. P. Tetrahedron: Asymmetry1996, 7, 2417. Blumenstein, M.; Schwarzkopf, K.; Metzger, J. O., Angew. Chem., Int. Ed. Eng. 1997,36, 235-236. Curran, D. P.; Gualtieri, G., Synlett 2001, 1038-1041.

  21. Hydrosilylation of Alkenes • • • Cai, Y.; Roberts, B. P.; Tocher, D. A., J. Chem. Soc. Perkin Trans. 1 2002, 1376-1386. Haque, M. B.; Roberts, B. P., Tetrahedron Lett. 1996,37, 9123-9126. Haque, M. B.; Roberts, B. P.; Tocher, D. A., J. Chem. Soc., Perkin Trans. 1 1998, 2881-2890.

  22. Halogen Atom Transfer • • Addition of R-X to C-C double bond • Good atom economy • Product has halide group, allowing for further functionalization • Reaction can be slow for R ≠ EWG • • * Mero, C. L.; Porter, N. A., J. Am. Chem. Soc. 1999,121, 5155-5160.

  23. Atom Transfer Radical Cyclizations • • Transfer of halogen atom from one C to another followed by ring formation • Halogen atom is retained in the product • Can be promoted or catalyzed by Lewis acids • • • •

  24. Radical Cyclizations • • a MS 4Å added; b ratio of 2b:2c; c ee for 2b/2c Yang, D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K., J. Am. Chem. Soc. 2001,123, 8612-8613.

  25. Tandem Atom Transfer Cyclizations • Sets four stereocenters in one step with a single diastereomer observed Yang, D.; Gu, S.; Yan, Y.-L.; Zhao, H.-W.; Zhu, N.-Y., Angew. Chem. Int. Ed. 2002,41, 3014-3017.

  26. Outline • Introduction to Radical Reactions • Atom Transfers • Reductive Alkylations • Fragmentations • Tandem Addition-Trapping Reactions • Oxidations • Summary

  27. Reductive Alkylations • Addition to carbon-carbon or carbon-heteroatom multiple bonds, followed by trapping with an H-atom source • Conjugate additions • Addition to imines • Cyclizations • Catalysis is possible with the use of Lewis acids • •

  28. Conjugate Additions Sibi, M. P.; Ji, J., J. Am. Chem. Soc. 1996,118, 9200. Sibi, M. P.; Ji, J., J. Org. Chem. 1997,62, 3800.

  29. Conjugate Additions Sibi, M. P.; Ji, J., J. Am. Chem. Soc. 1996,118, 9200. Sibi, M. P.; Ji, J., J. Org. Chem. 1997,62, 3800.

  30. Achiral Additives • Achiral additives were used in an attempt to increase selectivity Murakata, M.; Tsutsui, H.; Hoshino, O., Org. Lett. 2001,3, 299-302.

  31. Pyrazole Template Sibi, M. P.; Shay, J. J.; Ji, J., Tetrahedron Lett. 1997,38, 5955-5958.

  32. Other Lewis Acids • Lanthanide Lewis acids can be used Sibi, M. P.; Manyem, S., Org. Lett. 2002,4, 2929-2932. Sibi, M. P.; Petrovic, G. Tetrahedron: Asymmetry2003, 14, 2879.

  33. Aldol-Type Products • • • • β-Alkoxy groups prone to elimination with ionic nucleophiles • Nucleophilic radical addition avoids this Sibi, M.P.; Zimmerman, J.; Rheault, T. Angew. Chem. Int. Ed.2003, 42, 4521.

  34. Addition to Imines Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T., J. Org. Chem. 2000,65, 176-185. Halland, N.; Anker Jorgensen, K., J. Chem. Soc. Perkin Trans. 1 2001, 1290-1295. Friestad, G. K.; Shen, Y. H.; Ruggles, E. L., Angew. Chem. Int. Ed. 2003,42, 5061-5063.

  35. Enantioselective 5-Exo Cyclization Hiroi, K.; Ishii, M., Tetrahedron Lett. 2000,41, 7071-7074. • Cyclization using “memory of chirality” • Curran, D. P.; Liu, W.; Chen, C. H.-T., J. Am. Chem. Soc. 1999,121, 11012-11013.

  36. Outline • Introduction to Radical Reactions • Atom Transfers • Reductive Alkylations • Fragmentations • Tandem Addition-Trapping Reactions • Oxidations • Summary

  37. Fragmentation Reactions • Addition of radical to a neutral molecule • β-elimination of resultant radical to generate terminal olefin • • • X = halide; Z = Sn(Bu)3, Si(Me)3, Si(Si(Me)3)3

  38. Fragmentation Reactions Porter, N. A.; Wu, J. H.; Zhang, G.; Reed, A. D., J. Org. Chem. 1997,62, 6702-6703. Fhal, A.-R.; Renaud, P., Tetrahedron Lett. 1997,38, 2661-2664.

  39. Fragmentation Reactions Porter, N. A.; Feng, H.; Kavrakova, I. K., Tetrahedron Lett. 1999,40, 6713-6716.

  40. Fragmentation Reactions Porter, N. A.; Feng, H.; Kavrakova, I. K., Tetrahedron Lett. 1999,40, 6713-6716.

  41. Fragmentation Reactions of -Iodolactones • Single point binding chiral Lewis acid Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O., J. Am. Chem. Soc. 1997,119, 11713-11714. Murakata, M.; Jono, T.; Hoshino, O., Tetrahedron: Asymmetry 1998,9, 2087-2092.

  42. Allylation Using an Acyclic Template •• •• •• •• •• • Hiroi, K.; Ishii, M., Tetrahedron Lett. 2000,41, 7071-7074.

  43. Outline • Introduction to Radical Reactions • Atom Transfers • Reductive Alkylations • Fragmentations • Tandem Addition-Trapping Reactions • Oxidations • Summary

  44. Tandem Radical Reactions • Addition of a radical to a neutral molecule followed by trapping of the resultant radical • Potential of forming two stereogenic centers • Downside is possibility of reactive byproduct formed • • • • Z = Sn(Bu)3, Si(Me)3, Si(Si(Me)3)3

  45. Enantioselective Tandem Addition Wu, J. H.; Radinov, R.; Porter, N. A., J. Am. Chem. Soc. 1995,117, 11029-30.

  46. Tandem Reaction vs. Fragmentation • • ee of product • Higher selectivity of tandem reaction pathway may be due to catalysis of background reaction by tin bromide byproduct Wu, J. H.; Zhang, G.; Porter, N. A., Tetrahedron Lett. 1997,38, 2067-2070.

  47. Lanthanide Lewis Acids • Lanthanide triflates are generally air and moisture stable • Strong Lewis acidity • Ionic radii of lanthanide metals increase in a small and regular manner: easy to modify chiral environment Sibi, M. P.; Manyem, S.; Subramaniam, R. Tetrahedron2003, 59, 10575

  48. Allylation of an -Sulfonyl Radical Ar = 2-(1-benzylbenzimidazolyl) • • s-cis 0 kcal/mol s-trans 2.5 kcal/mol Watanabe, Y.; Mase, N.; Furue, R.; Toru, T. Tetrahedron Lett.2001, 42, 2981

  49. Control of  and β carbon selectivity X = O, R = Ph 2 X = O, R = CH33 X = CH2, R = CH34 Sibi, M. P.; Chen, J., J. Am. Chem. Soc. 2001,123, 9472-9473.

  50. Control of  and β carbon selectivity X = O, R = Ph 2 X = O, R = CH33 X = CH2, R = CH34 Sibi, M. P.; Chen, J., J. Am. Chem. Soc. 2001,123, 9472-9473.

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