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A Dash of proline to induce chirality

A Dash of proline to induce chirality. Christian Perreault Literature Meeting February 6 th , 2006. Synthesis of (-)-Littoralisone. David W. C. MacMillan et Al. J. Am. Chem. Soc. 2005 , 127 , 3696. Enantioselective Organocatalytic α -Oxidation of aldehydes.

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A Dash of proline to induce chirality

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  1. A Dash of proline to induce chirality Christian Perreault Literature Meeting February 6th, 2006

  2. Synthesis of (-)-Littoralisone David W. C. MacMillan et Al. J. Am. Chem. Soc. 2005, 127, 3696. • Enantioselective Organocatalytic α-Oxidation of aldehydes • 1,4 Selective Michaël addition induced by proline • Aldol reaction catalyzed by proline

  3. (-)-Littoralisone Challenge of the synthesis • Nine-membered lactone in an heptacyclic framework • Glycosidic unity : (β)-D-Glucose • Elaborated optically active cyclobutane • 14 stereocenters within a 24 carbon framework

  4. Origins (-)-Brasoside 1 (-)-Littoralisone 2 • Verbena littoralis grows in Costa Rica • It is a shrub widely used in folk medecine as an effective antidiarrhetic. • It has also been claimed as a remedy for typhoid fever, for relieving inflammations from insects bites and for cancer. • First isolation and structure elucidation of Littoralisone in 2001 • This heptacyclic iridolactone glucoside shown activity on PC12D nerve cells. Verbena littoralis (1) Castro, O., Umana, E. Int. J. Crude Drug Res. 1990, 28, 175 (2) Ohizumi, Y.,et al J. Org. Chem. 2001, 66, 2165.

  5. (-)-Littoralisone retrosynthesis Two steps approach carbohydrate synthesis Intramolecular organocatalysed 1,4-addition

  6. (-)-Littoralisone synthesis

  7. Enantioselective α-Oxidation of Aldehyde • Stork identified the usefullness of a condensed secondary amine on a carbonyl, for α-alkylation on the molecule R’= Alkyl-X, BzCl, Acrylonitrile Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc.1954, 76, 2029. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc.1963, 85, 207.

  8. (2) (1) Enantioselective α-Oxidation of Aldehyde (1) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239. (2) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl.1971, 10, 476.

  9. Enantioselective α-aminoxylation of Aldehyde (4-5) (2) (1) (3) (1) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2002, 122, 2395. (2) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc.2002, 124, 827. (3) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.2002, 124, 6798. (4) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc.2001, 123, 11273. (Proposed transition state) (5) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc.2000, 122, 2395 (Proposed transition state)

  10. Enantioselective α-amination of Aldehyde (1) (2) scheme 2 scheme 1 • First direct catalytic asymmetric α-amination of aldehyde • Good yield an ee • Product is a useful precursor for 2-oxazolidinones and other α-amino and α-hydrazino acid derivatives (1) List, B.; J. Am. Chem. Soc.2002, 124, 5657. (2) Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 2103.

  11. Enantioselective α-aminoxylation of Aldehyde scheme 3 scheme 1 scheme 2 • Broad scope of compatible functionnality (scheme 1) • Alternative for Aminohydroxylation and Dihydroxylation of terminal alkene (scheme 3) Zhong, G. Angew. Chem. Int. Ed.2003, 42, 4247. (June) MacMillan, D. W. C. et al.J. Am. Chem. Soc. 2003, 125, 10808. (July) Hayashi, Y.; Junichiro, Y.; Kazuhiro, H.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293 (August)

  12. Enantioselective α-aminoxylation of aldehyde + olefination in situ(1) scheme 2 (2) scheme 1 (1) • Eliminate problems of purification • Acceptable yield (for 2 steps) and good ee’s • Good method to create an allylic alcohol (1) Zhong, G.; Yongping, Y. Org. Lett.2004, 6, 1638. (2) Momiyama, N,; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038

  13. Donna Blackmond’s et al observation (1) • Rate is a lot faster (10min.) compared to other proline catalyzed reaction ex: Aldol reaction between acetone and isobutyraldehyde required 48h at 30mol% (2-3) • Rate of the reaction accelerate over time process • Experiment suggest an autocatalytic or autoinductive reactions! • Experiment suggest that the reaction is mediated by a proline-product adduct (1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed.2004, 43, 3317.(2) Nielsen, L. P. C. N.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc.2004, 126, 1360. (3) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc.2002, 124, 14104

  14. Donna Blackmond’s et al observation (1) • Enantiomeric excess was higher than that expected for a linear relationship • Clue to establish a model for the evolution of homochirality through precursor of low optical activity (Rate acceleration + ee’s improvement in time) (1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed.2004, 43, 3317.

  15. First proposition for the improved catalyst: α-effect and bronsted acid Finding the active specie (1) • This scheme showes a general mechanism for a product-induced reaction in which both rate and selectivity improve over time for the case in which one enantiomer is present in excess concentration relative to the other. (1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed.2004, 43, 3317.(2) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B.J. Am. Chem. Soc. 1986, 108, 2353 (first explanation for non-linear product enantioselectivity)

  16. Finding the active specie (1) • Rate enhancement is independent of the enantiomer of 3 and the proline utilized • No erosion of ee and final configuration dictated by the proline stereochemistry • Utilization of specie 6 improves efficiency (reaction rate) of other proline catalyzed transformations such as aldol and aminoxylation reaction. (1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.

  17. Finding the active specie (1) • This reaction presents same nonlinear effect than for the aminoxylation (1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 11770.

  18. Finding the active specie (1) a) 10mol% of 5b b) 10mol% of 5c c) 20mol% of 4L Reaction 2b • a) and b) presents the same kinetics properties: active specie cannot be 5b or 5c but help the formation of the super catalyst • a) and b) as well as c), show an acceleration proportionnal to the product concentration: acceleration is not due to a solvatation of proline in time (1) Iwamura, H.; Wells, D. H.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, 16312.

  19. Blackmond theory DFT calculation using B3LYP/6-31G • three-point hydrogen bonding help to increased the active specie concentration into the cycle • In aldol reaction, the two-point hydrogen bonding inhibited the formation of a more active species • Transition state (in this proposition) is similar to the first proposed by List and Houk • Blackmond, D. G. et alJ. Am. Chem. Soc. 2004, 126, 16312.

  20. (-)-Littoralisone synthesis

  21. (-)-Littoralisone synthesis

  22. Anomeric effect 2 anomeric effects VS 1 anomeric effect

  23. Organocatalyzed Michael addition Kinetic control

  24. Organocatalyzed Michael addition • 2 plausible reactive species

  25. Organocatalyzed Michael addition • 3 parameter to look at: 1) enol / enamine geometry: trans favored

  26. Organocatalyzed Michael addition 2) enol / enamine reactive face a) Allylic strain b) Proline’s asymmetric induction / hydrogen bonding In DMSO, Hydrogen bonding activation is questionable!

  27. Organocatalyzed Michael addition c) Relative orientation of nucleophile / electrophile 3) enone / eniminium reactive face a) Allylic strain

  28. Organocatalyzed Michael addition b) Proline asymmetric induction c) nucleophile / electrophile relative orientation

  29. Organocatalyzed Michael addition

  30. Organocatalyzed Michael addition

  31. Organocatalyzed Michael addition

  32. Organocatalyzed Michael addition

  33. Organocatalyzed Michael addition

  34. Organocatalyzed Michael addition Enol / Eniminium Enamine / Enone • The two combinations implying proline can be operative to explain stereochemistry observed • Hydrogen bonding to explain diastereoselectivity is questionnable • Others kinetic datas necessary to identified the reactive specie: • Which active specie you think it is involved? • Any other ideas?

  35. (-)-Littoralisone synthesis

  36. (-)-Littoralisone synthesis α:β = 8:1

  37. Glycosidic part done by a MacMillan methodology 1) Enantioselective organocatalyzed dimerisation of aldehydes 2) Mukaiyama aldol + Cyclisation Alan B. Northrup, David W. C. MacMillan, Sciences.2004, 305, 1752.

  38. Carbohydrate synthesis in two steps via 2 selective aldol reactions Alan B. Northrup, David W. C. MacMillan, Sciences.2004, 305, 1752. David W. C. MacMillan et Al. J. Am. Chem. Soc. 2003, 125, 10808. Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152 1) Enantioselective organocatalyzed dimerisation of aldehydes • α-hydroxyaldehyde must readily participate as both a nucleophilic and electrophilic coupling partner • product must be inert to enolization and or carbonyl addition

  39. Carbohydrate synthesis in two steps via 2 selective aldol reactions 2) Mukaiyama aldol + cyclisation catalysed by a lewis acid Alan B. Northrup, David W. C. MacMillan, Sciences.2004, 305, 1752.

  40. Carbohydrate synthesis in two steps via 2 selective aldol reactions Alan B. Northrup, David W. C. MacMillan, Sciences.2004, 305, 1752.

  41. (-)-Littoralisone synthesis α:β = 8:1 α:β = 12:1 β only

  42. (-)-Littoralisone synthesis

  43. Conclusion • Efficient and convergent synthesis • 13 steps for the longest sequence • 13% overall yield (average of 85% per step) • 13 stereocenters installed, 14th from chiral pool • 6 steps of protection / deprotection

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