ASYMMETRIC SYNTHESIS OF QUATERNARY CARBON CENTERS. Applied to total synthesis

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1 ASYMMETRIC SYNTHESIS OF QUATERNARY CARBON CENTERS Applied to total synthesis Ioulia Gorokhovik

2 2 Introduction Synthesis of chiral quaternary centers : challenge in synthesis. When the center is all-carbon, difficulty increased, steric hindrance. Many methods could be applied in theory, but in practice only a few are useful. Mostly developed the last years Presented here : Synthesis of quaternary centers with 4 non equivalent carbon substituents general methods, a few examples applied to synthesis Not presented : enzyme based reactions, use of chiral auxiliaries

3 3 Outline 1. Asymmetric Diels Alder reactions 2. Combination of carbon nucleophiles with carbon electrophiles 3. Transition metal-catalyzed reactions Heck reaction, Enyne cyclization, Pauson-Khand reaction C-H activation 4. Chirality-transfer reactions Epoxide rearrangements Cationic cyclizations Oxy-Cope and Claisen rearrangements

4 4 ASYMMETRIC DIELS- ALDER REACTIONS

5 5 Examples of chiral Lewis acids developed For references see : Corey, E.J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37,

6 Diels Alder with prochiral dienophile 6

7 7 Synthesis of colombiasin A Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. 2001, 40,

8 8 Synthesis of colombiasin A Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. 2001, 40, Suarez, D.; Sordo, T. L.; Sordo, J. A. J. Org. Chem. 1995, 60,

9 9 Synthesis of (-)-longithoronea Layton, M.E.; Morales, C.A.; Shair, M.D. J. Am. Chem. Soc. 2002, 124,

10 Diels-Alder with prochiral diene 10

11 11 Synthesis of norzoanthamine Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science, 2004, 305,

12 12 Synthesis of mangicol A core Exo compounds observed. Endo not possible because of the ring. DA outcome depends on stereochemistry of C3. Can be explained by energy differences of the transition states. Araki, K.; Saito, K.; Arimoto, H.; Uemura, D. Angew. Chem. Int. Ed. 2004, 43,

13 13 CARBON ELECTROPHILES WITH CARBON NUCLEOPHILES

14 Carbon nucleophiles and carbon electrophiles 14

15 15 Examples of prochiral nucleophiles Examples of prochiral electrophiles + others

16 16 Michael reaction : synthesis of the manzamine family Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D.J. J. Am. Chem. Soc. 2012, 134, Jakubec, P.; Cockfield, D.M.; Dixon, D.J. J. Am. Chem. Soc. 2009, 131,

17 17 Michael reaction : synthesis of (+)-gelsemine, Fukuyama Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42,

18 18 Mannich reaction : Studies on gelsemine, Fleming Clarke, C.; Fleming, I.; Fortunak, J.M.D.; Gallather, P.T.; Honan, M.C.; Mann, A.; Nubling, C.O.; Raithby, P.R.; Wolff, J.J. Tetrahedron, 1988, 44, Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42,

19 19 Robinson annulation for the synthesis of ketones Aldol reaction forming quaternary centers : very difficult -> solutions needed to favor it One possibility : enamine catalysis with amino-acids Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123,

20 20 MacMillan s LUMO catalysis Development of an organocatalyst that mimics the Lewis acids commonly used Austin, J. F.; Kim, S.G.; Sinz, C.J.; Xiao, W-J.; MacMillan, D.W.C. Proc. Natl. Acad. Sci. USA, 2004, 101,

21 Syntheses of (-)-flustramine B and diazonamide A 21 Austin, J. F.; Kim, S.G.; Sinz, C.J.; Xiao, W-J.; MacMillan, D.W.C. Proc. Natl. Acad. Sci. USA, 2004, 101, Knowles, R.R. ; Carpenter, J. ; Blakey, S.B. ; Kayano, A.; Mangion, I.K. ; Sinz, C.J.; MacMillan, D.W.C. Chem. Sci. 2011, 2,

22 22 Allylation reactions Hong, A.Y.; Stoltz, B.M. Eur. J. Org. Chem. ASAP

23 Pd-catalyzed allylations : synthesis of (+)-allocyathin B2 23 Trost, B.M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, GM. J. Am. Chem. Soc. 2004, 126, Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127, Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127,

24 24 SN2 catalyzed by copper : mechanism Perrone, S. PhD dissertation, Sofia, A.; Karlström, E.; Bäckvall, J.E. Chem. Eur. J. 2001, 7,

25 25 SN2 : synthesis of (-)-sporochnol Luchaco, C.A.L.; Mizutani, H.; Murphy, K.E.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2001, 40,

26 26 OTHER TRANSITION METAL- CATALYZED REACTIONS

27 Heck reaction 27

28 28 Synthesis of furaquinocin E Trost, B.M.; Thiel, O.R.; Tsui, H-C. J. Am. Chem. Soc. 2003, 125,

29 29 Synthesis of spirotryprostatine B Overman, L.E.; Rosen, M.D. Angew. Chem. Int. Ed. 2000, 39,

30 Other transition metalcatalyzed reactions 30

31 31 Pauson-Khand reaction : synthesis of magellanine Pauson-Khand : sensitive to steric factors in the transition state Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron, 2001, 61,

32 32 Pauson-Khand reaction : synthesis of magellanine Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron, 2001, 61,

33 33 C-H insertion with Rh carbenoid species Advantages : - Often the conditions are very mild - Extremely tolerant of functional groups - Low loadings of catalyst (1 mol%) Electronic, steric and conformational effects Direct C-H insertion Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, Davies, H.M.L.; Dick, A.R. Top. Curr. Chem. 2010, 292, Davies H.M.L. Angew. Chem. Int. Ed. 2006, 45, Davies H:M:L:, Beckwith, R.E.J. Chem. Rev. 2003, 103,

34 34 Synthesis of (+)-codeine and (+)-morphine White, J.D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1997, 62, White, J.D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64,

35 35 Enyne cyclization: synthesis of (+)-allocyathin B2 Trost, B.M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, GM. J. Am. Chem. Soc. 2004, 126, Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127, Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127,

36 36 Enyne cyclization: synthesis of (+)-allocyathin B2 Trost, B.M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, GM. J. Am. Chem. Soc. 2004, 126, Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127, Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127,

37 37 SELF-IMMOLATIVE REACTIONS

38 38 Self-immolative reactions A chiral center is sacrified to form another chiral center First center : created by enantioselective reaction Second center : created by intramolecular enantiospecific reaction Often : center bearing heteroatom is sacrificed to form a less readily established All-carbon quaternary center

39 Self-immolative reactions 39

40 40 Suzuki-Tsuchihashi epoxide rearrangement Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, Eom, K.D.; Raman, J.V.; Kim, H.; Cha, J.K J. Am. Chem. Soc. 2003, 125,

41 41 Synthesis of furaquinocin D Suzuki-Tsuchihashi gives compounds that can t be obtained with aldol reactions Model studies were made to check the migration of different substituents. Saito, T.; Suzuki, T.; Morimoto, M.; Akiyama, C.; Ochiai, T.; Takeuchi, K.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1998, 120,

42 42 Yamamoto epoxide rearrangement Omodani, T.; Shishido, K. J. Chem. Soc. Chem. Commun. 1994, Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111,

43 43 Fukumoto epoxide rearrangement Nemoto, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem. 1994, 59, Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org. Chem. 1992, 57,

44 44 Jung epoxide rearrangement Jung, M.E.; D Amico, D.C. J. Am. Chem. Soc. 1995, 117, Tonder, J.E.; Tanner, D. Tetrahedron, 2003, 59,

45 45 Jung epoxide rearrangement : synthesis of lyngbyatoxine A Solution : Jung, M.E.; D Amico, D.C. J. Am. Chem. Soc. 1995, 117, Tonder, J.E.; Tanner, D. Tetrahedron, 2003, 59,

46 Self-immolative reactions 46

47 Cationic cyclization reactions : synthesis of aegiceradienol 47 Formation of 3 quaternary carbon centers (and all the other asymmetric centers) in 1 step Corey, E.J.; Lee, J. J. Am. Chem. Soc. 1993, 115,

48 Self-immolative reactions 48

49 49 Cope and Claisen rearrangements Transfer of chirality from secondary alcohol to all-carbon quaternary center Allylic alcohol center easily prepared

50 50 Oxy-Cope : synthesis of (+)-dihydromayurone Chirality transfer very efficient because alkoxide favored in equatorial position during TS (better overlapping of orbitals and steric reasons) Lee, E.; Shin, I-J.; Kim, T-S. J. Am. Chem. Soc. 1990, 112,

51 51 Ireland-Claisen : synthesis of pinnatoxin Stivala, C.E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130,

52 52 Synthesis of gelsemine, Danishefsky Construction of the first quaternary center : Johnson-Claisen rearrangement Ng, F.W.; Lin, H.; Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124, Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42,

53 53 Synthesis of gelsemine, Danishefsky Construction of the second quaternary center : Eschenmoser-Claisen rearrangement (after many other attempts) This step : one of the most difficult of the synthesis (6 pages/13) Ng, F.W.; Lin, H.; Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124, Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42,

54 54 Other rearrangements : synthesis of (+)-gelsemine, Fukuyama Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42,

55 OTHER POSSIBILITIES 55

56 Not discussed today 56

57 57 Conclusion Good methods were developed good yields and ees Problem : find the precursor compatible with the synthesis and the structure of the target

58 58 Reviews and books on the topic Review : The catalytic enantioselective construction of molecules with quaternary carbon centers Corey, E.J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, Review : Asymmetric creation of quaternary carbon centers, Fuji, K. Chem. Rev. 1993, 93, Review : Enantioselective construction of quaternary centers, Christoffers, J.; Mann, A. Angwe. Chem. Int. Ed. 2001, 40, Perspective : Catalytic asymmetric synthesis of all-carbon quaternary stereocenters, Douglas, C.J.; Overman, L.E. Proc. Natl. Acad. Sci. USA 2004, 101, Book : Quaternary stereocenters : challenges and solutions for organic synthesis Edited by Christoffers, J.; Baro, A WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim. Review : Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems Das, J.P.; Marek, I. Chem. Commun. 2011, 47,

59 Thanks for your attention 59