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Cyclopropenes An Accessible Precursor to Enantioenriched Compounds Lucie ZimmerLiterature Meeting December 1st 2009.

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Presentation on theme: "Cyclopropenes An Accessible Precursor to Enantioenriched Compounds Lucie ZimmerLiterature Meeting December 1st 2009."— Presentation transcript:

1 Cyclopropenes An Accessible Precursor to Enantioenriched Compounds Lucie ZimmerLiterature Meeting December 1st 2009

2 Cyclopropenes: Naturally Occuring Products Cyclopropenes: Biologically Active Compounds

3 Cyclopropenes: Caracteristics 27.5 kcalmol kcalmol -1  caracter of the 3-membered ring

4 Cyclopropenes: Caracteristics 27.5 kcalmol kcalmol -1 +  caracter of the double bond = very reactive especially towards  philic transition metals  caracter of the 3-membered ring

5 1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses 2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes 3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn 4. Metathesis Summary

6 1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses 2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes 3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn 4. Metathesis Summary

7 Cyclopropenes: Large Scale Synthesis From cyclopropanes Bolesov’s method revisited by Rubin, M.; Gevorgyan, V. Synthesis 2004, 2004, g

8 Cyclopropenes: Large Scale Synthesis From Alkynes Rubin, M.; Gevorgyan, V. Synthesis 2004, 2004, No conversion was observed using 6 and 7 in presence of Rh 2 (OAc) 4 10 and 12 are obtained in a 10:1 ratio 12 untouched during the deprotection of 10

9 Cyclopropenes: Enantioselective Synthesis Kinetic resolution Breslow, R.; Douek, M. J. Am. Chem. Soc. 1968, 90, Liao, L.-a.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J. M. J. Am. Chem. Soc. 2004, 126,

10 Cyclopropenes: Enantioselective Synthesis First enantioselective synthesis Significance of the diazo Significance of the polarity of the diazo (e.g. hexyne, dimethylbutyne) Protopopova, M. N.; Doyle, M. P.; Müller, P.; Ene, D. J. Am. Chem. Soc. 1992, 114, Imogaï, H.; Bernardinelli, G.; Gränicher, C.; Moran, M.; Rossier, J.-C.; Müller, P. Helv. Chim. Acta 1998, 81,

11 Cyclopropenes: Enantioselective Synthesis Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am. Chem. Soc. 2005, 127,

12 Cyclopropenes: Enantioselective Synthesis Quaternary center formation Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6,

13 Cyclopropenes: Enantioselective Synthesis Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46,

14 Cyclopropenes: Large Scale Synthesis Cyclopropanation vs Cyclopropenation Doyle, M. P.; Ene, D. G.; Peterson, C. S.; Lynch, V. Angew. Chem., Int. Ed. 1999, 38,

15 1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses 2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes 3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn 4. Metathesis Summary

16 Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107,

17 H. G. Richey, Jr., R. M. Bension, J. Org. Chem. 1980, 45, Nakamura, M.; Isobe, H.; Nakamura, E. Chem. Rev. 2003, 103, Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2004, 126, hydrostannylation silastannylation stannastanylation hydroboration carbocupration hydrogenation... Cyclopropenes: Carbometallation Diastereo- and Enantioselective: Key metals Rh Pd

18 Cyclopropenes: Carbometallation Liao, L.-a.; Fox, J. M. J. Am. Chem. Soc. 2002, 124,

19 Cyclopropenes: Enantioselective Synthesis Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128,

20 Cyclopropenes: Enantioselective Synthesis Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, MeMgCl sparged with air can be replaced by MeOH (1 équiv.) Good yields Excellent ees 1,2- and 1,2,3-trisubstitued cyclopropanes

21 Cyclopropenes: Enantioselective Synthesis Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, But only MethylGrignard lead to good enantioselectivities...

22 Cyclopropenes: Carbometallation Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,

23 Cyclopropenes: Carbometallation Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,

24 Cyclopropenes: Enantio- Synthesis of Cyclopropanes Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, EntryR1R1 R2R2 R3R3 Yielddr (2:3) 1PhMeH8711:1 2p-Cl-C 6 H 4 MeH71*8:1 3p-F-C 6 H 4 MeH91*12:1 4PhCH 2 OMOMH7210:1 5PhCH 2 OAcH75*7:1 6PhCOOMeH901:1 7COOMeMeH6424:1 8CMe 2 OBnMeH912 only 9PhMe 80*7:1

25 Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, Cyclopropenes: Enantio- Synthesis of Cyclopropanes

26 Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, Cyclopropenes: Enantio- Synthesis of Cyclopropanes

27 Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, Cyclopropenes: Enantio- Synthesis of Cyclopropanes

28 1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses 2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes 3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn 4. Metathesis Summary

29 3.1 Diels-Alder Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

30 Cortistatin A Magnus, P.; Littich, R. Org. Lett. 2009, 11, Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

31 Endo kinetic preference seems to be eroded by the extremely exothermic relief of the cyclopropenyl ring strain in the transition state of the Diels Alder. LaRochelle, R. W.; Trost, B. M.; Krepski, L. J. Org. Chem. 1971, 36, 1126–1136. Al Dulayymi, A. R.; Al Dulayymi, J. R.; Baird, M. S. Tetrahedron, 2000, 56, 1115–1125. Van Royen, L. A.; Mijngheer, R.; De Clercq, P. J. Tetrahedron 1985, 41, 4667–4680.

32 Magnus, P.; Littich, R. Org. Lett. 2009, 11, Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

33 Magnus, P.; Littich, R. Org. Lett. 2009, 11, Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

34 3.2 Cycloaddition (3+2) Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

35 DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,

36 Cyclopropenes: Enantio-Synthesis of Cyclic Compounds DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,

37 3.3 Pauson-Kahn Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

38 Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7,

39 Cyclopropenes: Enantio-Synthesis of Cyclic Compounds Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7, Pallerla, M. K.; Yap, G. P. A.; Fox, J. M. J. Org. Chem. 2008, 73,

40 Cyclopropenes: Enantio-Synthesis of Cyclic Compounds Total Synthesis of (–)- pentalene

41 Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

42

43

44 1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses 2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes 3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn 4. Metathesis Summary

45 Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127,

46 Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

47 Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127,

48 Hoveyda, A. H.; Lombardi, P. J.; O'Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131, Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

49 Hoveyda, A. H.; Lombardi, P. J.; O'Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131, Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

50

51 Conclusion Pro-chiral and enantioenrichied cyclopropenes are easily accessible. Cyclopropenes are pretty stable reactive intermediates. They react by their intracyclic double bond. They can be used for the formation of cyclopropanes, engaged in various cycloaddition reactions as well as ring opening strategies.

52 Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107,

53 methylene and alhylidene derivatives Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46,


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