Steric and Electronic Controllers in Ring-Closing Metathesis Reactions. Jennifer E. Farrugia October 29, 2003

Transcription

1 Steric and Electronic Controllers in Ring-Closing Metathesis Reactions Jennifer E. Farrugia October 29, 2003

2 Steric and Electronic Controllers How do substrate sterics affect the reactivity/ selectivity in ring-closing metathesis (RCM)? How do substrate electronics affect the reactivity/selectivity in ring-closing metathesis (RCM)?

3 Outline Introduction to RCM Catalysts RCM Mechanism Steric Controllers Electronic Controllers Conclusion

4 Introduction Ring Closing Metathesis Driven primarily by entropy gained by release of ethylene or other volatile side products Very powerful method for the formation of unsaturated cyclic systems from acyclic dienes Proceeds via a sequence of formal [2+2] cycloadditions/ cycloreversions Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56,

5 Catalysts Molybdenum alkylidene complex Schrock Superior reactivity even toward highly substituted alkenes Stable for long periods in an inert atmosphere Sensitive to oxygen and moisture as well as protic compounds Ruthenium alkylidene complex Grubbs Ar = 2,6-i-Pr 2 C 6 H 3 Most widely used catalyst in organic synthesis for RCM and CM reactions Somewhat less active, but significantly more stable, easier to handle, and shows excellent compatibility with functional groups 2 nd generation ruthenium alkylidene complex Allow the formation of tri- and tetra-substituted cycloalkenes More robust than the original Grubbs carbene in solution as well as in the solid state R=2,4,6-trimethylphenyl Hoveyda, A.H.; Schrock, R.R. Chem. Eur. J. 2001, 7, Woo Lee, C.; Grubbs, R.H. J. Org. Chem. 2001, 66,

6 RCM Mechanism PCy3 - RCM Product 2,3-configuration -PCy3 -PCy3 PCy3-2,4-configuration Ulman, M.; Grubbs, R.H. Organometallics 1998, 17,

7 Steric Controllers Allylic substitution Alkene substitution Substrate branching Tuning substituent groups Conformational constraints

8 Sterics: Allylic Substitution linalool citronellene Hoye, T.R.; Zhao, H. Org. Lett. 1999, I,

9 Sterics: Allylic Substitution Increasing Reactivity linalool citronellene 5x (80%)* 1.5x (50%) 8x (60%) >200x (100%) Pairwise competition experiments: ~0.02M of each substrate 4-10 mol% Grubbs catalyst * mol% Grubbs catalyst Hoye, T.R.; Zhao, H. Org. Lett. 1999, I,

10 Sterics: Allylic Substitution teubrevin G teubrevin H Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,

11 Sterics: Allylic Substitution mol% A >1 week! 53% Catalyst A = Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,

12 Sterics: Alkene Substitution R R R R A: Yield = 93% B: No RCM product R R R R A: Yield = 61% B: No RCM product R = CO 2 Et Catalyst A = Catalyst B = Ar = 2,6-i-Pr 2 C 6 H 3 Kirkland, T.A.; Grubbs, R.H. J. Org. Chem. 1997, 62,

13 Sterics: Substrate Branching RCM A B 1. NaH 2. BuLi 3. Substrate B, THF, -78C Callipeltoside A 70% Hoye, T.R.; Zhao, H. Org. Lett. 1999, 1,

14 Sterics: Substituent Groups Double RCM Strategy a b c d ab/cd ac/bd fused bicycle One-Shot! dumbell bicycle C-N bond formation C-C bond formation Ma, S.; Ni, B. Org. Lett. 2002, 4,

15 Sterics: Substituent Groups 5 mol% A (R = Me) 23 h 64% (2 : 3 = 1 : 3.6) (R = n-pr) 14.5 h 41% (2 : 3 = 1 : 3.8) (R = H) 2 h 88% (2 : 3 = 21 : 1) Catalyst A = Ma, S.; Ni, B. Org. Lett. 2002, 4,

16 Sterics: Substituent Groups 1 mol% A 30 min 5 mol% A 1 h 23% 89% + Catalyst A = 39% Ma, S.; Ni, B. Org. Lett. 2002, 4,

17 Sterics: Conformational Constraints R R R R R R R R X A: Yield = 100% B: Yield = 96% A, B: No RCM product R R R R R R X R R R = CO 2 Et Catalyst A = Ar = 2,6-i-Pr 2 C 6 H 3 A: Yield = 96% B: Yield = 25% A, B: No RCM product Catalyst B = Kirkland, T.A.; Grubbs, R.H. J. Org. Chem. 1997, 62,

18 Sterics: Conformational Constraints 5-7 mol% A 2h 73% Yield (17% dimer) 5-7 mol% A 30 min 94% Yield (only product) Catalyst A = Crimmins, M.T.; Choy, A.L. J. Org. Chem. 1997, 62,

19 Electronic Controllers Allylic substitution Alkene substitution

20 Electronics: Allylic Substitution Increasing Reactivity linalool citronellene 1.5x (50%) 8x (60%) 10x (60%) >200x (100%) Pairwise competition experiments: ~0.02M of each substrate 4-10 mol% Grubbs catalyst * mol% Grubbs catalyst Hoye, T.R.; Zhao, H. Org. Lett. 1999, I,

21 Electronics: Allylic Substitution Fukuda, Y; Shindo, M.; Shishido, K. Org. Lett. 2003, 5,

22 Electronics: Allylic Substitution 1) 10 mol% A 48h 2) Hydrolysis R 1 = Bn, TMS, MOM, Bz R 2 = Me, Et, Ph R 1 R 2 Yield (%) dr TMS Et 84 86:14 Catalyst A = Fukuda, Y; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2002, 43,

23 Electronics: Allylic Substitution 10 mol% A 48h 1 2 Yield (%) of 2 diastereomeric R (recovered 1 (%)) ratio H 7 (81) 59:41 Bz 95 (5) 72:28 MOM 92 (5) 85:14 Bn 94 (6) 88:12 TMS quantitative (0) 87:13 Catalyst A = Fukuda, Y; Shindo, M.; Shishido, K. Org. Lett. 2003, 5,

24 Electronics: Allylic Substitution Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56,

25 Electronics: Allylic Substitution Catalyst Mol% Time (h) Yield (%) A B C B ! 77 C Catalyst A B C Ar = 2,6-i-Pr 2 C 6 H 3 R=2,4,6-trimethylphenyl Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56,

26 Electronics: Allylic Substitution mol% A >3 days 10 mol% B 34 h 35% 90% Catalyst A = Catalyst B = R=2,4,6-trimethylphenyl Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,

27 Electronics: Alkene Substitution ab/cd fused bicycle a b c d ac/bd dumbell bicycle 5 mol% A Only Product! Catalyst A = (R 1 = Me, R 2 = H) 5 h 86% (R 2 = H) (R 1 = H, R 2 = Me) 23 h 43% (R 2 = Me) Ma, S.; Ni, B. Org. Lett. 2002, 4,

28 Electronics: Alkene Substitution 5 mol% A + (R = H) 5 h, 77% (R = Me) 23 h, 76% mol% A + Catalyst A = 2h, 88% 21 1 Ma, S., Ni, B. Org. Lett. 2002, 4,

29 Electronics: Alkene Substitution R 5 mol% A Catalyst A = R k (1/min) Yield (%) CH 3 O CH 3 CO PhSO HOCH EtOOC H Basu, K.; Cabral, J.A.; Paquette, L.A. Tetrahedron Lett. 2002, 43,

30 Electronics: Alkene Substitution R R X R R X R = CO 2 Et X Yield (%) with A Yield (%) with B Ph CO 2 Me 89 5 CH 2 OH decomp. 98 CH 2 OAc Catalyst A = Catalyst B = Ar = 2,6-i-Pr 2 C 6 H 3 Kirkland, T.A.; Grubbs, R.H. J. Org. Chem. 1997, 62,

31 Allylic Hydroxyl Group Effects Hydroxyl Activating Effect Competing Mechanisms Catalyst Control

32 Hydroxyl Group: Activating Effect linalool citronellene 5x (80%)* 1.5x (50%) ~25x (80%)* >200x (100%) 10x (60%) 8x (60%) Pairwise competition experiments: ~0.02M of each substrate 4-10 mol% Grubbs catalyst * mol% Grubbs catalyst Hoye, T.R.; Zhao, H. Org. Lett. 1999, I,

33 Hydroxyl Group: Activating Effect Possible Explanations Rapid and reversible ligand exchange Alkoxy for chloride RO Cl Alcohol for phosphine Cl Cl (PCy 3 ) Ru CHR' (PCy 3 ) (ROH) Ru CHR' (PCy 3 ) Hydrogen bonding between hydroxy group and one of the chloride ligands Hoye, T.R.; Zhao, H. Org. Lett. 1999, I,

34 Hydroxyl Group: Allylic Substitution 1592U89 -potent inhibitor of HIV reverse transcriptase Crimmins, M.T.; King, B.W.; J. Org. Chem. 1996, 61,

35 Hydroxyl Group: Allylic Substitution 1 mol% A, 30 min 97% LiBH 4 THF, MeOH Catalyst A = Crimmins, M.T.; King, B.W.; J. Org. Chem. 1996, 61,

36 Hydroxyl Group: Mechanism 150 mol% A + 1 : 1.5 RCM Undesired Catalyst A = Hoye, T.R.; Zhao, H. Org. Lett. 1999, I,

37 Hydroxyl Group: Mechanism ~50 mol % A Catalyst A = Hoye, T.R.; Zhao, H. Org. Lett. 1999, 1,

38 Hydroxyl Group: Mechanism ~50 mol % A Catalyst A = Hoye, T.R.; Zhao, H. Org. Lett. 1999, 1,

39 Hydroxyl Group: Mechanism mol% A + 68% 20% Catalyst A = Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,

40 Hydroxyl Group: Mechanism Two Competing Mechanisms RCM Undesired RCM Undesired Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,

41 Hydroxyl Group: Catalyst Control 8 mol% B, 88% Catalyst B = R=2,4,6-trimethylphenyl Paquette, L.A.; Efremov, I. J. Am. Chem. Soc. 2001, 123,

42 Hydroxyl Group: Catalyst Control HO 5 mol% B, 1h R = Me, Et, and Ph gave the desired RCM products in 78, 75, and 92% yield. However, no diastereoselectivity was observed. Catalyst B = R=2,4,6-trimethylphenyl Fukuda, Y; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedron Lett. 2002, 43,

43 Hydroxyl Group: Catalyst Control Catalyst Mol% Time (h) Yield (%) A B C Cat. C Cat. B 69% 29% Catalyst A B C R=2,4,6-trimethylphenyl Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56,

44 Conclusion: Steric Controllers Allylic substitution: How? Fully substituted allylic centers Steric bulk (ie OTES) Alkene substitution: How? Less substituted alkenes Substrate branching: How? Additional substrate branching Tuning Substituent Groups: How? Introduction of an alkyl group Conformational constraints: How? The lack of conformational constraints

45 Conclusion: Electronic Controllers Allylic substitution: How? Alkyl-substituted olefins bearing electron-withdrawing substituents Alkene substitution: How? Electron-donating groups Electron-withdrawing groups

46 Conclusion: Allylic Hydroxyl Group Hydroxyl Activating Effect: How? Allylic hydroxyl groups greatly accelerate the rate Competing Mechanisms: How? Two competing mechanisms have been proposed Catalyst Control: How? Schrock s molybdenum catalyst The second generation Grubbs ruthenium complex

47 Thank You Dr. James Jackson Dr. Simona Marincean Dr. Mischa Redko Robert Gentner Tulika Datta Eric Bassett Dr. Dennis Miller Dr. Navine Asthana Mike Shafer Lars Peereboom

48 Questions?

49 Background Olefin metathesis was first observed in the 1950 s by industrial chemists In 1967, Nissim Calderon figured out that the unexpected products were due to cleavage and reformation of the olefins double bonds In 1971, Yves Chauvin and Jean-Louis Herisson proposed a mechanism, which turned out to be correct Many people credit Grubbs ruthenium carbene catalyst and Schrocks molybdenum alkylidene with putting olefin metathesis in the forefront of organic synthesis Schrock, R.R. Tetrahedron 1999, 55, Trnka, T.M.; Grubbs, R.H. Acc. Chem. Res. 2002, 34, 18-29

50 Advantages and Applications of RCM Provides an elegant pathway for the formation of small, medium, and large-ring carbo- and heterocycles Instrumental in natural product syntheses, including those of aspidosperma indole and bicyclic izidine alkaloids, as well as Callipeltoside A and conduritol derivatives Aids in the synthesis of optically pure materials Used in synthesis of carbocyclic nucleosides for the development of new antitumor and antiviral therapeutic agents Hoveyda, A.H., Schrock, R.R. Chem. Eur. J. 2001, 7,

51 PCy3-2,3-configuration PCy3 - -PCy3 RCM Product 2,3-configuration -PCy3 -PCy3 PCy3-2,4-configuration Ackermann, L.; Tom, D.E.; Furstner, A. Tetrahedron 2000, 56,

52 Electronics: Allylic Substitution RCM Catalyst = Royer, F.; Vilain, C.; Laurent, E.; Grimaud, L.; Org. Lett. 2003, 5,