Macrocyclization via ruthenium- catalyzed ring-closing metathesis: strategies and limitations Joseph Grim Kiessling Research Group October 8, 2009

2 Various methods for macrocyclization Stang, E.; Christina White, M. Nat. Chem. 2009, 1, 547. Kurti, L, Czako, B. Strategic Applications of Named Reactions in Organic Synthesis, 1st ed,; Elsevier: Amsterdam, Macrolactonization: Nozaki-Hiyama-Kishi Macrolactamization: Nozaki-Hiyama-Kishi C-H oxidation Enyne metathesisRing-closing metathesis

3 A brief history of ruthenium-catalyzed RCM Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, representative ring closing metathesis (RCM) Ru reacts with soft Lewis bases and π-olefins more functional group tolerant very low reactivity highly active toward metathesis highly oxophilic (low functional group tolerance)

4 The Chauvin mechanism for RCM Chen, P. and coworkers. J. Am. Chem. Soc. 2004, 126, 3496.

5 First generation catalysts Nolan, S. P. and coworkers. Organometallics 2003, 22, Nolan, S. P. and coworkers. Chem.--Eur. J. 2007, 13, SonBihn Hoveyda-Grubbs I dative bond replaces one phosphine more thermally stable than Grubbs I Grubbs I more donating phosphine stabilizes metallacyclobutane favors electron rich, monosubtituted olefins decomposes quickly RDS is metallacyclobutane formation

6 Second generation catalysts Nolan, S. P. and coworkers. Organometallics 2003, 22, Nolan, S. P. and coworkers. Chem.--Eur. J. 2007, 13, contain an N-heterocyclic carbene (NHC) H 2 IMes Grubbs II better σ-donors than IMes approaches reactivity of Schrock catalysts Hoveyda-Grubbs II phosphine free slower initiation improved activity toward electron deficient alkenes RDS is dissociation step IMes Grubbs II strong σ-donor with slight π-back bonding stable at high temperatures reactive with electron deficient, substituted olefins

7 Third generation catalysts Grela, K. and coworkers. Angew. Chem., Int. Ed. 2002, 41,114. Blechert, S. and coworkers. Angew. Chem., Int. Ed. 2002, 41, Blechert initiation rate promoted by relief of sterics Initiation rate increase by modification of aryl moieties Grela initiation rate promoted by decrease in electron density on oxygen Fine-tuning of sterics and electronics of catalysts

8 Many catalysts exist for olefin metathesis 1st generation catalysts: 2nd generation catalysts:3rd generation catalysts: Non-ruthenium based catalysts:

9 RCM macrocyclizations are useful in many areas of synthetic chemistry Peptide chemistry: Blackwell, H. et. al. J. Org. Chem. 2001, 66, Natural product synthesis: Nicolaou, K. and coworkers. J. Am. Chem. Soc. 2005, 127, Crown ether analogs: Grubbs, R. H and coworkers. Angew. Chem., Int. Ed. 2003, 42, Carbohydrate vaccines: Danishefsky, S. and coworkers. J. Am. Chem. Soc. 2009, ASAP

Nobel Prize in Chemistry “for the development of the metathesis method in organic synthesis” Yves Chauvin Institut Français du Pétrole Robert Grubbs California Institute of Technology Richard Schrock Massachusetts Institute of Technology

11 Representitive olefin metathesis transformations Ring closing metathesis (RCM) Acyclic diene metathesis polymerization (ADMET) Cyclodepolymerization metathesis (CDP) Ring opening metathesis polymerization (ROMP) Monfette, S.; Fogg, D. Chem. Rev. 2009, 109, 3783.

12 Ring closing metathesis exists in an equilibrium Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, RCM efficiency limited by competition between pathways fully reversible product distribution is “living” -- known as equilibrium ring closing metathesis (ERCM)

13 Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, loss of ethylene in monosubstituted olefins drives equilibrium important equilibrium is between ROMP and CPD Loss of ethylene simplifies equilibrium 1,2-disubstituted1,1,2-trisubstituted

14 Why is macrocyclization difficult? Anslyn, E., Dougherty, D. Modern Physical Organic Chemistry. University Science: Sausulito, Shorter length dienes have greater torsional mobility Higher probability for reactive ends to meet ring size strain energy (kcal/mol) Ring Strain of Cycloalkanes effective molarity (EM) = K intra K inter

15 Methods to perturb equilibrium Which product is the kinetic/thermodynamic? Reaction time Temperature Dilution factor Reactivity of catalyst

16 Increasing reaction time promotes ERCM Increasing reaction time allows for equilibration to occur oligomer product diene Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, diene product oligomer

17 Increasing reaction temperature promotes ERCM isolated from Monocillium nordinii exhibits a wide variety of antifungal and antibiotic properties has high affinity for heat shock protein 90 (Hsp 90), which stimulates depletion of oncogenic proteins Danishefsky, S. J. and coworkers. J. Am. Chem. Soc. 2001, 123,

18 Increasing reaction temperature promotes RCM Increasing the temperature favors the formation of the kinetic RCM product. Danishefsky, S. J. and coworkers. Tetrahedron Lett. 2003, 44, entryconditionsconcentration yield mono : dimer 1PhMe, 42 o C, 19 h0.5 mM27% : 48% 2PhH, 80 o C, 35 min0.5 mM33% : 36% 3PhMe, 110 o C, 10 min0.2 mM55% : 0 %

19 Decreasing concentration increases the effective molarity ansaymycin antiobiotic isolated from Streptomyces hygroscopicus shown to have anticancer activity due to its binding of Hsp 90 Bach, T.; Lemarchand, A. Synlett 2002, Lemarchand, A.; Bach, T. Tetrahedron 2004, 60, 9659.

20 Decreasing diene concentration increases the effective molarity Bach, T. et al. Synlett 2002, entryn =ring sizeconc. [mM]catalysttime [h]yield [%] 13206Grubbs I Grubbs I Grubbs I2066 Decreasing diene concentration promotes RCM

21 Increasing ring size increases the formation of RCM product Bach, T. et al. Synlett 2002, entryn =ring sizeconc. [mM]catalysttime [h]yield [%] Grubbs I Grubbs II Grubbs I Grubbs II Grubbs I Grubbs I400 increasing ring size increases the yield of RCM product

22 Addition of reactive catalyst promotes ERCM Ackermann, L. and coworkers. Org. Lett. 2001, 3, 449. Addition of a more reactive catalyst can promote ERCM not observed

23 Thermodynamic vs. Kinetic ERCM Favoring thermodynamic ERCM: ↑ reaction time ↑ temperature ↓ concentration try more reactive catalyst Favoring kinetic ERCM: ↓ reaction time ↓ temperature ↓ concentration use less reactive catalyst

24 Olefin geometry is difficult to control Grubbs, R. and coworkers. Org. Lett. 2000, 2, Thermodynamic product determines E/Z selectivity.

25 Applications in Process Chemistry: BILN 2061 Rajagopalan, R. et al. Biochemistry 2009, 48, developed by Boehringer Ingelheim Pharmaceuticals blocks replication of hepatitis C virus (HCV) binds HCV NS3 protease discontinued due to cardiotoxicity reported in testing on rhesus monkeys demonstrated utility of macrocyclization via RCM in industrial setting

26 BILN 2061: Retrosynthetic analysis Yee, N. et al. J. Org. Chem. 2006, 71, 7133.

27 BILN 2061: Initial macrocyclization had many issues Yee, N. et al. J. Org. Chem. 2006, 71, Four issues in industrial application: 1.high catalyst loading 2.long reaction time 3.dilution factor 4.RCM is reversible (lead to decomposition upon concentration of crude reaction)

28 BILN 2061: Catalyst chelates to amide? Zeng, X. et al. J. Org. Chem. 2006, 71, Shu, C. et al. Org. Lett. 2008, 10, observed carbene transfer of catalyst at the vinylcyclopropane chelation to ester ties up active catalyst? protecting the amide with a bulky group will disfavor chelation resting state of catalyst as determined by 1 H NMR

29 BILN 2061: Amide protection Shu, C. et al. Org. Lett. 2008, 10, R = H, 96% R = Boc, 100%

30 BILN 2061: Amide protection Shu, C. et al. Org. Lett. 2008, 10, entryR =conc. [M]cat. mol %temp [ o C]yield [%] 1H H H H

31 BILN 2061: Amide protection Shu, C. et al. Org. Lett. 2008, 10, entryR =conc. [M]cat. mol %temp [ o C]yield [%] 1Boc Boc Boc Boc Boc Boc H

32 BILN 2061: A computational study on the effect of Boc protection Shu, C. et al. Org. Lett. 2008, 10, vs. Does Boc protection stabilize the diene and product? ΔΔE was calculated (change in energy of open chain molecules with and without Boc substitution subtracted from change in energy of ring molecules with and without Boc substitution) methodOPLS01MM3MMFFsDFT/B3LYP ΔΔE [kcal/mol] Boc substitution reduces strain energy on ring molecule by ~2 kcal/mol

33 BILN 2061: Amide protection appears to effect the reaction two ways Shu, C. et al. Org. Lett. 2008, 10, induces allylic strain for coordination of catalyst to ester relieves forced planarity of both diene and product Effect of Boc protection appears two-fold:

34 BILN 2061: Results of optimization Farina, V. et al. Org. Process Res. Dev. 2009, 13, 250. Initial process: Optimized process:

35 BILN 2061: Results of optimization Farina, V. et al. Org. Process Res. Dev. 2009, 13, 250. Addressed all four initial issues with RCM in industrial setting: 1.high catalyst loading (from 5 mol% to 0.05 mol%) 2.long reaction time (from 40 hrs. to 30 min) 3.dilution factor (from 150,000L solvent to process 1 MT of diene to 7,500L!) 4.RCM is reversible (2-mercaptonicotinic acid quench affords <50 ppm Ru, no filtrations necessary)

36 Conclusions: The utility of macrocyclizations via RCM Pros simple reaction conditions simple work up functional group tolerance many catalysts Cons oligomerization side-reactions often requires very dilute conditions difficult to control E/Z selectivity often requires optimization Future Directions develop longer lasting catalysts develop a catalyst selective for E/Z

37 Acknowledgements ` Laura Kiessling Kiessling Research Group Practice Talk Attendees Chris Brown Becca Splain Shane Mangold Aaron Smith Katie Garber Paul White Teresa Beary Aaron McCoy Kelsey Mayer Mario Martinez Margaret Wong Rick McDonald Raja Annamalai