Recent Advancements in Outer Coordination Sphere Asymmetric Transfer Hydrogenation Emphasis on the Reduction of Prochiral Ketones and Imines

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1 Recent Advancements in uter Coordination Sphere Asymmetric Transfer ydrogenation Emphasis on the Reduction of Prochiral Ketones and Imines Samantha Taffner Michigan State University ovember 30, 2005

2 utline Background information Components of the reaction Catalytic cycles 2- propanol vs formic acid as hydrogen donors Advancements in catalysts Advancements in Rh catalysts Comparing catalysts Synthetic examples

3 Meerwein-Ponndorf-Verley (MPV) First example of transfer hydrogenation Mid 1920 s R 1 R 2 R 2 R R Al R 1 R 3 R 4 R 1 R Al 3 R 3 R 4 R 3 R 4 Meerwein,.; Schmidt, R.; Justus Liebigs Ann. Chem. 1925, 444, 221

4 Components of Transfer ydrogenation ydrogen donor Alcohols Formic acid ydrogen acceptor Catalyst A + D 2 A 2 + D D 2 = hydrogen donor A = hydrogen acceptor Carbonyl Imine Catalyst, Rh, Ir, Sm, Co, Fe complexes with chiral ligands + Chiral Catalyst + Zassinovich, G.; Mestroni, G.; Chem. Rev. 1992, 92,

5 Advantages to Transfer ydrogenation Mild conditions Chelation Control (Anti Cram Product) Steric Control (Cram Product) Eliminates hazards of working with hydrogen gas Inexpensive hydrogen source Relies on ligand control not substrate control eed a α- stereocenter R' Me M Et Example- Zn(B 4 ) 2 Me Et Example- LiAl(tBu) 3 R'

6 Inner Coordination Catalytic Cycle D A M Ligand dissociation Inner sphere coordination to metal D M M A Cis hydride transfer D M A 2 P 2 (P 3 ) 4 M A D Inner Sphere Coordination Catalysts apham, S.; adzovic, A.; Morris, R.; Coord. Chem. Rev. 2004, 248,

7 uter Coordination Catalytic Cycle D L D M D L L M M A L A A M Ligand activates carbonyl carbon uter sphere Coordintation Cyclic transfer of proton and hydride Results in enantioselectivity of prochiral substrate 2 apham, S.; adzovic, A.; Morris, R.; Coord. Chem. Rev. 2004, 248,

8 uter vs. Inner Catalytic Cycle D L M A D M A L D M A L M D M M A D L M A D M A D M A apham, S.; adzovic, A.; Morris, R.; Coord. Chem. Rev. 2004, 248,

9 Advantages to uter Coordination Transfer ydrogenation Absence of phosphane catalyst Catalyst can be selective to polar bonds D D 2 P L M A 2 (P 3 ) δ - 4 δ + A L M Inner Sphere Coordination L Catalysts M δ + δ- L M D A apham, S.; adzovic, A.; Morris, R.; Coord. Chem. Rev. 2004, 248,

10 Inherent Chemical Problems with an Alcohol as a ydrogen Donor When applied to an asymmetric reduction The reaction can reverse since the oxidized donor is structurally similar to the substrate + Chiral + Catalyst ydrogen Acceptor ydrogen Donor ydrogen Donor ydrogen Acceptor ashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; oyori; R.; J. Am. Chem. Soc. 1995, 117,

11 Why Does Enantiomeric Purity Degrade? % conversion Start 75% S/R 99:1 97:3 xidation of alcohol is 2 orders of magnitude faster than enantiomer Controlled by rate of reversion + Chiral Kinetically selective + rate = k Catalyst rate = 2k ydrogen Acceptor ydrogen Donor ydrogen Donor ydrogen Acceptor ashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; oyori; R.; J. Am. Chem. Soc. 1995, 117,

12 Formic Acid as a ydrogen Donor Makes the reaction irreversible Carbon dioxide as the byproduct R' R + Chiral Catalyst R R' + C 2 ydrogen Acceptor ydrogen Donor ydrogen Donor Fujii, A.; ashiguchi, S.; Uematsu,.; Ikariya, T.; oyori, R., J. Am. Chem. Soc. 1996, 118,

13 ow is the Catalyst Regenerated? + Chiral + C 2 C 2 D L M A R' Ac Catalyst R R' D A D δ+ δ - L M L M L M D A Fujii, A.; ashiguchi, S.; Uematsu,.; Ikariya, T.; oyori, R., J. Am. Chem. Soc. 1996, 118,

14 utline Background information Components of the reaction Catalytic cycles 2- propanol vs formic acid as hydrogen donors Advancements in catalysts Advancements in Rh catalysts Comparing catalysts Synthetic examples

15 Mid 1990 s D A The first group of catalysts for outer shell transfer hydrogenation were developed by oyori. δ + D ow is the Chirality induced? A δ - Me δ + δ - D A Matsummura, K.; ashiguchi, S.; Ikariya, T.; oyori, R., J. Am. Chem. Soc. 1997, 119, Yim, A.; Wills, M., Tetrahedron 2005, 61,

16 Mid 1990 s (R,R) catalyst

17 Mid 1990 s (S,S) catalyst ashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; oyori, R., J. Am. Chem. Soc. 1995, 117,

18 utcome Greatly Influenced by the Reaction Conditions R R C/(C 2 5 ) 3 R S/C C/(C 2 5 ) 3 Time (h) Yield (%) ee% -C : : : : : : Watanabe, M.; Murata, K.; Ikariya, T., J. rg. Chem. 2002, 67,

19 Creation of Two Stereocenters in ne Step mmol 1 C/Et 3 (5:2) 40 C, 3h, 89% 2 syn/anti 68:32 major / Favored Disfavored Eustache, F.; Dalko, P.; Cossy, J., rg. Lett. 2002, 4,

20 More Substrates R 2 R R 1 C/Et 3 (5:2) 50 C, 1h 2 3 Entry 1 R Yield (%) 2+3 2/3 2 ee (%) 2 conf. 1 a -C /8 96 2S, 3R 2 b -(C 2 ) 2 C=C /9 98 2S, 3R 3 4 c d /17 97/ S, 3S 2S, 3R Eustache, F.; Dalko, P.; Cossy, J., rg. Lett. 2002, 4,

21 Tethered thenium (II) Catalyst Goals To lock the ligand in the appropriate conformation for enantiocontrol Locking the aryl group permits control over the spatial positions of the substituents on the ring Should allow fine tuning of the catalyst 2 S 2 annedouche, J.; arkson, G.; Wills, M. J. Am. Chem. Soc. 2004, 126, ayes, A.; Morris, D.; arkson, G.; Wills, M., J. Am. Chem. Soc. 2005, 127,

22 Generation of Active Catalyst D A D A D A K or C 2 /Et 3 (5:2) - ydrogen Donor Yim, A.; Wills, M., Tetrahedron 2005, 61,

23 Tethered Results hydrogen donor Cat. Catalyst Temp ( C) Time (h) Yield % ee Config S R S R 2 S 2 2 S ashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; oyori, R., J. Am. Chem. Soc. 1995, 117, annedouche, J.; arkson, G.; Wills, M., J. Am. Chem. Soc. 2004, 126,

24 A closer look at the Amino Alcohol Ligand Why can t formic acid/triethylamine be used? The ligand isn t stable in this solvent system ow is the chirality induced? Favored Disfavored annedouche, J.; arkson, G.; Wills, M., J. Am. Chem. Soc. 2004, 126, Matharu, D.; Morris, D.; Kawamoto, A.; arkson, G.; Wills, M., rg. Lett. 2005, 24,

25 Roofed cis-diamine-(ii) Complex Conformationally rigid Sterically bulky igh catalytic activity igh enantioselectivity Matsunaga,.; Ishizuka, T.; Kunieda, T., Tett. Lett. 2005, 46,

26 Results of Roofed Catalyst vs. oyori s Catalyst Substrate Catalyst o 2 s Bottom Attack Time (h) Yield (%) ee(%) Side n Attack Config. S R R S R R S R - S R S R 3 Matsunaga,.; Ishizuka, T.; Kunieda, T., Tett. Lett. 2005, 46,

27 utline Background information Advancements in catalysts Advancements in Rh catalysts Comparing catalysts Synthetic examples Synthetic Example

28 oyori s Catalyst with Rhodium as the Metal Center Lower profile than the (II) catalyst Marketed as CATy catalysts by Avecia They have advantages over (II) Improved selectivity in reduction of α chloro ketones In reduction of imines Rh 2 2 Matharu, D.; Morris, D.; Kawamoto, A.; arkson, G.; Wills, M., rg. Lett. 2005, 24,

29 Reduction of Imines in Just a Few Minutes Imines Time (min) Yield (%) ee (%) Rh S Mao, J.; Baker, D.; rg. Lett. 1999, 1,

30 Improved Selectivity in the Reduction of α-chloro ketones Formic acid/triethylamine (5:2) R Catalyst (0.25 mol%) R Catalyst R Time (h) %conv. %ee Rh Cross, D.; Kenny, J.; ouson, I.; Campbell, L.; Walsgrove, T.; Wills, M., Tetrahedron: Asymmetry 2001, 12,

31 ther Ketones Substrate Yield (%) ee (%) Substrate Yield (%) ee (%) CF S Ms C 3 amada, T.; Torii, T.; Izawa, K.; Ikariya, T.; Tetrahedron 2004, 60,

32 Tethered vs ot Tethered Formic acid/triethylamine (5:2) Catalyst Catalyst R mol % Time % conv. % ee h 12 h h 2 h Rh Rh Cross, J.; ouson, I.; Kawamoto, A.; Wills, M.; Tetrahedron lett. 2004, 45, Matharu, D.; Morris, D.; Kawamoto, A.; arkson, G.; Wills, M., rg. Lett. 2005, 24,

33 ow can this Reduction be used? a aq 2-propanol ptically active aromatic Another synthesis epoxides are now Corey s widely CBS used reagent as important synthetic intermediates B Corey's CBS reagent C 2 a C 2 a C 2 a Glaxo Smith Kline β3- adrenergic receptor agonists hling, D. E.; Donaldson, K..; Deaton, D..; yman, C. E.; Sugg, E. E.; Barrett, D. G.; ughes, R. G.; Reitter, B.; Adkison, K. K Lancaster, M. E.; Lee, F.; art,.; Paulik, M. A.; Sherman, B. W.; True, T.; Cowman, C. J. Med. Chem. 2002, 45,

34 utline Background information Advancements in catalysts Advancements in Rh catalysts Comparing catalysts and Rh metals Transfer hydrogenation vs LiAl(tBu) 3, and ab 4 Synthetic examples

35 thenium (II) and Rhodium (III) Contrasting results Rh mol% 1 C 2 / ET 3 (5:2) 65% mol% 2 C 2 / ET 3 (5:2) 44% carbonate mol% mol% mol% 2 + C C 2 / ET 3 (5:2) C 3 formate 9 C 2 7 / ET 3 (5:2) carbonate 5 8 carbonate % 15% Cross, D.; Kenny, J.; ouson, I.; Campbell, L.; Walsgrove, T.; Wills, M., Tetrahedron: Asymmetry 2001, 12,

36 Mechanism mol% 2 C 2 / ET 3 (5:2) carbonate 5 70% % C 2 2 carbonate 5 Cross, D.; Kenny, J.; ouson, I.; Campbell, L.; Walsgrove, T.; Wills, M., Tetrahedron: Asymmetry 2001, 12,

37 Substrate vs. Ligand Control Boc Boc + Boc 1 2a 2b Reagent (2R,3S) 2a/(2S,3S) 2b Rh 1 ab 4 LiAl(-t- Bu) 3 (R,R) 1, C/(C 2 5 ) 3 (S,S) 1a, C/(C 2 5 ) 3 80:20 13:87 90:10 10:90 Use when there is not an α-stereocenter. amada, T.; Torii, T.; nishi, T.; Izawa, K.; Ikariya, T., J. rg. Chem. 2004, 69,

38 utline Background information Advancements in catalysts Advancements in Rh catalysts Comparing catalysts and Rh metals Transfer hydrogenation vs LiAl(tBu) 3, and ab 4 Synthetic examples

39 Alkaloids Diverse class of nitrogen heterocycles Found in plants and even mammals ver 12,000 alkaloids found to date Used as pharmaceuticals Examples include Coralydine Stimulants - caffeine Analgesics Codeine and morphine Szawkalo, J.; Czarnocki, Z.; Monatshefte für Chemie, 2005, 136,

40 Last step in the Synthesis of Coralydine chiral [] + 1 (R,R)-2 (R,S)-3 Chiral cat. Total yield of Ratio 2:3 %ee of 2 a Cbz C 3 B :1 17.4% :0 63% Szawkalo, J.; Czarnocki, Z.; Monatshefte für Chemie, 2005, 136,

41 Synthesis of dihydroisoquinoline 3 (R,R)-4 92%, 99 %ee Disfavored 4 4 Favored

42 Conclusions uter shell coordination is a powerful method for reducing polar bonds uter shell coordination of asymmetric catalytic transfer hydrogenation is useful in the laboratory and on a commercial scale because of its ease of handling, lower cost, and safety, compared with the typically used expensive, hazardous and dangerous reagents such as borane reagents and highpressure hydrogen gas

43 Acknowledgements Dr. Wagner Dr. Smith Dr. Tepe The Tepe group Adam, Brandon, Brian, Chris, Gwen, James, Jason, Sam, Thu, Vasudha icki

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47 Yamakawa, M.; Yamada, I.; oyori, R.; Angew. Chem. Int. Ed. Engl. 2001, 40, 281

48 Tethered thenium (II) Cat. C 1) 4A MS, DCM + 2) LiAl 4, TF, 2h 2 47% 1 2 4, Et 2, rt then 3 hydrate, Et, reflux 89% Pr, Et 3 56% 3 ayes, A.; Morris, D.; arkson, G.; Wills, M. J. Am. Chem. Soc. 2005, 127,

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50 Synthesis of Tethered Rh (III) Catalyst Br nbuli, Et 2-78 C, 1h, then 1-78 C -rt, 3h 3 3%, TF, acetone, rt, o/n + ab 3 C, Me mol Sieves, rt, 20 h 58% from % 4 Rh 3, 2, Me reflux, 24 h, then Et 3, 3h 26% 5 6 Rh Matharu, D.; Morris, D.; Kawamoto, A.; arkson, G.; Wills, M., rg. Lett. 2005, 24,

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