Development and Advancement of the Stetter Reaction. Christopher D. Hupp Michigan State University December 8, 2004

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1 Development and Advancement of the tetter eaction Christopher D. upp Michigan tate University December 8, 2004

2 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

3 Michael Addition Electrophile M C 3 C 3 ucleophile Electrophile? Electrophile ow do we couple two centers of identical polarity or affinity?

4 Definition of ynthon ynthons are structural units within a molecule which are related to possible synthetic operations E. J. Corey ynthon 1 ynthon 2 M C 3 C 3 Donor ynthon Acceptor ynthon Corey, E. J. Pure Appl. Chem. 1967, 14, 19 eebach, D. Angew. Chem. Int. Ed. 1979, 18, 239

5 omenclature for ynthons a n = Acceptor ynthon d n = Donor ynthon Electrophile M d 2 a 3 C 3 C 3 ucleophile a 1 Electrophile? 2 3 a Electrophile eebach, D. Angew. Chem. Int. Ed. 1979, 18, 239

6 ature Gives an Example Enzyme-Bound ThDP Acetolactate ynthase 2 C 2 Enzyme-Bound a 1 C 2 ThDP Pyruvate Acetolactate Acetolactate ynthase P 2 ThDP = Thiamine (Vitamin B 1 ) Diphosphate Pang,..; Duggleby,. G.; chowen,. L.; Guddat, L.. W. J. Biol. Chem. 2004, 279, 2242

7 Acetolactate ynthase 2 Base 2 2 a 1 C 2 2 B C 2 C 2 Enzyme-Bound ThDP 2 C a 1 2 C 2 2 d 1 Pang,..; Duggleby,. G.; chowen,. L.; Guddat, L.. W. J. Biol. Chem. 2004, 279, 2242

8 Umpolung eactivity a 1? a Umpolung reactivity is present in a reagent in which an a or d center is reversed. d 1 a eebach, D. Angew. Chem. Int. Ed. 1979, 18, 239

9 Methods of Umpolung eactivity eteroatom exchange omologation

10 eteroatom Exchange Use of a 1,3-dithiol a 1 Me 1 eq. Me LDA, -78 C Me Ts (cat.), Benzene TF d1 Li reflux 12 h C 2 Me 1 eq., TF -78 C to.t., 15 h 70% Griera,.; igat, L.; Alvarez, M.; Joule, J. A. J. Chem. oc., Perkin Trans 1, 1992, 10, 1223 Wadi, A.; Calahorra, F. L. Tetrahedron Lett. 1992, 33, 3679

11 Methods of Umpolung eactivity eteroatom exchange additional synthetic steps are needed more chances to lose potentially valuable material omologation aldehyde aldehyde coupling Benzoin condensation aldehyde α, β-unsaturated carbonyl coupling tetter reaction

12 Benzoin Condensation a 1 a 1 cat. C Me C - C C C C Proton Transfer C - d 1 C C C Lapworth, A. J. Chem. oc. 1903, 83, 995

13 Path of Benzoin Condensation Cyanide catalyzed benzoin condensation Proposed mechanism for cyanide catalyzed benzoin condensation Lapworth, 1903 Catalytic activity of natural thiamine is based on thiazolium unit Mizuhara et al., 1954 Thiazolium salt catalyzed benzoin condensation Ukai et al., 1943 Proposed mechanism for thiazolium salt catalyzed benzoin condensation Breslow, 1958 Ukai, T.; Tanaka,.; Dokawa, T. J. arm. oc. Jpn. 1943, 18, 239 Mizuhara,.; andler, P. J. Am. Chem. oc. 1954, 76, 571

14 Thiazolium alt-catalyzed Benzoin C Breslow Intermediate - C, 2 2 Breslow,. J. Am. Chem. oc. 1958, 80, 3719

15 Alternative Mechanistic Model 2 A Base 2 A C C 2 2 Castells, J.; Lopez-Calahorra, F.; Domingo, L. J. rg. Chem. 1988, 53, 4433

16 Methods of Umpolung eactivity eteroatom exchange additional synthetic steps are needed more chances to lose potentially valuable material omologation aldehyde aldehyde coupling Benzoin condensation aldehyde α, β-unsaturated carbonyl coupling tetter reaction

17 tetter eaction (1 eq.) 2 (1 eq.) = Aromatic or eterocyclic C (10 mol%) DMF, 35 C 48-98% eaction does not work with aliphatic aldehydes eaction does work with α, β-unsaturated ketones, esters, and nitriles 2 Me Bn Cl (10 mol%) (1 eq.) 2 (1 eq.) Et 3, DMF, 70 C 20-95% eaction does work with aliphatic, aromatic, and heterocyclic aldehydes eaction does work with α, β-unsaturated ketones, esters, and nitriles 2 tetter,. Angew. Chem. Int. Ed. 1976, 15, 639

18 Mechanism of tetter eaction 2 3 X Base 2 3 a 1 d Proton Transfer tetter,. Angew. Chem. Int. Ed. 1976, 15, 639

19 cope of the tetter eaction A E B C D C C 3 C tetter,. Angew. Chem. Int. Ed. 1976, 15, 639

20 First Application of the tetter eaction C C 3 C 2 C C 3 C C 3 Cl (2.3 eq.) Et 3, i-pr, 80 C, 67% C 2 C (±) - irsutic Acid C 3 C 2 C Trost, B.M.; huey, C. D.; Diinno Jr., F.; McElvain,.. J. Am. Chem. oc. 1979, 101, 1284

21 Comparison of Benzoin and tetter eactions Benzoin reaction eversible reaction Products only include benzoin adducts cat. C Me tetter reaction Irreversible reaction Products include tetter adducts as well as benzoin adducts Benzoin products can be used as substrates Thiazolium cat. Base, DMF

22 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

23 Intramolecular tetter eactions C C 2 Me 3 C Bn Cl 10 mol% DMF, reflux C 2 Me 39% Ciganek, E. ynthesis 1995, 1311

24 The Problem Using Cyanide C C 2 2 ac (2 eq.), DMF 25 C C 2 2 ac (2 eq.), DMF 25 C, 58% C 2 C 3 tandem vicinal difunctionalization C Ciganek, E. ynthesis 1995, 1311

25 Tandem Vicinal Difunctionalization C Me C Me C C 2 Me C Chapdelaine, M. J.; ulce, M. rg. eact. 1990, 38, 225

26 Intramolecular tetter eactions C C 2 Me 3 C Bn Cl 10 mol% DMF, reflux C 2 Me 39% C 3 C Bn Cl 10 mol% C 2 Me C 2 Me DMF, Et 3, 25 C or DMF, 120 C 86% Ciganek, E. ynthesis 1995, 1311

27 Importance of Benzopyranones Potential intermediates for the synthesis of heterocyclic analogs of steroids Important building blocks for the preparation of pterocarpans and isoflavanones strong fungicidal activity Me Pterocarpan Isoflavanone C 2 Me Benzopyranone Morand, P.; Lyall, J. Chem. ev. 1968, 68, 85 zaki, Y.; Mochida, K.; Kim,. W. J. Chem. oc., Perkin Trans , 1219 Vicario, J. L.; Badia, D.; Carrillo, L. Tetrahedron: Asymm. 2003, 14, 489

28 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

29 First Asymmetric Intermolecular tetter eaction 20 mol % cat. DMF, MPA, Et 3, 60 C * Yield = 30% ee = 40% Cl Me Me Me Catalyst Enders, D. Enzymemimetic C-C and C- Bond Formations. In tereoselective ynthesis; ttow, E.; choellkopf, K.; chulz, B. G., Eds.; pringer-verlag: Berlin-eidelberg, 1994; pp

30 First Asymmetric Intramolecular tetter eaction C 1 (20 mol%), K 2 C 3 (10 mol%), TF C 2 2 Yield = 44-73% ee = 41-74% C 2 2 Cl 4 3 C C 3 1 Enders, D.; Breuer, K.; unsink, J. elv. Chim. Acta 1996, 79, 1899

31 Transition tate Model Attack occurs from the si face of the Breslow intermediate si C 2 2 si Attack to the si face of the α, β- unsaturated carbonyl C 3 C 3 Enders, D.; Breuer, K.; unsink, J. elv. Chim. Acta 1996, 79, 1899

32 C Advancement of Enantioselective eactions 20 mol % catalyst C 2 X C 2 20 mol % KMD, xylenes, 25 C, 24 h ubstrate Product Cat. Yield(%) ee(%) X C 2 Et C 2 Et C 2 Me 1 Me C 2 Me BF 4 X = Bn BF 4 X X X = Me C 2 Et C 2 Et Kerr, M..; de Alaniz, J..; ovis, T. J. Am. Chem. oc. 2002, 124, 10298

33 tereochemical easoning si C 2 Et si Et Et 2 C Attack from the si face of the Breslow intermediate, to the si face of the α, β- unsaturated carbonyl re re C 2 Et Et C 2 Et Attack from the re face of the Breslow intermediate, to the re face of the α, β-unsaturated carbonyl What about racemization?

34 acemization with Benzofuranones C 2 C 3 BF 4 Bn 20 mol% 20 mol% KMD, xylenes, 25 C, 24 h C 2 C 3 90% yield <5% ee C 2 C 3 r C 2 C 3 Kerr, M..; de Alaniz, J..; ovis, T. J. Am. Chem. oc. 2002, 124, 10298

35 Effect of Michael Acceptor C Triazolium catalyst 20 mol % EWG EWG 20 mol % KMD, xylenes, 25 C, 24 h EWG Time Yield (%) ee (%) BF 4 2 Et 24 h 1 h Catalyst C 24 h h h 0 -- Kerr, M..; ovis, T. ynlett, 2003, 12, 1934

36 Aliphatic Enantioselective eactions C 2 Et 20 mol% Bn BF 4 C 2 Et 20 mol% KMD, xylenes, 25 C, 24 h 81% yield 95% ee C 2 Et Cl Bn 20 mol% 20 mol% KMD, xylenes, 25 C, 24 h C 2 Et C 2 Et C 2 Et 20 mol% Bn 20 mol% KMD, xylenes, 25 C, 36 h Cl C 2 Et Kerr, M..; ovis, T. ynlett, 2003, 12, % Yield 82% ee C 2 Et

37 ynthesis of Quaternary tereocenters EWG 20 mol % catalyst X 2 eq. Et 3, Me, 25 C, 24 h X EWG BF 4 F F F F F Catalyst Kerr, M..; ovis, T. J. Am. Chem. oc. 2004, 126, 8876

38 Aromatic ubstrates C 2 Me 20 mol % cat. Et Et 2 eq. Et 3, Me, 25 C, 24 h C 2 Me Yield = 96% ee = 97% C 2 Me 20 mol % cat. Et Et 2 eq. Et 3, Me, 25 C, 24 h C 2 Me Yield = 95% ee = 99% Me 20 mol % cat. 2 eq. Et 3, Me, 25 C, 24 h Me Yield = 55% ee = 99% Kerr, M..; ovis, T. J. Am. Chem. oc. 2004, 126, 8876

39 Aliphatic ubstrates Me Ar 20 mol% cat. Me 20 mol% KMD, Me, 25 C, 24 h Ar Ar = 4-Py Yield = 85% ee = 96% Ar = p- 2 Yield = 90% ee = 84% Me 20 mol% cat. Me 20 mol% KMD, Me, 25 C, 24 h = Me Yield = 81% ee = 95% Kerr, M..; ovis, T. J. Am. Chem. oc. 2004, 126, 8876

40 tereochemical easoning Me si C 2 Me si F F Me Me F F Me 2 C Me Attack from the si face of the Breslow intermediate, to the si face of the α, β-unsaturated carbonyl si Me re F F Me F F Me C() Attack from the re face of the Breslow intermediate, to the si face of the α, β-unsaturated carbonyl

41 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

42 tetter with Acylimine Acceptors Tol Cl 10 mol% Bn Et 3 (5-15 eq.), C 2 Cl 2, 35 C Yield (%) 4-pyridyl cyclohexyl 98 4-pyridyl Bn 96 t Bu 75 C 3 t Bu 62 Murray, J. A.; Frantz, D. E.; oheili, A.; Tillyer,.; Grabowski, E. J. J.; eider, P. J. J. Am. Chem. oc. 2001, 123, 9696

43 The Problem with Aliphatic 2 Tol 2 10 mol% Cat Et 3, C 2 Cl 2, 35 C Et 3 very low yields Murray, J. A.; Frantz, D. E.; oheili, A.; Tillyer,.; Grabowski, E. J. J.; eider, P. J. J. Am. Chem. oc. 2001, 123, 9696

44 Proposed Mechanism C X 3 2 G Tol 2 D 2 3 A 2 3 B E 3 2 F Murray, J. A.; Frantz, D. E.; oheili, A.; Tillyer,.; Grabowski, E. J. J.; eider, P. J. J. Am. Chem. oc. 2001, 123, 9696

45 Data to upport Mechanism 1. Mimic of intermediate Tol 2 10 mol% 1 Et 3, C 2 Cl 2, 35 C 85% 1 I D Murray, J. A.; Frantz, D. E.; oheili, A.; Tillyer,.; Grabowski, E. J. J.; eider, P. J. J. Am. Chem. oc. 2001, 123, 9696

46 Data to upport Mechanism 2. Deuterium incorporation experiment Tol 2 10 mol% D I D Et 3, C 2 Cl 2, 35 C >95% with D Consistent with the acylimine operating as an electrophile Murray, J. A.; Frantz, D. E.; oheili, A.; Tillyer,.; Grabowski, E. J. J.; eider, P. J. J. Am. Chem. oc. 2001, 123, 9696

47 Data to upport Mechanism 3. Crossover experiment 5 6 Tol mol% catalyst Et 3, C 2 Cl 2, 35 C o crossover products were observed Murray, J. A.; Frantz, D. E.; oheili, A.; Tillyer,.; Grabowski, E. J. J.; eider, P. J. J. Am. Chem. oc. 2001, 123, 9696

48 tetter vs. tetter with Acylimine tetter reaction Products include tetter adducts as well as benzoin adducts Benzoin products can be used as substrates Thiazolium cat. Base, DMF tetter with acylimine acceptor reaction Products include only tetter adducts Benzoin products can not be used as substrates Tol 2 Thiazolium Cat. 2 3 Base, DCM 3 2

49 ne-pot ynthesis of ubstituted Imidazoles Tol mol% Cat. Et 3, DCM, C 2 I 3 2 Ac Cat. 3 2 Frantz, D. E.; Morency, L.; oheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer,. D. rganic Letters, 2004, 6, 843

50 ne-pot ynthesis of Di-substituted Imidazoles Tol mol% catalyst Et 3, C 2 Cl 2, 35 C 2. 4 AC (15 eq.) reflux 12 h 76% Tol F mol% catalyst Et 3, C 2 Cl 2, 35 C 2. 4 AC (15 eq.) reflux 12 h F 82% Frantz, D. E.; Morency, L.; oheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer,. D. rganic Letters, 2004, 6, 843

51 ne-pot ynthesis of Tri-substituted Imidazoles Tol mol% catalyst Et 3, C 2 Cl 2, 35 C 2. 4 Ac (15 eq.) reflux 82% Tol 1.10 mol% catalyst 2 Et 3, C 2 Cl 2, 35 C 2.e (5 eq.) Acetic Acid (5 eq.) reflux 2 C 73% >98%ee Frantz, D. E.; Morency, L.; oheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer,. D. rganic Letters, 2004, 6, 843

52 Importance of Chiral Tri-substituted Imidazoles Implicated as an angiotensin II receptor antagonists yntheses have traditionally involved multistep sequences or resolutions 2 C Palkowitz, A. D. et al. J. Med. Chem. 1994, 37, 4508

53 ne-pot ynthesis of Tetra-substituted Imidazoles Tol mol% catalyst Et 3, C 2 Cl 2, 35 C 2. Et, Acetic Acid (5 eq.), 2 (5 eq.) 76% Tol mol% catalyst Et 3, C 2 Cl 2, 35 C 2. Et, Acetic Acid (5 eq.), 2 Me (5 eq.) Me 80% Me Me Frantz, D. E.; Morency, L.; oheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer,. D. rganic Letters, 2004, 6, 843

54 Importance of Tetra-substituted Imidazoles epresentative of a class of highly potent p38 kinase inhibitors helps to suppress a biological pathway that leads to inflammation Me Me Liverton,. J. et al. J. Med. Chem. 1999, 42, 2180

55 ne-pot ynthesis of Tri-substituted xazole and Thiazole Tol mol% catalyst Et 3, Me, 35 C 2. 3 P, I 2 77% Tol mol% catalyst Et 3, Me, 35 C 2. Lawesson's reagent (1.5 eq.) 50% Frantz, D. E.; Morency, L.; oheili, A.; Murray, J. A.; Brabowski, E. J. J.; Tillyer,. D. rganic Letters, 2004, 6, 843

56 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

57 ila-tetter eaction ix cat. A, DBU 2. TF, i-pr 3 2 Br Et C 3 Cat. A Mattson, A. E.; Bharadwaj, A..; cheidt, K. A. J. Am. Chem. oc. 2004, 126, 2314

58 Proposed Mechanism Br DBU ix 3 Brook rearrangement ix 3 ix ix 3 Benzoin Product Mattson, A. E.; Bharadwaj, A..; cheidt, K. A. J. Am. Chem. oc. 2004, 126, 2314

59 cope of ila-tetter eaction ime 3 30 mol% cat., DBU (30 mol%) i-pr, TF 84% Me 3 C i Me 30 mol% cat., DBU (30 mol%) i-pr, TF 3 C 70% ime 3 3 C 2 C C 3 30 mol% cat., DBU (30 mol%) i-pr, TF 3 C C 3 72% Mattson, A. E.; Bharadwaj, A..; cheidt, K. A. J. Am. Chem. oc. 2004, 126, 2314

60 tetter vs. ila-tetter eaction tetter reaction Products include tetter adducts as well as benzoin adducts Thiazolium cat. Base, DMF ila-tetter reaction Products include only tetter adducts ix Thiazolium cat., Base TF, i-pr 3 2

61 ne-pot ynthesis of Pyrroles ix mol% cat. DBU, TF i-pr Et Br Ts 4Å sieves Catalyst Bharadwaj, A..; cheidt, K. A. rg. Lett. 2004, 6, 2465

62 ne-pot ynthesis of Pyrroles ime mol% cat. DBU, TF,i-Pr 2.Ts,4Å sieves, 2 71% ime mol% cat. DBU, TF,i-Pr 2.Ts,4Å sieves, 2 70% ime 3 Cl mol% cat. DBU, TF,i-Pr 2.Ts,4Å sieves, 2 80% Cl Bharadwaj, A..; cheidt, K. A. rg. Lett. 2004, 6, 2465

63 ne-pot ynthesis of Pyrroles ime mol% cat. DBU, TF,i-Pr 2.Ts,4Å sieves, Amine Amine Yield(%) Br 2 71 C 3 (C 2 ) C C Ac 62 Bharadwaj, A..; cheidt, K. A. rg. Lett. 2004, 6, 2465

64 Importance of Chiral Pyrrole Compounds elated chiral pyrroles have been identified as highly selective potential treatments for diabetes Me Liu, K. G.; Lambert, M..; Ayscue, A..; enke, B..; Leesnitzer, L. M.; liver, W..; Plunket, K. D.; Xu,. E.; ternbach, D. D.; Willson, T. M. Bioorg. Med. Chem. Lett. 2001, 11, 3111

65 Microwave Assisted ynthesis ime 3 20 mol% cat. DBU, TF, i-pr µw (300 W), 160 C Ar 2, Ts, 4Å sieves µw (300 W), 160 C 55% Using conventional heating, rxn takes 16hr Using microwave heating, rxn takes 30min Bharadwaj, A..; cheidt, K. A. rg. Lett. 2004, 6, 2465

66 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

67 tetter eaction Using MPgel n 2 3 Me Me I DMF, Et 3, 80 C 3 2 MPgel = ing pening Metathesis Polymerization gel, which is a general class of high loading polymer supported reagents, catalysts, or scavengers Barrett, A. G. M.; Love, A. C.; Tedeschi, L. rganic Letters, 2004, 6, 3377

68 Preparation of MPgel-supported Thiazolium Iodide (10 eq.) 180 C, 53% MeI (1.5 eq.) n-bu, 80 C, 87% I Mes Cl u Cl Mes A (0.11 eq.), B (0.8 mol%), ClC 2 C 2 Cl, 50 C, 94% A PCy 3 B n Me Me I Barrett, A. G. M.; Love, A. C.; Tedeschi, L. rganic Letters, 2004, 6, 3377

69 tetter eaction with MPgel Me Me I n MPgel 4x

70 ynthesis of 1,4-Diketones using MPgel n-dec Cl MPgel (16 mol%) Catalyst DMF, Et 3, 80 C n-dec 99% yield Cl Me 4 MPgel (16 mol%) Catalyst DMF, Et 3, 80 C 4 Me 86% yield MPgel (16 mol%) Catalyst DMF, Et 3, 80 C 68% yield Barrett, A. G. M.; Love, A. C.; Tedeschi, L. rganic Letters, 2004, 6, 3377

71 Path of Presentation Development of tetter reaction Umpolung reactivity Methods of umpolung reactivity eteroatom exchange Benzoin condensation tetter reaction Conclusions Acknowledgements Advances in tetter reaction Intramolecular reactions Enantioselective reactions tetter reactions with acylimine acceptors ila-tetter reactions tetter reactions using MPgel

72 Conclusions The tetter reaction is only one way to make 1,4- dicarbonyl compounds Utilizes umpolung reactivity to react two synthons of identical polarity The tetter reaction can be used to make various substituted heterocycles Although enantioselective intramolecular reactions have been explored, there is still the need to develop the corresponding intermolecular reactions

73 Acknowledgements Dr. Babak Borhan Dr. Jetze Tepe Dr. Greg Baker Adam Mosey Jason Fisk Mahesh Peddibhotla Manasi Keni am Frawley Vasudha harma Amber Terry Kyoungsoo Lee oong-yun Kim