Chiral Phosphoric Acid Catalysis: Ac2va2on Modes and Relevant Examples

Transcription

1 Chiral hosphoric Acid Catalysis: Ac2va2on Modes and elevant Examples Eric ewcomb March 12 th, 2012

2 BIL In rganic Synthesis First Made as acemate by von ichter (1873) ()-BIL (S)-BIL Superstoichiometric BIAL reagent (1979) Li Al ' TF ( 2 equiv) good yields varying ee's von ichter, V. Chem. Ber. 1873, 6, Love, B. E. Curr. rg. Synth. 2006, 3, 169. oyori,.; Tanimoto, T. Y. J. Am. Chem. Soc. 1979, 101,

3 BIL Based eagents In rganic Synthesis umerous Examples of BIL eagents (and Derivatives) in Asymmetric Synthesis BIL Backbone Generally rovides Good Chiral Induction Asymmetric Mukiayama Aldol (1995) TMS 1) (S)-BIL / Ti(-ir) 4 (1:1) (20 mol%) 4Å MS, Et 2, -20 C = aryl, alkyl t-bus Asymmetric Epoxidation of Enones (2001) 2) + t-bus 70-90% yield 89-98% ee 1 2 1, 2 = aryl, alkyl ()-BIL (5 mol%) La(-ir) 3 (5 mol%) h 3 As() or h 3 () (5-15 mol%) tbu (1.2 equiv), 4Å MS TF, rt % yield 92-99% ee Asymmetric Addition of henylacetylene to Aldehydes (2005) = aryl, alkyl Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, emoto, T.; hshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, Takita,.; Yakura, K.; hshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, h InBr (10 mol%) ()-BIL (10 mol%) Cy 2 (50 mol%) C 2 Cl 2, 40 C h 84-95% yield 95-98% ee 3

4 Ac2va2on of olarized Func2onal Groups TADDL [M] [M] Bis-oxazolines h t-bu S S Z Chiral hosphoric Acid X [Ti] X Ti X X t-bu Ct-Bu Ti-BIL Thiourea Catalyst -Bond Catalysis Brønsted Acid Catalysis Lewis Acid Catalysis Can chiral Brønsted acids fill in gaps between -bonding catalysis and LA catalysis? e other modes of activation possible with chiral brønsted acids? 4

5 Different Modes of Ac2va2on 2 1 Dual Activation 1 -Bond/Ion-air Activation Bifunctional Activation Double -Bond Activation Et Z Et TIS -Bond/Ion-air Activation Y Ts Z Covalent Activation 5

6 ot Covered in Talk (But Worth n2oning) Asymmetric Counterion-Directed Catalysis (ACDC) Epoxidation C 2 ir cat (5 mol%) hi (1.2 equiv) benzene, rt, 2h 96% ee C 2 ir tbu tbu Mn tbu tbu tbu tbu!-allylation of Aldehydes i-r i-r i-r i-r cat h 2 i-r i-r (1.5 mol%) d(h 3 ) 4 (3 mol%) 2 1 Dual Catalysis 1 = aryl C h 2 =,, h 5Å MS, MTBE, 40 C, 8-24 h then 2 Cl, Et 2, rt, 30 min 1 C 40-89% yield 70-97% ee eactions which use the chiral acid with a metal, Lewis base, etc. Liao, S.; List, B. Angew. Chem. Int. Ed. 2009, 49, Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129,

7 The Ini2al ublica2ons: Mannich- Type Akiyama (2004) 2 Terada (2004) TMS h (1.0 equiv) (3 equiv) (10 mol%) 2 toluene, -78 C, 4 h C 2 h 96% yield 87% ee h Boc (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h h Boc Ac 99% yield 95% ee Ac 7

8 The Ini2al ublica2ons: Mannich- Type Akiyama (2004) 2 TMS h (1.0 equiv) (3 equiv) (10 mol%) 2 toluene, -78 C, 4 h h C 2 96% yield 87% ee 1 Dual Activation Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43,

9 Discovery and p2miza2on TMS Cat (30 mol%) toluene, -78 C C 2 h h (3 equiv) Cat t (h) Yield (%) ee (%) Cat t (h) Yield (%) ee (%) ighest reactivity and enantioselectivity Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43,

10 Ini2al Substrate Screen 2 TMS (10 mol%) toluene, -78 C 2 C 2 C 2 C 2 C 2 C 2 98% yield 89% ee (13 h) F Cl 100% yield 89% ee (24 h) 100% yield 85% ee (24 h) 100% yield 80% ee (24 h) A small number of 4-substituted aryl aldimines were screened and displayed excellent yields and good ee's Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43,

11 Diastereoselec2ve eac2on Scope 2 TMS (10 mol%) 2 3 toluene, -78 C, 24 h 1 C (1.0 equiv) (1.5 equiv) % yield 87:13 syn/anti 96% ee C 2 Et 100% yield 92:8 syn/anti 88% ee C 2 Et C 2 Et F Cl 100% yield 91:9 syn/anti 84% ee 100% yield 86:14 syn/anti 83% ee C 2 Et 100% yield 94:6 syn/anti 81% ee C 2 Et C 2 C 2 Et C 2 Et C 2 Et C 2 Et Sih 3 79% yield 100:1 syn/anti 91% ee S Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, % yield 94:6 syn/anti 88% ee 91% yield 95:5 syn/anti 90% ee 100% yield 93:7 syn/anti 91% ee 92% yield 93:7 syn/anti 87% ee 11

12 Changes to Aldimine are ot Tolerated 2 h X TMS (10 mol%) toluene, -78 C 2 X C 2 h C 2 C 2 C 2 C 2 98% yield 89% ee (13 h) 28% yield 20% ee (33 h) 56% yield 3% ee (46 h) 76% yield 39% ee (43 h) 2-hydroxyl substituent is essential for high reactivity and enantioselectivity Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129,

13 Two oten2al athways C2n monocoordination path C2i Cat h h h EI C1n dicoordination path C1i elative energy (kcal/mol) Cat + u + EI monocoordination path C2n C1n dicoordination path TS1t eaction coordinate C2i C1i -5.4 TS2i -8.8 TS1i to products h TMS h BandLY/6-31G level of theory u BIL instead of BIL was used in calculations h Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129,

14 ther Examples of Dual Ac2va2on Asymmetric Aza Diels-Alder i-r i-r TMS (5 mol%) i-r i-r i-r i-r Ac (1.2 equiv) toluene, -78 C 1 Dual Activation Asymmetric Inverse Electron-Domand Aza Diels-Alder % yield 76-91% ee toluene (10 mol%) = alkyl Akiyama, T.; Tamura, Y.; Itoh, J.; Morita,.; Fuchibe, K. Synlett 2005, Akiyama, T.; Morita,.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, = 9-anthryl 59-95% yield 88-97% ee 14

15 Direct Mannich eac2on Terada (2004) h Boc (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h h Boc Ac Ac 99% yield 95% ee 2 1 -Bond/Ion-air Activation 15 Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126,

16 Catalyst Evalua2on h Boc Cat (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h h Boc Ac Ac Cat Yield (%) ee (%) Cat Yield (%) ee (%) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, igh Enantioselectivity 16

17 Boc Ac Boc Ac Boc Ac Boc Ac Substrate Scope Boc (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h Boc Ac Ac Ac Ac Br Ac F Ac 93% yield 90% ee 98% yield 94% ee 96% yield 98% ee 94% yield 96% ee Boc Ac Boc Ac Ac Ac 94% yield 93% ee Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, % yield 92% ee Changes to are tolerated 17

18 roposed Ac2va2on Mode h Boc Cat (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h h Boc Ac Ac 2 Leads to the observed stereoselectivity trans-1 (0.0) cis-1 (6.9) Boc h h Boc trans-2 (0.8) cis-2 cannot locate h Boc Boc h 1 -Bond/Ion-air Activation Authors claim that in the trans-2 and cis-1 -bond complexes the imine is completely shielded by the bulky groups If Boc is changed to a benzyl or methyl ester errosion of ee is observed (26% and 6% ee, respectively) Calculations can provide useful data into reactivity, but ocassionally they do not reflect reality elative energy of activated imine complexes (kcal/mol) = biphenyl n the B3LY/6-31G(d, p) level of theory Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, Gridnev, I. D.; Kouchi, M.; Sorimachi, K.; Terada, M. Tet. Lett. 2007, 48,

19 Is the Acid the Catalyst? h Boc (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h = 4-(!-aph)-C 6 4 h Boc Ac Ac 99% yield 95% ee () Terada's original result (catalyst purified on silica gel) h Boc (2 mol%) acac (1.1 equiv), C 2 Cl 2, rt, 1 h = 4-(!-aph)-C 6 4 Boc Washed with Cl to remove alkali or alkaline-earth metals Ac h Gives poor selectivity and the opposite enantiomer Ac 88% yield >27% ee (S) h Boc Ca Boc 2 (2.5 mol%) Chiral calcium phosphate catalyst gives Ac acac (1.1 equiv), C 2 Cl 2, rt, 1 h h similar results to Tereda's original data = 4-(!-aph)-C 6 4 Ac >99% yield 92% ee () Washing with Cl to remove salts does not typically have such a drastic effect on selectivity atano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010, 49,

20 ther Examples of Imine Ac2va2on 2 1 -Bond/Ion-air Activation Aza-Friedel-Crafts Alkylation of Furan Boc (2 mol%) DCE, -35 C, 24 h = 3,5-dimesitylphenyl 80-96% yield 86-97% ee Boc Most transformations proceeding through imine activation are bifunctional (i.e. activate the nucleophile as well) Daisuke Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,

21 Moving ast Imine Substrates otential activation Z 2 of less polarized substrates Et 1 -Bond/Ion-air Activation TIS -Bond/Ion-air Activation 21

22 A ew Acid Catalyst Tf Tf Authors claim increase in acidty may cause better activation TIS Et (5 mol%) toluene, -78 C, 3 h <10 % yield ee not determined (1.5 equiv) i-r i-r TIS Et (1.5 equiv) (5 mol%) i-r i-r i-r Tf toluene, -78 C, 3 h i-r TIS Et 95% yield 92% ee >98/<2 endo/exo akashima, D.; Yamamoto,. J. Am. Chem. Soc. 2006, 128,

23 Substrate Scope i-r i-r Et (5 mol%) i-r i-r i-r Tf toluene, -78 C, 3 h i-r Et Et Et Et Et TBS TIS TIS TIS Bn 43% yield 92% ee 95% yield 92% ee 43% yield 88% ee 99% yield 85% ee Et Et Et Et TIS TIS TIS TIS TBS MM Bz 99% yield 92% ee 99% yield 87% ee 35% yield 82% ee 99% yield 91% ee akashima, D.; Yamamoto,. J. Am. Chem. Soc. 2006, 128, When methyl vinyl ketone was used, enantioselectivity decreased to ~50% ee 23

24 roposed Ac2va2on Mode Tf Et Tf Et TIS Et TIS TIS Ion-air Activation -Bonding Activation no proposed model of stereoinduction mentioned Tf TIS Could the silylated phosphoramide be the active catalyst? (lewis acid catalysis) i-r i-r i-r Tf i-r TIS h (25 mol%) C 2 Cl 2, rt, 30 min "silylated catalyst" Et -78 C TIS (1.5 equiv) -78 C, 3 h o eaction (5 mol%) i-r i-r silyl phosphoramide most likely is not the catalyst in the Diels-Alder reaction akashima, D.; Yamamoto,. J. Am. Chem. Soc. 2006, 128,

25 Is the Catalyst a Stronger Acid? Second and third pk a values are about 4 and 5 pk a units lower Tf i-r i-r i-r i-r i-r i-r! pk a is about 1 pk a unit in DMS (25 C) i-r i-r Tf i-r i-r i-r pk a = 4.22 pk a = 3.34 i-r Acidity may be playing a role but aryl substituent on BIL seems to have greatest impact Still, -triflyl phosphoramides do tend to activate carbonyls more efficiently than the analogous phosphoric acids akashima, D.; Yamamoto,. J. Am. Chem. Soc. 2006, 128, Burlingham, B. T.; Widlanski, T. S. J. rg. Chem. 2001, 66, Christ,.; Lindsay, A. G.; Vormittag, S. S.; eudörfl, J-M.; Berkessel, A.; 'Donoghue, A. C. Chem. Eur. J. 2011, 17,

26 An Example of Stronger Acid Ion- air Ac2va2on Z Et TIS -Bond/Ion-air Activation Carbonyl-Ene Tf (1 mol%) CF 3 Et 2 C Et 2 C CF 3 o-xylene, 10 C, 34 h = aryl = p-c % yield 92-97% ee ueping, M.; Theissmann, T.; Kuenkel, E.; Koenigs,. Angew. Chem. Int. Ed. 2008, 47,

27 Ac2va2on of Aldehydes: Aza- Ene Type eac2on Terada (2008) C 2 (5 mol%) C Et 2 C h 4Å MS, C 2 Cl 2, rt, 1 h Et 2 C h Et 2 C 93% yield 95% ee h C 2 (5 mol%) C Et 2 C 4Å MS, C 2 Cl 2, rt, 1 h Et 2 C Et 2 C 78% yield 95% ee Et Double -Bond Activation Terada, M.; Soga, K.; Momiyama,. Angew. Chem., Int. Ed. 2008, 47,

28 Catalyst Evalua2on C 2 (5 mol%) 3 + Et 2 C h C 2 Cl 2, 4 Å MS, rt, 1 h Et2C h Yield (%) ee (%) 4-C 3 C t-bu 4-CF 3 C t-BuC igh yield and enantioselectivity 3,5-t-Bu 2 C t-bu 2,4,6-(C 3 ) 3 C Terada, M.; Soga, K.; Momiyama,. Angew. Chem., Int. Ed. 2008, 47,

29 Substrate Scope t-bu (E)-enecarbamates were used Et 2 C Et 2 C 73% yield >99 : <1 anti:syn >99% ee (anti) 53% ee (syn) 73% yield 96 : 4 anti:syn 99% ee (anti) 56% ee (syn) h Et Et 2 C 1 C 2 2 Et 2 C (5 mol %) C 2 Cl 2, 4 Å MS, rt Then, % yield 89 : 11 anti:syn 99% ee (anti) 98% ee (syn) t-bu Et 2 C Et 2 C Extremely high enantioselectivites and anti selectivities were observed in the reactions of (E)-enecarbamates oor enantioselectivities and diastereoselectivities were observed in the reactions of (Z)-enecarbamates Terada, M.; Soga, K.; Momiyama,. Angew. Chem., Int. Ed. 2008, 47, (Z)-enecarbamates were used Et 2 C Et 2 C 11% yield 72 : 28 anti:syn 26% ee (anti) 88% ee (syn) 74% yield 50 : 50 anti:syn 28% ee (anti) 69% ee (syn) 29 h Et

30 roposed Ac2va2on Mode Et Double -bond activation Double -bond activation agrees with enantioselectivity C Et 2 C h Et2C 93% yield 95% ee h Double -bond activation can help explain lack of reactivity and enantioselectivity C Et 2 C h Terada, M.; Soga, K.; Momiyama,. Angew. Chem., Int. Ed. 2008, 47, The aryl substituents force a comformational change in catalyst blocking both faces towards attack Et2C 40% yield 8% ee 30 h

31 Examples of Double - Bond Ac2va2on etero Diels-Alder Et 2 1 (5 mol %) 2 1 Double -Bond Activation 3 4 C 2 Et toluene, 4 Å MS, rt, h = henyl 3 C 2 Et % yield 79->99% anti 97-99% ee Aldol X 1 n C 2 2 (5 mol %) toluene, 0-50 C, 72 h X 1 C 2 2 n X =, S, C 2 = 2,4,6-() 3 C % yield 50/ syn/anti 48-84% ee Momiyama,.; Tabuse,.; Terada, J. J. Am. Chem. Soc. 2009, 131, ousse, G.; Le Cavelier, F.; umphreys, L.; ouden, J.; Blanchet, J. rg. Lett. 2010, 12,

32 Chiral hosphoric Acid Catalyzed xida2on Ding (2008) h (10 mol %) 2 2(aq) (30%), CCl 3, -40 C = yren-1-yl h 99% yield 88% ee Bifunctional Activation Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47,

33 Catalyst Evalua2on h Cat (10 mol %) 2 2(aq) (30%), CCl 3, rt h Cat Z t (h) yield (%) ee (%) C C C Z 2,4,6-(i-r) 3 C henanthr-9-yl henanthr-9-yl Tf yren-1-yl triflyl phosphoramide is very active but gives poor enantioselectivity yren-1-yl Z yren-1-yl yren-1-yl yren-1-yl (0 C) 88 (-40 C) 88 (-40 C) Cooling the reaction and washing with 4 Cl increases yield Better reactivity is observed with catalyst that is washed with Cl More typical effect than the reversal of stereoselectivity discussed earlier Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47,

34 Substrate Scope 1 (10 mol %) (aq) (30%), CCl 3, -40 C 2 = yren-1-yl X 99% yield 88% ee 99% yield 93% ee 99% yield 85% ee 99% yield 83% ee (X = Br) 82% ee (X = Cl) 84% ee (X = F) 91% yield 86% ee (1 mol % cat), 80 h 99% yield 83% ee 99% yield 58% ee 99% yield 57% ee 99% yield 55% ee 36 h Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, % yield 61% ee 24 h 34

35 roposed chanism ath A 2 ath B Experimental data and DFT calculations indicate the oxidation of the catalyst by hydrogen peroxide is unlikely 2 Based on DFT calculations, the hydrogen bonds lower the energy barrier in both the attack of the peroxide and the collapse of the Criegee intermediate Xu, S.; Wang, Z.; Zhang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed. 2008, 47, Xu, S.; Wang, Z.; Li, Y.; Zhang, X.; Wang,.; Ding, K. Chem. Eur. J. 2010, 16,

36 ther Examples of Bifunc2onal Ac2va2on 1,4 Addition of Substituted Indoles 1 (10 mol %) 3 2 DCE/sitylene (1:1), -40 C, 3 Å MS = 2,4-(CF 3 ) 2 -C 6 3 Bromocyclization Dipolar Cycloaddition X X =, Ts, Trisyl Br C 2 Cl 2, 0 C 1 (10 mol %) = 2,4,6-(i-r) 3 C % yield 58-92% ee X Br 36-97% yield Up to 91% ee 2 Bifunctional Activation 2 C 2 Et C 2 Et 3 2 (10 mol %) C 2 Cl 2, 3 Å MS, 25 C = 2-apthyl T. Sakamoto, T. Itoh, J.; Mori, K.; Akiyama, T. rg. Biomol. Chem. 2010, 8, uang, D.; Wang, ; Xue, F.; Guan,.; Lijun Li, L.; eng, X.; Shi, Y. rg. Lett. 2011, 13, Chen, X-.; Qiang Wei, Q.; Luo, S-W.; Xiao,.; Gong, L-Z. J. Am. Chem. Soc. 2009, 131, Ac Ac C 2 Et C 2 Et 59-97% yield 81-98% ee 36

37 eac2ons with Unac2vated Alkenes u cat u Chiral phosphoric acids have been shown to activate polarized FGs (imines, carbonyls, etc.) Is it possible to utilize these acids in asymmetric reactions of less polarized FGs? otential for reactivity not found in either Lewis acid catalysis or -bonding catalysis Ackerman (2008) CF 3 CF 3 h h Ackerman, L.; Althammer, A. Synlett 2008, Althammer, A. h.d. Thesis, Georg-August-Universitaet Goettingen, ct Bn (10 mol %) 1,4-dioxane, 130 C, 20 h h h Bn 72% yield 17% ee Sole example of this catalyst in asymmetric hydroamination of unactivated alkene until 2011 CF 3 CF 3 37

38 Intramolecular ydroamina2on Toste (2011) Ts S S (10 mol %) hf, 4 Å MS, 23 C, 48 h Ts 99% yield 96% ee = 10-(2,4,6-(C 3 ) 3 -C 6 2 )-9-anthracenyl Ts Y Z Covalent Activation Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470,

39 Intramolecular ydroamina2on: Ini2al Screen Ts cat (10 mol %) Ts solvent, temp, 48 h Catalyst substituents Solvent Temp ( C) Yield (%) ee (%) 1 X = Z = S, = 1-napthyl CDCl X Z 2 X = Z =, = 1-napthyl 3 X = S, Z = Tf, = 1-napthyl CDCl 3 CDCl A 46 4 X =, Z = Tf, = 1-napthyl CDCl A S S S Tf Structure used to guide optimization Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470, Any derivitization of this thio phosphoramide structure led to low yields 39

40 Intramolecular ydroamina2on: p2miza2on Ts cat (10 mol %) Ts solvent, temp, 48 h Catalyst substituents Solvent Temp ( C) Yield (%) ee (%) S S 5 = 9-anthracenyl 5 = 9-anthracenyl 6 = 10-phenylanthracenyl 7 = 10-(3,5-bis-t-Bu-C 6 3 )-9-anthracenyl 8 = 10-(2,4,6-(C 3 ) 3 -C 6 2 )-9-anthracenyl CDCl 3 hf hf hf hf tbu tbu S S Bulky dithiophosphoric acids 7 and 8 provided the best yields and enantioselectivities in the hydroamination reaction S S tbu tbu Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470,

41 Substrate Scope S S 7 = 10-(3,5-bis-t-Bu-C 6 3 )-9-anthracenyl 8 = 10-(2,4,6-(C 3 ) 3 -C 6 2 )-9-anthracenyl Dienes Allenes Ts 7 (10 mol%) hf, 4 Å MS 30 C, 48 h Ts 70% yield 94% ee s 8 (10 mol%) hf, 4 Å MS 23 C, 48 h s 81% yield 90% ee Ts 7 (10 mol%) hf, 4 Å MS 30 C, 48 h Ts Et 90% yield, 4.7:1 (E/Z) 95% ee (E), 90% ee (Z) Ts 8 (10 mol%) hf, 4 Å MS 23 C, 48 h Ts 70% yield 90% ee n Ts 8 (10 mol%) hf, 4 Å MS 23 C, 48 h Ts n n = 1 99% yield 96% ee n = 2 91% yield 97% ee Ts 8 (20 mol%) hf, 4 Å MS 60 C, 48 h Ts 67% yield 92% ee Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470,

42 Expansion to (Ac2vated) Carbon ucleophiles E E S S (20 mol%) E E hf, 4 Å MS, 48 h, rt = 10-phenylanthracenyl 75% yield 91% ee 16 examples of the asymmetric hydroamination reaction Good yields and ee's Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470,

43 chanis2c Studies roposed chanism Ts Ts S S Ts S S Covalent activation? bserved in TF-MS of aliquots from reaction mixture h h S 1:1 CDCl 3 /D 2 S 23 C, 48 h >95% D incorportation >95% cis product D S h h S S Et Et S S h h S Labile under D 2 conditions Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470,

44 robing the ypothesized chanism roposed chanism Ts Br Ts S S S 2' Ts S 2 S (+/-) SD Br 1:1 CDCl 3 /D 2, 50 C, 48 h 4:1 cis/trans S 2 D S 2' reactions are known to proceed via a syn pathway (producing the observed product) When using TfD as a catalyst: 1:1 cis/trans S SD S S syn addition Shapiro,. D.; auniyar, V.; amilton, G. L.; Wu, J.; Toste, F. D. ature 2011, 470, ouk, K..; addon-ow, M..; ondan,. G. J. Mol. Struct. 1983, 103, Borrmann, T.; Stohrer, W-D. Liebigs Ann. 1996, D S S 1,4 syn product D 44

45 o ther roposals of Covalent Ac2va2on Ts Y Z Covalent Activation 45

46 verview 2 1 Dual Activation 1 -Bond/Ion-air Activation Bifunctional Activation Double -Bond Activation Et Z Et TIS -Bond/Ion-air Activation Y Ts Z Covalent Activation 46

47 Expanding A Young Field Stereochemical Induction ene - ene Interactions -bonding/ion-air Activation Exploration of ew eactivity Allylic Substitution via Chiral Ion-air Tf (5-10 mol%) toluene, -78 C Tf 80-95% yield 84-94% ee ueping, M.; Uria, U.; Lin, M-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133,

48 Acknowledgments 48