Chiral Proton Catalysis in rganic Synthesis Samantha M. Frawley rganic Seminar September 14 th, 2005
Seminar utline Introduction Lewis Acid-assisted Chiral Brønsted Acids Enantioselective protonation for silyl enol ethers Chiral Brønsted Acid Catalysis: Polar Covalent Enantioselective synthesis using chiral phosphoric acids Enantioselective synthesis using di-ol Brønsted acids Chiral Brønsted Acid Catalysis: Polar Ionic Difficulties in formation First successful use Enantioselective synthesis using a chiral proton Conclusion
Lewis Acid Catalysis Advantages Structural diversity and reactivity enabling the design for a variety of ligands Easily adapted for asymmetric reactions Disadvantages Many are metals Toxic Expensive reagents Costly waste disposal
Brønsted Acid Catalysis Advantages Mild reaction conditions on-toxic waste Inexpensive and stable catalysts Disadvantages Difficult to accomplish asymmetrically ard to tune for various reactions Dalko,.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726. List, B.; Lerner,.; Barbas III, C. J. Am. Chem. Soc. 2000, 122, 2395.
Tips From ature 1 + 2 1 2 1 2 * L + 2 1 1 2 L * 1 2
Methods in Chiral Proton Catalysis Lewis Acid-assisted Chiral Brønsted Acids * M + substrate * substrate Chiral Brønsted Acids: Polar Covalent * L + substrate * substrate Chiral Brønsted Acids: Polar Ionic * L + substrate * substrate
Seminar utline Introduction Lewis Acid-assisted Chiral Brønsted Acids Enantioselective protonation for silyl enol ethers Chiral Brønsted Acid Catalysis: Polar Covalent Enantioselective synthesis using chiral phosphoric acids Enantioselective synthesis using di-ol Brønsted acids Chiral Brønsted Acid Catalysis: Polar Ionic Difficulties in formation First successful use Enantioselective synthesis using a chiral proton Conclusion
Lewis Acid-assisted Chiral Brønsted Acids (LBA) Brønsted acids coordinate to Lewis acids estricting orientation of protons aising the acidity of the protons SnCl 4 Ar Ar SnCl 4 akamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto,. J. Am. Chem. Soc. 2000, 122, 8120. Ishihara, K.; akashima, D.; iraiwa, Y.; Yamamoto,. J. Am. Chem. Soc. 2003, 125, 24.
Enantioselective Protonation of Silyl Enol Ethers using an LBA Ph SiMe 3 + SnCl 4 toluene -78 o C, 1 h >99% yield Ph Ar Ar Si 3 () LBA Si 3 Ar Cl Sn Cl Cl Cl akamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto,. J. Am. Chem. Soc. 2000, 122, 8120. Ishihara, K.; akashima, D.; iraiwa, Y.; Yamamoto,. J. Am. Chem. Soc. 2003, 125, 24.
Enantioselective Protonation of Silyl Enol Ethers-esults Ar Si 3 BIL 1-SnCl 4 Ar 3 toluene, -78 o C, 1 h 100 % conv. 4 entry 3 (Ar, 3 Si) ee (%), (config) 1 2 3 4 5 6 3a (Ph, Me 3 Si) 3b (Ph, t-bume 2 Si) 3b (Ph, t-bume 2 Si) 3c (p-mec 6 4, t-bume 2 Si) 3d (p-mec 6 4, Me 3 Si) 3e (2-naphthyl, Me 3 Si) 91, (S) 86, (S) 86, () 82, (S) 96, (S) 91, (S) 7 3f (2-naphthyl, t-bume 2 Si) 91, (S) akamura, S.; Kaneeda, M.; Ishihara, K.; Yamamoto,. J. Am. Chem. Soc. 2000, 122, 8120.
Enantioselective Protonation of Silyl Enol Ethers Acetals Using Various (,)-LBAs SiMe 3 Ar Ph solvent Ph + SnCl 4 Ar -78 o C, 1 h >99% yield entry LBA solvent ee (%) 1 2 1-SnCl 4 2-SnCl 4 toluene-c 2 Cl 2 (1:1) toluene 66 [S] 51 [S] Ar Ar SnCl 4 3 4 5 3-SnCl 4 4-SnCl 4 6-SnCl 4 toluene toluene toluene 35 [S] 96 [S] 96 [S] 1: Ar = Phenyl; = 2: Ar = 3,4,5-F 3 C 6 2 ; = 3: Ar = C 6 F 5 ; = 4: Ar = 3,5-(CF 3 ) 2 C 6 3 ; = 6: Ar = 3,5-(CF 3 ) 2 C 6 3 ; = Bn Ishihara, K.; akashima, D.; iraiwa, Y.; Yamamoto,. J. Am. Chem. Soc. 2003, 125, 24.
Enantioselective Protonation of Ketene Disilyl Acetals Ar C 3 SiMe 3 SiMe 3 SnCl 4 Ar toluene, -78 o C >95% yield C 3 C 2 F 3 C Me 3 Si Ar SiMe 3 Cl Me Cl Sn Cl Cl F 3 C Cl Ar Me Cl Sn Cl Cl SiMe 3 CF 3 CF 3 SiMe 3 Favored Unfavored Ishihara, K.; akashima, D.; iraiwa, Y.; Yamamoto,. J. Am. Chem. Soc. 2003, 125, 24.
Enantioselective Protonation of Ketene Disilyl Acetals with (,)- LBAs 1 SiMe 3 Chiral LBA 2 2 C 2 SiMe toluene, -78 o C 3 >95% yield 1 entry LBA solvent product ee (%) i-pr CF 3 1 2 3 4 5 (,)-6-SnCl 4 (,)-7-SnCl 4 (,)-7-SnCl 4 (,)-8-SnCl 4 (,)-7-SnCl 4 toluene toluene toluene toluene toluene Me Ph i-bu C 2 C 2 C 2 Ph C 2 C 2 76 [S] 86 [S] 90 [S] 90 [S] 85 [S] F 3 C F 3 C CF 3 SnCl 4 6: = Bn 7: = o-fc 6 4 C 2 8: = Me 6 (,)-7-SnCl 4 toluene Ph Me C 2 85 [S] Ishihara, K.; akashima, D.; iraiwa, Y.; Yamamoto,. J. Am. Chem. Soc. 2003, 125, 24.
Final Thoughts on Lewis Acidassisted Chiral Brønsted Acid Advantages Increases the acidity of the proton in the Brønsted acid Preorganizes the orientation of the proton, which improves enantioselectivity Disadvantages Still using metals
Seminar utline Introduction Lewis Acid-assisted Chiral Brønsted Acids Enantioselective protonation for silyl enol ethers Chiral Brønsted Acid Catalysis: Polar Covalent Enantioselective synthesis using chiral phosphoric acids Enantioselective synthesis using di-ol Brønsted acids Chiral Brønsted Acid Catalysis: Polar Ionic Difficulties in formation First successful use Enantioselective synthesis using a chiral proton Conclusion
Polar Covalent ydrogen Bond-An Introduction * L + substrate * substrate rientational flexibility on proton is limited The proton is acidic enough so there is no need for a Lewis acid Facial preference of proton donation can be promoted by chiral acid to yield a enantiomeric/diastereomeric product
Using Chiral Phosphoric Acids to Promote Enantioselectivity BIL-derived phosphoric acid: forcing selective nucleophilic attack P Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
Mannich-Type eaction Catalyzed by a Chiral Phosphoric Acid 1 + TMS Me 10 mol% P toluene -78 o C, 24 h 1 C 2 Me P uc Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
Effects of the Aromatic Substituents on Chiral Phosphoric Acids Ar P + TMS Me 30 mol% Ar toluene -78 o C 1 C 2 Me Entry Ar t [hr] Yield [%] ee [%] 1 22 57 0 2 Ph 20 100 27 3 2,4,6-Me 3 C 6 2 27 100 60 4 4-MeC 6 4 46 99 52 5 4-2 C 6 4 4 96 87 Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
Enantioselective Mannich-type eaction esults 2 P 1 + TMS Me 10 mol% toluene -78 o C, 24 h 2 1 C 2 Me Entry 1 Yield [%] ee [%] 1 Ph 98 89 2 p-mec 6 4 100 89 3 p-fc 6 4 100 85 4 p-clc 6 4 100 80 Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
Diastereoselective Mannich-Type eaction: Mechanistic Insight 2 + P TMS 10 mol% 3 2 C 2 3 2 + C 2 3 2 2 3 2 TMS P 2 Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
Diastereoselective Mannich-type eaction esults 2 1 + TMS P 10 mol% 3 2 C 2 3 2 1 2 + C 2 3 1 2 Entry 1 2 3 Yield [%] syn / anti ee [%] 1 2 3 4 5 6 7 8 9 10 Ph p-mec 6 4 p-fc 6 4 p-mec 6 4 2-Thienyl PhC=C Ph p-mec 6 4 PhC=C Ph Me Me Me Me Me Me PhC 2 PhC 2 PhC 2 Ph 3 Si Et Et Et Et Et Et Et Et Et Me 100 100 100 100 81 91 100 92 65 79 87:13 92:8 91:9 94:6 94:6 95:5 93:7 93:7 95:5 100:0 96 88 84 81 88 90 91 87 90 91 Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
Enantioselective ydrophosphonylation of Imines CF 3 CF 3 P CF 3 Me + i-pr P i - -Pr 10 mol% m-xylene rt CF 3 Me P(i-Pr) 2 Akiyama, T.; Morita,.; Itoh, J.; Fuchibe, K. rg. Lett. 2005, 7, 2583.
Enantioselective ydrophosphonylation-esults 1 + Me i-pr 10 mol% chiral Phosphoric Acid P i-pr m-xylene, rt 1 P(i-Pr) 2 Me Entry 1 time (h) Yield [%] ee [%] 1 2 3 4 5 6 7 8 9 Ph o-mec 6 4 o- 2 C 6 4 p-c 3 C 6 4 C=C p-clc 6 4 C=C o-c 3 C 6 4 C=C o-clc 6 4 C=C o- 2 C 6 4 C=C o-cf 3 C 6 4 C=C 24 46 24 170 145 171 70 49 46 84 76 72 88 97 80 82 92 86 52 69 77 86 83 82 87 88 90 F 3 C P F 3 C CF 3 CF 3 Akiyama, T.; Morita,.; Itoh, J.; Fuchibe, K. rg. Lett. 2005, 7, 2583.
Mechanistic Insight and Experimental Support F 3 C F 3 C CF 3 P P Ar CF 3 P CF 3 CF 3 P F 3 C Me P Ph 10 mol% PMP PMP F 3 C + u Ph P() m-xylene 2 rt Entry u Yield [%] ee [%] 1 2 P(-i-Pr) 2 P(-i-Pr) 3 92 23 84 3 Akiyama, T.; Morita,.; Itoh, J.; Fuchibe, K. rg. Lett. 2005, 7, 2583.
Enantioselective eduction of Imines Using antzsch Dihydropyridine Et Et 2 1 Ar P 2 * 1 5 mol% Ar ueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. rg. Lett. 2005, 7, 3781.
Catalytic cycle for the Transfer ydrogenation Et Et 2 1 * Ar P Ar Et Et * Ar P Ar 2 * Ar P 1 Ar 2 Et Et * 1 ueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. rg. Lett. 2005, 7, 3781.
Catalytic Enatioselective eduction esults Me Et Et Me C 3 benzene, 60 o C 5 mol% Bronsted acid * C 3 Entry Yield [%] ee [%] F 3 C 1 p-cf 3 C 6 4 71 72 2 Ph 76 74 CF 3 3 4 o-fc 6 4 o-c 3 C 6 4 82 74 84 78 P 5 2,4-Me 2 C 6 3 91 78 CF 3 6 7 biphenyl p-mec 6 4 71 76 74 72 F 3 C 8 m-brc 6 4 62 72 9 o-cf 3 C 6 4 46 82 ueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. rg. Lett. 2005, 7, 3781.
Seminar utline Introduction Lewis Acid-assisted Chiral Brønsted Acids Enantioselective protonation for silyl enol ethers Chiral Brønsted Acid Catalysis: Polar Covalent Enantioselective synthesis using chiral phosphoric acids Enantioselective synthesis using di-ol Brønsted acids Chiral Brønsted Acid Catalysis: Polar Ionic Difficulties in formation First successful use Enantioselective synthesis using a Chiral proton Conclusion
Chiral Brønsted Acid Catalyzed Asymmetric Morita-Baylis-illman Ph + 2 mol% Bronsted acid Et 3 P TF, 0 o C entry catalyst % yield %ee 1 2 1 5 74 32 Ph X C 3 3 4 5 6 5a 5b 6a 73 73 43 48 79 5c 36 74 3 X 5a X = 5b X = Br 5c X = CPh 2 7 C 3 Ar 7 8 6b 15 7 13 5 3 X 9 10 11 12 13 8a 8b 8c 8e 69 70 84 9 86 88 86 8d 68 86 31 6a X = 6b X = Br C 3 X Ar 8a Ar = Ph 8b Ar = 3,5 Me 2 Ph 8c Ar = 3,5 (CF 3 ) 2 Ph 8d Ar = biphenyl 8e Ar = 2,4,6 Me 3 Ph McDougal,.; Trevellini, W.; odgen, S.; Kliman, L.; Schaus, S. Adv. Synth. Catal. 2004, 346, 1231.
Asymmetric Morita-Baylis-illman eaction esults Ar + 10 mol % catalyst Et 3 P TF -10 o C Ar 8b Ar = 3,5 Me 2 Ph 8c Ar = 3,5 (CF 3 ) 2 Ph Entry Aldehyde Catalyst Yield [%] % ee 1 Ph 8c 88 90 2 n-pent 8b 86 91 3 8b 80 90 Et 4 8b 72 96 5 Bn 8c 74 82 6 Bn 8b 56 55 7 8b 71 96 Entry Aldehyde Catalyst Yield [%] % ee 8 8b 82 95 9 8c 70 92 10 8b 40 67 11 2 8b 30 34 12 Ph 8b 39 81 McDougal,.; Trevellini, W.; odgen, S.; Kliman, L.; Schaus, S. Adv. Synth. Catal. 2004, 346, 1231.
Brønsted Acid vs. Lewis Acid Catalyzed Morita-Baylis-illman Bronsted Acid Catalyzed esults Entry Aldehyde Time (h) Yield [%] % ee 1 48 88 90 Ph 2 48 71 96 3 48 82 95 4 Ph 48 40 67 eterobimetallic Catalyst esults Time (h) Yield [%] % ee 240 48 288 120 49 71 94 32 58 63 99 15 B s-bu s-bu Li Ar Ar 8b Ar = 3,5 Me 2 Ph 8c Ar = 3,5 (CF 3 ) 2 Ph Matsui, K.; Takizawa, S.; Sasai,. Tetrahedron Lett. 2005, 46, 1943. McDougal,.; Trevellini, W.; odgen, S.; Kliman, L.; Schaus, S. Adv. Synth. Catal. 2004, 346, 1231.
Brønsted Acid Catalyzed Enantioselective itroso Aldol eaction ' ' n + (30mol%) toluene -78 o C, 2h n Momiyama,.; Yamamoto,. J. Am. Chem. Soc. 2005, 127, 1080.
-itroso Aldol Synthesis esults X X = C: 1b X = : 1c X = S: 1d ' ' n + (30mol%) toluene -78 o C, 2h entry enamine n, % Yield % ee n 1 1b 0, <1 1e 2 3 4 5 6 1b 1b 1b 1b 1c 1 1 1 2 1, Me, Me _ (C 2 C 2 ) _,, 81 78 63 67 91 83 82 91 65 79 7 1d 1, 88 77 8 1e 1, 81 80 Momiyama,.; Yamamoto,. J. Am. Chem. Soc. 2005, 127, 1080.
Final Thoughts on Chiral Brønsted Acids: Polar Covalent Advantages o more metals in the reaction The acid works to activate the substrate and control the stereochemistry Mild reaction conditions Limitations Very dependant on acidity Substrate dependent
Seminar utline Introduction Lewis Acid-assisted Chiral Brønsted Acids Enantioselective protonation for silyl enol ethers Chiral Brønsted Acid Catalysis: Polar Covalent Enantioselective synthesis using chiral phosphoric acids Enantioselective synthesis using di-ol Brønsted acids Chiral Brønsted Acid Catalysis: Polar Ionic Difficulties in formation First successful use Enantioselective synthesis using a chiral proton Conclusion
Developing Enantioselective Polar Ionic ydrogen Bonds * L + substrate * substrate Benefits o acidity/basicity catalyst limitations Ligands serve only as a binding pocket to deliver a proton asymmetrically to the substrate Challenges Spherical nature of empty 1s orbital Proton s nucleus is more promiscuous than other Lewis acids Chiral complex leads to achiral catalysis by solventcoordinated Brønsted acid ugent, B.; Yoder,.; Johnston, J. J. Am. Chem. Soc. 2004, 126, 3418.
The First Use of Polar Ionic Bonds as Stereocontrol Elements Me + ' C 2 Cl 2 4-5 o C -27 o C * Me 5a + Me 6a 3 C( 2 C) 14 2 catalyst (5a + ent-5a): (equiv) % yield (6a + ent-6a) %ee of 5a %ee of 6a 7 2 no catalyst 7a (1) 8a (1) 9a (1) <3 46 70 83 <0.1:1 2.4:1 2.5:1 2.8:1 0 11 22 9a * (1) 73 2.8:1 26 0 0 0 15 28 33 9b (1) 35 1.0:1 1 2 a: Counterion = tetrakis(3,5-bis(trifouoromethyl)phenyl)borate b: Counterion = picrate 8 9 Schuster, T.; Bauch, M.; Dürner, G.; Göbel, M. rg. Lett. 2000, 2, 179.
Mechanistic Insight on Major Product Formation The diene is shielded from the backside due to the phenylnaphthalene moiety Cycloaddition occurs at the front unfavored favored Schuster, T.; Bauch, M.; Dürner, G.; Göbel, M. rg. Lett. 2000, 2, 179.
Enantioselective Diels-Alder with Amidinium Ions-esults Me + ' C 2 Cl 2 4-5 o C -27 o C * Me 5b + Me 6b entry catalyst (equiv) % yield (5b + ent-5b): (6b + ent-6b) %ee of 5b %ee of 6b 1 7(1) 33 2.8:1 0 0 2 3 4 5 9a (0.1) 9a (0.25) 9a (0.5) 9a (1) 20 70 89 83 3.1:1 3.1:1 3.0:1 2.9:1 39 40 40 40 42 44 45 46 6 9a (1) * 94 3.2:1 43 50 3 C( 2 C) 14 2 7 2 Schuster, T.; Bauch, M.; Dürner, G.; Göbel, M. rg. Lett. 2000, 2, 179. 9a
Did Polar Ionic ydrogen Bonds eally Play a ole in the Enantioselectivity? The amidinium ion induced facial selectivity based on one face was sterically blocked When a stronger counterion was used, the stereoselectivity disappeared This work lead to the thought can we design a chiral proton?
Enantioselective Aza-enry eaction using a Polar Ionic ydrogen Bond 10 mol% Tf 1 -C 6 4 Boc Boc + 2 2 1 -C 6 2 4-20 o C 2 Boc 2 2 ugent, B.; Yoder,.; Johnston, J. J. Am. Chem. Soc. 2004, 126, 3418.
Aza-enry esults 1 -C 6 4 Boc 10 mol% Boc Quin-BAM-Tf + 2 2-20 o 1 -C 6 2 4 C 2 entry 1 2 % Yield dr % ee 1 57-60 2 p- 2 61-82 Tf 3 4 5 m- 2 p-cf 3 C 3 C 3 65 69 53-14:1 19:1 95 59 81 6 p-cl C 3 59 17:1 82 7 m- 2 C 3 51 11:1 89 8 o- 2 C 3 62 7:1 82 9 p-cf 3 C 3 50 19:1 84 10 p- 2 C 3 60 7:1 90 ugent, B.; Yoder,.; Johnston, J. J. Am. Chem. Soc. 2004, 126, 3418.
Final Thoughts on Chiral Brønsted Acids: Polar Ionic Advantages: source of a chiral proton Ability to circumnavigate previous problems associated with forming a chiral proton Chiral proton is used both to activate and control stereochemistry Limitations Substrate dependent-has to fit in the binding pocket of the acid in order to be efficient
Conclusion Chiral Brønsted acids are successful at enantioselective proton donation Advantages o metals eusable catalyst Mild reaction conditions Disadvantages eactions are very substrate dependent equires different catalyst for different reactions Development of other reactions Development of new catalysts
Acknowledgements Dr. Wagner Dr. Tepe Group Members Vasudha Teri Jason Chris Adam Manasi James Gwen Sam 2 Brandon