Organocatalysis: Chiral Amines in Asymmetric Synthesis Natalie Nguyen March 4, 2003

Chiral Organocatalysts in Asymmetric Synthesis Acylation of Alcohols and Amines Kinetic Resolution Baylis-Hillman Reaction R = OMe (Quinine) R = H (Cinchonidine) R = OMe (Quinidine) R = H (Cinchonine) -Lactone and -Lactam formation An increasing number of reactions are being catalyzed by chiral nucleophiles. A major contributor to this new area is the use of chiral amines. As in the natural products Quinine and it’s analogues, quinidine, cinchonidine and cinchonin. other nucleophiles and Lewis bases are also being used Nuclephilic Chiral Amines as Catalysts in Asymmetric Synthesis….Chem. Rev. 2003 103, 2985 Aldol Reaction Mannich Reaction Michael Additions Friedel-Crafts Alkylation Indole Alkylation Diels-Alder Cycloadditon France, S.; Guerin, D.J.; Miller, S.J.; Lectka, T. Chem. Rev. 2003, 2985

Chiral Amines in Asymmetric Synthesis Proline Catalyzed: Aldol Reaction Mannich Reaction Imidazolidinone Catalyzed: Diels – Alder Cycloaddition Total Synthesis of (+)-Hapalindole Q

Proline: Enzyme Mimic Inexpensive Available in both enantiomeric forms “Chemzyme”: Mode of action very similar to enzymes (S)-proline (R)-proline Bifunctional Acid and Base Hydrogen-bond donor and acceptor Iminium Enamine

Proline in Asymmetric Synthesis The proline catalyzed Robinson annulation was one of the earliest examples of an enantioselective reaction Yamada, 1969 Yamada, S.; Otani, G. Tetrahedron Lett. 1969, 4237

Proline in Asymmetric Synthesis Hajos and Parrish, 1974 Synthesis of Taxol (Danishefsky, 1996) Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615 Danishefsky, S. et al. J. Am. Chem. Soc. 1996, 118, 2843

Intramolecular Aldol Reaction: Solvents and Catalyst Intramolecular aldol cyclization works best in aprotic polar solvents Protic solvents lower the enantioselectivity drastically Catalyst Screening Pyrrolidine ring, secondary nitrogen and carboxylic acid are important to catalysis S-proline produced the s configuration Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615 Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1976, 9, 412

Intramolecular Aldol Reaction: Mechanism Brown, K.L.; Damm, L.; Dunitz, J.D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta. 1978, 61, 3108

Intramolecular Aldol Reaction: Proposed Transition State Agami, 1984-1986 Houk, 2001-2003 Attack occurs on the face opposite the carboxylic acid Transition state is controlled and stablized by N-H-----O hydrogen bonding Transition state is controlled and stablized by O-H-----O hydrogen bonding Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984, 40, 1031 Bahmanyar, S; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

Intramolecular Aldol Reaction: Proposed Transition State Agami, 1984-1986 Houk, 2001-2003 Attack occurs on the face opposite the carboxylic acid Transition state is controlled and stablized by N-H-----O hydrogen bonding Transition state is controlled and stablized by O-H-----O hydrogen bonding Favorable electrostatic interactions +NCH-----O - (2.4 Å) Agami, C.; Meynier, F.; Puchot, C.; Guilhem, J.; Pascard, C. Tetrahedron 1984, 40, 1031 Bahmanyar, S; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

Intramolecular Aldol Reaction: Proposed Transition State Agami, 1984-1986 Houk, 2001-2003 List, 2003 Reaction is second order in proline A negative non-linear effect was observed Two prolines are involved Reaction is first order in proline A linear effect was observed One proline involved Agami, C.; Puchot, C.; Sevestre, H. Tetrahedron Lett. 1986, 27, 1501 Hoang, L.; Bahmanyar, S.; Houk, K.N.; List, B. J. Am. Chem. Soc. 2003, 125, 16

Intramolecular Aldol Reaction: Proposed Transition State si-face attack re-face attack The hydrogen bonding allows the iminium double bond to be almost planer Favorable electrostatic interactions +NCH-----O - (2.4 Å) The hydrogen bonding forces the iminium double bond out of planarity Small electrostatic interaction +NCH-----O - (3.4 Å) Transition state is 3.4 kcal/mol higher in energy Observed first order kinetics and a linear effect Suggesting only one proline involved Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911

Intermolecular Aldol Reaction Evans’ Oxazolidinone Chiral auxillary First Proline Catalyzed Direct Aldol Reaction (List, 2000) List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395

Intermolecular Aldol Reaction: Mechanism Based on calculated transition states, the N-H hydrogen bond does not lower the relative energy of the transition state Previously proposed Zimmerman-Traxler transition state is unlikely because N-H bonding does not occur List, B. Tetrahedron, 2002, 58, 5573 Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 11273

Intermolecular Aldol Reaction: Amino Acid Catalysts Yield ee 68% 76% (L)-His, (L)-Val (L)-Tyr, (L)-Phe <10% - 55% 40% Catalyst Yield ee <10% - 67% 73% 66% 86% Direct Catalytic asymmetric aldo reactions of Aldehydes…Jorgenson Chem. Commun. 2002, 620 Proline Catalyzed Direct Aldol..List, JACS, 2000, 122, 2395 List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260

Intermolecular Aldol Reaction: Amino Acid Catalysts Yield ee 68% 76% (L)-His, (L)-Val (L)-Tyr, (L)-Phe <10% - 55% 40% Catalyst Yield ee <10% - 67% 73% 66% 86% List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260

Intermolecular Aldol Reaction: Substrate Scope Product Yield ee 1 2 68% 60% 76% 86% 85% 99% 34% 72% 0% - 1 2 Reaction works best with large excess of ketone Reaction is general to: aromatic aldehydes -substituted aldehydes -Unsubstituted aldehydes: Aldol condensation product was the major product List, B.; Lerner, R.A.; Barbas III, C.F. J. Am. Chem. Soc. 2000, 122, 2395 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260

Intermolecular Aldol Reaction: Anti-Aldol Products Yield anti/syn ee 1 2 60% 45% 20:1 99% 95% 85% 1:1 (anti) 85% (syn) 76% 68% 97% 1 2 Thiaproline (2): Not as general as proline Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386 Sakthivel, K.; Notz, W.; Bui, T.; Barbas III, C.F. J. Am. Chem. Soc. 2001, 123, 5260 List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573

Cross Aldol Reaction Product Yield ee Transition State anti/syn 88% 3:1 97% 81% 95% 80% 24:1 82% 99% Transition State Aldehydes polymerize under metal catalyzed conditions Tendency for homodimerization Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 6798

Mannich Reaction The rate of the Mannich reaction must be faster than the rate of aldol reaction First Proline Catalyzed Direct Mannich Reaction (List, 2000) Alpha-Amination of aldehydes…Jorgenson, Angew. Chem. 2002, 41, 1790 List, B. J. Am. Chem. Soc. 2000, 122, 9336 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Transition State (E)-enamine (E)-enamine List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Transition State (E)-imine (E)-enamine (E)-enamine List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Transition State Nonbonding interactions (E)-imine (E)-enamine (E)-enamine List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827 List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Amino Acid Catalysts Yield ee 90% 93% 56% 76% 22% 15% 60% 16% List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Amino Acid Catalysts Yield ee 90% 93% 56% 76% 22% 15% 60% 16% List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Variation in Aldehydes Yield ee 50% 94% 90% 93% 35% 96% 56% 70% Transition State Despite competition with the Aldol reaction, high yields and enantioselectivites were observed Products have opposite stereochemistry of aldol products List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Mannich Reaction: Variation in Ketones Product Yield ee 96% 2.5:1 99% 94% 93% 98% Transition State List, B.; Pojarliev, P.; Biller, W.T.; Martin, H.J. J. Am. Chem. Soc. 2002, 124, 827

Aldol and Mannich Reaction Direct Aldol Deprotonation or silylation is not required Direct Mannich Imine electrophile can be generated in situ Proline proved to the optimal catalyst Nontoxic Inexpensive Both enantiomers available Can be used in wet solvents and open to air Can be removed from reaction mixture by aqueous workup (S)-proline

Organocatalyzed Diels-Alder Cycloaddition Asymmetric Diels-Alder Reaction by Chiral Bases (Kagan, 1989) Transition State Riant, O.; Kagan, H.B.; Tetrahedron, 1989, 30, 7403

Diels-Alder Cycloaddition Exo vs Endo exo endo Enantioselectivity in Diels Alder Reaction

Diels-Alder Cycloaddition : Lewis Acids and Iminiums lowers the energy of the LUMO Energy

Organocatalytic Diels-Alder Cycloaddition MacMillan’s Catalyst Design: Lowers the energy of LUMO of the dienophile Kinetically labile ligand for catalytic turnover Chiral molecule would induce stereoselectivity Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Catalyst Screening Yield endo:exo exo ee 81% 1:2.7 48% 92% 1:2.6 57% 82% 1:3.6 74% 99% 1:1.3 93% Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Catalyst Screening Yield endo:exo exo ee 81% 1:2.7 48% 92% 1:2.6 57% 82% 1:3.6 74% 99% 1:1.3 93% Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Variation in Dienophiles Yield endo:exo exo ee endo ee 75% 1:1 86% 90% 81% 84% 93% 99% 1:1.3 20% 1:7 - Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Variation in Dienes Yield endo:exo endo ee 82% 14:1 94% 90% - 83% 75% 5:1 72% 11:1 85% Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Transition State Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls Benzyl group shields the top face leaving the si-face exposed Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Transition State Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls Benzyl group shields the top face leaving the si-face exposed Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Transition State Formation of (E)-imine to avoid nonbonding interactions between the geminal methyls Benzyl group shields the top face leaving the si-face exposed Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Catalyst Screening Yield endo:exo ee 20% 7:1 - 89% 25:1 90% Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Variation in Dienophiles Yield endo:exo ee 89% 24:1 90% 78% 6:1 24% 8:1 Transition State Bulky R2 groups give poor enantioselectivities Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloaddition: Variation in Dienes Yield endo:exo endo ee 88% 200:1 94% 91% 100:1 89% 92% 83% 90% Transition State Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2000, 122, 4243

Diels-Alder Cycloadditon: Conclusions Organocatalyzed Diels-Alder Cycloadditions Highly enantioselective Applicable to a variety of substrates Chiral Amines Nontoxic Can be used in wet solvents and open to air Can be removed from reaction mixture by aqueous workup

Aaron C. Kinsman and Michael Kerr The Total Synthesis of (+)-Hapalindole Q by an Organomediated Diels-Alder Reaction Aaron C. Kinsman and Michael Kerr J. Am. Chem. Soc. 2003, 125, 14120 Isolated from the terrestrial blue-green algae Hapalosiphon fontinalis Cyanobacterium indigenous to the Marshall Islands Isolated in 1984 by Moore and co-workers Exhibits antimycotic activity through its ability to directly inhibit RNA polymerase Has been synthesized by 5 groups Hapalindoles R1 = NC, NCS R2 = H, Cl, OH

(+)-Hapalindole Q: Retrosynthesis

(+)- Hapalindole Q: Synthesis

(+)- Hapalindole Q: Synthesis

(+)- Hapalindole Q: Synthesis

(+)- Hapalindole Q: Synthesis

(+)- Hapalindole Q: Synthesis

(+)- Hapalindole Q: Conclusion The first total synthesis utilizing an organomediated Diels-Alder reaction It was the most structurally complex molecule used with MacMillan’s catalyst (+)-Hapalindole Q was synthesized in 12 steps in 1.7% overall yield

Conclusions The First Proline Catalyzed Direct Aldol reaction Direct Mannich reaction Organocatalyzed Diels-Alder Cycloadditions Highly enantioselective Applicable to a variety of substrates Key step in the synthesis of (+)-Hapalindole Q (S)-proline

Acknowledgements Dr. Alex Fallis The Fallis Group Megan ApSimon Dr. Christophe Benard Matt Clay Aaron Dumas Dr. Nancy Lamb Dr. Sara Palmier Jeremy Praetorius Thiva Thurugam Kelly VanCrey

Diels-Alder Reaction: Synthesis of Catalyst Ahrendt, K.A.; Borths, C.J.; MacMillan, D.W.C. J. Amer. Chem. Soc. 2000, 122, 4243