Term “phase-transfer catalysis” coined in 1971 by Starks. “An alternative solution
to .... Strategy that combines multiple catalyst activations into one mechanism.
“Organocatalysis” • The use of small molecules to catalyze organic transformations (emphasis on asymmetric variants) • Term first used in 2000 MacMillan, J. Am. Chem. Soc., 2000.
MacMillan, J. Am. Chem. Soc., 2000.
What’s in a name?
MacMillan, D.W.C.; Nature, 2008. “What’s in a name? That which we call a rose by any other name would smell as sweet.”
The Field Explodes • “Organocatalysis” unified the field and attracted the scientific community • Cheap • Large chiral pool • Non-toxic • Insensitive to moisture and air • Industrial interest = more $$$
History Lesson in Organocatalysis Liebig, 1860
Yamada, 1969
Hajos and Parrish, 1974
History Lesson in Organocatalysis II Epoxidations Shi, 1996
Denmark, 1997
Yang, 1996
Aldol
Strecker
List, Lerner, and Barbas, 2000
Jacobsen, 1998
Cooperative Catalysis and Ion Pairing in Organocatalysis
Cooperative Catalysis and Ion Pairing in Organocatalysis Organocatalytic general mode of activation.
Cooperative ion pairing in asymmetric organocatalysis.
Asymmetric Acyl Transfer: Steglich Rearrangement:
Chiral ammonium betaine
Briere, J-F.; Oudeyer, S.; Dalla, V.; Levacher, V.; Chem Soc. Rev. 2011,.
Cooperative Taming of Reactive Catalysts
(1) Schreiner, P. Science 2010;327: 965 (2) Jacobsen et al. Science 2010;327:986-990
Model Povarov reaction : Catalyzed by NBSA acid and chiral ureas
(B) Some of the chiral catalysts evaluated in optimization studies. Best conditions : NBSA + bifunctional sulfinamido urea (1a) (C) Results of catalyst structurereactivity/enantioselectivity studies. Jacobsen et al. Science 2010;327:986-990
Model Povarov reaction: Catalyzed by NBSA acid and chiral ureas
(C) Martinelline (11), a natural-product inhibitor of bradykinin B1 and B2 G protein-coupled receptors
Jacobsen et al. Science 2010;327:986-990
Phase-Transfer Catalysis and Oxidation in Organocatalysis
Phase-Transfer Catalysis (PTC)
C6H13
Cl
NaCN H2O, 105 C
C6H13
CN
NO REACTION
• Early work in the 1950s by Hennis and 1960s by Makosza and Brändström • Term “phase-transfer catalysis” coined in 1971 by Starks
“An alternative solution to the heterogeneity problem, phase-transfer catalysis, is introduced here. Reaction is brought about by the use of small quantities of an agent which transfers one reactant across the interface into the other phase to that reaction can proceed.” Starks, C. M. “Phase Transfer Catalysts. I. Heterogeneous Reactions Involving Anion Transfer by Quaternary Ammonium and Phosphonium Salts”, J. Am. Chem. Soc. 1971, 93, 195.
Phase-Transfer Catalysis (PTC)
C6H13
Cl
Bu3P+(CH2)15CH3Br- (1.5 mol %) NaCN, H2O, 105 C
C6H13
Bu3P(CH2)15CH3 CN
NaCl
Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195.
Organic Phase
Interface
Aqueous Phase Bu3P(CH2)15CH3 Cl
NaCN
CN
Advantages of Phase-Transfer Catalysis •
1984: Asymmetric alkylations promoted by modified chincona alkaloids
Cl Cl
O
Cl
50% aq NaOH toluene 20 C, 18 h
MeO
95% yield 92% ee
O
N+ N
Ph Me
MeO
Br-
OH
N Cl
H
Cl CF3
phase transfer catalyst
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446.
O
Cl
MeCl, 10 mol % cat
H
N+
O CF3
MeO H-bonding/pi-stacking
Phase Transfer Alkylation
Shi Epoxidation
Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-9807; Kurti, L.; Czako, B. Strategic Applications of Name Reactions in Organic Synthesis; Elsevier Academic Press, Boston, 2005.
Mechanism
Kurti, L.; Czako, B. Strategic Applications of Name Reactions in Organic Synthesis; Elsevier Academic Press, Boston, 2005.
Organocatalyzed Epoxidations
Organocatalyzed Epoxidations
Organocatalytic Alpha-Oxidations
Product ground state structure is oligomeric, making isolation difficult
Synthetic applications
Proposed transition state
Brown, S.P.; Brochu, M.P.; Sinz, C.J.; MacMillan, D.W.C J. Am. Chem. Soc. 2003, 125, 10808. Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247.
Alpha-oxyamination with TEMPO
Switching to a metal known to form metal-TEMPO complexes gave better results:
Sibi, M.P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124. Simonovich, S.P.; Van Humbeck, J.F.; MacMillan, D.W.C Chem. Sci. 2011.
Dihydrobenzofuran Synthesis via Oxidation
compound Pd source additive time yield ee 1 spPd(THA)2 Ca(OH)2 36h 87% 81% 3 spPd(THA)2 Ca(OH)2 60h@55C 57% 90% Trend RM, Ramtohul YK, Ferreira EM, Stoltz BM. Angew. Chemie. Intl. Ed. 2003;42(25):2892-5.
Pelly SC, Govender S, Fernandes MA, Schmalz H-, De Koning CB. J. Org. Chem. 2007;72(8):2857-64.
Quaternary ammonium (hypo)iodite Catalysis for Enantioselective Oxidative Cycloetherification
Uyanik M, Okamoto H, Yasui T, Ishihara K. Science 2010; 328(5984):1376-9.
Proposed mechanism
Uyanik M, Okamoto H, Yasui T, Ishihara K. Science 2010; 328(5984):1376-9.
A Mild Condition Realized by PTC
Uyanik M, Okamoto H, Yasui T, Ishihara K. Science 2010; 328(5984):1376-9.
Hydroaminations and AsymmetryInduced by Covalent Interactions in Organocatalysis
Examples of covalent organocatalysis: Enantioselective Amine Addition Reactions Catalytic Entities
Reaction being catalyzed
1
2
3
Roesky, P.W.; Müller,T.E. Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710
4
5
Roesky, P.W.; Müller,T.E. Angew. Chem. Int. Ed. 2003, 42, 2708 – 2710
Examples of covalent organocatalysis: Enamine and Iminium Ion Catalysis Enamine catalysis
List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122, 2395-2396.
• Nucleophilic enamine reacts with various electrophiles •α-functionalizations • HOMO activation
Iminium Ion catalysis
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243-4244. List, B. Chem. Commun. 2006, 819-824.
• Electrophilic iminium reacts with various nucleophiles •β-functionalizations • LUMO activation
Examples of covalent organocatalysis: Brønsted Acid Catalysis
•Phosphoric acid diester catalysis of intramolecular hydroamination.
•Catalytic hydroamination with acyclic phosphoric acid diesters.
3b: R = 3,5-(F3C)2C6H3
• Chiral phosphoric acid diester as catalyst for asymmetric hydroamination. Ackerman, L. Synlett 2008, 7, 995-998. Zigang, L.; Zhang, J.; Brouwer, C.; Yang, .; Reich, N.W.; He, C. Org. Lett. 2006, 8, 4175-4178. Hartwig, J.F.; Schlummer, B. Org. Lett. 2006, 4, 1471-1474.
• Proposed catalytic cycle for cyclization of aminoalkenes catalyzed by triflic or sulfuric acid in toluene.
Asymmetric Additions to Dienes chiral Brønsted acid protonation
nucleophilic acid/SN2'
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.
SGB
Asymmetric Additions to Dienes
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.
SGB
Asymmetric Additions to Dienes Substrate
Temp
Product
yield ee
Mechanistic Work Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249.
SAD
Organocascades and Organocatalyzed Cycloadditions
Organocascade Catalysis • Tandem reactive processes inspired by nature • Strategy that combines multiple catalyst activations into one mechanism
• More efficient than the “stop and go” method of synthesis • Build complexity very quickly • More practical for industrial applications
Organocascade Catalysis • Conversion of squalene to lanosterol
Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem., 2010, 2, 167-178.
Organocascade Catalysis • Organocatalysis in cascades – Compatible, functional group tolerant, specific, controlled
64% dr
Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron, 1998, 58, 5471-5484.
Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem. Int. Ed., 2009, 48, 4349-4353.
Organocascade to generate common intermediate
Functionalization of the intermediate generates multiple alkaloids
Nice work, guys!