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“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
Shi, 1996 Denmark, 1997 Yang, 1996
Epoxidations
Aldol List, Lerner, and Barbas, 2000
Strecker
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:
Briere, J-F.; Oudeyer, S.; Dalla, V.; Levacher, V.; Chem Soc. Rev. 2011,.
Chiral ammonium betaine
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 structure-
reactivity/enantioselectivity studies.
Jacobsen et al. Science 2010;327:986-990
Model Povarov reaction: Catalyzed by NBSA acid and chiral ureas
Jacobsen et al. Science 2010;327:986-990
(C) Martinelline (11), a
natural-product inhibitor of
bradykinin B1 and B2 G
protein-coupled receptors
Phase-Transfer Catalysis and
Oxidation in Organocatalysis
Phase-Transfer Catalysis (PTC)
• 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.
C6H13
ClNaCN
H2O, 105 CC6H13
CN
NO REACTION
Phase-Transfer Catalysis (PTC)
C6H13
ClBu3P+(CH2)15CH3Br- (1.5 mol %)
NaCN, H2O, 105 CC6H13
CN
Bu3P(CH2)15CH3 CN
NaCl
NaCN
Bu3P(CH2)15CH3 Cl
Organic Phase
Interface
Aqueous Phase
Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195.
Advantages of Phase-Transfer Catalysis
• 1984: Asymmetric alkylations promoted by modified chincona alkaloids
Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446.
OCl
Cl
MeO
MeCl, 10 mol % cat
50% aq NaOHtoluene
20 C, 18 h95% yield92% ee
OCl
Cl
MeO
Ph
Me
N+
N
OH
H
CF3
Br-
phase transfer catalyst
N+
N
O
CF3
H
OCl
Cl
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
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.
Proposed transition state
Product ground state structure is oligomeric, making isolation difficult
Synthetic applications
Alpha-oxyamination with TEMPO
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.
Switching to a metal known to form metal-TEMPO complexes gave better results:
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%
Pelly SC, Govender S, Fernandes MA, Schmalz H-, De Koning CB. J. Org. Chem. 2007;72(8):2857-64.
Trend RM, Ramtohul YK, Ferreira EM, Stoltz BM. Angew. Chemie. Intl. Ed. 2003;42(25):2892-5.
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 Asymmetry-
Induced 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
• Nucleophilic enamine reacts with various electrophiles •α-functionalizations • HOMO activation
• Electrophilic iminium reacts with various nucleophiles •β-functionalizations • LUMO activation
List, B. Chem. Commun. 2006, 819-824.
Enamine catalysis
Iminium Ion catalysis
Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243-4244.
List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122, 2395-2396.
Examples of covalent organocatalysis: Brønsted Acid Catalysis
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.
•Catalytic hydroamination with acyclic phosphoric acid diesters.
•Phosphoric acid diester catalysis of intramolecular hydroamination.
• Chiral phosphoric acid diester as catalyst for asymmetric hydroamination.
3b: R = 3,5-(F3C)2C6H3
• Proposed catalytic cycle for cyclization of aminoalkenes catalyzed by triflic or sulfuric acid in toluene.
Asymmetric Additions to Dienes
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249. SGB
chiral Brønsted acid protonation
nucleophilic acid/SN2'
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
Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245-249. SAD
Temp Substrate Product ee yield
Mechanistic Work
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
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.
64% dr
Organocascade to generate common intermediate
Functionalization of the intermediate generates multiple alkaloids
Nice work, guys!
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