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.

Whats in a name?

MacMillan, D.W.C.; Nature, 2008. Whats 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
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:

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)

Cl NaCN H2O, 105 C NO REACTION C6H13 CN

C6H13

Early work in the 1950s by Hennis and 1960s by Makosza and Brndstrm 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

CN Organic Phase

Bu3P(CH2)15CH3 CN

Interface

NaCl Bu3P(CH2)15CH3 Cl NaCN

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

Cl Cl Cl MeO O MeCl, 10 mol % cat 50% aq NaOH toluene 20 C, 18 h Cl MeO

O Ph Me

95% yield 92% ee

OH N+ N H

BrN Cl Cl CF3 MeO

N+

O CF3

phase transfer catalyst

H-bonding/pi-stacking

Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446.

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 1 Reaction being catalyzed

Roesky, P.W.; Mller,T.E. Angew. Chem. Int. Ed. 2003, 42, 2708 2710

Roesky, P.W.; Mller,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 -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 -functionalizations LUMO activation

Examples of covalent organocatalysis: Brnsted 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 Brnsted 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!