“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!