Recent Advances in Organocatalysis

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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!