IOWA STATE UNIVERSITYDepartment of Chemistry

Catalytic Enantioselective Trioxygenation of Enals

Gayan A. Abeykoon and Jason Chen

Chen, J. S., Abeykoon G. A. Org. Lett. 2015, 17, 6050 – 6053.

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Organocatalytic Chiral Oxygenations• α-Oxygenation (enamine catalysis)

• β-Oxygenation (iminium catalysis)

• -Oxygenation (dienamine catalysis)

O O

ONR1

2

Chiral amine cat.,TEMPO

R R

O OChiral amine cat.,ROH

R RO

R1

O OChiral amine cat.,TEMPOR R

ONR1

2

Zhong et al. Angew. Chem., Int. Ed. 2003, 42, 4247. Sibi et al. J. Am. Chem. Soc. 2007, 129, 4124.MacMillan et al. Chem. Sci. 2012, 3, 58. Casas et al. J. Am. Chem. Soc. 2004, 126, 8914

Jørgensen et al. J. Am. Chem. Soc. 2007, 129, 1536.Maruoka et al. Tetrahedron 2007, 63, 8658. Urones et al. Synlett 2009, 390. Brenner-Moyer et al. Org. Lett. 2011, 13, 6460.Deng et al. J. Am. Chem. Soc. 2015, 137, 8400.

Jang et al. Catal. Sci. Technol. 2014, 4, 1914.

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Organocatalytic Cascades• α,β-Difunctionalization

No α,β-dioxygenation precedent

• β,-Difunctionalization

• No precedent for cascade α,β,-trifunctionalization of enals

• Ipso,α,β-trifunctionalization

O OChiral amine cat.R R

Nu

E

O OChiral amine cat.R R

Nu

E

O OChiral amine cat.R R

Nu

X Nu

E

MacMillan et al. J. Am. Chem. Soc. 2005, 127, 3240.Jang et al. Org. Lett. 2012, 14, 3272.Arvidsson et al. Tetrahedron: Asymmetry 2006, 17, 1763.

Jørgensen et al. J. Am. Chem. Soc. 2012, 134, 2543. Carrillo et al. Angew. Chem., Int. Ed. 2012, 51, 4104. Brenner-Moyer. J. Org. Chem. 2012, 77, 8828.

Fu et al. Chem. Commun. 2006, 2604. Smith et al. Chem. Sci. 2013, 4, 2193. Romo et al. Nature Chemistry 2013, 5, 1049.

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Catalysis by Chiral Imidazolidinones• Enamine Catalysis

• Iminium Catalysis

• Mismatch in catalytic modes

A·HX (cat.),TEMPO,R

O

R

O

ON

CuCl2 (cat.), O2

R

OA·HX (cat.)

R

CHO

XX

N

NH

O

RA

Sibi et al. J. Am. Chem. Soc. 2007, 129, 4124.MacMillan et al. Chem. Sci. 2012, 3, 58.

MacMillan et al. J. Am. Chem. Soc. 2000, 122, 4243.

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What If an Enal?

A·HX (cat.),TEMPO, CuCl2 (cat.), O2

O

O

ON

R

R

OR

Nu O

ON

R

N

NH

O

RA

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Novel α,β,-TrioxygenationO B·HCl (cat.),TEMPO,

CuCl2 (cat.), O2, acetone

Same condition(3 equiv. A)31%

A

Same condition(5 equiv. TEMPO)26%, 5.6:1 dr

Same condition(5 equiv. TEMPO)

59%, >20:1 dr

NH

NO

Bn

O

O

OH

ONN

O

ON

O

ON

B

Our WorkJang et. al. Catal. Sci. Technol. 2014, 4, 1914.

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Fluorinated Aromatics as Solvents?O

Amine·HOAc (30 mol%)CuCl2 (30 mol%),TEMPO

O

O

OH

ONN

O2, Solvent, 0°C

Amine Solvent Yield % dr er

Acetone 78 (57) 4.1:1 61:39THF 39 9.0:1 64:39

DMSO 0 ND NDCHCl3 0 ND ND

PhMe 42 5.5:1 73:27

PhCF3 69 (52) 5.0:1 71:29

Pentafluorobenzene 66 (59) >20:1 70:30PhCF3 45 (36) 6.4:1 84:16

Pentaflurobenzene 59 (51) 8.9:1 85:15

N

NH

O

Bn

N

NH

O

NBn

Yield of majordiastereomer

Combined yield of two diastereomers

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Optimization of -Oxygenation

Enal as limiting reagent

TEMPO as limiting reagent

O

B (10 mol%), CuBr2 (10 mol%),TEMPO (1 equiv.), O2, Toluene, RT

68%3 equiv.

NH

Ph

PhOTMS

B

O

ON

O

A·HCl (30 mol%),CuCl2 (30 mol%),TEMPO (5 equiv.), O2, DMF, 0°C

71% NH

O

OH

A

O

ON

Chen, J. S., Abeykoon G. A. Org. Lett. 2015, 17, 6050.

Jang et. al. Catal. Sci. Technol. 2014, 4, 1914.

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Dynamic Kinetic Resolution

12.5% from (R)-A +52% from major enantiomer of B with (R) configuration at -position

64.5% combined yields of compounds with (R) configuration at -position

C·AcOH (30 mol%),TEMPO, CuCl2 (cat.),O2, C6HF5, 0°C, 24h N

NH

O

NBn

63%, 82:18 er (B)25% recovered (±)-A

(±)-A B

O

O

OH

ONN

O

ON

C

10

fast

slownBu

H

O

O

H

H

N

O

stabilizing hydrogenbond

O

O

OH

ONN

OOH

ON

O

ON

O

ON

OOH

ON

ON

NR2

Chen et al. J. Org. Chem. 2015, 80, 9967.

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Conclusion• Discovery of the first ever catalytic, enantioselective α,β,-trifunctionalization of

enals with moderate ee.

• Development of mechanistic insight on the novel trioxygenation.

• Improvement of -oxygenation using enal as the limiting reagent

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Acnowledgement• Department of Chemistry, Iowa State University• Prof. Jason Chen• Chen Group Members