Post on 17-Feb-2017
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