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Transcript of 1 SOMO catalysis and Photoredox Organocatalysis: Work of David W.C. MacMillan Dominic Fiset...
1
SOMO catalysis and
NH
amine catalysis
H
O
R
aldehyde- H2O
Iminium catalysisLUMO activation
N
H
+ 2 e-
Enamine catalysisHOMO activation
N
R
H
- 1 e-
SOMO catalysisSOMO activation
N
RH
R
Photoredox Organocatalysis:Work of David W.C. MacMillan
Dominic Fiset05/10/11
Light
Asymmetric One-Electron MediatedOrganic Transformation
RuN
N N
N
N
N
Organocatalysis Photoredox catalysis
NH
NMeO
H2O
2+
About Me2
RIP 1972-1995
About Me3
Outline4
Introduction David W.C. MacMillan First Developments in Organocatalysis Aminocatalysis: Activation modes
Singly-Occupied Molecular Orbital catalysis Previously Reported Radical Alkylation Mechanistic Considerations Scope and Limitations
Photoredox Organocatalysis Merging SOMO Catalysis with Photoredox Chemistry Mechanistic Considerations Synthetic Utility
Pr. David W.C. MacMillan5
- Born in Bellshill, Scotland, in 1968 - 1987-91: Undergrad with Dr. Ernie Colvin at the University of Glasgow - 1991- 96: PhD. with Professor Larry E. Overman - 1996-98: Postdoctoral research fellow with Professor David E. Evans- 1998-2000: Independent Research at University of California, Berkeley-2000-2006: Professor of Chemistry at the California Institute of Technology -2006-...: Professor of Chemistry at Princeton University-2o10-…: Editor-in-Chief of Chemical Science published by RSC
Biography
Research Interests- Organocatalysis
- Mechanist investigation- SOMO catalysis- Merging photoredox catalysis and organocatalysis
- Total synthesis of complex natural products1. h http://www.princeton.edu/chemistry/macmillan/index.xml
Birth of Organocatalysis6
Hajos-Parrisch-Eder-Sauer-Wiechert reaction (1970s)
1. (a) Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; Celebi-Olcum, N.; Houk, K. N. Chem. Rev. 2011, 111, 5042 (b) Hajos, A. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1612(c) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496.
O
O
OMe N
HCO2H
3 mol% catalystDMF
Me
OH
O
O
NH
CO2H
NO
Me
O
O
O
H
NOH
Me
O
O
O
Me
OH
O
O
99%, 93% e.e.
O
O
NMe
O
O
OMe
CO2
Advent of Mordern Organocatalysis: Asymmetric Aminocatalysis
7
Enamine catalysis: Aldol reaction
1. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395.(b) List, B. Synlett 2001, 1675
2. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243
Iminium catalysis: Diels-Alder reaction
O
O2N
H
O
+
NH
CO2H
(30 mol%)
DMSOrt., 1h O2N
OH O
68%, 76% ee
N CO2H
1 : 1.381%, 93% ee
Ph+
NH
NMeOMe
MeBn
.HCl(10 mol%)
MeOH/H2Ort.
CHOPh
PhCHO
endo exo
+N
NMeO
MeMe
BnH
O
H
Ph
Asymmetric aminocatalysis: Activation Modes
8
1. (a) Grondal, C.; Jeanty, M.; Enders, D. Nat .Chem. 2010, 2, 167.(b) MacMillan, D. W. C. Nature 2008, 455, 304
Enamine catalysisHOMO activation
N
RH
Over 20 new reactions
- Aldehyde-aldehyde cross aldol coupling- Mannich reaction- -Amination--Oxygenation--Halogenation- -Sulphenylation
Enamine activation ofaldehydes and ketones
(HOMO raising)
Iminium catalysisLUMO activation
N
H
- Mukaiyama-Michael reaction- Diels-Alder reaction- Conjugate Friedel-Crafts reaction- Conjugate amination- Conjugate oxygenation- Conjugate sulphenylation- Conjugated hydride reduction- Cyclopropanation- Epoxidation, aziridination
Over 50 new reactions
Iminium activation of-unsaturated aldehydes
(LUMO lowering)
R
The Holy Grail Reaction9
1. (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 126, 450(b) Ibrahem, I.; Córdova, A. Angew. Chem. Int. Ed. 2006, 45, 1952
2. Melchiorre, P. Angew. Chem. Int. Ed. 2009, 48, 1360
Catalytic asymmetric intermolecular α-alkylation of aldehydes
O
Me
O
MeCatalyst
Alkyl-BrAlkyl
H H
Major Drawbacks:- Self-Aldol condensation- Cannizaro reaction- Tischenko reaction- O vs C alkylation- Racemization
Pioneering work by List and Córdeva
I
H
O
EtO2CEtO2C
NH
CO2H
Me
(10 mol%)
NEt3 (1 eq.), CHCl3-30C, 24h
H
O
EtO2CEtO2C
92%. 95% ee
H
O
Ph
+
Pd(Ph)4(5 mol%)
(10 mol%)DMSO, rt.
Ph
O
H
Ph
OH
72%
Pyrrolidine
[Red]OAc
The Holy Grail Reaction: A New Activation Mode
10
1. MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf
Asymmetric intermolecular α-alkylation of aldehyde
O O
R
H H
- No Alkylation product- Only Self Dimerization observed
NH
I
MeI
BnBr
or
or
Is there a solution ?
N O
RH H
I
R
+H
O
R N
H
R
H2O
XCatalytic amount Stoichiometric amount
+
A New Activation Mode: Singly-Occupied Molecular Orbital
Catalysis 11
1. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
NH
amine catalysis
H
O
R
aldehyde- H2O
Iminium catalysisLUMO activation
N
H
+ 2 e-
Enamine catalysisHOMO activation
N
R
H
- 1 e-
SOMO catalysisSOMO activation
N
RH
3--electrons radical cation
R4--electrons2--electrons
Aminocatalysis: A new activation mode 1
SOMO catalysis: A new synthetic paradigm
N
R
H
- 1 eN
R
H
+
Electron-richSOMOphile
OX
- é
X-
N
R
HO
H2OO
R
HOH
H
H
Electrophilic radical
Enamine oxidation: Racemic SOMO catalysis
12
Cation radicals of enamines: work of Murakami and coworkers
N
O
+
Ph
OTBSCAN (2 eq.)
MeCNrt., 30 min.
O
Ph
O
CAN= Cerium ammonium nitrate ((NH)4Ce(NO3)6)
63%
Construction of quaternary center: work of Cossy
N
N
O
R i) Mn(OAc)2ii) H3O+ N
O
R
O
38%1. Renaud, P.; Schubert, S. Synlett 1990, 6242. Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem. Lett. 1992, 21, 20993. (a) Cossy, J.; Bouzide, A. J. Chem. Soc., Chem. Commun. 1993, 1218 (b) Cossy, J.; Bouzide, A.; Leblanc, C. Synlett 1993, 202
Stereoselective addition of radicals to chiral enamines: work of Shubert
SO O
ClAIBN
Bu3SnH SO O
+N
OMe
NOMe
SO2Ph
40%, >95:5 cis/trans>95:5 Re/Si
SOMO catalysis: Work of D.W.C. MacMillan
13
1. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
14
1. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
Intermolecular Allylation of Aldehydes
O
H CAN (2 eq.)NaHCO3, 24hDME, -20°C
R
O
HR
R1
SiMe3
R1
+
NH
NMeO
t-BuBn
(20 mol%)TFA
H
O
Me4
81%, 91% ee
H
O2
72%, 87% ee
O
Me H
O
70%, 93% ee
NBoc
H
O
OBz7
72%, 95% ee
H
O
Me4
77%, 88% ee
PhH
O
Me4
81%, 90% ee
CO2Et
15
Potential for a Broad Scope
H
O
Me4 +
N
BocCAN (2 eq.)
NaHCO3, 24hDME, -20C
(20 mol%) H
O
Me4
NBoc
85%, 84% ee
CAN (2 eq.)LiCl, 24h
THF, -10C
(20 mol%)
85%, dr 8:1, 95% ee
Catalyst
H
OMe
O HCl
MeH
Catalyst
1. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
16
1. (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582(b) Le Tadic-Biadatti, M.-H.; Newcomb, M. Journal of the Chemical Society, Perkin Transactions 2 1996, 1467
SOMO Catalysis: Evidence for Radical Pathway
H
O
Me4
+CAN (2 eq.)
NaHCO3,, -20Cd6-acetone
(20 mol%) H
O4
Only product observed, 65%
OMe
Ph
Radical Clock
OMe
Ph
ONO2Me
OMe
Ph
Radical pathway
Cationic additionmechanism
OMe
Ph
OMe
Ph PhOMe
Nu
Ph
OMe
-e-, NuPh
OMe
Nu
Nu
Ph
OMe
Bond cleavage
Bond cleavage
Catalyst
SOMOphile
17
1. (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582(b) Le Tadic-Biadatti, M.-H.; Newcomb, M. Journal of the Chemical Society, Perkin Transactions 2 1996, 1467
Organo-SOMO Catalysis
O
HR TMSN
NMeO
t-BuBn
CeIV CeIII
NH
NMeO
t-BuBn
R
N
NMeO
t-BuBn
RH2O
H2OO
HR
N
NMeO
t-BuBn
RTMS-Nu
N
NMeO
t-BuBn
R
TMS
N
NMeO
t-BuBn
R
TMS
CeIV
CeIII
A
B C
D
EF
Fast
Mechanistic requirements:- Enamine must undergo selective oxidation over reaction partners- High levels of enantiocontrol by the amine catalyst- Catalytic turnovers
18
1. (a) Devery, J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers, R. A. Angew. Chem. Int. Ed. 2010, 49, 6106(b) Beel, R.; Kobialka, S.; Schmidt, M. L.; Engeser, M. Chem. Commun. 2011, 47, 3293(c) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001
Chemoselective Oxidation
N
NMeO
t-BuBn
CeIV CeIII
R B
Fast
H
O
Me
NH
NMeO
t-BuBn N
NMeO
t-BuBn
RPropanalIP9.8 eV
CatalystIP8.8 eV
EnamineIP7.2 eV
Undetected in situ by stopped-flow spectrophotometer
Ionization potential (IP) = measurement of the energy required to remove an electron from the species
- Detected by electrospray mass spectroscopy
- Best characterized as an alkyl radical conjugated to iminium cation (C-centered radical)
N
NMeO
t-BuBn
R C
19
Origin of the Enantioselectivity
TMS
N
NMeO
t-BuBn
R
TMS
C D
N
NMeO
t-BuBn
R
Steric Control Approach
N
NMeO
t-BuBn
R
1) 3--electrons system away from the bulky t-Bu
2) E configuration to minimize A1,3 strain
3) Benzyl group shields the Re face of the radical cation
exposing the Si face
1. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582
TMS
20
1. (a) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582(b) Devery, J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers, R. A. Angew. Chem. Int. Ed. 2010, 49, 6106
Catalytic Turnovers
NH
NMeO
t-BuBn
H2O
O
HR
N
NMeO
t-BuBn
R AF
Water Plays a Key Role- Concentration of catalyst is maintained by H2O (below 2.00 eq, the catalyst is deactivated)- Effect on the phase-transfer process that controls the homogenous concentration of the oxidant (CAN)- Bench-grade DME contains sufficient water to achieve optimal results
N
NMeO
t-BuBn
R
N
NMeO
t-BuBn
RHA1,3 strain
-H+
Low temperature
21
1. (a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124(b) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012
SOMO catalysis: Work of M. P. Sibi
Ph
O
H
Ph OH
O
NNH
NMe
Me
Me
O
Bn
HBF4
1)(20 mol%)
TEMPO (2 eq), FeCl3 (10 mol%)NaNO2 (30 mol%), O2, DMF
2) NaBH4 (2 eq), rt. up to 80%, 90% ee
NH
NMe
Me
Me
O
Bn
-H2OH
O
R
N
NMe
Me
Me
O
Bn
H
R
+H2OR
O
TMPOH
R
TMPOH
N
NMe
Me
Me
O
Bn
N
O
FeIII
FeII
NaNO2O2
22
1. (a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124(b) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012
Work of M. P. Sibi: Revisited by MacMillan
HEnamine
catalysis pathway
O
H
O
OTMP
OBn OBn
cis-cyclopropane
H
O
OBn
H
OBn
N
NMe
Me
Me
O
Bn
H
N
NMe
Me
Me
O
BnOxidation
H
OBn
N
NMe
Me
Me
O
Bn
AmineCatalyst
OBn
H
OBn
N
NMe
Me
Me
O
Bn
TEMPO
H
O
OTMP
OBn- Isomerization only possible via SOMO-catalysis
- Cis-cyclopropane observed in 95% yield trans-cyclopropane
23
1. (a) Van Humbeck, J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012(b) Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C. Chemical Science 2011, ASAP, DOI: 10.1039/C1SC00556A
Work of M. P. Sibi: Revisited by MacMillan
TEMPO (2 eq) FeCl3 DMF, rt.
H
O
R
-H2O
N
NMe
Me
Me
O
Bn
H
R
+H2O
R
O
TMPOH
R
TMPOH
N
NMe
Me
Me
O
Bn
O
NFeCl2(dmf)3
NH
NMe
Me
Me
O
Bn
TEMPO
TEMPOH
FeCl2
FeCl2(dmf)3TEMPO
Ionic electrophile
Conditions Recently Re-Optimized by MacMillan: ‘’Synergistic catalysis’’
10 mol% CuCl2TEMPO (2 eq),
Acetone, air-30C, 24h.
H
O
RR
O
TMPOH
NH
NMe
Me
Me
O
NBn
(20 mol%) 15 examples77-90% yield90-95% ee
+
24
1. Jang, H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004
-Enolation of Aldehydes
O
H H2O, CAN (2 eq.)DME, DTBP 24h, -20°C
R
O
HR
O
OSiX3
R1
+
NH
NMeO
t-BuBn
(20 mol%)
H
O
Me4
85%, 90% ee
H
O
OBn2
71%, 84% ee
H
O
84%, 95% ee
NBoc
H
O
Me4
72%, 92% ee
H
O
Me4
H
O3
79%, 91% ee
O O O
OO
if SIX3= TMS: 39%, 73% ee TBDPS: 67%, 86% ee
Me
O
O
Ph Ph Ph
R1
Me Me
25
1. Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008 130, 39
-Vinylation of Aldehydes: Mechanism
NH
NMeO
t-BuBn
H
O
R
KF3BR1
R2
H
O
R
R1
R2
(20 mol%)CAN (2.5 eq), H2O
NaHCO3, DME-50C, 24h
H
O
R NH
NMeO
t-BuBn+ -H2O
-1 e-N
NMeO
t-BuBn
R
KF3BR1
R2 N
NMeO
t-BuBn
R
R2
KF3B
-1 e-
N
NMeO
t-BuBn
R
R2
KF3B
-BF3K
Peterson trans-selective
N
NMeO
t-BuBn
R
R2
H2O-cat.
H
O
R
R1
R2
R1
R1 R1
+
Synthetic Application
26
-Vinylation of Aldehydes: Scope
H
O
72%, 94% ee 78%, 95% ee 77%, 95% ee
61%, 95% ee 82%, 89% ee93%, 94% ee
H
O
n-hex KF3BPh
Me+
i) -Vinylation ii) Vinyl Grignard
THF-78C to rt.
OH
n-hex
Ph
Me
76%, 1:1 anti/syn
KH, 18-C-9THF, rt.
Oxy-Cope
n-hexH
O
Me Ph
80%, >20:1 dr, 94% ee
Me
H
O
Et
H
O
n-hex
Cl
H
O
n-hex
OMe
H
O
Me MeH
O
Me
Me6
1. Kim, H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008 130, 39
27
1. Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494.
Carbo-oxidation of Styrenes
X-
NH
NMe O
t-Bu Me
H
O
R
Ar (20 mol%)CAN (2.5 eq), H2O
NaHCO3, DME-40C, 24h
-1 e-
+
N
NMe O
t-Bu Me
R
N
NMe O
t-Bu Me
R
Ar
ArN
NMe O
t-Bu Me
R
Ar
H2O-cat.
H
O
R
Ar
X
H
O
R
Ar
ONO2
H
O
n-hex ONO2
91%, 3:1 anti/syn96% ee
H
O
n-hex ONO2
95%, 3:1 anti/syn92% ee
NO2
H
O
n-hex ONO2
86%, 6:1 anti/syn94% ee
Me
H
O
n-hex ONO2
83%, 4:1 anti/syn89% ee
Me
(2.0 eq) (1.0 eq)
28
1. Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 16494.
Carbo-oxidation of Styrenes
H
O
n-hex
+
O
R
1) Carbo-oxidationsConditions
2) Pd/C, H2, rt.H
92%, 92% ee 82%, 92% ee 82%, 92% ee 82%,91% ee
Me Ph
X X
Homobenzylation of aldehyde
Rapid Acess to Heterocyclic Rings
O
n-hex
H
ONO2
NaBH494%
CrO394%
Zn, AcOHCrO399%
NaBH(OAc)3allylamine 3:1 dr, 96% ee
O Ph
n-hex
O Ph
n-hex
O
O Ph
n-hex
ON Ph
n-hex
allyl
trans--lactone3:1 dr, 94% ee
cis--lactone3:1 dr, 96% ee
pyrrolidine3:1 dr, 96% ee
tetrahydrofuran3:1 dr, 95% ee
91%
29
1. Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015
Organo-SOMO Cascade Cycloadditions
NH
NMe O
t-Bu Me
H
O
R(20 mol%)
Fe(phen)3SbF6 (2.5 eq)NaH2PO4, THF
-10C, 12h
-1 e-
+
N
NMe O
t-Bu Me N
NMe O
t-Bu Me
R
H2O-cat.
Nu
Nu
Nu
R
O
H
Nu
R
O
H
Nu
Nu
R2NH
R+
H
Chair-like Transition State
R
30
1. Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015
Organo-SOMO Cascade Cycloadditions
Ph
O
H
OMe
76%, >20:1 dr, 94% ee
Ph
O
H
70%, 10:1 dr, 92% ee
NSO2Ph Ph
O
H85%, 8:1 dr, 93% ee
O
Ph
O
H
79%, 11:1 dr, 90% ee
S
p-tol
O
H
82%, 15:1 dr, 91% ee
S
O
H
90%, >20:1 dr, 90% ee
SMe
O
H
72%, 13:1 dr, 88% ee
S
O
H
86%, 6:1 dr, 70% ee
SMe
MeMe
31
1. Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10015
Organo-SOMO Cascade Cycloadditions
PhMe
H
O
TMS
O
HSi(OEt)3
Me Ph
O
H
Me
Ph
Me
Ph
R2NMe
Ph+
TMS
+
74%, 4:1 dr, 89% ee
Me
PhH
R2N
H
Si(OEt)3
+
68%, 8:1:1:<1 dr, 88% ee
O
H
32
1. Pham, P. V.; Ashton, K.; MacMillan, D. W. C. Chemical Science 2011, 2, 1470
Intramolecular -Allylation
Catalyst –controlled stereoselective piperidine formation
NH
NMe O
t-Bu Bn
(20 mol%)CAN (2.2 eq)
H2O, NaHCO3DME, -20C, 24h
O
R
TMS
nn
O
H
R
H
OMe
Me
H
OMe
Me
73%, 4:1 dr 64%, 6:1 dr
O
O
H
74%, >20:1 dr, 91% ee
H
O
73%, 60% ee
NTs
O
HNTs
TMSO
H
(E)-Allylsilane
NTs
O
H
(Z)-Allylsilane
TMS86%, 20:1 dr89% ee
78%, 11:1 dr91% ee
H
33
1. (a) Nicolaou, K. C.; Reingruber, R. d.; Sarlah, D.; Brase, S. J. Am. Chem. Soc. 2009, 131, 6640(b) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11640(c) Um, J. M.; Gutierrez, O.; Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 6001
Intramolecular-Arylation of Aldehydes
NH
NMe O
Bn t-Bu
CANsolvent
Additives
80%, 98% ee 86%, 95% ee 73%, 96% ee 96%, 90% ee
OH
EDG
OH
EDG
OHOMe
TsN
OHOMe OH OH
O
82%, 96% ee
OH
BocN
58%, 94% ee
OH
OMe
OMe
para-meta-selective
NMe2OMe
OMe
ortho meta transition statedistorted from planarity
34
1. Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121
-Chlorination and Terminal Epoxide Formation
NH
NMeO
t-BuBnH
O
+ H
O
Cl
n-hexNaClor
LiCl
feedstock
TFA
amine catalyst 1
n-hex +
-40C= 95%, 92% ee 23C= 27%, 47% ee
rt.
CAN
NH
NMe O
R1 XH
O
Cl
RY+
k1
k-1 k-2
k2
N
NMe O
R1 XY
N
NMe O
R1 XY
R R
ClCl96% ee(initial)
NH
NMe O
t-Bu
catalyst 1
Bn
k1k2= fast at 23C
NH
NMe O
t-Bu
catalyst 2
Me
k1k2= slow at 23C
TFA TFA
35
1. Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121
-Chlorination and Terminal Epoxide Formation
NH
NMe O
t-Bu
catalyst 2
Me
Lone-pair shieldedk1k2= slow at 23C
No post-product racemization
N
NMe O
t-Bu Me
R
High kinetic enantiocontrolEnamine or Somo catalysis
NH
NMe O
t-Bu Bn
catalyst 1
Lone-pair exposedk1k2= fast at 23C
Post-product racemization
36
1. Amatore, M.; Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009, 48, 5121
-Chlorination and Terminal Epoxide Formation
H
O
+ H
O
Cl
R
(1.5 eq.)R Li-Cl
20 mol% cat. 250 mol% Cu(TFA)2Na2S2O8, MeCNH2O, 4h, 10C
H
O
Me3Cl
90%, 96% ee
H
O
2Cl
89%, 96% ee
EtH
O
2
Cl
95%, 95% ee
H
O
Cl95%, 95% ee
NBoc
H
O
+R
(1.5 eq.)R Li-Cl
i) 20 mol% cat. 2, Na2S2O8,H2O, MeCN
50 mol% Cu(TFA)2ii) NaBH4, 0C, 15 min
iii) KOH, rt., 30 min
Me3
85%, 95% ee
2
80%, 95% ee
Et2
82%, 94% ee 73%, 94% ee
NBoc
O
O O O O
37
1. (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458(b) Mastracchio, A.; Warkentin, A. A.; Walji, A. M.; MacMillan, D. W. C. Proceedings of the National Academy of Sciences 2010, 107, 20648
-Allylation of Ketones
NH
NMe O
Bn
(20 mol%)CAN (2.20 eq)H2O, NaHCO3
THF, -20C, 24hn n
O
TMS
R+
O O
R
O
Bn
OO O
MeMe
66%, 91% ee 71%, 99% ee 85%, 91% ee 70%, 5:1 dr, 99% ee
(2.00 eq) (1.00 eq)
38
1. (a) MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf(b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Polyene Cyclization
NH
NMeO
Bnt-Bu
2 x 1e- oxidant
R
O
R R
R
R RR
O
R
Amine catalyst
-H2O, , 1e-
R RR
R
N
NMeO
Bnt-Bu
R RR
R
-Amine catalyst
-H+, 1e-
N
NMeO
Bnt-Bu
39
1. (a) MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf(b) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Polyene Cyclization: Mechanism
MeCNMe
CN
N
NMeO
Bnt-Bu
Electrophilicradical
Electron-donating
MeCNMe
CN
N
NMeO
Bnt-Bu
Nucleophilicradical
Electron-withdrawing
MeCNMe
CN
N
NMeO
Bnt-BuElectron-donating
Electrophilicradical
MeCNMe
O
CN
- Polyolefins must incorporate an alternating sequence of polarity- inverted C=C bonds
6-endo-trig 6-endo-trig
40
1. Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Polyene Cyclization: Scope
O
Me
70%, 87% ee 61%, 91% ee
H
HH
Me CN
OMe
OMe
O H
63%, 93% ee
H
H
Me CN
OMe
OMe
Me CN
H
H
O H
Me
CNMe
H H
H
O H
CN
56%, 92% ee
Me
CNMe
H H
H
CN
- 6 new C-C bonds
- 11 contiguous stereocenters
- 5 all-carbon quaternary stereocenters
- 92% per bond formation
Me CN
H
H
O H62%
H
41
1. Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027
Merging SOMO and Photoredox catalysis
N
R
H
- 1 eN
R
H
+
Electron-richSOMOphile
OX
- é
X-
N
R
HO
H2OO
R
HO
H
H
Electrophilic radical
N
R
H
+
Electron-richSOMOphile
EWG
Electrophilic radical
EWGBrh
Photolytic bond homolysis
orPhotoredox
Catalysis
Reversing the role of the aminocatalyst
42
1 Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102
Light Photoredox Catalysis
Ru(bpy)32+ Ru(bpy)3
2+*Visible light Source
~ 452 nm
Metal to ligand charge transfer(MLCT)
e-
+ 0.84V
Ru(bpy)3+
e-
- 1.33V
e-
- 0.86VRu(bpy)3
3+e-
+ 1.29V
Reductive Quenching Cycle
Oxidative Quenching Cycle
RuN
N N
N
N
N
2+
Ru(bpy)32+
Single electron reductantor oxidant
43
1 Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85
Light Photoredox Catalysis
RuN
N N
N
N
N
2+
RuN
N N
N
N
N
2+*
h
452 nmWeak visible
Light
M
L
L
M
L
M
L
M
+ 0.84V
+ 0.84V
Strong oxidant
Strong reductant
Strong reductant- 1.33 V
Strong oxidant+1.29
MLCT
Ground State Excited State
Ground state
44
Merging SOMO and Photoredox catalysis
Light
Asymmetric One-Electron MediatedOrganic Transformation
RepresentativeTransformations
AldolFriedel-Craft
VinylationAllylationArylation
EnolalationEnal reducction
Diels-AlderPolyclization
RepresentativeUtility
H2 Production
O2 Production
CH4 Production
Energy Storage
RuN
N N
N
N
N
Organocatalysis Photoredox catalysis
NH
NMeO
H2O
2+
R
H +
Electron-richSOMOphile
EWG
Electrophilic radical
OrganocatalysisPhotoredox catalysisBr
O
R
H
O
EWG
1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
45
Merging SOMO and Photoredox catalysis
R
H + FG Fluorescent lightRu(bpy)3Cl2 (0.5 mol%)
2,6-lutidine, DMFrt
Br
O
R
H
O
FG
R1NH
NMe
t-BuMe
O
TfOH
(20 mol%)
R1
H
O CO2Et
CO2Et
Et
86%, 90% ee
H
O CO2Et
CO2Et
Ph
92%, 90% ee
H
O CO2Et
CO2Et
63%, 93% ee
H
O
OCH2CF3
O
80%, 92% ee
n-hex
H
O
O
87%, 96% ee
n-hex
OMe
H
O
O
84%, 95% ee
n-hex
NO2
70%, 5:1 dr, 99% ee
n-hex O
t-BuO2C
O
1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
R
H
O
R
H
O
EWG
NH
NMe
t-Bu Me
O
N
NMe
t-Bu Me
O
R
N
NMe
t-Bu Me
O
REWG
N
NMe
t-Bu Me
O
REWG
EWG
Organocatalyticcycle
Electron-deficient Radical
46
Photoredox organocatalysis: Mechanism
Ru(bpy)32+
Photoredox catalyst
Ru(bpy)32+*
OxidantRu(bpy)3
+
Reductant
SETEWGBr
Electron-deficient Radical
EWG
Photoredoxcatalytic cycle
h ~452 nm
SET
1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
47
Photoredox Organocatalysis: Control Experiments
1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77
- Rigorous exclusion of light: No alkylation product
- Removal of Ru(bpy)32+:
<10% of alkylation product over an extended timeframe (24h)- Ru(bpy)3
2+ can be replaced by high-energy UV irradiation sourceReaction efficiency over 80%
- Fluorescent quenching experiments with Ru(bpy)32+*
N
NMe
t-BuMe
O
R
O
BrEtO
O
OEt
O
Br
Ru(bpy)32+* excited state behaves as an oxidant in the photoredox cycle
48
R
H +Fluorescent light
Ir(ppy)2(dtb-bpy)C+ (0.5 mol%)2,6-lutidine, DMF
-20C
O
R
H
O
CF3
NH
NMe
t-BuMe
O
TfOH
(20 mol%)
H
O
CF3
n-hex
79%, 99% ee
R-F2C I
H
O
CF3
86%, 97% ee
CO2Et2 H
O
CF3
68%, >20:1 dr, 99% ee
Ph
Me
H
O
CF3
Ph
Me
62%, >20:1 dr, 99% ee
H
O
n-hex
CF2CF3
73%, 96% ee
H
O
n-hex
72%, 98% ee
F3C
CF3
FH
O
n-hex
68%, 99% ee
Br
F F
H
O
n-hex
85%, 98% ee
C6F6
F F
1 Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875
IrN
N N
N
N
N
+
tBu
tBu
Ir(bpy)2(dtb-bpy)+
Enantioselective -Trifluoromethylation
49
Enantioselective -Trifluoromethylation
H
O
Bn
CF3
75%, 97% ee
TEMPOPhI(OAc)2
HO
O
Bn
CF3
-CF3 acid94%, 96% ee
-CF3 amine88%, 92% ee
i) TEMPOPhI(OAc)2
ii) DPPA, KOtBut-BuOH, 100C
Bn
CF3BocN
HO
Bn
CF3
-CF3 alcohol99%, 97% ee
NaBH4MeOH, DCM
BnHN
Bn
CF3
-CF3 amine95%, 87% ee
BnNH2AcOHNaCNBH3
DCM
1 Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875
50
R
H +Fluorescent light
f ac-Ir(ppy)3 (0.5 mol%)2,6-lutidine, DMSO
rt.
O
R
H
ONH
NMe
MeBn
O
TfOH
(20 mol%)
H
O
n-hex
86%, 90% ee
ArBr Ar
NH
O
Cy
73%, 90% ee
NO2
NO2
H
O
n-hex
76%, 93% ee
CO2Me
NO2
H
O
n-hex
90%, 82% ee
NH
O
n-hex
78%, 87% ee
N
N
H
O
n-hex
0%
ClH
O
n-hex
81%, 88% ee
N
NMe
H
O
n-hex
74%,90% ee
N
NO2
IrN N
N
f ac-Ir(ppy)3
Enantioselective -Benzylation
1 Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600
R
H
O
R
H
O
Ar
NH
NMe
BnMe
O
N
NMe
BnMe
O
R
N
NMe
BnMe
O
R
Ar
N
NMe
BnMe
O
R
Ar
Ar
Organocatalyticcycle
Electron-deficient Radical
51
f ac-IrIII(ppy)3*
Photoredox catalystOxidant
f ac-IrIV(ppy)3+
Reductant
SET
ArBr
Electron-deficient Radical
Ar
Photoredoxcatalytic cycle
Visible light
SET
f ac-IrIII(ppy)3
1 Shih, H.-W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600
Enantioselective -Benzylation: Mechanism
52
Conclusion
NH
amine catalysis
H
O
R
aldehyde- H2O
Iminium catalysisLUMO activation
N
H
+ 2 e-
Enamine catalysisHOMO activation
N
R
H
- 1 e-
SOMO catalysisSOMO activation
N
RH
R
1. MacMillan, D.W.C. Lecture 4: New acctivation mode (SET pathways), available online at http://www.princeton.edu/chemistry/macmillan/research/MacMillan%20Lecture%204.pdf
Light
Asymmetric One-Electron MediatedOrganic Transformation
RuN
N N
N
N
N
Organocatalysis Photoredox catalysis
NH
NMeO
H2O
2+