SOMO catalysis and

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


N

RH

Over 20 new reactions

- Aldehyde-aldehyde cross aldol coupling- Mannich reaction- -Amination--Oxygenation--Halogenation- -Sulphenylation

Enamine activation ofaldehydes and ketones

(HOMO raising)


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


N

H

+ 2 e-


N

R

H

- 1 e-


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


14


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


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


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



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



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



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



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

+


OX

- é

X-

N

R

HO

H2OO

R

HO

H

H


N

R

H

+


EWG


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


Light


RepresentativeTransformations

AldolFriedel-Craft

VinylationAllylationArylation

EnolalationEnal reducction

Diels-AlderPolyclization

RepresentativeUtility

H2 Production

O2 Production

CH4 Production

Energy Storage

RuN

N N

N

N

N


NH

NMeO

H2O

2+

R

H +


EWG


OrganocatalysisPhotoredox catalysisBr

O

R

H

O

EWG

1 Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77

45


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


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


EWG

Photoredoxcatalytic cycle

h ~452 nm

SET


47

Photoredox Organocatalysis: Control Experiments


- 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


51

f ac-IrIII(ppy)3*

Photoredox catalystOxidant

f ac-IrIV(ppy)3+

Reductant

SET

ArBr


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


N

H

+ 2 e-


N

R

H

- 1 e-


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


RuN

N N

N

N

N


NH

NMeO

H2O

2+

SOMO catalysis and

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