macmillan lecture 4

! Last 10 years, organocatalysis has delivered many new asymmetric transforms (~150-200)

Im

N

O Me

Ph

+

Iminium catalysis

Me

R

with Jorgensen, K. A.

~50 new reactions

En

NHO2C

Enamine catalysis

Hajos-Wiechert

~20 new reactions

H+H-bond catalysis

JacobsenAkiyama

~30 new reactions

R

Barbas-List

X N N

S

H H

Me

Y

Me

R H

O

! These 3 activation modes cover a large portion of the organocatalysis landscape

Me

Organocatalysis

The rapid growth of organocatalysis over the

last 10 years was fueled by the development

of a small number of generic activation modes

Enantioselective Organocatalysis: A Valuable Strategy for Chemical Synthesis

Im

N

O Me

Ph

+

Iminium catalysis

Me

R

~50 new reactions

En

NHO2C

Enamine catalysis

Hajos-Wiechert

~20 new reactions

H+H-bond catalysis

JacobsenAkiyama

~30 new reactions

R

Barbas-List

X N N

S

H H

Me

Y

Me

R H

O

Me

Organocatalysis

Im

N

O Me

Ph

+

Iminium catalysis

Me

R

~50 new reactions

En

NHO2C

Enamine catalysis

Hajos-Wiechert

~20 new reactions

H+H-bond catalysis

JacobsenAkiyama

~30 new reactions

R

Barbas-List

X N N

S

H H

Me

Y

Me

R H

O

Me

Organocatalysis

Im

N

O Me

Ph

+

Iminium catalysis

Me

R

~50 new reactions

En

NHO2C

Enamine catalysis

Hajos-Wiechert

~20 new reactions

H+H-bond catalysis

JacobsenAkiyama

~30 new reactions

R

Barbas-List

X N N

S

H H

Me

Y

Me

R H

O

Me

Organocatalysis

Im

N

O Me

Ph

+

Iminium catalysis

Me

R

~50 new reactions

En

NHO2C

Enamine catalysis

Hajos-Wiechert

~20 new reactions

H+H-bond catalysis

JacobsenAkiyama

~30 new reactions

R

Barbas-List

X N N

S

H H

Me

Y

Me

R H

O

Me

Organocatalysis

Im

N

O Me

Ph

+

Iminium catalysis

Me

R

~50 new reactions

En

NHO2C

Enamine catalysis

Hajos-Wiechert

~20 new reactions

H+H-bond catalysis

JacobsenAkiyama

~30 new reactions

R

Barbas-List

X N N

S

H H

Me

Y

Me

R H

O

Me

Organocatalysis

Organometallic Catalysis: Few Activation Concepts Many Powerful Reactions

!

!-bond insertion

! Relatively few activation modes have resulted in literally thousands of new chemical reactions

CC bond coupling

!-bond insertion

CN, S, O coupling"-bond insertion

!"

Lewis acid catalysis Olefin metathesis Atom transfer catalysis

At

Suzuki

Negishi

Stille

Kumada

Fu

Buchwald

Hartwig

Yates

Corey

Evans

Shibasaki

Mukaiyama

Grubbs

Schrock

Hoveyda

Furstner

Sharpless

Jacobsen

Shi

Doyle

RuLa

Noyori

Toste

Heck

Feringa

Krische

Why don't we focus on the invention of new, useful catalytic activation modes?

Relatively Few Catalysis Activation Concepts Many Powerful Reactions

Instead of focusing completely on the invention of individual catalytic reactions

using long-established activation modes

Design of an entirely new catalyst activation mode is extremely challenging

So

OrganoSOMO

! Two new modes of catalyst activation using organocatalysts

Photoredox

+e

organocatalysiscatalysis

So

OrganoSOMO

Photoredox

+e

So

OrganoSOMO

Photoredox

+e

So

OrganoSOMO

Photoredox

+e

So

OrganoSOMO

! A new mode of organocatalytic activation

catalysis

Photoredox

+e

organocatalysis

Holy Grails in Asymmetric Catalysis: Asymmetric !-Carbonyl Alyklation

Me

O catalyst

alkylBr

Me

O

alkyl

Holy Grails in Asymmetric Catalysis: Enolate Alyklation

! Chiral Auxiliary Controlled 1982, Evans, Meyers

NO

O

Me

O

NO

O

Me

O

Bn

93% yield

120:1 dr

! Catalytic Ketone Variant: Abby Doyle, Eric Jacobsen

LDA;

BnBr

Ph Ph

OSnBu3

Me

Br

5 mol% cat

OMe

N N

O

t-Bu

t-Bu t-BuO

t-Bu

Cr

Cl

salen catalyst84% yield

94% ee

! Fu has also introduced an elegant enantioselective alkyl-halide alkylation reaction

! O'Donnell, Corey and Maruoka: glycine imine alkylation via PTC (seminal contributions )

NO

O

Me

O

NO

O

Me

O

Bn

93% yield

120:1 dr

LDA;

BnBr

Ph Ph

OSnBu3

Me

Br

5 mol% cat

OMe

N N

O

t-Bu

t-Bu t-BuO

t-Bu

Cr

Cl

94% ee

NO

O

Me

O

NO

O

Me

O

Bn

93% yield

120:1 dr

LDA;

BnBr

Ph Ph

OSnBu3

Me

Br

5 mol% cat

OMe

N N

O

t-Bu

t-Bu t-BuO

t-Bu

Cr

Cl

94% ee

Can we use Enamine Catalysis to Solve Asymmetric Catalytic Carbonyl Alkylation

H

O I

MeI BnBr

or

NH

Initial idea: to perform asymmetric alkylation on aldehydes!

aldehyde enamine

catalyst

H

O

no alkylation product

Me

Teresa Beeson: 3rd Year Graduate Student!

Only products of aldehyde self dimerization were observed!

Can we use Enamine Catalysis to Solve Asymmetric Catalytic Carbonyl Alkylation

H

O I

MeI BnBr

or

NH

Initial idea: to perform asymmetric alkylation on aldehydes!

aldehyde enamine

catalyst

H

O

no alkylation product

Me

Teresa Beeson: 3rd Year Graduate Student!

Only products of aldehyde self dimerization were observed!

Inherent Problems for Enamine Catalysis and Asymmetric Catalytic Alkylation

HR

O

NH

Potential Issues for Enantioselective Alkylation using Enamine Catalysis!

aldehyde enamine

catalyst

NR

insufficient e- density

to react with

sp3-electrophile

H I

HHMeI

NR

sufficient e- density

to react with

sp2-aldehyde

in comparison to sp2-aldehyde

HO

R

H

+

H

O

aldehyde-aldehyde

R

OH

aldol dominates

Intramolecular aldehyde alkylation can be accomplished (List and coworkers)!

Designing a New Organocatalytic Catalysis Concept: SOMO Catalysis

Trying to force a reaction to work within the confines

of a known catalysis concept or activation mode

(square peg, round hole)

N

H

O

R

HR

N

R

H

not

+

X

! Can we utilize the one electron species that lies between iminium and enamine catalysis

LUMOactivation

N

O Me

Ph

+

HOMOactivation

N

O Me

Ph

iminium catalysis enamine catalysis

SOMOactivation

N

O Me

Ph

somo catalysis

Reface

activated

Reface

activated

Me

MeMe

Me

MeMe

Me

+2 e 1 e

[oxid]

R R R

LUMOactivation

N

O Me

Ph

+

HOMOactivation

N

O Me

Ph

SOMOactivation

N

O Me

Ph

somo catalysis

Reface

activated

Reface

activated

Me

MeMe

Me

MeMe

Me

+2 e 1 e

[oxid]

R R R

LUMOactivation

N

O Me

Ph

+

HOMOactivation

N

O Me

Ph

SOMOactivation

N

O Me

Ph

somo catalysis

Reface

activated

Reface

activated

Me

MeMe

Me

MeMe

Me

+2 e 1 e

[oxid]

R R R

LUMOactivation

N

O Me

Ph

+

HOMOactivation

N

O Me

Ph

SOMOactivation

N

O Me

Ph

somo catalysis

Reface

activated

Reface

activated

Me

MeMe

Me

MeMe

Me

+2 e 1 e

[oxid]

R R R

LUMOactivation

N

O Me

Ph

+

HOMOactivation

N

O Me

Ph

SOMOactivation

N

O Me

Ph

somo catalysis

Reface

activated

Reface

activated

Me

MeMe

Me

MeMe

Me

+2 e 1 e

[oxid]

R R R

SOMO Catalysis: Potential Utility of New Catalysis Platform

H

O

H

O

N

O Me

Ph Me

Me

oxidantCAN

!-allyl aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

SiMe3

with SOMOphile

Br

not electrophile

SOMO species

H

O

H

O

N

O Me

Ph Me

Me

oxidantCAN

!-allyl aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

SiMe3

with SOMOphile

Br

not electrophile

SOMO species

H

O

H

O

N

O Me

Ph Me

Me

oxidantCAN

!-allyl aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

SiMe3

with SOMOphile

Br

not electrophile

SOMO species

H

O

H

O

N

O Me

Ph Me

Me

oxidantCAN

!-allyl aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

SiMe3

with SOMOphile

Br

not electrophile

SOMO species

H

O

H

O

N

O Me

Ph Me

Me

oxidantCAN

!-allyl aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

SiMe3

with SOMOphile

Br

not electrophile

SOMO species

H

O

H

O

enantiopure

!-oxy aldehydes

N

O Me

Ph Me

Me

oxidant

H

O

H

O

Ph

O

H

O

OR

CAN!-aryl aldehydes

1,4-keto-aldehydesenantiopure

enantiopure

!-allyl aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

!"vinylation

H

O

H

ring formation

SOMO species

SOMO catalysis concept

O

RNH

R+ N

R

HCl

substrate catalyst SOMOactivationoxidant

1 e

Oxidant should selectively reract with transient enamine to generate radical iminium cation

Why will there be selective oxidation: oxidation potentials

NHH

ON

H

butanal pyrrolidine 1-(but-1-enyl)pyrrolidine

IP = 9.84 eV IP = 8.8 eV IP = 7.24 eV

O

RNH

R+ N

R

HCl

substrate catalyst SOMOactivationoxidant

1 e

Oxidant should selectively reract with transient enamine to generate radical iminium cation

Why will there be selective oxidation: oxidation potentials

NHH

ON

H

butanal pyrrolidine 1-(but-1-enyl)pyrrolidine

IP = 9.84 eV IP = 8.8 eV IP = 7.24 eV

Could this be a third general platform of induction for the imidazolidinone catalyst family

Reface

SOMO nucleophiles

N

NH

O Me

organocatalyst

+

Iminium geometry control

!-carbon radical geometry control

substrate

Requirements for enantioselectivity:

Me

O

RNH

R+ N

R

HCl

substrate catalyst SOMOactivation

O

oxidant

1 e

Ph

oxidant

CAN+

activated to

Studies to determine the utility of SOMO catalysis for aldehyde alkylation

N

NH

Bn

O Me

tBu

TMSH

O

aldehyde allyl silane 2 eq CAN

10 mol%

DME

!

H

O

aldehyde aldol (undesired)

OH

N

NH

Bn

O Me

tBu

TMSH

O

10 mol%

DME

!

N

NH

Bn

O Me

tBu

TMSH

O

10 mol%

DME

!

H

O

aldehyde aldol (undesired)

OH

N

NH

Bn

O Me

tBu

TMSH

O

10 mol%

DME

!

N

NH

Bn

O Me

tBu

TMSH

O

!-alkylated aldehyde

H

O

10 mol%

DME

81% yield

91% ee

! Varying the allylsilane and the aldehyde component

H

O

H

O

Me

H

O

CO2Et

81% yield

91% ee

88% yield

91% ee

81% yield

90% ee

H

O

H

O

Ph

H

O

58% yield

94% ee

87% yield

90% ee

70% yield

93% ee

NBoc

!

with Beeson, Masstrachio, Hong, Ashton, Science, 2007, 316, 582

Me

N

NH

Bn

O Me

tBu

TMSH

O

H

O

10 mol%

DME

81% yield

91% ee

! Varying the allylsilane and the aldehyde component

H

O

H

O

Me

H

O

CO2Et

81% yield

91% ee

88% yield

91% ee

81% yield

90% ee

H

O

H

O

Ph

H

O

58% yield

94% ee

87% yield

90% ee

70% yield

93% ee

NBoc

!

with Beeson, Masstrachio, Hong, Ashton, Science, 2007, 316, 582

Me

! OrganoSOMO Aldehyde Alkylation

Enantioselective OrganoSOMO Catalysis: Possible Catalytic Cycle

N

NH

But

Ph

MeO

O

R

H

1e

cat A

+

radical-cation ?

O

H

Ph

SiMe3

! Mechanistic Evidence for radical cation

10% catalyst A

2 eq CAN

O

H

PhO2NO

68 %

N

H

Ph

N

H

Ph

N

H

Ph

1e

O

H

Ph

10% catalyst A

O

H

Ph

82 %

2 eq NCS Cl

O

H

Ph

radical-clock substrate

used to detect

SOMO catalysis versus

enamine catalysis

! Enamine catalysis

N

H

Ph

1e

stable unstable

O

H

Ph

not

observed

! SOMO catalysis

N

NH

But

Ph

MeO

O

R

H

1e

cat A

+

radical-cation ?

O

H

Ph

SiMe3

10% catalyst A

2 eq CAN

O

H

PhO2NO

68 %

N

H

Ph

N

H

Ph

N

H

Ph

1e

O

H

Ph

10% catalyst A

O

H

Ph

82 %

2 eq NCS Cl

O

H

Ph

used to detect

enamine catalysis

! Enamine catalysis

N

H

Ph

1e

stable unstable

O

H

Ph

not

observed

! SOMO catalysis

N

NH

But

Ph

MeO

O

R

H

1e

cat A

+

radical-cation ?

O

H

Ph

SiMe3

10% catalyst A

2 eq CAN

O

H

PhO2NO

68 %

N

H

Ph

N

H

Ph

N

H

Ph

1e

O

H

Ph

10% catalyst A

O

H

Ph

82 %

2 eq NCS Cl

O

H

Ph

used to detect

enamine catalysis

! Enamine catalysis

N

H

Ph

1e

stable unstable

O

H

Ph

not

observed

! SOMO catalysis

N

NH

But

Ph

MeO

O

R

H

1e

cat A

+

radical-cation ?

O

H

Ph

SiMe3

10% catalyst A

2 eq CAN

O

H

PhO2NO

68 %

N

H

Ph

N

H

Ph

N

H

Ph

1e

O

H

Ph

10% catalyst A

O

H

Ph

82 %

2 eq NCS Cl

O

H

Ph

used to detect

enamine catalysis

! Enamine catalysis

N

H

Ph

1e

stable unstable

O

H

Ph

not

observed

! SOMO catalysis

N

NH

But

Ph

MeO

O

R

H

1e

cat A

+

radical-cation ?

O

H

Ph

SiMe3

10% catalyst A

2 eq CAN

O

H

PhO2NO

68 %

N

H

Ph

N

H

Ph

N

H

Ph

1e

O

H

Ph

10% catalyst A

O

H

Ph

82 %

2 eq NCS Cl

O

H

Ph

used to detect

enamine catalysis

! Enamine catalysis

N

H

Ph

1e

stable unstable

O

H

Ph

not

observed

! SOMO catalysis

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

cat A

+

SOMOphile addition?

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

cat A

+

SOMOphile addition?

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

cat A

+

! Newcombe radical vs cation discrimination

N

H

Newcombe: to detect

2e !-addition pathway

versus

1e SOMOphile additionMeO Ph

! Test for SOMOphile

N

H

OMe

Ph

MeO Ph

N

H

OMe

Ph

N

H

OMe

PhX

O

HPh

O

H

10% catalyst A

2 eq CAN 57%

olefin B

B

O

Bu

H

OMe

PhO2NO

O

HB

+ +

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

cat A

+

N

H

Newcombe: to detect

versus

N

H

OMe

Ph

MeO Ph

N

H

OMe

Ph

N

H

OMe

PhX

O

HPh

O

H

10% catalyst A

2 eq CAN 57%

olefin B

B

O

Bu

H

OMe

PhO2NO

O

HB

+ +

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

cat A

+

N

H

Newcombe: to detect

versus

N

H

OMe

Ph

MeO Ph

N

H

OMe

Ph

N

H

OMe

PhX

O

HPh

O

H

10% catalyst A

2 eq CAN 57%

olefin B

B

O

Bu

H

OMe

PhO2NO

O

HB

+ +

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

cat A

+

N

H

Newcombe: to detect

versus

N

H

OMe

Ph

MeO Ph

N

H

OMe

Ph

N

H

OMe

PhX

O

HPh

O

H

10% catalyst A

2 eq CAN 57%

olefin B

B

O

Bu

H

OMe

PhO2NO

O

HB

+ +

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

X-

N

N BntBu

Me O

R

SiMe3

cat A

+

! This catalytic cycle would require 2 oxidation events

! Second oxidation is

important ?

! Test for second oxidation

O

Bu

H

SiMe3

10% catalyst A

X eq CAN

O

Bu

H

X eq CAN % Yield

1.0

1.5

2.0

3.0

37%

61%

88%

87%

SiMe3SiMe3

! !-silyl radical readily oxidized

1e

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

X-

N

N BntBu

Me O

R

SiMe3

cat A

+

important ?

O

Bu

H

SiMe3

10% catalyst A

X eq CAN

O

Bu

H

X eq CAN % Yield

1.0

1.5

2.0

3.0

37%

61%

88%

87%

SiMe3SiMe3

1e

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

X-

N

N BntBu

Me O

R

SiMe3

cat A

+

important ?

O

Bu

H

SiMe3

10% catalyst A

X eq CAN

O

Bu

H

X eq CAN % Yield

1.0

1.5

2.0

3.0

37%

61%

88%

87%

SiMe3SiMe3

1e

O

Bu

H

SiMe3

10% catalyst A

X eq CAN

O

Bu

H

X eq CAN % Yield

1.0

1.5

2.0

3.0

37%

61%

88%

87%

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

1e

X-

N

N BntBu

Me O

R

SiMe3

cat A

+

important ?

O

Bu

H

SiMe3

10% catalyst A

X eq CAN

O

Bu

H

X eq CAN % Yield

1.0

1.5

2.0

3.0

37%

61%

88%

87%

SiMe3SiMe3

1e

O

Bu

H

SiMe3

10% catalyst A

X eq CAN

O

Bu

H

X eq CAN % Yield

1.0

1.5

2.0

3.0

37%

61%

88%

87%

SOMO

SiMe3

N

NH

But

Ph

MeO

X-

N

N BntBu

Me O

R

SiMe3

O

R

H

R

O

H

!-allyl aldehyde

1e

cycle

+ H2O

X-

N

N BntBu

Me O

R

SiMe3

oxidant = 1ecat A

SiMe3+

! Loss of TMS-cation

important

+

Aldehyde !-allylation Aldehyde !-enolation

Aldehyde !-vinylation

"-Nitro-!-alkyl aldehyde

91% ee

96% ee

90% ee

94% ee

91% ee

SOMO activation strategy is useful for a variety of organocatalytic reactions

Olefin carbo-oxidation !-Chlorination/epoxidation

Science 2007, 316, 582 JACS 2007,129, 7004

JACS 2008, 130, 398

94% ee

H

O

hex

HPh

O

hex O

HPh

O

hex

HPh

O

hex ONO2

HMe

O

hex

NO2

Cascade Cycloaddition

90% ee

JACS 2009, 131, 11332

JACS 2008, 130, 16494

JACS 2010, 132, asap

ACIE 2009, 48, 5121

PhO

ACIE 2010, asap (Flowers)

Intramolecular !-arylation

98% ee

OH

JACS 2009, 131, 11640

OMe

JACS 2009, 131, 2086 (Nicolaou)

JACS 2010, 132, 6001 (Houk)

O

Me Me

CN

H

Polyene cyclization

JACS 2010, 132, 5027

92% eeS

N

NO

H

Bn

Multiple Radical Bond Formations

Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 5027.

O

R

RR

R

N

OMe

Ar

R

R R

R

RR

R

O

R

RR

R

N

OMe

Ar

N

NH

Me O

Ar

2 x 1e oxidant

amine catalyst

H2O, 1e

Direct and enantioselective access to steroid-type scaffolds

1e, H+

amine catalyst

What oxidant favorsa long-lived radicalfor polycyclization?

What substituentpattern will favorpolycyclization?

O

R

RR

R

N

OMe

Ar

R

R R

R

RR

R

O

R

RR

R

N

OMe

Ar

N

NH

Me O

Ar

2 x 1e oxidant

amine catalyst

H2O, 1e

1e, H+

amine catalyst

What oxidant favors

What substituents

polycyclization?

favor polycyclization?

O

R

RR

R

N

OMe

Ar

R

R R

R

RR

R

O

R

RR

R

N

OMe

Ar

N

NH

Me O

Ar

2 x 1e oxidant

amine catalyst

H2O, 1e

1e, H+

amine catalyst

What oxidant favors

What substituents

polycyclization?

favor polycyclization?

Radical vs. Cation Propagating Species in Polycyclization

Me

HO

Me

MeMe

TFA

Me

MeMe

Me

MeMe

Johnson, W. S.; Semmelhack, M. F.; Sultanbawa, M. U. S.; Dolak, L. A. J. Am. Chem. Soc. 1968, 90, 2994.

Propagating species is carbocation: electron rich double bonds favor cyclization

N

OMe

ArMe CN

Me

Electrophillic

Electron

N

OMe

ArMe CN

Me

Nucleophillic

Electron

N

OMe

ArMeCN

Me

Propagating species is radical: alternating polarity favors cyclization

radical

donating

radical

withdrawing

Me

HO

Me

MeMe

TFA

Me

MeMe

Me

MeMe

N

OMe

ArMe CN

Me

Electrophillic

Electron

N

OMe

ArMe CN

Me

Nucleophillic

Electron

N

OMe

ArMeCN

Me

radical

donating

radical

withdrawing

Me

HO

Me

MeMe

TFA

Me

MeMe

Me

MeMe

N

OMe

ArMe CN

Me

Electrophillic

Electron

N

OMe

ArMe CN

Me

Nucleophillic

Electron

N

OMe

ArMeCN

Me

radical

donating

radical

withdrawing

Me

HO

Me

MeMe

TFA

Me

MeMe

Me

MeMe

N

OMe

ArMe CN

Me

Electrophillic

Electron

N

OMe

ArMe CN

Me

Nucleophillic

Electron

N

OMe

ArMeCN

Me

radical

donating

radical

withdrawing

Me

HO

Me

MeMe

TFA

Me

MeMe

Me

MeMe

N

OMe

ArMe CN

Me

Electrophillic

Electron

N

OMe

ArMe CN

Me

Nucleophillic

Electron

N

OMe

ArMeCN

Me

radical

donating

radical

withdrawing

Me

HO

Me

MeMe

TFA

Me

MeMe

Me

MeMe

N

OMe

ArMe CN

Me

Electrophillic

Electron

N

OMe

ArMe CN

Me

Nucleophillic

Electron

N

OMe

ArMeCN

Me

radical

donating

radical

withdrawing

Competition with Premature Radical Oxidation

O

MeN

NH

Me O

Ar

CANor

Fe(phen)3(PF6)3

O

Further oxidation

H

N

OMe

ArMe

N

OMe

ArMe

N

OMe

Ar

Bicyclization

outcompetes cyclization

precursor

Monocylization

product

O

MeN

NH

Me O

Ar

CANor

Fe(phen)3(PF6)3

O

Further oxidation

H

N

OMe

ArMe

N

OMe

ArMe

N

OMe

Ar

Bicyclization

precursor

Monocylization

product

O

MeN

NH

Me O

Ar

CANor

Fe(phen)3(PF6)3

O

Further oxidation

H

N

OMe

ArMe

N

OMe

ArMe

N

OMe

Ar

Bicyclization

precursor

Monocylization

product

O

MeN

NH

Me O

Ar

CANor

Fe(phen)3(PF6)3

O

Further oxidation

H

N

OMe

ArMe

N

OMe

ArMe

N

OMe

Ar

Bicyclization

precursor

Monocylization

product

Copper Oxidant Allows for Efficient Bicyclization

O

Me

N

NH

Me O

1-Np

Cu(OTf)2

i-PrCN/DME, 23 CO

Me

H

70% yield

87% ee

O

Me

H

O

Me

H

O

Me

H

O

Me

H

F MeO

CN CO2Me

65% yield

90% ee

75% yield

88% ee

74% yield

88% ee

77% yield

87% ee

Alternating Polarity of Olefins Allows for Multicyclization

CN

N

OMe

ArMe CN

Me

Will alternating polarity

OMe

CNMe

H

O

CN

Me

CNMe

HH

H

O

Me CN

OMe

OMeH

HH

H

O

Me CN

H

HH

H

CN

H

Me

61% yield

91% ee

56% yield

92% ee

63% yield

93% ee

62% yield

Tricyclization Tetracyclization

Pentacyclization Hexacyclization

6 new CC bonds

11 contiguous stereocenters

5 all-carbon quaternarystereocenters

92% yield per bond formation

enable multicyclization?

CN

N

OMe

ArMe CN

Me

OMe

CNMe

H

O

CN

Me

CNMe

HH

H

O

Me CN

OMe

OMeH

HH

H

O

Me CN

H

HH

H

CN

H

Me

61% yield

91% ee

56% yield

92% ee

63% yield

93% ee

62% yield

6 new CC bonds

CN

N

OMe

ArMe CN

Me

OMe

CNMe

H

O

CN

Me

CNMe

HH

H

O

Me CN

OMe

OMeH

HH

H

O

Me CN

H

HH

H

CN

H

Me

61% yield

91% ee

56% yield

92% ee

63% yield

93% ee

62% yield

6 new CC bonds

CN

N

OMe

ArMe CN

Me

OMe

CNMe

H

O

CN

Me

CNMe

HH

H

O

Me CN

OMe

OMeH

HH

H

O

Me CN

H

HH

H

CN

H

Me

61% yield

91% ee

56% yield

92% ee

63% yield

93% ee

62% yield

6 new CC bonds

CN

N

OMe

ArMe CN

Me

OMe

CNMe

H

O

CN

Me

CNMe

HH

H

O

Me CN

OMe

OMeH

HH

H

O

Me CN

H

HH

H

CN

H

Me

61% yield

91% ee

56% yield

92% ee

63% yield

93% ee

62% yield

6 new CC bonds

So

OrganoSOMO

catalysis

Photoredox

+e

organocatalysis

The Utility of Merging Different Catalysis Areas: New Catalytic Bond Constructions

N

NRu2+

N

Photoredox Catalysis

Light

H2 Production

O2 Production

CH4 Production

Energy Storage

Representative

Utility

NN

N

NRu2+

N

Photoredox CatalysisOrganocatalysis

N

NH

MeO

Light

Aldol

Friedel-Crafts

Vinylation

Allylation

Enolation

Enal Reduction

Diels-Alder

H2 Production

O2 Production

CH4 Production

Energy Storage

Representative

Transformations

Representative

Utility

NN

N

H2O

amine

N

NRu2+

N

NH

MeO

Light

Aldol

Friedel-Crafts

Vinylation

Allylation

Enolation

Enal Reduction

Diels-Alder

H2 Production

O2 Production

CH4 Production

Energy Storage

Representative

Transformations

Representative

Utility

NN

N

H2O

amine

N

NRu2+

N

NH

MeO

Light

Aldol

Friedel-Crafts

Vinylation

Allylation

Enolation

Enal Reduction

Diels-Alder

H2 Production

O2 Production

CH4 Production

Energy Storage

Representative

Transformations

Representative

Utility

NN

N

H2O

amine

New Organic Transformations with Enantioselective Induction

How can we use Photoredox Catalysis to Enable Aldehyde !-Alkylation

Can we electronically reverse the role of the catalyst!

O

HSo

SOMO catalysis, activated species reacts with electron rich "-systems!

N

O Me

Ph Me

Me

oxidant SOMO-phile

So

N

O Me

Ph Me

Me

SOMO-philes =

KF3B

SiMe3

Me

OSiMe3

Ph

ON

N

O Me

Ph Me

Me

enamine SOMO-activated

(SOMO-phile) (!-acyl radical)

h# O

Brphotolytic

bond homolysis

SOMO-

activated

h# = photobox!

O

HSo

N

O Me

Ph Me

Me

oxidant SOMO-phile

So

N

O Me

Ph Me

Me

SOMO-philes =

KF3B

SiMe3

Me

OSiMe3

Ph

ON

N

O Me

Ph Me

Me

h# O

Brphotolytic

bond homolysis

SOMO-

activated

h# = photobox!

O

HSo

N

O Me

Ph Me

Me

oxidant SOMO-phile

So

N

O Me

Ph Me

Me

SOMO-philes =

KF3B

SiMe3

Me

OSiMe3

Ph

ON

N

O Me

Ph Me

Me

h# O

Brphotolytic

bond homolysis

SOMO-

activated

h# = photobox!

O

HSo

N

O Me

Ph Me

Me

oxidant SOMO-phile

So

N

O Me

Ph Me

Me

SOMO-philes =

KF3B

SiMe3

Me

OSiMe3

Ph

ON

N

O Me

Ph Me

Me

h# O

Brphotolytic

bond homolysis

SOMO-

activated

h# = photobox!

O

HSo

N

O Me

Ph Me

Me

oxidant SOMO-phile

So

N

O Me

Ph Me

Me

SOMO-philes =

KF3B

SiMe3

Me

OSiMe3

Ph

ON

N

O Me

Ph Me

Me

h# O

Brphotolytic

bond homolysis

SOMO-

activated

h# = photobox!

Visible MLCT absorption at 452 nm (weak visible light)!

Long-lived excited state (~ 620ns)!

! High quantum yield (~0.05 - H2O/298K)

! Effective excited state oxidant and reductant

Inexpensive ($38/g - Strem 2008)!

N

NRu

N

NN

N

2+

Used extensively as electron transfer catalyst!

Coord. Chem. Rev. 1982, 46, 159.

Ru(bpy)3X2

Ru(bpy)3: A Versatile and Extensively Utilized Photredox Catalyst

NNRu

N

NN

N

2+

Ru(bpy)3: Electronic Properties that Enable Photredox Catalysis

Ru-centeredorbitals (t2g)

Ligand-centered

orbital (!*)

Metal-Based Ground State

Excitation

Excited, Ligand-Based State

Strong Oxidant

Strong Reductant

E = 0.84V

E = 0.86V

Balzani, A. J. V.; Barigelletti, F.; Campagna, S.; Belser, P.; von Zewelsky, A. Coord. Chem. Rev. 1988, 84, 85.

Ru(bpy)32+

Photon

N

NRu

N

NN

N

2+ *

*Ru(bpy)3

2+

Ru(bpy)33+

Ru(bpy)31+

with weak

visible light

How can we use Photoredox Catalysis to Enable Single Electron Pathways

N

NRu

N

NN

N

2+

15W

Ru(bpy)32+

Fluorescent bulb

Ru(bpy)32+

N

NRu

N

NN

N

2+

N

NRu

N

NN

N

2+*

*

(excited state)

O

Brabsorbs

photon

15W

Br

SOMO-activated

Ru(bpy)32+

SETSET

SETSET = single electron transfer

Fluorescent bulb

Ru(bpy)32+

N

NRu

N

NN

N

2+

N

NRu

N

NN

N

2+*

N

NRu

N

NN

N

1+

*

(excited state)*

O

Brabsorbs

photon

15W

Br

SOMO-activated

Ru(bpy)31+

Ru(bpy)32+

SETSET

O

Br

SOMO-activated

SETSET

Fluorescent bulb

Ru(bpy)32+

N

NRu

N

NN

N

2+

N

NRu

N

NN

N

2+*

N

NRu

N

NN

N

1+

*

(excited state)*

O

Brabsorbs

photon

15W

Br

SOMO-activated

Ru(bpy)31+

Ru(bpy)32+

SETSET

O

Br

SOMO-activated

SETSET

Fluorescent bulb

Using a household 15W light bulb with Ru(bpy)! highly reactive one-electron species

Merging Enantioselective Organocatalysis and Photoredox Catalysis

Photoredox Catalytic

Cycle

Ru(bpy)32+

photoredox catalyst 1

15W Fluorescent bulb

Cycle

Ru(bpy)32+

Cycle

oxidant

!Ru(bpy)32+

Ru(bpy)32+

2

Cycle

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

2

Br

Cycle

alkyl halide

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

2

Ph

O

substrate

alkyl halide

substrate

Br

Cycle

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

SET

electron-deficient

2

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

NH

O

R

H

Organocatalytic

Cycle

Br

Me t-Bu

Cycle

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

SET

electron-deficient

2

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

MeO

N

NH

MeO

R

O

R

H

Organocatalytic

Cycle

Br

Me t-Bu

Cycle

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

SET

electron-deficient

2

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

MeO

N

NH

MeO

R

O

R

H

Organocatalytic

Cycle

Br

Me t-Bu

Cycle

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

SET

electron-deficient

2

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

MeO

N

NH

MeO

R

O

R

H

Organocatalytic

Cycle

Br

Me t-Bu

Cycle

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

openSi-face

SET

radical A

electron-deficient

2

O

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

MeO

N

NH

MeO

R

O

R

H

N

Me O

R

Organocatalytic

Cycle

Br

Me t-Bu

Met-Bu

Cycle

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

openSi-face

SET

radical A

electron-deficient

2

O

Ph

O

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

MeO

N

NH

MeO

R

N

O

H

O

R

H

N

Me O

R

Organocatalytic

Cycle

Br

Me t-Bu

Met-Bu Met-Bu

R

Cycle

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

!Ru(bpy)32+

Ru(bpy)32+

+

openSi-face

SETSET

SET

radical A

Me

electron-deficient

2

O

Ph

O

PhPh

O

Ph

O

Ph

O

substrate

alkyl halide

substrate

N

MeO

N

NH

MeO

R

N

O

H

O

R

O

R

H

N

Me O

R

Organocatalytic

Cycle

Br

Me t-Bu

Met-Bu Met-Bu

R

Cycle

enantioenriched

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

"Ru(bpy)32+

Ru(bpy)32+

+

openSi-face

SETSET

SET

radical A

Me

electron-deficient

2

O

Ph

O

PhPh

O

Ph

O

Ph

O

Ph

substrate

alkyl halide

substrate

Merging Photoredox and Enantioselective Organocatalysis: Initial Results!

Ru(bpy)3Cl2 B (0.5 mol%)organocatalyst A (20 mol%)

N

NH

Me

HOTfN

NRu

N

NN

N

Catalyst Combination Photon Source

15 W fluorescent light bulb

O

N

NH

Me

HOTfN

NRu

N

NN

N

O

84% yield

96% ee

preliminary experiments revealed that the asymmetric tandem catalysis mechanism was possible

O

H

O

Hex

H

2,6-lutidine, DMF,

fluorescent light

octanal

organocatalyst A

Ru(bpy)3Cl2 B

23 C enantioenriched!-bromoketone

Bu

O

Br O

Photoredox and Organocatalysis: Bromocarbonyl Scope!

A variety of alkylation substrates can be used that are outside the realm of 2e pathways

2,6-lutidine, DMF, 23 C

15 W fluorescent light

N

NH

Me

HOTf

0.5 mol% Ru(bpy)3Cl2enantioenriched

O

20 mol% catalyst

O

Hex

H

octanal

!-bromocarbonyl

87% yield, 96% ee

FG

R

Br

O

H

Y

FG

R

racemic

O

H

Hex O

O

MeOBr

OMe

84% yield, 95% ee

O

H

Hex O

O

O2NBr

NO2

80% yield, 92% ee

O

HOR

Hex O

RO

O

Br

80% yield, 88% ee

EtO2C CO2Et

Br Me

O

H CO2Et

Hex

Me CO2Et

!-bromocarbonyl alkylation product !-bromocarbonyl alkylation product

catalyst combination

N

NH

Me

HOTfN

NRu

N

NN

N

O

2,6-lutidine, DMF,

fluorescent light

octanal!-alkylated aldehyde

organocatalyst A

Ru(bpy)3Cl2 B

23 C enantioenriched

!-bromoketone

O

Hex

H O

Hex

EtO2C

O

CO2Et

Br

racemic

70% yield,

5:1 dr, 99% ee

with David Nicewicz, Science, 2008, 3, 77 (published online Thurs, Sept 4th)

Photoredox Organocatalysis: Potential Utility of New Catalysis Platform

H

O

N

O Me

Ph Me

Me

N

NH

O Me

catalyst

Me

MePh

substrate

N

NRu

N

NN

N

catalystsubstrate

FG

Br

H

O

N

O Me

Ph Me

Me

H

O

!-malonyl aldehydes

enantiopure

N

NH

O Me

catalyst

Me

MePh

substrateEtO2C CO2Et

"-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

!-benzyl aldehydesenantiopure

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

Merging Photoredox and Organocatalysis: !-Perfluoroalkylation!

Enantioselective !-perfluoralkylation of formyl could provide new entry to pharmacaphores

SMe

O O

HN

CF3Me

MeF

O

NH

NC

Odanacatib (Merck)

NH

N

CO2Me

N

H

F

Me

OMe

Me

H

OH

CO2MeOAc

H

Et

Vinflunine

(BMS)

H

O

Versatile synthon for medicinal agent synthesis

R

CF3

No known catalytic routes to !-formyl CF3

Enhance potency, elevate lipophilicity

and/or improve metabolic stability

Photoredox and Organocatalysis: Trifluoromethylation!

2,6-lutidine, THF, 20 C

!-trifluoromethylation

N

NH

Me

HOTf

0.5 mol% Ir(ppy)2bpyenantioenriched

O

20 mol% catalyst

O

H

aldehyde

79% yield, 99% ee

O

H

CF3

R

trifluoromethyl iodide

70% yield, 98% ee

61% yield, 93% ee

aldehyde trifluoromethylation product

CF3 IR

O

H

CF3

O

H

O

H5

( )

CF3

NBoc

O

H

CF3

O

H

NBoc

73% yield, 90% ee

O

H

O

H

CF3

OMe

O

H

OMe

with Nagib, Scott, JACS, 2009, 131, 10875

Photoredox and Organocatalysis: Trifluoromethylation!

!-trifluoromethylation

N

NH

Me

HOTf

O

20 mol% catalyst

O

H

aldehyde

79% yield, 99% ee

O

H

CF3

R

trifluoromethyl iodide

70% yield, 98% ee

61% yield, 93% ee

CF3 IR

O

H

NBoc

O

H

CF3

O

H

O

H5

( )

CF3

NBoc

O

H

CF3

O

H

73% yield, 90% ee

O

H

O

H

CF3

OMe

Photoredox and Organocatalysis: perfluoroalkylation!

!-perfluoroalkylation

N

NH

Me

HOTf

O

20 mol% catalyst

O

H

aldehyde

73% yield, 96% ee

O

H

n-hex

R

fluoroalkyl iodide

72% yield, 98% ee

89% yield, 99% ee

RFnI fluoroalkylation product

RF2 In-hex

RFnI fluoroalkylation product

O

H

n-hex

CF3

F3CF

I CF3

F3CF

85% yield, 98% ee

O

H

n-hex

F FF F

I

H

O

CF2CF3

n-hex

H

O

CF2CO2Et

n-hex

I CF2CF2

I CO2Et

F F

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

H

O

H

CF3

O

enantioselective

!-alkylcyanation

N

O Me

Ph Me

Me

H

O

H

O

!-malonyl aldehydes

enantiopure

!-CF3-aldehydes

N

NH

O Me

catalyst

Me

MePh

substrate

enantiopure

EtO2C CO2Et

enantiopure

!"amino aldehydes

H

O

NR2

#-keto aldehydes

N

NRu

N

NN

N

catalystsubstrate

FG

Br

Me

H

O

R

O

H

O

CN

N

MeO

N

NH

MeO

R

N

O

H

O

R

O

R

H

N

Me O

R

Organocatalytic

Cycle

Br

Me t-Bu

Met-Bu Met-Bu

R

Cycle

enantioenriched

catalyst

aldehyde

alkyl halide

radical A

Ru(bpy)31+ 3

reductant oxidant

"Ru(bpy)32+

Ru(bpy)32+

+

openSi-face

SETSET

SET

radical A

Me

electron-deficient

2

O

Ph

O

PhPh

O

Ph

O

Ph

O

Ph

substrate

alkyl halide

substrate

Photoredox Catalysis: New Directions for Organic Synthesis

! Visible Light Photocatalysis of [2+2] Enone Cycloadditions

visible light

O

Ph

O

Ph

O

Ph Ph

O

H HMeCN

5 mol% Ru(bpy)3Cl2

i-Pr2NEt, LiBF4

! Photoredox Catalysis: Hydro-dehalogenation of alkanes

89%

>10:1 d.r.

NN

Br

HBoc

Bocvisible light

DMF

2.5 mol% Ru(bpy)3Cl2

i-Pr2NEt, HCO2H

NN

H

HBoc

Boc

Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12866-12887.

J. Am. Chem. Soc. 2009, 131, 14604-14605.

90%

Stephenson, C. R. J. J. Am. Chem. Soc. 2008, 130, 12866-12887.

Photoredox Catalysis: New Directions for Organic Synthesis

! Visible Light Photocatalysis of [2+2] Enone Cycloadditions

visible light

O

Ph

O

Ph

O

Ph Ph

O

H HMeCN

5 mol% Ru(bpy)3Cl2

i-Pr2NEt, LiBF4

! Photoredox Catalysis: Hydro-dehalogenation of alkanes

89%

>10:1 d.r.

NN

Br

HBoc

Bocvisible light

DMF

2.5 mol% Ru(bpy)3Cl2

i-Pr2NEt, HCO2H

NN

H

HBoc

Boc

Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12866-12887.

J. Am. Chem. Soc. 2009, 131, 14604-14605.

90%

Stephenson, C. R. J. J. Am. Chem. Soc. 2008, 130, 12866-12887.

Putting Science, Catalysis and Organocatalysis in Context

# of Hits for Google Keyword Search:

Overview of Chemistry Hot Topics Google Hits

600,000

537,000

435,000

417,000

253,000

159,000

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Organocatalytic

Activation Modes

600,000

537,000

435,000

417,000

253,000

159,000

137,000

Organocatalytic

Activation Modes

Emerging

Important Areas

600,000

537,000

435,000

417,000

253,000

159,000

137,000

The early years: Berkeley

Vy Dong

MacMillan Group (1st Year)

Wendy Jen

Tristan Lambert

Tehshik Yoon

Kateri Ahrendt

Chris Borths Jake Wiener

Naiomi Anchor (UG)

Dr. Jeongbob Seo

Vy Dong

MacMillan Group Caltech 2002

Wendy Jen

Tristan Lambert Tehshik Yoon

Chris Borths Jake Wiener

Joel Austin Ian Mangion

Rebecca WilsonNick Paras

Dr. Jeongbob Seo

Sean Brown

James Falsey

Julie Park

Alan Northrup

Brian Kwan

Craig Countryman Dr. Wenjing XiaoDr. Seongon Kim

Nikki Goodwin Dr. Chris Sinz

Dr. Claudia Roberson

Catharine Larsen

MacMillan Group Present

Dr. Muriel Amatore

Dr. Kate Ashton

Teresa Beeson

Joe Carpenter

Diane Carrera

Dr. Jay Conrad

Dr. Tom Graham

Dr. Christoph Grondal

Dr. Pilar Garcia Garcia

Dr. J. B. Hong

Jeff Van Humbeck

Casey Jones

Spencer Jones

Nate Jui

Dr. Mark Kerr

Dr. Hahn Kim

Rob Knowles

Sandra Lee

Dr. Jon Martel

Tony Mastracchio

David Nagib

Dr. David Nicewicz

Atsushi Ohigashi

Phong Pham

Dr. Trevor Rainey

Dr.Maud Reiter

Katie Saliba

Bryon Simmons

Grace Wang

Dr. Abbas Walji

Alex Warkentin

Ben Zegarelli

MacMillan Group Present

Anna Allen

Anthony Casarez

Joe Carpenter

Diane Carrera

Dr. Giuseppe Cecera

Dr. Jay Conrad

Jae Won Lee

Dr. Andrew Dilger

Dr. Rebecca Grange

Benjamin Horning

Jeff Van Humbeck

Spencer Jones

Nate Jui

Dr. Hahn Kim

Dr. Chris Kokotos

Brian Laforteza

Dr. Esther Lee

Tony Mastracchio

Dr. Andrew McNally

David Nagib

Phong Pham

Dr. Mark Pickworth

Dr. Seb Rendler

Hui-Wen Shih

Bryon Simmons

Scott Simonovich

Dr. Feili Tang

Mark Vander Wal

Jeff Van Humbeck

Alex Warkentin

SiYi Wang

Dr. Alan Watson

Funding (pharmaceutical)

Acknowledgments

Funding (non-profit)

Petroleum Research Foundation

UC AIDSResearch Fund

NSF

NIH

Cottrell Scholar

Innovation Award

Research Corporation

Sloan Fellowship(NIGMS)

macmillan lecture 4

Documents

new asymmetric transforms

valuable strategy

large portion

chemical synthesis