chemistry - applications of radical reactions in asymmetric … · 2008-11-26 · an introduction...

Applications of Radical Reactionsin Asymmetric Synthesis

Brandon MeyersMichigan State UniversityDepartment of Chemistry

November 19, 2008

Outline

• Introduction– Importance of radical reactions– Challenges of stereochemistry

• Methods employed to achieve asymmetriccontrol– Chiral Auxiliary– Chiral Acid– Organocatalysis

General Bond Forming Conditions

• Acidic (Cationic)

• Basic (Anionic)

• Neutral (Radical)

n

-HF3B!O

H

HF3B!OH

I

H

HHHO

H

HH

HO IHO

H

HH

! !

INa Na

H3C Br H3C Br

Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry. Oxford: University Press. 2001

Reversal of Reactivity

Giese, B.; Tetrahedron, 1985, 41, 4025

OLDA

O

OBu3SnHO

Br

LDA!H

Bu3Sn!Br

nucleophilic carbanion

electrophilicradicalAIBN

I

Homolytic

Cleavage

Heterolytic

CleavageI

I

electrophilic carbocation

nucleophilicradical

Radicals Stabilized by ElectronDonating Groups

Parsons, A.F. An Introduction to Free Radical Chemistry, Oxford: Blackwell Science, 2000, p. 40

O

R

O

R

Energ

y nonbondinglone pairs

RadicalSOMO

Nucleophilic Radical

Radicals Stabilized by ElectronWithdrawing Groups

O

Energ

y

!

Ononbondinglone pairs

O !"RadicalSOMO

Parsons, A.F. An Introduction to Free Radical Chemistry, Oxford: Blackwell Science, 2000, p. 40

O

H

H !!

Electrophilic Radical

Early Problems of Stereochemistry

• Synthesis of Sativene & Capocamphene

Br

O

Bu3SnH

PhCO3tBu, h!

benzene

X X

X = O (37%)X = CH2 - Sativene

X = O (25%)X = CH2 - Capocamphene

Bakuzis, P.; Campos, O.O.S.; Bakuzis, M.L.F. J. Org. Chem., 1976, 41, 3261

Methods for Asymmetric Control

Chiral Auxiliary, XC

Chiral Acid, AC

Organocatalysis

XC

O

N

R1

ORXC

OHN OR

R1

*

O

AC

R

R1 O

AC

R

R1

*

N

N

R

O

R1!LGO

R

R1*H

Sultam & Oxazolidinone Auxiliaries

Dipole-dipolecontrol

Lewis acid chelation

S

N H

R'O

O

O O

N

O

OMR'

H

RR* *

Dipole-Dipole Chiral Auxiliary

Naito, T; Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K. J. Org. Chem., 2000, 65, 176-185

S

NHMeO

O

H

NOBn

1.0 eq. Me3Al

Cl(CH2)2Cl

reflux

O

H

NOBn

SO2

N

90% yield

O

O

(1R)-(+)-2,10-camphorsultam0.67 eq.glyoxylic

oxime ether

O

H

NOBn

SO2

N

5.0 eq. R-I, CH2Cl22.5 eq. Bu3SnH

2.0 eq. BF3·OEt25.0 eq. Et3B, -78 ˚C

O

R

NHOBn

SO2

N

Mechanism

Bu3Sn I!R Bu3Sn!I R

O

NOBn

S

N

O

OR

O

NHOBn

S

N

O

OR

HSnBu3

ONOBn

S

N

O

OR

O

NOBn

S

N

O

OR

Substrate Scope

O

H

NOBn

SO2

N


2.0 eq. BF3·OEt25.0 eq. Et3B, -78 ˚C

O

R

NHOBn

SO2

N

1

Entry RI Product

Isolated

Yield (%) dr of 1

1 i-Pr-I 1a 80 096 : 4

2 Et-I 1b 80 095 : 5

3 t-Bu-I 1c 83 >98 : 2

4 i-Bu-I 1d 83 097 : 3

5 c-Hex-I 1e 86 096 : 4


Preferred Site of Addition


anti, s-cis

anti, s-trans syn, s-cis syn, s-trans

Note: =O O

ONOBn

S

N

O

O

R

R

O

NOBnS

N

O

O

S

N

O

O

NOBn

OS

N

O

O

O

BnON

Reduction of Oxime Ether andRemoval of Chiral Auxiliary


O

R

NHOBn

SO2

N 0.7 eq. Mo(CO)6

H2O, MeCN, reflux

O

R

NH2

SO2

N

1 N LiOH-THF (1:4)O

R

NH2HO

R = i-Pr, 88% yield

Synthesis of D-Valine

R = i-Pr, 88% yield

O

R

NH2

SO2

N

55% overall yield, 4 steps

Lewis Acid Chelationto Chiral Auxiliary

Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem., 2002, 67, 1738-1745

HO CO2Et

O 1. (COCl)2, THF

2.

n-BuLi, -78 ˚C

CO2Et

O

87% yield, two steps

HN

OO

Ph

Ph

NO

O

Ph

Ph

CO2Et

O i-Pr!I (10 eq)

Sm(OTf)3 (1.0 eq)

Bu3SnH (6.0 eq)

Et3B (3.0 eq), O2

CH2Cl2/THF (4:1), -78 ˚C

95% yielddr = 29:1

NO

O

Ph

Ph

N CO2Et

O

O

O

Ph

Ph

Stereoselective Model


Activates !"carbon to imidecarbonyl

BlocksSi-face

N CO2Et

O

O

O

PhPh

Sm

OTf

OTfTfO

i-Pr

i-Pr

O

OOH

OH

Synthetic Application:(−)-Enterolactone

• Previous Synthesis:– Chenevert, R.; et al. 7 steps, 35%

yield• Key Step: Enzyme-catalyzed

esterification

Chenevert, R.; Mohammadi-Ziarani, G.; Caron, D.; Dasser, M.; Can. J. Chem., 1999, 77, 223


Lewis Acid Chelationto Chiral Auxiliary

N CO2Et

O Et

O

O

Ph

Ph

17% yield

BEt3 O2 Et2BOO Et

CO2Et

O

Sm(OTf)3 (1.0 eq)

Bu3SnH (6.0 eq)

Et3B (3.0 eq), O2

CH2Cl2/THF (4:1), -78 ˚C

OCH3Br

71% yield

NO

O

Ph

Ph

N CO2Et

O

O

O

Ph

Ph

OMe

(10 eq)

Total Synthesis of (–)-Enterolactone


N CO2Et

O

O

O

Ph

Ph

OMe

3-OMeC6H4-CH2I

NaHMDS, THF

-78 ˚C to -54 ˚C N CO2Et

O

O

O

OMe

PhPh

OMe

LiOH

H2O2 HO CO2Et

O

OMe

OMe

1.1.5 eq. BH3/THF

-15 ˚C

2. PPTS, reflux

50% yield 88% yield

O

OOMe

OMe

78% yield,two steps

4.0 eq. BBr3

0 ˚C to -18 ˚C

O

OOH

OH

88% yield

1



Chiral Acid, AC

Organocatalysis

N

N

R

O

R1!LGO

R

R1*H

XC

O

N

R1

ORXC

OHN OR

R1

*

O

AC

R

R1 O

AC

R

R1

*

Types of Chiral Acids

• Lewis Acids

• Brønsted Acid

N

H H N

OH

OCH3

H2PO2

Quinine, QP

N

OO

N

MgI2

O

N N

O

Ph PhMgBr2

Chiral Lewis Acid Chelation


O

H

NOBn

SO2

N


2.0 eq. BF3·OEt25.0 eq. Et3B, -78 ˚C

O

R

NHOBn

SO2

N

R = i-Pr 80% yield, dr = 96:4

MeONOBn

O

H

O

N N

O

Ph PhMgBr2

i-Pr-I, Bu3SnHBEt3, -78 ˚C

MeONHOBn

O

97% yield, 52% ee

Model for Selectivity


Re-face open

R

N

Mg

N

O

O

N

OMeH

O

BnO

Cho, D.K.; Jang, D.O. Chem. Commun., 2006, 5045-5047

Chiral Brønsted Acids

• Quaternary Ammonium Salts ofHypophosphorous Acid

N

H H N

OH

OCH3

N

HHN

OH

OCH3

H2PO2

H2PO2

Quinine, QP Quinidine, QDP

Entry RI Product

Isolated

Yield (%)

2a Yield

(%)

er of 2

R : S

1 i-Pr-I 2b 83 7 21 : 79

2 c-Hex-I 2c 80 10 21 : 79

3 t-Bu-I 2d 60 30 01 : >99

4 1-Ad-I 2e 45 35 01 : >99

5 n-Oct-I 2f 50 25 40 : 60


Quinine Results

N

H H N

OH

OCH3

H2PO2

Quinine, QP

HO

O

H

NOBn

2 eq. QP, 5 eq. R-I0.5 eq. BEt3, O2

CH2Cl2/H2O (1:1)4 h, rt

HO

O

R

NHOBnHO

O

Et

NHOBn

1 2 2a

Entry RI Product

Isolated

Yield (%)

2a Yield

(%)

er of 2

R : S

1 i-Pr-I 2b 82 10 >62 : 38

2 c-Hex-I 2c 82 9 >72 : 28

3 t-Bu-I 2d 62 27 >99 : 1

4 1-Ad-I 2e 47 37 >99 : 1

5 n-Oct-I 2f 48 30 >58 : 42


Quinidine Results

N

HHN

OH

OCH3

H2PO2

Quinidine, QDP

HO

O

H

NOBn

2 eq. QDP, 5 eq. R-I0.5 eq. BEt3, O2

CH2Cl2/H2O (1:1)4 h, rt

HO

O

R

NHOBnHO

O

Et

NHOBn

1 2 2a

Model for Enantioselectivity

• Quinine versus Quinidine


N

H H N

OH

OCH3

H

NO

HO

O

R

Si-faceopen

H2PO2 N

HHN

OH

OCH3

H2PO2

H

N O

OH

O

R

Re-faceopen

Sibi, M.P.; Lee, S.; Lim, C.J.; Kim, S.; Subramaniam, R.; Zimmerman, J. Org. Lett., 2006, 8, 4311-4313

O

N N

O

Ph Ph

Mg(NTf2)2

Chiral Lewis Acid

HO

O

Ph I

66% yield, 75% ee

HO

O

Ph

0.3 eq. Chiral L.A.

2.0 eq. Bu3SnH

3.0 eq. Et3B/O2

CH2Cl2, -78 0C, 24 h

Conjugate Radical Addition

• Enantioselective addition to α'-hydroxy enone

Scope of α'-Hydroxy Enone andAlkyl Halide Substrates


Entry R1 R2 Product

Isolated

Yield (%) ee (%)

1 CH2CH2Ph t-Bu 1a 66 75

2 CH2CH2Ph i-Pr 1b 85 68

3 CH2CH2Ph n-Pr 1c 63 72

4 CH2CH2Ph Et 1d 87 72

5 Ph t-Bu 2a 90 78

6 Ph i-Pr 2b 78 78

7 Ph n-Pr 2c 68 86

8 Ph Et 2d 82 80

HO

O

R1

0.3 eq. Chiral L.A.

2.0 eq. Bu3SnH

3.0 eq. Et3B/O2

CH2Cl2, -78 0C, 24 h

HO

O

R1

R2

5.0 eq. R2-I

1 R = CH2CH2Ph2 R = Ph

1a-d

2a-d

O

N N

O

Ph PhMg(NTf2)2

Chiral Lewis Acid



X=NTf2

MgN

N

O

O

O

X

O

X

H

R1

R2

Re-faceopen

Synthetic Application: (+)-Ricciocarpin A

Agapiou, K.; Krishe, M. Org. Lett., 2003, 5, 1737-1740

O

O

O

H

H

Ricciocarpin A

• Previous Synthesis:– Krishe, M.; Agapiou, K.– 6 steps, 14% yield– Key step: Michael

cycloisomerization(+)-

Radical Conjugate Addition

Sibi, M.P.; He, L. Org. Lett., 2004, 6, 1749-1752

N

O

O

N

NO

OO

OBn

Mg

R

N

O

O

O

OBn

N

OO

N

MgI2

BrCl

5.0 eq. Et3B / O2, -78 ˚C

N

O

O

O

OBn

Cl

5.0 eq. Bu3SnH

5.0 eq.84% yield, 97% ee

O

O

O

H

H

Ricciocarpin A

Preparation of AldehydeIntermediate


Sm(OTf)3CH3OH

MeO

O

OBn

Cl

NaIAcetone

98%

LiHMDS-78 ˚C to rt

97%

OMe

O

H

H

OBn

1. Pd(OH)2/H2, Hex/EtOAc, -10 ˚C

2. TEMPO, KBr, NaOCl, std. NaHCO3, 0 ˚COMe

O

H

H

CHO76% over two steps

N

O

O

O

OBn

Cl

OMe

O

HOBn

I

95%

O

O

O

H

H

Ricciocarpin A

Synthesis of Ricciocarpin A


OMe

O

H

H

CHO

O

(i-PrO)3Ti

Solvent, -78 ˚C2.0 eq. s-BuLi

O

OH

H

O

Ricciocarpin A

O

OH

H

O

2.0 eq.

41% overall yield

85%

5.7 : 1



Chiral Acid, AC

Organocatalysis

XC

O

N

R1

ORXC

OHN OR

R1

*

O

AC

R

R1 O

AC

R

R1

*

N

N

R

O

R1!LGO

R

R1*H

MacMillan Enamine Chemistry

Beeson, T.D.; Mastracchio, A.; Hong, J.B.; Ashton, K.; MacMillan, D.W.C. Science, 2007, 316, 582-585

NH

N

O

R1 R2

Me

H

O

R

N

N

O

R1 R2

Me

R

N

N

O

R1 R2

Me

R

SET

N

N

O

R1 R2

Me

R

N

N

O

R1 R2

Me

R

TMS O

R

*H

Previous Organocatalytic Research

• Iminium & Enamine Organocatalysis


NH

H

O

R N

R

-H2O -2 e-

N

R

Enamine ActivationHOMO catalysis

Iminium ActivationLUMO catalysis

aldehyde amine catalyst

“These two modes of catalyst activation haveprovided more than 60 asymmetric metricmethodologies over the past 7 years.”

- Dr. David MacMillan

Hypothesis - SOMO Activation


NH

H

O

N

Et

N

Et

SET

Butanal

IP = 9.8 eV

Pyrrolidine

IP = 8.8 eV

Enamine

IP = 7.2 eV

Et

SOMO-activated

N

N

O Me

Ph

N

N

O Me

Ph

Hypothesis - Enantioselectivity

• Density Functional Theory Model ofImidazolidinone Catalyst


N

N

O Me

Ph

Applications of SOMO-Organocatalysis

• α-Substitution of Aldehydes– Allylation − Enolation

– Oxyamination − Alkylation

– Vinylation

H

O

R R1

*

α-Allylation of Aldehydes

• General Reaction


CAN = Ceric Ammonium Nitrate

(NH4)2Ce(NO3)6

H

O

R

R1

SiMe3 NH

NO

Ph

CAN (2.5 equiv.)

NaHCO3, 24 hDME, -20 ˚C

H

O

R

R1

aldehyde2.5 equiv.allylsilane 20 mol% cat. 1 product

CF3COOH


H

O

81% yield, 91% ee

H

O

75% yield, 92% ee

H

O

O

72% yield, 87% ee

H

O

OBz

72% yield, 95% ee

H

O

75% yield, 94% ee

H

O

70% yield, 93% ee

NBoc

Organocatalytic Allylation:Scope of Aldehyde Substrate

H

O

R SiMe3 H

O

R20 mol%

CAN (2.5 eq.), -20 ˚C

NaHCO3, DME, 24 h

NH

NO

Ph

TFA

Organocatalytic Allylation:Scope of Allylsilane Substrate


H

O

C6H13

88% yield, 91% ee

H

O

C6H13

77% yield, 88% ee

Ph

H

O

C6H13

87% yield, 90% ee

H

O

C6H13

81% yield, 90% ee

Ph CO2Et

H

O

C6H13 SiMe3H

O

RR1

R1

20 mol%NH

NO

Ph

TFA

CAN (2.5 eq.), -20 ˚C

NaHCO3, DME, 24 h

α-Heteroarylation &Olefin Cyclization of Aldehydes


H

O

C6H13 N

Boc

H

O

NBoc 85% yield

84% ee

H

O 20 mol%

CAN (2.5 eq.), -10 ˚C

LiCl, THF, 24 h

85% yield

dr >8:1

95% ee

H

O

Cl

NH

NO

Ph

TFA

20 mol%

CAN (2.5 eq.), -20 ˚C

NaHCO3, DME, 24 h

NH

NO

Ph

TFA

+

Mechanistic Investigation


H

N

C6H13

OMe

Ph

2.5 equiv.

H

N

C6H13Ph

OMe

N

N

O

Bn t-Bu

O

Bn t-Bu

H

N

C6H13Ph

OMe

NO

Bn t-Bu

radical

cation

Mechanistic Investigation


H

O

C6H13

OMe

Ph

ONO2

65% yield

H

O

C6H13

Ph

OMe

ONO2

H

N

C6H13H

N

C6H13

OMe

Ph

Ph

OMe

N N

O O

Bn t-BuBn t-Bu

H

N

C6H13

Ph

OMe

NO

Bn t-Bu

not observed

H

N

C6H13Ph

OMe

NO

Bn t-Bu

radical

cation




– Vinylation

H

O

R R1

*

H

O

R

O

N

Sibi, M.P.; Hasegawa, M. J. Am. Chem. Soc., 2007, 129, 4124-4125

α-Oxyamination of Aldehydes

H

O

N

O

1. Catalyst,

Cp2FeBF4

2. NaBH4, rt4.0 eq.

H

OH

Ph Ph

O

Zn(OAc)2

H

OH

Ph

OH

enantioselective1,2-diol synthesis

N


Catalyst Optimization

Entry Catalyst mol % time, h

Isolated

Yield (%) ee (%)

1 none 24 79

2 1 100 1 61

3 2 100 1 63 76

4 2 20 1 78 64

5 3 20 1 87 80

6 4 20 1 71 -3

NH

CO2HNH

NH

N

O

Ph

NH

N

O

Ph

HOTf

HBF4

1 2

3 4

H

O

N

O

1. Catalyst, THF (1.0 M), rt

1.0 eq. Cp2FeBF4

2. 2.0 eq. NaBH4, rt

4.0 eq.

H

OH

Ph Ph

OTEMP

Scope of Aldehydes


Entry R Temp, ˚C time, h

Isolated

Yield (%) ee (%)

1 C6H5 r.t. 2 74 32

2 C6H5CH2 r.t. 2 80 71

3 -10 24 68 82

4 C6H5CH2CH2 r.t. 2 78 60

5 -10 24 64 84

6 4-MeO-C6H4CH2CH2 r.t. 2 77 81

7 -10 24 64 86

8 4-NO2-C6H4CH2CH2 r.t. 2 74 75

9 -10 24 75 82

10 (CH3)2CH r.t. 24 74 0

HR

O

N

O

1. 20 mol% 3, DMF (1.0 M)

0.1 eq. FeCl3, 0.3 eq. NaNO2

temp., time

2. 2.0 eq. NaBH4, rt

4.0 eq.

HR

OH

OTEMP

NH

N

O

PhHBF4

3



N

NO

PhN

NO

Si-faceopen


• α-Substitution of Aldehydes– Allylation − Vinylation


– Enolation

H

O

R R1

*

H

O

R

O

N

H

O

R

R1

O

*

α-Enolation of Aldehydes

Jang, H.Y.; Hong, J.B.; MacMillan, D.W.C. J. Am. Chem. Soc., 2007, 129, 7004-7005

Importance of Reaction:

H

O

R

OTMS

R1H

O

R

R1

O

!-substituted1,4-dicarbonyl

One step reaction to form umpolung polarity without going through anionic mechanism

Organocatalytic Enolation:Scope of Aldehyde Substrate


H

O

ROTMS

PhH

O

R

Ph

O

20 mol%

CAN (2 eq.), DTBP (2 eq.)

acetone, H2O, 24 h, -20˚C

NH

NO

Ph

TFA

H

O

hexyl

Ph 85% yield

90% eeO

H

O

Ph

O7

H

O

Ph

O

H

O

Ph

O

92% yield

92% ee

74% yield

93% ee

77% yield

91% ee

H

O

Ph

O

OBn

2

71% yield

90% ee

H

O

Ph

O

NBoc

84% yield

95% ee

Organocatalytic Enolation:Scope of Enolsilane Substrate


t-Bu

OTBS

H

O

hexyl

t-Bu

O

74% yield

96% ee

OTBS

t-BuH

O

hexyl O

55% yield

92% ee

Enolsilane Product Enolsilane Product

H

O

hexylOSiR3

R1 H

O

hexyl

R1

O

20 mol%

CAN (2 eq.), DTBP (2 eq.)

DME, H2O, 24 h, -20˚C

NH

NO

Ph

TFA

H

O

hexyl

77% yield

92% eeO

O

H

O

hexyl

77% yield

92% eeO

OTMS

O

OTMS


• α-Substitution of Aldehydes– Allylation − Vinylation


– Enolation

H

O

R R1

*

H

O

R

R1

O

*

H

O

R

R1

H

O

R

O

N

Kim, H.; MacMillan, D.W.C. J. Am. Chem. Soc., 2008, 130, 398-399

H

O

R H

O

R

R1

20 mol%NH

N

O

Ph

TFA

KF3BR1

enantioenriched!-vinyl aldehyde

aldehyde vinyl-BF3K

Organocatalytic α-Vinylation ofAldehydes

Importance of Reaction:

Form β,γ-unsaturated aldehydes without olefin transpostion

Organocatalytic Vinylation ofAldehydes

H

O

R H

O

R

R1

20 mol%NH

N

O

Ph

TFA

KF3BR1

enantioenriched!-vinyl aldehyde

aldehyde vinyl-BF3K

BF3K

R1

N

NO

R

N

N

O

Ph

R

KF3B

R1

- 1 e-N

N

O

Ph

R

KF3B

R1


Organocatalytic Vinylation:Scope of Aldehyde Substrate


H

O

RH

O

R

Ph20 mol%

CAN (2.5 eq.), -50 ˚C

NaHCO3, DME, H2O, 24 h

NH

NO

Ph

TFA

KF3BPh

H

O

Me

Ph 72% yield

94% eeH

O

Ph

4

H

O

Ph

H

O

Ph

78% yield

95% ee

82% yield

96% ee

79% yield

93% ee

H

O

Ph

OBn

2

78% yield

93% ee

H

O

Ph

NBoc

76% yield

96% ee

Et

Organocatalytic Vinylation:Scope of Vinyl Trifluoroborate Salt


H

O

hexylH

O

hexyl

R

R1

20 mol%

CAN (2.5 eq.), -50 ˚C

NaHCO3, DME, H2O, 24 h

NH

NO

Ph

TFA

KF3BR

R1

R1 = H, Me

H

O

hexyl Me

78% yield

95% eeH

O

hexyl

81% yield

94% ee

H

O

hexyl

77% yield

95% ee

Cl

H

O

hexyl

61% yield

95% ee

OMe

H

O

hexyl

82% yield

89% ee6

H

O

hexyl

84% yield

90% ee




– Vinylation

H

O

R R1

*

H

O

R

R1

O

*

H

O

R

R1

H

O

R

O

N

H

O

R

R1

R2

O

**

α-Alkylation of Aldehydes

Nicewicz, D.A.; MacMillan, D.W.C. Science, 2008, 322, 77-80

H

O

RR2

O

Br

R1

H

O

R

R2

O

R1

aldehyderacemic

!-bromocarbonyl

enantioenriched!-alkylated

"-ketoaldehyde

NH

N

MeO

MeMe

Me

Me

TfOH

Ru2+

N

N

N N

N N

Photoredox CatalystOrganocatalyst

Organocatalysis

Photoredox Catalysis

Catalytic Cycles


N

N

R

t-Bu

O

NH

N

t-Bu

O

H

O

R

catalyst 6aldehyde 7

8Organocatalytic

Cycle

N

N

R

OH3C

Si-faceopen5

R1

ON

N

t-Bu

O

R

R1

9

Ru(bpy)3+ (3)

reductant

*Ru(bpy)32+ (2)

oxidant

Ru(bpy)32+

photoredox catalyst 1

PhotoredoxCatalyticCycle

SET

Br!

R1(O)C Br

4

photon source

5

R1

O

SET

N

N

R

t-Bu

O

R1

10

H R1

O

R

11

Organocatalytic Alkylation:Scope of Aldehyde Substrate


H

O

hexyl

93% yield

90% eeH CO2Et

O

4

H CO2Et

O

H CO2Et

O

86% yield

90% ee

83% yield

95% ee

92% yield

90% ee

H CO2Et

O

63% yield

93% ee

H CO2Et

O

NBoc

66% yield

91% ee

Et

CO2Et

CO2Et

CO2Et

CO2Et

CO2Et

CO2Et

CO2Et

H

O

R

EtO

O

Br

O

OEt

NH

NMeO

MeMe

MeMe

TFA20 mol%

H

O

R

CO2Et

CO2Et

0.5 mol% Ru(bpy)3Cl2 2.0 eq 2,6-lutidine, DMFfluorescent light, 23 ˚C2.0 eq.

Organocatalytic Alkylation:Scope of α-Bromocarbonyl Substrate


H

O

Hex

R

Br

O

R1

NH

NMeO

MeMe

MeMe

TFA20 mol%

0.5 mol% Ru(bpy)3Cl2 2.0 eq 2,6-lutidine, DMFfluorescent light, 23 ˚C

H

O

Hex

R

R1

O

2.0 eq.

H

O

Hex O

80% yield

92% ee

H

O

Hex

84% yield

96% ee

H

O

Hex

84% yield

95% ee

NO2

H

O

Hex

87% yield

96% ee

OMe

H

O

Hex

CO2Et 80% yield

88% ee

O

Hex

70% yield

5:1 dr, 99% ee

O

O

O

CH2CF3 CO2Et

t-BuO2C

OO

To Sum Up…

• Asymmetric control is difficult in radicalsynthesis– Fast reactivity– “Planar” structure

• Methods that have been used to controlasymmetry– Chiral Auxiliary– Chiral Acid Chelation– Organocatalysis

Acknowledgements

• Dr. Jetze Tepe• Dr. Babak Borhan• Group Membes: Brandon, Chris, Daljinder,

Jason, Mike, Rahman, Samantha, Thu,Amanda

• Arvind, Camille, Carmin

chemistry - applications of radical reactions in asymmetric … · 2008-11-26 · an introduction...

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