gm 11-14-05 - atropisomerism · atropisomerism axial chirality in nature and synthesis kevin allan...

AtropisomerismAxial Chirality in Nature and Synthesis

Kevin AllanStoltz Group Literature Meeting

Monday 11/14/20058 pm

147 Noyes

R

RMLn

*

R

R

O

O

OH

MeO

MeO

OH

OMe

OMe

OH

OH

O

O

OH OH

Me

OH

Me

O

MeO

MeO

*

*

*

*

O

OAl

OEt

HLi

N

NH

Me

OMe

OMe

Me

O

O

Nu

X

X

Y

Y

X

X

Y

Y

OO

Nu

Outline

I. Introduction

a. History and Background b. Conditions for Axial Chirality

II. Direct Atroposelective Aryl-Aryl Coupling

a. Diastereoselective Coupling b. Enantioselective Coupling

III. Resolution/Desymmetrization of Prostereogenic Biaryls

a. Configurationally Stable, Axially Achiral b. Configurationally Unstable, Axially Chiral i. Atropodiastereoselective Bridge Formation ii. Atroposelective Bridge Cleavage / The "Lactone Method"

IV. Atroposelective Construction of an Aromatic Ring

For a general review of biaryls in synthesis: Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. I. E. 2005, 44, 5384-5427.

Biaryl cross-coupling: Stanforth, S. P. Tetrahedron. 1998, 54, 263-303. Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145-157. Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128.

Lactone Methodology: Bringmann, G.; Breuning, M.; Tasler, S. Synthesis, 1999, 4, 525-558. Bringmann, G.; Tasler, S.; Pfeifer, R.-M.; Breuning, M. J. Organomet. Chem. 2002, 661, 49-65.

Matthias BreuningUniversitat Wurzburg

Gerhard BringmannUniversitat Wurzburg

Motokazu Uemura (right) andKen Kamikawa (left)

Osaka Prefecture University

Albert I. MeyersColorado State University

Atropisomerism is Everywhere

OHO

OH

HO OH

O

CH3(CH2)10

OH

Myristinin BMyristica cinnamomea

COX 2 inhibitor

HN

NH

OH OMe

MeO OH

HO

OH

OH

OH

Michellamine BAncistrocladus korupensis

Protein kinase C inhibitor, anti-HIV-1,2

O

O

O

NH

HN

O

O

O

HOHO

OH

O

OHHO

OH

Cl

Cl

OMe

NH2HO

Me

HN

O

HO2C

HO

NH

O HN

O

NH

OHO

Me

Me

NHMe

H

H2N

O

P

VancomycinAmycolatopsis orientalis

Antibiotic (Gram-positive)

P

M

Me

HO Me

HN

Atropisomerism is Everywhere

N N

Ph

O

Ph

O

Ru

Cl

NO

catalyzes asymmetric homo-couplingof 2-naphthols

Katsuki, T. Synlett, 2000, 1433-1436.

P P

N

N

HO

HOO

O

R

R

catalyzes enantioselectiveallylation of aldehydes

Hayashi, T. J. Org. Chem. 2003, 68, 6329-6337.

Me

Me

Me

Ph2P

M

P

catalyzes enantioselectivehydrosilations

Bringmann, G. Tetrahedron: Asymm. 1999, 10, 3025-3031.

Me

HO Me

HN

Me

OH

OH

HN

MMM

catalyzes enantioselectivealkylation of aldehydes

Bringmann, G. J. Org. Chem. 2003, 68, 6859-6863.

AtropisomerismHistory & Background

Atropisomerism: a term coined by Richard Kuhn in 1933, it refers to stereoisomerism resulting from hindered rotation around a single bond such that the isolation of individual conformers is possible.

From Greek: a - not tropos - to turn

• The first atropisomer was reported in 1922 by G. H. Christie and J. Kenner. A single enantiomer of 6,6'-dinitro-2,2'-diphenic acid was isolated from the racemic mixture via diastereoselective crystallization with a chiral resolving agent:

NO2HO2C

CO2HO2N

Kuhn, R. "Molekulare Asymmetrie" in Stereochemie. Freudenberg, K. ed. Franz-Deutike: Leipzig-Wien, 1933, p. 803.Christie, G. H.; Kenner, J. J. Chem. Soc. 1922, 121, 614-620.

AtropisomerismConditions for Axial Chirality

The Rules:

• A generally accepted--though arbitrary--rule states atropisomers are considered physically separable when they have a

half-life at room temperature of >1000 s (16.7 min).

• !G200 K = 61.6 kJ mol-1

• !G300 K = 93.5 kJ mol-1

• Steric hindrance at the ortho positions (and to a lesser extent, electron donating/withdrawing character of each of the

substituents around each aryl ring) determines the ability of a biaryl system to display atropisomeric behavior.

• When referring to axial (helical) chirality, S and R notation become P (plus) and M (minus), respectively.

• Hierarchy of functionality is identical to the determination of central (sp3 ) chirality (highest atomic number, etc.).

• Hierarchy of aryl substitution is as follows: endocyclic ortho --> ortho --> meta --> para

HO OH

HO

OH

S = P

OH

OH

R = M

(P )-2,2'-dihydroxybiphenyl (M )-2,2'-dihydroxybiphenyl

HO OH

OHHO

HO OH

OH

OH

pro-P pro-M OHHO

HO OH

1

23

4

5 6

1'

2' 3'

4'

5'6'

OHHO

1

2 3

4

56

1'

2'3'

4'

5' 6'

Bringmann, G. Angew. Chem. I. E. 2005, 44, 5384-5427.

Direct Atroposelective Aryl-Aryl CouplingDiastereoselective Coupling

XX

*

Chiral Tether Influences Configuration During Intramolecular Coupling

* *

MLn

Ortho Chiral Auxiliary Influences Configuration During Intermolecular

Coupling

Planar Chiral Element Influences Configuration During Intermolecular

Coupling

X

Y*

X

+

*

MLn

Y*

LnM'

X

X

+

MLn

*

LnM'

Central-to-axial transfer of chirality Central-to-axial transfer of chirality Planar-to-axial transfer of chirality

Diastereoselective Aryl-Aryl CouplingIntramolecular Coupling with Chiral Tethers - Toward Desertorin A-C

TBSO

TBSOOBn

OBn 3 steps

R

R O

O

OBn

OBn

Br

Me OMe

Br

MeO Me

S

S

Lipshutz, B. H.; Kayser, F.; Lui, Z.-P. Angew. Chem., I. E. Engl. 1994, 33, 1842-1844.Kyasnoor, R. V.; Sargent, M. V. Chem. Commun. 1998, 2713-2714.


TBSO

TBSOOBn

OBn 3 steps

R

R O

O

OBn

OBn

Br

Me OMe

Br

MeO Me

S

S

1. BuLi, -78 °C

2. CuCN, TMEDA-78 to -40 °C3. O2, -78 °C40% over 3 steps

O

O

P

OMe

Me

MeO

Me OBn

OBn

single diastereomer

O

O

O

O

OMeMe

RO

Me OR

MeO

Desertorin A-C



TBSO

TBSOOBn

OBn 3 steps

R

R O

O

OBn

OBn

Br

Me OMe

Br

MeO Me

S

S

1. BuLi, -78 °C

2. CuCN, TMEDA-78 to -40 °C3. O2, -78 °C40% over 3 steps

O

O

P

OMe

Me

MeO

Me OBn

OBn

H

O CH2OBn

H

CH2OBnO

Me

MeO

OBn substituents prefer gauche conformation as opposed to axial anti-coplanar

single diastereomer

O

O

O

O

OMeMe

RO

Me OR

MeO

Desertorin A-C


Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Asymmetric Suzuki Coupling

Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5(18), 3281-3284.

I

OMe

O I O

S

O

pTol

SpTolMe

LDA, THF80%

DIBAL

ZnCl2, THF74% I OH

S

O

pTolR1 R1 R1

O


Broutin, P.-E.; Colobert, F. Org. Lett. 2003, 5(18), 3281-3284.

I

OMe

O I O

S

O

pTol

B(OH)2

R2

R2

SpTolMe

LDA, THF80%

DIBAL

ZnCl2, THF74% I OH

S

O

pTol

I OH

S

O

pTol

+S

OH

R1

R1

O

pTolPd(OAc)2, dppf

CsF, dioxane70 °C

R1 R2 Yield (%) dr*

Me Me 60 70:30

Me OMe 27 90:10

OMe OMe 61 93:7

*determined by 1H NMR

(absolute configuration unknown)

R1 R1 R1

Entry

1

2

3

O

*


I

OMe

O I O

S

O

pTolLDA, THF

80%

DIBAL

ZnCl2, THF74% I OH

S

O

pTolR1 R1 R1

NaH, MeIDMF, -20 °C

99%

I OMe

S

O

pTolR1

SpTolMe

O

Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128.


I

OMe

O I O

S

O

pTolLDA, THF

80%

DIBAL

ZnCl2, THF74% I OH

S

O

pTolR1 R1 R1

NaH, MeIDMF, -20 °C

99%

I OMe

S

O

pTolR1

B(OR3)2

R2

+

Pd(OAc)2dppf or PPh3CsF, dioxane

70 °C

R2

S

OMe

R1

O

pTol

*

R4

R5

R1 R2 Yield (%) dr*

78 75:25

89 80:20

86 90:10

Entry

1

2

3

R3 R4 R5

4

5

6

7

8

Me Me CH2 H H

Me OMe CH2 H H

OMe Me CH2 H H

OMe OMe H H H 80 85:15

H Me H 99 >99:1

H OMe H 99 >99:1

Me H CH2 88 90:10

OMe H CH2 95:586

*determined by 1H NMR (absolute configuration unknown)

SpTolMe

O

Broutin, P.-E.; Colobert, F. Eur. J. Org. Chem. 2005, 1113-1128.

R4

R5

R Yield (%) dr (P :M )

90 20:80

75 40:60

80 42:58

79 90:10

73 93:7

CH2OMe

CH2OBn

Me

CH2OTBS

O

O

Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron, 2004, 60, 4459-4473.

Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Aryl Grignard Coupling

O

N

MeO

Br

R

OMe

MeO

i-Pr+

Mg

THF, !

OMe

MeO

R

O

N

i-Pr

P

Grignard additions require EWG at ortho or para position to stabilize developing negative charge.

Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Aryl Grignard Coupling

O

N

MeO

Br

R

OMe

MeO

i-Pr+

Mg

THF, !

OMe

MeO

R

O

N

i-Pr

P

Grignard additions require EWG at ortho or para position to stabilize developing negative charge.

O

NMeOMeO Mg

Br

OMeR

i-PrO

NMeOMeO Mg

Br

i-Pr

OMeR

O

N

MeOMeO

Mgi-Pr

R OMe

Br

O

N

MeOMeO

Mgi-Pr

MeO R

Br

180° rotation

Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron, 2004, 60, 4459-4473.

Diastereoselective Aryl-Aryl CouplingOrtho Chiral Auxiliaries - Ullmann Homocoupling

Cu

DMF, 150 °C40 h

O

NBr

MeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

P

58%93:7 dr

Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061-3062.Nelson, T. D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259-3262.


Cu

DMF, 150 °C1 h

O

NBr

MeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

P

56%62:38 dr


O

NMeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

P Cu

O

NMeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

M Cu!

O

N

O

N

Cu

H

i-Pr

i-Pr

H

O

N

O

N

Cu

i-Pr

H

H

i-Pr

M P

Non-selective couplingthen

thermodynamic deracemization


Cu

DMF, 150 °C40 h

O

NBr

MeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

O

NMeO

i-Pr

MeO

OMe

P


Diastereoselective Aryl-Aryl CouplingPlanar Arene-Metal Complexes - Asymmetric Suzuki Coupling

B(OH)2

Br

R1

R2 OMe

+Pd(PPh3)4, Na2CO3

MeOH/H2O

R1

R2 OMe

Cr(CO)3

Cr(CO)3

R1

MeO R2

(CO)3Cr

+

syn anti

P M

Kamikawa, K.; Watanabe, T.; Uemura, M. J. Org. Chem. 1996, 61, 1375-1384.

major minor


B(OH)2

Br

R1

R2 OMe

+Pd(PPh3)4, Na2CO3

MeOH/H2O

R1

R2 OMe

Cr(CO)3

Cr(CO)3

R1

MeO R2

(CO)3Cr

+

syn anti

!

toluene or xylenes

P M



B(OH)2

Br

R1

R2 OMe

+Pd(PPh3)4, Na2CO3

MeOH/H2O

R1

R2 OMe

Cr(CO)3

Cr(CO)3

R1

MeO R2

(CO)3Cr

+

syn anti

!

toluene or xylenes

P M

Entry R1 R2 Yield (%) dr (P :M )

1

2

3

4

5

6

7

Me Me 96 100:0

Me CH2OH 77 100:0

OMe Me 94 97:3

CHO Me 95 0:100

CHO CHO 43 0:100

OMe CHO 85 4:96

Me CHO 82 100:0



B(OH)2

Br

R1

R2 OMe

+Pd(PPh3)4, Na2CO3

MeOH/H2O

R1

R2 OMe

Cr(CO)3

Cr(CO)3

R1

MeO R2

(CO)3Cr

+

syn anti

!

toluene or xylenes

P M


1

2

3

4

5

6

7

Me Me 96 100:0

Me CH2OH 77 100:0

OMe Me 94 97:3

CHO Me 95 0:100

CHO CHO 43 0:100

OMe CHO 85 4:96

Me CHO 82 100:0

o-carbonyl substituents may result in chemical atropisomerization to the more thermodynamically stable (anti ) product.



B(OH)2

Br

R1

R2 OMe

+Pd(PPh3)4, Na2CO3

MeOH/H2O

R1

R2 OMe

Cr(CO)3

Cr(CO)3

R1

MeO R2

(CO)3Cr

+

syn anti

P M


1

2

3

4

5

6

7

Me Me 96 100:0

Me CH2OH 77 100:0

OMe Me 94 97:3

CHO Me 95 0:100

CHO CHO 43 0:100

OMe CHO 85 4:96

Me CHO 82 100:0


h!, O2

R1

R2 OMe

R1

MeO R2+P M

RS

OMe


Kamikawa, K.; Uemura, M. Synlett 2000, 7, 938-949.

H

R

OMe

RS

Cr(CO)3

Pd

Ph3P PPh3

R

H

OMe

RS

Cr(CO)3

Pd

Ph3P PPh3

Pd

H

R

PPh3

PPh3(CO)3Cr

RS

OMe

Pd

R

H

PPh3

PPh3(CO)3Crrotation to form the biaryl axis during reductive elimination occurs so as to minimize steric interactions with the bulky PPh3 ligands.

R

H

OMe

RS

(CO)3Cr

P

H

R

OMe

RS

(CO)3Cr

M


Kamikawa, K.; Uemura, M. Synlett 2000, 7, 938-949.


1

2

3

4

5

6

7

OMe Me 88 100:0

OMe CHO 89 100:0

OMe 86 100:0

OMe Me 85 100:0

Me H 70 85:15

OMe H 71 71:29

Me H 78 97:3

R3

B(OH)2

Br

R3

R2 R1

+Pd(PPh3)4, Na2CO3

MeOH/H2O R2 R1

Cr(CO)3

Cr(CO)3

R1 R2

(CO)3Cr

+

syn anti

P M

R3 R3

H

H

CH2OH H

O

O

Me

Me

OMe

Direct Atroposelective Aryl-Aryl CouplingEnantioselective Coupling

Chiral Leaving Group Influences Configuration During Intermolecular

Coupling

*

MLn

Central-to-axial transfer of chirality

X*

Y

+

X

Y

+

*

MLn*

Central-to-axial transfer of chirality

Redox-Neutral:• Kumada• Suzuki• Aryl-Lead Species

Oxidative:• Copper• Vanadium

Chiral Metal Complex Influences Configuration During Intermolecular Coupling

Enantioselective Aryl-Aryl CouplingChiral Leaving Groups

R*O

O

N

Wilson, J. A.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 881-884.Wilson, J. A.; Cram, D. J. J. Org. Chem. 1984, 49, 4930-4943.

O

NBr

R*ONa

DMF, 50 °C


R*O

O

N

+


THF, -20 °C

1-10 h

O

NBr

R*ONa

DMF, 50 °C

Li

OMe

N

O

OMe

M


R*O

O

N

+


THF, -20 °C

1-10 h

O

NBr

R*ONa

DMF, 50 °C

Li

OMe

N

O

OMe

M

R* =O

O

O

N

O

MeO

N

H

N

HH

N

MeO

O

quinidinyl

quininyl

!-fenchyl

(R )-menthylbornyl


R*O

O

N

+


THF, -20 °C

1-10 h

O

NBr

R*ONa

DMF, 50 °C

Li

OMe

N

O

OMe

M

R* =O

O

O

N

O

MeO

N

H

N

HH

N

MeO

O

quinidinyl22% yield-84% ee

quininyl20% yield

87% ee

!-fenchyl88% yield

77% ee

(R )-menthyl68% yield>95% ee

bornyl67% yield

8% ee

Enantioselective Aryl-Aryl CouplingChiral Leaving Groups - Menthol


CO2R

O

MgBr MgBr

OMe

THF, -20 °CPhH, 80 °C

CO2R CO2R

% Yield % ee R % Yield % ee

95 80 i-Pr 92 97

93 76 (R )-menthyl 81 98

74 91 (R )-phenylethyl 85 91

P MOMe

Enantioselective Aryl-Aryl CouplingChiral Leaving Groups - Menthol


OO

OR

RLRM

H

Mg

Br

R

OO

OR

Mg

Br

R

RMRLH

OMe

O

RMRLH

O

ORMg

Br O

RMRLH

O

ORMg

Br

chelationcontrol

non-chelationcontrol

CO2RP

CO2RM

naphO

H

i-Pr

RM

RL

OMe

Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Copper

• Copper-amine complexes are the most widely investigated due to the ease of ligand screening.

H2N NH2

Ph Ph

H2N NH2NH

NEt

Ph NH

HN R1

R2

N N

N

N

R1

R2

OH

CO2Me CuI (2-10 mol%)diamine L* (2-10 mol%)

O2, CH2Cl248 h

OH

CO2Me

OH

CO2Me

M

Li, X.; Yang, J.; Kozlowski, M. Org. Lett. 2001, 3(8), 1137-1140.

Ligand Screen



H2N NH2

Ph Ph

H2N NH2NH

NEt

Ph NH

HN R1

R2

N N

N

N

R1

R2

OH


O2, CH2Cl248 h

OH

CO2Me

OH

CO2Me

M


Ligand Screen



N

N

R1

R2

OH


O2, CH2Cl248 h

OH

CO2Me

OH

CO2Me

M


Ligand Screen

R1 = R2 = H

R1 = H, R2 = Me

R1 = R2 = Me

R1 = R2 = Bn

R1 = R2 = CH2CF3

60 91

53 79

43 3

72 22

% Yield % ee

NR



OH


O2, CH2Cl248 h

OH

CO2Me

OH

CO2Me

M

Li, X.; Yang, J.; Hewgley, B.; Mulrooney, C. A.; Yang, J.; Kozlowski, M. J. Org. Chem. 2003, 68, 5500-5511.

N

N

CuII

H

H

O

MeOO

N

N

CuI

H

H

O

MeOO

H

N

N

CuI

H

H

O

MeO O

H

CO2Me

OHN

N

CuII

H

H

HO

blocked

open

H2O O2

cat-Sub

cat

cat

rotation of aromatic ring away from ligand and tautomerization to binol

Enantioselective Aryl-Aryl CouplingOxidative Homocoupling - Vanadium

R1

R2 OH

R3

OH

R3

OH

R3R1

R2

R2

R1

VO(acac)2, O2

CH2Cl2

Hwang, D.-R.; Chen, C.-P.; Uang, B.-J. Chem. Commun. 1999, 1207-1208.Chu, C.-Y.; Hwang, D.-R.; Wang, S.-K.; Uang, B.-J. Chem. Commun. 2001, 980-981.Chu, C.-Y.; Uang, B.-J. Tetrahedron: Asymm. 2003, 14, 53-55.

Entry R1 R2 R3 % Yield

1

2

3

H H H 92

Br H H 90

H OMe H 76

4 H H CO2Me 35

Mechanism unknown


R1

R2 OH

R3

OH

R3

OH

R3R1

R2

R2

R1

catalyst, O2

TMSCl or TMSOTfCH2Cl2

Hwang, D.-R.; Chen, C.-P.; Uang, B.-J. Chem. Commun. 1999, 1207-1208.Chu, C.-Y.; Hwang, D.-R.; Wang, S.-K.; Uang, B.-J. Chem. Commun. 2001, 980-981.Chu, C.-Y.; Uang, B.-J. Tetrahedron: Asymm. 2003, 14, 53-55.

O

V

N O

OBn

O

Me

H

catalyst


1

2

3

H H H 82

Br H H 91

H OMe H 50

4 H H CO2Me trace

% ee

51

51

51

---

M

Mechanism unknown


R1

R2 OH

R3

catalyst, O2

TMSCl or TMSOTfCH2Cl2

Luo, Z.; Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y. Angew. Chem. I. E. 2002, 41(23), 4532-4535.

catalyst


1

2

3

H H H 62

Br H H 98

H OMe H 95

4

% ee

90

90

95

N

O

O

N

O

O

O

O

V

V

O

O

O

i-Bu

i-Bu

H OEt H 99 96

5 H On-Bu H 99 94

6 H OBn H 80 95

7 H H OBn trace ---

OH

R3

OH

R3R1

R2

R2

R1

M

Mechanism unknown

Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Kumada Cross-Coupling

R2

MgBr

Br

R1

+R1

R2P

FePh2PR3

Me

4-10 mol%

NiBr2 (2-5 mol %)Et2O/toluene

< -15 °C

Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156.

Entry R1 R2 R3 % Yield % ee

1

2

3

4

5

Me Me OMe 69 95

Me H OMe 25 16

H Me OMe 92 83

H Me OEt 82 68

H Me H 81 1

Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Kumada Cross-Coupling

R2

MgBr

Br

R1

+R1

R2P

FePh2PR3

Me

4-10 mol%

NiBr2 (2-5 mol %)Et2O/toluene

< -15 °C

Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153-8156.


1

2

3

4

5

Me Me OMe 69 95

Me H OMe 25 16

H Me OMe 92 83

H Me OEt 82 68

H Me H 81 1

MeOP

Mg

Me Br

R2

Fe

Ph

Ph

Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Suzuki Cross-Coupling

• Suzuki cross-coupling is a convenient, versatile method for the formation of atropisomeric biaryls with a wide range of functionality due to the mild nature of boronic acids/esters as nucleophilic arene species.

Me

B(OR2)2

I

R1

+R2

P6 mol%

PdCl2 (3 mol%)Ba(OH)2

DME/H2O, reflux

Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723-1724.

R1

FePh2PR3

Me


1

2

3*

OMe 74 14

H NMe2 44 63

Me NMe2 50 85

H

H

H

CH2

* used DME as solvent, CsF as additive, 6 days.


Me

B(OR2)2

I

R1

+R2

P6 mol%

PdCl2 (3 mol%)Ba(OH)2

DME/H2O, reflux

Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000, 1723-1724.

R1

FePh2PR3

Me

Entry R1 R2 % Yield % ee*

1

2

3

98 87 (+)

Et 96 92 (+)

OEt 89 85 (+)

OEt

OEt

Me

i-Pr


R2

B(OH)2

Br

P

+R2Pd2(dba)3 (0.5-2 mol%)

K3PO4

toluene, 60-80 °C

Buchwald, S. L.; Yin, J. J. Am. Chem. Soc. 2000, 122, 12051-12052.

P

O

(OR1)2

*

PCy2

NMe2

0.8-3.3 mol%

4

5

OEt Ph 74 74 (+)

OMe Me 91 84 (+)

* absolute configuration undetermined.

O

(OR1)2

Enantioselective Aryl-Aryl CouplingRedox-Neutral Coupling - Aryl-Lead Triacetate

Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 8943-8944.Kano, T.; Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 5365-5373.

OH

R

Pb(OAc)3

R'+pyr (xs)

OH

R

R'

+ Pb(OAc)2



OH

R

Pb(OAc)3

R'+pyr (xs)

OH

R

R'

O

R

Pb

R'

NAcO

AcO

+ Pb(OAc)2



OLi

R

Pb(OAc)3

R'+brucine (6 equiv)

toluene, -40 °C

OH

R

R'

+ Pb(OAc)2

Entry Phenol Aryl-Lead Product% Yield

(dl:meso ) % ee

1

2

3

4

5

OH

OH

OH

MeO OMe

OH

Ph

Pb(OAc)3

Pb(OAc)3

Pb(OAc)3

Ph

i-Pr

Pb(OAc)3

Pb(OAc)3

Ph Ph

OH

OH

MeO OMePh Ph

OH

OH OH

Ph

OH

68(>99:1)

83

>99(2:1)

51

55(6.9:1)

93

99 85

99 20

N

MeO

MeO

N

O

H

H

H

H

H

O

brucine



OLi Pb(OAc)3

+brucine (6 equiv)

toluene, -40 °C

Pb OO

OO

O

Ph

OLiO

Ph

axial attack

brucine- AcOLi

pseudo-rotation PbO

Ph

L

L L

LL

-or-

L = brucine or AcO

O

Ph H

O

Ph

H

OH

Ph

R S

M fast

Pb O

Ph

L

LL

LL

Resolution/Desymmetrization of Prostereogenic Biaryls

Configurationally Stable, Axially Achiral

Introduction/Transformation of ArylSubstituent

(Desymmetrization)

Introduction of Chiral Bridge

(Resolution)

Atroposelective Cleavage of a Bridge(The Lactone Method)

(Resolution)

Configurationally Unstable, Axially Chiral

X X

Y

Z

CS-symmetric

Z X

Y

*

X

Y

A

A

X

Y

*

**

macroscopically achiral

X

Y

Nuc*H

X

Y

Nuc*

H

macroscopically achiral

*

• Biaryl axis formed non-selectively prior to introduction of axial chirality.

Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction/Transformation of an Ortho Substituent

• Very little investigation into this method.• Usually no rationalization of stereochemistry.• Most systems lack broad applicability due to substrate requirements or have low functional group tolerance.

Me Me

MeMe

N N

(-)-sparteine1. n-BuLi,

2. CO2

Me

Me

CO2H

HO2C

Engelhardt, L. M.; Leung, W.-P.; Raston, C. L.; Salem, G.; Twiss, P.; White, A. H. J. Chem. Soc. Dalton Trans. 1988, 2403-2409.

70% yield40% ee

P

Pd

N Cl

Cl

Me Me

Ph Ph

Me

PdCl2[(S )-alaphos]

Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction/Transformation of an Ortho Substituent

• Very little investigation into this method.• Usually no rationalization of stereochemistry.• Most systems lack broad applicability due to substrate requirements or have low functional group tolerance.

R1

R2

TfO OTf

R3MgBr

LiBr or LiI

R1

R2

R3 OTfM

Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am. Chem. Soc. 1995, 117, 9101-9102.Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455-3466.

Entry R1 R2 Yield (%) % ee

1

2

3

4

5

6

R3

H Me

H Me

H Ph

H Ph

Ph 85 95

87 85

Ph 80 94

88 99

Ph 92 94

88 92

Ph3Si

Ph3Si

Ph3Si

Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction of a Chiral Bridge

XO

O

RO

H2NOH

Ph

toluene, reflux

X

N

O

OMe

PhX

N

O

OMe

Ph

+

major minor

Penhoat, M.; Levachet, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520.

X = CH2: 95%, >95% deX = N: 72%, >95% de

Resolution/Desymmetrization of Prostereogenic BiarylsIntroduction of a Chiral Bridge

XO

O

RO

H2NOH

Ph

toluene, reflux

X

N

O

OMe

PhX

N

O

OMe

Ph

+

major minor

O

HN Me

Ph

X

Ph rings oriented trans,axis rotates away fromoxazolidine Ph. O

N Me

Ph

X

Ph rings oriented cis,axis rotates away frombenzylic Me.

OOR

ORO H

XO

RO

XO

ROO

HN

O

HN

Ph

Ph

Me

Me

+

Penhoat, M.; Levachet, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517-9520.

Resolution/Desymmetrization of Prostereogenic BiarylsAtroposelective Cleavage of a Bridge - The Lactone Method

O O

O O

Br

O

O

R

R

R

R

R

R

catalyst

NaOAcDMA

130 °C

catalyst A: Pd(OAc)2 (10 mol%) PPh3 (20 mol%)

catalyst B: (1 mol%)O

Pd

O O

Pd

O

Me

Me

P

PAr2

Ar2

Entry R A B

1

2

4

5

6

3

H 80 91

Me 75 87

Et 71 83

i-Pr 72 82

t-Bu 44 81

OMe 77 90

Coupling Yields

M P

Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J. Org. Synth. 2002, 79, 72-83.


O O

O O

R

R

R

R

M P

OB

N

PhPh

H

Me

, BH3, THF, 30 °C

O

Al

O

OEt

HP

Li

KHN

Me MeNaO

Sp-Tol

OLi

RHO

R

OH

RHO

R

HN

O Me

S

MeHO

Me

O

O Me

OH

S

O

p-Tol

O

Me

Me

R = OMe: 70%, 82% deR = Me: 85%, 90% de

73%, 0% dechemically atropisomerizes

R = OMe: 97%, 76% deR = Me: 95%, 86% de

R = OMe: 94%, 95% deR = Me: 97%, 94% de

R = OMe: 88%, 91% deR = Me: 78%, 94% de

Bringmann, G. Org. Synth. 2002, 79, 72-83.Bringmann, G. Angew. Chem. I. E. Engl. 1992, 31, 761-762.Bringmann, G. Synthesis 1999, 525-558.Bringmann, G. Eur. J. Org. Chem. 1999, 3047-3055.Bringmann, G. Chem. Eur. J. 1999, 5, 3029-3038.


Bringmann, G. Synthesis 1999, 4, 525-558.

O

O

R

R

OH

RHO

R

, BH3, THF, 30 °C

R = OMe: 88%, 91% deR = Me: 78%, 94% de

OB

N

PhPh

Me

H

M



O

O

R

R

OH

RHO

R

, BH3, THF, 30 °C

R = OMe: 88%, 91% deR = Me: 78%, 94% de

OB

N

PhPh

Me

H

M

NB

O Me

B

O

O

R

R

H

H

H

Ph

Ph

Re


O

O

O

O


eq

ax

ax

eq

R

R

R

R

H

H

H

H


O

O

O

O


eq

ax

ax

eq

R

R

R

R

H

H

H

H


O

O

O

O


O

H

O

OO

H

eq

ax

ax

eq

R

R

R

R R

R

R

R

Re face

attack

Si face

attack

H

H

H

H


O

O

O

O


O

H

O

OO

H

eq

ax

ax

eq

H

O

O

R

R

R

R

R

R R

R

R

R

Re face

attack

Si face

attack

OH

O

R

R

RHO

R

H

O

major

OHR

R

H

O

minor

H+

H+

H

H

H

H


O

O

O

O


O

H

O

OO

H

eq

ax

ax

eq

H

O

O

R

R

R

R

R

R R

R

R

R

Re face

attack

Si face

attack

OH

O

R

R

O

O

H

R

R

OH

O

R

R

RHO

R

H

O

major

OHR

R

H

O

minor

H+

H+

stereochemicalleakage

stereochemicalleakage

rate?

rate?

H

H

H

H


O

O

O

O


OO

H

eq

ax

ax

eq

H

O

O

R

R

R

R R

R

R

R

Re face

attack

RHO

R

H

O

major

H+

H

H

H

H

For optimal selectivity:• use a reactive nucleophile in cases involving an intermediate ketone or aldehyde, in order to avoid "stereochemical leakage"• use bulkier chiral nucleophiles for better facial selectivity.• optimal reactivity/selectivity with Me-CBS and catechol borane.

RHO

R

OH

major

[H]

OB

N

PhPh

H

Me

O

B

O

H

• Newest and least developed method for the formation of atropisomeric biaryls.• Most intermediates/transition states unknown.

Transfer of Chirality from Benzylic

sp3 Center to Biaryl Axis[2+2+2] Cycloaddition with Chiral Metal Complexes

*

*

M

*

Atroposelective Construction of an Aromatic Ring

Me

Cl

Cl

OH

Nishii, Y.; Yoshida, T.; Tanabe, Y. Tetrahedron Lett. 1997, 38(41), 7195-7198.Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358-5359.

Me

Cl

Me

Cl

Cl

OH

TiCl4

CH2Cl2, -78 °C

TBSOTf

CH2Cl2, 0 °C

Atroposelective Construction of an Aromatic RingCentral-to-Axial Transfer of Chirality - Diaryl-2,2-dichlorocyclopropylmethanols

Me

Cl

Cl

OH


Me

Cl

Me

Cl

Cl

OH

TiCl4

CH2Cl2, -78 °C

TBSOTf

CH2Cl2, 0 °C


R1 R2 R2R1 R1

Entry % YieldR1 R2 % ee

1

2

3

4

5

Cl H 97 >99

Cl Cl 70 >99

OMe Me 71 >99

OMe Cl 65 >99

Me Cl 47 >99

Entry % YieldR1 R2 % ee

1

R2

Me H 41 45

Me

Cl

Cl

OH


Me

Cl

Me

Cl

Cl

OH

TiCl4

CH2Cl2, -78 °C

TBSOTf

CH2Cl2, 0 °C


R1 R2 R2R1 R1 R2

Me

Cl

Cl

OHR1 R2

TiCl4 Me

Cl

Cl

OHR1 R2

SiR3

OTf

R1 rotates away from

chelated TiCl4


chelated TBSOTf

Me

Cl

Cl

OH


Me

Cl

Me

Cl

Cl

OH

TiCl4

CH2Cl2, -78 °C

TBSOTf

CH2Cl2, 0 °C


R1 R2 R2R1 R1 R2

Me

Cl

Cl

OHR1 R2

TiCl4 Me

Cl

Cl

OHR1 R2

SiR3

OTf


chelated TiCl4


chelated TBSOTf

Me

Cl Cl

R1 R2

rotation aroundpre-axis bond

(unknown mechanism)

Me

Cl

Cl

OH


Me

Cl

Me

Cl

Cl

OH

TiCl4

CH2Cl2, -78 °C

TBSOTf

CH2Cl2, 0 °C


R1 R2 R2R1 R1 R2

Me

Cl

Cl

OHR1 R2

TiCl4 Me

Cl

Cl

OHR1 R2

SiR3

OTf


chelated TiCl4


chelated TBSOTf

Me

Cl Cl

R1 R2

Me

R1 R2

ClCl

- H , - HCl

rotation aroundpre-axis bond

(unknown mechanism)

Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions

CN

OR1

R2

R2

catalysth! (" = 420 nm)

THF, 3 °C

R2R2


THF, 3 °C

N

R2

R2N

R2

R2

R2

R2

Gutnov, A. Angew. Chem. I. E. Engl. 2004, 43, 3795-3797.

OR1 OR1


Co Co Co Co

CN

OR1

R2

R2


THF, 3 °C

R2R2


THF, 3 °C

N

R2

R2N

R2

R2

R2

R2

O

O

Co

O

O

Co

O

O

Catalyst Screen


OR1 OR1


Co Co Co Co

CN

OR1

R2

R2


THF, 3 °C

R2R2


THF, 3 °C

N

R2

R2N

R2

R2

R2

R2

O

O

Co

O

O

Co

O

O

Catalyst Screen


OR1 OR1


CN

OR1

R2

R2


THF, 3 °C

R2R2


THF, 3 °C

N

R2

R2N

R2

R2

R2

R2


Co

Catalyst

Entry

OR1 OR1

R1 R2 % Yield % ee Entry R1 R2 % Yield % ee

1 1

2

3

2

3

Me n-pentyl 33 38

Me n-Pr 8 32

Bn n-pentyl 7 39

Me Et 10 64

Bn Et 3 59

Me n-pentyl 2 63


OR1


THF, 3 °C

R2R2


THF, 3 °C

N N

R2

R2

R2

R2


Co

Catalyst

Entry

OR1 OR1

R1 R2 % Yield % ee Entry R1 R2 % Yield % ee

1 1

2

3

2

3

Me Me 88 88

Me Ph 86 89

Me t-Bu 74 88

Me Et 10 64

Bn Et 3 59

Me n-pentyl 2 63

R2

R2CN

Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions - Helicenes

Stara, I. G. Tetrahedron Lett. 1999, 40, 1993-1996.

• First reported asymmetric synthesis of a helicene derivative.

CO2Me

R = OHR = Br

PBr3, THF, 0 °C

THF, -78 °C

R

R

R = TIPSR = H

n-Bu4NF, THF, rt

CO2Me

Red-Al

toluene, 0 °C

R

R

Ni(cod)2

(S)-(-)-MOPTHF, -20 °C

tetrahydro[6]helicene

TIPS

Li

PPh2

(S)-(-)-MOP

Atroposelective Construction of an Aromatic Ring[2+2+2] Cycloadditions - Helicenes

Stara, I. G. Tetrahedron Lett. 1999, 40, 1993-1996.

• First reported asymmetric synthesis of a helicene derivative.

CO2Me

R = OHR = Br

PBr3, THF, 0 °C

THF, -78 °C

R

R

R = TIPSR = H

n-Bu4NF, THF, rt

CO2Me

Red-Al

toluene, 0 °C

R

R

Ni(cod)2

(S)-(-)-MOPTHF, -20 °C

tetrahydro[6]helicene

TIPS

Li

PPh2

(S)-(-)-MOP

P

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