Ph.D. Project Summary

Asymmetric Catalysis with Axially Chiral Ligands

William Fleming

National University of Ireland

University College Dublin

September 2009

• Chirality: An object is said to be chiral if it has a Non-Superimposable Mirror Image.

• Axially Chiral: Restricted rotation about a single bond.

PPh2

PPh2

Ph2P

Ph2P

Introduction

PPh2

PPh2

Ph2P

Ph2P

• Used to prepare (R)-propane-1,2-diol, precursor of the antibiotic Levofloxacin.

Axially Chiral Ligands

N

O

HO

O

F

N

NO

O

OH

((R)-BINAP)Ru2+

H2, 70 bar OH

OH

Levofloxacin

Binap

Noyori; JACS., 1980, 7932

PPh2

PPh2

• Rhodium-catalysed hydroboration of olefins.

• Importance of substitution at the 3-position of Quinap.

Axially Chiral Ligands

OH

Rh-QuinapTHF

96 % ee, 90 % yield

rt, 1h

Binap

Noyori; JACS., 1980, 7932

PPh2

PPh2N

PPh2

Quinap

Brown; Tett. Asym. 1993, 743

• Rhodium-catalysed hydroborations of olefins.

Binap

Noyori; JACS., 1980, 7932

N

PPh2

Quinap

Brown; Tett. Asym. 1993, 743

N

N

PPh2

R

Quinazolinap

Guiry; Tett. Asym. 1999, 2797

PPh2

PPh2

N

N

PPh2

2-methyl Quinazolinap

Axially Chiral Ligands

Rh-QuinapTHF

rt, 1h

> 99.5 % ee, >99:1 quant. conv.

OH

• A range of the 2-substituted Quinazolinap ligands have been prepared to date:

N

N

PPh2

R

R= H, Me, i-Pr, t-Bu, cBu,Ph, Bn.

N

N

PPh2

R

R= OMe, CF3

Quinazolinap Ligands

My Targets:

Prepare ligands with electronic diversity at the 7-position.

N

N

PPh2

R

N

N

PPh2

R

Quinazolinap Ligands

N

N

PPh2

RCl

N

N

OMe

RCl N

N

OMe

RCl

Cl

B(OH)2

R = Me i-Pr

Retrosynthetic Analysis

Quinazolinone:

Ligand Synthesis

N

N R

Cl

Cl

NH

N R

O

ClPOCl3, N,N-diethylanaline

PhH, reflux, 24 h

R = Me 67 % i-Pr 69 %

Chlorination of the quinazolinone:

NH2Cl R

O

Cl N

NH

RCl

O

R = Me 98 % (2 steps) i-Pr 89 % (2 steps)

CH2Cl2, Pyridine, 20 mins, rt

2) KOH aq., 1h, refluxO

NH2

1)

Suzuki-Miyaura cross coupling:

B(OH)2

OMe+

N

NCl

Cl

R N

N RCl

OMe

3 mol% Pd(PPh3)4

CsF, reflux, 6 hDME

R = Me 73 % i-Pr 55 %

Ligand Synthesis

Demethylation / Triflation

N

N RCl

OMe

N

N RCl

OH24 h, CH2Cl2, rt

BBr3

R = Me 67 % (2 steps) i-Pr 82 % (2 steps)

Tf2O, DMAP

24 h, CH2Cl2, rt

N

N RCl

OTf

Ligand Synthesis

Phosphinylation:

Unexpected product:

N

N RCl

OTf

N

N RCl

PPh2

Ph2PHNiCl2dppe

DABCO, DMF100 oC

R = Me 35 %R = i-Pr 33 %

N

N RPh2P

PPh2

Cai, D. et al. JOC, 1994, 7180

Ligand Synthesis

N

N R

PPh2

N MeMe2

Pd

Cl

2+

N

N

PPh2

N MeMe2

Pd+

MeOH

RCl

Cl

N

N

PPh2

N MeMe2

Pd+

RCl

(Sa, R) (Ra, R)

KPF6, rt

PF6- PF6

-

(R)

R = Me 34 %R = i-Pr 31 % R = i-Pr 34 %

+

Resolution

N

N

PPh2

N MeMe2

Pd+

Cl

(Sa, R)

N

N

PPh2

N MeMe2

Pd+

Cl

(Sa, R)

Resolution

Decomplexation:

DPPE N

N

PPh2

Cl R

R = Me 95 %R = i-Pr 93 %

N

N

PPh2

N MeMe2

Pd+

RCl

(Sa, R)

CH2Cl2, 3 h, rt

Resolution

Post-resolution Modifications

N

NCl

PPh2

N

NPh2P

PPh2

10 % NiCl2dppe, PHPh2

DABCO, DMF, 100oC

70 %

N

NR'RN

PPh2

5 % Pd2dba3, 10 % dppfNaOt-Bu, aminetoluene, 125 oC

R = R' = Bu (33 %)R = H, R' = Ph (70 %)

Asymmetric Allylic Alkylations

Trost, B. et al. Chem. Rev. 2003, 2921

Ph Ph

OAc+

MeO OMe

OO

Ph Ph

OMeMeO

O O(allyl-PdCl)2 (2.5 mol %)Ligand (6 mol %), BSA, NaOAc

CH2Cl2, rt, 24 h

Optimised conditions:

Conv.: 100 %Ee: 78 % (S) (MW 82 %)

Conv.: 100 %Ee: 85 %

R=R’=Bu: Conv.: 100 %Ee: 51 %

R=H, R’=Ph: Conv.: 100 %Ee: 64 %

N

N

PPh2

Cl

N

N

PPh2

ClN

N

PPh2

R'RN

N

N

PPh2

Ph2P

Conv.: 100 %Ee: 58 %

Asymmetric Allylic Alkylations

•Products of borations provide versatile synthetic intermediates.

Borations

Ar

Chiral catalyst-'M'

OBH

O

Ar

BOO

Ar

OH

Ar

CO2H

Ar

CH2OH

Ar

NH2

Guiry, P. J. et al. Adv. Synth. Catal. 2005, 609

Rhodium-Catalysed Asymmetric Hydroborations

RhO

O+

Cl

PPh2

TMS Triflate

THF

N

NCl

PPh2

Rh+

-OTf

R R R

OH

OH+

Rh-Ligand (1 mol %)catecholborane

THF, 2h[O]

entry X temp. (oC) conv. (%) α:β ee (%)

1 H rt 100 80:20 65 (S)

2 H 0 94 83:17 66 (S)

3a H 0 30 45:55 -

4 OMe rt 100 68:32 60 (S)

5 OMe 0 20 51:49 11 (S)

6a OMe 0 12 42:58 -

7 Cl rt 100 62:38 11 (S)

8 Cl 0 26 56:44 0

9a Cl 0 24 58:42 -

aRh(COD)(acac) only, no ligand

OHRh-Ligand (1 mol %)catecholborane

THF, 2h[O]

OH

+

XX

X

Rhodium-Catalysed Asymmetric Hydroborations

N

NCl

PPh2

Rh+

-OTf

entry substrate temp. (oC) conv. (%) α:β ee (%) cis:transa

1 cis rt 94 >99:1 62 (S) 0:100

2 cis 0 6 >99:1 10 (S) 75:25

3 trans rt 72 90:10 68 (S) -

4 trans 0 10 >99:1 62 (S) -

aRatio of cis:trans β-methylstyrene after 2h reaction time.

OHRh-Ligand (1 mol %)

catecholborane

THF, 2h[O]

OH+

Rhodium-Catalysed Asymmetric Hydroborations

N

NCl

PPh2

Rh+

-OTf

entry X = temp. (oC) conv. (%) α:β ee (%)

1 H rt 50 85:15 60 (S)

2 H 0 70 87:13 60 (S)

3 OMe rt 55 83:17 54 (S)

4 OMe 0 35 91:9 58 (S)

Rhodium-Catalysed Asymmetric Hydroborations

N

NCl

PPh2

Rh+

-OTf

OHRh-Ligand (1 mol %)

catecholborane

THF, 2h[O]

OH+

MeO

X

MeO

X

MeO

X

entry substrate temp. (oC) conv. (%) ee (%) cis:transa

1 cis rt 41 30 (S) 26:74

2 cis 0 1 - 88:12

3 trans rt 34 20 (S) -

4 trans 0 2 - -

aRatio of cis:trans stilbene after 2h reaction time.

OHRh-Ligand (1 mol %)catecholborane

THF, 2h[O]

Rhodium-Catalysed Asymmetric Hydroborations

N

NCl

PPh2

Rh+

-OTf

entry n = temp. (oC) conv. (%) α:β ee (%)

1 1 rt 100 >99:1 55 (S)

2 1 0 100 >99:1 57 (S)

3 2 rt 70 >99:1 64 (S)

4 2 0 15 >99:1 35 (S)

n

Rh-Ligand (1 mol %)catecholborane

THF, 2h[O] n

OH

nOH+

Rhodium-Catalysed Asymmetric Hydroborations

N

NCl

PPh2

Rh+

-OTf

entrya substrate catalyst conv. (%) α:β ee (%)

1

1

2

100

100

80:20

77:23

65

87

2

MeO

1

2

100

100

68:32

76:24

60

92

3

Cl

1

2

100

100

62:38

81:19

11

73

4

1

2

72

100

90:10

91:9

68

88

5

1

2

94

100

>99:1

96:4

62

96

6b

MeO

1

2

70

97

87:13

68:32

60

87

a1 mol % cat, THF, 2 h, rt b Temp = 0 oC

Rhodium-Catalysed Asymmetric Hydroborations

Guiry, P. J. et al. JOC, 2004, 6572

N

NCl

PPh2

Rh+

-OTf

N

N

PPh2

Rh+

-OTf

2

1

entrya substrate catalyst conv. (%) α:β ee (%)

7

MeO

OMe

1

2

55

72

83:17

82:18

54

85

8 Ph

1

2

34

7

-

-

20

64

9

Ph

1

2

41

84

-

-

30

99

10

1

2

100

100

>99:1

98:2

55

84

11

1

2

70

91

>99:1

>99:1

64

86 a1 mol % cat, THF, 2 h, rt

Rhodium-Catalysed Asymmetric Hydroborations

Guiry, P. J. et al. JOC, 2004, 6572

N

NCl

PPh2

Rh+

-OTf

N

N

PPh2

Rh+

-OTf

2

1

Kabalka et al.Tett. Lett., 2002, 43, 2323; Yun et al. Angew. Chem. Int. Ed. 2008, 47, 145

Copper-Catalysed β-Boration of α,β-Unsaturated Esters

OR

O

OR

OBPinB2pin2 B2pin2

CuCl, ligand,NaOtBu

* B

B

O O

OO

•Active new research topic

N

N

PPh2

N

N

PPh2

N

N Ph

PPh2

N

N

PPh2

N

N

PPh2

N

PPh2

Cl

N

N

1 2 3

4 5 6

Copper-Catalysed β-Boration of α,β-Unsaturated Esters

Asymmetric Boration of Methyl Crotonate.

Entry Ligand Conversion (%) Ee (%)

1 1 100 40

2 2 65 51

3 3 100 25

4 4 71 13

5 5 95 20

6 6 100 50

N

NCl

PPh2

N

N

PPh2

N

N

PPh2

N

N

PPh2

N

N

N

PPh2

N

N

PPh2

1

2

3

4

5

6

OMe

OB2pin2, CuCl (2 mol %)

NaOt-Bu (3 mol %)

Ligand (4 mol %), MeOHTHF, RT OMe

OBPin

Asymmetric Boration of Ethyl Crotonate.

Entry Ligand Conversion (%) Ee (%)

1 1 98 38

2 2 75 40

3 3 99 12

4 4 82 15

5 5 100 34

6 6 100 72

N

NCl

PPh2

N

N

PPh2

N

N

PPh2

N

N

PPh2

N

N

N

PPh2

N

N

PPh2

1

2

3

4

5

6

OEt

O

OEt

OBPinB2pin2, CuCl (2 mol %)

NaOt-Bu (3 mol %)

Ligand (4 mol %), MeOHTHF, RT

Asymmetric Boration of i-Butyl Crotonate.

N

NCl

PPh2

N

N

PPh2

Entry Ligand Conversion (%) Ee (%)

1 1 23 48

2 2 100 42

3 3 100 20

4 4 26 20

5 5 100 35

6 6 100 79

N

N

PPh2

N

N

PPh2

N

N

N

PPh2

N

N

PPh2

1

2

3

4

5

6

Oi-Bu

O

Oi-Bu

OBPinB2pin2, CuCl (2 mol %)

NaOt-Bu (3 mol %)

Ligand (4 mol %), MeOHTHF, RT

Asymmetric Boration of t-Butyl Crotonate.

Entry Ligand Conversion (%) Ee (%)

1 1 100 43

5 5 100 42

6 6 100 72

N

NCl

PPh2

N

N

PPh2

N

PPh2

1

5

6

Ot-Bu

O

Ot-Bu

OBPinB2pin2, CuCl (2 mol %)

NaOt-Bu (3 mol %)

Ligand (4 mol %), MeOHTHF, RT

Quinap in Asymmetric β-Boration of Crotonates

N

PPh2

OMe

OBpin

OEt

OBpin

Oi-Bu

OBpin

50 % ee 71 % ee

79 % ee

Ot-Bu

OBpin

72 % ee

Fleming, W. J.; Muller-Bunz, H.; Lillo, V.; Fernandez, E.; Guiry, P. J. OBC 2009, 2520

Conclusions•5 new quinazolinap ligands have been prepared.

Ph Ph

OAc+

MeO OMe

OO

Ph Ph

OMeMeO

O O

Chiral "Pd" catalysis

100 % conv.ee values up to 85%

•Applied to asymmetric allylic alkylations

N

N

PPh2

Cl

N

N

PPh2

Cl

N

N

PPh2

Ph2P

N

NR'RN

PPh2

R = R' = BuR = H, R' = Ph

OR

O

OR

OBPinB2Pin2 B2pin2

Cu-ligand,NaOt-Bu

* B

B

O O

OO

100 % conv.ee values up to 79 %

•First comprehensive study of the application of P-N ligands to β-borations of ,ß-unsaturated esters.

•Applied to the Rh-catalysed hydroboration of olefins

R R R

OH

OH+

100 % conv.ee values up to 79 %

Conclusions

Acknowledgements•Pat Guiry’s group since 2005

•Colm Duffy

•Martin Fitzpatrick

•Therese Brennan

•Sean Mc Keon

•Miriam Aylward

•Raymond Bronger

•Xin Li

•Caroline Barth

•Ludovic Milhau

•Aoife Maxwell

•Tomasz Fekner

•Cathal Murphy

•Tasadaque Ali Shah

•Celine Franc

•Theresa Ahern

•Brian Sweetman

•Vincent Coeffard

•Surendra Singh

•Jerome Fakhry

•Anthony Coyne

•Michael Carroll

•Elena Fernández’s group

•Vanessa Lillo

•Amadeu Bonet

•Mike Geier

•School of Chemistry, UCD

•Helge Müller-Bunz

•Geraldine Fitzpatrick

•Ken Glass

•Yannick Ortin

•Jimmy Muldoon

•Dilip Rai

•Adam Coburn

•Kevin Conboy

•Gavin Haberlin

•Lina Søbjergø

•Grainne Hargaden

•Declan Cusack