enantioselective catalysis - uroxazoline).pdf · principles of enantioselective catalysis catalyst...

Enantioselective Catalysis

Oliver ReiserUniversity of Regensburg

Importance of Chiral Compounds

Market Value for chiral fine chemicals (2000)

TotalPharmaceuticsOther (Agro, Flavors etc)

6600 Mill US$5400 Mill US$1200 Mill US$

Any new drug that’s chiral is likely to be

developed and marketed as a single

enantiomer. You win more than you lose

with single enantiomers.

Chem. Eng. News 2003

Important Factors when Deciding the Application of Catalysis

• Product - availability of competitive alternative routes time frame for development cost vs added value

• Catalytic reaction maturity - known scope / limitations catalyst availability development time IP situation required equipment / techniques cost

• Chemist & education, acceptance of novel methods Company catalytic know how and facilities

Adapted from H.U-Blaser, Solvias

Top Catalysis Reactions in Industry

Adapted from H.U-Blaser, Solvias

Principles of Enantioselective Catalysis

Synthesis of (L)-Dopa (Monsanto)

CO2H

NHAc

AcO OMe

H2, Rh-DiPAMP

CO2H

NHAc

AcO OMe

H3O

CO2H

NH2

HO OH

95% ee, TON 10000, TOF 1000/hEnantiomerically pure product crystallizes

Separation from catalyst and undesired racemate

P PPh

Ph

MeO

OMeDiPAMP

Knowles et al.

Principles of Enantioselective Catalysis

Catalyst design: Metal–chiral ligand combination

• more than 2000 chiral ligands to choose from

• enhancement of selectivity• regio- / chemoselectivity• diastereoselectivity• enantioselectivity

• enhancement of reactivity• LAC - Ligand Accelerated Catalysis

Give me reactivity, and I will give you selectivity laterB. Sharpless, nobel laureate 2001

Ligand Accelerated Catalysis

• change of the electronic properties donor / acceptor ( and )

CO (cm–1)

(CO)5W OEt2

(CO)5W PMe3

CH2

CH2

(CO)5W P(OPh)3

(CO)5W

1908

1947

1965

1973

CO Bindung becomes stronger, sinceback bond to CO becomes weaker

back bonding to other ligand (not CO) becomes stronger

Complex pKa (MeCN)

8.4

15.4

11.4Increasing ability of the ligands to stabilizethe conjugate base by back bonding

H—Co(CO)4

H—Co(CO)3[PPh3]

H—Co(CO)3[P(OPh)3]

Ligand Accelerated Catalysis

• change of reagent geometry

Et Zn Et

O

HRx no reaction

180•

Me2N OH

ZnOMe2N

EtEt

100•

O

HR

R Et

HO H

Privileged Ligand Classes

X

X

X = PPh2

X = OH

X = P(O)Ph2

X = NH2

X = OPPh2

X = NHPPh2

X = N CHAr

X = AsPh2

Noyori

Binaphthyls Bis(oxazolines)

N

O X

N

O

R1 R1

Evans, Pfaltz, Masamune

OH

N N

HO

R R

Jacobsen, Katsuki

Salen

P PR

R

R

R

DUPHOS

Burk

HNNHO O

PPh2Ph2P

PNNP

Trost

NBO

R

PhPh

H

Oxabor

Corey

L-Menthol (Takasago)

NEt2 Rh(I)-BINAP NEt2HO

>1000t/year 97.6% ee, TON 40000, TOF 1300/h

(S)-BINAP (R)-BINAP

blocked quadrants

P PRu

H

H

(R)-BINAP

Review: T. Wabnitz, O. Reiser Organic Synthesis Highlights IV (Eds. H. G. Schmalz, H. Waldmann), VCH Weinheim, 2000, 155-165

Epoxidation of Allyl Alcohol

OHTi(OiPr)4

OHO

HO OH

PrO2iC CO2

iPr88-90% eeTON >40; TOF < 1/h

• Arco–GGP-Sipsy, multi ton scale (discontinued)

• good selectivity

• low TON and TOF

Oxazoline-Ligands for Catalysis

N

O

N

O

RR

R1 R1N

ORN

N

O

R1 R1N

O

R1PPh2

N

O

R1

N

N

O

R1

N

XX

N

OO

N

Y Yn n

n n

BoxEvans, Pfaltz, Masamune

AzaboxReiser

PyboxNishiyama

P,N-OxazolinesPfaltz, Helmchen, Williams

(NX2)-box Reiser

N

O

R

Ph

FeOH

Ph

Ferrocene-ox Bolm

N

O

R1

N

N,N-Oxazolines Brunner

N

O

R1OH

O,N-Oxazolines Bolm

But

NO2

Reviews: P. Guiry, Chem. Rev. 2004, 104, 4151 M. Glos, O. Reiser in Organic Synthesis Highlights IV VCH Weinheim, 2000, 17

Oxazolines as Chiral Auxiliaries

R CN

HO

H2N

Ph

OH

O

N

RPh

OMe

N

O

Ph

R

OLiH

R1

X

O

N

RPh

OMe

R1

R CO2H

R1

Me

+1) LDA

2) R1X

75-85% ee

45-85%

HCl

A. I. Meyers, G. Knaus, K. Kamata, M. E. Ford, J. Am. Chem. Soc. 1976, 98, 567Review: T. G. Grant, A. I. Meyers, Tetrahedron 1994, 50, 2297

Synthesis of bis(oxazoline) ligands

H2N OH

R

ClOC COCl

R2 R2

O

N

R2

N

O

R2

RR1)

2) Activation / Cyclization

R'R' R'

R'R'

R'

NC CN

R2 R2

ZnCl2

Activation / Cyclization: ZnCl2; NEt3 /TsCl; SOCl2/NaOH; Burgess-Reagent…

Synthesis of bis(oxazoline) ligands

NHCbz

OH

NH2

OH

N N

O O

2-Naph 2-Naph

BnOCONClNa

4% K2OsO2(OH)4

(DHQD)2PHAL

H2, Pd/C

ClOC COCl1)

2) SOCl2,

3) NaOH,

G. Desimoni et al., Tetrahedron, 1998, 54, 15721

Synthesis of azabis(oxazoline) ligands

HN

N N

O O

R RH2N OH

RBrCN

N O

NH2

R

TsOH, PhCHO

MeOH Toluol, , 58-59%89 %

R=iPr,tBu

N O

OEt

R1

HN

N N

O O

R R1

30-75%

R = t-Bu, i-Pr

R, R1 = t-Bu, i-Pr, Ph, CO2Et

n-BuLi

Br

N

N N

O O

R R1

MeOPEG; Polystyrene, Tentagel, Dendrimers

M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045H. Werner, A. Gißibl, R. Vicha, O. Reiser, J. Org. Chem. 2003, 68, 10166

Virus bound Azabis(oxazolines)

*NNN

N

N R

R

x

M

Collaboration withM. G. Finn, Scripps

Polymer-supported Bis(oxazoline) ligands

N

N N

O O

R R

1a : R = i-Pr

1b: R = t-Bu

N N

O O

R R

2a : R = Ph

2b: R = t-Bu

n

N N

O O

R R

3

H3C

OO n

N N

O O

R R

4

H3C 4

n

O

Reiser et al.Org. Lett. 2000, 2, 2048

Fraile, Mayoral et al.Org. Lett. 2000, 2, 3905

Cozzi et al.J. Org.Chem. 2001, 66, 3160

Salvadori et al.Angew. Chem. 2001, 40, No 13

OO

n

Review: Le Maire et al., Chem. Rev. 2002, 102, 3467

Oxazoline Ligands in Catalysis - The Beginning

N

N

O

R

H3C

O

H3C

OH

RhCl3 •L* (1 mol%)1) Ph2SiH2

2) H+

L* =

86% ee

H. Brunner, U. Obermann, Chem. Ber. 1989, 122, 499

Semicorrins in Catalysis – Pd(0)-catalyzedAllylations

H. Fritschi, U. Leutenegger, A. Pfaltz, Angew. Chem. 1986, 98, 1005

Ligand (2.5 mol%)

[Pd(C3H5)Cl]2 (1 mol%)OAc

PhPh

CH(CO2Me)2

PhPhN

N

N

CH3

OR RO

R = SiMe2tBu

Pd

Ph

Ph

N

N

O

OBn

BnPh Ph

Ph Ph

Nu

Nu

+Nu

a

b

a

b

95% ee

X-ray structure

A. Pfaltz et al., Helv. Chim. Acta 1995, 78, 265

Pd(0)-catalyzed allylations

C. Moberg, Tetrahedron: Asymmetry 2001, 12, 1475

OAc

PhPh

CH(CO2Me)2

PhPh

94-95% ee

N N

O O

Ph Ph

O

OOO

O n

x

m

A

[Pd(C3H5)Cl]2

Multiple runs, high enantioselectivity, variable yields

28-70%

A

P, N-oxazolines – Pd(0)-catalyzed Allylations

Pd

Ph

PhRN

P

O

Pd

Ph

Ph

RN

P

O

Ph

a

b

+

b

a

Ligand (2.5 mol%)

[Pd(C3H5)Cl]2 (1 mol%)OAc

PhPh

CH(CO2Me)2

PhPh

99% eeN

O

Ph

PPh2

1:8

Ph PhPh

Attack via a is observed but stereoelectronics should favor attack via b

Original report: A. Pfaltz et al., Angew. Chem. Int. Ed. Engl. 1993, 32, 566; b) J. G. Helmchen et al., TetrahedronLett. 1993, 34, 1769-1772; c) J. M. J. Williams et al., Tetrahedron Lett. 1993, 34, 3149Mechanistic discussion: O. Reiser, Angew. Chem. Int. Engl. Ed., 1993, 32, 547-549Mechanism: G. Helmchen, Angew. Chem. Int. Ed. Engl. 1996, 34, 2687

Cu(I)-catalyzed Cyclopropanation (Sumitomo)

+ N2

O

OEt

CO2EtCu(I)–L

O

N

Bn

R

ORCu

2

Intermediate for cilastatin (dehydropeptidase); small scale

Critical issue: preparation and handling of diazoester

92% ee100-200 TON

Cu(I)-box catalyzed cyclopropanation

Org. Lett. 2000, 2, 2045

J. Am. Chem. Soc. 1991, 113, 726

Tetrahedron Lett. 1990, 31, 6005

Tetrahedron 1992, 48, 2143

Helv. Chim. Acta1988, 71, 1533

N

N N

PhMe2SiO OSiMe2Ph

N2CO2Et

Cu(I)•L"

N

O

N

O

CH3H3C

But But

N

O N

N

O

But But

Me

O

NH N

O

But But

Ph

CO2Et CO2EtPh

2-3 : 1

99% ee 92% ee

Me

95% ee 98% ee

CuN

N

O

O

CO2RR

R

Ph

good enantiocontrol

low enantiocontrol

Copper(I)-Catalyzed Cyclopropanation

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11

cycles

%

yield

ee 15

Org. Lett. 2000, 2, 2045J. Mater. Sci. 2002, 14, 1

N

N N

O O

But tBu

Ph

O

OMeN2Ph

CO2MeCu(OTf)2 / PhNHNH2+

1 mol%

PEG-bound aza(box)

Immobilization on nafion by anion exchange

No leaching of ligand

Multiple cycles possible

Leaching of ligand

BnN

N N

O O

tButBu

Cu

+

N N

O O

tButBu

Cu

+

In collaboration with J. Mayoral, Chem. Eur. J. 2004, 10, 2997

Cu(I)-catalyzed cyclopropanations – Applications

Cl

Cl

N2 CO2R

CO2R

Cl

ClCO2RCl

Cl

R = MenthylL 88 12

92% ee 85% ee

+

R = (Dicyclohexylmethyl) 99 192% ee

L*

CuClO4(CH3CN)4

N

O

N

O

PhPh

Ph Ph

S. Masamune et al., Tetrahedron Lett. 1991, 32, 7373

OMeO2C

N2 CO2Et

OMeO2C

H

H

CO2Et

Cu(OTf)2/L* (1 mol%) PhNHNH2

O

N N

O

Pri Pri

85-90 % ee >99 % ee (32%)

single recrystallization

45% yield (large scale, 77% based on conversion)

2 steps

OO

CHO

Nu

Eur. J. Org. Chem. 2000, 2955–2965Org. Lett. 2001, 3, 1315–1318Chemistry 2003, 9, 260–270Org. Lett. 2003, 5, 914

Cu(II) or Mg(II)-catalyzed Diels-Alder reactions (1)

O

N

O

O

COXCOX

N

O

NO

Mg

Ph

Ph

H

H

N

O

NO

Cu

But

But

H

H

O

O

N

O

Cu(OTf)2• Box-Ph

MgI2• Box-But > 95

O

ONO

< 5

< 2 > 98

COXCOX

N

O

N

O

CH3H3C

R RBox-R

E. J. Corey et al.,Tetrahedron Lett. 1992, 33,6807

D. A. Evans et al., J. Am.Chem. Soc. 1993, 115, 6460

Cu(II)-catalyzed Diels-Alder reaction (2)

J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325

O

N

O

O

COX

CuX2• Box-But

(10 mol%)

N

O

N

O

CH3H3C

R RBox-R

25°C, 8h

counterion endo ee yield

X = TfO–

X = SbF6–

94% ee

96% ee

95%

98%R = Me

R

R

X = TfO–

X = SbF6–

90% ee

96% ee

85%

95%R = Ph

X = TfO–

X = SbF6–

53% ee

94% ee

–

95%R = Cl

Cu(II)-box catalyzed Diels-Alder reaction

M. Lemaire, Org. Lett. 2001, 3, 2493-2496

O

N

O

O

CuX2• Si-Box (10 mol%)

r.t.

OR

N N

O O

O O

NH

O

HN

O

(H2C)3(CH2)3Si SiOR OR

Si-Box: R = H, SiMe3

Silica R endo / exo % ee

H 85:15 65OH 86:14 81 (92 at –78°C)

COX

Cu(II)-box catalyzed reactions

J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325

Cu(II)-box-catalyzed Michael reactions

N

O

N

O

CH3H3C

R R1

Cu

2+

2 SbF6–More reactive

Direct reduction toaldehyde possible

`J. S. Johnson, D. A. Evans, Acc.Chem. Res. 2000, 33, 325

Cu(II)-box catalyzed electrohilic amination

J. S. Johnson, D. A. Evans, Acc.Chem. Res. 2000, 33, 325

N

O

N

O

CH3H3C

R R1

Cu

2+

2 SbF6–

Cu(II)-box catalyzed Mukaiyama syn-aldol reactions

D. A. Evans et al. J. Am. Chem. Soc., 1999, 121, 685

N N

OO

Cu

2+

O

MeMeO

O

OTMS

S-tBu

R

MeOS-tBu

OOHMe

O

=B

R

R=H: 99%ee (96%)R=Me: 96%ee 94:6 syn:anti

1-10 mol% B+

2SbF6

alkyl iButyl

H, Me, Et, iPr, iBu

Me, Ph

PM3

Cu(II)-box catalyzed Mukaiyama aldol reaction

O

MeMeO

O

OTMS

S-tBu

R

MeOS-tBu

OMeHO

O+

N N

O O

tButBu

CH3

O

n

4

8 runs: 52-97% yield (GLC), 88-95% ee

MeOS-tBu

OMeMe3SiO

O

Cu

TfO OTf

A

P. Salvadori et al., Angew. Chem. Int. Ed. Engl. 2001, 40, 2519-2521.

R = H

Cu(II)-pybox catalyzed Mukaiyama syn-aldolreactions

D. A. Evans et al., J. Am. Chem. Soc., 1999, 121, 669

Limited scope

NN

OO

Ph Ph

Cu

2+

O

HBnO

OTMS

SEt

R

BnOS-tBu

OOH

R

0.5-10 mol% A

R=H: 98%ee (95%)R=Me: 97%ee 97:3 syn:anti

+

2OTf

=A

Nu (Si face)

X-ray

Sn(II)-pybox catalyzed Mukaiyama anti-aldol reactions

O

MeMeO

O

OTMS

S-tBu

R

MeOS-tBu

OMeHO

O R

1-10 mol% C+

NN

OO

Ph Ph

Sn

2+

2OTf

=C

R = Me, Et, iBu

97% ee, 98:2 anti/syn

D. A. Evans et al., J. Am. Chem. Soc. 1997, 119, 10859

Ni(II)-box catalyzed aldol reaction


D

NS

Me

OS

+ RCHOD (10 mol%),

2,6-lutidine, TMSOTf (1 equiv)NS

Me

OS

R

OH

R = Aryl, Vinyl, enolizable(!) Alkyl

syn:anti 88:12, 90% ee

Cu(II)-catalyzed Baeyer-Villager Oxidation

O

Ph

O2N

tBu

O

O

N

Cu

tBu

O

PhO

O

Ph

O2 / tBuCHO

CuL2

O

O

NCuL2 =

NO2

tBu

tBu

+

69% ee

C. Bolm et al., Angew. Chem. 1994, 106, 1944

Cu(I)-box catalyzed heteroatom transfer

Ph

TsN

CO2PhH

CO2Ph

PhI NTs

HPh

+97% ee

RR

PhCO3tBu

OBz

up to 84% ee

+

N N

O O

tButBu

Cu

OTf

A

A


A. Pfaltz, Tetrahedron Lett. 1995, 36, 1831

Cu(II)-catalyzed benzoylations

Ligand Time [h] Yield (%) ee (%) Configuration

1 2 48 99 (R,R)

2 3 48 86 (R,R)

3 3 46 93 (S,S)

4 (0.5 mol%) 3 44 97 (S,S)

5 (5 cycles) 3 40-44 92-97 (R,R)

Y. Matsumura et. al., J. Am. Chem. Soc., 2003, 125, 2052-2053

PhPh PhPh

HO OHOH HO

PhPh PhPh

HO OHOBz HO

Ligand (5mol%)

CuCl2 (5mol%)

PhCOCl (0.5 eq)

DIPEA (1.0 eq)

CH2Cl2, 0°C

RNO

N N

OHNO

N N

O NO

N N

O

Me

1 2 4: R = H5: R = Bn-PEG5000

3

O

N N

O

A. Gissibl, M. G. Finn, O. Reiser Org. Lett. 2005, 7, 2325

Co(II)-catalyzed conjugate reduction

A. Pfaltz et al., Angew. Chem. 1989, 101, 61

C. Geiger, P. Kreitmeier, O. Reiser, Adv. Synth. Catal. 2005, 347, 249

R

O

OEt R

O

OEtEtOH/diglyme24h rt

CoCl2, L*

NaBH4

N

N

Me

N* N

ON

Me

O

N

Ph Ph

Me3SiO Me3SiO

R yield % ee % ee Konfiguration86 95 90 S (E)

(Z) 89 81 73 R

86 93 94 R (E)(Z) 86 97 94 S

88 96 94 R (E)(Z) 87 96 94 R

TBDMSO (E)

85 95 – S

Cu(II)-catalyzed benzoylations

O

OH

O

O O

O

OH

Ligand (5mol%)

CuCl2 (5mol%)

PhCOCl (0.5 eq)

DIPEA (1.0 eq)

CH2Cl2, 0°C

* +

A. Gissibl, M. G. Finn, O. Reiser Org. Lett. 2005, 7, 2325

HNO

N N

O

HNO

N N

O

HNO

N N

O

38%, 81% ee

HNO

N N

O

36%, 10% ee

45%, –39%ee 32%, 77%ee

MeNO

N N

O

32%, 27%ee

Dendrimers for immobilization of aza(bisoxazolines)

P

NP

N

PNCl

Cl

ClCl

Cl

Cl

Gc0

P

NP

N

PNO

O

OO

O

O

OHCCHO

OHC

CHO

CHO

CHOCHOHO

THF

K2CO3

reflux

Gc'0

H2NN

Me

P

S

Cl

Cl

CHCl3

K2CO3

-63°CP

NP

N

PN

O

O

OO

N

N P

S

Cl

Cl

NN

PS Cl

Cl

O

N

NPS

ClCl

N

NP

S

ClCl

NN

PSCl

Cl

O

NN

PSCl

Cl

Gc1

OHC ONa

PN

PNP

NO

O

OO

N

N P

S

NN

PS

O

N

NPS

N

NP

S

NN

PS

O

NN

PS

Gc'1

OHC

OHCOHC

CHO

CHO

CHO

CHO

CHOCHO

OHC

CHO

OHC

THF, rt

up to 8th generation with1536 aldehyde functions

O

O

OO

O

O

O

O

OO

O

O

J.-P. Majoral, Acc. Chem. Res. 2004, 37, 341


Gc0-3 P

SCl

Cl+

O

N N

ON

OH

Cs2CO3THF

T.A.

Gc0-3 P

S O

N

NO

N

O

O N

N

O

N

O

F. Jaroschik, in collaboration with J.-P- Majoral

Dendrimers with 6, 12, 24, 48 azabis(oxazolines)


P

NP

N

PN

O

O

OO

N

N P

S

NN

P

S

O

N

N

PS

N

N

PS

N

NP

S

O

N

N

PS

O

N N

ON

O

O N

N

O

N

O ON

N

O

N

O

O

N

NO

N

O

ON

N

O

NO

O

N

NO

N

O

O

NN

ON

O

O

N

N

O

N

O

O

N

NO

N

O

ON

N

O

N

O

ON

N

ON

O

O

N

N

O

NO

Chemical Formula: C294H398N51O42P9S6

Exact Mass: 5785.65

Gc1-dendrimer



73 %42 %Gc0

ee (R,R)yieldCatalyst

72 %40 %Gc3

82 %41 %Gc2

78 %34 %Gc1

74 %32 %Aza-BOX-linker

71 %45 %Aza-BOX

OH

OH

(±)

Ligand (5mol%)

CuCl2 (5mol%)

PhCOCl (0.5 eq)

DIPEA (1.0 eq)

CH2Cl2, 0°C

OBz

OH

+OH

OH

3 cycles possible


Pybox – Synthesis of the ligand

H. Nishiyama et al., Organometallics 1991, 10, 500Review: Desimoni et al., Chem. Rev. 2003, 103, 3119

Pybox – Synthesis of the ligand

NNC CN

NH2

OH

R

R1

ZnCl2, chlorobenzene,

N

N

OO

N

R R1R1 R

Ph

NH2R

OH

NMeO

NH

OMe

NH

NCl

O

Cl

O N

N

OO

N

R R1

Ph PhN

N

OO

N

R R1

Ph Ph

retentioninversion

G. Celucci et al., Tetrahedron: Asymmetry 1999, 10, 3803

P. Reider et al., J. Org. Chem. 1996, 61, 9629

Polymer bound pybox ligands

N

N

OO

N

Pri iPr

Br

SnBu3

Pd(PPh3)2Cl2

N

N

OO

N

Pri iPr

styrne/DVB AIBN

N

N

OO

N

Pri iPr

A. J. Mayoral et al., Org. Lett. 2002, 4, 3927

Ruthenium complexes were prepared andtested in cyclopropanation reactions

Metal complexes of pybox ligands

RhCl3•pybox Re(CO)3Cl•pybox

J. Chem. Soc., Dalton Trans. 1997, 1083Organometallics 1989, 8, 846

[Cu(BnOCH2CHO)•pybox]2+ La(OTf2)(H2O)4•pyboxTetrahedron 2001, 57, 10203J. Am. Chem. Soc. 1999, 121, 669

La(III)-pybox catalyzed reaction

OTMSO

O

N O

O

+La(OTf)3 • L*

or Ce(OTf)4•L*

O

O

NH

O O

O

N

N

OO

N

Ph iPr

G. Desimoni et al., Tetrahedron 2001, 57, 10203

complete stereoselectivity

Rh(III)-catalyzed hydrosilylation

N

N

O

R

Alkyl

O

Alkyl

OH

RhCl3 •L* (1 mol%)1) Ph2SiH2

2) H+

L* =

up to 99% eeAlkyl = Me, Et

X

AgBF4

X

O

N

R

R = i-Pr > s-Bu > t-Bu > Et

H. Nishiyama et al., Organometallics 1989, 8, 846; Organometallics 1991, 10, 500; J. Org. Chem. 1992, 57, 4306

Metal-pybox catalyzed reactions (=X transfer)

• Ru(II)-catalyzed cyclopropanations (alkene + diazoacetates)• Cu(II)-catalyzed aziridinations (alkene + phenyliodonium ylides)

inferior or similar results compared to box

• Ru(II)-catalyzed epoxidations

PhPh + PhI(OAc)2

toluene, 0°C

Ru(II)•L*

OPh H

H Ph N

N

O

R

O

N

RRu

NO

O

O

Oup to 74% ee

H. Nishiyama et al., Chem. Commun. 1997, 1863

C2-chiral Bis(oxazolines) with Secondary Binding Sites

Secondary Interaction throughHydrogen Bond Donor or AcceptorLewis-Acid or Lewis-Base

R

N

O

N

OSPACER

MN

O

N

OSPACER

M R

X

X

Asymmetric Diethylzinc Addition to Enones

O

Et2Zn / –30°C

OO

P NCH3

CH3NP

OPh

Me

NMe2

Pri

CuOTf or Cu(OTf)2

O

N S

N O

Pri

Ph

Ligand

B. Feringa, 1997Alexakis, 1997

32 %ee 98 %ee

B. Feringa, R. M. Kellog, 1997

62 %ee

Mechanism for the Copper Catalyzed 1,4-Addition of Diethylzinc?!

• Activation of the Enone by Zinc• Asymmetric Alkyl Transfer from Copper to the Enone

OZn

Et

OZn

Et CuL

L

Et

Et

EtH+

O

Et

Cu-Bis(oxazolines) in 1,4-conjugated Additions

M. Schinnerl, 2000

• similar unsuccessful results were reported by A. Pfaltz with semicorrines Tetrahedron 2000, 56, 2879

O

Et2Zn

O

N N

O

But ButCu

TfO OTf

O

65%

racemic!

2-10 mol%

Bis(oxazoline) Ligands for Zn and Cu?

YO

N N

O

OH HO

RR

R1

R1R1

R1

O

R

Zn

Et

YO

N N

O

O

R

R1

R1

R1

R1 OH HO

RR

Cu

X

YO

N N

O

R1

R1

R1

R1

YO

N N

O

OZnX HO

RR

Cu

XR1

R1

R1

R1

Zn

Zn(II)-catalysis: Diethylzinc addition to aldehydes

O

H

Et2Zn

N

O

N

O

OH HO

N

O

N

OPhPh

OH HO

N

O

N

OArAr

OH HO

N

O

N

O

OH HO

R

R

R

R

Et

OH

N

O

N

OPhPh

OH HO

2 mol% Ligand

toluene / hexane / 0°C

Ph Ph

no reaction 5%, racemic

N

O

N

OPhPh

OH HO

N

53%, 50 %ee31%, 49 %ee

Ar = Ph: 96%, 93%eeAr = p-SMe-Ph: 56%, 83% ee

no reaction 19%, racemic

Org. Lett 2001, 3, 4259

Necessity of Hydroxymethylene Side Chains

O

H

R

Et2Zn

O

N N

O

But But

Et

R

OHtoluene / hexane / 0°C

60%

20% ee

Enantioselective Catalytic Alkylations

R Yield [%] ee [%]

H 96 93

p-OMe 99 95

p-Cl 76 83

p-F 74 88

2 mol% n-BuLi 92%, 87%ee

84%, 87%ee

O

H

R

Et2Zn

O

N N

O

OH HO

PhPh

Et

R

(1 mol%)

toluene / hexane / 0°C

OH

Org. Lett 2001, 3, 4259

Asymmetric Conjugated 1,4-Additions

Temperature [°C] Yield (%) % ee

+20 82 77

+10 83 89

+5 81 92

0 93 94

–18 80 67

Solvent: CH3CN

Toluol: 72 %eeCH2Cl2: 63 %eeTHF: 27 %ee

Additives: TMSCl: 79%, racemic H2O: 81%, 32 %ee

Org. Lett 2001, 3, 4259

O

Et2Zn (1.4 eq)

O

N N

O

HOH2C CH2OH

O

Cu(OTf)2 (2.4 mol%)

(2.8 mol%)

PhPh

YO

N N

O

CH2OHO

RR

Cu

OZn

Et

Asymmetric Conjugated 1,4-Additions

O

R2Zn (1.4 eq)

O

N N

O

HOH2C CH2OH

PhPh

O

RCu(OTf)2 (2.4 mol%)

n n

R1 R1 R1 R1

Et

O

Et2Zn: 93%, 94 %ee

Ph

O

Ph2Zn: no reaction

Ph2Zn / Et2Zn: 53%, 69 %ee (41%, 79 %ee)

Ph2Zn / Me2Zn: 73%, 74 %ee

O

Et

Et2Zn: 71%, 41 %ee

Et

O

Et2Zn: 42%, 8 %ee

Org. Lett 2001, 3, 4259

Helical-Chiral Transition Metal Complexes

CM(R/S)( / )

Design of Pentacoordinating Bis(oxazoline) Ligands

A. Borovik et al., Science 2001

SpacerO

N N

O

XH HX

RR

Y Y

Y Y

n n

SpacerO

N N

O

X X

RRFe

OOH

YYY Y

n n

N FeNN

X

NO

OO

NR

R

N

O

R

H H

H

X = O, OH

Second Generation Bis(oxazoline) Ligands for Iron

N

XX

N

OO

N

Y Yn n

O

N N

O

X X

Y Y

n n

N

m m

1st generation 2nd generation

n n

Oxazolines as Modular Building Blocks

N

XX

N

OO

N

Y Yn n

N

XX

O

N

Yn

Lg

O

N

Y n

Lg

N

LgLg

O

N

Yn

X

O

N

Y n

X

Nucleophile / Electrophile

N

YY

N OO N

X Xn n

N

XX

O

N

Lgn

X

O

N

Lgn

X

O

N

Yn

X

O

N

Yn

X

Nucleophile / Electrophile

N

LgLg

Pentadentate Bis(oxazolines)

NH3Cl

MeO

O

OH

NH

OEtPh

N

O

O

OMe

Ph

N

OPh

MsO

NMeHN NHMe

N

NN

N

OO

N

PhPh

N

OPh

HO

20h, 85˚C

88% (crude)

DIBAH (3.0 eq)91% (>97% ee)

or

LiAlH4 (0.51 eq)

64% (>97% ee)

MsCl , NEt3

96%K2CO3, CH3CN,

reflux, 31 h

46%+

N(NN)2

Adv. Synth. & Catal. 2004, 346, 737


N(SN)2

N

S S

O

N N

O

Ph Ph

N

HS SH

Ph

N

O

+

(2.1 equiv) (1.0 equiv.)

72%

NaH (2.1 equiv.)

DMF, 0°C to rt, 18 h

MsO

Adv. Synth. & Catal. 2004, 346, 737


N

O O

O

N N

O

Ph Ph

N

Cl Cl

Ph

N

O

+

(2.1 equiv) (1.0 equiv.)

73%

NaH (2.1 equiv.)

DMF, 0°C to rt, 15 h

HO

N(ON)2

Adv. Synth. & Catal. 2004, 346, 737

Complex Preparation

N

X X

O

N N

O

Ph Ph

+

M(ClO4)n

N

X X

O

N N

O

Ph Ph

X = O, S

M

N(XN)2-Perchlorates - Rainbow Chemistry

MII-N(ON)2

MII-N(SN)2

Mn Fe Ni Cu Zn

Mn Fe Ni Cu Zn

What did we get?

Possible Configurations with Linear Pentadentate Ligands A-B-C-B-A:

22achiral

each as pair of enantiomers

[Ru(N(SN)2)Cl]Cl and [Co(N(SN)2)(THF)](OTf)2

Front View (Ru) Front View (Co)

2

N(SN)2-Complexes in Solution

M

2

2 configuration also in solution?

Ru

Fe

Co

N(SN)2-Complexes in Solution

CD-spectroscopy of M(II)-N(SN)2-Perchlorates

2 configuration for all complexes (?)

M

2

N(ON)2-Complexes in Solution

CD-spectroscopy of M(II)-N(ON)2-Perchlorates

2 configuration for Cu and Ni, 2 for Zn?

M

2

M

2

Cu(II)-complexes

CD-spectroscopy of Cu(II)-N(XN)2-Perchlorates

2 configuration, analogous complexation

M

2

Zn(II)-complexes

CD-spectroscopy of Zn(II)-N(XN)2-Perchlorates

2 -configuration for N(SN)2, 2 for N(ON)2 !

–––– Zn-N(SN)2

•••••• Zn-N(ON)2

M

2

M

2

Zn(N(ON)2

Zn(N(SN)2

Ligand dependant helical conformation

2 for [Zn(II)-N(ON)2](ClO4)22 for [Zn(II)-N(SN)2](ClO4)2

Angew. Chem. Int. Ed. 2005, 44, 2422

Fe(II), Cd(II) and Mg(II) complexes

N

OO

O

N N

O

Ph PhFeII(ClO4)2 * 6 H2OCdII(ClO4)2 * 6 H2OMgII(ClO4)2 * x H2O THF

[FeII(L)(H2O)2](ClO4)2 * THF [CdII(L)(H2O)2](ClO4)2 * x solv. [MgII(L)(H2O)2](ClO4)2 * x solv.

Inorg. Chem. 2005, 44, 4630

CdCl2CdBr2

Inorganic-Organic Hybrid Polymers

J. Am. Chem. Soc. 2004, 126, 11426

N

OO

O

N N

OPh Ph

MeOH, reflux

CdX2 (1.0 equiv.)

Coordination Chemistry of N(XN)2 Bis(oxazolines)

J. W oon BooC. BoehmR. B. ChhorE. JezekB. NosseA. Gheorghe

M. HaqueA. SchallM. SeitzS. SoergelY. Shinde

Deutsche ForschungsgemeinschaftDAAD / BMBF (IQN)BACATECFonds der Chemischen IndustrieStudienstiftung des Deutschen V.MateriaC-TriDegussaNovartisSelectide

F. GnadS. De PolR. PatilG. HeimgärtnerZ. ChangDr. A. Matsuno

A. KaiserA. Gißib lC. GeigerR. W eisserS. Eibauer

A. RoithmeierK. DöhringG. AdolinR. TomahaghY. RotermundH. Ohli

Dr. P. Kreitmeier Dr. C. Hirtreiter (IQN) Dr. M. Zabel (Xray)

KooperationspartnerProf. A. Beck-Sickinger, LeipzigProf. H. Waldmann, DortmundDr. O. Zerbe, ZürichProf. Mayoral, ZaragossaProf. Majoral, TolouseProf. M. G. Finn, Scripps

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