Post on 17-Sep-2018
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
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. A. Evans et al., J. Am. Chem. Soc. 2003, 125, 8706
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
D. A. Evans et al., J. Am. Chem. Soc. 1993, 115, 5328
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
Dendrimers for immobilization of aza(bisoxazolines)
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)
Dendrimers for immobilization of aza(bisoxazolines)
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
F. Jaroschik, in collaboration with J.-P- Majoral
Dendrimers for immobilization of aza(bisoxazolines)
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
F. Jaroschik, in collaboration with J.-P- Majoral
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
Pentadentate Bis(oxazolines)
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
Pentadentate Bis(oxazolines)
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