T. Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
- the atropisomerism phenomenon arises from the hindered rotation around the biaryl bond
HO
- at least two bulky substituents in ortho position to the biaryl axis are needed
HO NH2
HO
iPr
O
O
CHO
OH
P
HO
OHC
OH MeO
MeO
OH
*
HO
Me
P
R
OBz
R OBz
*
MeO
Me
R
S
*
O
O
MeO
S
S
H
N
M
*
M
O
Ph
Ph
*
S
M
OH
*
PPh2
O
Cl
P
E
H O
B
*
R
H O
N
H
O
H
S N
R
R
H O
OH
H O
N
H
F
NHMe
R
Me
G
Me
NH2
OH
OH
vancomycin
the configuration at a biaryl axis often plays an
important role for pharmacological properties
of bioactive compounds and is a fundamental basis for
useful reagents and catalysts in asymmetric synthesis
R
M
R = PPh2: BINOL
R = OMe: MOP
BINOL
H
RN
P
A
OH
*
O
D
O
N
H
NH
HO
Mn
O
H
O
O
O
Cl
R
S
HO2C
(-)-steganone
Me
H
N
HO
OMe
HO
O
calphostine A
Me Me
M
P
C
H
H
Me
O
Me
iPr
(+)-gossypol
O
O
Me
O
O
Me
O
Me
Me
HO
Me
OH
OH
OAc
assigment of the absolute configuration in chiral biaryls:
A A'
A
A'
B'
B
M
*
B B'
B'
A B'
A
A
A'
B'
A'
B
B
M
P
*
B A'
A
A'
B'
B
P
1
T. Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
- intramolecular coupling with chiral tethers
in principle, 3 different strategies are know
1,2-diols as tethers (Lipshutz et al.)
R
R
R
X
X
*
A
X
°
Y
Y
Y
resolution or desymmetrization
of stereochemically not
defined biaryls
direct atroposelective
coupling
O
N
Boc
Me
B
OBn
I
I
Boc
N
Me
Me
NiCl2(PPh3)2 R
nBuLi
PPh3
R
O
Me
P *
50%
O
O
OBn
O R
O R
OBn
OBn
R
R
Cnon-aryl
sugars as tethers (Feldman et al.)
O
Ph
atroposelective biaryl formation by
construction of an aromatic ring
G': R = Bn
G:R=H
Ph
O
OTBDMS
O
TBDMSO
1. Asymmetric C,C coupling
RO
OR
Ph
Ph
OR
- intramolecular coupling with chiral diesters
O
R
O
O
Cu, DMF
X
X
M *
X = Br, I
O
RO
O
M *
O
R'
85-'100' % de
O
O
OBn
O
G'O
73%
*
R'O
R'
O
O
G'O
P
O
*
O
O
OR'
RO
RO
R
O
Pb(OAc)4
RO
Miyano et al.
O
O 4
6
O
OBn
O
GO
R',R' = H
R,R = CPh2
H2, Pd/C
O
tellimagrandin I
(82%)
GO
only one atropisomer
bad yields with bulky substituents ortho to the axis
2
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
chiral amino alcohols as tethers (Schreiber et al.)
peptides as a chiral backbone
R = NHAc
R' = H
R =H
R' = NHAc
Cl
BzO
Cl
O
O
NH
MeHN
VOF3
OH
Cα
O
H
R'
N
* R
H
O
I
avoid 1,3-allylic
repulsion
R
S
R
Cl
BzO
M *
S
N
H
R
N
H
OMe
OMe
OMe
OMe
OMe
Cl
O
*
OMe
OMe
OMe
P
N
H
VOF3
B
heating,
2d
O
S
I
A
MeO
1. nBuLi
2. CuCN
R
de P
de M
Me
Et
iBu
Bn
tBu
94
92
94
88
60
71
80
82
83
33
OMe
BzO
- intermolecular coupling with chiral ortho substituents
OH
O
Cl
Cl
H
H
NHAc
OMe
H
O
OH
O
N R
H
NH
O
A
HP
*
MeHN
OMe
B
OMe
MeO
N
H
NH
O H
O
B
MeO
P,R
Grignard reactions (Meyers et al.)
A
M
MeHN
S
NHAc
H
OMe
MeO
*
Br
OMe
OMe
62%, >94% de
unnatural M-atropisomer
natural S-configuration at Ca
MeO
M *
RN
MeO
+
O
MeO
P
RN
*
O
iPr
OMe N
MeO
O
O
CH2OMe CHOBn CH3
R
OTBS
O
dr
Evans et al.
iPr
iPr
MeO
+
M,S
57%, >94% de
natural P-atropisomer
unnatural R-configuration at Ca
Mg, THF
R
80:20
60:40
58:42 10:90
7:93
electron-donating property of R
3
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
Mechanism and stereochemical course of the SN2 Ar reaction
Ullman reaction (Meyers et al.)
Cu, DMF
O
O
Br
N
P
S
N
S
*
R
O
R
R
de
Ph
iPr
tBu
34%
60%
90%
R
N
only symmetric biaryls are accessible
Suzuki reaction (Colbort et al.)
Pd(OAc)2,
dppf,
S pTol
CsF
R
R
I
+
OH
:
Tanja Gulder
R
M
O
*
99%
B(OH)2
R
:
S pTol
OH
OMe O
OMe
>98% de
like configuration in the side chain necessary (matched case)
O
O
O
O
R Me
I
OH
1. Pd(OAc)2, L
Ba(OH)2
2. NaH, BnBr
P
63%
+
*
MeO
MOM
Cy2P
MeO
OMe
MeO
OMe
NMe2
OBn
MOM
B(pin)
MeO
L=
R Me
Baudoin et al.
68% de
4
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
- intermolecular coupling with planar-to-axial chirality transfer
reaction with chiral dioxocyclophanes (Miyano et al.)
O
O(CH2)10OH
reaction with chiral chromium complexes (Uemura et al.)
Pd(PPh3)4
aq. Na2CO3
MeOH
OHC
Me
M
80%
B(OH)2
(CH2)10
P
hυ, O2
Me
*
OMe
OHC
M
Me
*
*
OMe
CO2iPr
rt
CO2iPr
O
R=H
P
R = OMe
+
*
CO2iPr
OMe
MgBr
OMe
R
(OC)3Cr
~ 50%
- intermolecular coupling with chiral leaving groups
CHO
75%
Br
OHC
OMe
Cr(CO)2
Pd(PPh3)4
aq. Na2CO3
xylene
(OC)3Cr
P
*
hυ, O2
Me
OMe
OHC
P
*
Me
OMe
chiral alcohols
OMe
OMe
anti
MeO
if a carbonyl group is present ortho to the biaryl axis,
both atropisomers are accessible due to a lower rotational barrier
Et2O, benzene
rt
Me
+
R
92%
Me
Me
OMe
xylene, 2h
OHC
P
*
MeO
Me
94% ee
MeO
Me
OMe
98% yield,
96% de
Miyano et al.
chiral sulfoxides
:
tBu
syn
S OO
THF, rt
M
+
(OC)3Cr
O
*
O
Me
*
Me
O
axial isomerization under thermal conditions
M
MeO
M
MgBr
stereochemical inconsistent results
(OC)3Cr
rt
pR
syn
+
OHC
O(CH2)10OH
anti
R
O
*
R
MgBr
thermodynamic favored
Baker and Sargent
R = OiPr 90%, 95% ee
R = NMe2 65%, 95% ee
5
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
10 mol%
- Oxidative Coupling with Chiral Additives
Ph
S
coupling with copper salts
H
CO2Me
R
CuI, O2 H
80%
I
MeO
MeO
HO
HO
P
MeO
S
*
R
O
Me
Me
CO2Me
OMe
OH
81% ee
+
CO2Me
78% ee
CO2Me
20 mol%
(-)-spartein,
CuCl2
P
45%
OH
OH
*
OH
71% ee
Kozlowski et al.
H
O
O
Me
hypocrellin A
OH
I
OH
P
OH
*
I
*
AcO
OMe
M
Nakajima et al.
MeO2C
O
CuCl
OMe
N
HO
MeO
MeO2C
CO2Me
Me
85%
OH
AcO
R
OAc
OMe
H
10 mol%
N
MeO2C
N
H
N
coupling with salen-Ru(II)-nitroso complexes
Mechanism of the homocoupling
Br
OH
H
N
catalyst
hυ, air
82%
Ru
O
Br
M
M
H
NO N
*
O
Cl
Ph
Ph
* M
OH
*
OH
Br
68% ee
Katsuki et al.
6
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
coupling with chiral dinuclear V(-complexes
V-complex,
air
Me 2 mol%
Me
OH
P
*
OH
MgBr
+
OH
MeO
Ph2P
Fe
Br
NiBr2
tBu
tBu
S
S
O
O V
O
O
O
O
O
V
O
N
M *
S
M *
O
O V
O
O
O
O
O
V
O
N
S
tBu
Br
O
O
O V
O O
O
Gong et al.
*
Me
+
M
*
*
Me
MgBr
tBu
Me
99% ee
84:16
O
tBu
76% yield, 91% ee
95% yield, 83% ee
N
Me
Me
*
89%
Me
Me
N
N
M
Rp,S
99% yield, 84% ee
Sasai et al.
Chen and Barhate
using a Negishi coupling
- cross coupling using chiral ligands
20 mol%
using a Kumada coupling
Fe
Me 2-5 mol%
Me
MeO
Ph2P
2
Fe
+
P
Me
*
Br
M
Br
Sp,R
5 mol% Pd2dba3
+
NiBr2
MgBr
OMe
PPh2
Me
Zn
Rp,S
Me
Me
*
R
Me
Me
95%
R
85% ee
Espinet et al.
R=H, Me
Hayashi and Itoh
R=H: 92% yield, 83% ee
R=Me: 69% yield, 95% ee
7
Tanja Gulder
Atroposelective Biaryl Synthesis
Me
using Suzuki coupling
Studies on the Biaryl Fragment of Vancomycin
2-5 mol%
R
Ph2P
Fe
O
Rp,S
O
B(OH)
B(OH)2
Me
PdCl2, Ba(OH)2
+
*
MeO
R
R=OMe: 74% yield, 14% ee
R=NMe2: 44% yield, 63% ee
Cammidge et al.
Me H
Me
I
H
Br
S Me
B(OH)2
N S
H
S
Me
MeO2C
P
Me
+
HO
O
O
H
N
H
H O
P
MeO2C
+
MeO
OMe
MeO
H
S
R N
N
H
H O
M
OH
*
* OMe
*
61%
OMe
R N
H Me
K3PO4
Me
H O
O
S
Iwasa et al.
H
R N
N
H
OMe
O
Pd
MeO2C
Pd(OAc)2 (20 mol-%),
ligand (60 mol-%),
O
S N
S
I
stronger electron donor needed to precoordinate the less basic boronic acid
in the same way as the methoxy substituent does with the magnesium cation
of the aryl Grignard reagent in the Kumada coupling
O
O
+
Me
M
I
+
Baran Group Meeting
10/28/2008
OMe
MeO
49% ee
Me
OH
5 mol%
Pd(OAc)2,
20 mol%
(M)-BINAP
Ligand
M
M
OMe
*
*
PPh2
PPh2
PPh3
(M)-BINAP
(P)-BINAP
Yield [%]
80
40
40
(P):(M)
50:50
>95: 5
< 5:95
OMe
O
Br
Miura et al.
Me
Me
83% yield, 63% ee
(M)-BINAP
Nicolaou et al.
8
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
2. Atroposelctive Transformation of
prostereogenic Biaryls
asymmetric coupling using lead reagents
nBuLi
H
N
MeO
H
OH
MeO
+
1. nonstereoselective C,C-coupling reaction
2. establishing of the absolute configuration
N
brucine
Pb(OAc)3
H
OH
M *
H
precondition of the substrate:
PH2
O
either biaryl has to be
Ph
83% yield, 89% ee
rotational hindered
but achiral
Yamamoto et al.
or
chiral but
configurationally unstable
asymmetric coupling using a organo lithium species
MeO
R
MeO
OMe
R
Ar
OMe
Me
O
Li
N
Li
F
iPr
enantiotopos-differentiating
transformations
Ph
dynamic kinetic resolution
Ph
O
Me
- Desymmetrization configurationally stable but achiral
biaryls compounds
+
F
by an atropoenantiomer-differenting bridge formation
N
iPr
Tomioka et al.
HO
OH
HO
OH
MsO S Me
+
Me
CsCO3
HO
HO
P
O
*
R
O
MsO
M
N
*
Ar
Harada et al.
single diastereomer
stereocontrol is achieved during the second SN2 reaction
9
Tanja Gulder
Atroposelective Biaryl Synthesis
Ph Ph
P
Cl
Pd
Cl
P
atropoenantiomer-differentiating manipulation of ortho substituents
pro M
pro P
TBSO
OTBS
O
Me
TBSO
*
KOtBu, MeI
OTBS
OH
*
Hayashi et al.
Me Me
R''MgCl
90%
*
TfO
R
R
OTf
LiBr or LiI
P
Ph
*
OTf
Me
Me
Ku et al.
HN
HN
Me
Baran Group Meeting
10/28/2008
92% yield, 94%ee
Me Me
Me
- atropselective conversion of axially chiral but configurationally unstable biaryls
central-to-axial chirality transfer
selective introdction of a ortho substituent
MeO
MeO
O
°
1. TBAF
2. PPH3, DEAD
H
Me
HN
Me Me
M
Me
OTBS
OTBS
*
Sp,R
Fe
OMe
PPh2
Me
70%
anti-inflammatory
drug candidate
A-240610.0
98% de
HN
Me
Et
°
Rh(Cl(cyclooctene)2)2
ethene
N
AcO
R
OAc
Candida antarctica
or
Pseudomonas capacia
lipase
M
*
AcO
Matsumoto
et al.
Me
N
Et
37% yield, 49%ee
atropodiasteroselective bridge formation
R
Ph
OH
°
R
Me
Me Me
Murai et al.
*
°
CH2OBn
CAL: 80%, 97%ee 57%, 99%ee 68%, 99%ee
PCL: 86%, 99%ee 67%, 96%ee 94%, 98%ee
COCl
O
O
O
HO
3
HO 2
OMe
COCl
Nativi et al.
Ph
O
O
O
3
O
O
O 2
O
OMe
P
NaH
*
40%, single
atropdiastereomer
10
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
H2N
R
Ph
R
COCl
* M
HO
N
+
HO
°
COCl
HO
O
X
N
°
OEt
* M
P
O
R
O
toluene
∆
*
O
MeO2C
MeO2C
N
O
R
COOH
R
N
°
57-80% yield, single diastereomer
DCC
DMAP
NBoc2
O
P
*
HO
N
65%, single atropisomer
R
N
HO
O
M *
O
HO
R
N
atropodiastereoselective metal bridge formation
O
O
R
R
Yield
ee
H
Me
Ph
tBu
67%
66%
67%
52%
89%
92%
89%
67%
OTf
R
R
S
O
Hayashi et al.
H
N O
Boc
Feldman et al.
N
NBoc2
O
N
Boc
1. mCPBA
2. NaOH
R
N
O
OH
HO
O
Me
atroposelective macrolactonization of the diazonamide model
M *
O
1. mCPBA
2. NaOH
N
M *
S
N
O
* M
N
O
HN R
Ph
Levacher et al.
R
N
°
Me
NEt3
rt
O
X
OEt
Me
R
O
O
toluene
O
O
Ph
N
O
°
N
N
CuOTf
S
O
R
O
*
P Cu
N
R=iPr, tBu, Ph, Bn
R
single diastereomer
Ikeda et al.
cyclopropanation catalyst
M atropoisomer disfavored due to severe steric interactions of Rs
11
Tanja Gulder
Atroposelective Biaryl Synthesis
1. H2N
Me
R'
S
S
Ar2
P
RuCl2
P
Ar2
°
Baran Group Meeting
10/28/2008
H2N
Ar2
Cl H
N
P
Ru
P Cl N
H
Ar2
Me
P
2. iPrOH, ∆
*
Me
R
R
R
ligand
R''MgBr, Ni(cod)2
S
P
R'
Noyori et al.
14--95% ee
*
PPh2
*
R
Me
P
R''
R
SH
R
'100%' de after heating
O
Hayashi et al.
- atroposelective cleavage of bridges
PPh2 N
S
Lactone concept (Bringmann et al.)
R
iPr
DCC,
DMAP
OH
+
O
3. Asymmetric Biaryl Synthesis by Construction
of an Aromatic Ring
Br
CO2H
R
Br
O
[2+2+2]-cycloaddition
R
R
10 mol%Pd(OAc)2,
PPH3, NaOAc
dynamic kinetic resolution
R
OMe
H Ph
R
°
°
R
O
O
H Ph
N
B
O
N
lactone can also
be opened by chiral
N and O nucleophils,
e.g.
OH
*
OH
89% ee
or HO
OMe
10 mol% IrCl(cod)2,
20 mol% Me duphos
+
X
*
Me
OH
R
R
O
Me
BH3
NH2
Me R
R
B
R
R
BH3
M
OMe
R
Me
R
Gutnov and Heller
Ph
S
*
hυ
N
Ph
M
Me
+ C
O
O
N
Co
1 mol%
R
P
*
Me
OMe
OH
P S
Me
Me
R=O, NTs, CH2, C(CO2Et)
R
Shibata et al.
OMe
X
S
OMe
*
P S
Me duphos
S
Me
>99% ee
12
Tanja Gulder
Baran Group Meeting
10/28/2008
Atroposelective Biaryl Synthesis
Dötz benzannulation of Fischer carbenes
central-to-axial chirality transfer
Cl
Cl
Cl
S
TiCl4, -78°C
S
Me
R
OH
R'
THF, ∆
O R Me
M *
R
Nishii and Tanabe
HO
Ph
(OC)3Cr
+
R'
Me
Ph
Ph
O
P *
O
Me
O R Me
(OC)3Cr
Ph
Wulff et al.
HO
4. Literature
G. Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser,
J. Garner, M. Breuning; Atroposelective synthesis of axially chiral
biaryl compounds- Angew. Chem. Int. Ed. 2005, 44, 5384.
J. Hassan, M. Sevignon, C. Gossi, E. Schulz, M. Lemaire; Aryl-aryl
bond formation one century after the discovery of the Ullmann
reaction.Chem. Rev. 2002, 102, 1359.
O
Me
Yb(OTf)3
OMe
OH
Me
R
+
OMe
R
single
diastereomer
MgBr
R
(CF2CO)2O
Hattori and
Miyano
M
*
OMe
Me
DDQ
M
*
OMe
Me
K. Kamikawa, M. Uemura; Stereoselective synthesis of axially chiral
biaryls utilizing planar chirality. Synlett 2000, 938.
M.S. Sigman, D.R. Jensen, S. Rajaam; Catalytic enantioselective
oxidations using molecular oxygen. Curr. Opin. Drug Discov. Develop.
2002, 5, 860.
T.D. Nelson, R.D. Crouch Cu, Ni and Pd mediated homocoupling
reactions in biaryl synthesis, Vol.63, Wiley, New Yersey, 2004, 265-555.
O. Baudoin; The asymmetric Suzuki coupling route to axially
chiral biaryls. Eur. J. Org. Chem. 2005, 4223-4229
G. Bringmann, T. Gulder, T.A.M. Gulder; Asymmetric synthesis of
biaryls by the 'lactone method', in Asymmetric Synthesis 2007, 246.
13