Synthesis and Applications of Highly Stable Non-Symmetrical Heterocyclic Carbenium Ions
Cyril Nicolas
Group of Prof. Jérôme Lacour
Department of Organic Chemistry
April, 28th 2008
Highly Stable Carbocations
The higher the pKR+ value, the higher the stability of the cation
pKR+ = Hx + log
R3C+ + H2O R3COH + H+
[R3C+]
[R3COH]
KR+
Articles: J. Am. Chem. Soc. 1988, 110, 633 J. Am. Chem. Soc. 1977, 99, 4721 J. Am. Chem. Soc. 1971, 93, 4715 J. Chem. Soc. 1949, 1724
pKR+ = 10
pKR+ = 13
O O
O
pKR+ = 9.1
pKR+ = 4.2
N
pKR+ = 9.75
S
pKR+ = 0.1
O
pKR+ = 1.1
Diffenbach, R. A.
Thame, N. G.
J. C. Martin
Komatsu, K.
Phillips, J. N.
Freedman, H. H
N N
pKR+ = 9.36
N N
N
Malachite Green Crystal Violet
Phillips, J. N.
Phillips, J. N.
O OHO
COOH
Fluoresceine
Laursen, B. W.; Krebs, F. C. Angew. Chem., Int. Ed. 2000, 39, 3432
MeO OMeOMe
OO
OMe
Me
MeN
N
R
RN
R
Y-
180 °C, NMP
RNH2 (excess)
R = Me, nPr, nHex, nOct
Y-
Y- = PF6-, BF4
-
Synthesis
Triazatriangulenium Cations and Derivatives - Synthesis
MeOOMe
O
OMe
O
MeMe
H2N R
MeO OMeOMe
O
OMe
O
MeMe
NH2
R
NR
HMeO N
O
OMe
O
MeMe
R
OMe
-MeOH -H+ -MeOH
MeO N
O
OMe
O
MeMe
R
Y- Y- Y- Y-
c 10-5 M (CH2Cl2)Light absorption Light emission
Triazatriangulenium Cations and Derivatives – Synthesis and Properties
OMe
O O
OMeMeO OMe
Me Me
pKR+ ~ 6.1
OMeN OMeR
O O
Me Me
pKR+ ~ 11
RNH2
rt
RNH2
N
O
N
O
MeMe
RR
pKR+ ~ 19
110 °C
RNH2
NNRR
N
R
pKR+ ~ 24
180 °C
J. Am. Chem. Soc. 1983, 105, 2889
Ito
J. Org. Chem. 1999, 64, 5815
Triazatriangulenium Cations and Derivatives – Stability
OMe
O O
OMeMeO OMe
Me Me
pKR+ ~ 6.1
OMeN OMeR
O O
Me Me
pKR+ ~ 11
RNH2
rt
RNH2
N
O
N
O
MeMe
RR
pKR+ ~ 19
110 °C
RNH2
NNRR
N
R
pKR+ ~ 24
180 °C
C2-Symmetric [4]Helicenium - Synthesis and Configurational Stability
Synthesis
PF6-
MeO OMeOMe
O
OMe
O
MeMe PF6-
N
O
N
O
MeMe
RR
110 °C, NMP
RNH2 (excess)
R = Me, nPr
pkR+ ~ 19
O
NN
O
nPrnPr
M-Enantiomer
X-ray : R = Pr
O
N N
O
nPrnPr
P-EnantiomerFrom the X-ray of
Laursen, B. W. and Krebs, F. C.
C2-Symmetric [4]Helicenium - Synthesis and Configurational Stability
Synthesis
PF6-
MeO OMeOMe
O
OMe
O
MeMe PF6-
N
O
N
O
MeMe
RR
110 °C, NMP
RNH2 (excess)
R = Me, nPr
pkR+ ~ 19
Angew. Chem. Int. Ed. 2003, 42, 3162
Resolution process: Ion pairing with enantiopure BINPHAT anion
PO
O
OO
ClCl
Cl
Cl
Cl
ClCl
Cl
O
O
From (R)-BINOL
()-BINPHAT
d.e. > 96%
Me2NH2
Ph.D thesis A. Londez, 2000.
O
NN
O
nPrnPr
Ph.D thesis C. Herse, 2003.
Org. Lett. 2000, 2, 4185
Configuration assignment (VCD spectroscopy)
Angew. Chem. Int. Ed. 2003, 42, 3162
t1/2 = 13.4 min (196 °C)
154.3 kJ.mol-165-67 kJ.mol-1t1/2 = 1 h (57 °C)
98 kJ.mol-1
Hellwinkel, Martin
65-67 kJ.mol-1t1/2 = 1 h (57 °C)
98 kJ.mol-1
Hellwinkel, Martin
Hellwinkel, Martin
C2-Symmetric [4]Helicenium - Synthesis and Configurational Stability
Synthesis
PF6-
MeO OMeOMe
O
OMe
O
MeMe PF6-
N
O
N
O
MeMe
RR
110 °C, NMP
RNH2 (excess)
R = Me, nPr
pkR+ ~ 19
Racemization Barrier (determined using CSP-HPLC after derivatization into neutral adducts)
Addition adducts
X
O
NN
O
RR
R-M
O
NN
O
RR
R
R = CH3, CH2CN, CH2SO2R, CH2S(O)pTol*
Addition adducts – New Resolution Method
50
-50
0
400250 300 350
[nm]
---
(M)
[]D=-650
c = 0.1, CH2Cl2
1
CD (CH2Cl2, 10-5 M)X-ray
1
O
NN
O
iPriPr
S
O
p-Tol
(R)
racemic
O
NN
O
RR
R = nPr, iPr, nOct, cHex, ...
MeS
p-Tol
O
(R)
(SiO2, Et2O)
LDA O
NN
O
RR
S
O
p-Tol
(R)
1:1 mixture of diastereomers78-88% yield
Scaled-up to 10 mmol of cation (5g)
THF, 0 °C
R = nPr
Sulfoxides
Angew. Chem. Int. Ed. 2005, 44, 1879Ph.D thesis B. Laleu, 2006
[]D=+830
c = 0.1, CH2Cl2
2
(P)
50
-50
0
400250 300 350
[nm]
---
(M)
CD (CH2Cl2, 10-5 M)X-ray
racemic
O
NN
O
RR
R = nPr, iPr, nOct, cHex, ...
MeS
p-Tol
O
(R)
LDA O
NN
O
RR
S
O
p-Tol
(R)
1:1 mixture of diastereomers78-88% yield
Scaled-up to 10 mmol of cation (5g)
THF, 0 °C
Sulfoxides(SiO2, Et2O)
1
R = nPr
2
O
N N
O
iPriPr
S
O
p-Tol
(R)
Addition adducts – New Resolution Method
Angew. Chem. Int. Ed. 2005, 44, 1879Ph.D thesis B. Laleu, 2006
[]D=-650
c = 0.1, CH2Cl2
1
racemic
O
NN
O
RR
R = nPr, iPr, nOct, cHex, ...
MeS
p-Tol
O
(R)
LDA O
NN
O
RR
S
O
p-Tol
(R)
1:1 mixture of diastereomers78-88% yield
Scaled-up to 10 mmol of cation (5g)
THF, 0 °C
Sulfoxides(SiO2, Et2O)
1
R = nPr
2
O
NN
O
RR
S
O
p-Tol
(R)
E+
(M)O
NN
O
RR
S
EO
p-TolH
O
NN
O
RR
S
p-Tol
Addition adducts – New Resolution Method
Angew. Chem. Int. Ed. 2005, 44, 1879Ph.D thesis B. Laleu, 2006
[]D=-650
c = 0.1, CH2Cl2
1
Pummerer rearrangement
racemic
O
NN
O
RR
R = nPr, iPr, nOct, cHex, ...
MeS
p-Tol
O
(R)
LDA O
NN
O
RR
S
O
p-Tol
(R)
1:1 mixture of diastereomers78-88% yield
Scaled-up to 10 mmol of cation (5g)
THF, 0 °C
Sulfoxides(SiO2, Et2O)
1
R = nPr
2
O
NN
O
RR
S
O
p-Tol
(R)
E+
(M)O
NN
O
RR
S
EO
p-TolH
O
NN
O
RR
S
p-Tol
Addition adducts – New Resolution Method
Angew. Chem. Int. Ed. 2005, 44, 1879Ph.D thesis B. Laleu, 2006
[]D=-650
c = 0.1, CH2Cl2
1
Pummerer rearrangement
racemic
O
NN
O
RR
R = nPr, iPr, nOct, cHex, ...
MeS
p-Tol
O
(R)
LDA O
NN
O
RR
S
O
p-Tol
(R)
1:1 mixture of diastereomers78-88% yield
Scaled-up to 10 mmol of cation (5g)
THF, 0 °C
Sulfoxides(SiO2, Et2O)
1
R = nPr
2
O
NN
O
RR
S
O
p-Tol
(R)
E+
(M)O
NN
O
RR
S
EO
p-TolH
O
NN
O
RR
S
p-Tol
Addition adducts – New Resolution Method
Angew. Chem. Int. Ed. 2005, 44, 1879Ph.D thesis B. Laleu, 2006
[]D=-650
c = 0.1, CH2Cl2
1
Pummerer fragmentation
racemic
O
NN
O
RR
R = nPr, iPr, nOct, cHex, ...
MeS
p-Tol
O
(R)
LDA O
NN
O
RR
S
O
p-Tol
(R)
1:1 mixture of diastereomers78-88% yield
Scaled-up to 10 mmol of cation (5g)
THF, 0 °C
Sulfoxides(SiO2, Et2O)
1
R = nPr
2
O
NN
O
RR
S
O
p-Tol
(R)
E+
O
NN
O
RR
S
EO
p-TolH
97%
(M)O
NN
O
RR
Addition adducts – New Resolution Method
Angew. Chem. Int. Ed. 2005, 44, 1879Ph.D thesis B. Laleu, 2006
-50
0
50
100
235 335 435 535 635
0
25
50
75
CD / UV
x
103
(M -1
·cm
-1)
(
M -1
·cm
-1)
PF6-
O
N N
O
iPriPr
e.e. > 96%
[ ]365 = + 10200 (c = 5.7•10-3, CH2Cl2)[ ]435 = + 7600 (c = 5.7•10-3, CH2Cl2)
PF6-
O
NN
O
iPriPr
e.e. > 96%
[ ]365 = - 10000 (c = 5.7•10-3, CH2Cl2)[ ]435 = - 7300 (c = 5.7•10-3, CH2Cl2)
Addition adducts – New Resolution Method
1
2
3
4
(SiO2, Et2O)
Ratio: 30, 21.5, 35, 13.5%
35%
30%
21.5%
13.5%
Me
S
O
pTol(R)
LDA
THF, 0 °C, 76%
110 °C, NMP
nPrNH2 (excess)
90 min, 65%
OMeN OMePh
O O
Me Me
pKR+ ~ 11
BF4-
110 °C, NMP
PhNH2 (excess)
90 min, 95%
OMe
O O
OMeMeO OMe
Me Me
pKR+ ~ 6.1
BF4-
N
O
N
O
MeMe
nPrPh
pKR+ ~ 19
BF4-
Addition adducts – New Resolution Method
Ph.D thesis B. Laleu, 2006
O
(R)NN
O
Ph
S
O
pTol(R)
O
(S)NN
O
nPrPh
O
SpTol
(R)
nPr
(M) (M)1 2
O
(S)N N
O
PhnPr
O
(R)N N
O
PhnPr
S
O
pTol(R) S
O
pTol(R)
(P)(P)3 4
Test reactions
Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis
BF4-
180 °C, NMP
MeO OMeOMe
O
OMe
O
MeMe
RNH2 (excess)N N
N
R R
RBF4
-
pkR+ ~ 24
R = (CH2)2OH, nPr, nHex,nOct
Synthesis of Triazatriangulenium salts
T+
~ 45%
-Ketoester alkylation
Aziridination of styrene
Epoxidation of trans-chalcone
Addition of Dichlorocarbene to Styrene
Org. Lett. 2006, 8, 4343
Is it possible to use them as phase-transfer catalyst (PTC) ?
Test reactions
Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis
BF4-
180 °C, NMP
MeO OMeOMe
O
OMe
O
MeMe
RNH2 (excess)N N
N
R R
RBF4
-
pkR+ ~ 24
R = (CH2)2OH, nPr, nHex,nOct
Synthesis of Triazatriangulenium salts
T+
~ 45%
-Ketoester alkylation
Aziridination of styrene
Epoxidation of trans-chalcone
Addition of Dichlorocarbene to Styrene
O
CO2Me
catalyst (mol %)PhCH2Br
OCO2Me
Ph50% KOH aq, 20 °CCH2Cl2
entry catalyst yield (%)amol %
1
432
567
time (h)
55R = n-prop65
R = n-oct
0TBABb
R = n-hex
50R = (CH2)2OH
85
19 011
111
none
101010
1010
95c3 5R = n-oct
aYield measured by 1H-NMR spectroscopy using mesit--ylene as internal reference. b TBAB = [N+(nBu)4]Br-.c85% isolated yield.
-
Org. Lett. 2006, 8, 4343
Test reactions
Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis
BF4-
180 °C, NMP
MeO OMeOMe
O
OMe
O
MeMe
RNH2 (excess)N N
N
R R
RBF4
-
pkR+ ~ 24
R = (CH2)2OH, nPr, nHex,nOct
Synthesis of Triazatriangulenium salts
T+
~ 45%
-Ketoester alkylation
Aziridination of styrene
Epoxidation of trans-chalcone
Addition of Dichlorocarbene to Styrene
Org. Lett. 2006, 8, 4343
Ph Ph
Ocatalyst (10 mol %)
30% H2O2
Ph Ph
OO
50% KOH aq Triton X-100 (1 mol %)
iPr2O, 20 °C
aConversion determined by HPLC analysis (Nucleosil 50-5,hexane : iPrOH 99:1, 0.5 mL·min-1, 23 °C, 230 nm); bIsolatedyields after chromatography (SiO2, hexane : EtOAc 9:1, Rf 0.22).
catalyst yield (%)bconversion (%)a
time (h)
no 18 0 0TBAB 17 45 35
162117R = (CH2)2OH232717R = n-prop222617R = n-hex445017R = n-oct
Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis
BF4-
180 °C, NMP
MeO OMeOMe
O
OMe
O
MeMe
RNH2 (excess)N N
N
R R
RBF4
-
pkR+ ~ 24
R = (CH2)2OH, nPr, nHex,nOct
Synthesis of Triazatriangulenium salts
T+
~ 45%
Org. Lett. 2006, 8, 4343
Ph PhCl
ClCHCl3, KOH powder
catalyst (2 mol %)CH2Cl2, 40 °C, 6 h
catalyst yield (%)aconversion (%)a
equiv. CHCl3 / KOH
no 5 12 10TBAB 5 100 100
16165R = (CH2)2OH27285R = n-prop27275R = n-hex26265R = n-oct
18-C-6 5 100 >95c
182020no68d7020R = n-oct
aConversions and yields determined by 1H-NMR using mesityleneas internal reference. c 90% isolated yield obtained by distillation on a 10 mmol scale of styrene. d 65% isolated yield obtained bydistillation on a 10 mmol scale of styrene.
Test reactions
Triazatriangulenium Cations: Highly Stable Carbocations for Phase-transfer Catalysis
BF4-
180 °C, NMP
MeO OMeOMe
O
OMe
O
MeMe
RNH2 (excess)N N
N
R R
RBF4
-
pkR+ ~ 24
R = (CH2)2OH, nPr, nHex,nOct
Synthesis of Triazatriangulenium salts
T+
~ 45%
-Ketoester alkylation
Aziridination of styrene
Epoxidation of trans-chalcone
Addition of Dichlorocarbene to Styrene
Org. Lett. 2006, 8, 4343
Ph + MeS
O
O
NCl
Na Ph
N
Tscatalyst (10 mol %)
CH2Cl2 : H2OI2, 20 °C
entry catalyst yield (%)bconversion (%)a
1
432
9 7232816
567
20
8
573037
R = n-propR = n-hexR = n-oct
R = (CH2)2OHTBAB
no 35
aConversion was determined by HPLC analysis (Nucleosil 50-5,hexane, 0.5 mL·min-1, 23 °C, 254 nm; tR: 6.19 min (styrene), 7.99 min (phenanthrene)). bYield of isolated product after columnchromatography (SiO2, hexane : EtOAc 9:1, Rf 0.26)
time (h)
555
5524
R = n-hex 24 82~1008095TBAB 15
O
CO2MePhCH2Br (1.2eq)
OCO2Me
Ph50% KOHaq, 25 °C
entry catalyst yield (%)atemperature°C
1
54
2
0
678
25
time (h)
none
75[1][BF4]
~10025rac-[2][BF4]
TBAB
25 60rac-[2][BF4]
2525 85
1.5 551.51.51.51.5
19
1.5 531.5 28
25250
M-[2][BF4]
M-[2][BF4]P-[2][BF4]
aYield measured by 1H-NMR spectroscopy using mesitylene as internalreference.bThe enantiomeric excesses were determined by CSP-HPLC (Chiralpak-IB DAICEL, 0.5 ml.min-1, hexane/iPrOH 95:5, 23 °C, 254.4 nm.
ee (%)bmol %
-
1010102.72.72.72.7
-
----000
3
[1][BF4]
Phase-Transfer Catalysis with Enantiopure C2-Symmetric [4]Helicenium Ions
(M)-[3][BF4](P)-[3][BF4]
O
CO2MePhCH2Br (1.2eq)
OCO2Me
Ph50% KOHaq, 25 °C
entry catalyst yield (%)atemperature°C
1
2
time (h)
(rac)-[3][BF4] -5 17
2.2 20
2.2
2.2 20
-5
-5
(M)-[3][BF4]
(P)-[3][BF4]
aYield measured by 1H-NMR spectroscopy using mesitylene as internal reference. cTheenantiomeric excesses were determined by CSP-HPLC (Chiralpak-IB DAICEL, 0.5 ml.min-1, hexane:iPrOH 95:5, 23 °C, 254.4 nm.
ee (%)bmol %
2.7
2.7
2.7
0
0
03
Phase-Transfer Catalysis with Non-Symmetrical [4]Helicenium Ions
Geodesic Polyarenes and Carbon Nanotubes
O
O
X
(f,sC)-C76-D2
Diederich, F.
Agranat , Curl, Dresselhaus, Haddon, Hirsch, Kroto, Mehta,
Paquette, Prakash, Rabideau,
Scott, Siegel, Smalley
C60
OO
OMe
X
X
X
OO
OMe
X
XX
Siegel, J.
J. Org. Chem. 1992, 57, 61
MeMe
Me
Me
Me
Me
D3
Ar
Ar
Ar
Ar
Ar
N
N
Siegel, J.
Mascal, M.
Galow, T. H
Rabideau, P. W
J. Am. Chem. Soc. 2007, 129, 13193
J. Org. Chem. 2007, 72, 4323
J. Am. Chem. Soc. 2007, 128, 6870
J. Am. Chem. Soc. 1995, 117, 6410
Reviews: Chem. Rev. 2006, 106, 5049 Chem. Rev. 2006, 106, 4843 Chirality 2005, 17, 404 Chem. Rev. 2006, 106, 4868 Tetrahedron 1998, 54, 13325
Trioxatricornan – a Chiral Cup-Like Molecule
OO
O
O O
OMeLi
(R)
R'M
ZY
X
Y Z
XR'
(R)
X, Y, Z = NR or O
Synthesis and Resolution of a Chiral Cup-Like Molecule
OMe
O O
OMeMeO OMe
N
O
N
O
MeMe
PrPh
OMeN OMePh
O OMeMe MeMe
NNPrPh
O
NN
O
Ph PrN N
O
PhPr
MeLi, THF
0 °C, 16 h, 97%
NH2
110 °C, 1.5 h
95%
nPrNH2, NMP
120 °C, 2 h, 65%
LiI, NMP, 64%
180 °C, 1.5 h
(S) (R)
Synthesis
Synthesis and Resolution of a Chiral Cup-Like Molecule
Inte
nsity
(ar
b un
its)
time (min)
Chromatographic Resolution
Daicel OJ-H (99.5/0.5 hex / i-PrOH), 0.5 mL/minIn collaboration with E. Francotte (Novartis)
17.2 min
30.8 min[]589 = +16.1 ± 1.4 (c = 1 mg / 1 mL)
[]589 = -13.2 ± 1.6 (c = 1 mg / 1 mL)
(R) Enantiomer (S) EnantiomerN N
O
PhPr
(R)NN
O
Ph Pr
(S)
ECD Spectra
First eluted fraction(dextrogyre)
-5
0
5
400300 350Wavelength[nm]
C = 4 10-5 mol.l-1
Second eluted fraction(levogyre)
Synthesis and Resolution of a Chiral Cup-Like Molecule
VCD spectra
Wavenumber / cm -112001300140015001600
A
-1.5e-5
-1.0e-5
-5.0e-6
0.0
5.0e-6
1.0e-5
1.5e-5
ECD Spectra
First eluted fraction(dextrogyre)
-5
0
5
400300 350Wavelength[nm]
C = 4 10-5 mol.l-1
Second eluted fraction(levogyre)
First eluted fraction (dextrogyre)
Second eluted fraction (levogyre)
(R) Enantiomer (S) EnantiomerN N
O
PhPr
(R)NN
O
Ph Pr
(S)
Synthesis and Resolution of a Chiral Cup-Like Molecule
In collaboration with T. Bürgi (Neuchâtel)
(S) Enantiomer
In collaboration with T. Bürgi (Neuchâtel)
1, 2.91 kcal/mol 2, 2.86 kcal/mol 3, 0.0 kcal/mol
4, 1.70 kcal/mol
6, 2.30 kcal/mol
8, 1.66 kcal/mol 9, 2.20 kcal/mol
5, not stable
7, not stable
DFT (b3pw91, 6-31++G(d,p))
possible conformers of enantiomer (S)
Synthesis and Resolution of a Chiral Cup-Like Molecule
NN
O
Pr
(S)
NN
O
Ph Pr
(S)
In collaboration with T. Bürgi (Neuchâtel)
DFT (b3pw91, 6-31++G(d,p))
IR spectrum
1, 2.91 kcal/mol 2, 2.86 kcal/mol 3, 0.0 kcal/mol
4, 1.70 kcal/mol 6, 2.30 kcal/mol
8, 1.66 kcal/mol 9, 2.20 kcal/mol
5, not stable
7, not stable
(S) Enantiomer
VCD spectrum
(S)-conformer 3
Wavenumber / cm-1
12001300140015001600
Boltzmannaverage
DFT (b3pw91, 6-31++G(d,p))
85%
Wavenumber / cm-1
12001300140015001600
Boltzmann average
conformer 3
conformer 3
Synthesis and Resolution of a Chiral Cup-Like Molecule
IR spectrum Calculated structure (S enantiomer)
1, 2.91 kcal/mol 2, 2.86 kcal/mol 3, 0.0 kcal/mol
4, 1.70 kcal/mol 6, 2.30 kcal/mol
8, 1.66 kcal/mol 9, 2.20 kcal/mol
5, not stable
7, not stable
DFT (b3pw91, 6-31++G(d,p))
In collaboration with T. Bürgi (Neuchatel)
exp
From Second eluted (levogyre) fraction
Conformer 3A
0.0
0.5
1.0
1.5
2.0
12
3
3
4
4
5
5
6
6
7
7
8
9
10
11
12
10
13
13
14
15
16
14
16
18
18
17
17
12
19
911
12
20
21
22
23
19
20
2122
23
Wavenumber / cm-1
12001300140015001600
A
0.0
0.5
1.0
1.5
2.0
12
3
3
4
4
5
5
6
6
7
7
8
9
10
11
12
10
13
13
14
15
16
14
16
18
18
17
17
12
19
911
12
20
21
22
23
19
20
2122
23
Wavenumber / cm-1
12001300140015001600
(R) Enantiomer (S) EnantiomerN N
O
PhPr
(R)NN
O
Ph Pr
(S)
Synthesis and Resolution of a Chiral Cup-Like Molecule
VCD spectrum
DFT (b3pw91, 6-31++G(d,p))
In collaboration with T. Bürgi (Neuchâtel)
Calculated structure (S enantiomer)From Second eluted
(levogyre) fraction
Wavenumber / cm-1
12001300140015001600
A
0
2e-5
4e-5
12
3
345
6
7
9
10
11
1314
15
16
17
18
19
2123
22
9
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
Wavenumber / cm-1
1400
-5
4e 5
12
3
345
6
7
9
10
11
1314
15
16
17
18
19
2123
22
9
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
exp
Conformer 3
1, 2.91 kcal/mol 2, 2.86 kcal/mol 3, 0.0 kcal/mol
4, 1.70 kcal/mol 6, 2.30 kcal/mol
8, 1.66 kcal/mol 9, 2.20 kcal/mol
5, not stable
7, not stable
(R) Enantiomer (S) EnantiomerN N
O
PhPr
(R)NN
O
Ph Pr
(S)
Synthesis and Resolution of a Chiral Cup-Like Molecule
(S) Enantiomer; []365 = -300 (c = 0.06 g / 100 mL)
VCD spectrum
DFT (b3pw91, 6-31++G(d,p))
In collaboration with T. Bürgi (Neuchâtel)
Calculated structure (S enantiomer)From Second eluted
(levogyre) fraction
Wavenumber / cm-1
12001300140015001600
A
0
2e-5
4e-5
12
3
345
6
7
9
10
11
1314
15
16
17
18
19
2123
22
9
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
Wavenumber / cm-1
1400
-5
4e 5
12
3
345
6
7
9
10
11
1314
15
16
17
18
19
2123
22
9
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
1245
6
7
10
13
16
1721
2219
exp
1, 2.91 kcal/mol 2, 2.86 kcal/mol 3, 0.0 kcal/mol
4, 1.70 kcal/mol 6, 2.30 kcal/mol
8, 1.66 kcal/mol 9, 2.20 kcal/mol
5, not stable
7, not stable
NN
O
Ph Pr
(S)
[]589 = -13.2 ± 1.6 (c = 1 mg / 1 mL)
Conformer 3
Synthesis and Resolution of a Chiral Cup-Like Molecule
What has been achieved
TRIAZATRIANGULENIUM CATIONS
Synthesis: Facile Highly Stable Toward Reactive Bases and
Nucleophiles. Efficient Phase-Transfer Catalysts
CHIRAL CUP-LIKE MOLECULES
Synthesis: Straightforward, Versatile Easy Separation of the Enantiomers by
Preparative CSP-HPLC Determination of the Absolute configuration
by VCD Measurements1, 2.91 kcal/mol 2, 2.86 kcal/mol 3, 0.0 kcal/mol
4, 1.70 kcal/mol 6, 2.30 kcal/mol
8, 1.66 kcal/mol 9, 2.20 kcal/mol
5, not stable
7, not stable
Acknowledgments
Prof. Alexandre Alexakis and Bo. W. Laursen
Prof. Jérôme Lacour
Dr. Gérald Bernardinelli (X-Ray Structures)
Dr. Damien Jeannerat, André Pinto, Jean-Paul Saulnier, Bruno Vitorge (NMR)
Prof. Thomas Bürgi (DFT calculations)
Dr Eric Francotte (HPLC analyses)
Prof. Rainer Herges, Olaf Magnussen (Nanoparticles)
Prof. Robert Deschenaux, Stéphane Frein (Liquid Crystals)
Alexandre Fürstenberg, Prof. Eric Vauthey (DNA Intercalation)
Sandrine Perrothon, Benjamin Elias, Thomas Frossard
Members of the Lacour’s group (past and present)
Christelle Herse
Benoît Laleu
Dr. Pierre Mobian
Members of the Department of Organic Chemistry
Acknowledgments
Nathalie Mehanna (Lacour group)
Mylene Cargouet
Swiss National Science Foundation (SNSF)
Département de l’Instruction Publique (DIP)
Société Académique de Genève
My family, my wife, my two children
Schlegel diagrams
vertice
edges Euler's formula: f+v = e+2
Thilgen, C.; Diederich, F. Chem. Rev. 2006, 106, 5049
1
2
3
4
(SiO2, Et2O)
Ratio: 30, 21.5, 35, 13.5%
35%
30%
21.5%
13.5%
Me
S
O
pTol(R)
LDA
THF, 0 °C, 76%
110 °C, NMP
nPrNH2 (excess)
90 min, 65%
OMeN OMePh
O O
Me Me
pKR+ ~ 11
BF4-
110 °C, NMP
PhNH2 (excess)
90 min, 95%
OMe
O O
OMeMeO OMe
Me Me
pKR+ ~ 6.1
BF4-
N
O
N
O
MeMe
nPrPh
pKR+ ~ 19
BF4-
O
(R)NN
O
Ph
S
O
pTol(R)
O
(S)NN
O
nPrPh
O
SpTol
(R)
nPr
(M) (M)
O
(S)N N
O
PhnPr
O
(R)N N
O
PhnPr
S
O
pTol(R) S
O
pTol(R)
(P)(P)
Addition adducts – New Resolution Method
Ph.D thesis B. Laleu, 2006
-80
-60
-40
-20
20
40
60
330 430 530 630 730
0
(
M -1
·cm
-1)
[ ]D = - 430 (c = 0.06, CH2Cl2)
[ ]D = + 680 (c = 0.06, CH2Cl2)
[ ]D = - 450 (c = 0.06, CH2Cl2)
[ ]D = + 590 (c = 0.06, CH2Cl2)
4
12
3
(M)
(P)
Ratio: 30, 21.5, 35, 13.5%
1
2
3
4
(SiO2, Et2O)
35%
30%
21.5%
13.5%
CD (CH2Cl2 ,10-5 M)
Wavelenght (nm)
Addition adducts – New Resolution Method
Ratio: 30, 21.5, 35, 13.5%
1
2
3
4
(SiO2, Et2O)
35%
30%
21.5%
13.5%
1 2
10-5 M, CH2Cl2
(
M -1
·cm
-1)
-75
-25
25
75
230 330 430 530 630 730
Wavelenght (nm)
50
100
x
103
(M -1
·cm
-1)
0
CD / UV
[ ]435 = - 4600 (c = 0. 6; CH2Cl2)
O
(R)NN
O
Ph
S
O
pTol(R)
O
(S)NN
O
nPrPh
O
SpTol
(R)
nPr HBF4 aq. (30.0 eq.)
(-)-(R,R,M)
Acetone, rt, 6h
(-)-(R,S,M)
+
(M) (M)
Addition adducts – New Resolution Method
Ratio: 30, 21.5, 35, 13.5%
1
2
3
4
(SiO2, Et2O)
35%
30%
21.5%
13.5%
10-5 M, CH2Cl2
(
M -1
·cm
-1)
-75
-25
25
75
230 330 430 530 630 730
Wavelenght (nm)
50
100
x
103
(M -1
·cm
-1)
0
CD / UV
4 3(-)-(R,R,P) (-)-(R,S,P)
+O
(S)N N
O
Ph nPr
S
O
pTol(R)
(P)O
(R)N N
O
nPr Ph
S
O
pTol(R)
(P)
HBF4 aq. (30.0 eq.)
Acetone, rt, 6hO
N N
O
Ph nPr
(P)
e.e. > 98%
[ ]435 = + 4800 (c = 0. 6; CH2Cl2)
Addition adducts – New Resolution Method
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