stereochemical relay through oligoureas - is it possible to control the orientation of the helix...
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Stereochemical relay through oligoureas
- Is it possible to control the orientation of the helix with a chiral group A?- Is it possible to control a stereoselective reaction on B ?
P M
n
(1, 21+6n) diastereoselectivity
N
O
NN
O
N N
O
N
N
O
NA* B
N
O
NN
O
N N
O
N
N
O
N
N
O
N N
O
NN
O
N
N
O
N
Racemic mixture of interconverting helices
cis
11/11/2004
Synthesis
BnN
+ NNC
OC
ON
O
N N N
O
Bn Bn
ii) NaH 3 eqMeI 3 eq
THF
56% (2 steps)
H
NH2
+ NNC
OC
ON
O
N N N
Oii) NaH 5 eqMeI 5 eq
THF
R = i-Pr 85%R = Et 83%
R
R R
(2 steps)
R'
R' = H
R' = R = Et 75%
H2N NH2+
NC
O
THF
overnight
MeN
O
MeN
MeN
MeN
O
HN
O
HN
HN
HN
O
1) NaH
2) MeI
73% (2 steps)
THFovernight
Br
NH2
+N
CO
NO2THF NaH 3 eq
MeI 3 eq
N N
O
NO2
Br
H H
N N
O
NO2
Br
K2CO3 5 eq
MeI 5 eq
99%
NaOH 3 eq
MeI 3 eq 20 %
H2N NH2+
NC
O
THF
4h
HN
O
HN
HN
HN
O
HN
O
HN
HN
HN
O
NO2 O2N NO2
Pd-C, H224h
DMF
H2N NH2THF
NC
O
O2N
N
O
N NO2NN
O
O2N
3
1)
2) NaH, MeI overngiht
4h
Synthesis
Br
NH2
+ NNC
OC
ON
O
N N N
OBr Br
ii) NaOH 3 eqMeI 3 eq
THF
46% (2 steps)NaH 3 eqMeI 3 eq
NH2
+ NC
O
COOMe
R
NH
NH
C
OR
MeOOC
NH
+
N
O
N N N
OPyridine 2 eq
DCMR OPhCl
O COOMe
N OPh
O
NaH or Pyridineor n-BuLi
HN
HN R R
R = COOMe 97%R = COPh 88%
Synthesis
NH2
+
N
O
N NO2
H
Pyridine 2 eq
DCMBr OPhCl
O Br
N OPh
O
H AlMe3Toluene 50°C
HN NO2
Br91%
17%
Synthesis
nn AA BB StepsSteps YieldsYields
11 ss-Bu-Bu HH 44 57%57%
22 ss-Bu-Bu HH 66 47%47%
33 ss-Bu-Bu HH 88 48%48%
33 ss-Bu-Bu ii-Pr-Pr 88 35%35%
33 ss-Bu-Bu BrBr 88 ??%??%
33 ii-Pr-Pr BrBr 88 17%17%
ii) H2, Pd/C iv) NaH, MeI
OCN NO2i) OCN
B
iii)
NH2
AN N
O
N N
O
A B
n
n times
Synthesis
Symmetrical oligoureas
HN
HN
O
NH2
i-Pr
N N
O
N N
O
i-Pr
N
O
N
i-Pr
N N
O
N N
O
i-Pr
N
O
N N
O
N
i-Pr
58% (4 steps)
45% (4 steps)
i) CDITHF, 60°C
i) THF, r.t.NCOOCN
ii) NaH, MeI
Synthesis
i) CDITHF, 60°C
HN
HN
O
HN
HN
O
i-PrHN
O
HN NH2
ii) NaH, MeI
N N
O
N N
O
i-Pr
N
O
N N NN
O
NN
O
i-Pr
N
O
NN
O
15% (8 steps)
ii) NaH, MeIi) THF, t.a.
NCOOCN
N N
O
N N
O
i-Pr
N
O
N N NN
O
NN
O
N
O
NN
O
N N
O
i-Pr
18% (8 steps)
Symmetrical oligoureas
Synthesis
N N
O
N N
O
Br Br
i) n-BuLi 1 or 2 eq.
ii)
OS
O
N N
O
N N
O
Br
N
O
N N N
O
i-Pr
i) n-BuLi ii) 1.2 eq
OS
O
N N
O
N N
O
S
N
O
N N N
O
i-PrTol O
-90°C60%
Conformation of the ureas
NO
N
NO
N
H
R
R
NO
N
NO
N
H(Et) 5.81 ppm(i-Pr) 5.88 ppm 5.65 ppm
≈ 10 Å
Conformation in solution (CDCl3) and in the single cristal
Two conformations at low temperature
R = Et2 conformers 50/50 à -60°C
R = i-Pr2 conformers 55/45 à -30°C
Conformation of the ureasConformation in solution (CDCl3) and in the single cristal
NO
N
NO
NNO
N
NO
N
H5.96 ppm
With an asymmetric centre (s-Bu, racemic)
M P
Two enantiomer helicesEach imposes a different conformation of a same enantiomer of the s-Bu
Conformation of the ureasConformation in solution (CDCl3) of the oligoureas
6.02 ppm
5.91 ppm
6.03 ppm
5.91 ppm
N
O
NN
O
N N
O
N
N
O
NHH
HN
O
NN
O
N N
O
N
N
O
NHH
H
Symmetrical tetraurea unsymmetrical tetraurea
5.91 ppm
6.00 ppm
6.00 ppm
N
O
NN
O
N N
O
N
N
O
NH
N
O
N
N
O
N
H
HH
N
O
N N
O
N
symmetrical octaurea
Conformation of the ureasConformation in solution (CDCl3) of the oligoureas
N
O
NN
O
N N
O
N
N
O
N
Si) n-BuLi
ii)
60%
OS
O
O
Tol
H
H H
6.03 ppm
5.92 ppm6.05 ppm
Chiral sulfoxide
N
O
NN
O
N N
O
N
N
O
N
Br HH
H
5.93 ppm6.01 ppm
6.04 ppm
A chiral i-propyl group as a sensor
H2N CD3 H2N 13CH3
??
How to know if the sulfoxide controls the sense of the helix in solution ?
NH2∗
SO Tol R
SO Tol
∗
Chiral i-propyl as a sensor
Thayumanavan, S.; Basu, A.; Beak P. J. Am. Chem. Soc. 1997, 119, 8209-8216
Dynamic Thermodynamic Resolution
NH
O
i) s-BuLi
ii) Sparteine 1at -25°C
NLiPiv Li
NLiPiv Li 1
1 NLiPiv E
NLiPiv E
NLiPiv Li
NLiPiv Li 1
1
Cool to
-78°C
E
E
NH
Oi) s-BuLiSpartéine
ii) RI
NH
O
R HCl 10M
EtOHReflux 60h
NH2 R
OCN
DCM
HN
RHN
O
R = CD3 de = 65%R = 13CH3 de = 81%R = CD3 87%
R = 13CH3 77%R = CD3 52%R = 13CH3 68%