Chemistry Reference
In-Depth Information
AcO
Boc
AcO
Boc
Grela's catalysts
97
(0.1 mol%; added as PhMe
solution over 75 min)
PhMe (0.1 M)
11 0 º C , 2
CO
2
Me
N
CO
2
Me
N
N
N
N
O
N
O
O
O
O
O
O
3h
93% (assay yield)
−
O
96
(2.0 kg)
98
Telescoped as PhMe solution
NH
i
-P r
Br
N
S
aqueous workup
concentration
MeSO
3
H, MeOH
60 ºC, 15 h
NaOH , MeOH , 40 ºC
aqueous workup
crystallization
from MTBE/THF
i.
ii.
iii.
MeO
N
HO
O
H
O
H
N
MeHN
CH
2
OH
CO
2
H
N
N
O
OH
OH
O
iv.
v.
vi .
O
N
O
CO
2
H
N
O
N
O
O
99
(1.09 kg)
O
100
(BI 201302)
O
75% yield (2 steps)
Scheme 15.21
Synthesis of BI 201302 (100) via RCM.
N
CO
2
Me
N
N
CO
2
Me
CO
2
Me
O
0.01 M
R=H
O
O
+
PCy
3
Ru
Cy
3
P
Cl
Ru
PCy
3
Cl
Ph
AcO
Cl
R
Cl
102
CO
2
Me
N
N
104
PCy
3
105
103
O
R'HN
O
Boc
Boc
CO
2
Me
N
CO
2
Me
101
,R=H,R'=CpCO
2
96
, R = Boc, R' = CpCO
2
N
O
R=Boc
0. 1
−
0.2 M
O
H
Cy
3
P
Cl
Ru
PCy
3
Cl
106
98
Scheme 15.22 Preliminary studies to investigate the effect of N-substituents on the
RCM step.
effects and the reduced ability of the ester group to stabilize the Ru species
due to its electron-withdrawing effect. This simple change increased the
reaction rate by 3-4-fold, the effective molarity (k
intra
/k
inter
) of the reaction by
one order of magnitude (0.1-0.2 M) and avoided epimerization on the
cyclopropyl ring. The Boc substituent is therefore believed to have both a
kinetic and a thermodynamic effect, the latter due to reduced ring strain in
98 through conformational changes.
In the plant, the RCM step was carried out by heating a solution of diene
96 in toluene (2 kg of 96 in 30 L of solvent) to 110 1C. A toluene solution of
Grela's catalysts 97
126
(Figure 15.7; no mention was made about why this
catalyst is preferred over first-generation Grubbs catalyst, but it may be due
Search WWH ::
Custom Search