conducted with a sequence of three columns; column X was filled with MS4A, and
columns II-1 and II-2 were filled with polymer-supported chiral calcium catalyst
(PS-(S)-pybox-calcium chloride, where pybox is pyridinebisoxazoline). The reaction was conducted at 0
C, introducing a solution of nitroalkene 8 synthesized in
O
MeO
OMe
O
NO 2
MeO
O
O
NH
MeO
O
MeO
O
Chiral
Rolipram (12)
O
MeO
OMe
O
+
OMe
O
OMe
O
OHC
+
CH 3 NO 2
*
*
O 2 N
Intermediate (8)
Intermediate (10)
Intermediate (11)
ArCHO (9)
Malonate (7)
Scheme 10 Retrosynthetic scheme to access chiral Rolipram
75 °C
Si-NH 2 /CaCl 2
ArCHO (9)
CH 3 NO 2
in toluene
0 °C
PS-Pybox –CaCl 2
Malonate (7)
Et 3 N
in toluene
Pd/(DMPSi- Al 2 O 3 )
H 2
100 °C
120 °C
Rolipram (12)
H 2
Si-COOH
Z
o-Xylene
Y
X
OMe
O 2 N
MeO
OMe
O
O
NO 2
MeO
O
*
NH
MeO
O
O
O
MeO
NH
O
O
MeO
*
*
H 2 O
Intermediate (8)
Intermediate (10)
Intermediate (11)
column I
column II
column III
column IV
Fig. 13 Sequential continuous-flow synthesis of chiral Rolipram
224
H. Miyamura and S. Kobayashi