Biomedical Engineering Reference
In-Depth Information
Cl
, CH(OMe)
3
HO
OMe
90°C, 100 min
OH
NH
2
O
O
96
MeOH
Cl
OMe
97
(95%)
O
100 psi bpr
CSA
+
O
(0.1 equiv)
(1.2 equiv)
SCHEME 11.20
First step in the synthesis of BDA-protected glycolate
100
.
OMe
O
O
Cl
70°C, 70 min
OMe
97
OMe
O
O
THF
100 psi bpr
OMe
98
(81%)
t
-BuOK
SCHEME 11.21
Second step in the synthesis of BDA-protected glycolate
100
.
S
OsEnCat
OMe
N
H
NH
2
OMe
SO
3
H
NMe
3
IO
4
O
O
O
O
O
OMe
100
(85%)
100 psi bpr
OMe
98
NMO, THF/H
2
O (2:1)
recycle
0.3 mL/min, 7 h
SCHEME 11.22
Synthesis of BDA-protected glycolate
100
.
This new flow procedure, nevertheless, consistently produced more of the
desired product in an
exo
/
endo
ratio of 24:1 compared to between 15:1 and 5:1 for the
batch procedure. The final double bond cleavage employed a combination of osmium
EnCat
and sodiumperiodate to give the corresponding lactone (Scheme 11.22) [35].
However, when periodate in solution was used for this transformation, formation of a
side product was noticed due to periodic acid fragmentation of
99
. The optimized
procedure,
therefore,
involved a recycling procedure through a mixed bed of
OsEnCat
and immobilized periodate, with morpholine as a solution-phase reoxi-
dant. The reaction stream was then passed through a sulfonic acid resin to scavenge
themorpholine and an immobilized thiourea to scavenge any leached osmium in order
to generate the pure lactone
100
(Scheme 11.22).
11.4.2. Yne-Ones and Pyrazoles as Primary Building Blocks
The flow synthesis of yne-ones with inline purification provides reactive building
blocks for further transformation to numerous heterocyclic scaffolds [36]. The nice
feature of this process is the ability to split the product stream and divert these to
different product outcomes by varying the subsequent coupling agents.
After a rapid screen, conditions were found that could transform an acid
chloride and acetylene into an yne-one using palladium catalysis (Scheme 11.23).
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