Biomedical Engineering Reference
In-Depth Information
impossible to cover it entirely in this chapter. Therefore, what follows is necessarily
something of a personal overview that can skim a very rich pool of organic chemistry
and draw the reader's attention to what the authors consider to be some of the more
prominent and pertinent aspects of the field currently. Accordingly, numerous
valuable contributions of our colleagues in this area could not be included here.
12.1.1. Heparin Pentasaccharide Synthesis
Heparin is an anticoagulant oligosaccharide that prevents the formation of blood clots
and is used for the control of deep vein thrombosis. Itsmode of action involves binding
to antithrombin III, which inactivates thrombin and other proteases, most notably
factor X. The porcine form used as the commercial drug preparation is obtained
by partial degradation of the isolate from porcine intestines and is consequently a
heterogeneous mixture of different oligomer lengths [3]. The need for well-defined
synthetic samples is particularly acute owing to the ill-defined heterogeneous nature
of biological extracts, which not only severely hinders careful study of the mechan-
isms of action, but also lends itself to problems of reproducibility, sometimes with
tragic results as in the recent problems with Chinese heparin [3]. Following the metic-
ulous studies of the Sina
y group [4], the binding motif was defined as a pentasac-
charide, which opened the door for the development of a totally synthetic material
that avoids the potential hazards of the biological isolate.
In this synthesis (Scheme 12.1), the first glycosidic bond was introduced by
means of the orthoester method [5], essentially a variant of neighboring group
participation in which the intermediate cyclic dioxolenium ion is derived by abstrac-
tion of a leaving group from the donor. A second 1,2-
cis
-equatorial glycosidic bond
was obtained by a heterogeneous reaction in which the stereochemical outcome is
determined by the mode of absorption of the donor onto the promoter surface, with
additional assistance from the electron-withdrawing ester at
O-
4 [6]. After removal
€
O
Ag
2
CO
3
MS 4 Å
CH
2
Cl
2
OAc
O
N
3
Br
O
OAc
MeO
2
C
MeO
2
C
BnO
MeO
2
C
BnO
O
BnO
O
ClAcO
AcO
O
OBn
O
OBn
ClAcO
BnO
ClAcO
+
O
N
3
O
O
6 days, rt
50%
OH
N
3
Br
OAc
OBn
CbzHN
BnO
O
OAc
O
1. DMPP, PhCl
15 min, reflux
1. AgOTf, 2,6-lutidine
DCE (-20°C to rt)
OBn
OBn
O
CbzHN
OAc
MeO
2
C
O
HO
MeO
2
C
O
O
+
BnO
2. Deprotection
40% (2 steps)
2. Deprotection
Ot-Bu
ClAcO
O
OBn
OH
OAc
30% (2 steps)
OBn
CbzHN
NaO
3
SHN
HO
OH
BnO
O
O
O
O
OBn
OH
OAc
MeO
2
C
O
OSO
3
Na
NaO
2
C
O
OSO
3
Na
O
OAc
HO
O
NaO
3
SNH
O
OAc
OSO
3
Na
N
3
NaO
3
SHN
NaO
3
SO
MeO
2
C
BnO
HO
1. AgOTf, 2,6-lutidine
AcO
O
O
OBn
BnO
NaO
2
C
HO
HO
O
O
+
O
OH
O
BnO
O
O
DCE, -20°C to rt (89%)
OAc
N
3
Br
2. Deprotectio/sulfation
OSO
3
Na
DMPP: 2,6-dimethylpyridinium perchlorate
SCHEME 12.1
Synthesis of the heparin pentasaccharide by Sinay and coworkers.
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