Chemistry Reference
In-Depth Information
Recently, a key player in the ginkgolide biosynthesis has been isolated and char-
acterized: A cDNA that encodes G. biloba levopimaradiene synthase, a diterpene
synthase involved in ginkgolide biosynthesis, was isolated and characterized.
52
Similarly, a new geranylgeranyl diphosphate synthase gene from G. biloba, was
characterized.
53
7.1.4
Chemistry of Ginkgolides
Since the discovery of the ginkgolides in 1967, numerous studies have explored the
chemistry of these structures. The ginkgolide skeleton is made up of six highly oxy-
genated rings including 10-12 stereogenic centers, and a tert-butyl group, which
provides an enormous challenge for total synthesis. Total syntheses of both GA
54
and GB
55
was achieved by Corey et al. in 1988, which rank among the greatest
achievements in total synthesis of natural products. Recently, a novel synthesis
of GB was been achieved by Crimmins et al.
56,57
Several synthetic studies of ginkgolides have been accomplished by Weinges et
al.
58-63
Most recently, they described an approach to the preparation of radiolabeled
ginkgolides, in this case [
14
C]-GA, although the actual radioligand was not synthe-
sized.
64
In 2004, two radiolabeled analogs of ginkgolides were in fact prepared,
including [
3
H]GB
65
and GB labeled with [
18
F] for positron emission tomography
(PET) studies.
66
Thus, it is anticipated that these radiotracers will provide important
information on biodistribution and binding sites of ginkgolides.
O
O
HO
HO
O
O
HO
HO
O
O
O
O
O
O
Me
Me
HO
HO
O
O
3
H
18
F
O
O
A few studies have looked at the conversion of GC into GB, which includes
elimination of the 7-OH group present in GC. Weinges and Schick and Corey et
al. have independently described similar four-step procedures, involving protection
of 1-OH of GC followed by alcohol deoxygenation, and deprotection to provide
GB.
67,68
A convenient, two-step procedure was described in a patent by Teng,
69
in which GC was reacted with triflic anhydride yielding exclusively 7-O-triflate-
GC that was reduced with Bu
4
NBH
4
to give GB. These studies revealed different
reactivities of 1-, 7-, and 10-OH of ginkgolides. Generally, 1- and 10-OH are the
most reactive OH-groups
68,70
: A bulky silyl group reacts preferentially at 1-OH,
whereas all benzyl reagents react at the 10-OH, and triflic anhydride reacts
exclusively at 7-OH. Similarly, it was recently shown that acetylation, which
generally takes place at 10-OH under strongly acidic conditions takes place at
7-OH of GC.
70
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