Biomedical Engineering Reference
In-Depth Information
The scope of this work has yet to be extended to the glycosylation of unnatural
aglycones; however, throughout this chapter, several examples have been presented
that demonstrate the tolerance of unnatural substrates by polyketide glycosyltrans-
ferases. Despite the lack of an unnatural aglycone in this study, the simplicity of this
approach along with its potential utility in many diverse total synthetic efforts
warranted its inclusion here. It requires neither the genetic manipulation of the host
or the expression and purification of active protein and as such is arguably the simplest
system discussed thus far in which competition from the wild-type pathway has been
eliminated.
There are multiple examples of glycosylated natural products for which the
sugars are absolutely essential for the bioactivity. Strategies such as the one used for
apoptolidin utilizing the native glycosylation systems to install sugars on a synthetic
aglycone in a perfectly selective manner has the potential to greatly simplify the late
stages of the total syntheses of such compounds.
14.4.3.2. Cryptophycin The cryptophycins, of which cryptophycin 1
has
been found to be of the most interest (Scheme 14.12), are a group of compounds that
were isolated throughout the 1990s from a series of related cyanobacteria. These
compounds show much promise in the treatments of cancer as they are potent
inhibitors of microtubule. Not only do they exhibit more potent activity than currently
available paclitaxel, docetaxel, or vinca alkaloids, but they have also been found to be
71
O
O
N
SNAC
R
1
H
O
R
4
R
3
OH
O
O
O
R
2
65
(R
1
= H; R
2
= H; R
3
= H; R
4
= H)
66
(R
1
= Ph; R
2
= H; R
3
= H; R
4
= H)
67
(R
1
= Ph; R
2
= Cl; R
3
= Me; R
4
= H)
68
(R
1
= Ph; R
2
= Cl; R
3
= Me; R
4
= Me)
69
(R
1
= Ph; R
2
= Cl; R
3
= H; R
4
= H)
O
R
1
R
2
O
O
O
O
H
O
O
R
3
R
4
O
70
(R
1
= Ph; R
2
= H; R
3
= H; R
4
= H)
71
(R
1
= Ph; R
2
= Cl; R
3
= Me; R
4
= H)
72
(R
1
= Ph; R
2
= Cl; R
3
= Me; R
4
= Me)
73
(R
1
= Ph; R
2
= Cl; R
3
= H; R
4
= H)
R
1
O
R
2
O
O
O
O
H
O
O
R
3
R
4
SCHEME 14.12
In vitro
cyclization and epoxidation of
seco
-cryptophycin analogues.
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