Chemistry Reference
In-Depth Information
5.2.4
C-2 Analogues of Taxol
The observation in the total synthesis of taxol by Nicolaou [182] (see Section 5.2.1)
that the 1,2-cyclocarbonate 248 can be opened strictly regioselectively with phenyl-
lithium to give 249 in good yield, led to consideration as to whether the reaction of
248 with other nucleophiles would provide easy access to other C-2 analogues.
As a result, Nicolaou developed a preparative method for converting 10-deacetyl-
13-oxo-7-TES-baccatin III 273 (available from naturally occurring 10-deacetyl-
baccatin III) into 10-deacetyl-13-oxo-7-TES-baccatin III 1,2-cyclocarbonate 274 with
phosgene [198]. The latter can be ring-opened chemoselectively and regioselec-
tively by various nucleophiles RLi to yield C-2 analogues 275, which are reduced at
C-13 and coupled with the requisite side chain to give C-2 taxol analogues [199].
O
H
O
H
O
OTES
OTES
COCl
2
(10 equiv.)
10
7
7
O
O
13
1
pyridine
25°C, 30 min
1
2
O
2
O
H
H
O
OAc
H
OAc
O
OBz
274
65 %
273
O
10-deacetyl-13-oxo-
7-TES-baccatin III
R
-Li
THF
-78°C
10-90 min
H
O
O
OTES
7
C-2 Taxol analogues
O
13
1
2
O
H
H
O
OAc
O
R
60-95 %
275
O
R
=
TMS
N
Me
Me
O
S
N
Me
5.2.5
Water-Soluble Prodrugs
To achieve high bioavailability of taxol, it needs to be highly soluble in water, but,
in fact, it suffers from extremely low solubility in water (
10
6
<
5
m). Thus, taxol
