STRUCTURE MODIFICATIONS AND THEIR INFLUENCES ON ANTITUMOR AND OTHER RELATED ACTIVITIES OF TAXOL AND ITS ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 82

the 13-keto group in 13-keto-7-TES-baccatin III (16a) to C-13a N-substitutions by
directly reductive amination conditions. After many tests, they found that when all
hydroxyls in baccatin III were protected by silyl groups and the 4-acetyl group was
removed, 13a-OH in the starting material 17a can be transformed into desired 13a-
azido baccatin 17b by double S N 2 conversion with CBr 4 /PPh 3 in 50% yield and
NaN 3 /DMF in 63% yield. The reason for the necessity to remove 4-acetyl is that
the reactivity of 13a-OH is reduced because of its intramolecular hydrogen bonding
to the 4-acetyl group. Reduction of the 13a-azido group was also found to be diffi-
cult, unless heating it with PhSeH/Et 3 Nat60 C to furnish 13a-amino baccatin 17c
in 80% yield. Besides the C-13 amide-linked paclitaxel analog 18a being inactive in
both tubulin polymerization and cytotoxicity assays, the C-4 methyl carbonate and
3 0 -furyl analog 18b were found to be inactive (these changes in paclitaxel have been
proven to enhance activity). 46
4-OH in 13-keto-4-deacetyl-7-TES baccatin III (16b) was used for transannular
hydride transfer during reduction of the C-13 keto group in this compound, because
these two groups are in proximity in space. In contrast to the hydride's attack of the
C-13 keto group in baccatin III-like taxanes, which usually occured from the b-face
because of the rigid convex conformation of baccatins, Me 4 NBH(OAc) 3 reduced
C-13 keto in 16b to 13b-OH in 19, which demonstrates that the hydride was trans-
ferred from the a-face of the C-13 keto group. It was disappointing to find that the
13-epi paclitaxel and docetaxel analogs could not promote tubulin polymerization. 47

AcO AcO

O O

OTES OTES

R

O

DMSO

HO H

H

O O

RO

RO

BzO

BzO

17a R = OH
17b R = N 3
17c R = NH 2

16a R = Ac
16b R = H

Bz

AcO

AcO

NH

O

O

O

OH

OTES

R 1 O

HO

OH

HO

H

O

HO

H

R 2 O

O

BzO

HO

BzO

18a R 1 = Ph , R 2 = Ac
18b R 1 = 2-furyl , R 2 = MeOCO

19

During the reduction of 11,12-olefinin16a with Zn in acetic acid, baccatin 20 in
stable enol form was unexpectedly obtained (Scheme 3-4). However, this baccatin
was tautomerized to more stable keto form 21a with silica gel. It was also