CA2147854C - Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them - Google Patents

Abstract

Taxane derivatives having an alkyl substituted C13 side-chain, having the following formula:

wherein X1 is -OX6, -SX7, or -NX8X9; X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl; or heteroaryl; X3 is optionally substituted alkyl; X4 is hydrogen; X5 is -COX10 or -SO2X11; X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group; X5 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; X9 is an amino protecting group; X10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, t-butoxy or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OX10, or -NX8X14; X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate; R2 is hydrogen, hydroxy, -OCOR31 together with R2a forms an oxo; R2a is hydrogen or taken together with R2 forms an oxo or; R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring; R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR30, or together with R4 forms an oxo, oxirane or methylene; R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring; R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo; R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo; R7 is hydrogen or together with R7A forms an oxo; R7A is halogen, hydroxy, or together with R7 forms an oxo; R9 together with R9a forms an oxo; R9a together with R9 forms an oxo; R10 is hydrogen; R10a is -OCOR29, hydroxy, or protected hydroxy; R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate; R14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R29 and R30 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl; and R31 is hydrogen, alkyl, alkenyl, phenyl or monocyclic heteroaryl. The taxane derivatives of the present invention are useful as antileukemia and antitumor agents.

Description

TAXANES HAVING AN AhRYh SUBSTITUTED
SIDE-CHAIN AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
BACKGROUND OF THE INVENTION
The present invention is directed to novel =i taxanes which have utility as antileukemia and antitumor agents.
The taxane family of terpenes, of which taxol is a member, has att~~acted considerable interest in both the biological and chemical arts . Ta:xoi ~'is a promising IO cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibit:.ng activity. Taxol has a 2'R, 3'S configuration and the following structural formula:
OAc 'o ~ ~s O H

\ ~5 17 0llil 111 » a 7 CsHS ~ ~" s OH ' a s 0 H = H \,~y = OA~\zo~0 C~H5C00 (1) 15 wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
Colin et al. reported in U.S. Patent No.
4,814,470 that taxol derivatives having structural 20 formula (2) below, have an activity ~~ignificantly greater than that of taxol (1).

~~ CH~H

2 'CH-A
C6H~r-CH-R ' ' ' OH ~ H 0 3 ' ~~ OCOCH3 OCOCSHS
(2j R' represents hydrogen or acetyl and one of R " and R " ' represents hydroxy and the other represents tert-butoxy-carbonylamino and their stereoisomeric forms, and mixtures thereof. The compound of formula (2) in which R " is hydroxy, R " ' is tert-butoxycarbonylamino having the 2'R, 3'S configuration is commonly referred to as TM
taxotere.
TM TIA
Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of novel taxane derivatives which are valuable antileukemia and antitumor agents.
Briefly, therefore, the present invention is directed to taxane derivatives having a C13 side chain which includes an alkyl substituent. In a preferred embodiment, the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula:

~14~.8~4 ~,~VO 94/10997 ~ ';', 8 , ~ ~ PCT/US93/10816 R 1 Oa 1e Rlo~ R9 ~ X4 X3 O ~ 11 R9a R~
. 1Z 1~ 19 2 1 ~\ ~ 17 R7a \ 16 ~1, 1 6 R6 X2 X~ 2 3 4 S~R6a R~4 ~ R~ ' R5a R R2a ~R48 R5 14a wherein (3) X1 is -OX6, -SX~, or -NX8X9;
Xz is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 is alkyl;
X4 i s hydrogen ;
XS is -COXlo, -COOXIO, -COSXIO, -CONXBXlo, or -SOZX11 X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X9 is an amino protecting group;
Xlo is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OXlo, or -NXeXl4:
X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
SUBSTITUTE SIrtEET (~~~ E 2~~

WO 94/10997 s., ~~'i'~~'°~'~~:~ ~ PCT/US93/1(~,S

RZ is hydrogen, hydroxy, -OCOR~1 together with R2, forms an oxo ;
RZa is hydrogen or taken together with RZ forms , an oxo;
R4 is hydrogen, together with R4a forms an oxo, , oxirane or methylene, or together with Rsa and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR3o, or together with R4 forms an oxo, oxirane or methylene;
RS is hydrogen or together with RS, forms an oxo, Rsa is hydrogen, hydroxy, protected hydroxy, acyloxy, together with RS forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;

R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together wi th Rba forms an oxo ;

R6, is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together wi th R6 forms an oxo ;

R~ is hydrogen or together with R~, forms an oxo, R,a is hydrogen, halogen, protected hydroxy, -ORzB, or together with R~ forms an oxo;
R9 is hydrogen or together with R9, forms an oxo, R9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R9 forms an oxo;
R,o is hydrogen or together with Rloa forms an oxo, Rlo, is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with Rio forms an oxo;

Rlq is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
Rlqa is hydrogen, alkyl, alkenyl, alkynyl, aryl, or 5 heteroaryl;
R28 is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative; and R29, R3o, and R31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl.
According to one aspect of the present invention, there is provided a taxane derivative having the formula 18 ' -m Xq X3 19 ~7 R7a X5 \N 3 2 1 0~~~~~~~~~ 13 15 17 8 7 R6 1 z q 5 ~R6a H X2 X1 n Rlq ~ R1 \ \ -,..
R2a ~ ~ R5 Rq Rqa (3) Rlqa R2 wherein X1 is -OX6;
XZ is hydrogen;
X3 is optionally substituted C3_6alkyl, for example optionally substituted cycloalkyl or optionally substituted linear or branched alkyl;
Xq is hydrogen;

5a X5 is -COXla;
X6 is hydrogen;
Xlo is alkyl, alkenyl, alkynyl, aryl, heteroaryl, t-butoxy or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R1 is hydroxy;
R2 is -OCOR3i:
RZa is hydrogen;
Rq together with R5a and the carbon atoms to which they are attached form an oxetane ring;
Rqa iS -OCOR3o%
RS is hydrogen;
R5a together with Rq and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen;
R6a is hydrogen;
R7 is hydrogen or together with Rya forms an oxo;
R7a is halogen, hydroxy, or together with R~ forms an oxo;
R9 together with R9a forms an oxo;
R9a together with R9 forms an oxo;
Rlo is hydrogen;
Rloa is -OCOR29, hydroxy, or protected hydroxy;

5b R14 is hydrogen;
Rl4a is hydrogen;
R29 and R3o are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;
and R31 is hydrogen, alkyl, alkenyl, phenyl or monocyclic heteroaryl.
According to another aspect of the present invention, there is provided a taxane derivative described herein wherein X3 is cyclohexyl, cyclopentyl, propyl, or butyl.
According to still another aspect of the present invention, there is provided a taxane derivative described herein wherein X5 is -COXlo, Xlo is as defined above, and X3 is cyclohexyl, cyclopentyl, propyl, or butyl.
According to yet another aspect of the present invention, there is provided a pharmaceutical composition comprising a taxane derivative as described herein and one or more pharmacologically acceptable, inert or physiologically active diluents, adjuvants or carriers.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein "Ar" means aryl; "Ph" means phenyl;
"Ac" means acetyl; "Et" means ethyl; "R" means alkyl unless otherwise defined; "Bu" means butyl; "Pr" means propyl; "TES"
means triethylsilyl; "TMS" means trimethylsilyl; "TPAP" means tetrapropylammonium perruthenate; "DMAP" means p-dimethylamino pyridine; "DMF" means dimethylformamide; "LDA" means lithium diisopropylamide; "LHMDS" means lithium hexamethyldisilazide;

5c "LAH" means lithium aluminum hydride; "Red-A1" means sodium bis(2-methoxyethoxy) aluminum hydride; "AIBN" means azo-(bis)-isobutyronitrile; "10-DAB" means 10-desacetylbaccatin III; FAR
means 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means -OR wherein R is a hydroxy protecting group; ~~sulfhydryl protecting group" includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; "amine protecting group"
includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and W094/10997 ~~~.~: ~ PCT/US93/1(~,5 "hydroxy protecting group" includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether;
esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1_6 alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in "Protective Groups in Organic Synthesis" by T.
W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms.
They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like.
The alkenyl groups described herein, either alone or with the various substituents defined herein are i~,'WO 94/10997 preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon ' atoms. They may be substituted, straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
The alkynyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
The aryl moieties described herein, either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, aryl, acyloxy, vitro, amino, amido, etc. Phenyl is the more preferred aryl.
The heteroaryl moieties described herein, either alone or with various substituents, contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, aryl, acyloxy, vitro, amino, and amido.
The acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
The substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein, may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, vitro, amino, and keto.
In accordance with the present invention, it has been discovered that compounds corresponding to structural formula 3 show remarkable properties, in vitro, and are valuable antileukemia and antitumor agents. Their biological activity has been determined in vitro, using tubulin assays according to the method of Parness et al., J. Cell Bioloav, 91: 479-487 (1981? and human cancer cell lines, and is comparable to that exhibited by taxolT"" and taxotere'""
In one embodiment of the present invention, the substituents of the cyclic nucleus of the taxane (other than the C13 substituent) correspond to the substituents present on baccatin III or 10-DAH. That is, R1, and R1,, are hydrogen, Rlo is hydrogen, Rlo, is hydroxy or acetoxy, R9 and R9, together form an oxo, R~ is hydrogen, R7, is hydroxy, RS is hydrogen, R5, and R, and the carbons to which they are attached form an oxetane ring, R" is acetoxy, Rz is hydrogen, Rz, is benzoyloxy, and R1 is hydroxy. In other embodiments, the taxane has a structure which differs from that Of taxolT""or taxotereTN
with respect to the C13 side chain and at least one other substituent. For example, R1, may be hydroxy, RZ may be hydroxy or -OCOR~1 wherein R31 is hydrogen, alkyl or selected from the group comprising z z z z 0 0 , o , Q~d o ~z wherein Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl. R9, may be hydrogen and R9 may be hydrogen or hydroxy, Rya may be hydrogen and R~ may be acetoxy or other acyloxy or halogen, or Rlo and Rla, may each be hydrogen or together form an oxo.
With respect to the C13 side-chain, in a preferred embodiment X1 is -OH, Xz is hydrogen, X3 is alkyl, X4 is hydrogen, X~ is -COXIO or -COOXlo, and X1o is alkyl, alkenyl, alkynyl, aryl, furyl, thienyl or other heteroaryl and the taxane has the 2'R, 3'S configuration.
In a particularly preferred embodiment, X3 is isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclopentyl, cyclohexyl or the substituted analogs thereof, XS is -COXlo or -COOXlo and Xlo is furyl, thienyl, pyridyl, alkyl substituted furyl or thienyl, tert-, iso- or n-butyl, ethyl, iso- or n-propyl, cyclopropyl, cyclohexyl, allyl, crotyl, 1,3-diethoxy-2-propyl, 2-methoxyethyl, amyl, neopentyl, PhCH20-, -NPhz, -NHnPr, -NHPh, or -NHEt.
Taxanes having the general formula 3 may be obtained by reacting a i~-lactam with alkoxides having the taxane tricyclic or tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a i3-amido.ester substituent at C-13. The ii-lactams have the following structural formula:
X5\N ~0 ~s 3 X4 X~

wherein X; - X~ are as defined above.
The i3-lactams can be prepared from readily available materials, as is illustrated in schemes A and B
below:

WO 94/10997 ~: ,'-~:y:, ' PCT/US93/10' .
Scheme A

'~/~' C I + X . \ I ~' / 0 0 3 OCH3 N / .
X 4 ~~~i X OAc b XS~N //0 a HEN // ~d ~N //
X4 1 X4 1 X4 //~~OAC

Scheme B
0 X1 OLi f X ~OEt 1 X2 OEt --\N /~

X3X4C0 ~ X3~/
a ~N ~~

5 reagents: (a) triethylamine, CHzCl2, 25°C, 18h; (b) 4 equiv ceric ammonium nitrate, CH3CN, -lOaC, 10 min; (c) _ KOH, THF, H20, OoC, 30 min, or pyrolidine, pyridine, 25 °C, 3h, (d) TESC1, pyridine, 25 °C, 30 min or 2- , methoxypropene toluene sulfonic acid (cat.), THF, O~C, 10 2h; (e) n-butyllithium, THF, -78 °C, 30 min; and an acyl chloride or chloroformate (XS = -COX,o), sulfonyl chloride (XS = -COSXlo) or isocyanate (XS = -CONXeXlo) ; ( f ) lithium SUBSTITUTE SHEET (RULE 26) diisopropyl amide, THF -78oC to -50oC; (g) lithium hexamethyldisilazide, THF -78oC to OaC; (h) THF, -78oC to ~ 25°C, 12h.
The starting materials are readily available.
- 5 In scheme A, a-acetoxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenyl group can be readily removed through oxidation with ceric ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones. In Scheme B, ethyl-a-triethylsilyloxyacetate is readily prepared from glycolic acid.
In Schemes A and B, X1 is preferably -0X6 and X6 is a hydroxy protecting group. Protecting groups such as 2-methoxypropyl ("MOP"), 1-ethoxyethyl ("EE") are preferred, but a variety of other standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups may be used. As noted above, additional hydroxy protecting groups and the synthesis thereof may be found in "Protective groups in Organic Synthesis" by T.W. Greene, John Wiley & Sons, 1981.
The racemic i~-lactams may be resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reaction described hereinbelow in which the !3-amido ester side chain is attached has the advantage of being highly - diastereoselective, thus permitting the use of a racemic mixture of side chain precursor.
The alkoxides having the tricyclic or tetracyclic taxane nucleus and a C-13 metallic oxide or ammonium oxide substituent have the following structural formula:

..
WO 94/10997 ':'~ ~: PCT/US93/10'~
. . _ . 12 R~oa ,s R~O~ Rs ,1 Rsa R~

MOIIIII ~~ ~~ Rya ,s ~" ~ - a ~ s R
~R 6 a R~4 2 ~ 5 R~ ' R R5a R2a .R4a 5 Rl4a R2 R4 wherein R1 - Rl4a are as previously defined and M
comprises ammonium or is a metal optionally selected from the group comprising Group IA, Group IIA and transition metals, and preferably, Li, Mg, Na, K or Ti. Most preferably, the alkoxide has the tetracyclic taxane nucleus and corresponds to the structural formula:
R'IOa R9 R9a R~
M O I I I I I '\~~~ R 7 a HO

R4a 0 wherein M, R2, Rqa, R~, Rya, R9, R9a, R10, and RlOa are as previously defined.
The alkoxides can be prepared by reacting an alcohol having the taxane nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Most preferably, the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al.
in JACS 110: 5917 (1988) or by other routes) or 7,10-bis-0-triethylsilyl baccatin III.
As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-0-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme : S~g~p SHEET (i~LE 26~

,~ WO 94/10997 PCT/US93/10816 OH
OH
CH3 1p ~H3 . CH3~.
~ , H ~ 0 i r OH ~ ' 1. (C2H5]3SiCl, C5H5N
2. CH3COC1, CSHSN
OR
CH /~ OSI(C2H5]3 1p H3 r 0 H
OH ~ OCOCH3 (4) a, R=H
b, R=COCH3 Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (CZHS)3SiC1 at 23~C under an argon atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (4a) as a reaction product in 84-86~ yield after purification. The reaction product may then optionally be acetylated with 5 equivalents of CH3COC1 and 25 mL of pyridine/mmol of 4a at 0 ~C under an argon atmosphere for 48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (4b).
Greene, et al. in JAGS 110, 5917 at 5918 (1988).
The 7-protected baccatin III (4b) is reacted with an organometallic compound such as LHNmS in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III as shown in the following reaction scheme:
~U~~ a f TU'~E SHEET (RI~~E 26 WO 94/10997 ~= ~ PCT/US93/1Q

OR
CH3 ~ 0 - lo~~CH3 OS 1 ~ C2H5~ 3 LHMDS + HO---\ CH3 ~C H ,~ , OH
' ' THF
OR

/ CH3 OS 1 ~ C2H5~ 3 L I 0-_- 13 CH3 ~C H ,~
OH ~ H 4 ' ' ' ' 0 ' As shown in the following reaction scheme, 13-O-lithium-7-O-triethylsilyl baccatin III reacts with a i3-lactam in which X1 is preferably -OX6, (X6 being a 5 hydroxy protecting group) and XZ - XS are as previously defined to provide an intermediate in which the C-7 and C-2' hydroxyl groups are protected. The protecting groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane 10 substituents. -SUBSTITUTE SHEET (RULE 26) ~ ~ 4 7 8 5 4 PCT/US93/10816 ice, WO 94/ I 0997 14-1 ~~ .
.~
ACO
r o - ' OTES
M OI I 1 I I ~~~ X 5 \ ~ 0 N
HO
_ PhC00 (:'I] THF
t; 2] HF, Pyr i d i ne, CH3CN
ACO

X5~ ~ - ~ OH
N ~ ~OIIII
H X~ X2 HO __ PhC00 ~~
A c 0\~0 SUBSTITUTE SHEET (RU~.E 263 WO 94/10997 . - ~~ ' PCT/US93/1 214~8~4 Both the conversion of the alcohol to the alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel.
Preferably, the i~-lactani is added to the reaction vessel 5 after formation therein of the alkoxide.
Compounds of formula 3 of the instant invention are useful for inhibiting tumor growth in animals including humans and are preferably administered in the form of a pharmaceutical composition comprising an 10 effective antitumor amount of compound of the instant invention in combination with a pharmaceutically acceptable carrier or diluent.
Antitumor compositions herein may be made up in any suitable form appropriate for desired use; e.g., 15 oral, parenteral or topical administration. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration.
The diluent or carrier ingredients should not be such as to diminish the therapeutic effects of the antitumor compounds.
Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs. Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose and talc. Tablets may also contain granulating and disintegrating agents such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or may be coated by unknown techniques;
e.g., to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate and kaolin. Suspensions, syrups and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, 21 ~ 7854 ~. WO 94/10997 , PCT/US93/10816 . °, q such as lecithin and polyoxyethylene stearate; and preservatives, e.g., ethyl- p-hydroxybenzoate.
Dosage forms suitable for parenteral administration include solutions, suspensions, S dispersions, emulsions and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain suspending or dispersing agents known in the art.
The water solubility of compounds of formula (3) may be improved by modification of the C2' and/or C7 substituents. For instance, water solubility may be increased if X1 is -OX6 and R7a is -OR28, and X6 and R28 are independently hydrogen or -COGCORI wherein G is ethylene, propylene, -CH=CH-, 1,2-cyclohexane, or 1,2-phenylene, R1 = OH base, NR~R', OR3, SR', OCHzCONR''R5, OH
RZ = hydrogen, methyl R3 = ( CHZ ) "NR6R' ; ( CH= ) "N~R6R'ReXe n - 1 to 3 R4 - hydrogen, lower alkyl containing 1 to 4 carbons RS = hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CHZCOZH, dimethylaminoethyl R6R' = lower alkyl containing 1 or 2 carbons, benzyl or R6 and R' together with the nitrogen atom of NR6R' form the following rings U

k3 = lower alkyl containing 1 or '? carbons, benzyl X~ - halide bas a = NH3 , ( HOCZH4 ) ~~I, N ( CH3 ) 3 , CH3N ( CZH40H ) 2 , NHS (CHI) 6NH2, N-mechyLglucam~ne, NaOH, KOH.
The preparation of compounds ~n which X1 or XZ is -COGCOR1 is set forth in Haugwitz U.S. Patent 4,942,184.
Alternati~~ely, solubility may be increased when X1 is -0X6 and X6 is a radical having the fornual -COCX=CHX or -COX-CHX-CHX-SO20-i~ wherein X is hydrogen, alkyl or aryl and M is hydroge:~, alkaline metal or an ammonio group as described in Kingston et al., U.S.
lei Patent No. 5, 0~~9, 699.
Taxanes having alternative C9 keto substituent may be prepared by selectivelyy reduced to yield the corresponding C:9 (3-hydroxy derivative. The reducing agent is preferably a borohydride and, most preferably, 20 tetrabutylammoniumboro-hydride (Bu4N'EH4) or triacetoxyborohydride.
As illustrated in Reaction Scheme 1, the reaction of bac.catir~. III with Bu$NBH4 in methylene chloride yields 9-desoxo-9~i-hydroxybaccatin III 5. After 2.'i the C7 hydroxy group is protected with the triethylsil.yl protecting group, for example, a suitable side chain may be attached. to 7-protected-9~i-hydroxy derivative 6 as elsewhere described herein. Removal of the remaining protecting groups thus yields 9~-hydroxy-desoxo taxol or 30 other 9~3-hydroxytetracylic taxane having a C13 side chain.

WO 94/ 10997 ~ ~ ~ PCT/ US93/ 10816 , OAc OAc ' - ~ OH - OH
HOIi~~ HOIi~
'~i 8u4NBH4 '~i H CH2CI2 H _ 0 ~~., 0 Ph~ Ac0 0 Ph~ Ac0 0 ~~0 TESCI

OAc OH
- OTES
HOIi~~.
'~, '~i H
0 ~~
Ph~ AcO~ 0 \\0 Alternatively, the C13 hydroxy group of 7-protected-9[3-hydroxy derivative 6 may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 2, to enable further selective manipulation of the various substituents of the taxane. For example, reaction of 7,13-protected-9(3-hydroxy derivative 7 with KH causes the acetate group to migrate from C10 to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8. Protection of the C10 hydroxy group of 10-desacetyl derivative 8 with triethylsilyl yields derivative 9. Selective removal of the C13 hydroxy protecting group from derivative 9 yields derivative 10 to which a suitable side chain may be attached as described above.
SUBSTITUTE S~iEET RULE 26) . , c' PCT/US93/10' 94/10997 ~~ O ~
W

REACTION SCHEME

OAc OAc OH OH

- OTES - OTES

HOI~~~ TMSOIi~
., ,.

.ii yi 1J TMSCI, Et3N

H . H _-~

0 '~ 0 0 Ph~ Ac0 , h Ac0'~0 ~~ P

OTES OH

OAc OAc - OTES - OTES

TMSOIi~ TMSOIi~~

TESCI

H H __-.

_ 0 0 '' E T N ph Ac0 ~0 ' 0 3 pfi~ Ac0 0 \\

HF

pyridine OTES

OAc - OTES

HOIn ....

~i H

p '':
Ac0 ~0 Ph ~~0 As shown in Reactio n Scheme 3, 10-oxo derivative 11 by oxidation can be provided of 10-SUBSTITUTE SHEE'~
i,RU~E 2fi~

,.WO 94/10997 ~ ~ ~ ~ ~ ~ PCT/US93/10816 desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-~ acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic 5 taxanes having a C13 side chain. Alternatively, the C9 - acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13 hydroxy protecting group can be 10 selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes having a C13 side chain.

OAc OAc - OTES
- OTES
TMSOii~~~
'~i TPAP TMSOIi~~.
'~i H
H _=
Ph OAcO~ 0 0 Ph Ac0 0 8 '~ '~ S m I 2 - OTES
TMSOIi~~~
..,.~i H
p ph~ Ac0 0 ~~0 SUBSTiTUT~ SHEET (RULE z6~

WO 94/10997 ' ~ . PCT/US93/10,~

Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13. The C7 and C10 hydroxyl groups of pentaol 13 can then be selectively ' protected with the triethylsilyl or another protecting group to produce triol 14 to which a C13 side chain can SUBSTITUTE SHEET (Rt~~~ 26~

2I478~~
~WO 94/10997 _ ~ PCT/US93/10816 be attached as described above or, alternatively, after further modification of the tetracylic substituents.

OH OH
\ ~ 0 \ ~ OH
~ OH - OH
HOI~~~ HOIi~
'~i Bu4N8H4 '~i H CHzCIZ H
0 ~~ 0 ph~ AcO~ 0 Ph~ AcO~ 0 \\0 ~~0 TESCI

OTES
OH
-~ ~ TES
HOI~~
HO \\~~ //
0 ~, ' Ph Ac0 ~0 ~0 'I 4 Taxanes having C9 and/or C10 acyloxy substituents other than acetate can be prepared using 10-DAB as a starting material as illustrated in Reaction Scheme 5. Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of 7-protected 10-DAB 15 may then be - readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent.
Selective reduction of the C9 keto substituent of derivative 16 yields 9f3-hydroxy derivative 17 to which a C13 side chain may be attached. Alternatively, the C10 SUBSTITUTE SHEET (RULE 2fi) and C9 groups can be caused to migrate as set forth in Reaction Scheme 2, above.
REACTION SCHEME 5 .
OH OH
0 \
- i OH - ' OTES
HOIIII , TESC I HO1111 pyrldlne HO ~ ~~ HO
0 Hvv 0 Hv \~0 ACO 0 ph~ Ac0 Ph 0 ~~0 1 S
Acylatlng agent 1 ~H ~ 1 0 - OTES - OTES
HOIIII , 1] HF HO1111 2] Bu4N8H4 HO
3] TESC I HO ~ H '~
Ph~ AcO~~ 0 Ph~ ACO~~ 0 ~ 'I 7 ~~~ 'I 6 Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials. The C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-A1, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.
Alternatively, the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a SUBSTITUTE SHEET (RULE 26) 214 ~ 8 ~ (~ PCT/US93/10816 ~WO 94/10997 .

suitable base such as LDA followed by an acylating agent such as an acid chloride.
Baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can be prepared as - 5 set forth in Reaction Schemes 6-10. To simplify the description, 10-DAB is used as the starting material. It should be understood, however, that baccatin III
derivatives or analogs may be produced using the same series of reactions (except for the protection of the C10 hydroxy group) by simply replacing 10-DAB with baccatin III as the starting material. 9-desoxo derivatives of the baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can then be prepared by reducing the C9 keto substituent of these analogs and carrying out the other reactions described above.
In Reaction Scheme 6, protected 10-DAB 3 is converted to the triol 18 with lithium aluminum hydride.
Triol 18 is then converted to the corresponding C4 ester using ClzCO in pyridine followed by a nucleophilic agent (e. g., Grignard reagents or alkyllithium reagents).

WO 94/10997 ~~~ ~ ~ PCT/US93/1Q~ s Scheme 6 OTES OTES
i~ \ / 0 -~ DOTES - ~ OTES
TMSOIIII ,~~ \/~~ TMSOIIIII _ L A H ~~ii, HO

Ph~ Ac0 0 HO H''~
H 0~ 0 pyridine TES OTES

- ~ OTES TES
TMSO1111 ,~~ TMSOIIII
R3~~i or HO . H R3~MgBr 0 ~~~~

\\0 0 Deprotonation of triol 18 with LDA followed by 5 introduction of an acid chloride selectively gives the C4 ester. For example, when acetyl chloride was used, triol 18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 7.
Triol 18 can also readily be converted to the 10 1,2 carbonate 19. Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 8; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in 15 Reaction Scheme 6.
SUBSTITUTE SHEET (RULE 26) WO 94/10997 ~ ~~~~ PCT/US93/10816 F
7 x Scheme 7 OTES

- ~ OTES LDA

i,~~ R3~COC I TMSOIIII
HO
H 0 H ''~
H0~~0 'I 8 4 Scheme 8 OTES

OTES C1ZC0 - ~ OTES
TMSOIiIII
Pyridine TMSOIIII
~~~i, HO
H 0 ~~~ = H
H0~ 0 /j 0 H0~''' 0 '1 8 ~/ '1 9 DMAP
OTES

- ~~ ~ TES
TMSOIiII i, 0 ._ ~0 ACO ~0 2 'I
SUBSTITUTE SHEET (RLfLE 26) WO 94/ 10997 . , . ~ ': ~ .. PCT/ US93/ 109' S

As set forth in Reaction Scheme 9, other C4 substituents can be provided by reacting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or SUBSTITUTE SiiEET (RULE 26~

8~,~ PCT/US93/10816 r-w WO 94/10997 '~''' 2 6 Grignard reagents to provide 10-DAB derivatives having new substituents at C2.
Scheme 9 OTES
\ OTES
\ 1 0 - ~ OTES C12C0 - ~ ~ OTES
TMSOIIIII ~~~ pyr t d I ne TMSOIIII
ii i~~~

H 0 H O'''~0 ~/ 0 H '''' '18 ° '19 R3oCOCl pyridine DMAP
OTES OTES
1 ,~ \ 1 0 - ~ OTES - ~ OTES
TMSOIIIII ,~~ R L i or TMSOIIII
i ~/ 31 HO = H ~ R MgBr 0 R3~C00 'y'~ 31 ~ H ' R3~C00 0 ~~oC00~' '0 Alternatively, baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using C12C0 and pyridine, and carbonate 25 is acylated at C10 with an acid chloride - and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10.
SUBSTfTUTE SHEET (F~U~E ~~~

WO 94/10997 . ~_'; ~ :: ~ PCT/US93/109' ~

Scheme 10 OAc OAc - ~ OH - ~ OTES

1] TESCI, py HO = ~ 2] TMSCI, DMAP HO
H

ph AcO~\'' 0 I m i dazo I e, DMF Ph AcO~~'\
\\0 LAH
OH OH

- OTES ~ OTES
CI CO -TMSOIIII ,~~ pyr i d i ne TMSOI111 0 _. H ' H0 = H
~0 H0~'' '0 HO

° 2S 24 pyridine SUBSTITUTE S~fEET (RULE 26) WO 94/10997 - .. .. PCT/US93/10816 ~.'-,..

OCOR29 \ OCORO9 I/ ,/0 - OTES - OTES

~~ii D M A P ~~i~

H
- ~0 HO O O/ Ac0 O

R3~Lt v r 0 TMSOIIII
n R3~~ Ac0 OTES
SUBSTITUTE SHEEP~~JIE 26~

W094/10997 ~ , PCT/US93/10°'6 10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium diiodide. . Reaction between the tetracyclic taxane having a C10 leaving group and samarium diiodide may be carried out at 0°C in a solvent such as tetrahydrofuran. Advantageously, the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed. Thereafter, the C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9(3-hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 11, 12 and 12a.

WO 94/10997 , PCT/US93/10816 r ~ ,' OAc OAc OH - ~ OC
H OIIII N a H H 01111 ' S C H 3 iii C S 2 ~~i HO , H~ CH31 H0 ~ H
0 ~~~ 0 Ph~ AcO~ 0 Ph~ AcO~ 0 \\0 \\0 nBu3SnH
AIBN (cat]
to I uene (ref I ux]
OAc .0 HOIIII( H

ph~ Ac0 ~~0 SUBSTITUTE SHEET (RULE 26) W094/10997 ' PCT/US93/10°'6 2~.4'~~4 -' OAc OAc - ~ OH - ~ F
HOIm~
HOIm~
'~.
FAR
H H
~0 ~~. /0 Ph~ Ac0 O Ph~ Ac0 0 ~~0 \\0 OAc OAc - ~ OH - ~ CI
HOIm, ~, HOIi~
Ms C I
Et3N
H ~ '~, Et3NHCi H ' Ph AcO~ 0 Ph~ Ac0 ~0 SUBSTITUTE SHEET ifiHLE 26) WO 94/10997 ~~~~' PCT/US93/10816 '~
REACTION SCHEME 12a 0 o OAc OAc - ~ OTES - ~ OTES
TMSOIIIII ~~~/ HF, pY HOIIIII
ii ii HO = ~~ HO
0 '~~~ 0 ph~ Ac0 0 Ph~ Ac0 \\0 1 1 \\0 LHMOS

OAc - OTES X5~ /0 L i O I I I I I ,~~ /N
~~i HO

Ph~ Ac0 0 l; 1~ THF
~ 2~ HF, Pyr i d i ne, CH3CN
OH

X5 - ~ OAc \N \01111 X
H 1 2 ) HO
PhC00 Ac0 0 As shown in Reaction Scheme 12, Baccatin III
may be converted into 7-fluoro baccatin III by treatment 5 with FAR at room temperature in THF solution. Other baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride 10 solution containing an excess of triethylamine hydrochloride.
SUBST~fUTE SHEEt (RULE 2~

PGT/US93/109' S
WO 94/ 10997 ; .. ; .~:; '.
~...
214'~~5~

Taxanes having C7 acyloxy substituents can be prepared as set forth in Reaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 is converted to its corresponding C13 alkoxic~e by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a (3-lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
SU8ST1TUTE SHEET RULE 26) WO 94/10997 ~ ~~ PCT/US93/10816 1,,., 31 A wide variety of tricyclic taxanes are naturally occurring, and through manipulations analogous to those described herein, an appropriate side chain can be attached to the C13 oxygen of these substances.
Alternatively, as shown in Reaction Scheme 13, 7-O-triethylsilyl baccatin III can be converted to a tricyclic taxane through the action of trimethyloxonium tetrafluoroborate in methylene chloride solution. The product diol then reacts with lead tetraacetate to provide the corresponding C4 ketone.

Ac OAc 0 \ ~ 0 - ' OTES - ' OTES
HOii~~. .,~ Me308Fg HOii~~.
~i '~i H~ Hd O
Ph~ Ac0 0 ph~ HO OAc \\0 ~~0 H O
Pb~0Ac~4 Ac - ~ OTES
HOIi~
.,..~i Hd ph~ O OAc \\0 Recently a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) has been discovered in an extract of yew needles (C&EN, p 36-37, April 12, 1993).
Derivatives of this hydroxylated taxane having the various C2, C4, etc. functional groups described above SUBSTITUTE S~fEET (~n~~.E 2S) W0 94/ 10997 y' PCT/ US93/ 109' ~
. ..., may also be prepared by using this hydroxylated taxane.
In addition, the C14 hydroxy group together with the C1 hydroxy group of 10-DAB can be converted to a 1,2-carbonate as described in C&EN or it may be converted to a variety of esters or other functional groups as otherwise described herein in connection with the C2, C4, C9 and C10 substituents.
The following examples are provided to more fully illustrate the invention.

21:'~ ~~5'4 0 OAc - ~ OH
0 ( \ N 01111 ~ _ .hiii H OH
HO

Ph~ ' 0 \\ ACO

(59-4) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(2-furoyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(70.0 mg, 0.1 mmol) in 0.8 mL of THF at -45 °C was added dropwise 0.11 mL of a 1.00 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-(2'-furoyl)-3-(2-methoxy-2-propoxy)-4-isopropyl-azetidin-2-one (76.0 mg, 0.26 mmol) in 0.8 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 87.9 mg of a mixture containing (2'R,3'S)- 2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isopropyl-7-triethylsilyl-N-debenzoyl-N-(2-furoyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 87.9 mg (0.083 mmol) of the mixture obtained from the previous reaction in 7.0 mL of acetonitrile and 0.40 mL of pyridine at 0 °C was added 0.90 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave SUF~STfTUT~ ~HE~' l,R~.ILE 26) WO 94/10997 ' PCT/US93/10~'~

69.8 mg of material which was purified by flash chromatography to give 43.4 mg (65%) of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(2-furoyl) taxol, which was reczystallized from methanol/water.
m.p.143-145°C; [oc)=tea -56.2° (c 0.0023, CHC1,) .
1H I~t (CDC1" 300 MHz) 8 8.18(d, J=7.2 Hz, 2H, benzoate ortho), 7.63(m, 1H, benzoate para), 7.53(m, 2H, benzoate meta), 7.43(d, J=0.9 Hz, 1H, furoyl), 6.93(d, J=0.3 Hz, 1H, furoyl), 6.53(d, J=9.6 Hz, 1H, NH), 6.44(dd, J=0.9, 0.3 Hz, 1H, furoyl), 6.27(s, 1H, H10), 6.22 (dd, J=8.1, 8.1 Hz, 1H, H13), 5.68(d, J=7.2 Hz, 1H, H2~i), 4.96(dd, J=7.8, 2.4 Hz, 1H, HS), 4.58(dd, J=5.4, 1.8 Hz, 1H, H2'), 4.41(m, 1H, H7), 4.30(d, J=8.4 Hz, 1H, H20a), 4.20(d, J=8.4 Hz, 1H, H20~), 4.18(ddd, J=8.7, 8.7, 1.8 Hz, 1H, H3'), 3.80(d, J= 7.2 Hz, 1H, H3), 3.58(d, J= 6.6 Hz, 1H, 2'0H), 2.55(m, 1H, H6a), 2.50(d, J=3.9 Hz, 1H, 70H), 2.44(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.27(s, 3H, lOAc), 2.24(br s, 3H, Mel8), 1.98(m, 1H, CH3CHCH3 isopropyl) 1.88(m, 1H, H6(3), 1.82(s, 3H, Mel9), 1.75(s, 1H, 10H), 1.27(s, 3H, Mel7), 1.16(s, 3H, Mel6), 1.13(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/10997 .- ~ ~ p~/US93/10816 OAc - ~ off \ N 01111 HO

Ph~ ' 0 \\ ACO

(59-3) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-5 N-(2-thienoyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(50.0 mg, 0.071 mmol) in 0.8 mL of THF at -45 °C was added dropwise 0.08 mL of a 1.00 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45 °C, a solution of 10 cis-1-(2-thienoyl)-3-(2- methoxy-2-propoxy)-4-isopropyl-azetidin-2-one (57.2 mg, 0.21 mmol) in 0.8 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was 15 partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 66.4 mg of a mixture containing (2'R,3'S)- 2'-(2-methoxy-2-propoxy)-3'-desphenyl-3' 20 isopropyl-7-triethylsilyl-N-debenzoyl-N-(2-thienoyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 66.4 mg (0.059 mmol) of the mixture obtained from the previous reaction in 6.0 mL of acetonitrile and 0.35 mL of pyridine at 0 °C was added 25 0.72 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave SUBSTITUTE SHtET (RULE 26~

WO 94/10997 ~ ~, PCT/US93/10R~6 57.2 mg of material which was purified by flash chromatography to give 38.1 mg (68%) of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(2-thienoyl) taxol, which was reczystallized from methanol/water.
m.p.151-152°C; [oc]~~a -59.2° (c 0.0019, CHC1,) .
iH NMR (CDC1" 300 MHz) b 8.17(d, J=7.2 Hz, 2H, benzoate ortho), 7.62(m, 1H, benzoate para), 7.53(m, 2H, benzoate meta), 7.42(m, 2H thienoyl), 7.03(t, J=4.5 Hz, 1H, thienoyl), 6.50(d, J=9.3 Hz, 1H, NH), 6.26(s, 1H, H10), l0 6.19 (dd, J= 9.3, 9.3 Hz, 1H, H13), 5.67(d, J=7.2 Hz, 1H, H2~3), 4.96(d, J=7.8 Hz, 1H, H5), 4.57(m, 1H, H2'), 4.40(m, 1H, H7), 4.30(d, J=7.8 Hz, 1H, H20oc), 4.19(d, J=7.8 Hz, 1H, H20~), 3.79(d, J= 7.1 Hz, 1H, H3), 3.68(ddd, J= 8.8, 8.8, 3.3 Hz, 1H, H3'), 3.61(d, J=4.5 Hz, 1H, 2'0H), 2.55(m, 1H, H6oc), 2.48(s. 3H, 4Ac), 2.41(d, J=3.9 Hz, 1H, 70H), 2.38(m, 2H, H14), 2.22(s, 3H, lOAc), 2.03(br s, 3H, Mel8), 1.96(m, 1H, CH3CHCH3 isopropyl), 1.83(m, 1H, H6(3), 1.68 (s, 3H, Mel9), 1.21(s, 3H, Mel7), 1.16 (s, 3H, Mel6), 1.08 (d, J=6.6 Hz, 3H, Me isopropyl), 1.03 (d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/10997 2~ 4 7854 PCT/US93/10816 OAc - ~ OH
Et0 N _ 0~~~~
. H OH
~'o Ph \\0 Ac0 (50-3) Preparation of N-debenzoyl-N-(ethoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol.
To a solution of 7-triethylsilyl baccatin III
(50.0 mg, 0.072 mmol) in 0.5 mL of THF at -45°C was added dropwise 0.05 mL of a 1.64 M solution of n-BuLi in hexane. After 0.5 h at -45°C, a solution of cis-1-ethoxycarbonyl-3-triethyl-silyloxy-4-isopropyl azetidin-2-one (31.8 mg, 0.100 mmol) in 0.3 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 0.5 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 54.2 mg.of a mixture containing (2'R,3'S)- 2',7-(bis)triethylsilyl-N-debenzoyl-N-(ethoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 54.2 mg (0:053 mmol) of the mixture obtained from the previous reaction in 3 mL of acetonitrile and 0.14 mL of pyridine at 0°C was added 0.42 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 53.8 mg of material which was purified by flash chromatography to SUBSTITUTE SHEET (RULE 26) WO 94/10997 , ' ~.~' ~ ~~~ ,,~ ~ ~ ~ PCT/US93/10~' ~

give 33.9 mg (78%) of N-debenzoyl-N-(ethoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol, which was recrystallized from methanol/water.
m.p .147-148°C; [DG] ~~a -55 . 0° ( c 0 . 002 . 2 , CHC1, ) .
1H NMR (CDC1" 300 MHz) b 8.15(d, J=7.1 Hz, 2H, benzoate ortho), 7.62(m, 1H, benzoate para), 7.53(m, 2H, benzoate meta), 6.30(s, 1H, H10), 6.25 (dd, J = 7.7, 7.7 Hz, 1H, H13), 5.69(d, J = 7.1 Hz, 1H, H2~i), 4.97(d, J= 7.7, 1H, H5), 4.86(d, J=8.2 Hz, 1H, NH), 4.52(m, 1H, H2'), 4.41(m, 1H, H7), 4.32(d, J=7.8 Hz, 1H, H20a), 4.20(d, J=7.8 Hz, 1H, H20(3) , 3 .95 (q, J= 6. 6 Hz, 2H, -CHzCH3 ethoxy) , 3 .81 (d, J= 7.1 Hz, 1H, H3), 3.75(ddd, J= 8.8, 8.8, 3.3 Hz, 1H, H3'), 3.19 (d, J= 6.6 Hz, 1H, 2'0H), 2.54(m, 1H, H6a), 2.47(d, J=3.9 Hz, 1H, 70H), 2.42(s, 3H, 4Ac), 2.38(m, 2H, H14), 2.24(s, 3H, lOAc), 2.22(br s, 3H, Mel8), 1.98 (m, 1H, CH3CHCH3 isopropyl) 1.89 (m, 1H, H6~i), 1.87(s, 3H, Mel9), 1.26(s, 3H, Mel7), 1.18(s, 3H, Mel6), 1.09(t, J= 6.6 Hz, 3H, Me ethoxy), 1.08(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/10997 , PCT/US93/10816 OAc - ~ OH
tBuO N 01111 _ ~iii~~
- H OH
HO H

Ph~ ~ 0 \\ ACO

(47-2) Preparation of N-debenzoyl-N-(t-butoxycarbonyl)-3'-desphenyl- 3'-(isopropyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(25.0 mg, 0.036 mmol) in 0.4 mL of THF at -45°C was added dropwise 0.04 mL of a 1.00 M solution of LiN(SiMe3)z in hexane. After 0.5 h at -45 °C, a solution of cis-1-t-butoxycarbonyl-3- triethylsilyloxy-4-isopropyl-azetidin-2-one (31.8 mg, 0.100 mmol) in 0.3 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 35.3 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(t-butoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 35.3 mg (0.035 mmol) of the mixture obtained from the previous reaction in 2 mL of acetonitrile and 0.1 mL of pyridine at 0°C was added 0.3 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 30.8 mg of SUBSTITUTE SHEE T RULE 26~

WO 94/10997 PCT/US93/10s~~6 ~~~47854 '.
material which was purified by flash chromatography to give 20.3 mg (71%) of N-debenzoyl-N-(t-butoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol, which was recrystallized from methanol/water.
5 m.p.162-163°C; [a]~~a -53.0° (C 0.0026, CHC1,) .
1H I~t (CDC1" 300 MHz) 8 8.15 (d, J=7 .1 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.28(s, 1H, H10), 6.22 (dd, J= 7.7, 7.7 Hz, 1H, H13), 5.63(d, J= 7.1 Hz, 1H, H2~), 4.97(d, J= 7.7, 1H, 10 HS), 4.73(d, J=8.2 Hz, 1H, NH), 4.53(m, 1H, H2'), 4.41(m, 1H, H7), 4.31(d, J=7.8 Hz, 1H, H20a), 4.19(d, J=7.8 Hz, 1H, H20~i), 3.80(d, J= 7.1 Hz, 1H, H3), 3.68(ddd, J= 8.8, 8.8, 3.3 Hz, 1H, H3'), 3.22 (d, J= 6.6 Hz, 1H, 2'0H), 2.54(m, 1H, H6a), 2.48(d, J=3.9 Hz, 1H, 70H), 2.40(s, 3H, 15 4Ac), 2.38(m, 2H, H14), 2.23(s, 3H, lOAc), 2.16(br s, 3H, Mel8) , 1.96 (m, 1H, CH3CHCH3 isopropyl) 1.89 (m, 1H, H6~i) , 1.88(s, 3H, Mel9), 1.33(s, 9H, Me t-Buotoxy), 1.25(s, 3H, Mel7), 1.16(s, 3H, Mel6), 1.08(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

~. WO 94/10997 PCT/US93/10816 41- ~

OAc hI t _ ~ O H
n8u0 N ~ OI111 _ . iii H OH

Ph~ ~ 0 \\ Ac0 (50-4) Preparation of N-debenzoyl-N-(n-butoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol.
To a solution of 7-triethylsilyl baccatin III
(50.0 mg, 0.072 mmol) in 1.0 mL of THF at -45°C was added dropwise 0.05 mL of a 1.64 M solution of n-BuLi in hexane. After 0.5 h at -45°C, a solution of cis-1-(n-butoxycarbonyl)-3-triethylsilyloxy-4-isopropyl-azetidin-2-one (67.1 mg, 0.215 mmol) in 0.5 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 73.3 mg of a mixture containing (2'R,3'S)- 2',7-(bis)triethylsilyl-N-debenzoyl-N-(n-butoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 73.3 mg (0.07 mmol) of the mixture obtained from the previous reaction in 4 mL of acetonitrile and 0.19 mL of pyridine at 0°C was added 0.57 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate splution gave 59.6 mg of SUBSTITUTE SHEET (RUIN 26'~

WO 94/10997 PCT/US93/10~' b ~, . r w material which was purified by flash chromatography to give 44.2 mg (77%) of N-debenzoyl-N-(n-butoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol, which was reczystallized from methanol/water.
m.p.139-141°0 [a]~~,a -57.5° (c 0.002, CHC1,) .
1H NMFt (CDC1" 300 MHz) b 8.15(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta) , 6.30 (s, 1H, C10) 6.29 (d, d, J=7.7, 7.7 Hz, 1H, H13), 5.68 (d, J= 7.lHz, 1H, H2~), 4.96(d, J=7.7 Hz, 1H, H5), 4.87(d, J=8.2 Hz, 1H, NH), 4.50(m, 1H, H2') 4.42(m, 1H, H7) , 4.30 (d, J=7.8 Hz, H20Q), 4.18(d, J= 7.8 Hz, 1H, H20(i) , 3.82 (d, J= 7.1 Hz, 1H, H3) , 3 .79 (m, 1H, H3' ) 3.75(t, 2H, J=6.6 Hz, 2H, n-butyl), 3.37(d, J= 6.6 Hz, 1H, 2'0H), 2.54(m, 1H, H6a), 2.45(d, J=3.9 Hz, 1H, 70H), 2.42(m, 2H, H14), 2.27(s, 3H, 4Ac) " 2.24 (s, 3H, lOAc), 2.09(br s, 3H, Mel8), 1.84 (m, 1H, H6~), 1.68 (s, 3H, Mel9), 1.43(brs, 5H, n-butyl and isopropyl), 1.24(s, 3H, Mel7), 1.15 (s, 3H, Mel6),1.06 (d, J=6.6, Me isopropyl), 1.02(d, J=6.6, Me isopropyl), 0.81(t. J=7.5, Me n-butyl).

OAc - ~ OH
iHuO N O~lii ~ iiii H OH
HO

Ph~ , 0 \\ Ac0' (51-1) Preparation of N-debenzoyl-N-(2-methylpropanoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol.
To a solution of 7-triethylsilyl baccatin III
(30.0 mg, 0.043 mmol) in 0.5 mL of THF at -45°C was added dropwise 0.03 mL of a 1.64 M solution of n-BuLi in hexane. After 0.5 h at -45°C, a solution of cis-1-(2-methylpropanoxycarbonyl)-3-triethylsilyloxy-4-isopropylazetidin-2-one (44.2 mg, 0.13 mmol) in 0.5 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 0.2 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 41.6 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-N-debenzoyl-N-(2-methylpropanoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 41.2 mg (0.039 mmol) of the mixture obtained from the previous reaction in 2 mL of acetonitrile and 0.1 mL of pyridine at 0°C was added 0.3 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE SHEE'~' (RUSE 26 WO 94/ 10997 PCT/ US93/ 10~' ~
..~.l~~g~,~

Evaporation of the ethyl acetate solution gave 33.1 mg of material which was purified by flash chromatography to give 22.6 mg (71%) of N-debenzoyl-N-(2-methylpropanoxy- , carbonyl)-3'-desphenyl-3'-isopropyl taxol, which was recrystallized from methanol/water.
m.p.143-145°C; [a)i~a -57.9° (c 0.0024, CHC1,) .
1H NMR (CDC1" 300 MHz) S 8.15(d, J=7.1 Hz, 2H, benzoate ortho), 7.62(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.28(s, 1H, H10), 6.22(dd, J = 7.7, 7.7 Hz, 1H, H13) , 5.64 (d, J = 7.1 Hz, 1H, H2~i) , 4.97 (d, J= 7.7, 1H, H5), 4.83(d, J=8.2 Hz, 1H, NH), 4.51(m, 1H, H2'), 4.40(m, 1H, H7), 4.31(d, J=7.8 Hz, 1H, H20a), 4.18(d, J=7.8 Hz, 1H, H20(3), 3.80(d, J= 7.1 Hz, 1H, H3), 3.76(q, J= 6.6 Hz, 2H, -CHzCH (CH3) Z isobutoxy) , 3 . 67 (ddd, J= 8 .8, 8 . 8, 3 .3 Hz, 1H, H3'), 3.32 (d, J= 6.6 Hz, 1H, 2'0H), 2.55(m, 1H, H6a), 2.48(d, J=3.9 Hz, 1H, 70H), 2.42 (s, 3H, 4Ac), 2.37(m, 2H, H14), 2.23(s, 3H, lOAc), 2.18(br s, 3H, Mel8), 1.95(m, 1H, CH3CHCH3 isopropyl) 1.88(m, 1H, H6(i), 1.86 (s, 3H, Mel9), 1.62(m, 1H, -CH2-CH-(CH3)2 isopropyl), 1.24(s, 3H, Mel7), 1.16(s, 3H, Mel6), 1.08(d, J=6.6 Hz, 3H, Me isopropyl), 1.03 (d, J= 6.6 Hz, 3H, Me isopropyl).
0.88(d, J= 6.6 Hz, Me isobutoxy), 0.83(d, J= 6.6 Hz, Me isobutoxy).

WO 94/10997 . PCT/US93/10816 ~- ,,~~I~, OAc ~ OH
iPrO N ~ OIIII
hiii H OH
Ph~ _ (53-4) Preparation of N-debenzoyl-N-(isopropoxycarbonyl)-3'-5 desphenyl-3'-isopropyl taxol.
To a solution of 7-triethylsilyl baccatin III
(75.0 mg, 0.092 mmol) in 0.8 mL of THF at -45°C was added dropwise 0.10 mL of a 1.0 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45°C, a solution of cis-1-isopropoxyca.rbonyl-3- triethylsilyloxy-4-isopropyl azetidin-2-one (106.2 mg, 0.32 mmol) in 0.8 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1.0 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 98.3 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(iso-propoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 98.3 mg (0.09 mmol) of the mixture obtained from the previous reaction in 5.0 mL of acetonitrile and 0.23 mL of pyridine at 0°C was added 0.70 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 70.8 mg of SUBSTITUTE SH~~' ~~UL~ 26) WO 94/10997 PCT/US93/10~'6 material which was purified by flash chromatography to give 58.5 mg (82g) of N-debenzoyl-N-(isopropoxycarbonyl)-3'-desphenyl-3'-isopropyl taxol, which was recrystallized from methanol/water.
m.p.144-148.5°0 (ocJi~xa -61.0° (c 0.0024, CHC1,) .
1H I~t (CDC1" 300 MHz) 8 8.15(d, J=6.9 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.29(s, 1H, H10), 6.24(dd, J = 6.6, 6.6 Hz, 1H, H13), 5.68(d, J = 7.2 Hz, 1H, H2(3), 4.96(d, J= 8.4, 1H, H5), 4.81(d, J=6.6 Hz, 1H, NH), 4.70(m, 1H, isopropyloxy), 4.48(m, 1H, H2'), 4.41(m, 1H, H7), 4.31(d, J=8.1 Hz, 1H, H20a), 4.19(d, J=8.1 Hz, 1H, H20(3), 3.80(d, J=7.2 Hz, 1H, H3), 3.68(ddd, J= 8.8, 8.8, 1,8 Hz, 1H, H3' ) , 3 .33 (d, J=5.7 Hz, 1H, 2'0H) , 2.53 (m, 1H, H6a) , 2.46(d, J=3.9 Hz, 1H, 70H), 2.42(s, 3H, 4Ac), 2.38(m, 2H, H14), 2.26(s, 3H, lOAc), 2.13(br s, 3H, Mel8), 1.96(m, 1H, CH3CHCH3 isopropyl), 1.90(m, 1H, H6~), 1.88(s, 3H, Mel9), 1.75(s, 1H, 100H), 1.25(s, 3H, Mel7), 1.16(s, 3H, Mel6), 1.14(d, J=6.6Hz, 3H, Me isopropyloxy), 1.12(d, J=6.6Hz, 3H, Me isopropyloxy), 1.08(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

~ WO 94/10997 214 ~8~~ PCT/US93/10816 4 7 ~ E. a.~

OAc - /
off H OH
H 0 = H _, Ph~O_ (51-2) Preparation of 3'-desphenyl-3'-isopropyl-N-desbenzoyl-N-(allyloxycarbonyl) taxol.
To a solution of 7-O-triethylsilyl baccatin III
(50.0 mg, 0.072 mmol) in 0.5 mL of THF at -45 °C was added dropwise 0.05 mL of a 1.64 M solution of n-BuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-allyloxycarbonyl- 3-triethylsilyloxy-4-(isopropyl) azetidin-2-one (70.1mg, 0.214 mmol) in 0.5 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 0.3 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 61.2 mg of a mixture containing (2'R,3'S)- 2',7-(bis)-O-triethylsilyl-3'-desphenyl-3'-isopropyl-N-desbenzoyl-N-(allyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 61.2 mg (0.06 mmol) of the mixture obtained from the previous reaction in 3.5 mL of acetonitrile and 0.16 mL of pyridine at 0 °C was added ' 25 0.48 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave SUBSTITUTE SHEET (RULE 26) ' PCT/ US93/ 10°' 6 21~~~

57.8 mg of material which was purified by flash chromatography to give 40.3 mg (82$) of 3'-desphenyl-3'-isopropyl-N-desbenzoyl-N-(allyloxycarbonyl) taxol, which was reczystallized from methanol/water.
m.p.135-136°C; [a]"Na -51.1.0° (c 0.0023, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.15(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.30(s, 1H, H10), 6.24(dd, J = 7.7, 7.7 Hz, 1H, H13), 5.78(m, 1H, Olefine), 5.69(d, J = 7.1 Hz, 1H, H2(3), 5.11(m, 2H, olefine), 4.97(d, J= 7.7, 1H, H5), 4.50(d, J=8.2 Hz, 1H, NH), 4.43(m, 1H, H2'), 4.41(m, 1H, H7), 4.31(d, J=7.8 Hz, 1H, H20a), 4.20(d, J=7.8 Hz, 1H, H20~), 3.80(d, J= 7.1 Hz, 1H, H3), 3.75(ddd, J= 8.8, 8.8, 1,8 Hz, 1H, H3'), 3.34(d, J= 6.6 Hz, 1H, 2'0H), 2.54(m, 1H, H6a), 2.50(d, J=3.9 Hz, 1H, 70H), 2.44(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.27(s, 3H, lOAc), 2.25(br s, 3H, Mel8), 1.98(m, 1H, CH3CHCH3 isopropyl) 1.88 (m, 1H~, H6~3), 1.84(s, 3H, Mel9), 1.27(s, 3H, Mel7), 1.15(s, 3H, Mel6), 1.11(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/10997 ~ '. ~ ~ ~ ~a'~ ~ ~ P~/US93/10816 OAc - ~ OH
PhCH20 N OIIII
~ iiii H OH
HO

Ph~ ~ 0 ~~ Ac0 (53-3 ) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(50.0 mg, 0.071 mmol) in 0.8 mL of THF at -45°C was added dropwise 0.08 mL of a 1.00 M solution of LiN(SiMe3)z in hexane. After 0.5 h at -45 °C, a solution of cis-1-benzyloxycarbonyl-3-tri-ethylsilyloxy-4-iso-propylazetidin-2-one (81.0 mg, 0.21 mmol) in 0.8 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 61.4 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 61.4 mg (0.057 mmol) of the mixture obtained from the previous reaction in 3.5 mL of acetonitrile and 0.17 mL of pyridine at 0°C was added 0.48 . 25 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 50.3 mg of SUBSTITUTE SHEfT (RULE 26~

.., WO 94/ 10997 PCT/US93/ 10~' ~
material which was purified by flash chromatography to give 32.7 mg (68%) of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol, which was _ reczystallized from methanol/water.
5 m.p.143-145°0 [a]~~a -56.1° (c 0.002, CHCl,) .
1H NMR (CDC1" 300 MHz) 8 8.15(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 7.23-7.21 (m, 3H, benzyl), 7.10-7.05(m, 2H, benzyl), 6.28(s, 1H, H10), 6.22 (dd, J= 7.7, 7.7 Hz, 1H, 10 H13 ) , 5 . 69 (d, J= 7 .1 Hz, 1H, H2~i) , 5.03 (d, J=12 .3 Hz, 1H, benzyl), 4.97(d, J= 7.7, 1H, H5), 4.89( d, J=12.3 Hz, 1H, benzyl), 4.81(d, J=8.2 Hz, 1H, NH), 4.53(m, 1H, H2'), 4.41(m, 1H, H7), 4.30(d, J=7.8 Hz, 1H, H20a), 4.19(d, J=7.8 Hz, 1H, H20~), 3.80(d, J= 7.1 Hz, 1H, H3), 15 3.68(ddd, J= 8.8, 8.8, 3.3 Hz, 1H, H3'), 3.21 (d, J= 6.6 Hz, 1H, 2'0H), 2.53(m, 1H, H6a), 2.48(d, J=3.9 Hz, 1H, 70H), 2.42(s, 3H, 4Ac), 2.38(m, 2H, H14), 2.23(s, 3H, lOAc), 2.16(br s, 3H, Mel8), 1.96(m, 1H, CH3CHCH3 isopropyl) 1.89(m, 1H, H6~), 1.86(s, 3H, Mel9), 1.23(s, 20 3H, Mel7), 1.16 (s, 3H, Mel6), 1.08(d, J=6.6 Hz, 3H, Me isopropyl), 1.03 (d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/ 10997 ~ ~ ~ ~ PCf/ US93/ 10816 51 ~ , , ''x OAc - ~ OH
o~ N _ of m , - . iii _ i H OH
_ ' ' HO
0 ' Ph ~ 0 0 Ac0 (54-4) Preparation of N-debenzoyl-N-(3-butynyloxycarbonyl)-3'-desphenyl-3'-isopropyl taxol.
To a solution of 7-triethylsilyl baccatin III
(100.0 mg, 0.123 mmol) in 1.5 mL of THF at -45°C was added dropwise 0.14 mL of a 1.0 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45°C, a solution of cis-1-(3-butynyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isopropyl-azetidin-2-one (109.6mg, 0.369 mmol) in 1.0 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1.0 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 116.7 mg. of a mixture containing (2'R,3'S)- 2'-O-(2-methoxy-2-propoxy)-7-triethylsilyl-N-debenzoyl-N-(3-butynyloxycarbonyl)-3'-desphenyl-3'-isopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 116.7 mg (0.12 mmol) of the ' mixture obtained from the previous reaction in 8.0 mL of acetonitrile and 0.5 mL of pyridine at 0°C was added 1.30 mL of 48~ aqueous HF. The mixture was stirred at 0°C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 91.2 mg of SUBSTITUTE SHEET (RULE 26~

PCT/US93/ 10R' 6 Evaporation of the ethyl acetate solution gave 91.2 mg of material which was purified by flash chromatography to give 68.7 mg (72~) of N-debenzoyl-N-(3-butynyloxy-carbonyl)-3'-desphenyl-3'-isopropyl taxol, which was recrystallized from methanol/water.
m.p.140-143.5°C~ [a)~~tra -56.0° (C 0.0019, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.63(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.30(s, 1H, H10), 6.28(dd, J =8.1, 8.1 Hz, 1H, H13), 5.68(d,.J=6.9 Hz, 1H, H2~3), 4.95(d, J=7.8 Hz, 1H, H5), 4.93(s, 1H, butylnyloxy), 4.50(d, J=8.2 Hz, 1H, NH), 4.42(m, 1H, H2'), 4.40(m, 1H, H7), 4.32(d, J=8.4 Hz, 1H, H20a), 4.20(d, J=8.4 Hz, 1H, H20(3), 4.00(t, J=6.6 Hz, 2H, butylnyloxy), 3.80(d, J= 7.2 Hz, 1H, H3), 3.75(ddd, J=
8.7, 8.7, 1,8 Hz, 1H, H3'), 3.30(d, J= 6.6 Hz, 1H, 2'0H), 2.55(m, 1H, H6a), 2.50(d, J=3.9 Hz, 1H, 70H), 2.44(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.27(s, 3H, lOAc), 2.25(br s, 3H, MelB), 1.98(m, 1H, CH3CHCH3 isopropyl) 1.88 (m, 1H, H6(3), 1.84(s, 3H, Mel9), 1.75(s, 1H, 10H), 1.27(s, 3H, Mel7), 1.15(s, 3H, Mel6), 1.11(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl), 0.88(t, J=6.6 Hz, 3H, butylnyloxy).

WO 94/ 10997 ~ ~ PCT/ US93/ 10816 OAc - / OH
0 N Oilll i~~
H OH
_, I HO . H , Ph~ ~ 0 Ac0 (57-4) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(crotyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100.0 mg, 0.142 mmol) in 1.0 mL of THF at -45 °C was added dropwise 0.16 mL of a 1.0 M solution of LiN(SiMe3)a in hexane. After 0.5 h at -45 °C, a solution of cis-1-(3'-crotyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-(isopropyl)azetidin-2-one (128.2 mg, 0.43 mmol) in 1.0 mL
of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1.0 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 128.9 mg of a mixture containing (2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isopropyl-7-triethylsilyl-N-debenzoyl-N-(crotyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
' To a solution of 128.9 mg (0.116 mmol) of the mixture obtained from the previous reaction in 9.0 mL of ' 25 acetonitrile and 0.5 mL of pyridine at 0 °C was added 1.30 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE SHEt T (RULE 26) W0 94/10997 'S, ' , '. PCT/US93/10~'' ~
21.4' 8 ~ 4 '.~

Evaporation of the ethyl acetate solution gave 131.4 mg of material which was purified by flash chromatography to give 71.7 mg (76~) of 3'-desphenyl-3'-(isopropyl)-N-debenzoyl-N-(crotyloxycarbonyl) taxol, which was reczystallized from methanol/water.
m.p.146-148°C; [a]=tea -56.2° (c 0.0026, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.63(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.28(s, 1H, H10), 6.21(dd, J =8.1, 8.1 Hz, 1H, H13), 5.68(d, J=6.9 Hz, 1H, H2(3), 5.62(m, 1H, crotyl), 5.44(m, 1H, crotyl), 4.96(d, J=7.8 Hz, 1H, H5), 4.51(d, J=8.2 Hz, 1H, NH), 4.42(m, 1H, H2'), 4.40(m, 1H, H7), 4.35(m, 2H, crotyl), 4.28(d, J=8.4 Hz, 1H, H20oc), 4.20(d, J=8.4 Hz, 1H, H20~i), 3.88(d, J= 7.2 Hz, 1H, H3), 3.73(ddd, J= 8.7, 8.7, 1,8 Hz, 1H, H3'), 3.34(d, J= 6.6 Hz, 1H, 2'0H), 2.55(m, 1H, H6oc), 2.52(d, J=3.9 Hz, 1H, 70H), 2.32(s, 3H, 4Ac), 2.28(m, 2H, H14), 2.24(s, 3H, lOAc), 2.19(br s, 3H, Mel8), 1.98(m, 1H, CH3CHCH3 isopropyl) 1.88 (m, 1H, H6(3), 1.72(s, 3H, Mel9), 1.69(s, 1H, 10H), 1.61(d, J=6.6Hz, 3H, crotyl), 1.27(s, 3H, Mel7), 1.15(s, 3H, Mel6), 1.11(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

~WO 94/10997 $~ ~ PCT/US93/10816 OAc - - ~ OH

_ I _ _ ii H OH
' HO ' H
0 ' P h _~ 0 ACO

(58-2) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(cyclohexyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(50.0 mg, 0.071 mmol) in 0.8 mL of THF at -45 °C was added dropwise 0.08 mL of a 1.00 M solution of LiN(SiMe3)z in hexane. After 0.5 h at -45 °C, a solution of cis-1-(cyclohexyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isopropylazetidin-2-one (73.0 mg, 0.22 mmol) in 0.8 mL
of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 62.3 mg of a mixture containing (2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isopropyl-7-triethylsilyl-N-debenzoyl-N-(cyclohexyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 62.3 mg (0.055 mmol) of the mixture obtained from the previous reaction in 6.5 mL of acetonitrile and 0.30 mL of pyridine at 0 °C was added 0.65 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE SHEET (RULE-26) WO 94/10997 '' ~ ~ PCT/US93/10f~' ~

Evaporation of the ethyl acetate solution gave 55.6 mg of material which was purified by flash chromatography to give 32.9 mg (73%) of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(cyclohexylpxycarbonyl) taxol, which was recxystallized from methanol/water.
m.p.148-150°0 [ocJ~~,a -57.4° (c 0.0024, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.29(s, 1H, H10), 6.25 (dd, J=7.8, 7.8 Hz, 1H, H13), 5.49(d, J= 7.2 Hz, 1H, H2(3), 4.89(d, J=7.8, 1H, H5), 4.73(d, J=8:1 Hz, 1H, NH), 4.55(m, 1H, H2'), 4.43(m, 1H, H7), 4.39(m, 1H, cyclohexyloxy), 4.34(d, J=7.8 Hz, 1H, H20a), 4.20(d, J=7.8 Hz, 1H, H20(3), 3.82(d, J= 7.1 Hz, 1H, H3), 3.68(ddd, J= 8.8, 8.8, 3.3 Hz, 1H, H3'), 3.24 (d, J= 6.6 Hz, 1H, 2'0H), 2.52(m, 1H, H6a), 2.47(d, J=3.6 Hz, 1H, 70H), 2.39(s, 3H, 4Ac), 2.36(m, 2H, H14), 2.22(s, 3H, lOAc), 2.15(br s, 3H, Mel8), 1.96(m, 1H, CH3CFiCH3 isopropyl ) , 1. 89 (m, 1H, H6~i) , 1. 88 ( s, 3H, Mel9 ) , 1.72(m, 2H, cyclohexyloxy), 1.53(m, 4H, cyclohexyloxy), 1.35(m, 2H, cyclohexyloxy), 1.25(s, 3H, Mel7), 1.15(s, 3H, Mel6), 1.06(d, J=6.6 Hz, 3H, Me isopropyl), 1.02(d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/10997 " PCT/US93/10816 OAC

t - _ ~ 0H

' ~ _ H OH
HO
H _ OMe 0 ~ 0 Fh \\ Ac0 (60-2) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(2-methoxyethoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(50.0 mg, 0.71 mmol) in 0.7 mL of THF at -45 °C was added dropwise 0.08 mL of a 1.0 M solution of LiN(SiMe3)z in hexane. After 0.5 h at -45 °C, a solution of cis-1-(2-methoxyethoxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isopropylazetidin-2-one (75.1 mg, 0.21 mmol) in 0.7 mL
of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1.0 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 60.2 mg of a mixture containing (2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isopropyl-7-triethylsilyl-N-debenzoyl-N-(2-methoxyethoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 60.2 mg (0.58 mmol) of the mixture obtained from the previous reaction in 5.0 mL of ' 25 acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.65 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE SHEET ~R~JLE 26~

WO 94/10997 k ~~~, PCT/US93/10'' S

Evaporation of the ethyl acetate solution gave 48.2 mg of material which was purified by flash chromatography to give 36.1 mg (76~) of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(2-methoxyethoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.151-153°C; [a]=SNa -56.0° (c 0.0018, CHC1,) .
1H I~t (CDC1" 300 MHz) b 8.08(d, J=7.2 Hz, 2H, benzoate ortho), 7.62(m, 1H, benzoate para), 7.49(m, 2H, benzoate meta), 6.31(s, 1H, H10), 5.91(dd, J =8.1, 8.1 Hz, 1H, ZO H13), 5.64(d, J=6.9 Hz, 1H, H2(3), 4.97(d, J=7.8 Hz, 1H, H5), 4.58(d, J=8.2 Hz, 1H, NH), 4.46 (m, 1H, H2'), 4.38(m, 1H, H7), 4.34(d, J=8.4 Hz, 1H, H20a), 4.28(t, J=4.5 Hz, 2H, Me0-CHZC~O) , 4.14 (d, J=8.4 Hz, 1H, H20(3) , 3.86(d, J= 7.2 Hz, 1H, H3), 3,65(t, J=4.5 Hz, 2H, Me0-CH CH20), 3.63(ddd, J=8.7, 8.7, 1,8 Hz, 1H, H3'), 3.41(s, 3H, Me0-), 3.38(d, J= 6.6 Hz, 1H, 2'0H), 2.56(m, 1H, H6a), 2.47(d, J=3.9 Hz, 1H, 70H), 2.39(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.26(s, 3H, lOAc), 2.24(br s, 3H, Mel8), 1.96(m, 1H, CH3CIiCH3 isopropyl) 1.88(m, 1H, H6~i), 1.86(s, 3H, Mel9), 1.75(s, 1H, 10H), 1.27(s, 3H, Mel7), 1.15(s, 3H, Mel6), 1.11(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J= 6.6 Hz, 3H, Me isopropyl).

WO 94/10997 ~8~' PCT/US93/10816 59 ' OAc _ 0 0 0 ' - / OH

_ ~ . iii H OH
HO
H

P h ~ _~ 0 Ac0 (58-1) Preparation of 3'-desphenyl-3'-isopropyl-N-debenzoyl-N-(neopentyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100.0 mg, 0.142 mmol) in 1.4 mL of THF at -45 °C was added dropwise 0.16 mL of a 1.00 M solution of LiN(SiMe3)a in hexane. After 0.5 h at -45 °C, a solution of cis-1-(neopenthyloxycarbonyl)-3-(2-methoxy-2-propoxy)-4-isoprop yl-azetidin-2-one (135.5 mg, 0.43 mmol) in 1.4 mL of THF
was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 123.1 mg of a mixture containing (2'R,3'S)-2'-(2-methoxy-2-propoxy)-3'-desphenyl-3'-isopropyl-7-triethylsilyl-N-debenzoyl-N-(neopentyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 123.1 mg (0.109 mmol) of the mixture obtained from the previous reaction in 9.0 mL of acetonitrile and 0.48 mL of pyridine at 0 °C was added 1.25 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl SUBSTITUTE SHEET (RULE 26) WO 94/ 10997 " ~ PCT/ US93/ 1 t'°' 6 ~~14'~8~4 acetate. Evaporation of the ethyl acetate solution gave 114.7 mg of material which was purified by flash chromatography to give 68.4 mg (81~) of 3'-desphenyl-3'-(isopropyl)-N-debenzoyl-N-(neopentyloxycarbonyl) taxol, 5 which was recrystallized from methanol/water.
m.p.145-147°C; [a]~sNa -56.8° (c 0.0023, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.32(s, 1H, H10), 6.24 (dd, J=7.8, 7,8 Hz, 1H, 10 H13), 5.57(d, J= 7.2 Hz, 1H, H2~i), 4.89(d, J=7.8, 1H, H5), 4.74(d, J=8.2 Hz, 1H, NH), 4.52(m, 1H, H2'), 4.39(m, 1H, H7), 4.32(d, J=7.8 Hz, 1H, H20a), 4.17(d, J=7.8 Hz, 1H, H20(3), 3.78(s, 2H, neopenthyloxy), 3.69(d, J= 7.1 Hz, 1H, H3), 3.65(ddd, J=8.1, 8.1, 3.3 Hz, 1H, H3'), 3.20 (d, 15 J= 6.6 Hz, 1H, 2'0H), 2.53(m, 1H, H6a), 2.46(d, J=3.6 Hz, 1H, 70H), 2.38(s, 3H, 4Ac), 2.36(m, 2H, H14), 2.22(s, 3H, lOAc), 2.14(br s, 3H, Mel8), 1.96(m, 1H, CH3CHCH3 isopropyl) 1.87(m, 1H, H6(3), 1.83(s, 3H, Mel9), 1.21(s, 9H, Me neopenthyloxy), 1.19(s, 3H, Mel7), 1.14(s, 3H, 20 Mel6), 1.06(d, J=6.6 Hz, 3H, Me isopropyl), 1.03(d, J=
6.6 Hz, 3H, Me isopropyl).

WO 94/10997 ,~~~~ PCT/US93/10816 61.

OAc _ 0 0 0 t _ ~ 0H
O N OIIII

TMS HO
H

Ph~ ~ 0 \\ Ac0 (60-1) Preparation of 3'-desphenyl-3'-isopropyl-N-desbenzoyl-N-(trimethylsilylmethyloxycarbonyl) taxol.
To a solution of 7-O-triethylsilyl baccatin III
(50.0 mg, 0.71 mmol) in 0.7 mL of THF at -45 °C was added dropwise 0.08 mL of a 1.0 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-(3'-trimethylsilylmethyloxycarbonyl)-3-(2-methoxyiso-propoxy)-4-(isopropyl)azetidin-2-one (58.0 mg, 0.21 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1.0 mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a-residue which was purified by filtration through silica gel to give 66.4 mg of a mixture containing (2'R,3'S)-2'-O-(2-methoxyisopropyl)-7-O-triethylsilyl-3'-desphenyl-3'-isopropyl-N-desbenzoyl-N-(trimethylsilyl-methyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 66.4 mg (0.58 mmol) of the mixture obtained from the previous reaction in 6.0 mL of acetonitrile and 0.35 mL of pyridine at 0 °C was added 0.72 mL of 48$ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl SUBSTITUTE SHEET (RULE 26~

WO 94/10997 PCT/US93/1P"' S

acetate. Evaporation of the ethyl acetate solution gave 54.4 mg of material which was purified by flash chromatography to give 35.4 mg (72%) of 3'-desphenyl-3'-isopropyl-N-desbenzoyl-N-(trimethylsilylmethyloxy-carbonyl) taxol, which was recrystallized from _ methanol/water.
m.p.149-150°0 (oc]~~a -55.7° (c 0.0026, CHC1,) .
1H NMR (CDC1" 300 N~iz) 8 8.15(d, J=7.2 Hz, 2H, benzoate ortho), 7.62(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.30(s, 1H, H10), 6.28(dd, J =8.1, 8.1 Hz, 1H, H13), 5.68(d, J=6.9 Hz, 1H, H2~i), 4.95(d, J=7.8 Hz, 1H, H5), 4.77(d, J=8.2 Hz, 1H, NH), 4.48(m, 1H, H2'), 4.40(m, 1H, H7), 4.32(d, J=8.4 Hz, 1H, H20oc), 4.20(d, J=8.4 Hz, 1H, H20~3), 3.80(d, J= 7.2 Hz, 1H, H3), 3.75(ddd, J= 8.7, 8.7, 1,8 Hz, 1H, H3'), 3.61(d, J=14.28 Hz, 1H, CH TMS), 3.51(d, J=14.28 Hz, 1H, CHzTMS), 3.40(d, J= 6.6 Hz, 1H, 2'0H), 2.55(m, 1H, H6a), 2.50(d, J=3.9 Hz, 1H, 70H), 2.44(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.25(s, 3H, lOAc), 2.03(br s, 3H, MelB), 1.98(m, 1H, CH3CHCH3 isopropyl) 1.84 (m, 1H, H6~i) , 1.73 (s, 3H, Mel9) , 1.67 (s, 1H, 10H) , 1.27(s, 3H, Mel7), 1.15(s, 3H, Mel6), 1.11(d, J=6.6 Hz, 3H, Me isopropyl), 1.03.(d, J= 6.6 Hz, 3H, Me isopropyl), -0.03 (s, 9H, Me,Si-) .

WO 94/ 10997 ~ ~ $ ~ PCT/US93/ 10816 63 , .

OAc _ 0 0 0 - ~ OH
Ph N _ OIIII
_ ~ _ iii H OH
Ph U
Ac0 (67-4 ) Preparation of 3'-desphenyl-3'-cyclopropyl taxol.
To a solution of 7-triethylsilyl baccatin III
(50 mg, 0.071 mmol) in 0.5 mL of THF at -45 °C was added dropwise 0.086 mL of a 1. OM solution of (TMS)zNLi in THF.
After 1 h at -45 °C, a solution of cis-1-(benzoyl)-3-triethylsilyloxy-4-cyclopropylazetidin-2-one (240 mg, 0.696 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C during 10h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 52 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-cyclopropyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 52 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 109 mg of material which was purified by flash chromatography to give 33 mg (81~) of SUBSTITUTE SHEET (RlJLE 26) WO 94/10997 - PCT/US93/10°'~
...%

3'-desphenyl-3'- cyclopropyl taxol, which was recrystallized from ether/hexane.
m.p. 161-163 °C; [a]~~a -50.0 ° (c 0.13 , CHC1,) .
1H NMFt (CDC1" 300 MHz) 8 8.13 (m, 2H, benzoate ortho), 7.69 (m, 2H, benzamide, ortho), 7.61 (m, 1H, benzoate, para), , 7.50 (m, 3H, benzoate, meta, and benzamide, para ), 7.39 (m, 2H, benzamide, meta), 6.52 (d, J = 8.8 Hz, 1H, NH), 6.28 (s, 1H, H10), 6.20 (br t, J - 9.0 Hz, 1H, H13 ) , 5. 68 (d, J = 6. 9 Hz, 1H, H2 (3) , 4 . 97 (dd, J = 9 . 6, 1.8 Hz, 1H, H5), 4.54 (dd, J = 5.5, 2.2 Hz, 1H, H2'), 4.42 (m, 1H, H7), 4.32 (d, J = 8.4 Hz, 1H, H20a), 4.20 (d, J = 8.4 Hz, 1H, H20(3), 3.84 (br t, J = 9.9 Hz, 1H, H3'), 3.80 (d, J = 6.9 Hz, 1H, H3), 3.63 ( d, J = 6.0 Hz, 1H, 2'0H), 2.56 (m, 1H, H6a), 2.42 (s, 3H, 4Ac), 2.32 (m, 2H, Hl4a and H14(3),2.23 (s, 3H, lOAc), 1.87 (d, J = 1.1 Hz,3H, Mel8), 1.83 (s, 1H, 1 OH), 1.68 (s, 3H, Mel9), 1.39 (m, 1H, cyclopropyl), 1.23 (s, 3H, Mel7), 1.13 (s, 3H, Mel6), 0.68 (m, 2H, cyclopropyl), 0.52 (m, 1H, cyclopropyl), 0.39 (m, 1H, cyclopropyl).

WO 94/ 10997 ~~ PCT/ US93/ 10816 6 5 ,. ~ , OAc - ~ off _ Et0 N _ 01111 _ ~~ii H OH
..
0 ~ 0 Ph~ _, \'0 Ac0 (56-2) Preparation of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(ethoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 2 mL of THF at -45 °C was added dropwise 0.157 mL of a 1. OM solution of (TMS)zNLi in THF.
After 1 h at -45 °C, a solution of cis-1-(ethoxycarbonyl)-3-triethyl-silyloxy-4-cyclopropylazetidin-2-one (225 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C during 6h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/ hexane.
Evaporation of the organic layer gave a residue which was purified by filtration~through silica gel to give 125 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclopropyl-N-debenzoy 1-N-(ethoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 125 mg of the mixture ' obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 ' 25 mL of 48o aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 93 mg of SUBSTITUTE SHEET (RULE 26) WO 94/10997 PCT/US93/10g'~
~.~i 2~14~~~~

material which was purified by flash chromatography to give 82 mg (85~) of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(ethoxy-carbonyl) taxol, which was recrystallized from.ether/hexane.
m.p. 140-142 °C; [a]"Na -65.0° (c 0.08, CHC1,) .
1H NMFt (CDC1" 300 N~iz) 8 8.10 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.60 (m, 1H, benzoate, para), 7.49 (t, J
- 7.2 Hz, 2H, benzoate, meta), 6.29 (s, 1H, H10), 6.22 (br t, J - 8.7 Hz, 1H, H13), 5.66 (d, J = 6.9 Hz, 1H, H2~), 5.08 (d, J = 9.3 Hz, 1H, NH), 4.95 (dd, J = 9.3, 1.5 Hz, 1H, H5), 4.43 (dd, J = 6.0, 2.1 Hz,lH, H2'), 4.40 (m, 1H, H7), 4.30 (d, J = 8.1 Hz, 1H, H20a), 4.17 (d, J =
8.1 Hz, 1H, H20(3), 3.96 (q, J = 7.2 Hz, 2H, OCH2), 3.79 (d, J = 6.9 Hz, 1H, H3), 3.47 (d, J = 6.0 Hz, 1H, 2'0H), 3.35 (dt, J = 9.3, 2.1 Hz, 1H, H3'), 2.52 (m, 2H, H6a, 70H), 2.36 (s, 3H, 4Ac), 2.23 (s, 3H, lOAc), 1.88 (s, 3H, Mel8), 1.67 (s, 3H, Mel9), 1.47 (m, 2H, CH2), 1.24 (s, 3H, Mel7), 1.14 (s, 3H, Mel6), 1.11 (t, J = 7.2 Hz, Me), 0.64 (m, 2H, cyclopropyl), 0.47 (m, 1H, cyclopropyl), 0.29 (m, 1H, cyclopropyl).

WO 94/10997 ~~ PCT/US93/10816 67 i , .

OAc - ~ off t Bu0 N OIIII
~ _ iii H OH
P h U _' ~'0 Ac0 (49-1 ) Preparation of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of (TMS)ZNLi in THF.
After ~, h at -45 °C, a solution of cis-1- (t-butoxy-carbonyl)-3-triethylsilyloxy-4-cyclopropylazetidin-2-one (170 mg, 0.5 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C
during 6h before 1 mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 140 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 140 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned,between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 109 mg of material which was purified by flash chromatography to SUBSTITUTE SHEEt (RULE 26~

WO 94/10997 . ' PCT/US93/10°'6 °~~' 21~'~8~4 give 106 mg (97$) of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol, which was recrystallized from ether/hexane.
m.p. 167-169 °C; [a]~~a -74.0° (c 0.1, CHC1,) .
1H NMR (CDC1" 300 MHz) S 8.10 (d, J = 7.5 Hz, 2H, benzoate ortho), 7.61 (m, 1H, benzoate, para), 7.49 (t, J
- 7.5 Hz, 2H, benzoate, meta), 6.30 (s, 1H, H10), 6.16 (br t, J - 8.7 Hz, 1H, H13), 5.67 (d, J = 7.2 Hz, 1H, H2~), 4.96 (dd, J = 9.3, 1.5 Hz, 1H, H5), 4.91 (d, J =
9.3 Hz, 1H, NH), 4.41 (m, 1H, H7), 4.39 (dd, J = 6.6, 1.8 Hz, 1H, H2' ) , 4.31 (d, J = 8.1 Hz, 1H, H200c) , 4.16 (d, J
- 8 .1 Hz, 1H, H20~i) , 3 .79 (d, J = 7 .2 Hz, 1H, H3 ) , 3 .37 (d, J = 6.6 Hz, 1H, 2'0H), 3.29 (dt, J = 9.3, 1.8 Hz, 1H, H3'). 2.55 (m, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.35 (s, 3H, 4Ac), 2.30 (br d, J = 9.3 Hz, 2H, H14), 2.23 (s, 3H, lOAc), 1.89 (d, J = 0.9 Hz, 3H, Mel8), 1.74 (s, 1H, 10H), 1.66 (s, 3H, Mel9), 1.31 (s, 9H, t-Bu), 1.24 (s, 3H, Mel7), 1.14 (s, 3H, Mel6), 0.63 (m, 2H, cyclopropyl), 0.46 (m, 1H, cyclopropyl), 0.25 (m, 1H, cyclopropyl).

WO 94/10997 214 ~$~~ PCT/US93/10816 OAc _ 0 0 0 - ~ OH
nBuO N 0~~~~
iii H OH
P h p " ~~ 0 0 Ac0 (56-3) Preparation of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(n-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1.5 mL of THF at -45 °C was added dropwise 0.157 mL of a 1. OM solution of (TMS)2NLi in THF.
After 1 h at -45 °C, a solution of cis-1-(n-butoxy-carbonyl)-3-triethyl-silyloxy-4-cyclopropylazetidin-2-one (170 mg, 0.5 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C
during 6h before l mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/ hexane.
Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 145 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethyl-silyl-3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(n-butoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 145 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 ' 25 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 108 mg of SUBSTITUTE SHEET (RULE 26) W0 94/ 10997 .. PCT/US93/ 1 P°' 6 ~~~~,2 ~. 4'~ $ ~ ~
material which was purified by flash chromatography to give 98 mg (87$) of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(n-butoxycarbonyl) taxol, which was _ recrystallized from etY~er/hexane.
5 m.p. 132-134 °C; [a]~~xa -64.0° (c 0.175, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.11 (d, J = 7.8 Hz, 2H, benzoate ortho), 7.60 (m, 1H, benzoate, para), 7.49 (t, J
- 7.8 Hz, 2H, benzoate, meta), 6.29 (s, 1H, H10), 6.22 (br t, J - 9.3 Hz, 1H, H13), 5.66 (d, J = 6.9 Hz, 1H, 10 H2~), 5.04 (d, J = 9.3 Hz, 1H, NH), 4.95 (dd, J = 9.6, 1.8 Hz, 1H, H5), 4.43 (dd, J = 5.4, 2.1 Hz,lH, H2'), 4.40 (m, 1H, H7) , 4.30 (d, J = 8.7 Hz, 1H, H20a) , 4.17 (d, J =
8.7 Hz, 1H, H20~3), 3.89 (m, 2H, OCH2), 3.79 (d, J = 6.9 Hz, 1H, H3), 3.43 (d, J = 5.4 Hz, 1H, 2'0H), 3.36 (dt, J
15 - 9.3, 2.1 Hz, 1H, H3'), 2.55 (m, 1H, H6a), 2.49 (d, J =
4.5 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.24 (s, 3H, lOAc), 1.88 (s, 3H, Mel8), 1.75 (s, 1H, 10H), 1.67 (s, 3H, Mel9), 1.47 (m, 2H, CH2), 1.26 (s, 3H, Mel7), 1.23 (m, 2H, CH2), 1.14 (s, 3H, Mel6), 0.82 (t, J = 7.2 Hz, 3H, 20 Me), 0.64 (m, 2H, cyclopropyl), 0.47 (m, 1H, cyclopropyl), 0.29 (m, 1H, cyclopropyl).

~ ~ WO 94/10997 ~~ PCT/US93/10816 ,a ' OAc - ~ OH

~ iiii i H OH
HO
H

P h ~ _~ 0 0 Ac0 (63-1 ) Preparation of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(isobutoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 2 mL of THF at -45 °C was added dropwise 0.157 mL of a 1. OM solution of (TMS)2NLi in THF.
After 1 h at -45 °C, a solution of cis-1-(isobutoxy-carbonyl)-3-triethylsilyloxy-4-cyclopropylazetidin-2-one (244 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C
during 6h before 1 mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 145 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(isobutoxy-carbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 145 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 " 25 mL of 48o aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 95 mg of SUBSTITU1'E ~IiEET (RULE 26~

WO 94/10997 r ' ~ ; ':. ~~ ~~ ~ PCT/US93/10 material which was purified by flash chromatography to give 87 mg (85~) of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(isobutoxycarbonyl) taxol, which was recrystallized from eth2r/hexane.
m.p. 130-132 °C; (a]~~xa -64.0° (c 0.15, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.12 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.61 (m, 1H, benzoate, para), 7.50 (t, J
- 7.2 Hz, 2H, benzoate, meta), 6.29 (s, 1H, H10), 6.22 (br t, J - 8.7 Hz, 1H, H13), 5.67 (d, J = 7.2 Hz, 1H, H2~), 5.05 (d, J = 9.6 Hz, 1H, NH), 4.96 (dd, J = 9.3, 1.8 Hz, 1H, H5), 4.43 (dd, J = 5.4, 2.1 Hz, 1 H, H2'), 4.41 (m, 1H, H7), 4.30 (d, J = 8.4 Hz, 1H, H20a), 4.17 (d, J = 8.4 Hz, 1H, H20(3) , 3 .79 (d, J = 7.2 Hz, 1H, H3) , 3.67 (m, 2H, i-Bu), 3.39 (d, J = 5.4 Hz, 1H, 2'0H), 3.37 ( dt, J = 9.3, 2.1 Hz, 1H, H3'), 2.55 (m, 1H, H6a), 2.48 (d, J = 3.9 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.24 (s, 3H, lOAc), 1.88 (s, 3H, Mel8), 1.67 (s, 3H, Mel9), 1.25 (s, 3H, Mel7), 1.14 (s, 3H, Mel6), 0.80 (d, J = 6.6 Hz, 3H, Me), 0.76 (d, J = 6.6 Hz, 3H, Me), 0.64 (m, 2H, cyclopropyl), 0.48 (m, 1H, cyclopropyl), 0.29 (m, 1H, cyclopropyl).

~l''~ PCT/US93/10816 w WO 94/10997 ~,.",. 7 3 OAc _ 0 0 0 - ~ off 0 N _ OIIII
- I - iii H OH
0 1 ' ~~0 Ph \\ Ac0 ( 62-3 ) Preparation of 3'-desphenyl-3'-cyclopropyl-N-desb~nzoyl-N-(isopropoxycarbonyl) taxol. _ To a solution of 7-O-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 2 mL of THF at -45 °C was added dropwise 0.157 mL of a 1. OM solution of (TMS)2NLi in THF.
After 1 h at -45 °C, a solution of cis-1-(isopropoxy-carbonyl)-3-triethylsilyloxy-4-cyclopropylazetidin-2-one (145 mg, 0.429 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C
during 9h before 1 mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 145 mg of a mixture containing (2'R,3'S)-2',7-(bis)-O-triethylsilyl-3'-desphenyl-3'-cyclopropyl-N-desbenzoyl-N-(isopropoxy-carbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 145 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 ' 25 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 111 mg of SI~STITUT~ SHEET (RULE 26) WO94/10997 '..~~ - PCT/US93/109'~
...s material which was purified by flash chromatography to give 95 mg (84%) of 3'-desphenyl-3'-cyclopropyl-N-desbenzoyl-N-(isopropoxycarbonyl) taxol, which was reczystallized from ether/hexane.
m.p. 142-144 °C; [a]~~a -77.06° (c 0.17, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.11 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.61 (m, 1H, benzoate, para), 7.49 (t, J
- 7.2 Hz, 2H, benzoate, meta), 6.29 (s, 1H, H10), 6.20 (br t, J - 9.0 Hz, 1H, H13), 5.67 (d, J = 7.2 Hz, 1H, H2~), 4.97 (d, J = 9.6 Hz, 1H, NH), 4.96 (dd, J = 9.3, 1.8 Hz, 1H, H5), 4.71 (m, 1H, isopropyl), 4.42 (m, 2H, H7 and H2' ) , 4.31 (d, J = 8.4 Hz, 1H, H20a) , 4.17 (d, J =
8.4 Hz, 1H, H20~), 3.79 (d, J = 7.2 Hz, 1H, H3), 3.39 (d, J = 6.0 Hz, 1H, 2'0H), 3.35 ( dt, J = 9.3, 2.1 Hz, 1H, H3'), 2.55 (m, 1H, H6a), 2.48 (d, J = 3.9 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.24 (s, 3H, lOAc), 1.88 (s, 3H, Mel8), 1.67 (s, 3H, Mel9), 1.25 (s, 3H, Mel7), 1.14 (s, 3H, Mel6), 1.14 (d, J = 6.0 Hz, 3H, isopropyl), 1.05 (d, J = 6.0 Hz, 3H, isopropyl), 0.64 (m, 2H, cyclopropyl), 0.47 (m, 1H, cyclopropyl), 0.28 (m, 1H, cyclopropyl).

' 'W0 94/10997 ~~~'. - PCT/US93/10816 75 .

OAc ~ - - ~ off iii H OH _ HO

P h ~ _~ 0 Ac0 (56-4) Preparation of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(allyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 2 mL of THF at -45 °C was added dropwise 0.157 mL of a 1. OM solution of (TMS)2NLi in THF.
After 1 h at -45 °C, a solution of cis-1-(allyloxy-carbonyl)-3-triethyl-silyloxy-4-cyclopropylazetidin-2-one (220 mg, 0.672 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C
during 6h before 1 mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/ hexane.
Evaporation of the organic layer gave a residue which was purified by filtration thro-ugh silica gel to give 125 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(allyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 120 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 87 mg of SUBSTITUTE SHEET (RUSE 26~

WO 94/10997 ~ ~ ~' PCT/US93/10~' S

material which was purified by flash chromatography to give 79 mg (85~) of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(allyloxycarbonyl) taxol, which was recrystallized from ether/hexane.
m.p. 138-140 °C; [a]~~xa -68.2° (c 0.085, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.12 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.61 (m, 1H, benzoate, para), 7.50 (t, J
- 7.2 Hz, 2H, benzoate, meta), 6.29 (s, 1H, H10), 6.22 (br t, J - 8.4 Hz, 1H, H13), 5.78 (m, 1H, allyl), 5.67 (d, J = 7.2 Hz, 1H, H2~), 5.14 (m, 2H, allyl), 5.09 (d, J
- 9.6 Hz, 1H, NH), 4.96 (dd, J = 9.3, 2.4 Hz, 1H, H5), 4.43 (m, 4H, OCH2, H7 and H2'), 4.30 (d, J = 8.4 Hz, 1H, H20a) , 4.18 (d, J = 8.4 Hz, 1H, H20(3) , 3 .79 (d, J = 6.9 Hz, 1H, H3), 3.39 (dt, J = 9.6, 1.8 Hz, 1H, H3'), 3.35( d, J = 5.4 Hz, 1H, 2'0H), 2.55 (m, 1H, H6a), 2.45 (d, J =
3.9 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac), 2.24 (s, 3H, lOAc), 1.88 (s, 3H, Mel8), 1.68 (s, 3H, Mel9), 1.26 (s, 3H, Mel7), 1.14 (s, 3H, Mel6), 0.64 (m, 2H, cyclopropyl), 0.48 (m, 1H, cyclopropyl), 0.29 (m, 1H, cyclopropyl).

WO 94/ 10997 ~ PCT/ US93/ 10816 OAc ~ OH

_ J -_ .,,,, H OH
Ph HO
H

P h ~ _~ 0 0 Ac0 (62-4 ) Preparation of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 2 mL of THF at -45 °C was added dropwise 0.157 mL of a 1. OM solution of (TMS)aNLi in THF.
After 1 h at -45 °C, a solution of cis-1-(benzyloxy-carbonyl)-3-triethylsilyloxy-4-cyclopropylazetidin-2-one (264 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C
during 10h before 1 mL of a 10~ solution of AcOH in THF
was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 144 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-esphenyl-3'-cyclopropyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 144 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 109 mg of material which was purified by flash chromatography to SUBSTITUTE SHEET (RULE 26~

WO 94/ 10997 ~ PCT/US93/ 1 P°' 6 give 97 mg (86~) of 3'-desphenyl-3'-cyclopropyl-N-debenzoyl-N-(benzyloxycarbonyl) taxol, which was recxystallized from ether/hexane.
m.p. 128-130 °C; [a]~~a -64.21° (c 0.19, CHC1,) . .
1H NMR (CDC1" 300 MHz) 8 8.11 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.60 (m, 1H, benzoate, para), 7.49 (t, J
- 7.2 Hz, 2H, benzoate, meta), 7.25 (m, 3H, benzyl), 7.14 (m, 2H, benzyl), 6.26 (s, 1H, H10), 6.18 (br t, J - 8.7 Hz, 1H, HI3), 5.64 (d, J = 7.2 Hz, 1H, H2~i), 5.24 (d, J =
9.3 Hz, 1H, NH), 5.01 (d, J = 12.6 Hz, 1H, benzyl), 4.94 (dd, J = 9.3, 1.5 Hz, 1H, H5), 4.91 (d, J = 12.6 Hz, 1H, benzyl), 4.44 (br s, 1 H, H2'), 4.40 (dd, J = 11.1, 6,6 Hz, 1H, H7) , 4.28 (d, J = 8.4 Hz, 1H, H20a) , 4.18 (d, J =
8.4 Hz, 1H, H20(3), 3.75 (d, J = 7.2 Hz, 1H, H3), 3.44 (br s, 1H, 2'0H), 3.41 ( dt, J = 9.3, 2.1 Hz, 1H, H3'), 2.53 (m, 2H, H6a), 2.36 (s, 3H, 4Ac), 2.23 (s, 3H, lOAc), 1.83 (s, 3H, Mel8), 1.67 (s, 3H, Mel9), 1.21 (s, 3H, Mel7), 1.12 (s, 3H, Mel6), 0.64 (m, 2H, cyclopropyl), 0.47 (m, 1H, cyclopropyl), 0.29 (m, 1H, cyclopropyl).

~WO94/10997 i~,~~~~~ PCT/US93/10816 OAc _ 0 0 0 _ ~ 0H
P h N 01111 _ ~ _ ~i~~~
H OH
P h U ~ ~'0 Ac0 (60-4) Preparation of 3'-desphenyl-3'-t-butyl taxol.
To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 °C was added dropwise 0.188 mL of a 1.00 M solution of lithium bis(trimethyl-silyl)amide in THF. After 0.5 h at -45 °C, a solution of cis-1-benzoyl-3-triethylsilyloxy-4-t-butylazetidin-2-one (308 mg, 0.855 mmol) in 1.2 mL of THF
was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 181.4 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-t-butyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 181.4 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 142 mg of material which was purified by flash chromatography to SUBSTITUTE SHEET (RULE 26) WO 94/10997 PCT/US93/10°'6 214'~8~4 ~-' give 71.2 mg (50%) of 3'-desphenyl-3'-t-butyl taxol, which was recrystallized from methanol/water.
m.p.161-163 °C; [a]~~a -420° (c 0.0048, CHC1,) .
5 1H NMR (CDC1" 300 MHz) 8 8.18(d, J=7.7 Hz, 2H, benzoate, ortho), 7.67-7.36 (m, 8H, aromatic), 6.47 (d, J=10 Hz, 1H, NH), 6.27(s, 1H, H10), 6.21(dd, J = 8.9, 8.9 Hz, 1H, H13 ) , 5 . 69 (d, J = 7 .3 Hz, 1H, H2 (3) , 4 . 97 (d, J = 9 . 6 Hz, 1H, H5), 4.68(d, J=3.2 Hz, 1H, H2'), 4.41(m, 2H, H3', 10 H7), 4.36(d, J=8.8 Hz, 1H, H20a),4.23(d, J=8.8 Hz, H20(3), 3.80(d, J=6.8 Hz, 1H ,H3) , 3.28(d, J=4.1 Hz, 1H, 2'OH),2.57(m, 1H, H6oc), 2.52(s, 3H, 4Ac), 2.45(d, J=4.5 Hz, 1H, 70H), 2.35(m, 2H, H14), 2.24 (s, 3H, lOAc), 1.95 (m, 1H, H6(3), 1.87(br s, 3H, Mel8), 1.76(s, 1H, 15 lOH),1.70(s, 3H, Mel9), 1.24(s, 3H, Mel7), 1.15(s, 12H, Mel6, t-butyl).

- WO 94/10997 ~$ ~,~ PCT/US93/10816 OAc _ 0 0 0 ~ OH
teuo N o~~~~ ,, ~ _ .
H OH
P h p " ~~ 0 Ac0 (61-2) Preparation of 3'-desphenyl-3'-t-butyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 °C was added dropwise 0.188 mL of a 1.00 M solution of lithium bis(trimethyl-silyl)amide in THF. After 0.5 h at -45 °C, a solution of cis-1-(t-butoxycarbonyl)-3-triethyl-silyloxy-4-t-butylazetidin-2-one (303 mg, 0.855 mmol) in 1.2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 180.4 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-t-butyl-N-debenzoyl-N- (t-butoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 180.4 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 141 mg of SUBSTITU1E SHEEN (RULE 26) WO 94/10997 t.p.'f' ~' ~.~ ~~ ~ . PCT/US93/10°'6 material which was purified by flash chromatography to give 133 mg (92~) of 3'-desphenyl-3'-t-butyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.158-159 °C; [a]~sNa -44.0° (c 0.0055, CHC1,) .
~H NMR (CDC1" 300 Mfiz) 8 8.13(d, J=7.7 Hz, 2H, benzoate, ortho), 7.61-7.47(m, 3H, aromatic), 6.29(s, 1H, H10), 6.18(dd, J = 8.9, 8.9 Hz, 1H, H13), 5.68(d, J = 7.1 Hz, 1H, H2 (3) , 4.97 (d, J = 9.3 Hz, 1H, HS) , 4.87 (d, J=10.4 Hz, 1H, NH), 4.56 (d, J=5.5 Hz, 1H, H3'), 4.41(m, 1H, H7) , 4.32 (d, J=8.8 Hz, 1H, H20a) , 4.17 (d, J=8.8 Hz, HZO(3), 3.79(m, 2H, H2', H3), 3 .07 (d, J= 5 Hz, 1H, 2'0H) , 2 .61 (m, 1H, H6a), 2.45(d, J=4.5 Hz, 1H, 70H), 2.41(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.24 (s, 3H, lOAc),1.95 (m, 1H, H6~), 1.88(br s, 3H, Mel8), 1.68(s, 1H, 10H), 1.67(s, 3H, Mel9), 1.30(s, 9H, t-butoxyl), 1.26(s, 3H, Mel7), 1.14(s, 3H, Mel6), 1.04(s, 9H t-butyl).

WO 94/10997 ~~ ~8~' PCT/US93/10816 OAc - ~ OH
_ t8u0 N 01111 iii H OH
HO

P h ~ _~ 0 Ac0 (61-3) Preparation of 3'-desphenyl-3'-cyclobutyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 °C was added dropwise 0.188 mL of a 1.00 M solution of lithium bis(trimethylsilyl)-amide in THF. After 0.5 h at -45 °C, a solution of cis-1-(t-butoxycarbonyl)-3-triethyl-silyloxy-4-cyclobutylazetidin-2-one (303 mg, 0.855 mmol) in 1.2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a.residue which was purified by filtration through silica gel to give 180.5 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclobutyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 180.5 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and O.SS mL of pyridine at 0 °C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 141 mg of SUBSTITUTE SHEET (RULE 26) PCT/US93/10R~ 6 material which was purified by flash chromatography to give 133 mg (92%) of 3'-desphenyl-3'-cyclobutyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.168-169 °C; [OC]~~a -41.0° (C 0.006, CHC1,) .
1H NMR (CDC1" 300 MHz) S 8.13(d, J=7.7 Hz, 2H, benzoate, ortho), 7.62-7.48(m, 3H, aromatic), 6.30(s, 1H, H10), 6.18(dd, J = 8.9, 8.9 Hz, 1H, H13), 5.68(d, J = 7.1 Hz, 1H, H2~3), 4.98(d, J = 9.9 Hz, 1H, H5), 4.57(d, J=9.3 Hz, 1H, NH),4.42(m, 1H, H7), 4.33(d, J=8.8 Hz, 1H, H20a), 4.22-4.16(m, 2H, H20~i, H2'), 3.94(dd, J=9.3,6.0 Hz, 1H, H3'), 3.80(d, J=6.6 Hz, 1H, H3), 3.13(d, J= 6 Hz, 1H, 2'0H), 2.60(m, 1H, H6oc), 2.45(d, J=4.5 Hz, 1H, 70H), 2.43(s, 3H, 4Ac), 2.35(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.95 (m, 1H, H6(3), 1.88(br s, 3H, Mel8), 1.80-1.78 (m, 7H,cyclobutyl), 1.77(s, 1H, 10H), (1.67, s, 3H, Mel9), 1.30 (s, 9H, t-butoxy), 1.25(s, 3H, Mel7), 1.15(s, 3H, Mel6).

X14 ?'8~.
~WO 94/10997 i : ~ .. ~ PCT/US93/t0816 OAc Ph N OIIII
i~~
H OH
a Ph~ ~ 0 \\ Ac0 (57-1) Preparation of 3'-desphenyl-3'-(cyclopentyl) taxol.
5 To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 °C was added dropwise 0.188 mL of a 1.00 M solution of lithium bis(trimethyl-silyl)amide in THF. After 0.5 h at -45 °C, a solution of cis-1-benzoyl-3-triethylsilyloxy-4-cyclo-10 pentylazetidin-2-one (319 mg, 0.855 mmol) in 1.2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, 15 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 183 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(cyclopentyl) taxol and a small amount of 20 the (2'S,3'R) isomer.
To a solution of 183mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 25 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 144.5 mg SUBST(lUTf SHEET (RULE 26) WO 94/ 10997 4 , ~.~ ;. PCT/ US93/ 1 P°' 6 of material which was purified by flash chromatography to give 123 mg (85%) of 3'-desphenyl-3'-(cyclopentyl) taxol, which was reczystallized from methanol/water. .
m.p.165-166 °C; [a]~~xa -35.0° (C 0.0052, CHC1,) .
1H 1~ (CDC1" 300 MHz) 8 8.16 (d, J=8.2 Hz, 2H, benzoate, ortho), 7.6-7.3(m, 8H, aromatic), 6.32(s, J=9.3 Hz, 1H, NH), 6.27(s, 1H, H10), 6.21(dd,J = 8.8, 8.8 Hz,lH, H13), 5. 68 (d, J = 7 .7 Hz, 1H, H2~3) , 4. 96 (d, J = 7 .1 Hz, 1H, H5), 4.48-4.20(m, 5H, H20's, H2',H3',H7), 3.80(d, J= 7.7 Hz, 1H, H3), 3.62(d, J= 5.5 Hz, 1H, 2'0H), 2.54(m, 1H, H6a), 2.48(s, 3H, 4Ac), 2.45(d, J=4.4 Hz, 1H, 70H), 2.33 (m, 2H, H14) , 2.22 (s, 3H, lOAc) , 1.89 (m, 1H, H6~3) , 1.84(br s, 3H, Mel8), 1.79(s, 1H, 10H), 1.68 (s, 3H, Mel9), 1.32-1.23(m, 9H, cyclopentyl), 1.22(s, 3H, Mel7), 1.13 (s, 3H, Mel6) .

~WO 94/10997 . 5~~ PCT/US93/10816 8 7 '- . . . '.

OAc ~ off ta~0 ~ 0~~~~ ,, i _ H OH

Ph~ ~ 0 \\ Ac0 (61-1) Preparation of 3'-desphenyl-3'-cyclopentyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 °C was added dropwise 0.188 mL of a 1.00 M solution of lithium bis(trimethylsilyl)-amide in THF. After 0.5 h at -45 °C, a solution of cis-1- (t-butoxycarbonyl)-3-triethyl-silyloxy-4-cyclopentylazetidin- 2-one (316 mg, 0.855 mmol) in 1.2 mL of THF was added dropwise to the mixture.
The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH
in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane.
Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 183 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethyl-silyl-3'-desphenyl-3'-cyclopentyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol and a small amount of the (2'S,3'R) . isomer.
To a solution of 183mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between SUBSTITUTE SHEET (BILE 26~

WO 94/ 10997 1 x ~ PCT/US93/ 1 P

saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 144 mg of material which was purified by flash chromatography to -give 136 mg (94%) of 3'=desphenyl-3'-cyclopentyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.164-165 °C; [a]~~xa -37.0° (c 0.0055, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.11 (d, J=8.2 Hz, 2H, benzoate, ortho), 7.61-7.47(m, 3H, aromatic), 6.30(s, 1H, H10), 6.20(dd, J = 8.9, 8.9 Hz, 1H, H13), 5.67(d, J = 7.1 Hz, 1H, H2~i) , 4.95 (d, J = 7.7 Hz, 1H, H5) , 4.72 (d, J=9.3 Hz, 1H, NH)4.40(m, 1H, H7), 4.35-4.16(m, 3H, H20's, H3'), 3 .79 (m, ZH, H3, H2' ) , 3 .23 (d, J= 6 Hz, 1H, 2'0H) , 2.55 (m, 1H, H6a), 2.40(s, 3H, 4Ac), 2.45(d, J=4.5 Hz, 1H, 70H), 2.35(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.95 (m, 1H, H6(3), 1.88(br s, 3H, Mel8), 1.79(s, 1H, 10H), (1.67,s, 3H, Mel9), 1.32-1.23(m, 18H, cyclopentyl, butoxy), 1.21(s, 3H, Mel7), 1.12(s, 3H, Mel6).

W094/10997 ~~~ PCT/US93/10816 89.
. .. .: a OAc - ~ off I err. _ om~ , -_ H OH
P h o _~ ~'0 Ac0 (62-2) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(2-furoyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF. After 1 h at -45 °C, a solution of cis-1- (2-furoyl)-3-triethylsilyloxy-4-cyclohexylazetidin-2-one (270 mg, 0.715 mmol) in 1 mL
of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10°s solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 154.2 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(2-furoyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 154.2 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUgSTITUf E SHEET (RULE 26) WO 94/10997 ~ ~~~ ,'1 , PCT/US93/1P~ 5 .,.,r Evaporation of the ethyl acetate solution gave 121.5 mg of material which was purified by flash chromatography to give 83.5 mg (68.7 ~) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(2-furoyl~ taxol, which was recrystallized 5 from methanol/water.
m.p.171-173°0 [a]~~a -24.3° (c 0.0028, CHC1,) .
1H N1~ (CDC1" 300 MHz) 8 8.17(d, J=7.15 Hz, 2H, benzoate ortho). 7.63(m, 1H, benzoate para), 7.53(m, 2H, benzoate 10 meta), 7.42(d, J= 1.65 Hz, 1H, furyl), 6.92(d, J= 2.74 Hz, 1H, furyl). 6.5(d, J= 9.34 Hz, 1H, NH), 6.43(dd, J=
2.74 Hz, 1.65 Hz, 1H, furyl) ,6.26(s, 1H, H10), 6.22(m, 1H, H13), 5.67(d, J = 7.15 Hz, 1H, H2(3), 4.96(dd, J =
9.34 Hz, 2.2 Hz, 1H, H5), 4.59(bs, 1H, H2'), 4.41(dd, J=
15 10.71 Hz, 6.6 Hz, 1H, H7), 4.31(d, J= 8.24 Hz, 1H, H20a), 4.26 (m, 1H, H3' ) , 4.21 (d, J=8 .24 Hz, 1H, H20~i) , 3 .79 (d, J= 7.14 Hz, 1H, H3), 3.63(bs, 1H, 2'0H), 2.55(m, 1H, H6a), 2.48(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.22 (s, 3H, lOAc), 1.87 (s, 3H, Mel8), 1.83(m, 1H, H6(3), 1.73-1.64(m, 20 6H, cyclohexyl), 1.68(s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.25(s, 3H, Mel7), 1.13(s, 3H, Mel6).

WO 94/10997 _ "1~'~~ PCT/US93/10816 OAc - ~ OH
_ OIIII
__ ~~i H OH

Ph~ ~ 0 ~~ Ac0 (57-2) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(2-thienoyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethyl-silyl)amide in THF. After 1 h at -45 °C, a solution of cis-1-(2-thienoyl)-3-triethylsilyloxy-4-cyclohexylazetidin-2-one (281 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate./hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 156.5 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(2-thienoyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 156.5 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
t'~E~ SiiE~T (RULE 26~

WO 94/10997 PCT/US93/10°'6 " . ~ ..,r Evaporation of the ethyl acetate solution gave 121.5 mg of material which was purified by flash chromatography to give 87.4 mg (70.5 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(2-thienoyl) taxol, which was recrystallized from methanol/water.
m.p.162-164°C; [a]~~a -29.2° (c 0.0026, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.16(d, J=7.14 Hz, 2H, benzoate ortho), 7.62(m, 1H, benzoate para), 7.53(m, 2H, benzoate meta), 7.42(d, J= 4.39 Hz, 2H, thienyl), 7.02(m, 1H, thienyl), 6.26(s, 1H, H10), 6.22(m, 1H, H13), 6.17(d, J=
9.89 Hz, 1H, NH), 5.67(d, J = 7.15 Hz, 1H, H2(3), 4.96(dd, J = 9.61 Hz, 2.2 Hz, 1H, H5),4.60(d, J= 2.2 Hz, 1H, H2'), 4.41(dd, J= 10.99 Hz, 6.6 Hz, 1H, H7), 4.30(d, J= 8.24 Hz, 1H, H20a), 4.25(m, 1H, H3'), 4.21 (d, J=8.24 Hz, 1H, H20~i), 3.78(d, J= 7.14 Hz, 1H, H3), 2.55(m, 1H, H6a), 2.48(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.22 (s, 3H, lOAc), 1.86(m, 1H, H6~) 1.83(s, 3H, Mel8), 1.73-1.64(m, 6H, cyclohexyl), 1.68(s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.24(s, 3H, Mel7), 1.12(s, 3H, Mel6).

WO 94/10997 y~' PCf/US93/10816 EXAMPLE'31 OAc - ~ OH
Et0 ~. Omn - ~~~ii H OH
0 , ~ ~~0 Ph \\0 Ac0 (51-4) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-ethoxycarbonyl taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF. After 1 h at -45 °C, a solution of cis-1- (ethoxycarbonyl)-3-triethylsilyloxy-4-cyclohexylazetidin-2-one (254 mg, 0.715 mmol) in 1 mL
of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 151 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-ethoxycarbonyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 151 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITtlrE SHEET (RULE 26) WO 94/10997 ~ PCT/US93/lrw6 ~:,. ~....5".. . - . .. : ..../
~~~7~~~ 94 Evaporation of the ethyl acetate solution gave 118 mg of material which was purified by flash chromatography to give 100.6 mg (85 %) of 3'-desphenyl-3'-cyclohexyl-N- .
debenzoyl-N-ethoxycarbonyl taxol, which was recrystallized from methanol/water.
m.p.157-160 °C; [aJ~~a -62.6° (c 0.0027, CHC1,) .
IH NMR (CDC1" 300 MHz) 8 8.14(d, J=7.15 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.28 (s, 1H, H10), 6.27(m, 1H, H13), 5.67(d, J =
7.14 Hz, 1H, H2(3), 4.96 (dd, J = 8.8, 1.1 Hz, 1H, H5), 4.81(d,J= 9.89 Hz, 1H, NH), 4.50(b s, 1H, H2'), 4.42(dd, J= 10.99, 6.59 Hz, 1H, H7), 4.30(d, ~T= 8.24 Hz, 1H, H20a), 4.19 (d, J=8.79 Hz, 1H, H20(3),3.93(q, J= 7.14 Hz, 2H, CH2, ethyl), 3.79(d, J= 6.59 Hz, 1H, H3),3.76(m, 1H, H3'), 3.36(m, 1H, 2'0H), 2.55(m, 1H, H6a), 2.43(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.24 (s, 3H, lOAc), 1.87 (s, 3H, Mel8), 1.83(m, 1H, H6(3),1.73-1.64(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.33-1.17(m, 5H, cyclohexyl), 1.26(s, 3H, Mel7), 1.14(s, 3H, Mel6), 1.09 (t, J= 7.14 Hz, 3H, Me, ethyl).

,~ WO 94/10997 ~ ~PCT/US93/10816 OAc - ~ OH
teuo r, om~
H OH
P h~ ' 0 ~~0 ACO
(47-3) Preparation of 3'-desphenyl-3'-(cyclohexyl)-N-debenzoyl-5 N-(t-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethyl-silyl)amide in THF. After 1 h at -45 °C, a 10 solution of cis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-(cyclohexyl)-azetidin-2-one (274 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added.
15 The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 155 mg of a mixture containing (2'R,3'S)-2',7- (bis)triethylsilyl-3'-20 desphenyl-3'-(cyclohexyl)-N-debenzoyl- N-(t-butoxy-carbonyl)taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 155 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of 25 acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between SUBSTITUTE SHEET (RULE 26~

WO 94/ 10997 ~ ~ PCT/US93/ 1 P"' 6 ~en. . a, :..

saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 122 mg of material which was purified by flash chromatography to give 106 mg (86.6 %) of 3'-desphenyl-3'-(cyclohexyl)-N-debenzoyl-N-(t-butoxycarbonyl) taxol, which was reczystallized from methanol/water.
m.p.163-166 °C; [oc)~fNa -71.0° (c 0.00255, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.12(d, J=7.14 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.5(m, 2H, benzoate meta), 6.29 (s, 1H, H10), 6.20(bt, J=8.8 Hz, 1H, H13), 5.67(d, J = 7.14 Hz, 1H, H2~i), 4.96 (dd, J = 9.61, 2.2 Hz, 1H, H5), 4.67(d,J= 9.89 Hz, 1H, NH), 4.47(dd, J=
4.94, 1.65 Hz, 1H, H2'), 4.41(m, 1H, H7), 4.31(d, J= 8.24 Hz, 1H, H20ot) , 4.17 (d, J=8.24 Hz, 1H, H20~i) , 3 .79 (d, J=
7.14 Hz, 1H, H3),3.71(m, 1H, H3'), 3.25(d, J= 4.95 Hz, 1H, 2'0H), 2.55(m, 1H, H6a),2.47(m, 1H, 70H), 2.41(s, 3H, 4Ac), 2.32(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.87 (s, 3H, Mel8), 1.83(m, 1H, H6(3),1.73-1.58(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.28(s, 9H, tert-butyl), 1.25(s, 3H, Mel7), 1.14(s, 3H, Mel6).

WO 94/10997 ~~ PCT/US93/10816 OAc - ~ OH
nBuO P. OIIII
- .hiii H OH
0 . , ~~ 0 Ph~ _, \\0 Ac0 Preparation of 3'-desphenyl-3'-cyclohexyl-N-desbenzoyl-N-(n-butoxycarbonyl) taxol.
To a solution of 7-O-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 10 M solution of lithium bis(tri-methylsilyl)-amide in THF. After 1 h at -45 °C, a solution of cis-1-(n-butoxycarbonyl)-3-triethylsilyloxy-4-cyclohexylazetidin-2-one (274 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 155 mg of a mixture containing (2'R,3'S)-2',7-(bis)-O-triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-desbenzoyl-N-(n-butoxy-carbonyl) taxol and a small amount of the (2'S,3'R) ' isomer.
To a solution of 155 mg (0.143 mmol) of the - mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between SUBStlTUTE SHEET (RULE 26) WO 94/ 10997 . PCT/US93/ 1 P°' ~
a ~~v''~854 saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 122 mg of material which was purified by flash chromatography to give 111 mg (90 %) of 3'-desphenyl-3'-cyclohexyl-N-desbenzoyl-N-(n-butoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.140-143 °C; [a]~~a -62.9° (c 0.0031, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.13 (d, J=7.69 Hz, 2H, benzoate ortho) ,7.60(m, 1H, benzoate para), 7.49(m, 2H, benzoate meta) , 6.27(s, 1H, H10), 6.25 (m, 1H, H13), 5.66(d, J =
7.14 Hz, 1H, H2~), 4.95(d, J = 8.24 Hz, 1H, H5), 4.87(d,J= 9.89 Hz, 1H, NH), 4.50(b s, 1H, H2'), 4.41(dd, J = 10.98, 6.6 Hz, 1H, H7), 4.29(d, J= 8.24 Hz, 1H, H20a), 4.17 (d, J=8.25 Hz, 1H, H20~), 3.87(m, 2H, n-butyl), 3.78(d, J= 7.14 Hz, 1H, H3),3.76(m, 1H, H3'), 3.44(bs, 1H, 2'0H), 2.55(m, 1H, H6a), 2.43(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.23(s, 3H, lOAc), 1.86(s, 3H, Mel8) 1.83(m, 1H, H6~i), 1.75(s, 1H, 10H), 1.73-1.64(m, 6H, cyclohexyl), 1.66 (s, 3H, Mel9),1.43(m, 2H, n-butyl), 1.31-1.1.13(m, 7H, cyclohexyl, n-butyl), 1.26(s, 3H, Mel7), 1.14(s, 3H, Mel6), 0.791(t, J= 7.14 Hz, 3H, n-butyl).

WO 94/10997 ~ PCT/US93/10816 9 9 ,. 't OAc - / OH
o r, o m ~
.iiii i H OH
HO
H

Ph~ ' 0 \\ Ac0 ( 48-2 ) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(isobutoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethyl-silyl)amide in THF. After 1 h at -45 °C, a solution of cis-1-(isobutoxycarbonyl)-3-triethyl-silyloxy-4-cyclohexyl azetidin-2-one (274 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 155 mg of a mixture containing (2'R,3'S)-2',7- (bis)triethylsilyl-3'-des-phenyl-3'-cyclohexyl-N-debenzoyl-N-(isobutoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 155 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE SU~~'t' (~~~.~ ~6~

WO 94/10997 , ' PCT/US93/10~~6 Evaporation of the ethyl acetate solution gave 122 mg of material which was purified by flash chromatography to give 110 mg (90 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(isobutoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.145-148 °C; [a]'°Na -54.0° (c 0.0025, CHC1,) .
1H I~t (CDC1" 300 MHz) 8 8.14 (d, J=7.14 Hz, 2H, benzoate ortho) ,7.60 (m, 1H, benzoate para), 7.50 (m, 2H, benzoate meta), 6.28 (s, 1H, H10), 6.26 (m, 1H, H13), 5.66(d, J = 7.14 Hz, 1H, H2~i), 4.95(dd, J = 9.61,2.2 Hz, 1H, H5), 4.84(d,J= 9.89 Hz, 1H, NH), 4.51(d, J=1.65 Hz, 1H, H2'), 4.42(dd, J = 10.44, 6.59 Hz, 1H, H7), 4.30(d, J= 8.24 Hz, 1H, H20a), 4.18 (d, J=8.24 Hz, 1H, H20(3), Z5 3.78(d, J= 7.69 Hz, 1H, H3),3.73(m, 1H, H3'),3.70(dd, J=
10.44 Hz, 6.59 Hz, 1H, isobutyl), 3.60(dd, J= 10.44 Hz, 6.59 Hz, 1H, isobutyl), 3.35(b s, 1H, 2'0H), 2.55(m, 1H, H6a), 2.44(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.23(s, 3H, lOAc), 1.86 (s, 3H, Mel8), 1.83(m, 1H, H6~i), 1.75(m, 1H, isobutyl), 1.73-1.58(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.25(s, 3H, Mel7), 1.13(s, 3H, Mel6), 0.76(d, J=7.15 Hz, 3H, Me, isobutyl), 0.71(d, J=6.59 Hz, 3H, Me, isobutyl).

W0 94/10997 ~ ~~r~ PCT/US93/10816 101 s OAc - ~ OH
iPrO h _ Oiiii H OH

HO

Ph~ , 0 \' Ac0 Preparation of 3'-desphenyl-3'-cyclohexyl-N-desbenzoyl-N-(isopropoxycarbonyl) taxol.
To a solution of 7-O-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 10 M solution of lithium bis(trimethylsilyl)amide in THF. After 1 h at -45 °C, a solution of cis-1-(isopropoxycarbonyl)-3-triethyl-silyloxy-4-cyclohexylazetidin-2-one (264 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 153 mg of a mixture containing (2'R,3'S)-2',7-(bis)-O-triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-desbenzoyl-N-(isopropoxy carbonyl) taxol and a small amount of the (2'S,3'R) ' isomer.
To a solution of 153 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between SUBSTITUTE SHEET (RULE 26) 214'854 102 PCT/ US93/ 10°' 6 saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 122 mg of material which was purified by flash chromatography to give 109.4 mg (90.8 %) of 3'-desphenyl-3'-cyclohexyl-N-desbenzoyl-N-(isopropoxycarbonyl) taxol, which was reczystallized from methanol/water.
m.p.150-153 °C; [a]~~a -64.1° (C 0.0031, CHC13) .
1H NMR (CDC1" 300 MHz) 8 8.14(d, J=7.14 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta) , 6.29(s, 1H, H10), 6.25(m, 1H, H13), 5.67(d, J =
7.14 Hz, 1H, H2~i), 4.96(dd, J = 10.01,2.2 Hz, 1H, H5), 4.76(d,J= 9.89 Hz, 1H, NH),4.69(m, 1H, isopropyl) 4.49(d, J= 1.65 Hz, 1H, H2'), 4.41(dd, J = 10.99, 6.59 Hz, 1H, H7), 4.30(d, J= 8.24 Hz, 1H, H20a), 4.18 (d, J= 8.24 Hz, 1H, H20(3), 3.79(d, J= 6.6 Hz, 1H, H3), 3.76(m, 1H, H3'), 3.32(b s, 1H, 2'0H), 2.55(m, 1H, H6a), 2.43(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.87(s, 3H, Mel8), 1.83(m, 1H, H6(3), 1.73-1.64(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.26(s, 3H, Mel7), 1.14(s, 3H, Mel6), 1.11(d, J= 6.04 Hz, 3H, isopropyl), 1.01(d, J= 6.04 Hz, 3H, isopropyl).

y ~-- WO 94/10997 OAc _ - ~ OH
o r, o m ~
_ ~iiiii H OH
HO . H

Ph~ ; 0 Ac0 (62-1) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(allyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF. After 1 h at -45 °C, a solution of cis-1-(allyloxycarbonyl)-3-triethylsilyloxy-4-cyclohexylazetidin- 2-one (262.8 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl a-cetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 152.8 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethyl-silyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(allyloxycarbonyl) taxol and a small amount of the ' (2'S,3'R) isomer.
To a solution of 152.8 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between SUBSTITUTE S~iEE T ~~U~S 26~

WO 94/ 10997 ~ PCT/US93/ i 0°' ~
:' saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 120 mg of material which was purified by flash chromatography to give 110.7 mg (92 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(allyloxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.136-138 °C: [a]'tea -61.1° (c 0.0026, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.13(d, J=7.14 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.28(s, 1H, H10), 6.25(m, 1H, H13), 5.75(m, 1H, allyl), 5.66(d, J = 7.15 Hz, 1H, H2~i), 5.15(m, 1H, allyl), 5.09(m, 1H, allyl), 4.95 (m, 1H, H5), 4.92 (d, J=
10.24 Hz, 1H, NH), 4.51(d, J= 1.64 Hz, 1H, H2'), 4.41(m, 1H, H7), 4.39(m, 2H, allyl), 4.29(d, J= 8.79 Hz, 1H, H20a), 4.19 (d, J=8.79 Hz, 1H, H20(3), 3.79(m, 1H, H3'), 3.78(m, 1H, H3), 3.25(bs, 1H, 2'0H), 2.55(m, 1H, H6a), 2.42(s, 3H, 4Ac), 2.34(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.86 (s, 3H, Mel8), 1.83(m, 1H, H6(3),1.73-1.58(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.24(s, 3H, Mel7), 1.14(s, 3H, Mel6).

WO 94/10997 PCf/US93/10816 ~ OAc - ~ OH
PhCH20 ~. 01111 . iiii H OH
0 ~ ~ ~~ 0 P h ~ _, 0 Ac0 (52-1) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-benzyloxycarbonyl taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethyl-silyl)amide in THF. After 1 h at -45 °C, a solution of cis-1-(benzyloxycarbonyl)-3-triethylsilyloxy-4-cyclohexylazetidin-2-one (298 mg, 0.715 mmol) in 1 mL
of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 160 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-benzyloxycarbonyl taxol and a small amount of the (2'S,3'R) isomer.
' To a solution of 160 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE ~i;EE ~ (RULE ~~) W0 94/10997 ~ , PCT/US93/10P'~
. 106 Evaporation of the ethyl acetate solution gave 127 mg of material which was purified by flash chromatography to give 110 mg (86 ~) of 3'-desphenyl-3'-cyclohexyl-N- .
debenzoyl-N-benzyloxycarbonyl taxol, which was recrystallized from methanol/water.
m.p.149-152 °C; [a]~SNa -46.5° (c 0.0023, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.14(d, J=8.8 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 7.24-7.21(m, 3H, benzyl), 7.10-7.06(m, 2H, benzyl), 6.24 (s, 1H, H10), 6.21(m, 1H, H13), 5.63(d, J =
7.15 Hz, 1H, H2(3), 5.01(d, J= 12.64 Hz, 1H, benzyl),5.00(d,J= 8.79 Hz, 1H, NH),4.94 (dd, J = 9.61, 2.2 Hz, 1H, H5),4.87(d, J= 12.64 Hz, 1H, benzyl), 4.51(b s, 1H, H2'), 4.4(dd, J= 11, 7 Hz, 1H, H7), 4.28(d, J=
8.79 Hz, 1H, H20a), 4.20 (d, J=8.79 Hz, 1H, H20~), 3 .82 (m, 1H, H3' ) 3 .74 (d, J= 7 .15 Hz, 1H, H3 ) , 3 .37 (m, 1H, 2'0H), 2.53(m, 1H, H6a), 2.43(s, 3H, 4Ac), 2.31(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.83(m, 1H, H6(3) 1.81 (s, 3H, Mel8), 1.73-1.60(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.33-1.2(m, 5H, cyclohexyl), 1.24(s, 3H, Mel7), 1.11(s, 3H, Mel6).

WO 94/10997 ~PCT/US93/10816 - OAc - ~ OH
o r. om ~
H OH
I HO 0 H ~ _ Ph~ ~ 0 ', Ac0 (66-3) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(crotyloxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III

(100 mg, 0.143 mmol) in 1 mL of THF at -45 C was added dropwise 0.157 mL of a 10 M solution of lithium bis(trimethylsilyl)-amide in THF. After 1 h at -45 C, a solution of cis-1- (crotyloxycarbonyl)-3-triethyl-silyloxy-4-cyclohexylazetidin- 2-one (273 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 154.8 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(crotyloxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.

' To a solution of 154.8 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of ' acetonitrile and 0.3 mL of pyridine at 0 C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 C for 3 h, then at 25 C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.

SUBSTf TOTE SHEET tRULf 26) WO 94/ 10997 ' PCT/ US93/ 1 Q
i i ..v.

Evaporation of the ethyl acetate solution gave 122 mg of material which was purified by flash chromatography to give 113 mg (92.5 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(crotyloxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.139-141 °C~ [oc]=sNa -66.8° (c 0.00265, CHCl,) .
1H I~t (CDC1" 300 MHz) 8 8.13(d, J=8.79 Hz, 2H, benzoate ortho) ,7.60(m, 1H, benzoate para),7.50(m, 2H, benzoate meta), 6.28 (s, 1H, H10), 6.26 (m, 1H, H13), 5.66(d, J =
7.15 Hz, 1H, H2(3),5.58(m, 1H, crotyl), 5.44(m, 1H, crotyl), 4.95(dd, J = 9.89 Hz, 2.2 Hz, 1H, H5), 4.86(d,J=
9.89 Hz,IH,NH), 4.50( dd, J= 4.9 Hz, 1.92 Hz, 1H, H2'), 4.42(m, 1H, H7), 4.31(m, 2H, crotyl), 4.29(d, J= 8.24 Hz, 1H, H20oc), 4.18 (d, J=8.24 Hz, 1H, H20(3), 3.79(d, J= 7.69 Hz, 1H, H3),3.75(m, 1H, H3'), 3.39(d, J= 4.9 Hz, 1H, 2'0H), 2.55(m, 1H, H6a), 2.43(s, 3H, 4Ac), 2.31(m, 2H, H14), 2.23 (s, 3H, lOAc),1.86(s, 3H, Mel8), 1.83 (m, 1H, H6(3), 1.73-1.64(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9),1.60 (d, J= 6.6 Hz, 3H, crotyl), 1.33-1.17(m, 5H, cyclohexyl), 1.26(s, 3H, Mel7), 1.14(s, 3H, Mel6).

~WO 94/10997 ~~,~~, PCT/US93/10816 OAc - ~ OH
C6H~~0 01111 H OH
Ph 0 Ac0 ( 52-2 ) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-cyclohexyloxycarbonyl taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF. After 1 h at -45 °C, a solution of cis-1- (cyclohexyloxycarbonyl)-3-triethyl-silyloxy-4-cyclohexyl-azetidin-2-one (293 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silir.a gel to give 159 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-cyclohexyloxy-carbonyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 159 mg (0.143 mmol) of the r mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between SUBSTITUtE SHEET (i~llf 26) WO 94/10997 ,;7 ' PCT/US93/108t v....r saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 126 mg of material which was purified by flash chromatography to give 120 mg (95 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-cyclohexyloxycarbonyl taxol, which was reczystallized from methanol/water.
m.p.164-167 °C; [a)~~a -56.5° (c 0.0026, CHC1,) .
1H lit (CDC1" 300 MHz) S 8.15(d, J=8.8 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.28 (s, 1H, H10), 6.25(m, 1H, H13), 5.66(d, J =
7.15 Hz, 1H, H2~),4.96 (dd, J = 8,79, 1.65 Hz, 1H, H5) 4.76(d,J= 9.89 Hz, 1H, NH), 4.50(b s, 1H, H2'), 4.41(m, 2 H, H7, cyclohexyl); 4.29(d, J= 8.79 Hz, 1H, H20a), 4.18 (d, J=8.79 Hz, 1H, H20~), 3.79(d, J= 7.15 Hz, 1H, H3 ) , 3 .78 (m, 1H, H3' ) , 3 .27 (m, 1H, 2'0H) , 2 .53 (m, 1H, H6a), 2.44(s, 3H, 4Ac), 2.31(m, 2H, H14), 2.24 (s, 3H, lOAc),1.87 (s, 3H, Mel8) 1.83(m, 1H, H6~),1.9-0.9 (m, 21H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.2(s, 3H, Mel7), 1.14(s, 3H, Mel6).

~r0 94/10997 111 , , OAc OH
~ N 01111 iii H OH
P h ~ , ~--=0 (61-4) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(neopentoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III

(100 mg, 0.143 mmol) in 1 mL of THF at -45 C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethylsilyl)-amide in THF. After 1 h at -45 C, a solution of cis-1-(neopentoxycarbonyl)-3-triethyl-silyloxy-4-cyclohexyl-azetidin-2-one (284.3 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture.

The solution was warmed to 0 C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH

in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.

Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 157 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethyl-silyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(neopentoxycarbony1) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 157 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 C for 3 h, then at 25 C for 13 h, and partitioned between SUBSTITUTE SNEET (RULt 26) WO 94/10997 ~. ~ PCT/US93/108~

saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 124.4 mg of material which was purified by flash chromatography to give 106 mg (85.2 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(neopentoxycarbonyl) taxol, which was _ recrystallized from methanol/water.
m.p.159-161°C; [a]=~xa -60.0° (C 0.0026, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.15(d, J=7.14 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.28(s, 1H, H10), 6.25(m, 1H, H13), 5.66(d, J =
7.15 Hz, 1H, H2~), 4.95(dd, J = 9.61, 1.65 Hz, 1H, H5), 4.86(d,J= 9.89 Hz, 1H, NH), 4.52(d, J= 1.65 Hz, 1H, H2'), 4.42(dd, J= 10.99 Hz, 6.6 Hz, 1H, H7), 4.30(d, J= 8.24 Hz, 1H, H20a), 4.18(d, J=8.24 Hz, 1H, H20~), 3.79(d, J=
7.15 Hz, 1H, H3), 3.78(m, 1H, H3'), 3.65(d, J= 10.44 Hz, 1H, neopentyl),3.52(d, J= 10.44 Hz, 1H, neopentyl), 3.25(bs, 1H, 2'0H), 2.55(m, 1H, H6a), 2.44(s,3H, 4Ac), 2.32(m, 2H, H14), 2.23 (s, 3H, lOAc), 1.86 (s, 3H, Mel8), 1.83(m, 1H, H6~), 1.73-1.58 (m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.25(s, 3H, Mel7), 1.13(s, 3H, Mel6), 0.76(s, 9H, neopentyl).

CVO 94/ i 0997 ~ ~ PCT/ US93/ 108 i 6 113 ,.,, s~~~

OAc - ~ OH
0 _ 01111 = iii H OH
TMS
0 ., ~~0 P h ~ _, Ac0 (57-3) Preparation of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(trimethylsilylmethoxycarbonyl)-taxol.
To a solution of 7-triethylsilyl baccatin III

(100 mg, 0.143 mmol) in 1 mL of THF at -45 C was added dropwise 0.157 mL of a 1.0 M solution of lithium bis(trimethyl-silyl)amide in THF. After 1 h at -45 C, a solution of cis-1-(trimethylsilylmethoxycarbonyl)-3-triethylsilyloxy-4- cyclohexylazetidin-2-one (295.8 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH

in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.

Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 159.4 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethyl-silyl-3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-_ (trimethylsilylmethoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 159.4 mg (0.143 mmol) of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 C was added 0.9 mL of 48~ aqueous HF. The mixture was stirred at 0 C for 3 h, then at 25 C for 13 h, and partitioned between SUBSTITUTE SHEE T (RU~.E 26~

WO 94/10997 PCT/US93/108~
,~", 214784 m4 saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 126.7 mg of material which was purified by flash chromatography to give 116 mg (91.5 %) of 3'-desphenyl-3'-cyclohexyl-N-debenzoyl-N-(trimethylsilylmethoxycarbonyl) taxol, which was recrystallized from methanol/water.
m.p.147-149°C; [aJ~~a -56.4° (C 0.0025, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.15(d, J=7.15 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.50(m, 2H, benzoate meta), 6.28(s, 1H, H10), 6.26(m, 1H, H13), 5.67(d, J =
7.15 Hz, 1H, H2~). 4.96 (dd, J = 9.61, 2.2 Hz, 1H, H5), 4.80(d,J= 9.89 Hz, 1H, NH), 4.51(dd, J= 4.95, 1.65 Hz, 1H, H2'), 4.42(m, 1H, H7), 4.30(d, J= 8.24 Hz, 1H, H20a), 4.18(d, J=8.24 Hz, 1H, H20~), 3.79(d, J= 7.14 Hz, 1H, H3), 3.76 (m, 1H, H3'), 3.62(d, J= 14.28 Hz, 1H, CH2TMS),3.53(d, J= 14.28 Hz, 1H,CH2TMS), 3.41(d, J= 4.95 Hz, 1H, 2'0H), 2.55(m, 1H, H6a), 2.47(m, 1H, 70H), 2.44(s, 3H, 4Ac), 2.32(m, 2H, H14), 2.23(s, 3H, lOAc), 1.86(s, 3H, Mel8), 1.83(m, 1H, H6~3), 1.73-1.58(m, 6H, cyclohexyl), 1.67 (s, 3H, Mel9), 1.37-1.2(m, 5H, cyclohexyl), 1.26(s, 3H, Mel7), 1.14(s, 3H, Mel6), -0.05(s, 9H, (CH3)3Si).

CVO 94/ 10997 ~~~ CT/ US93/ 10816 0 OAc - ~ OH
Ph P, OIIII
_ iii H OH

Ph~ ~ 0 \\ _, Ac0 (29-2) Preparation of 3'-desphenyl-3'-(cyclohexyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 ~C was added dropwise 0.104 mL of a 1.63M solution of nBuLi in hexane.
After 0.5 h at -45 °C, a solution of cis-1-benzoyl-3-triethylsilyloxy-4-(cyclohexyl)azetidin-2-one (331 mg, 0.885 mmol) in 1.2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10g solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 186 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(cyclohexyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 186 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave SUBSnTU~E SHEET (MILE 26) WO 94/10997 ~ PCT/US93/108' ~2147~~4 147 mg of material which was purified by flash chromatography to give 107 mg (73%) of 3'-desphenyl-3'-(cyclohexyl) taxol, which was recrystallized from methanol/water.
m.p.163-164 oC; [a]ZS~,a-32.Oa (c 0.0049, CHC13) .
1H lit (CDC13, 300 MHz) w 8.I6 (d, J=7.2 Hz, 2H, benzoate ortho),7.65(d, J=7.4 Hz, 2H, benzamide ortho), 7.64-7.33(m, 6H, aromatic), 6.29(s, J=9.9 Hz, 1H, NH), 6.26 (s, 1H, H10), 6.20(dd, J = 9.35, 9.35 Hz, 1H, H13), 5.68(d, J = 7.7 Hz, 1H, H2i~), 4.97 (d, J = 7.7 Hz, 1H, H5), 4.60(dd, J= 4.9,1.4 Hz, 1H, H2'), 4.40(m, 1H, H7), 4.27 (m, 1H, H3' ) , 4.26 (d, J= 8 .2 Hz, 1H, H20oc) , 4.21 (d, J=8.2 Hz, 1H, H20i~), 3.78(d, J= 7.7 Hz, 1H, H3), 3.66(d, J= 4.9 Hz, 1H, 2'0H), 2.58(m, 1H, H6a), 2.50(s, 3H, 4Ac), 2.45(d, J=3.9 Hz, 1H, 70H), , 2.31(m, 2H, H14), 2.22 (s, 3H, lOAc), 1.86 (m, 1H, H6i3), 1.83(br s, 3H, Mel8), 1.75(s, 1H, 10H), 1.68 (s, 3H, Mel9), 1.27-1.2(m, 11H, cyclohexyl), 1.20(s, 3H, Mel7), 1.11(s, 3H, Mel6).

~~O 94/10997 ~ ~l ~~8 PCT/US93/10816 117 ~ ~~

OAc ~ - ~ off Ph N OIIII
_ ~ _ iii H OH
HO
H

Ph~ ~ 0 \\0 A C O
(36-2) Preparation of 3'-desphenyl-3'-(methyl) taxol To a solution of 7-triethylsilyl baccatin III

(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 C was added dropwise 0.104 mL of a 1.63M solution of nBuLi in hexane.

After 0.5 h at -45 C, a solution of cis-1-(benzoyl)-3-triethylsilyloxy-4-(methyl) azetidin-2-one (282 mg, 0.885 mmol) in 1.2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH

in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.

Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 174 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethyl-silyl-3'-desphenyl-3'-(methyl) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 174 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 C for 3 h, then at 25 C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.

Evaporation of the ethyl acetate solution gave 135 mg of material which was purified by flash chromatography to SUBSTITUTE -SHEET (RUl 26~

. ~ ~~.478~4 give 108 mg (80~) of 3'-desphenyl-3'-(methyl) taxol, which was recxystallized from methanol/water.
m.p.151-152 °C; (a]~~a -48.0° (c 0.0041, CHC1,) .
1H NMR (CDC1" 300 MHz) b 8.13 (d, J=8.1 Hz, 2H, benzoate ortho), 7.66(d, J=9.3, benzamide ortho), 7.61-7.38 (m, SH, aromatic), 6.35 (d, J = 9.3 Hz, 1H, NH), 6.29 (s, 1H, H10), 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.68 (d, J
=7.1 Hz, 1H, H2~), 4.96(d, J = 9.3 Hz, 1H, HS), 4.74(m, 1H, H3'), 4.42(m, 1H, H7), 4.32 (m, 2H, H2', H20a), 4.21 (d, J = 8.8 Hz, 1H, H20~), 3.82(d, J = 7.1 Hz, 1H, H3), 3.51(br s, 1H, 2'0H), 2.54 (m, 1H, H6a), 2.43 (s, 3H, 4Ac), 2.36 (m, 1H, 70H), 2.29 (m, 2H, H14), 2.22 (s, 3H, lOAc), 1.89 (m, 1H, H6~), 1.87 (br s, 3H, Mel8), 1.68 (s, 3H, Mel9), 1.67(s, 1H, 10H), 1.23 (s, 3H, Mel7), 1.14(s, 3H, Mel6).
..

'V 94/ 7 ~~ . / 93/10816 ~ O 1099 $ ~~ PCT US

HO OAc - / OH
t Hu0 N 01111 H OH
., 0 , 0 Ph~ _, \\O Ac0 (67-2) Preparation of 3'-desphenyl-3'-hydroxymethyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.157 mL of a 1.00 M solution of lithium bis(trimethyl-silyl)amide in THF. After 0.5 h at -45 °C, a solution of cis-1-(t-butoxycarbonyl)-3-triethylsilyloxy-4-triethylsilyl-oxymethylazetidin-2-one (316 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture.
The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH
in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.
Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 163.5 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethyl-silyl-3'-desphenyl-3'-hydroxymethyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 163.5 mg of the mixture obtained from the previous reaction in 4 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 1.2 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 24 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
SUBSTITUTE SHEET (RULE 26) WO 94/10997 PCT/US93/108' 21~4'~8~4 Evaporation of the ethyl acetate solution gave 114.9 mg of material which was purified by plug filtration and reczystallization from methanol/water to give 109.0 mg (95%) of 3'-desphenyl-3'-hydroxymethyl-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
m.p. 162-163 °C; [a)~~a -60 (c 0.001, CHC1,) .
1H NMR (CDC1" 500 MHz) 8 8.10(d, J = 7.3 Hz, 2H, benzoate ortho), 7.70-7.40(m, 3H, aromatic), 6.31(s, 1H, H10), 6.20 (dd, J = 9.3,9.3 Hz, 1H, H13), 5.67(d, J=6.8, 1H , H2~), 4.96(m, 2H, H5+ NH),4.57(dd, J=5.4,2.2 Hz,lH, H2'), 4.42 (m, 1H, H7), 4.37(d, J = 8.2 Hz, IH, H20a), 4.18 (br, 2H, H3'+ H20(~), 3.82 (m,2H, H3+CH20H), 3.35(d, J=2.2 Hz.lH,H2'), 2.56(m, 1H, H6oc), 2.47(m, 1H, 70H), 2.39 (s, 3H, 4Ac), 2.34(m, 2H, Hl4s), 2.24(s, 3H, lOAc), 2,18(brs, 1H,CH20H), 1.90(br s, 3H, Mel8), 1.83(m, 1H, H6~>, 1.71 (s, 1H, 10H), 1.67(s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1.22(s, 9H, t-butyl), 1.14(s, 3H, Mel6).

TWO 94/10997 "r PCT/US93/10816 OAc . 1I I I _ / 0H
Ph N Olill _ .hiii H OH
HO
H

Ph _, 0 Ac0 (29-1) Preparation of 3'-desphenyl-3'-(isopropyl) taxol.
To a solution of 7-triethylsilyl baccatin III
(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 °C was added dropwise 0.104 mL of a 1.63M solution of nBuLi in hexane.
After 0.5 h at -45 °C, a solution of cis-1-benzoyl-3-triethylsilyloxy-4-(isopropyl)azetidin-2-one (296 mg, 0.885 mmol) in 1.2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 179 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(isopropyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 179 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added 1.7 mL of 48$ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 140 mg of material which was purified by flash SUBSTITUTE SHEET RULE 26) WO 94/10997 ~ . v ,' PCT/US93/108' chromatography to give 112.0 mg (80~) of 3'-desphenyl-3'-(isopropyl) taxol, which was recrystallized from methanol/water.
m.p. 162-163 °C; [oc]ZSNa-33.0° (c 0.0068, CHC13) .
1H NMR (CDC13, 300 MHz) 8 8.16 (d, J=7.2 Hz, 2H, benzoate ortho), 7.65(d, J = 8.4 Hz, 2H, benzamide ortho), 7.62-7.32(m, 6H, aromatic), 6.33(d, J= 9.3 Hz, 1H, NH), 6.26 (s, 1H, H10), 6.19 (dd, J = 8.2,8.2 Hz, 1H, H13), 5.67(d, J = 7.1 Hz, 1H, H2~), 4.96 (d, J = 9.8 Hz, 1H, H5), 4.59(d, J= 2.7 Hz, 1H, H2'), 4.40(m, 1H, H7), 4.31(d, J=
9.2 Hz, 1H, H20oc), 4.22 (m, 2H, H3' H20~), 3.79(d, J= 6.6 Hz, 1H, H3), 3.64(d, J= 4.4 Hz, 1H, 2'0H), 2.54(m, 1H, H6a), 2.49(s, 3H, 4Ac), 2.47(m, 1H, 70H), 2.40(m, 1H,CH-Me), 2.29(m, 2H, H14), 2.21 (s, 3H, lOAc), 1.88 (m, 1H, H6(3), 1.84(br s, 3H, Mel8), 1.78 (s, 1H, 10H), 1.68 (s, 3H, Mel9), 1.20(s, 3H, Mel7), 1.14-1.04(m, 9H, Mel6+
Meisopropyl).

X094/10997 ~~' PCT/US93/10816 12 3 ~ ,. , OAc - ~ OH
Ph P. Olill _ ~~ii H OH
Ph U
ACO

(28-4) Preparation of 3'-desphenyl-3'-(n-butyl) taxol.
To a solution of 7-triethylsilyl baccatin III

(120 mg, 0.171 mmol) in 1.2 mL of THF at -45 C was added dropwise 0.104 mL of a 1.63M solution of nBuLi in hexane.

After 0.5 h at -45 C, a solution of cis-1-benzoyl-3-triethylsilyloxy-4-(n-butyl)azetidin-2-one (309 mg, 0.885 mmol) in 1.2 mL of THF was added dropwise to the mixture.

The solution was warmed to 0 C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOH

in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/hexane.

Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 182 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(n-butyl) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 182 mg (0.171 mmol) of the mixture obtained from the previous reaction in 11 mL of acetonitrile and 0.55 mL of pyridine at 0 C was added 1.7 mL of 48~ aqueous HF. The mixture was stirred at 0 C for 3 h, then at 25 C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave SUg$TI'~UTE SHEET (RULE 26) WO 94/10997 ~ i,~ . ~ ~ ~'~ PCT/US93/108' 143 mg of material which was purified by flash chromatography to give 114.0 mg (80%) of 3'-desphenyl-3'-(n-butyl) taxol, which was recrystallized from methanol/water.
m.p. 187-188 °C; [oc]ZSNa-40.0° (c 0.005, CHC13) .
1H NMR (CDC13, 300 MHz) S 8.13 (d, J=7.2 Hz, 2H, benzoate ortho), 7.66(d, J=8.3 Hz, 2H, benzamide ortho), 7.61-7.34(m, 6H, aromatic), 6.30(d, J=9.3 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.23 (dd, J = 8.2,8.2 Hz, 1H, H13), 5.68 (d, J = 7.1 Hz, 1H, H2~i), 4.96 (d, J = 9.3 Hz, 1H, H5), 4.55(dd, J= 8.8, 4.5 Hz, H3'), 4.41(m, 1H, H7), 4.35(d, J= 1.65 Hz, 1H, H2'), 4.31 (d, J= 8.2 Hz, 1H, H20a), 4.20 (d, J = 8.2 Hz, 1H, H20~), 3.80(d, J= 7.1 Hz, 1H, H3), 3.61(d, J= 5.5 Hz, 1H, 2'0H) " 2.49 (m, 1H, H6a), 2.48(d, J=3.3 Hz, 1H, 70H), 2.45(s, 3H, 4Ac), 2.25(m, 2H, H14), 2.22 (s, 3H, lOAc), 1.88 (m, 1H, H6~), 1.85(br s, 3H, Mel8),1.81(m, 2H, CH2), 1.73 (s, 1H, 10H), 1.68 (s, 3H, Mel9), 1.40(m, 4H, CH2), 1.22(s, 3H, Mel7), 1.13(s, 3H, Mel6), 0.99(m, 3H, CH3).
.

TWO 94/10997 ~ , PGT/US93/1Q~

The taxanes of the preceding examples were evaluated in in vitro cytotoxicity activity against human colon carcinoma cells HCT-116. Cytotoxicity was assessed in HCT116 human colon carcinoma cells by XTT (2,3-bis(2-methoxy-4-vitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) assay (Scudiero et al, 'Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines", Cancer Res. 48:4827-4833, 1988). Cells were plated at 4000 cells/well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted. The cells were incubated at 37°C for 72 hours at which time the tetrazolium dye, XTT, was added.
A dehydrogenase enzyme in live cells reduces the XTT to a form that absorbs light at 450 nm which can be quantitated spectrophotometrically. The greater the absorbance the greater the number of live cells. The results are expressed as an ICSO which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450 nm) to 50% of that of untreated control cells.
Except for compounds 36-2 (Example 43) and 67-2 (Example 44), all compounds had an ICso of less than 0.1 indicating that they are cytotoxically active. Compounds 36-2 and 67-2 had an ICso of >.078 and, >.097, respectively.

Claims (8)

CLAIMS:

1. A taxane derivative having the formula wherein X1 is -OX6;
X2 is hydrogen;
X3 is unsubstituted or substituted C3-6alkyl wherein the substituent is selected from alkyl, alkenyl, alkynyl, aryl, methoxy, ethoxy, butoxy, halogen, nitro, amino, keto, and heteroaryl with one or more heteroatoms selected from nitrogen, oxygen and sulfur;
X4 is hydrogen;
X5 is -COX10:
X6 is hydrogen;
X10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, t-butoxy or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl wherein the substituent is selected from alkyl, alkenyl, alkynyl, aryl, methoxy, ethoxy, butoxy, halogen, nitro, amino, keto, and heteroaryl with one or more heteroatoms selected from nitrogen, oxygen and sulfur;

R1 is hydroxy;
R2 is -OCOR31:
R2a is hydrogen;
R4 together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is -OCOR30;
R5 is hydrogen;
R5a together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen;
R6a is hydrogen;
R7 is hydrogen or together with R7a forms an oxo;
R7a is halogen, hydroxy, or together with R7 forms an oxo;
R9 together with R9a forms an oxo;
R9a together with R9 forms an oxo;
R10 is hydrogen;
R10a is -OCOR29, hydroxy, or protected hydroxy;
R14 is hydrogen;
R14a is hydrogen; and R29 and R30 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;
and R31 is hydrogen, alkyl, alkenyl, phenyl or monocyclic heteroaryl.

2. The taxane derivative of claim 1, wherein X3 is optionally substituted C3-6 cycloalkyl.

3. The taxane derivative of claim 1, wherein X3 is optionally substituted C3-6 linear or branched alkyl.

4. The taxane derivative of claim 1 wherein X3 is cyclohexyl, cyclopentyl, propyl, or butyl.

5. The taxane derivative of any one of claims 1 to 4, wherein R10a is hydroxy or -OCOR29;
R7 is hydrogen;
R7a is halogen or hydroxy.

6. The taxane derivative of claim 4, wherein X5 is -COX10 and X10 is t-butoxy, furyl or thienyl.

7. The taxane derivative of claim 1, wherein X5 is -COX10, X10 is as defined in claim 1, and X3 is cyclohexyl, cyclopentyl, propyl, or butyl.

8. A pharmaceutical composition comprising the taxane derivative of any one of claims 1 to 7 and one or more pharmacologically acceptable, inert or physiologically active diluents, adjuvants or carriers.