CA2221190C

CA2221190C - Novel substituted taxanes and pharmaceutical compositions containing them

Info

Publication number: CA2221190C
Application number: CA002221190A
Authority: CA
Inventors: Robert A. Holton; Ronald J. Biediger; Hossain Nadizadeh; Soekchan Kim
Original assignee: Florida State University
Current assignee: Florida State University
Priority date: 1991-09-23
Filing date: 1992-09-02
Publication date: 2002-02-12
Anticipated expiration: 2012-09-02
Also published as: FI924228A0; HUT63155A; DE69232895T2; ES2191005T3; AU2212492A; ATE231139T1; EP0534709A1; CA2077394A1; CA2077394C; JPH06199824A; JP3182231B2; HU9203024D0; NO923679L; AU655493B2; FI924228A; NO305205B1; NZ244457A; EP0534709B1; HU215110B; CA2221190A1

Abstract

The invention relates to a .beta.-lactam of the formula (see fig. I) wherein R1 and R3 are independently selected from phenyl, naphthyl, C6H5CHCH-, and (see fig. II) (see fig. III) or (see fig. IV) Q is CH3-, (CH3)3C-, CH3)-, Cl, Br, F, or NO2; and R2 is hydrogen or hydroxy protecting group. The .beta.-lactams are useful as intermediates in the preparation of a taxane derivative of the formula (see fig. IV) wherein R1 and R3 are independently selected from the group comprising phenyl, naphthalene, C6H5CHCH-, (see fig. V), (see fig. VI) and (see fig. VII) provided, however, R1 and R3 are not both phenyl;

Q is CH3-, (CH3)3C-, CH3O-, Cl, Br, F, or NO2;

Z is -OT1;
T1 is hydrogen, hydroxyl protecting group, or -COT2;
T2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or monocylic aryl;
Ac is acetyl; and E1 and E2 are independently selected from hydrogen and functional groups which increase the water solubility of the taxane derivative are useful as antitumor agents.

Description

NOVEL SUBSTITUTED TAXANES AND
PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
BACKGROUND OF THE INVENTION
The present divisional application is divided out of parent application Serial No. 2,077,394 filed on September 2, 1992.
The invention of the parent application relates to novel taxanes which have utility as antileukemia and antitumor agents.
The invention of the present divisional application relates to certain beta-lactams useful as intermediates in the preparation of the taxanes of the parent application.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol* is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has a 2'R, 3'S
configuration and the following structural formula:

2 o OAc OH
(1) *Trade-mark 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 formula (2) below, have an activity significantly greater than that of taxol (1).
R'O
__ _ _ ~~ / I I
~-R. , 2 ' ' Y = \0 ~5-~-R~ . . ~H H
~3 i ~6H5 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 hydrogen, R " is hydroxy, R " ' is tert-butoxycarbonylamino having the 2'R, 3'S configuration is commonly referred to as taxotere.
Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective.
Accordingly, a need remains for additional chemotherapeutic agent s .
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of novel taxane derivatives which 2a are valuable antileukemia and antitumor agents.
Briefly, therefore, one aspect of the invention of the parent application is directed to taxane derivatives of the formula:

I
3 2 1 I ~ 9 1 OEz N ~O""" I14 I ~ ( ) ~ IG

OH
CbHsC00 wherein R1 and R3 are independently selected from the group consisting of phenyl, naphthyl, C6H5CEiCH-, and and Q ~ , 'O

provided, however, R1 and R3 are not both phenyl]
Q is CH3-, (CH3}3C-, CH30-, C1, Hr, F, or -N02~
Z 1s -OT1~
T1 is hydrogen, hydroxyl protecting group, or -COT2s T2 1s H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or monocyclic aryls Ac is acetyl; and E1 and E2 are independently selected from hydrogen, and functional groups which increase the water solubility of the taxane derivative.
Other ob~ects and features of this invention will 64725-55fl be in part apparent and in part pointed out hereinafter.
According to one aspect of the present divisional application there is provided a ~i-lactam of the formula O
O
R3 IV ~ 2 R~ OR2 wherein R1 and R3 are independently selected from phenyl, naphthyl, C6HSCHCH-, and o~ 1~~

O ~ \OCH3 Q is CH3-, (CH3) 3C-, CH30-, Cl, Br, F, or N02; and R2 is hydrogen or hydroxy protecting group.
According to another aspect of the present divisional application there is provided a process for the preparation of a ,Q-lactam of the formula 4a O
O

4 3 (4) or an enantiomer or diastereoisomer thereof, which process comprises cyclocondensing a compound having the structure H O-M
(II) R2- O-C=C-OR22 with an imine having the structure R1-C=N-R11 (III) to form an azetidine having the structure O

4 3 (N), and treating said azetidine with an acyl chloride of formula R3C(O)Cl in the presence of a base to form the a-lactam of formula (4), wherein R1 and R3 are independently selected from phenyl , naphthyl , C6HSCHCH- , and 4b O \OCH3 ' Q is CH3-, (CH3) 3C-, CH30-, C1, Br, F, or N02; and R2 is hydrogen or hydroxy protecting group; Rll is trialkylsilyl or triarylsilyl; R22 is alkyl; and M is metal.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
It has been discovered that compounds having 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 Biology, 91: 479-487 (1981) and human cancer cell lines, and is comparable to that exhibited by taxol and taxotere.
Taxane derivatives having formula (3) may be obtained by reacting a ~3-lactam with metal alkoxides having the taxane tetracyclic nucleus and a C-l3 metallic oxide substituent to form compounds having a ~i-amido ester substituent at C-13. The ~i-lactams have the following structural formula:
O
O
R3 N~

R~ OR2 ' 64725-558D
4c wherein R1 and R3 are as previously defined, and Rz is a hydroxy protecting group, a-lactams (4) can be prepared from readily available starting materials, as is illustrated by the following reaction scheme:

0 oLi a f25S:E0 OCEEzCEf3 __ ~ RSS10 O( N-TrlS
ArCHO ~ Ar-~/
C
H\ O
N~ a d N 2 \\\\\\\\ //////// \\\\\\ //////
Ar OS i R5 \ /
Ar OS i R5 reagents 5 (a) LDA, THF, -78°C to -50°C;
(b) LHMDS, THF, -78°C to 0°C;
(c) THF, -78°C to 25°C, (2h); and (d) triethylamine and an acyl chloride I~3 ~O or C,~ ~ n The 3-hydroxyl protecting group shown in the above reaction scheme is -SIRS wherein R5 is trialkyl or triaryl such as triethyl. The 3-hydroxyl may be protected with other standard protecting groups such as 1-etlioxy-ethyl, or 2,2,2-trichloroethoxymethyl. 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 B-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 diastereo-selective, thus permitting the use of a racemic mixture of side chain precursor.
The metal alkoxides having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent have the following structural formula:

MOilni( i t10 _ PhG00 ''~' Ac0'~~O
(5) wiuerein Z is -OT,; T~ is hydrogen, hydroxyl protecting group, or -COT2; Tz i.s II, C~-C6 alkyl, C2-Ce al.kenyl, Cz-C6 alkynyl or monocylic aryl; T3 is a hydroxy protecting group;
and M is a metal, preferably selected from the group comprising Group IA, Group IIA and transition metals, and most preferably, Li, Mg, Na, K or Ti.
The metal alkoxides are prepared by reacting an alcohol having the taxane tetracyclic nucleus and a C-13 hydroxyl group with an organornetallic cornpound in a suitable solvent. Preferably, the alCOho1 is a protected baccatin III, in particular, 7--O-triethylsi.lyl. baccatin III
(wtnich can be obtained as described by Greene, et al. in .1ACS 110: 5917 (1988) or by other routes) or 7,10-bis-O-trietliylsi.l.yl baccatin TII.

As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme:
OH
CH3 '~ OH OR
to-'~CHa CH3 ~ '~ Os1(Cafi3)3 ~ O ~ i3 'H3 ~ 1. (C~ti~)~81C1, C~ttsH ' -f!O -- 1 3 _ - H3 ' CH3 ~ 2. Ctf~COCl. C~rlyN HO -- 1 3 ' ~~CH3~ , OH ~ H 'I
OCOCaHsOCOCH3 OH ; H

OCOC6 H~
(6) (7) a, Tl=H
b, T1=COCH3 Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2f~5)3SiC1 at 23°C under an argon l0 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 (7a) 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 rnl. of pyridine/lnrnol of 7a at 0 °C under an argon atmosphere for 48 hours to provide 86%
yield of 7-O-triethylsilyl baccatin III (7b). Greene, et al. in JACS 110_, 5917 at 5918 (1988).
The 7-O-triethylsilyl baccatin III (7b) is reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III (8) as shown in the following reaction scheme:
OR
Ci~3 O
~o~~/
- H Cii3 OSi(CZii5)3 CH3CH2CHzCH2Li + HO-- ~
'~CH-,~
OH ~ H :I
c THF

'°~~Cii3 OS1(CZHS)3 CH3CH2CHzCH3 + Li0-- ~3 H3 '~CH~~ ( OH ~ H

As shown in the Following reaction scheme, 13-O-lithium-7-O-triethylsilyl baccatin III (8) reacts with f3-lactam (4) in which R2 is triethylsilyl to provide an LO intermediate in which the C-7 and C-2' hydroxyl groups axe protected with a triethylsilyl. group. 'the triethylsilyl groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents.

OTES O
/ (i) ~ R3 N _ O..
Li0""" , R ~ O
(2) HF, Pyridine, CH3CH H HO
HO
PhC00 R1 OTES
(l0) (4) wherein R1 and R3 are as previously defined, Ac0 Ac is acetyl, TES is triethylsilyl and Ph is phenyl.
Both the conversion of the alcohol to the metal alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel. Preferably, the ~i-lactam is added to the reaction vessel after formation therein of the metal alkoxide.
There is also provided pharmaceutical compositions containing a compound of formula (3) in combination with one or more pharmaceutically acceptable, inert or physiologically active, diluents or adjuvants.
These compositions may be presented in any form appropriate for the administration route envisaged. The parenteral route, and especially the intravenous route, is the preferential route for administration.
The compositions for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol,wegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be used as the solvent or the vehicle. These compositions may also 5 contain adjuvants, especially wetting agents, emulsifiers or dispersants. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be in tire form of 10 sterile solid compositions which may be dissolved or dispersed in sterile water or any other injectable sterile medium.
The products of general formula (3) are more particularly used in the treatment of acute leukemias and solid tumors, at daily doses which are generally between 1 and 2 mg/kg by the intravenous (perfusion) route for an adult.
The water solubility of compounds of formula (3) may be improved by modificat=i.on of the C2' and/or C7 substituerrts to incorporate appropriate fmncti.onal groups, Ei and Ez. For increased water solubility, Er and EZ may independently be hydrogen and -COGCOR' wherein:
G is ethylene, propylene, CIICIi, 1, 2-cyclo-hexylene, or 1,2-phenylene;
R' - OH base, NRZR3, OR', SR', OCLi2CONR4R5, or OII;
RZ - hydrogen or methyl;
R' - (Cllz) "NR6R~~ or (Cliz) "NRm~R~ReX";
n - 1 to 3;
R1 - hydrogen or lower alkyl co»taini.ng 1 to 4 carbons;
RS - hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, tydroxyethyl , CLIzCO2Ii, or dimet=my lami noethy 1 ;
R6 and R' - independent;ly se:lecteci from lower alkyl containing 1 or 2 carbons or benzyl, or R6 and R' together with tl~e nitrogen atom of NR6R7 forms one of the following rings N N N N N
or ;
O S N
I

R8 - lower alkyl containing 1 or 2 carbons or benzyl;
Xe - halide; and base = NH3, (HOC2H4)3N, N(CH3)3, CH3N(C2H40H)2, NH2(CH2)6NH2, N-methylglucamine, NaOH, or KOH.
The preparation of compounds in which E1 or E2 is -COGCOR1 is set forth in Hangwitz U.S. patent 4,942,184.
The following examples illustrate the invention of both the parent application and the present divisional application.

Ac O P1 i O
OH
Ph N O"""
I .,, , H OH
HO
Ph C~
Ac0\ O
O

wherein Npl is Preparation of 3'-desphenyl-3'-(1-naphthyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(1-naphthyl)azetidin-2-one (620 mg, 1.43 mmol) in 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 Na~iC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 325 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(1-naphthyl.) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 325 mg (0.287 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48~
aqueous HF. The mixture was stirred at 0 °C for 3 h, then at °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give 166 mg (64$) of 3'-(1-naphthyl) taxol, which was recrystallized from methanol/-water.

' 13 m. p. 164-165 °C; [a]25NA-52.6° (c 0.005, CHC13).
1H NMR (CDC13, 300 MHz) d 8.11 (d, J = 7.1 Hz, 2H, benzoate ortho), 8.11 (m, 3H, aromatic), 7.91 (m, 3H, aromatic), 7.70 (m, 2H, aromatic), 7.63-7.46 (m, 7H, aromatic), 6.75 (d, J =
8.8 Hz, 1H, NH), 6.52 (dd, J = 8.8, 1.6 Hz, 1H, H3'), 6.27 (s, 1H, H10), 6.27 (dd, J = 9.1, 9.1 Hz, 1H, H13), 5.68 (d, J = 7.1 Hz, 1H, H2s), 4.85 (dd, J = 7.6, 2.2 Hz, lEi, H5), 4.97 (dd, J = 1.6 Hz, 1H, H2'), 4.39 (m, 1H, H7), 4.24 (d, J = 8.5 Ffz, 1H, H20a), 4.17 (d, = Hz, 1H, H20S), 3.80 J 8.S

(d, J = 7.1 Hz, 1H, H3), 3.65 (br, 1H, 2'OH), 2.55 1H, (m, H6a), 2.48 (br, 1H, 70H), 2.41 (s, 3H, 4Ac), 2.38 (m, 1H, f-fl4) , 1.96 (s, 3H, lOAc) , 1.86 (m, 1H, H6S) , 1.80 (br s, 3H, MelB), 1.76 (s, 1H, lOH), 1.69 (s, 3H, Mel9), 1.28 (s, 3H, Mel7), 1.16 (s, 3H, Mel6).
LTV T AAT1T T'.~ '1 OAc O Np2 O
)H
Ph N O~ii~in H OH
Ph ~~O
wherein Np2 is Preparation of 3'-desphenyl-3'-(2-naphthyl) taxol.

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(2-naphthyl)acetidin-2-one (620 mg, 1.43 mmol) in 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 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(2-naphthyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 320 mg (0.283 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 255 mg of material which was purified by flash chromatography to give 166 mg (64$) of 3'-desphenyl-3'-(2-naphthyl) taxol, which was recrystallized from methanol/water.
m. p. 164-165 °C; [a]25Na-52.6° (c 0.005, CHC13).
1H NMR (CDC13, 300 MHz) d 8.14 (d, J = 7.3 Hz, 2H, benzoate ortho), 7.96 (m, 1H, aromatic), 7.90 (m, 1H, aromatic), 7.85 (m, 2H, aromatic), 7.76 (m, 2H, aromatic), 7.60 (m, 3H, aromatic), 7.52 (m, 4ii, aromatic), 7.41 (m, 2H, aromatic), 7.01 (d, J = 8.8 Hz, 1H, NH) , 6.27 (s, lii, H10) , 6.26 (dd, J = 9.2, 9.2 Hz, 1H, H13), 5.97 (dd, J = 8.8, 2.5 Hz, 1H, H3'), 5.68 (d, J = 7.1 Hz, 1H, H2S), 4.93 (m, 1H, H5), 4.92 (m, 1H, H2'), 4.39 (m, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H H20a), 4.20 (d, J = 8.5 Hz, 1H, H20S), 3.81 (d, J = 7.1 Hz, 1H, H3), 3.60 (d, J = 5 Hz, 1H, 2'OH), 2.48 (m, 1H, H6a), 2.45 (br, 1H, 70H), 2.39 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.24 (s, 3H, lOAc), 1.83 (m, 1H, H6S) , 1.82 (br s, 3H, Mel8) , 1.68 (s, lii, lOii) , 1.68 10 (s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).
LTV T ~.1TT T "f OAc O ~ O
)H
Ph N O~~~i H OH
Preparation of 3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-benzoyl-3-tri.ethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (590 mg, 1.43 mmol) in 2 mh of THF was added dropwise to the mixture. The solution was Ph~ Ac0 ~~O

warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10~ solution of AcOII in THE' 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 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 320 mg (0.288 mmol) of the mixture obtained from the previous reaction in 18 rnL of acetonitrile and 0.93 mI. of pyridine at 0 °C was added 2.8 m1. 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 255 mg of material which was purified by flash chromatography to give 172 mg (68$) of 3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water.
m. p. 174-176 °C; [a]25Na-48.86° (c 0.05, CEiCl3).
1fI NMR (CDC13, 300 MI3z) 8 8.12 (d, J = 7.1 iiz, 2H, benzoate ortho), 7.72 (m, 2H, aromatic), 7.59 (m, 1H, aromatic), 7.53-7.36 (m, 8H, aromatic), 6.96 (d, J = 8.8 Hz, 1H, NH), 6.90 (m, 2H, aromatic), 6.26 (s, 1H, H10), 6.21 (dd, J = 9.3, 9.3 Hz, 1H, Iil3) , 5. 70 (dd, J = 8.8, 2. 7 Hz, ltE, H3' ) , 5.66 (d, J = 6.8 Hz, 1H, H2S), 4.93 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4 . 74 (dd, J = 5. 5, 2 . 7 Hz, 1H, H2' ) , 4 . 39 (m, 1H, H7 ) , 4 . 29 (d, J = 8. 8 Hz, 1H, H20a) , 4.18 (d, J = 8.8 Hz, 1H, II20S) , 3.78 (d, J = 6.8 fiz, 1H, fi3) , 3.78 (s, 3H, ArOMe) , 3.67 (d, J = 5.5 Hz, 1H, 2'OH), 2.61 (m, 1H, H6a), 2.50 (d, J = 4.4 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.22 (s, 3H, lOAc), 1.84 (m, 1H, H6S), 1.79 (br s, 3H, Mel8), 1.79 (s, 1H, lOH), 1.67 (s, 3H, Mel9), 1.22 (s, 3H, Mel7), 1.13 (s, 3H, Mel6).
LTV T ~ATT r A

OAC
O \ ~ O
Ph~N H
_- Oul~~l H OH
Preparation of 3'-desphenyl-3'-(4-chlorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-benzoyl-3-triethylsil.yloxy-4-(4-chlorophenyl)azetidin-2-one (595 mg, 1.43 mmol) in 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 NafiC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic 1_ayer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(4-chlorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 320 mg (0.287 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 255 mg of material which was purified by flash chromatography to give 158 mg (62~) of 3'-desphenyl-3'-(4-chlorophenyl) taxol, which was recrystallized from methanol/water.
m. p. 173-175 °C; [a]25Na-50.8° (c 0.01, CHC13).
1F~ NMR (CDC13, 300 MHz) 6 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.72 (d, J = 8.2 Hz, 2H, benzamide ortho), 7.65-7.35 (m, lOFi, aromatic) , 6.97 (d, J = 8.8 Hz, lFi, NH) , 6 .27 (s, 1H, H10), 6.25 (dd, J = 8.3, 8.3 Hz, 1H, H13), 5.78 (dd, J = 8.8, 2.2 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2S), 4.95 (dd, J = 8.8, 2.2 Hz, 1H, H5), 4.77 (br s, 1H, H2'), 4.40 (m, 1H, H7), 4.31 (d, J = 8.2 Hz, 1H, H20a), 4.19 (d, J = 8.2 Hz, 1H, H20S) , 3.80 (d, J = 7.1 Hz, 1H, Fi3) , 3.61 (br s, lFi, 2'OH) , 2.54 (m, 1H, H6a), 2.38 (s, 3H, 4Ac), 2.32 (m, 2H, H14), 2.24 (s, 3EI, lOAc) , 1.85 (m, 1H, Ei6 S) , 1.80 (br s, 3H, Mel8) , 1.68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).

. T9 Br OAc O O
~N OH
Ph I _ ~~iiii~
H OH
Ph Preparation of 3'-desphenyl-3'-(4-bromophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(4-bromophenyl)azetidin-2-one (660 mg, 1.43 mmol) in 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 way partitioned between saturated aqueous NaiiC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(4-bromophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 330 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile E>4 725-558 and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48$ aqueous EIF. 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 265 mg of material which was purified by flash chromatography to give 186 mg (64~) of 3'-desphenyl-3'-(4-bromophenyl) taxol, which was recrystallized from methanol/-water.
m, p. 170-172 °C; [a]25Na-50.94° (c 0.01, CHC13).
10 1H NMR (CDC13, 300 MHz) d 8.12 (d, J = 7.2 FIz, 2EI, benzoate ortho), 7.71 (m, 2H, aromatic), 7.61 (m, 1H, aromatic), 7.50-7.47 (m, 6H, aromatic), 7.38 (m, 3H~, aromatic), 7.09 (d, J =
8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.23 (dd, J = 8.2, 8.2 Hz, 1H, H13), 5.75 (dd, J = 8.8, 2.2 Hz, 1H, H3'), 5.66 (d, J =
7.1 Hz, 1H, H2S) , 4.94 (dd, J = 9.3, 1.7 FIz, 1H, H5) , 4.75 (dd, J = 2.2 Hz, 1H, H2'), 4.38 (m, 1H, H7), 4.29 (d, J = 8.2 Hz, 1H, H20a), 4.18 (d, J = 8.2 Hz, 1H, H20S), 3.79 (d, J = 7.1 Hz, 1H, H3), 3.7 (br, 1H, 2'OH), 2.53 (m, 1H, H6a), 2.38 (br, 1H, 70H), 2.37 (s~ 3H, 4Ac), 2.30 (m, 2H, H14), 2.23 (s, 3H, lOAc), 20 1.87 (m, 1H, H6S) , 1.80 (br s, 3Fi, Mel8) , 1.80 (s, 1H, lOH) , 1.67 (s, 3H, Mel9) , 1.22 (s, 3H, Mel7) , 1.13 (s, 3H, Mel_6) .

F~rantnr ~ ~
O~O
OAc O ~ O O
OH
Ph N OI 1 W n , HO = H
O
Ac O~ O
Ph O
Preparation of 3'-desphenyl-3'-(3,4-methylenedioxy-phenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(3,4-methylenedioxyphenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of TfiF 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 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(3,4-methylenedioxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 320 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitr_ile and 0.93 mL of pyridine at 0 °C was added 2.8 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 113 mg of material which was purified by flash chromatography to give 165 mg (64~) of 3'-desphenyl-3'-(3,4-methylenedioxyphenyl) taxol, which was recrystallized from methanol/water.
m. p. 178-180 °C; [a]25Na-46.6° (c 0.005, CHC13).
1H NMR (CDC13, 300 MHz) d 8.14 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.72 (m, 2H, aromatic), 7.15 (m, 1H, aromatic), 7.50 (m, 2II, aromatic) , 7. 38 (m, 2Ii, aromatic) , 7.0 (m, lII, aromatic), 6.94 (m, 2H, aromatic), 6.88 (d, J = 9.1 Hz, 1H, NH), 6.83 (m, 1H, aromatic), 6.28 (s, 1H, H10), 6.23 (dd, J =
9.1, 9. 1 Iiz, 1H, H13) , 5.97 (s, 2H, methylene) , 5.69 (dd, J =
9.1, 2.5 Hz, 1H, H3'), 5.68 (d, J = 6.9 Hz, 1H, H2S), 4.95 (dd, ,7 = 9.6, 2.2 Hz, 1H, H5) , 4 : 72 (dd, J = 2. 5 IIz, 1H, Ii2' ) , 4.91 (m, 1H, H7), 4.31 (d, J = 8.4 Hz, 1H, H20a), 4.20 (d, J = 8.4 Hz, 1H, H20S), 3.81 (d, J = 6.9 Hz, 1H, H3), 3.60 (br, 1H, 2'OH) , 2.56 (m, 1H, H6a)', 2.43 (d, J = 4. 1 Hz, lli, 70H) , 2.39 (s, 3H, 4Ac) , 2.31 (m, 2H, H14) , 2.24 (s, 3II, 1_OAc) , 1.88 (m, 1H, H6S), 1.82 (br s, 3H, Mel8), 1.69 (s, 1H, lOH), 1.68 (s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1.15 (s, 3H, Mel6).

OAc ~N
Ph ~ - O~iiiii~~~ OH
..
H OH
HO _ H~s O
....
Ph-~ AcO

Preparation of 3'-desphenyl-3'-(3,4-dimethoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(3,4-dimethoxyphenyl)azetidin-2-one (630 mg, 1.43 mmol) in 2 mL of THk' 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 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(3,4-dimethoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 330 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 260 mg of material which was purified by flash chromatography to give 175 mg (67%) of 3'-desphenyl-3'-(3,4-dimethoxyphenyl) taxol, which was recrystallized from methanol/water.
m. p. 165-167 °C; (a)25Na-42.0° (c 0.005, CHC13).
1H NMR (CDC13, 300 MHz) d 8.12 (d, J = 8.3 Hz, 2H, benzoate ortho), 7.73 (d, J = 8.2 Hz, 2ii, benzamide ortho), 7.65-7.35 (m, 6H, aromatic), 7.1-7.0 (m, 2H, aromatic), 6.94 (d, J = 8.8 Hz, 1H, Nii) , 6.88 (d, J = 8.3 Hz, 2H, aromatic) , 6. 27 (s, lii, H10), 6.21 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.69 (m, 2H, H3, H2S), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.77 (d, J = 2.8 iiz, 1H, H2'), 4.39 (dd, J = 11.0, 6.6 Hz, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20a), 4.19 (d, J = 8.5 Hz, 1H, H20S), 3.88 (s, 3H, ArOMe), 3.87 (s, 3H, ArOMe), 3.80 (d, J = 7.1 Hz, 1H, H3) , 3.59 (d, J = 4.4 Hz, 1H, 2'OH) , 2. 54 (m, 1H, H6a) , 2. 38 (s, 3H, 4Ac) , 2.36 (m, 2H, Fil4a, H14S) , 2.23 (s, 3H, lOAc) , 1.86 (m, 1H, H6S), 1.80 (br s, 3H, Mel8), 1.68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 ('s, 3H, Mel6).

z5 ~'YTMT)T~L~ Q

0 ~ O
N w, Ph I = O annul H OH
Preparation of 3'-desphenyl-3'-(4-nitrophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(4-nitrophenyl)azetidin-2-one (610 mg, 1.43 mmol) in 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 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(4-nitrophenyl) taxol and a small amount of the (2'S,3'R) isomer.

Pt. 'O ~,~"

To a solution of 320 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 255 mg of material which was purified by flash chromatography to give 197 mg (57$) of 3'-desphenyl-3'-(4-nitrophenyl) taxol, which was recrystallized from methanol/water.
m. p. 188-190 °C; [a)25Na-63.7° (c 0.01, CiiCl3).
1H NMR (CDC13, 300 MHz) d 8.26 (d, J = 8.8 Hz, 2H, benzoate ortho), 8.20 (m, 2H, aromatic), 7.73 (m, 4iI, aromatic), 7.60 (m, 1H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 1H, aromatic) , 7.15 (d, J = 8.8 Hz, 1H, 1'IH) , 6.26 (s, 1H, H10) , 6.26 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.93 (dd, J = 8.8, 2.8 Hz, lii, H3'), 5.66 (d, J = 6.6 Hz, 1H, H2S), 4.94 (dd, J =
9.3, 1.7 iiz, 1H, H5) , 4.82 (dd, J = 3.9, 2.8 Hz, 1H, H2' ) , 4.38 (m, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20a), 4.19 (d, J = 8.8 Hz, 1H, H20S), 3.86 (d, J = 3.9 Hz, 1H, 2'OFi), 3.79 (d, J = 6.6 Hz, 1H, H3), 2.55 (m, 1H, H6a), 2.46 (d, J = 3.8 Hz, 1H, ~70H), 2.41 (s, 3H, 4Ac), 2.38 (m, 2H, H14), 2.23 (s, 3H, lOAc) , 1.82 (m, 1H, H6~) , 1.80 (br s, 3H, Ptel8) , 1. 74 (s, 1H, lOH), 1.68 (s, 3H, Mel9), 1.21 (s, 3H Mel7), 1.13 (s, 3H, Mel6).
F
OAc O O
OH
Ph i - Om~u %, H OH
O
Preparation of 3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 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-(4-fluorophenyl)azetidin-2-one (570 mg, 1.43 mmol) in 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 ... ....... ....... .. t.

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 315 mg of a mixture containing (2'R,3'S)-2',7-(bis)-triethylsilyl-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 315 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 250 mg of material which was purified by flash chromatography to give 160 mg (64$) of 3'-desphenyl-3'-(4-fluorophenyl) taxol, which was recrystallized from methanol/water.
m, p. 171-173 °C; [a]25Na-49.0° (c 0.005, CHC13).
1H NMR (CDC13, 300 MHz) 6 8.13 (d, J = 7.5 Hz, 2fi, benzoate ortho), 7.25 (m, 2H, aromatic), 7.61 (m, 1H, aromatic), 7.50 (m, 4H, aromatic), 7.43 (m, 2H, aromatic), 7.10 (m, 2H, aromatic),-6.96 (d, J = 8.7 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.25 (dd, J = 8.7, 8.7 EIz, lii, Fil3) , 5.79 (dd, J = 8.7, 2.4 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2S), 4.45 (dd, J =
7.9 Hz, 1H, H5), 4.76 (dd, J = 4.8, 2.4 Hz, 1F~, H2'), 4.39 ' ' 29 (m, 1H, Ii7) , 4.31 (d, J = 8. 9 Hz, 1H, H20a) , 4 . 20 (d, J = 8.9 Hz, 1H, H20S), 3.80 (d, J = 7.1 Hz, 1H, H3), 3.57 (d, J = 4.8 Hz, 1H, 2'OH) , 2. 58 (m, 1H, H6a) , 2. 43 (d, J = 4 . 3 Hz, 1H, 70H), 2.38 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.24 (s, 3H, lOAc), 1.85 (m, 1H, H6S), 1.80 (br s, 3H, Mel8), 1.69 (s, 1H, lOH), 1.55 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).

EXAMPLE:10_ O Ac O Ph 7 ~ O
~~ OH
~Onnui ,' '' H OH _ _ Ph~O
Ac O
O
Preparation of N-debenzoyl-N-(4-chlorobenzoyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of (+)-cis-1-(9-chlorobenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (215 mg, 0.515 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 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 320 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(9-chlorobenzoyl) taxol.
To a solution of 320 mg (0.286 mmol) of this crude product in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 252 mg of material which was purified by flash chromatography to give 213 mg (89~) of N-debenzoyl-N-(4-chlorobenzoyl) taxol, which was recrystallized from methanol/water.

:n.p. 179-181 'C; [a)ZSya -49.8° (c 0.01, CHC13) .
-H ::NiR (CDC13, 300 MHz) 8 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.69 (m, 2H, aromatic), 7.60 (m, 1H, aromatic), 7.49 (m, 9H, aromatic) , 7 .03 (d, J = 8.8 Hz, 1H, NH) , 6. 26 (s, 1H, H10) , 6. 21 (dd, J = 8 .2, 8 .2 Hz, 1H, H13) , 5 . 76 (dd, J = 8 . 8, 2 . 2 Hz, 1H, H3' ) , 5 . 66 (d, J = 7 . 1 Hz, 1H, H2p) , 4 . 92 (dd, J =
9 . 9, 1 . 1 Hz, 1H, H5) , 4 . 77 (dd, J = 5 . 5, 2 .2 Hz, 1H, H2' ) , 9 . 38 (m, 1H, H7 ) , 4 . 29 (d, J = 8 . 8 Hz, 1H, H20a) , 4 . 18 (d, J = 8 . 5 Hz, 1H, H20~) , 3 .78 (d, J = 6. 6 Hz, 1H, H3) , 3. 35 (d, J = 5. 5 Hz, 1H, 2'OH), 2.55 (m, 1H, H6a), 2.99 (d, J = 4.2 Hz, 1H, 70H), 2.36 (s, 3H, 9Ac), 2.28 (m, 2H, H14), 2.22 (s, 3H, lOAc), 1 . 85 (m, 1H, H6~3) , 1 .77 (br s, 3H, MelB) , 1 .76 (s, 1H, lOH) , 1.67 (s, 3H, Mel9), 1.22 (s, 3H, Mel7), 1.13 (s, 3H, Mel6).

E_YAMP_LE 11 O Ac O Ph O O
~ / OH
/ N~ ~Omun I ~o H OH _ Br Hp O
Ph \' AcO
O
Preparatoion of N-debenzoyl-N-(9-bromobenzoyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 ~C, a solution of (+) -cis-1- (4-bromobenzoyl) -3-triethylsilyloxy-4-phenylazetidin-2-one (236 mg, 0.513 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 h before 1 :nI. of a 10~ solution of AcOH in THF was added. The mixture :,ras 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 322 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-bromobenzoyi) taxol.
To a solution of 322 mg of this crude product in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL or ~3~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then aL 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 312.2 mg of material which was purified by flash chromatography to give 254 mg (96~) of N-debenzoyl-N-(4-bromobenzoyl) taxol, which was recrystallized from methanol/water.

m. p. 182.5-185 °C; [a]25 -47.8° (c 0.0051, CHC13).
Na 1H NMR (CDC13, 300 MHz) 8 8.14 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.7-7.3 (m, 12H, aromatic), 6.96 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.22 (dd, J = 9.1, 9.1 Hz, 1H, H13), 5.77 (dd, J = 8.8, 2.2 Hz, 1H, H3'), 5.67 (d, J = 7.2 Hz, 1H, H2S), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.78 (dd, J =
5.0, 2.7 Hz, 1H, H2'), 4.40 (m, 1H, H7), 4.30 (d, J = 8.5 Hz,lH, H20a), 4.19 (d, J = 8.5 Hz, 1H, H20S), 3.79 (d, J = 7.2 Hz, 1H, H3), 3.98 (d, J = 5.0 Hz, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.45 (d, J = 4.4 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.30 (m, 2H, Hl4a, H14S) , 2.24 (s, 3H, lOAc) , 1.88 (m, lii, H6p) , 1.78 (br s, 3H, Mel8), 1.68 (s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1. 14 (s, 3H, Mel6 ) .

OAc O Ph O
- ~~ ~ off I ~N ~ o.......
i ,,,,,,,,, H OH _ O
Ph \' Ac0 O
Preparation of N-debenzoyl-N-(4-methylbenzoyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 ~C, a solution of (+)-cis-1-(4-methylbenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (203 mg, 0.513 mmol) in 2 mL of THF was added dropwise to the mixture. The solution ~.aas warmed to 0 °C and kept at that temperature for 2 h betore 1 mL of a 10~ solution of AcOH in THF was added. The mixture ~.~as partitioned between saturated aqueous NaHC03 and 60/40 et'~yl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 386 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-methylbenzoyl) taxol.
To a solution of 386 mg of this crude product in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of =)8o 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 283 mg of material which was purified by flash chromatography to give 240 mg (97~) of N-debenzoyl-N-(4-methylbenzoyl) taxol, which was recrystallized from methanol/water.

m. p. 175-176.5 °C; [a]25Na-50.9° (c 0.00975, CHC13).
1H NMR (CDC13, 300 MHz) 6 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.7-7.3 (m, lOH, aromatic), 7.19 (d, J = 7.7 Hz, 2H, benzoate meta), 6.94 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.22 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.77 (dd, J = 9.3, 2.8 Hz, 1H, H3'), 5.67 (d, J = 7.2 Hz, 1H, H2S), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.78 (dd, J = 4.9, 2.8 Hz, 1H, H2' ) , 4 .42 (m, 1H, H7) , 4.30 (d, J = 8.5 Hz, lEi, Fi20a) , 9 . 19 (d, J = 8. 5 Hz, lEi, H20 f3) , 3.79 (d, J = 7. 2 EEz, 10 1H, H3), 3.60 (d, J = 4.9 Hz, 1H, 2'OH), 2.53 (m, 1H, H6a), 2. 46 (d, J = 4.4 Hz, 1H, 70Ei) , 2. 38 (s, 3H, 4Ac) , 2. 37 (s, 3H, ArMe) , 2. 31 (m, 2H, Hl4a, H14 S) , 2. 23 (s, 3H, lOAc) , 1.87 (m, 1H H6 ~) , 1. 78 (br s, 3H, Mel8) , 1.68 (s, 3H, Mel9) , 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).

OAc O Ph O O
OH
N _ O~liiii~
H OH
(CH3 ) 3C
HO
p H s O
Ac0 Ph O

Preparation of N-debenzoyl-N-(4-t-butylbenzoyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of (+)-cis-1-(9-t-butylbenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (226 mg, 0.515 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 h before 1 mL of a 10~ solution of AcOH in THF was added.
The mixture was partitioned between saturated aqueous rdafIC03 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of crude (2'R,3'S)-2',7-(bis)-triethylsilyl-N-debenzoyl-N-(4-t-butylbenzoyl) taxol.
To a solution of 330 mg (0.289 mmol) of this crude product in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48$ aqueous FIF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and 2U partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation. of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give 240 mg (92$) of N-debenzoyl-N-(4-t-butylbenzoyl) taxol, which was recrystallized from methanol/-water.

m. p. 171-173 °C; [a]25Na-49.1° (c 0.05, CHC13).
1H NMR (CDC13, 300 MHz) 6 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.76-7.25 (m, 12H, aromatic), 6.98 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.77 (dd, J = 8.8, 2.7 1H, H3' ), 5.67 (d, J =
Hz, 6.6 Hz, 1H, H2~), 4.94 (dd, = 9.3, 1.2 Hz, 1H, H5), 4.78 (dd, J

J = 4.4, 2.7 Hz, 1H, H2') , 4.38 (m, 1H, H7), 4.29 (d, J
=

8.2 Fiz, 1H, H20a) , 4.20 (d, J = 8.2 Hz, lFi, H20S) , 3.79 (d, J = 6.6 Hz, 1H, H3), 3.65 (d, J = 4.4 Hz, 1H, 2'OH), 2.57 (m, 1H, H6a), 2.48 (d, J = 4.1 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac) , 2.31 (m, 2Fi, H14) , 2.22 (s, 3H, lOAc) , 1.85 (m, 1H, H6S), 1.79 (br s, 3H, Mel8), 1.68 (s, 1H, lOH), 1.68 (s, 3H, Mel9), 1.29 (s, 9H, ArtBu), 1.23 (s, 3H, Mel7), 1.13 (s, 3H, Mel6).

OAc O Ph O
OH
/ N~/~~_ Onnui I I =-_ w J H OH

/O
Ph~~ Ac0 \\O
Preparation of N-debenzoyl-N-(4-methoxybenzoyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -95 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of (+)-cis-1-(4-methoxybenzoyl)-3-triethylsilyloxy-9-phenylazetidin-2-one (211 mg, 0.513 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 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 406 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(9-methoxybenzoyl) taxol.
To a solution of 406 mg (0.112 mmol) of this crude product in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 =C was added 1.8 mL of 98$ 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 308 mg of material which was purified by flash chromatography to give 236 mg (99~) of N-debenzoyl-N-(4-methoxybenzoyl) taxol, which was recrystallized from methanol/water.

p. 174.5-176 °C; [a]z5~d -49.5° (c 0.0084, CHC13) .
-:i CJMR (CDC13, 300 MHz) b 8.13 (d, J = 7.1 Hz, 2H, benzoate ~rth:~) , 7 .75-7 .3 (m, lOH, aromatic) , 6. 90 (d, J =8.2 Hz, 1H, CJH), 6.88 (d, J = 7.1 Hz, 2H, benzoate meta), 6.27 (s, 1H, H10), 6.22 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.76 (dd, J = 8.8, 2.7 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2), 4.94 (dd, J =
9. 9, 2 . 2 Hz, 1H, H5) , 4 . 78 (d, J = 2 .7 Hz, 1H, H2' ) , 4 . 40 (dd, J = 11.0, 7.1 Hz, 1H, H7), 9.30 (d, J = 8.5 Hz, 1H, H20a), 4.19 (d, J = 8.5 Hz, 1H, H20~3), 3.82 (s, 3H, OMe), 3.79 (d, J =
7 . 1 Hz, 1H, H3) , 2 . 55 (m, 1H, H6a) , 2 .38 (s, 3H, 4Ac) , 2 .30 (m, 2Ei, Hl4a, fil4(~) , 2 . 23 (s, 3H, lOAc) , 1 .87 (m, 1H, H6(3) , 1 . 78 (br s, 3H, MelB) , 1 . 68 (s, 3H, Mel9) , 1 .23 (s, 3H, Mel7) , 1 . 14 (s, 3H, Mel6) .

E
O Ac O
-\ _ 1 ~ OH
F ~ =
HO H
O
Ph " Ac0 O
Preparation of N-debenzoyl-N-(9-fluorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.179 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-fluorobenzoyl)-3-triethylsilyloxy-9-(4-fluorophenyl)azetidin-2-one (600 mg, 1.43 mmol) in 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 60/90 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 315 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 315 mg (0.282 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 250 mg of material which was purified by flash chromatography to give 160 mg (63~) of N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol, which was recrystallized from methanol/water.
m.p. 177-179 °C; [ocJzs,,a -48.8° (c 0.003, CHC13) .
=H NMR (CDC13, 300 MHz) b 8.11 (d, J = 7.1 Hz, 2H, benzoate ortho>, 7.76 (d, J = 8.7 Hz, 2H, benzamide ortho), 7.73 (m, 2H, aromatic), 7.61 (m, 1H, aromatic), 7.48 (m, 6H, aromatic),. 7.06 (m, 2H, aromatic), 7.02 (d, J = 8.8 Hz, 1H, NH), 6.26 (s, 1H, H10), 6.22 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.74 (dd, J = 8.8, 2 . 2 Hz, 1H, H3' ) , 5 . 66 (d, J = 7 . 1 Hz, 1H, H2(~) , 4 . 93 (dd, J =
9 . 3, 1 . 1 Hz, 1H, H5) , 9 . 74 (dd, J = 5 .0, 2 .2 Hz, 1H, H2' ) , 9 . 36 (m, 1H, H7 ) , 4 . 29 (d, J = 8 . 8 Hz, 1H, H200c) , 4 . 18 (d, J = $ . 8 Hz, 1H, H20p) , 3 . 77 (d, J = 7 . 1 Hz, 1H, H3) , 3 .70 (d, J = 5 . 0 Hz, 1H, 2' OH) , 2 . 77 (m, 1H, H6oc) , 2 . 52 (d, J = 4 . 4 Hz, lFi, 70H), 2.36 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.22 (s, 3H, lOAc), 1.86 (m, 1H, H6p), 1.78 (br S, 3H, MelB), 1.77 (s, 1H, lOH), 1 . 67 (s, 3H, Mel9) , 1 .21 (s, 3H, Mel7) , 1 . 13 (s, 3H, Mel6) .

O Ac O Ph O O
1 \ ~ - i pH
,, L i ,,",, H OH _ F HO O H ~~~
Ph \\ AcO
O
Preparation of N-debenzoyl-N-(4-fluoroobenzoyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -95 °C, a solution of (+)-cps-1-(4-fluorobenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (225 mg, 0.515 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/90 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 325 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl- N-debenzoyl-N-(9-fluorobenzoyl) taxol.
To a solution of 325 mg (0.286 mmol) of this crude product in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 260 mg of material which was purified by flash chromatography to give 240 mg (92%) of N-debenzoyl-N-(4-fluorobenzoyl) taxol, which was recrystallized from methanol/water.

m.p. 175-177 'C; (a]ZS,,a -51.2° (c 0.01, CHC13) .
-H tIMR (CDC13, 300 MHz) 8 8.13 (d, J = 7.1 Hz, 2fi, benzoate ortho), 7.74 (m, 2H, aromatic), 7.62 (m, 2H, aromatic), 7.46 (m, 6fi, aromatic) , 7 . 06 (m, 2H, aromatic) , 6. 95 (d, J = 8 . 8 Hz, 1H, NH) , 6.28 (s, 1H, H10) , 6.22 (dd, J = 8.2, 8 .2 Hz, 1H, H13), 5.76 (dd, J = 8.8, 2.8 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2~3) , 4 . 93 (dd, J = 9. 9, 2 . 2 Hz, 1H, H5) , 4 . 78 (dd, J =
5.5, 2.8 Hz, 1H, H2'), 4.39 (m, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20a) , 4 . 22 (d, J = 8 .8 Hz, 1H, H20(~) , 3 . 79 (d, J = 7 . 1 Hz, lfi, H3) , 3 . 54 (d, J = 5 .5 Hz, lfi, 2'OH) , 2.54 (m, 1H, H6a) , 2.46 (d, J = 4.4 Hz, 1H, 7pH), 2.37 (s, 3H, 4Ac), 2.30 (m, 2H, H14 ) , 2 .26 (s, 3H, lOAc) , 1 .87 (m, 1H, H6~3) , 1 .79 (br s, 3H, Mel8) , 1 . 79 (s, 1H, lOH) , 1 . 67 (s, 3H, Mel9) , 1 .24 (s, 3H, Mel7) , 1 . 12 (s, 3Ei, Mel6) .

/ OAc O \ ~ O
Ofi ~N _ Olnmll H OEi Preparation of N-debenzoyl-N-(4-methylbenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-methylbenzoyl)-3-triethyl-silyloxy-4-(4-chlorophenyl)azetidin-2-one (718 mg, 1.43 mmol) in 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 Ph O

layer gave a residue which was purified by filtration through silica gel to give 329 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-rJ-debenzoyl-N-(4-methylbenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 329 mg of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 48~ aqueous HF.
The mixture was stirred at 0 °C for 3 h, then at 25 °C for 10 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 376 mg of material which was purified by flash chromatography to give 175 mg (68~) of N-debenzoyl-N-(4-methylbenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol, which was recrystallized from methanol/water.
m. p. 167.5-171 °C; [a]25Na-53.7° (c 0.01105, CHC13).
1H NMR (CDC13, 300 MHz) d 8.12 (d, J = 8.2 Hz, 2H, benzoate ortho), 7.65-7.3 (m, 9H, aromatic), 7.19 (d, J = 8.2 Hz, 2H, benzoate meta), 6.97 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, 20 H10), 6.22 (dd, J = 9.9, 9.9 Hz, 1H, H13), 5.76 (dd, ,7 = 8.8, 2.2 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H H2s), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.76 (dd, J = 4.4, 2.2 Hz, 1H, H2'), 4.39 (m,:lH, H7), 4.30 (d, J = 8.8 Hz, lli, H20a), 4.19 (d, J = 8.8 Hz, 1H, H20S) , 3.79 (d, J = 7.1 Hz, 1H, H3) , 3.75 (d, J = 4.4 Hz, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.49 (d, J = 4.4 Hz, 1H, 70H), 2.38 (s, 3H, 4Ac), 2.37 (s, 3H, ArMe), 2.31 (m, 2H, Hl4a, H14S), 2.23 (s, 3H, lOAc), 1.87 (m, 1H, H6a), 1.80 (br s, 3H, Mel8), 1.68 (s, 3H, Mel9), 1.22 (s, 3H, Mel7), 1.13 (s, 3H, Mel6).

EXAMPLE 1~
F
UAC
O ~ O
ii~y El ort C 1 HO F~
O
Ph \' 11c0=

Preparation of N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 ~C, a solution of cis-1-(4-chlorobenzoyl)-3-triethylsilyloxy-4-(4-fluorophenyl)azetidin-2-one (630 mg, 1.43 mmol) in 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 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 330 mg (0.283 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 250 mg of material which was purified by flash chromatography to give 166 mg (65~) of N-debenzoyl-N-(4-':~lorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol, which :ras re~~ystallized from methanol/water.
m.p. 17.g-179 °C; [a)~S,,a -51.9° (c 0.01, CHC13) .
-H NMR (CDC13, 300 MHz) b 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.64 (m, 3H, aromatic), 7.49 (m, 4H, aromatic), 7.36 (m, 2H, aromatic) , 7 , 10 (m, 2H, aromatic) , 6. 97 (d, J = 8 . 8 Eiz, 1H, NH) , 6 . 27 (s, 1H, H10) , 6.21 (dd, J = 8.8, 8 .8 Hz, 1E~, Eil3 ) , 5 . 7 6 (dd, J = 8 . 8, 2 . 2 Hz, lfi, H3' ) , 5 . 6'7 (d, J = 7 . 2 Hz, lii, H2~3) , 4 . 94 (dd, J = 9. 3, 2 .2 Hz, 1H, H5) , 4 . 75 (dd, J =
4 . 4, 2 .2 Hz, 1H, Ei2' ) , 4 .39 (ddd, J = 11 .0, 6 . 6, 3 . 9 Hz, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20a), 4.19 (d, J = 8.8 Hz, 1H, H20(3) , 3 . 79 (d, J = 7 .2 Hz, 1H, H3) , 3. 60 (d, J = 4 . 4 Hz, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.47 (d, J = 3.9 Hz, 1H, 70H), 2.38 (s, 3H, 4Ac) , 2 .30 (m, 2H, H14) , 2 .28 (s, 3H, lOAc) , 1 .87 (m, 1H, H6(3) , 1 . 78 (br s, 3H, MelB) , 1 .78 (s, 1H, lOH) , 1 . 68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).

EXAMPLE 1~
F
O OAc O
no ~o EE OEi _ B r Fi0 Ph~o Ac O
O
Preparation of N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.087 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-bromobenzoyl)-3-triethylsilyloxy-4-(4-fluorophenyl)azetidin-2-one (689 mg, 1.93 mmol) in 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~s 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 433 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 433 mg of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 98~ 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 317 mg of material which was purified by flash chromatography to give 187 mg (69~) of N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol, which was recrystallized =om methanol/water.
m.p. 174.5-175.5 ~C; [a]ZSVa-46.9° (c 0.00735, CHC13) .
-H ~IMR (CDC13, 300 MHz) 8 8.13 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.7-7.4 (m, 9H, aromatic), 7.10 (dd, J = 8.3, 8.3 Hz, 2H, aromatic), 6.97 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 5.23 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.76 (dd, J = 8.8, 2.2 Hz, 1H, H3' ) , 5 . 67 (d, J = 7 . 1 Hz, 1H, H2(3) , 4 . 94 (dd, J = 9. 9, 2 . 2 Hz, 1H, H5) , 4 . 75 (dd, J = 4 .4, 2 . 2 Hz, 1H, H2' ) , 4 . 39 (m, 1H, H7), 9.31 (d, J = 8.5 Hz, 1H, H20a), 4.19 (d, J = 8.5 Hz, 1H, H20~3) , 3 . 79 (d, J = 7 . 1 Hz, 1H, H3) , 3 . 59 (d, J = 4 . 4 Fiz, 1H, 2'OH), 2.54 (m, 1H, H6a), 2.47 (d, J = 4.4 Hz, 1H, 70H), 2.36 (s, 3H, 4Ac) , 2 .30 (m, 2H, Hl4a, H14(~) , 2 .24 (s, 3H, lOAc) , 1.88 (m, 1H, H6a), 1.78 (br s, 3H, MelB), 1.74 (s, lFi, lOH), 1 . 68 (s, 3H, Mel9) , 1 .23 (s, 3H, Mel7) , 1. 14 (s, 3H, Mel6) .

E_XA_M_PLE 2 Q
F
Ac O
\ 1' ~ Ofi O
Ph~ Ac0 ~~O
Preparation of N-debenzoyl-N-(9-methylbenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-methylbenzoyl)-3-triethylsilyloxy-4-(4-fluorophenyl)azetidin-2-one (592 mg, 1.43 mmol) in 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 335 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-methylbenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 335 mg (0.30 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 280 mg of material which was purified by flash chromatography to give 163 mg (64~) of N-debenzoyl-N-(4-_, :r.ethylbenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol, which :cas =ecrystallized from methanol/water.
m.p. 172-173 °C; [a)z5"a -52.0° (c 0.01, CHC13) .
-H iIMR (CDC13, 300 MHz) S 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.61 (m, 3H, aromatic), 7.48 (m, 4H, aromatic), 7.18 (m, 2H, aromatic), 7.10 (m, 2H, aromatic), 6.95 (d, J = 8.8 Hz, 1H, rdH) , 6.27 (s, 1H, H10) , 6.21 (dd, J = 8. 8, 8. 8 Hz, 1H, j-i13 ) , 5 . 77 (dd, J = 8 . 8, 2 . 2 Hz, 1H, H3' ) , 5 . 67 (d, J = 7 . 2 Hz, 1H, H2~3) , 4 . 94 (dd, J = 9.3, 1 .7 Hz, 1H, H5) , 4 .75 (dd, J =
4.4, 2.2 Hz, 1H, H2'), 4.39 (ddd, J = 11.0, 6.6, 4.4 Hz, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20a), 4.19 (d, J = 8.8 Hz, 1H, H20~3), 3.79 (d, J = 7.2 Hz, 1H, H3), 3.67 (d, J = 4.4 Hz, 1H, 2'OH), 2.54 (ddd, J = 9.3, 14.8, 6.6 Hz, 1H, H6a), 2.46 (d, J =
4.4 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.36 (s, 3H, Ark,), 2.30 (m, 2H, H14), 2.23 (s, 3H, lOAc), 1.87 (ddd, J = 11.0, 14.8, 1.7 Hz, 1H, H6(~), 1.79 (br s, 3H, MelB), 1.79 (s, 1H, lOH), 1.68 (s, 3H, Mel9), 1.22 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).

OC Ha i F
~~ Ac0 O
Preparation of N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 'C, a solution of cis-1-(4-fluorobenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of TE~F 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 60/90 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 330 mg (0.292 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 260 mg of material which was purified by flash chromatography to give 155 mg (60%) of N-debenzoyl-N-(4-luorobenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, which -.gas recrystallized from methanol/water.
m. o . 169-170 °C: [a) 25,,a -50 . 9° (c 0 .01, CHC13) .
-H NMR (CDC13, 300 MHz) 8 8.14 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.57 (m, 7H, aromatic), 7.06 (m, 2H, aromatic), 6.94 (m, 2H, aromatic) , 6 . 85 (d, J = 8 . 8 Hz, 1H, NH) , 6. 27 (s, lEi, H10), 6.20 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.72 (dd, J = 8.8, 2 . 8 Hz, 1H, H3' ) , 5 . 67 (d, J = 7 . 2 Hz, 1H, H2(~) , 4 . 99 (dd, ,J =
9. 3, 2 . 1 Hz, lEi, H5) , 9 .74 (dd, J = 4 . 9, 2 .8 Hz, 1H, fit' ) , 4 . 40 (ddd, J = 11.0, 6.6, 3.9 Hz, 1H, H7), 4.31 (d, J = 8.8 Hz, 1H, H20a) , 4 . 19 (d, J = 8 . 8 Hz, 1H, H20~3) , 3 . 80 (d, J = 7 . 2 Hz, 1H, H3) , 3 . 79 (s, 3H, ArQ,~) , 3 .51 (d, J = 9 . 9 Hz, 1H, 2'OFi) , 2 . S4 (m, 1H, H6a), 2.50 (d, J = 3.9 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2 . 31 (m, 2H, H14) , 2 . 24 (s, 3H, lOAc) , 1 . 87 (m, 1H, H6p) , 1 . 79 (br s, 3H, MelB), 1.79 (s, 1H, lOH), 1.68 (s, 3H, Mel9), 1.24 (s, 3H, Mel7) , 1 . 14 (s, 3H, Mel6) .

AMA
OC i i, O
O
w -H OH _ Ph~O
Ac O
O
Preparation of N-debenzoyl-N-(4-methylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-methylbenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (610 mg, 1.43 mmol) in 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 325 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-methylbenzoyl)-3'-desphenyl-3'-(9-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 325 mg (0.289 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48~ aqueous HE. 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 265 mg of material which was purified by flash chromatography to give 165 mg (64~) of N-debenzoyl-N-(4-:~ethylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, :~hich :aas recrystallized from methanol/water.
m. p . 173-174 °C: [a] zSVa -50 . 2° (c 0 . O1, CHCl~) .
-H NMR (CDC13, 300 MHz) S 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.61 (m, 3H, aromatic), 7.51 (m, 2H, aromatic), 7.40 (m, 2H, aromatic), 7.19 (m, 2H, aromatic), 6.93 (m, 2H, aromatic) , 6.86 (d, J = 8.8 Hz, 1H, NH) , 6.27 (s, 1H, H10) , 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.70 (dd, J = 8.8, 2.8 Hz, 1H, H3' ) , 5 . 66 (d, J = 7 . 2 Hz, 1H, H2p) , 4 . 94 (dd, J = 9 , 9, 2 . 2 Hz, lEi, H5) , 4 . 74 (dd, J-= 5 .5, 2 . 8 Hz, 1H, H2' ) , 4 . 40 (ddd, J
- 11.0, 6.5, 3.8 Hz, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, Ei20a), 4 . 19 (d, J = 8. 8 Hz, 1H, H20~3) , 3. 79 (d, J = 7 . 2 Hz, 1H, H3) , 3.78 (s, 3H, ArQ~) , 3. 63 (d, J = 5.5 Hz, 1H, 2'OFi) , 2 . 59 (m, 1H, H6a), 2:46 (d, J = 3.8 Hz, 1H, 70H), 2.38 (s, 3H, Ark), 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.23 (s, 3H, lOAc), 1.88 (m, 1H, H6(3), 1.80 (br s, 3H, MelB), 1.80 (s, 1H, lOH), 1.68 (s, 3H, Mel9) , 1 .23 (s, 3H, Mel7) , 1 . 14 (s, 3H, Mel6) .

OAc O
- / OH
ni "~o~,,~
HO
Ph~ Ac01 \'O
Preparation of N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-fluorobenzoyl)-3-triethylsilyloxy-9-(4-chlorophenyl)azetidin-2-one (620 mg, 1.93 mmol) in 2 mL of TfiF 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 325 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 325 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 98% 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 260 mg of material which was purified by flash chromatography to give 161 mg (62%) of N-debenzoyl-N-(4-fluorobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol, which :gas recrystallized from methanol/water.
m.p. 172-174 °C; [OC]ZSVa -56.0° (c 0.01, CHC13) .
-H flhiR (CDC13, 300 MHz) 8 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.73 (m, 2H, aromatic), 7.60 (m, 1H, aromatic),7.50 (m, 2H, aromatic), 7.38 (m, 9H, aromatic), 7.06 (m, 2H, aromatic), 7 .05 (d, J = 8 . 8 Hz, 1H, NH) , 6. 27 (s, 1H, H10) , 6. 22 (dd, J =
7.7, 7.7 Hz, 1H, H13), 5.75 (dd, J = 8.8, 2.8 Hz, 1H, H3'), 5.65 (d, J = 7.1 Hz, 1H, H2~3), 4.92 (dd, J = 9.3, 1.6 Hz, 1H, H5), 4.75 (dd, J = 4.9, 2.8 Hz, 1H, H2'), 4.41 (m, 1H, H7), 4 .29 (d, J = 8 . 2 Hz, 1H, H200c) , 4 . 17 (d, J = 8 .2 Hz, 1H, H20(3) , 3 . 84 (d, J = 4 . 4 Hz, 1H, 2'OH) , 3 .78 (d, J = 7 . 1 Eiz, 1H, H3), 2.55 (d, J = 4.4 Hz, 1H, 70H), 2.52 (m, 1H, H6a), 2.36 (s, 3H, 9Ac), 2.29 (m, 2H, H14), 2.21 (s, 3H, lOAc), 1.86 (m, 1H, H6(3) , 1 .79 (br s, 3H, MelB) , 1 .78 (s, 1H, lOH) , 1 . 67 (s, 3H, Mel9) , 1 . 29 (s, 3H, Mel7) , 1 . 12 (s, 3H, Mel6) .

OAc / O
C 1 HO l..j O
ph " Ac0 O
Preparation of N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nHuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-chlorobenzoyl)-3-triethylsilyloxy-4-(4-chlorophenyl)azetidin-2-one (640 mg, 1.43 mmol) in 2 mL of TEIF 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 335 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-chloroobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 335 mg (0.291 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 98% 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 270 mg of material which was purified by flash chromatography to give 158 mg (60%) of N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol, which gas ~ecrystallized from methanol/water.
m.p. 184-185 'C: (oc]ZS,,a -52.5° (c 0.01, CHC13) .
-H NMR (CDC13, 300 MHz) 8 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho) , 7 . 51 (m, 11H, aromatic) , 6. 98 (d, J = 8 . 8 Hz, 1H, NH) , 6.27 (s, 1H, H10), 6.22 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.76 (dd, J = 8 . 8, 2 . 2 Hz, 1H, H3' ) , 5 . 67 (d, J = 7 .2 Hz, 1H, H2~3) , 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.76 (dd, J = 5.0, 2.2 Hz, 1H, H2'), 4.39 (ddd, J = 10.8, 6.5, 4.4 Hz, 1H, H7), 4.30 (d, J = 8 . 8 Hz, 1H, Fi20oc) , 4 . 19 (d, J = 8 .8 Hz, lFi, H20~3) , 3 , 79 (d, J = 7 .2 Hz, 1H, H3) , 3 . 68 (d, J = 5 .0 Hz, 1H, 2'OH) , 2 . 54 (ddd, J = 9 . 9, 14 . 8, 6 . 5 Hz, 1H, H60C) , 2 . 47 (d, J = 9 . 4 Hz, 1H, 70H) , 2.37 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.23 (s, 3H, lOAc), 1.87 (ddd, J = 10. 8, 14 .8, 2 .2 Hz, 1H, H6~3) , 1 .84 (br s, 3H, MelB) , 1 .79 (s, 1H, lOH) , 1. 68 (s, 3H, Mel9) , 1 .22 (s, 3H, Mel7) , 1 . 14 (s, 3H, Mel6) .

OAc O O
\ -II O H
Br f~0 ~ H
Ph~O
Ac O
O
Preparation of N-debenzoyl-N-(9-bromobenzoyl)-3'-desphenyl-3'-(9-chlorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cts-1-(4-bromobenzoyl)-3-triethylsilyloxy-4-(4-chlorophenyl)azetidin-2-one (359 mg, 0.715 mmol) in 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 355 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol and a small amount of the ( 2' S, 3' R) isomer .
To a solution of 355 mg of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 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 280 mg of material which was purified by flash chromatography to give 171 mg (62%) of N-debenzoyl-N-(4-bromobenzoyl)-3'-~esphenyl-3'-(4-chlorophenyl) taxol, which was recrystallized °rcm ~~ethanol/water.
m. p . 191-183 . 5 °C; [a] zs,,a -52 . 8° (c 0 .0064, CHC13) .
-H aIL~IR (CDC13, 300 MHz) $ 8.12 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.65-7.3 (m, 11H, aromatic), 7.03 (d, J = 8.8 Hz, 1H, c1H) , 6.27 (s, 1H, H10) , 6.22 (dd, J = 9.3, 9. 3 Hz, 1H, H13) , 5.75 (dd, J = 8.8, 2.2 Hz, 1H, H3'), 5.66 (d, J = 7.1 Hz, 1H, H2~3), 4.93 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.75 (dd, J = 5.0, 2 . 2 Hz, 1H, H2' ) , 4 . 40 (m, 1H, H7) , 4 .30 (d, J = 8 . 5 Eiz, 1H, H20ot) , 4 . 18 (d, J = 8 .5 Hz, 1H, H20(~) , 3.77 (m, 2H, H3, 2'OH) , 2.54 (m, 1H, H6a), 2.52 (d, J = 4.4 Hz, 1H, 70H), 2.36 (s, 3H, 9Ac) , 2 .29 (m, 2H, Hl4oc, H14~) , 2.22 (s, 3H, lOAc) , 1 .87 (m, lEI, Ei6oc) , 1.79 (br s, 3H, ,MelB) , 1.73 (s, 1H, lOH) , 1 . 67 (s, 3H, Mel9), 1.21 (s, 3H, Mel7), 1.13 (s, 3H, Mel6).

OAc O
- \ _ r ~ OFi (C:ti3)3C '' HO E; , O
Ph~ Ac0 \'O
Preparation of N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -95 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -95 'C, a solution of cps-1-(4-t-butylbenzoyl)-3-triethylsilyloxy-4-(4-chlorophenyl)azetidin-2-one (675 mg, 1.43 mmol) in 2 mL of TEiF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mI, of a loo solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC03 and 60/40 ethyl acetate/h exane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 317 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(9-chlorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 317 mg of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 48'b 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 354 mg of material which was purified by flash chromatography to give 186 mg (69~) of N-debenzoyl-N-(9-t-butylbenzoyl)-3'-desphenyl-3'-(4-chlorophenyl) taxol, which was recrystallized i-.gym :,~,ethanol/water.
m.p. 176.5-178 °C: (a]zSNa -51.8° (c 0.00985, CHC13) .
-H "dMR (CDC13, 300 MHz) S 8.19 (d, J = 8.8 Hz, 2H, benzoate ortho), 7.7-7.3 (m, 11H, aromatic), 6.94 (d, J = 8.8 Hz, lFi, rdH) , 6.27 (s, 1H, H10) , 6.24 (dd, J = 8 .3, 8. 3 Hz, 1H, H13) , 5.78 (dd, J = 9.3, 2.2 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2(3) , 4 . 95 (dd, J = 8 .8, 1 . 1 Hz, 1H, H5) , 4 .76 (dd, J = 5.0, 2 .2 Hz, 1H, H2' ) , 4 .90 (m, 1H, H7) , 4 .31 (d, J = 8 . 5 Hz, 1H, H20a) , 4 . 20 (d, J = 8 . 5 Hz, 1H, H20(3) , 3 .80 (d, J = 7 . 1 Hz, 1H, H3), 3.64 (d, J = S.0 Hz, 1H, 2'OH), 2.55 (m, 1H, H6a), 2.46 (d, J = 9.4 Hz, 1H, 70H), 2.38 (s, 3H, 4Ac), 2.32 (m, 2H, Hl4a, H14(3) , 2 . 23 (s, 3H, lOAc) , 1 . 88 (m, 1H, H6oc) , 1 . 82 (br s, 3H, Mel8) , 1 . 77 (s, 1H, lOH) , 1 . 67 (s, 3H, Mel9) , 1 .30 (s, 9H, t-Bu) , 1 .23 (s, 3H, Mel7) , 1 . 14 (s, 3H, Mel6) .

EXAM_P_LE 2 7 F
(CH3)3C
O
Ac O
Preparation of N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -95 °C, a solution of cis-1-(4-t-butylbenzoyl)-3-triethylsilyloxy-4-(9-fl.uorophenyl)azetidin-2-one (650 mg, 1.43 mmol) in 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 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(9-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
'ro a solution of 330 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 98% 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 260 mg of material which was purified by flash chromatography to give 168 mg (64%) of N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol, which was recrystallized from methanol/water.
m.p. 180-182 °C; [aj25"a -46.3° (C 0.01, CHC13) .
'-H NMR (CDC13, 300 MHz) $ 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.67 (m, 2H, aromatic), 7.60 (m, 1H, aromatic), 7.46 (m, 6H, aromatic), 7.08 (m, 2H, aromatic), 7.00 (d, J = 8.8 Hz, 1H, NH) , 6 . 27 ( s, 1H, H10) , 6. 23 (dd, J = 8 . 8, 8 . 8 Hz, 1H, H13) , 5 . 76 (dd, J = 8. 8, 2.7 Hz, lfi, H3' ) , 5. 67 (d, J = 7 . 1 Hz, 1H, H2(3) , 4 . 94 (dd, J = 9. 3, 1 . 7 Hz, 1H, H5) , 9 . 75 (dd, J =
4 . 9, 2 . 7 Hz, 1H, H2' ) , 4 .39 (m, 1H, H7) , Q .30 (d, J = 8 .2 Hz, 1H, H20a), 9.22 (d, J = 8.2 Hz, 1H, H20p), 3.78 (d, J = 7.1 Hz, 1H, H3), 3.55 (d, J = 4.9 Hz, 1H, 2'OH), 2.56 (m, 1H, H6a), 2.50 (d, J = 4.4 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.30 (m, 2H, H14 ) , 2 . 22 (s, 3H, lOAc) , 1 .88 (m, 1H, Ei6(3) , 1 . 79 (br s, 3fi, MelB) , 1 . 75 (s, 1H, lOH) , 1 . 67 (s, 3H, Mel9) , 1 .29 (s, 9Fi, Artgy) , 1 .22 (s, 3H, Mel7) , 1 .13 (s, 3H, Mel6) .

EXAMPLE 2$_ F
CIi30 OAc / O
O
Ac O
Preparation of N-debenzoyl-N-(9-methoxybenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-methoxybenzoyl)-3-triethylsilyloxy-4-(9-fluorophenyl)azetidin-2-one (619 mg, 1.43 mmol) in 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 362 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-methoxybenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 362 mg of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 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 269 mg of material which was purified by flash chromatography to give 183 mg (71%) of N-debenzoyl-N-(4-methoxybenzoyl)-3'-desphenyl-3'-(9-fluorophenyl) taxol, which was recrystallized from methanol/water.
m.p. 172.5-174.5 °C; [oc)15~a -47.0° (c 0.0044, CHC13) .
=H NMR (CDC13, 300 MHz) $ 8.13 (d, J = 7.2 Hz, 2H, benzoate ortho), 7.7-7.4 (m, 9H, aromatic), 7.10 (dd, J = 8.8, 8.8 Hz, 2f1, aromatic) , 6.97 (d, J = 8.8 Hz, lEi, NH) , 6.27 (s, lEE, EilO) , 6.23 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.76 (dd, J = 8.8, 2.2 Hz, 1H, EE3' ) , 5 . 67 (d, J = 7 . 1 Hz, 1H, H2p) , 4 . 94 (dd, J = 9. 9, 2 . 2 Hz, 1H, H5) , 4 . 75 (dd, J = 4 . 4, 2.2 Hz, 1H, H2' ) , 9 .39 (m, 1H, H7) , 4 . 31 (d, J = 8 . 5 Hz, 1H, H20a) , 4 . 19 (d, J = 8 . 5 Hz, 1H, H20~3) , 3. 79 (d, J = 7 . 1 Hz, 1H, H3) , 3 . 59 (d, J = 4 . 9 Hz, 1H, 2'OH) , 2 . 54 (m, 1H, H6a) , 2 . 47 (d, J = 4 . 4 Eiz, 1H, 70H) , 2 . 36 (s, 3H, 4Ac) , 2 . 30 (m, 2H, Hl4a, H14(3) , 2 . 29 (s, 3H, lOAc> , 1.88 (m, 1H, H6a), 1.78 (br s, 3H, MelB), 1.74 (s, 1H, lOEi), 1 . 68 (s, 3H, Mel9) , 1 .23 (s, 3H, Mel7) , 1 . 14 (s, 3H, Mel6) .

OC H, O O
- OH
iiio, ii w H OH _ C1 Hp ' H
Ph~o \\ AcO
O
Preparation of N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -95 °C, a solution of cis-1-(4-chlorobenzoyl)-3-triethylsilyloxy-4-(9-methoxyphenyl)azetidin-2-one (638 mg, 1.43 mmol) in 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 328 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 328 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 270 mg of material which was purified by flash chromatography to give 170 mg (65%) of N-debenzoyl-N-(4-chlorobenzoyl)-3'-desphenyl-3'-(9-methoxyphenyl) taxol, which was recrystallized from methanol/water.
m.p. 169-171 °C; [OCJzS~a -51.1° (c 0.035, CHC13) .
~H NMR (CDC13, 300 MHz) S 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.65 (d, J = 8.2 Hz, 2H, benzamide ortho), 7.51 (m, 2H, aromatic) , 7.36 (m, 5H, aromatic) , 6.91 (m, 2fi, aromatic) , 6.90 (d, J = 8 . 2 Hz, 1H, NH) , 6. 26 (s, 1H, H10) , 6.21 (dd, J = 7 . 7, 8 . 9 Hz, 1H, H13) , 5 . 69 (dd, J = 8 .2, 2 . 8 Hz, 1H, H3' ) , S . 67 (d, J = 6. 6 Hz, 1H, H2~3) , 4 . 94 (dd, J = 9. 9, 2 .2 Hz, 1H, H5) , 4 . 79 (dd, J = 9 . 9, 2 . 8 Hz, 1H, H2' ) , 9 . 39 (ddd, J = 11 . 0, 6 . 6, 3 . 8 Hz, 1H, H7) , 9 . 30 (d, J = 8 .2 Hz, 1H, H200c) , 4 . 19 (d, J = 8 . 2 Hz, 1H, H20~3), 3.79 (d, J = 6.6 Hz, 1H, H3), 3.79 (s, 3H, Ark), 3.57 (d, J = 4.9 Hz, 1H, 2'OH), 2.53 (ddd, J = 9.9, 14 . 4, 6. 6 Hz, 1H, H6oC) , 2 . 97 (d, J = 3 .8 Hz, 1H, 70H) , 2 .36 (s, 3H, 4Ac) , 2 . 33 (m, 2H, H14) , 2 .23 (s, 3H, lOAc) , 1 . 88 (ddd, J =
11 . 0, 14 . 4, 2 .2 Hz, 1H, H6(~) , 1 .79 (br s, 3H, MelB) , 1 . 78 (s, 1H, lOH), 1.68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6) .

EXAMPLE ~Q

OAc O O O
/ ~ N _ Onuni I °~~%
Fi OtF
B r Ftn _ O
Ac O
Preparation of N-debenzoyl-N-(9-bromobenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of neuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-bromobenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (696 mg, 1.43 mmol) in 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 321 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3'-(9-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 351 mg of the mixture obtained from the previous reaction in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 98% 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 320 mg of material which was purified by flash chromatography to give 189 mg (695) of N-debenzoyl-N-(4-bromobenzoyl)-3'-desphenyl-3'-(9-methoxyphenyl) taxol, which was recrystallized from methanol/water.
m.p. 173.5-176 °C: [a]ZSN, -48.9° (c 0.0065, CHC13) .
1H NMR (CDC13, 300 MHz) 8 8.13 (d, J = 7.2 Hz, 2H, benzoate ortho) , 7 . 7-7 . 3 (m, 9H, aromatic) , 6. 93 (d, J = 8 . 8, Hz, 2H, aromatic), 6.93 (d, J = 9.3 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.68 (m, 2H, H3', H2~3), 9.94 (dd, J = 8.8, 1.7 Hz, 1H, H5), 4.79 (dd, J = 9.9, 2.8 Hz, 1H, fit' ) , 4 . 40 (m, 1H, H7) , 4 . 31 (d, J = 8.2 Hz, 1H, H20a) , 4 . 19 (d, J = 8 . 2 Hz, lFi, H20~3) , 3 . 80 (d, J = 7 . 1 Hz, 1H, H3),3.80 (s, 3H, ArOMS). 3.51 (d, J = 4.9 Hz, 1H, 2'OH), 2.54 (m, 1H, H6a) , 2.46 (d, J = 9 .4 Hz, 1H, 70H) , 2 .37 (s, 3H, 4Ac) , 2 . 31 (m, 2H, Hl4a, H14~3) , 2 .24 (s, 3H, lOAc) , 1 . 87 (m, 1H, H6a) , 1 . 79 (br s, 3H, MelB) , 1 . 74 (s, 1H, lOH) , 1 . 68 (s, 3H, Mel9), 1.23 (s, 3H, Mel7), 1.14 (s, 3H, Mel6).

OC H.~
Ac O
~CH3)3C Ho O
Ph~ Ac0 ~~O
Preparation of N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -95 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 'C, a solution of cis-1-(4-t-butylbenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (670 mg, 1.93 mmol) in 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 340 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 340 mg (0.291 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 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 275 mg of material which was purified by flash chromatography to give 188 mg (70%) of N-debenzoyl-N-(4-_-DiltylbenZOyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, which ~..~as recrystallized from methanol/water.
m.p . 134-1 85 ~C; [a] ZS~a -50. 4° (C 0.01, CHC13) .
-H rJMR (CDC13, 300 MHz) 8 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.53 (m, 9H, aromatic), 6.92 (m, 2H, aromatic), 6.88 (d, J = 8 . S Hz, 1H, rrH) , 6.27 (s, 1H, H10) , 6 . 21 (dd, J = g . 8, 8 . 8 Eiz, 1H, Eil3) , 5.72 (dd, J = 8 .8, 2 .8 Hz, 1H, Ei3' ) , 5 . 67 (d, J = 7 . 1 Hz, 1H, H2~3) , 9 . 95 (dd, J = 9. $, 2 . 2 Hz, 1H, Ei5) , 4 . 74 (dd, J = 5.5, 2.8 Hz, 1H, H2'), 4.40 (ddd, J = 11.0, 6.6, 3.8 Hz, 1H, H7), 4.30 (d, J = 8.4 Hz, 1H, H20a), 4.19 (d, J = 8.4 Hz, 1H, H20(3) , 3.80 (d, J = 7. 1 Hz, 1H, H3) , 3.79 (s, 3H, Ark) , 3 . 63 (d, J = 5 . 5 Hz, 1H, 2'OH) , 2 .54 (m, 1H, H6a) , 2.46 (d, J = 3.8 Hz, 1H, 70H), 2.38 (s, 3H, 4Ac), 2.32 (m, 2Ei, H19), 2 . 23 (s, 3H, lOAc) , 1 .87 (ddd, J = 11 .0, 14 .7, 2 .2 fiz, 1H, H6~3) , 1 . 81 (br s, 3H, Mel8) , 1 .80 (s, 1H, lOH) , 1 . 68 (s, 3H, Mel9) , 1 . 30 (s, 9H, Artgu) , 1 .23 (s, 3H, Mel7 ) , 1 . 14 (s, 3H, Mel6) .

_..._ ...~_._ ~r ,.

0C H, O
Ac O
Preparation of N-debenzoyl-N-(4-methoxybenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol.
To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol)) in 2 mL of THF at -95 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1-(4-methoxybenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (630 mg, 1.43 mmol) in 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 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-N-debenzoyl-N-(4-methoxybenzoyl)-3'-desphenyl-3'-(9-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 330 mg (0.289 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 98~ 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 255 mg of material which was purified by Flash chromatography to give 183 mg (705) of N-debenzoyl-N-(4-:~.ethcxybenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water.
;n. p . 174-175 °C: [OC] zSVa -50 . 6° (c 0 . O1, CHC13) .
vH ~JMR (CDC13, 300 MHz) S 8.13 (d, J ~ 7.1 Hz, 2H, benzoate ortho), 7.69 (d, J = 8.8 Hz, 2H, benzamide ortho), 7.62 (m, 1H, aromatic), 7.51 (m, 2H, aromatic), 7.39 (m, 2H, aromatic), 6.90 (m, 9H, aromatic) , 6. 82 (d, J = 8 .2 Hz, 1H, NH) , 6. 27 (s, 1H, H10), 6.20 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.69 (dd, J = 8.2, 2 . 7 Hz, 1H, H3' ) , 5. 67 (d, J = 6. 6 Hz, 1H, H2~3) , 4 . 95 (dd, J =
7 . 7, 1 . 6 Hz, 1H, H5) , 9 .73 (dd, J = 5.5, 2 .7 Hz, 1H, H2' ) , 4 . 40 (ddd, J = 11.0, 6.6, 4.9 Hz, 1H, H7), 4.30 (d, J = 8.24 Hz, 1H, H20ot) , 4 . 19 (d, J = 8.24 Hz, 1H, H20p) , 3 .81 (s, 3H, ArQ~) , 3 . 80 (d, J = 6. 6 Hz, 1H, H3) , 3. 78 (s, 3H, Ark) , 3 . 71 (d, J = 5. 5 fiz, 1H, 2'OH) , 2.54 (ddd, J = 7 .7, 14 .3, 6. 6 Hz, 1H, H60c) , 2 . 97 (d, J = 4 .4 Hz, 1H, 70H) , 2.37 (s, 3H, 4Ac) , 2.31 (m, 2H, H14), 2.23 (s, 3H, lOAc), 1.89 (ddd, J = 11.0, 14 . 3, 1 . 6 Hz, 1H, H6(3) , 1 .79 (br s, 3H, MelB) , 1 . 69 (s, lEi, lOH) , 1 . 67 (s, 3H, Mel9) , 1 .23 (s, 3H, Mel7) , 1 . 13 (s, 3Ei, Mel6) .

Tubulin binding assays were performed using compounds from the previous Examples substantially as set forth in Parness et al., J_Cell BiolOgY 91: 479-487 (1981) and compared to taxol and taxotere. The results are presented in Table 1.

Tubulin Assay Init. Rel.
Comeound Peak Ra Example 1 0 0 60 f33 Taxol 100 98 Taxotere 100 IC50 data were obtained in vitro on a human cancer cell line (HCT 116) which is available from the National Cancer Institute, and a multidrug resistant cell line (HCT/VM46), which is resistant to a variety of hydrophobic agents, including taxol. Cytotoxicity was assessed in fiCT116 and PICT VM46 human colon carcinoma cells by XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenyl-amino)carbonyl. J-2tt-t_etrazol.ium I~ydroxic9e assay (Scudi.ero et al, "Evaluation of_ a soluble t~etrazoliam/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines", Cancer Res 48:9827-4833, 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 IC50 which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 950 nrn) to 50% of that of untreated control cells. The results are presented in Table 2. Lower numbers indicate greater activity.

HCT HCT

Compound 116 VM46 Example 1 .385 2.58 2 .084 1.89 3 .005 0.469 4 .018 0.825 .025 1.38 6 .021 1.7 7 .303 X7.8 8 .014 2.6 9 .014 0.817 .009 2.26 11 .014 1.85 12 .005 0.442 13 .006 0.651 14 .004 0.973 .005 2.17 Taxol 0.004 0.536 Taxotere 0.007 0.246 In view of the above, it will be seen that the several objects are achieved.
As various changes could be made in the above compositions without departing from f:he scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense.

Claims

CLAIMS:

1. A .beta.-lactam of the formula wherein R1 and R3 are independently selected from phenyl, naphthyl , C6H5CHCH- , and Q i s NO2 ; and R2 is hydrogen or hydroxy protecting group.

2. A .beta.-lactam of the formula wherein R1 is selected from phenyl, naphthyl, C6H5CHCH-, and R3 is selected from naphthyl, C6H5CHCH-, and Q i s NO2; and R2 is hydrogen or hydroxy protecting group.

3. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q i s NO2 ; and R2 is hydrogen or hydroxy protecting group.

4. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q i s NO2 ; and R2 is hydrogen or hydroxy protecting group.

5. A .beta.-lactam of the formula wherein R1 and R3 are independently selected from phenyl, naphthyl, C6H5CHCH-, and Q is-Cl, Br, or F; and R2 is hydrogen or hydroxy protecting group.

6. A .beta.-lactam of the formula wherein R1 is selected from phenyl, naphthyl, C6H5CHCH-, and R3 is selected from naphthyl, C6H5CHCH-, and Q is C1, Br, or F; and R2 is hydrogen or hydroxy protecting group.

7. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q is C1, Br, F; and R2 is hydrogen or hydroxy protecting group.

8. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q is C1, Br, F; and R2 is hydrogen or hydroxy protecting group.

9. A .beta.-lactam of the formula wherein R1 is selected from phenyl, naphthyl, C6H5CHCH-, and R3 is selected from naphthyl, C6H5CHCH-, and Q is CH3-, (CH3) 3C-, CH3O-, C1, Br, F, or NO2; and R2 is hydrogen or hydroxy protecting group.

10. A .beta.-lactam of the formula wherein R1 is selected from C6H5CHCH-, and R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q is CH3-, (CH3) 3C-, CH3O-, C1, Br, F, or NO2; and R2 is hydrogen or hydroxy protecting group.

11. A .beta.-lactam of the formula wherein R1 is R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q is Cl, Br, or F; and R2 is hydrogen or hydroxy protecting group.

12. A .beta.-lactam of the formula wherein R1 is R3 is selected from naphthyl, C6H5CHCH-, and Q is Cl, Br, or F; and R2 is hydrogen or hydroxy protecting group.

13. A .beta.-lactam of the formula wherein R1 is selected from phenyl, naphthyl, C6H5CHCH-, and R3 is Q is Cl, Br, or F; and R2 is hydrogen or hydroxy protecting group.

14. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is Q is C1, Br, or F; and R2 is hydrogen or hydroxy protecting group.

15. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is Q is Cl, Br, or F; and R2 is hydrogen or hydroxy protecting group.

16. A .beta.-lactam of the formula wherein R1 is R3 is selected from phenyl, naphthyl, C6H5CHCH-, and Q is NO2; and R2 is hydrogen or hydroxy protecting group.

17. A .beta.-lactam of the formula wherein R1 is R3 is selected from naphthyl, C6H5CHCH-, and Q is NO2; and R2 is hydrogen or hydroxy protecting group.

18. A .beta.-lactam of the formula wherein R1 is selected from phenyl, naphthyl, C6H5CHCH-, and R3 is Q i s NO2; and R2 is hydrogen or hydroxy protecting group.

19. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is Q i s NO2; and R2 is hydrogen or hydroxy protecting group.

20. A .beta.-lactam of the formula wherein R1 is selected from naphthyl, C6H5CHCH-, and R3 is Q i s NO2; and R2 is hydrogen or hydroxy protecting group.

21. A process for the preparation of a .beta.-lactam of the formula or an enantiomer or diastereoisomer thereof, which process comprises cyclocondensing a compound having the structure with an imine having the structure to form an azetidine having the structure treating said azetidine with an acyl chloride of formula R3C(C)Cl in the presence of a base to form the .beta.-lactam of formula (4), wherein R1 and R3 are independently selected from phenyl, naphthyl, C6H5CHCH-, and Q is CH3-, (CH3)3C-, CH3O-, Cl, Br, F, or NO2; and R2 is hydrogen or hydroxy protecting group;
R11 is trialkylsilyl or triarylsilyl;
R22 is alkyl; and M is a metal.

22. The process of claim 21, wherein R2 is trialkylsilyl or triarylsilyl; R11 is trimethylsilyl; R22 is ethyl; and M is lithium.

23. The process of claim 21 or 22, wherein R3 is selected from the group comprising naphthyl, C6H5CHCH-, and

24. The process of claim 21 or 22, wherein R1 is selected from the group comprising C6H5CHCH-, and

25. The process of claim 21 or 22, wherein R1 is and Q is Cl, Br or F.

26. The process of claim 21 or 22, wherein R3 is and Q is Cl, Br or F.

27. The process of claim 21 or 22, wherein R1 is and Q i s -NO2.

28. The process of claim 21 or 22, wherein R3 is and Q i s -NO2.