The present invention provides paclitaxel derivatives of formula I ##STR1## in which R.sup.1 is --COR.sup.z, in which R.sup.z is RR.sup.o N--, RHN--, RO-- or R; R.sup.2 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 cycloalkyl, or a radical of the formula --W--R.sup.x in which W is a bond, C.sub.2-6 alkenediyl, or --(CH.sub.2).sub.t --, in which t is one to six; and R.sup.x is naphthyl, phenyl, or heteroaryl, and furthermore R.sup.x can be optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups; R and R.sup.o are independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, or phenyl, optionally substituted with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups. Also provided by this invention are pharmaceutical formulations (compositions) and a method of treating mammalian tumors with a compound of formula I.

FIELD OF INVENTION 
The present invention provides compounds having antitumor activities. 
BACKGROUND OF INVENTION 
TAXOL.RTM. (paclitaxel) was first isolated from the stem bark of Western 
Yew, Taxus brevifolia Nut. (Taxaceae) and has the following structure 
(with the (C)2'-, 6-, 7-, and 13th-positions indicated): 
##STR2## 
It was recently approved for the treatment of ovarian cancer; and studies 
involving breast, colon, and lung cancers have shown promising results. 
Paclitaxel is unique among antimitotic drugs in that it promotes the 
assembly of stable microtubules from tubulin even under otherwise 
unfavorable conditions. The drug binds to microtubules, stabilizing them 
from depolymerization, thus disrupting the tubulin-microtubule equilibrium 
and consequently inhibiting mitosis. The mechanism of action, toxicology, 
clinical efficacy, etc. of paclitaxel are reviewed in a number of 
articles, such as in the article by Rowinsky et al. in Taxol: A Novel 
Investigational Antimicrotubule Agent, J. Natl. Cancer Inst., 82: pp 
1247-1259 (1990); and in "The Clinical Pharmacology and Use of 
Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac, Ther., 
52:35-84 (1991). 
Since the discovery of its significant effectiveness in cancer treatment, 
many laboratories have launched programs to design paclitaxel analogues in 
search of better pharmacological profiles. Out of such programs, for 
example, was the discovery of Taxotere.RTM. of the formula 
##STR3## 
See, Biologically Active Taxol Analogues with Deleted A-Ring Side Chain 
Substitutents and Variable C-2' Configurations, J. Med. Chem., 34, pp 
1176-1184 (1991); Relationships between the Structure of Taxol Analogues 
and Their Antimitotic Activity, J. Med. Chem., 34, pp 992-998 (1991). 
The present invention relates to structurally novel paclitaxel derivatives 
with antitumor activities. 
SUMMARY OF INVENTION 
The present invention provides paclitaxel derivatives of formula I 
##STR4## 
in which 
R.sup.1 is --COR.sup.z, in which R.sup.z is RR.sup.o N--, RHN--, RO-- or R; 
R.sup.2 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 
cycloalkyl, or a radical of the formula --W--R.sup.x in which W is a bond, 
C.sub.2-6 alkenediyl, or --(CH.sub.2).sub.t --, in which t is one to six; 
and R.sup.x is naphthyl, phenyl, or heteroaryl, and furthermore R.sup.x 
can be optionally substituted with one to three same or different 
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups; 
R and R.sup.o are independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, 
C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, or phenyl, optionally substituted 
with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 
halogen or --CF.sub.3 groups. 
Also provided by this invention are pharmaceutical formulations 
(compositions) and a method of treating mammalian tumors with a compound 
of formula I.

DETAILED DESCRIPTION OF INVENTION 
The present invention provides paclitaxel derivatives of formula I 
##STR5## 
in which 
R.sup.1 is --COR.sup.z, in which R.sup.z is RR.sup.o N--, RHN--, RO-- or R; 
R.sup.2 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-6 
cycloalkyl, or a radical of the formula --W--R.sup.x in which W is a bond, 
C.sub.2-6 alkenediyl, or --(CH.sub.2).sub.t --, in which t is one to six; 
and R.sup.x is naphthyl, phenyl, or heteroaryl, and furthermore R.sup.x 
can be optionally substituted with one to three same or different 
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen or --CF.sub.3 groups; 
R and R.sup.o are independently C.sub.1-6 alkyl, C.sub.2-6 alkenyl, 
C.sub.3-6 cycloalkyl, C.sub.2-6 alkynyl, or phenyl, optionally substituted 
with one to three same or different C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 
halogen or --CF.sub.3 groups. 
In the instant application, the numbers in subscript after the symbol "C" 
define the number of carbon atoms a particular group can contain. For 
example, C.sub.1-6 alkyl refers to straight and branched chain alkyl 
groups with one to six carbon atoms and such groups include methyl, ethyl, 
n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, 
or the like alkyl groups; C.sub.2-6 alkenyl refers to straight or branched 
alkenyl groups such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 
2-butenyl, 3-butenyl, methallyl, 1,1-dimethylallyl, 1-hexenyl, 2-hexenyl, 
or the like groups; C.sub.3-6 cycloalkyl refers to cyclopropyl, 
cyclobutyl, cyclopentyl, or cyclohexyl; C.sub.2-6 alkynyl refers to 
straight or branched alkynyl groups such as ethynyl, propargyl 
(2-propynyl), 1-propynyl, 2-butynyl, 3-butynyl, 1-hexynyl, 
4-methyl-2-pentynyl, and the like groups; C.sub.2-6 alkenediyl refers to 
groups such as ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl, 
2-hexene-1,6-diyl, and the like groups; C.sub.1-6 alkyloxy (alkoxy) refers 
to straight or branched alkyloxy groups such as methoxy, ethoxy, 
n-propoxy, i-propoxy, n-butoxy, t-butoxy (t-butyloxy), n-pentyloxy, 
n-hexyloxy, or 3-methylpentyloxy, to name a few; heteroaryl refers to a 
five-membered aromatic ring containing at least one heteroatom selected 
from sulfur, oxygen or nitrogen, but up to 1 sulfur, 1 oxygen or 4 
nitrogen atoms; heteroaryl also refers to a six-membered aromatic ring 
containing from 1 to 4 nitrogen atoms; and halogen refers to fluorine, 
chlorine, bromine, or iodine. Examples of heteroaryl include thienyl, 
furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, 
isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, 
thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 
triazinyl, tetrazinyl, and like rings. Azetidinone refers to 
azetidin-2-one. In the instant application all symbols once defined retain 
the same meaning until they are redefined. 
The synthesis of a compound of formula I can be accomplished by a wide 
variety of methods. The synthetic methods, descriptions and specific 
examples that follow are only intended for the purpose of illustration, 
and are not to be construed as limiting in any manner ways to make 
compounds of the present invention by any other methods. The methods 
disclosed herein can be readily modified and/or adapted to make additional 
compounds of formula I not specifically disclosed. 
In one embodiment, compound of formula Ia can be made by a process of 
Scheme I. In Step (a) of the Scheme, when compound of formula IIa is 
treated with DAST, compound of formula IIIa can be obtained. The DAST 
reaction can be conducted in a wide variety of solvents, including 
methylene chloride, tetrahydrofuran (THF), diethyl ether, toluene, and any 
combination thereof. In addition to compound IIIa, compounds of formula 
IVa and Va may be obtained as side products in the DAST reaction. It has 
been observed that the highest ratio of compound IIIa to compound IVa or 
Va is obtained when the reaction is run in a mixture of THF and toluene. 
In Step (b), compound IIIa is treated with dimethyldioxirane to afford 
epoxide of formula VIa. The oxidation with dimethyldioxirane can be 
conducted in a variety of solvents such as dichloromethane, 
1,2-dichloroethane, tetrahydrofuran, methanol, ethyl acetate, acetic acid, 
methyl ethyl ketone, or a mixture of any of the aforementioned with 
acetone. The most desirable condition is in acetone at a temperature 
between -20.degree. C. to 5.degree. C. Upon removal of Cbz group from 
compound of formula VIa in Step (c), compound of formula Ia is obtained. 
In a more general embodiment of Scheme II, when compound of formula Ia is 
treated with an ester reducing agent such as tetrabutylammonium 
borohydride in Step (a), C-13 side chain is reductively cleaved to afford 
compound of formula VIIIa. In Step (b), azetidinone VII, in which R.sup.3 
is a hydroxy protecting group, is reacted with compound VIIIa to afford a 
compound of formula VI. Reactions analogous to Step (b) are well known, 
and Step (b) can be carried out in substantially the same manner as 
described in European Patent Applications 0,400,971 A2, 0,534,709 A1, 
0,534,708 A1, and 0,534,707 A1; Tetrahedron, 48, No. 34, pp 6985-7012 
(1992); Bioorganic and Medicinal Chemistry Letters, 3, No. 11, pp 
2467-2470, pp 2479-2482 (1993); and Tetrahedron Letters, 34, No. 26, pp 
4149-4152 (1993). These references describe the reaction of class of 
azetidinones of formula VII with (C)13-hydroxy group of baccatin III 
derivatives or metal alkoxide thereof to afford paclitaxel analogues with 
a variety of (C)13-side chains. 
For example, the coupling reaction between a taxane of formula VIIIa and an 
azetidinone of formula VII is conducted in an inert organic solvent such 
as tetrahydrofuran at reduced temperature in the range of about 0.degree. 
C. to about -78.degree. C. The azetidinones of formula VII may be used as 
a racemic mixture; in such case, the azetidinone reactant is preferably 
used in at least 2 equivalents relative to the taxane reactant, and more 
preferably from about 3 to about 6 equivalents. Chiral azetidinones may 
also be used, and in such case one equivalent of the azetidinone relative 
to the taxane may be sufficient, but preferably the azetidinone is used in 
slight excess, for example up to 1.5 equivalents. 
Furthermore, for Step (b) of Scheme II, it is advantageous to convert the 
hydroxy group on the (C)13-carbon into a metal alkoxide before the 
coupling. The metal cation of said metal alkoxide is preferably selected 
from Group Ia or IIa metals. The formation of a desired metal alkoxide may 
be done by reacting a compound of formula VIIIa with a strong metal base, 
such as lithium diisopropylamide, C.sub.1-6 alkyllithium, lithium 
bis(trimethylsilyl)amide, phenyllithium, sodium hydride, potassium 
hydride, lithium hydride, or the like base. For example when lithium 
alkoxide is desired, a compound of formula VIIIa may be reacted with 
n-butyllithium in an inert solvent such as tetrahydrofuran. 
The general class of azetidinones of formula VII are also well known. Their 
syntheses or syntheses of their precursors have been reported such as by 
Holton in European Patent Application 0,400,971 A2 published on Dec. 5, 
1990; by Holton in European Patent Applications 0,534,709 A1, 0,534,708 
A1, and 0,534,707 A1, all three published on Mar. 31, 1993; also by 
Holton in PCT application WO 93/06079 published on Apr. 1, 1993; and in 
Bioorganic and Medicinal Chemistry Letters, 3, No. 11, pp 2475-2478 
(1993); by Ojima et al. in Tetrahedron, 48, No. 34, pp 6985-7012 (1992); 
Journal of Organic Chemistry, 56, pp 1681-1683 (1991); Bioorganic and 
Medicinal Chemistry Letters, 3, No. 11, pp 2479-2482 (1993); and 
Tetrahedron Letters, 33, No. 39, pp 5737-5740 (1992); by Brieva et al. in 
J. Org. Chem., 58, pp 1068-1075; by Palomo et al. in Tetrahedron Letters, 
31, No. 44, pp 6429-6432 (1990); by Gunda I. Georg et al in Bioorganic and 
Medicinal Chemistry Letters, 3, No. 11, pp 2467-2470 (1993); European 
Application 552,041 published on Jul. 21, 1993; and in our copending U.S. 
application Ser. No. 092,170 filed on Jul. 14, 1993: all aforementioned 
disclosures are herein incorporated by reference in their entirety. The 
methods that can be easily adapted to variations in order to produce other 
azetidinones within the scope of formula VII, but not specifically 
disclosed herein or in the above references or reported elsewhere, will be 
obvious to anyone skilled in the art. 
Upon removal of hydroxy protecting group R.sup.3 in Step (c), a compound of 
formula I can be obtained. As used herein, hydroxy protecting groups are 
moieties which can be employed to block or protect the hydroxy function 
and they are well known to those skilled in the art. Preferably, said 
groups are those which can be removed by methods which result in no 
appreciable destruction to the remaining portion of the molecule. Examples 
of such readily removable hydroxy protecting groups include chloroacetyl, 
methoxymethyl, 2,2,2-trichloroethyoxymethyl, 
2,2,2-trichloroethyloxycarbonyl, tetrahydropyranyl, tetrahydrofuranyl, 
t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, 
triC.sub.1-6 alkylsilyl, triphenylsilyl, 1-ethoxyethyl, and the like. 
Preferred protecting groups for the 2'-hydroxy group of paclitaxel and a 
derivative thereof are 1-ethoxyethyl, triethylsilyl, 
2,2,2-trichloroethyloxycarbonyl and benzyloxycarbonyl; even more preferred 
group is benzyloxycarbonyl, which can be removed conveniently by catalytic 
hydrogenolysis. Other suitable protecting groups which can be used are 
found in Chapter 2 of "Protecting Groups in Organic Synthesis", Second 
Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons); 
the disclosure thereof is herein incorporated by reference. 
##STR6## 
DESCRIPTION OF SPECIFIC EMBODIMENTS 
The structural formulae as drawn in the instant application are believed to 
best represent the structures of compounds of the present invention. 
However, some compounds within the scope of the invention may exist as 
other tautomeric forms, in which hydrogen atoms are transposed to other 
parts of the molecules and the chemical bonds between the atoms of the 
molecules are consequently rearranged. It should be understood that the 
structural formulae represent all tautomeric forms, insofar as they may 
exist. 
The specific examples which follow illustrate the synthesis of 
representative compounds of the instant invention and are not to be 
construed as limiting the invention in sphere or scope. The methods may be 
adapted to variations in order to produce compounds embraced by this 
invention but not specifically disclosed. Further, variations of the 
methods to produce the same compounds in somewhat different fashion will 
also be evident to one skilled in the art. 
All temperatures are understood to be in Centigrade (C) when not specified. 
The nuclear magnetic resonance (NMR) spectral characteristics refer to 
chemical shifts (.delta.) expressed in parts per million (ppm) versus 
tetramethylsilane (TMS) as reference standard. The relative area reported 
for the various shifts in the proton NMR spectral data corresponds to the 
number of hydrogen atoms of a particular functional type in the molecule. 
The nature of the shifts as to multiplicity is reported as broad singlet 
(bs), broad doublet (bd), broad triplet (bt), broad quartet (bq), singlet 
(s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of 
doublet (dd), doublet of triplet (dr), and doublet of quartet (dq). The 
solvents employed for taking NMR spectra are DMSO-d.sub.6 
(perdeuterodimethylsulfoxide), D.sub.2 O (deuterated water), CDCl.sub.3 
(deuterochloroform) and other conventional deuterated solvents. The 
infrared (IR) spectral description include only absorption wave numbers 
(cm.sup.-1) having functional group identification value. 
Celite is a registered trademark of the Johns-Manville Products Corporation 
for diatomaceous earth. 
The abbreviations used herein are conventional abbreviations widely 
employed in the art. Some of which are: 
CAN: ceric ammonium nitrate 
MS: mass spectrometry 
HRMS: high resolution mass spectrometry 
DAST: diethylaminosulfur trifluoride 
Ac: acetyl 
Ph: phenyl 
Ar: aryl 
DCI: desorption chemical ionization 
Y: yield 
v/v: volume/volume 
FAB: fast atom bombardment 
NOBA: m-nitrobenzylalcohol 
min: minute(s) 
h: hour(s) 
tBu: tertiarybutyl 
Cbz: benzyloxycarbonyl 
Bz: benzoyl 
TES: triethylsilyl 
EXAMPLE 1 
2'-O-(Benzyloxycarbonyl)paclitaxel (IIa) 
##STR7## 
To a stirred, room temperature solution of paclitaxel (150 mg, 0.176 mmol) 
and N,N-diisopropylethylamine (93 .mu.L, 0.534 mmol, 3 eq.) in anhydrous 
CH.sub.2 Cl.sub.2 (4 mL) was added benzyl chloroformate (75 .mu.L, 0.525 
mmol, 3 eq.) at room temperature. The reaction mixture was stirred at room 
temperature for 3 h. The reaction mixture was concentrated to 2 mL in 
volume and the product was purified on a silica gel column, using 1:1 of 
EtOAc/hexanes as eluent, to obtain 150 mg (0.152 mmol, Y: 86%) of the 
title compound, IIa, as a white powder; mp, 140.degree.-150.degree. C. 
(decomposition); [.alpha.].sub.D.sup.20 -53.5.degree. (c=0.2, 95% EtOH); 
.sup.1 H-NMR (300 MHz, acetone-d.sub.6) .delta. ppm: 1.18 (3H, s, 
17-H.sub.3), 1.92 (3H, s, 16-H.sub.3), 1.66 (3H, s, 19-H.sub.3), 1.96 (3H, 
s, 18-H.sub.3), 2.16 (3H, s, 10-OAc), 2.5 (3H, s, 4-OAc), 3.53 (1H, d, 
J=5.89 Hz, 7-OH, exchanged with D.sub.2 O), 3.85 (1H, d, J=7.19 Hz, 3-H), 
3.9 (1H, s, 1-OH, exchanged with D.sub.2 O), 4.17 (2H, ABq, 20-H.sub.2), 
4.25 (1H, m, 7-H), 4.97 (1H, d, J=9.56 Hz, 5-H), 5.19 (2H, ABq, OCH.sub.2 
C.sub.6 H.sub.5), 5.54 (1H, d, J=5.5 Hz, 2'-H), 5.68 (1H, d, J=7.13 Hz, 
2-H), 6.01 (1H, dd, J=5.5, 9.05 Hz, 3'-H), 6.17 (1H, bt, J=9.0 Hz, 13-H), 
6.42 (1H, s, 10-H), 7.28-7.69 (16H, m), 7.87 (2H, "d", J=8 Hz, 3'-NHCOPh), 
8.14 (2H, "d", J=8 Hz, 2-CO.sub.2 Ph), 8.55 (1H, d, J=9.06 Hz, NH, 
exchanged with D.sub.2 O); MS (FAB-NOBA/NaI+KI) m/e: 988 (M+H).sup.+, 1010 
(M+Na).sup.+, 1026 (M+K).sup.+ ; IR (KBr) .nu. max: 3448, 1748 (C.dbd.O), 
1726 (CONH), 1250 (C-O) cm.sup.-1 ; UV (MeOH:H.sub.2 O, 1:1) .lambda. max: 
198 (.epsilon. 7.3.times.10.sup.4), 230 nm (.epsilon. 2.7.times.10.sup.4 ; 
HRMS calcd for C.sub.55 H.sub.58 NO.sub.16 (MH.sup.+): 988.3756, found: 
988.3766. 
Anal. calcd for C.sub.55 H.sub.57 NO.sub.16 -H.sub.2 O: C, 65.67; H, 5.92; 
N, 1.40. Found: C, 65.99; H, 5.64; N, 1.33. 
EXAMPLE 2 
2'-O-Benzyloxycarbonyl-6,7-dehydropaclitaxel (IIIa) 
##STR8## 
2'-O-(Benzyloxycarbonyl)paclitaxel (IIa) (514 mg, 0.521 mmol) was dissolved 
in THF (3 mL) and Et.sub.2 O (6 mL). This solution was cooled to 
-78.degree. C. and DAST (0.134 mL, 1.040 mmol) was added dropwise. The 
reaction was stirred at -78.degree. C. for 3 h, and then left at room 
temperature overnight. When the reaction was complete, the solvent was 
partially removed in vacuo, and the residue was chromatographed with 
30-40% EtOAc in hexane to afford 73 mg (Y: 14.5%) of the desired product; 
.sup.1 H-NMR (CDCl.sub.3, 300 MHz) .delta. ppm: 8.15 (d, J=7.1 Hz, 2H), 
7.71 (d, J=7.1 Hz, 2H) 7.63- 7.24 (m, 16H) 6.90 (d, exch, J=9.3 Hz, 1H) 
6.25 (bt, 1H) 6.21 (s, 1H) 6.05 (dd, J.sub.1 =9.9 Hz, J.sub.2 =5.6 Hz, 1H) 
5.96 (dd, J.sub.1 =9.9 Hz, J.sub.2 =2.7 Hz, 1H) 5.86 - 5.82 (m, 2H) 5.42 
(d, J=2.5 Hz, 1H) 5.18- 5.09 (m, 3H) 4.37 (AB q, J=8.2 Hz, 2H) 4.00 (d, 
J=6.6 Hz, 1H) 2.48-1.12 (m, 21H, including s at 2.44, 3H; 2.18, 3H; 1.86, 
3H; 1.84, 3H; 1.23 3H; 1.13, 3H); .sup.13 C-NMR (CDCl.sub.3, 75 MHz) 
.delta. ppm: 205.5, 169.5, 169.1, 167.8, 167.1, 167.0, 154.1, 141.9, 
139.9, 136.8, 134.3, 133.7, 133.5, 132.0, 130.2, 129.2, 129.1, 128.9, 
128.7, 128.4, 127.2, 126.6, 126.2, 81.2, 81.1, 78.8, 76.9, 76.3, 75.9, 
75.7, 71.9, 70.7, 55.4, 52.7, 43.1, 41.4, 35.8, 26.4, 22.8, 22.1, 21.0, 
20.8, 20.5, 14.5. 
Alternate Run 2'-O-(Benzyloxycarbonyl)paclitaxel (IIa) (2.0 g, 2.04 mmol) 
was dissolved in toluene/THF (4:1, 50 mL) and cooled to -78.degree. C. 
under an inert atmosphere. To this was added DAST (0.69 mL, 5.1 mmol) and 
the resulting solution was allowed to gradually warm to ambient 
temperature over a 16 h period. The solution was quenched with saturated 
aqueous sodium bicarbonate and diluted with ethyl acetate. The organic 
fraction was then dried (MgSO4) and concentrated to furnish a crude 
mixture. The desired product was isolated by chromatography (silica gel, 
10% acetonitrile in dichloromethane) to furnish the title product as a 
white solid (410 mg, yield 21%). 
EXAMPLE 3 
2'-O-Benzyloxycarbonyll-6,7-.alpha.-epoxypaclitaxel (VIa) 
##STR9## 
A solution of compound IIIa (200 mg, 0.2 mmol) in acetone (1 mL) was cooled 
to -20.degree. and treated with a 0.14M acetone solution of freshly 
prepared dimethyldioxirane (5 mL, 0.7 mmol). The resulting solution was 
placed in a freezer (-20.degree. C.) and allowed to stand overnight. The 
solution was then evaporated. (.sup.1 H-NMR indicated that the reaction 
proceeded to give 30% of the desired product.) The crude material was then 
treated with additional dimethyldioxirane, as described above, until 
.sup.1 H-NMR indicated completion of the reaction. Evaporation of the 
solvent furnished the desired epoxide as a white solid (200 mg, 100%); 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta. 8.09 (d, 2H, J=21.0 Hz), 7.70 
(d, 2H, J=21.0 Hz), 7.58-7.23 (complex m, 16H), 6.93 (d, 1H, J=12.0 Hz), 
6.45 (s, 1H), 6.27-6.21 (m, 1H), 5.98 (dd, 1H, J=2.3, 9.4 Hz), 5.83 (d, 
1H, J=9.6 Hz), 5.47-5.43 (m, 2H), 5.14-5.09 (m, 2H), 4.41 (ABq, 2H, J-9.0, 
105.0 Hz), 3.95 (d, 1H, J=6.0 Hz), 3.24 (t, 1H, J=3.0 Hz), 3.01 (d, 1H, 
J=3.0 Hz), 2.64-2.56 (m, 1H), 2.52 (s, 3H), 2.65-2.17 (m, 4H, including 
singlet at 2.23), 1.98 (s, 3H), 1.88-1.72 (m, 4H, including singlet at 
1.86), 1.22 (s, 3H), 1.13 (s, 3H); .sup.13 C-NMR (75.6 MHz, CDCl.sub.3): 
.delta. 204.6, 169.3, 168.2, 167.9, 167.2, 166.7, 154.0, 142.1, 136.7, 
134.3, 133.7, 133.5, 133.0, 132.0, 130.2, 129.9, 129.0, 128.8, 128.7, 
128.5, 128.4, 128.3, 128.2, 128.1, 127.1, 126.5, 81.6, 81.2, 81.0, 78.7, 
78.2, 76.6, 76.5, 75.9, 75.7, 74.7, 71.9, 70.7, 66.9, 59.9, 53.4, 52.6, 
51.1, 43.2, 38.9, 35.3, 26.1, 22.9, 22.8, 22.0, 21.8, 20.7, 20.4, 15.4, 
14.6, 14.4. 
EXAMPLE 4 
6,7-.alpha.-Epoxypaclitaxel (Ia) 
##STR10## 
A solution of compound VIa (190 mg, 0.19 mmol) in ethyl acetate (4 mL) was 
flushed with argon in a Parr bottle and treated with palladium on carbon 
(12.0 mg). The resulting suspension was shaken under 50 psi of hydrogen 
for 3 h then was vented and filtered through a plug of celite. The 
filtrate was then evaporated and the residue was purified by silica gel 
chromatography (hexanes/ethyl acetate 1:1) to furnish the desired product 
as a white solid (126.6 mg, 77.6%). m.p. 186.degree.-187.degree. C.; 
.sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta. 8.07 (d, 2H, J=9.0 Hz), 
7.79-7.73 (m, 2H), 7.61-7.25 (complex m, 11H), 7.15 (d, 1H, 12.0 Hz), 6.42 
(s, 1H), 6.19-6.16 (m, 1H), 5.82 (dd, 1H, J=2.2, 9.3 Hz), 5.73 (d, 1H, 
J=6.0 Hz), 5.34 (d, 1H, J=3 Hz), 4.80-4.78 (m, 1H), 4.36 (ABq, 2H, J=9.0, 
65.0 Hz), 4.02 (d, 1H, J=6.0 Hz), 3.79 (d, 1H, J=3.0 Hz), 3.25 (t, 1H, 
J=3.0 Hz), 3.01 (d, 1H, J=3.0 Hz), 2.39-2.33 (m, 5H), 2.22 (s, 3H), 1.87 
(s, 3H), 1.80-1.66 (m, 5 H), 1.24-1.14 (m, 5H); .sup.13 C-NMR (75.6 MHz, 
CDCl.sub.3): .delta. 204.2, 172.0, 169.0, 141.4, 138.1, 133.8, 133.4, 
131.9, 129.9, 128.9, 128.8, 128.7, 128.2, 127.1, 127.0, 81.8, 78.9, 78.0, 
77.4, 74.5, 73.3, 71.8, 59.6, 54.6, 53.8, 51.2, 43.0, 38.8, 35.5, 26.1, 
22.8, 21.2, 20.7, 15.3, 14.7. 
EXAMPLE 5 
6,7-.alpha.-Epoxy Baccatin III (VIlla) 
##STR11## 
A solution of 6,7-.alpha.-epoxypaclitaxel (99 mg, 0.1 mmol) in 
dichloromethane/2% methanol (6 mL) was treated with tetrabutylammonium 
borohydride (59.7 mg, 0.2 mmol) and the resulting solution was allowed to 
stir at ambient temperature for 5 h. The reaction was quenched by addition 
of saturated aqueous ammonium chloride (2 mL) and the organic fraction was 
dried (MgSO.sub.4) and concentrated. The crude product was chromatographed 
on silica gel (eluted with 10% CH.sub.3 CN in CH.sub.2 Cl.sub.2) to 
furnish the desired product as a white foam (44.7 mg, 66%); .sup.1 H-NMR 
(300 MHz, CDCl.sub.3): .delta. 8.07-8.04 (m, 2H), 7.63-7.5 (m, 1H), 
7.50-7.44 (m, 2H), 6.44 (s, 1H), 5.68 (d, 1H, J=6.0 Hz), 5.32 (d, 1 H, 
J=2.7 Hz), 4.82 (broad q, 1H, J=6.0, 15.0 Hz), 4.34 (ABq, 2H, J=9.0, 63.0 
Hz), 4.14 (d, 1H, J=6.0 Hz), 3.45 (s, 1H), 3.24 (t, 1H, J=3.0 Hz), 3.00 
(d, 1H, J=3.0 Hz), 2.33-2.14 (m, 7H, including singlets at 2.28, 2.22), 
2.10 (s, 3H), 1.84-1.69 (m, 5H including singlets at 1.84, 1.72), 1.09 (s, 
6H); .sup.13 C-NMR (75.6 MHz, CDCl.sub.3): .delta. 204.6, 170.0, 169.4, 
166.7, 145.9, 133.7, 132.0, 130.0, 129.9, 129.1, 128.6, 82.0, 78.9, 78.1, 
77.4, 77.3, 74.5, 68.0, 59.6, 53.4, 51.2, 42.7, 39.0, 38.7, 26.0, 22.8, 
20.8, 15.2, 14.9. 
EXAMPLE 6 
3'-N-Debenzoyl-N-t-butoxycarbonyl-3'-desphenyl-3'-(2-furyl)-6,7-.alpha.-epo 
xypaclitaxel (Ib) 
##STR12## 
A solution of compound VIIIa (475.0 mg, 0.81 mmol) in dry THF (15 mL) was 
cooled to -55.degree. C. under an inert atmosphere and treated with a 
solution of lithium hexamethyldisilazane (1M in THF, 0.97 mL, 0.97 mmol). 
The resulting solution was allowed to stir for 5 min, then a THF solution 
(3 mL) of 
(3R,4R)-3-triethylsilyloxy-4-(2-furyl)-N-t-butoxycarbonylazetidin-2-one 
(295.0 mg, 0.81 mmol) was added over 5 min. The resulting solution was 
allowed to stir at -55.degree. C. for 10 min then the reaction was warmed 
to 0.degree. C. and allowed to stir for 30 min. The reaction was then 
quenched by addition of saturated NH.sub.4 Cl solution, transferred to a 
separatory funnel and extracted with ethyl acetate. The organic fraction 
was dried (MgSO.sub.4) and concentrated to give 2'-O-triethylsilyl 
protected taxane as a white foam. 
This crude product was then dissolved in acetonitrile (6 mL) and cooled to 
0.degree. C. in an ice bath. To this solution was added an aqueous 
solution of HCl (1M, 2.4 mL, 2.4 mmol). The resulting solution was allowed 
to stir at that temperature for 1.5 h then was quenched with saturated 
aqueous NaHCO.sub.3 and extracted with ethyl acetate. The organic fraction 
was then dried (MgSO.sub.4) and concentrated to give the product as a 
white foam. The crude product was purified by silica gel chromatography 
(eluted with hexanes/ethyl acetate 1:1) to furnish 467.6 mg (74% overall) 
of compound Ib as a white foam. 
The entire reaction can be repeated with racemic form of lactam VIIa. In 
such case 4-5 equivalents of lactam VIIa is used for 100% 
diastereoselection to afford the desired isomer Ib; .sup.1 H-NMR (300 MHz, 
CDCl.sub.3): .delta. 8.06 (d, 2H, J=9.0 Hz), 7.61 (t, 1H, J=6.0 Hz), 7.48 
(t, 2H, J=9.0 Hz), 7.41 (s, 1H), 6.47 (s, 1H), 6.38-6.36 (m, 1H)), 
6.32-6.31 (m, 1H), 6.20-6.17 (m, 1H), 5.75 (d, 1H, J=6.0 Hz), 5.39-5.25 
(m, 3H), 4.38 (ABq, 2H, J=6.0, 81.0 Hz), 4.02 (d, 1H, J=6.0 Hz), 3.26 (t, 
1H, J=3.0 Hz), 3.03 (d, 1H, J=3.8 Hz), 2.47-1.16 (complex m, 32H, 
including singlets at 2.33, 2.21, 1.99, 1.93, 1.87, 1.38, 1.25); .sup.13 
C-NMR (75.6 MHz, CDCl.sub.3): .delta. 204.2, 169.3, 168.6, 166.7, 155.2, 
151.4, 149.6, 142.3, 141.1, 136.0, 133.7, 133.2, 129.9, 129.0, 128.6, 
110.6, 107.3, 81.8, 80.3, 78.6, 78.1, 74.6, 72.2, 71.7, 59.7, 53.6, 51.7, 
51.1, 43.1, 38.8, 35.2, 29.6, 28.1, 25.9, 22.7, 21.5, 20.7, 15.3, 14.7. 
EXAMPLE 7 
3'-Desphenyl-3'-(2-furyl)-6,7-.alpha.-epoxypaclitaxel (Ic) 
##STR13## 
The title compound was prepared in an identical manner to compound Ib of 
Example 6 by using 5-6 equivalents of 
(.+-.)-cis-3-triethylsilyloxy-4-(2-furyl)-N-benzoylazetidin-2-one. The 
desired product was isolated as a white foam; .sup.1 H-NMR (300 MHz, 
CDCl.sub.3): .delta. 8.05 (d, 2H, J=7.6 Hz), 7.74 (d, 2H, J=7.2 Hz), 7.60 
(t, 1H, J=7.2 Hz), 7.52-7.38 (m, 5H), 6.93 (d, 1H, J=9.3 Hz), 6.43 (s, 
1H), 6.37 (s, 2H), 6.18 (t, 1H, J=8.2 Hz ), 5.88 (dd, 1H, J=2.2, 9.3 Hz), 
5.73 (d, 1H, J=6.0 Hz), 5.36 (d, 1H, J=3.0 Hz), 4.81 (bs, 1H), 4.49 (d, 
1H, J=8.0 Hz), 4.24 (d, 1H, J=8.0 Hz), 4.01 (d, 1H, J=6.0 Hz), 3.65 (bs, 
1H), 3.25 (t, 1H, J=3.0 Hz), 3.01 (d, 1H, J=4.0 Hz), 2.50-2.30 (m, 6H), 
2.21 (s, 3H), 1.87-1.86 (m, 6 H), 1.21 (s, 3H), 1.13 (s, 3H); .sup.13 
C-NMR (75.6 MHz, CDCl.sub.3): .delta. 204.3, 171.9, 169.3, 168.9, 166.9, 
166.7, 150.9, 142.6, 141.4, 133.8, 133.5, 132.0, 130.0, 129.0, 128.7, 
127.0, 110.7, 107.9, 81.8, 78.8, 78.1, 76.5, 74.5, 72.0, 71.7, 59.7, 53.7, 
51.2, 50.3, 43.1, 38.8, 35.4, 26.1, 22.7, 21.3, 20.7, 15.3, 14.7. 
EXAMPLE 8 
3'-N-Debenzoyl-N-t-butoxycarbonyl-3'-desphenyl-3'-isobutenyl-6,7-.alpha.-ep 
oxypaclitaxel (Id) 
##STR14## 
The title compound was prepared in an identical manner to compound Ib of 
Example 6 by using 5-6 equivalents of racemic lactam VIIc. The desired 
product was isolated as a white foam; .sup.1 H-NMR (300 MHz, CDCl.sub.3): 
.delta. 8.07-8.04 (m, 2H), 7.64-7.59 (m, 1H), 7.47 (t, 2H, J=9.0 Hz), 6.47 
(s, 1H), 6.13 (t, 1H, J=9.0 Hz), 5.74 (d, 1H, J=6.0 Hz), 5.38 (d, 1H, 
J=6.0 Hz), 5.28 (d, 1H, J=9.0 Hz), 4.87-4.49 (m, 3H), 4.50 (d, 1H, J=9.0 
Hz), 4.26-4.23 (m, 2H), 4.03 (d, 1H, J=6.0 Hz), 3.45 (t, 1H, J=3.0 Hz), 
3.03 (d, 1H, J=3.8 Hz), 2.40-1.16 (complex m, 35 H, including singlets at 
2.38, 2.23, 1.87, 1.83, 1.75, 1.37, 1.24, 1.16); .sup.13 C-NMR (75.6 MHz, 
CDCl.sub.3): .delta. 204.4, 169.35, 168.64, 166.71, 142.0, 137.9, 136.0, 
133.8, 133.1, 129.9, 129.0, 128.6, 120.7, 81.82, 79.8, 78.6, 78.2, 76.7, 
76.5, 74.6, 73.8, 71.8, 60.7, 59.7, 53.7, 51.4, 51.2, 44.6, 43.1, 38.8, 
35.4, 28.2, 28.0, 25.8, 25.7, 24.8, 24.3, 22.6, 21.4, 21.2, 18.6, 15.3, 
15.8. 
EXAMPLE 9 
Preparation of hydrobenzamide, PhCH(--N.dbd.CHPh)2 
To a 3 L 3-necked flask equipped with a mechanical stirrer and a 
thermometer was added 1 L of concentrated NH.sub.4 OH (ca 30%) (14.8 
moles). A solution of benzaldehyde (265 g, 2.50 mol) in 500 mL of 
2-propanol was added in one portion. The mixture was stirred vigorously at 
ca 22.degree. C. for 43 hours. The resulting slurry was filtered and the 
filter cake was washed with water (1 L). After drying in vacuo, 242.4 g 
of hydrobenzamide was obtained as a white solid (mp 
100.degree.-102.degree. C.) for a 97.4% yield. 
The above procedure can be followed to prepare bis-imines of the general 
formula R.sup.2 CH(--N.dbd.CHR.sup.2).sub.2 : i.e. hydrofuramide (R.sup.2 
=2-furyl) hydrothienamide (R.sup.2 =2-thienyl) 
EXAMPLE 10 
(.+-.)-cis-3-Acetyloxy-1-[(phenyl) 
(benzylidenimino)methyl]-4-phenylazetidn-2-one (IXa) 
##STR15## 
To a 1 L, 3-necked round bottom flask equipped with a thermometer, magnetic 
stirrer and dropping funnel was added hydrobenzamide (30.00 g, 100.5 mmol) 
and ethyl acetate (150 mL). With stirring and under a blanket of argon, 
the reaction mixture was cooled to 5.degree. C. and triethylamine (16.8 
mL, 121 mmol) was added. A solution of acetoxyacetyl chloride (12.4 mL, 
116 mmol) in ethyl acetate (300 mL) was then added dropwise over a 90 min 
period. After 16 h at this temperature, the reaction mixture was allowed 
to warm to 20.degree. C. (1.5 h) and transferred to a separatory funnel. 
The organic layer was washed successively with aqueous NH.sub.4 Cl (sat) 
(150 mL, 100 mL), aqueous NaHCO.sub.3 (saturated) (120 mL) and brine (120 
mL). For purposes of characterization, the title compound can be isolated 
at this stage by drying the organic phase over MgSO.sub.4, filtering, and 
removing the solvent in vacuo. This provided the desired product in 
quantitative crude yield as a red glass. 
HPLC purity (area): 87.9% (1:1 mixture of diastereomers); .sup.1 H-NMR 
(CDCl.sub.3, 200 MHz): .delta. 8.45 (s, 1H, N.dbd.CH), 7.80-7.85 (m, 1H, 
Ph), 7.60-7.65 (m, 1H, Ph), 7.26-7.50 (m, 9H, Ph), 7.00-7.10 (m, 4H, Ph), 
6.28 (s, 0.5H, NCHN), 6.23 (s, 0.5H, NCHN), 5.81 (d, J=4.8 Hz, 0.5 H, 
H-3), 5.76 (d, J=4.8 Hz, 0.5H, H-3), 5.30 (d, J=4.8 Hz, 0.5 H, H-4), 4.75 
(d, J=4.8 Hz, 0.5 H, H-4), 1.63 (s, 3H, CH.sub.3 CO); IR (KBr): .nu. 
(cm.sup.-1)=1763 (C.dbd.O), 1641 (C.dbd.N); UV (methanol): .lambda. max 
(nm)=216, 252. 
EXAMPLE 11 
(.+-.)-cis-3-Acetyloxy-4-phenylazetidin-2-one (Xa) 
##STR16## 
The solution of the compound of Example 10 in ethyl acetate (500 mL) from 
above was carefully transferred, under a stream of argon, to a 2.0 L Parr 
flask containing 10% palladium on activated charcoal (6.00 g). This 
mixture was treated with hydrogen (4 atm) for 20 h whereupon the catalyst 
was removed by filtration through a pad of Celite. The filter cake was 
slurried in ethyl acetate (200 mL), stirred (10 min) and filtered. The 
filter cake was rinsed with ethyl acetate (100 mL) and the filtrates 
combined. The organic layer was washed with 10% HCl (300 mL) and both 
layers filtered through a sintered glass funnel to remove the white 
precipitate (dibenzylamine-HCl) which was rinsed with ethyl acetate (100 
mL). The phases were separated and the organic layer was washed with 
another portion of 10% HCl (200 mL). The combined 10% HCl washes were 
re-extracted with ethyl acetate (200 mL) and the combined organic layers 
were washed with aqueous NaHCO.sub.3 (saturated) (300 mL) and brine (250 
mL). The organic layer was dried over MgSO.sub.4, filtered and 
concentrated in vacuo to a final volume of 75 mL. This mixture was cooled 
to 4.degree. C. and the precipitated product isolated by filtration. The 
filter cake was washed with hexane (200 mL) to provide 16.12 g (78.1% 
overall yield from hydrobenzamide) of the title compound as white needles. 
mp=150.degree.-151.degree. C.; HPLC purity (area): 99.8%; .sup.1 H-NMR 
(CDCl.sub.3, 200 MHz): .delta.=7.30-7.38 (m, 5H, Ph), 6.54 (bs, 
exchangeable, 1H, NH), 5.87 (dd, J=2.7, 4.7 Hz, 1H, H-3), 5.04 (d, J=4.7 
Hz, 1H, H-4), 1.67 (s, 3H, CH.sub.3 CO); IR (KBr): .nu. (cm.sup.-1)=3210 
(N-H), 1755, 1720 (C.dbd.O); KF: 0.17%. 
Anal. Calcd. for C.sub.11 H.sub.11 NO.sub.3 : C, 64.38; H, 5.40; N, 6.83. 
Found: C, 64.07; H, 5.34; N, 6.77. 
EXAMPLE 12 
(.+-.)-cis-3-Acetyloxy-1-[(2-furyl)(2-furylmethylenimino)methyl]-4-(2-furyl 
)azetidin-2-one (IXb) 
##STR17## 
The title compound was prepared according to the procedure described in 
Example 10 except that hydrofuramide was used instead of hydrobenzamide 
and the reaction was performed on 18.6 mmol (vs 100 mmol) scale. Thus, 
hydrofuramide (5.00 g, 18.6 mmol), triethylamine (3.11 mL, 22.3 mmol) and 
acetoxyacetyl chloride (2.30 mL, 21.4 mmol) gave 6.192 g (Y: 90.4%) of the 
title compound as a pale red syrup. 
Obtained as a 1:1 mixture of diastereomers; .sup.1 H -NMR (CDCl.sub.3 ; 200 
MHz): .delta. 8.211 (s, 0.5H, N.dbd.CH), 8.208 (s, 0.5H, N.dbd.CH), 
7.14-7.59 (m, 3H, furyl), 6.90 (d, J=3.5 Hz, 0.5H, furyl), 6.83 (d, J=3.5 
Hz, 0.5H, furyl), 6.10-6.53 (m, 6H, furyl, NCHN), 5.90 (d, J=4.9 Hz, 0.5H, 
H-3), 5.86 (d, J=4.8 Hz, 0.5H, H-3), 5.35 (d, J=4.8 Hz, 0.5H, H-4), 4.90 
(d, J=4.9 Hz, 0.5H, H-4), 1.91 (s, 1.5H, CH.sub.3 CO),1.88 (s, 1.5H, 
CH.sub.3 CO ); IR (film): .nu. (cm.sup.-1)=1778, 1753 (C.dbd.O), 1642 
(C.dbd.N); UV (methanol): .lambda. max (nm)=220, 278. 
EXAMPLE 13 
(.+-.)-cis-3-Acetyloxy-4-(2-furyl)azetidin-2-one (Xb) 
##STR18## 
The title compound was prepared according to the procedure described in 
Example 11 except that the product was isolated by preparative TLC and the 
reaction was performed on the 2.7 mmol scale based on the original amount 
of hydrofuramide. Thus, the crude product of Example 12 (1.00 g) was 
re-dissolved in ethyl acetate (50 mL) and added to 10% palladium on 
activated charcoal (150 mg). Purification of the crude solid by 
preparative TLC (2 mm silica gel, eluted with 1:1 ethyl acetate/hexane) 
gave 386 mg (65.8% corrected overall yield from hydrofuramide) of the 
title compound as a yellow solid. This was recrystallized from ethyl 
acetate/hexane. 
mp=118.degree.-119.degree. C.; HPLC purity (area): 99.4%; .sup.1 H-NMR 
(CDCl.sub.3, 200 MHz): .delta. 7.44 (t, J=l.3 Hz, 2H, furyl), 6.39 (d, 
J=1.3 Hz, 1H, furyl), 6.21 (bs, exchangeable, 1H, NH), 5.88 (dd, J=2.2, 
4.6 Hz, 1H, H-3), 5.05 (d, J=4.6 Hz, 1H, H-4), 1.92 (s, 3H, CH.sub.3 CO); 
IR (KBr): .nu. (cm.sup.-1)=3203 (N-H), 1756, 1726 (C.dbd.O); UV 
(methanol): .lambda. max (nm)=222. 
EXAMPLE 14 
(.+-.)-cis-3-Acetyloxy-1-[(2-thienyl) 
(2-thienylmethylenimino)methyl]-4-(2-thienyl)azetidin-2-one (Ixc) 
##STR19## 
The title compound was prepared according to the procedure described in 
Example 10 except that hydrothienamide was used instead of hydrobenzamide. 
Thus, hydrothienamide (30 g, 94.7 mmol), thiethylamine (15.84 mL, 114 
mmol) and acetoxyacetyl chloride (11.6 mL, 108 mmol) provided the title 
compound as viscous oil. The product obtained contained a mixture of 
diastereomers. .sup.1 H-NMR (CDCl.sub.3): .delta. 8.52 (s, 1H), 8.502 (s, 
1H), 7.51 (d, J=4.9 Hz, 1H), 7.45 (d, J=4.4 Hz, 1H), 7.41 (d, J=3.1 Hz, 
1H), 7.37 (d, 1H), 7.30 (m, 3H), 7.16 (m, 1H), 7.16 (m, 3H), 7.09 (m, 2H), 
6.94 (m, 1H), 6.89 (m, 1H), 6.81-6.74 (m, 4H), 6.48 (s, 1H), 6.43 (s, 1H), 
5.85 (m, 2H), 5.59 (d, J=4.8 Hz, 1H), 5.17 (d, J=4.8 Hz, 1H), 1.87 (s, 
3H), 1.86 (s, 3H). 
EXAMPLE 15 
(.+-.)-cis-3-Acetyloxy-4-(2-thienyl)azetidin-2-one (Xc) 
##STR20## 
A 70% aqueous solution of acetic acid (0.35 mL glacial acetic acid and 0.15 
mL water) was added in one portion to a stirred solution of compound IXc 
(0.431 g, 1.03 mmol) in dichloromethane (2.93 ml) at 25.degree. C. The 
reaction mixture was brought to reflux and stirred for 2.5 h. The reaction 
was diluted with 50 mL dichloromethane and then washed with two 75 mL 
portions of saturated aqueous sodium bicarbonate and then one 50 mL 
portion of saturated brine. The organic extract was concentrated in vacuo 
to a brown oil, dissolved in a minimal amount of dichloromethane, and then 
placed on a silica gel column measuring 4" by 0.5". Elution using a 
gradient of 10 through 60% EtOAc in hexane provided less polar side 
products and then the title compound (0.154 g, Y: 75%) as a white solid. 
.sup.1 H-NMR (CDCl.sub.3): .delta. 7.32 (dd, J=4.7, 1.5 Hz, 1H), 7.03 (m, 
2H), 6.75 (bs, 1H), 5.86 (dd, J=4.6, 2.7 Hz, 1H), 5.27 (d, J=5.3 Hz, 1H), 
1.83 (s, 3H); .sup.13 C-NMR (CDCl.sub.3): .delta. 169.3, 165.5, 138.4, 
127.1, 127.07, 126.2, 78.3, 54.0, 20.0. 
EXAMPLE 16 
(.+-.)-cis-3-Triethylsilyloxy-4-(2-furyl)-azetidin-2-one (XIIa) 
##STR21## 
Acetoxy lactam Xb (3.78 g, 19.4 mmol) in 60 mL of methanol was stirred with 
K.sub.2 CO.sub.3 (20 mg, 0.14 mmol) for 90 min and the solution 
neutralized with Dowex 50W-X8 and filtered. The filtrate was concentrated 
and the residue dissolved in 80 mL of anhydrous THF and stirred at 
0.degree. C. with imidazole (1.44 g, 21.2 mmol) and TESCl 
(triethylsilylchloride 3.4 mL, 20.2 mmol) for 30 min. The solution was 
diluted with ethyl acetate and washed with brine, dried over MgSO.sub.4 
and concentrated. The residue was chromatographed over silica gel (eluted 
with 3:1 hexane/ethyl acetate) to give 4.47 g (Y: 86%) of the title 
compound as a colorless oil; IR(film) 3276 (broad), 1768, 1184, 732 
cm.sup.-1 ; .sup.1 H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.38 (s, 1H), 6.39 
(bs, 1H), 6.35 (s, 2H), 5.05 (dd, J=4.6, 2.3 Hz, 1H), 4.78 (d, J=4.6Hz, 
1H), 0.82 (t, J=8.5 Hz, 6H), 0.50 (dq, J=8.5, 1.8 Hz, 9H); .sup.13 C-NMR 
(CDCl.sub.3, 75.5 Hz) .delta. 169.6, 150.4, 142.6, 110.5, 109.1, 79.6, 
53.2, 6.4, 4.4; FABMS (DCI) M+H calcd for C.sub.13 H.sub.21 NO.sub.3 Si: 
268, Found: 268. 
The racemic mixture obtained in Example 13 may be used as substrate for 
enzymatic hydrolysis using a lipase such as PS-30 from Pseudomonas sp. 
(Amano International Co.) to give 
(3R,4R)-3-hydroxy-4-(2-furyl)azetidin-2-one. The method of enzymatic 
resolution using the lipase PD-30 and other enzymes is disclosed in our 
co-pending application U.S. Ser. No. 092,170, filed Jul. 14, 1993 which is 
hereby incorporated by reference in its entirety. Subsequently, the 
pertinent part of this example may be followed to convert 
(3R,4R)-3-hydroxy-4-(2-furyl)azetidin-2-one to (3R, 
4R)-3-triethylsilyoxy-4-(2-furyl)azetidine-2-one. 
EXAMPLE 17 
(.+-.)-cis-3-Triethylsilyloxy-4-(2-furyl)-N-t-butoxycarbonylazetidin-2-one 
(VIIa) 
##STR22## 
Azetidinone XIIa (2.05 g, 7.7 mmol) in 30 mL of dichloromethane was stirred 
at 0.degree. C. with diisopropylethyl amine (1.5 mL, 8.6 mmol) and 
di-t-butyldicarbonate (2.0 g, 9.2 mmol) in addition to a catalytic amount 
of dimethylaminopyridine (DMAP). The solution was diluted with 
dichloromethane and washed with brine, dried over MgSO.sub.4 and 
concentrated. The residue was chromatographed over silica gel (eluted with 
8:1 hexane/ethyl acetate) to give 2.0 (Y: 70%) of the title compound as a 
waxy solid; IR(KBr) 1822, 1806, 1712, 1370, 1348, 1016 cm.sup.-1 ; .sup.1 
H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.38 (m, 1H), 6.34 (m, 2H), 5.04 (ABq, 
J=12.4, 5.5 Hz, 2H), 1.39 (s, 9H), 0.82 (t, 9H), 0.50 (m, 6H); .sup.13 
C-NMR (CDCl.sub.3, 75.5 Hz) .delta. 165.7, 148.0, 147.7, 142.8, 110.5, 
109.7, 83.4, 77.4, 56.0, 27.8, 6.3, 4.4; DCIMS M+H calcd for C.sub.18 
H.sub.29 NO.sub.5 Si: 368, Found: 368. 
EXAMPLE 18 
(.+-.)-cis-3-Triethylsilyloxy-4-(2-thienyl)-azetidin-2-one (XIIb) 
##STR23## 
A solution of 3-acetoxy lactam Xc (2.5 g, 11.8 mmol) was dissolved in 
methanol (10 mL) and treated with saturated aqueous sodium bicarbonate (10 
mL) and the resulting slurry was allowed to stir at ambient temperature 
for 3 h. The reaction was then diluted with ethyl acetate (20 mL) and 
washed with water (15 mL). The aqueous fraction was back extracted several 
times with ethyl acetate and the combined organic fractions were dried 
(MgSO.sub.4) and concentrated to give a yellow solid (Y: 1.7 g). The crude 
material was dissolved in dry tetrahydrofuran (20 mL) and the solution was 
cooled to 5.degree. C. in an ice/water bath. Imidazole (752 mg, 1.1 eq) 
was then added. After stirring 5 min, triethylchlorosilane (1.85 mL, 1.1 
eq) was added dropwise. The resulting suspension was allowed to stir for 3 
h at that temperature; then the solids were removed by filtration. The 
organic fraction was washed with water (2.times.20 mL) then dried 
(MgSO.sub. 4) and concentrated. The crude product was purified by silica 
gel column chromatography (eluted with hexanes/ethyl acetate 7:3) to give 
the desired product as a colorless solid (1.5 g, Y: 45%). m.p. 
70.degree.-71.degree. C.; .sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta. 
7.32-7.30 (m, 1H); 7.05-6.98 (m, 2H), 5.06-5.05 (m, 2H), 0.82 (t, 9H, J=8 
Hz), 0.55-0.46 (m, 6H); .sup.13 C-NMR (75.6 MHz, CDCl.sub.3): .delta. 
169.1, 139.7, 126.5, 126.4, 125.8, 79.4, 55.1, 6.3, 4.4. 
Alternate Run: 
Acetoxy lactam Xc (2.0 g, 9.37 mmol) in 40 mL of methanol was stirred with 
K.sub.2 CO.sub.3 (60 mg, 0.43 mmol) for 30 min and the solution 
neutralized with Dowex 50W-X8 and filtered. The filtrate was concentrated 
and the residue dissolved in 50 mL of anhydrous THF and stirred at 
0.degree. C. with imidazole (0.85 g, 11.3 mmol) and TESCl (1.9 mL, 12.5 
mmol) for 30 min. The solution was diluted with ethyl acetate and washed 
with brine, dried over MgSO.sub.4 and concentrated. The residue was 
chromatographed over silica gel (eluted with 3:1 hexane/ethyl acetate) to 
give 2.13g (Y: 86%) of the title product as a colorless oil. 
EXAMPLE 19 
(.+-.)-cis-3-Triethylsilyloxy-4-(2-thienyl)-N-t-butoxycarbonylazetidin-2-on 
e (VIIb) 
##STR24## 
A solution of the silyl azetidinone XIIb (425.7 mg, 1.48 mmol) was 
dissolved in dichloromethane (10 mL) and cooled to 5.degree. C. in an 
ice/water bath. The reaction was treated with a catalytic amount of DMAP 
then di-t-butyldicarbonate (388.4 mg, 1.2 eq). After stirring 2 h at that 
temperature the reaction was quenched with saturated aqueous sodium 
bicarbonate (5 mL) and the organic fraction was washed with water (5 mL) 
then dried (MgSO.sub.4), passed through a short plug of silica gel and 
concentrated to give the desired product as a colorless oil (525.3 mg, Y: 
93%); .sup.1 H-NMR (300 MHz, CDCl.sub.3): .delta. 7.31-7.29 (m, 1H), 
7.08-7.07 (m 1H), 7.00-6.58 (m, 1H), 5.31 (d, 1H, J=6 Hz), 5.03 (d, 1H, 
J=6 Hz), 1.40 (s, 9H), 0.83 (t, 9H, J=8 Hz), 0.56-0.47 (m, 6H); .sup.13 
C-NMR (75.6 MHz, CDCl.sub.3): .delta. 165.5, 147.5, 136.4, 127.6, 126.2, 
126.1, 83.3, 77.3, 57.9, 27.7, 6.2, 4.3. 
EXAMPLES 20-24 
(.+-.)-cis-3-Triethylsilyloxy-4-isobutenyl-N-t-butoxycarbonylazetidin-2-one 
(VIIc) can be made by the reaction sequence of Scheme III. 
##STR25## 
EXAMPLE 20 
N-4-methoxy-N-(3-methyl-2-butenyl)benzenamine (XIII) 
A solution of p-anisidine (5.7 g, 46.3 mmol) was dissolved in diethylether 
(100 mL) and was treated with a catalytic amount of p-toluensulfonic acid 
(10 mg). To this was added 3-methyl-2-butenal (2.67 mL, 50.9 mmol) in one 
portion and the reaction was allowed to stir at ambient temperature for 16 
h. The solvent was then evaporated on a rotary evaporator at 0.5 torr to 
furnish the desired imine (8.7 g, 100%) as a brown oil; .sup.1 H NMR 300 
MHz, CDCl.sub.3): .delta. 8.38 (d, 1H, J=9.5 Hz), 7.11 (dd, 2H, J=2.2, 6.7 
Hz), 6.88 (dd, 2H, J=2.2, 6.7 Hz), 6.22-6.18 (m, 1H), 3.81 (s, 3H), 2.01 
(s, 3H), 1.95 (s, 3H). 
EXAMPLE 21 
(.+-.)-cis-N-(4-methoxyphenyl)-3-acetyloxy-4-isobutenylazetidin-2-one (XIV) 
A solution of acetoxyacetyl chloride (6.9 g, 50.5 mmol) was dissolved in 
ethyl acetate (100 mL) and cooled to -30.degree. C. under an inert 
atmosphere. To this solution was added triethylamine (7.0 mL, 50.5 mmol) 
over a 5 min period. The resulting white slurry was then treated with an 
ethyl acetate solution of imine XIII (8.7 g, 40 mL) dropwise over a 20 min 
period. The resulting green-brown slurry was then gradually allowed to 
warm to ambient temperature over a 4 h period. The slurry was then 
filtered through a pad of celite and the filtrate was washed with water 
then brine. The organic fraction was dried (MgSO.sub.4) and concentrated 
to give a brown oil. The crude product was purified by careful silica gel 
chromatography (eluted with hexanes/ethyl acetate 8:2) to furnish an 
orange oil which solidified on standing. This was recrystallized from 
dichloromethane/hexanes to furnish the desired product as a pale yellow 
solid (4.4 g, 32%); .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 7.32 (d, 
2H, J=9.1 Hz), 6.86 (d, 2H, J=9.1 Hz), 5.59 (dd, 1H, J=3.0, 7.8 Hz), 
5.14-5.10 (m, 1H), 4.96 (dd, 1H, J=4.8, 9.3 Hz), 3.77 (s, 3H), 2.11 (s, 
3H, ), 1.81 (s, 3H), 1.78 (s, 3H). 
EXAMPLE 22 
(.+-.)-cis-3-Acetyloxy-4-isobutenylazetidin-2-one (XV) 
A solution of the N-aryl lactam XIV (4.88 g, 16.2 mmol) was dissolved in 
acetonitrile (50 mL) and cooled to 0.degree.-5.degree. C. in an ice bath. 
To this was added a cold solution of ceric ammonium nitrate (26.6 g, 48.6 
mmol, 50 mL) in one portion. The deep red reaction was allowed to stir for 
10 min and during that time the color gradually lightened to orange. The 
cold solution was transferred to a separatory funnel, diluted with water, 
and extracted with ethyl acetate. The organic fraction was washed with 
several portions of 10% aqueous sodium sulfite, followed by saturated 
aqueous sodium bicarbonate. The organic fraction was dried (MgSO.sub.4) 
and concentrated to give the desired product (2.71 g, 91%) as a 
yellow-orange solid that was used directly in the next step; .sup.1 H NMR 
(300 MHz, CDCl.sub.3): .delta. 6.11 (bs, 1H), 5.73 (dd, 1H, J=2.2, 4.7 
Hz), 5.12-5.08 (m, 1H), 4.63 (dd, 1H, 4.7, 9.1 Hz), 2.09 (s, 3H), 1.75 (s, 
3H), 1.67 (s, 3H). 
EXAMPLE 23 
(.+-.)-cis-3-Triethylsilyloxy-4-isobutenylazetidin-2-one (XVI) 
Acetoxy lactam XV (1.47 g, 8.0 mmol) was dissolved in methanol (15 mL) and 
was stirred with K.sub.2 CO.sub.3 (110.5 mg,0.8 mmol) for 3h at ambient 
temperature. The solution was then neutralized with Dowex 50W-X8 resin and 
then filtered. The filtrate was concentrated and the crude solid was 
dissolved in THF (25 mL) and cooled to 5.degree. C. in an ice bath. 
Imidazole (544.0 mg, 8.0 mmol) was added and once dissolved, triethylsilyl 
chloride (1.34 mL, 8.0 mmol) was added dropwise via syringe. The resulting 
slurry was allowed to warm to ambient temperature and stir overnight. The 
solution was filtered and the filtrate was washed with water, then brine. 
The organic fraction was dried (MgSO.sub.4) and concentrated. The crude 
solid was purified by silica gel chromatography (eluted with hexanes/ethyl 
acetate 3:1) to furnish the desired product (612 mg, 30%) as a pale yellow 
solid; .sup.1 H NMR (300 MHz, CDCl.sub.3): .delta. 5.87 (bs, 1H), 
5.31-5.26 (m, 1H), 4.90 (dd, 1H, J=2.2, 4.7 Hz), 4.42 (dd, 1H, J=4.7, 9.3 
Hz), 1.74 (s, 3H), 1.28 (s, 3H), 0.98-0.91 (m, 9H), 0.71-0.55 (m, 6H). 
EXAMPLE 24 
(.+-.)-cis-3-Triethylsilyloxy-4-isobutenyl-N-t-butoxycarbonyl-azetidin-2-on 
e (VIIc) 
Azetidinone XVI (1.01 g, 3.95 mmol) was dissolved in dichloromethane (20 
mL) and was treated with diisopropylethylamine (0.68 mL, 3.95 mmol) and a 
catalytic amount of dimethylaminopyridine. To this solution was added 
di-t-butyldicarbonate (1.02 g, 4.68 mmol) and the solution was allowed to 
stir for 24 h at ambient temperature. The solution was then diluted with 
additional dichloromethane and washed with water then brine. The organic 
fraction was dried (MgSO.sub.4) and concentrated. The residue was purified 
by silica gel chromatography (eluted with hexanes/ethyl acetate 8:2) to 
give the desired product (1.26 g, 90%) as a colorless oil; .sup.1 H NMR 
(300 MHz, CDCl.sub.3): .delta. 5.24 (d, 1H, J=9.6 Hz), 4.86 (d, 1H, J=5.7 
Hz), 4.72 (dd, 1H, J=6.0, 9.9 Hz), 1.78 (d, 3H, J=1.1 Hz), 1.75 (d, 3H, 
J=1.1 Hz), 1.47 (s, 9H), 0.96-0.91 (m, 9H), 0.64-0.55 (m, 6H). 
In Vitro Cytotoxicity Data 
Compounds of the present invention showed in vitro cytoxicity activity 
against human colon carcinoma cells HCT-116 and HCT-116/VM46. The 
HCT-116/VM46 cells are cells that have been previously selected for 
teniposide resistance and express the multi-drug resistance phenotype, 
including resistance to paclitaxel. Cytotoxicity was assessed in HCT-116 
human colon carcinoma cells by XTT 
(2,3-bis(2-methoxy-4-nitro-5-sulfphenyl)-5-[(phenylamino)carbonyl]2H-tetra 
zolium hydroxide) assay as reported in D. A. Scudiero, et al., "Evaluation 
of soluble tetrazolium/formazan assay for cell growth and drug sensitivity 
in culture using human and other tumor cell lines," Cancer Res. 
48:4827-4833, 1988. Cells were plated at 4000 cells/well in 96 well 
microtiter plates and 24 hours later drugs were added and serial diluted. 
The cells were incubated at 37.degree. 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 
IC.sub.50, which is the drug concentration required to inhibit cell 
proliferation (i.e., absorbance at 450 nm) to 50% of that of untreated 
control cells. The IC.sub.50 values for compounds evaluated in this assay 
are given in Table I. 
TABLE I 
______________________________________ 
In vitro cytotoxicity data against human 
colon carcinoma cells. 
IC.sub.50 HCT116/ 
COMPOUND IC.sub.50 HCT116 (nM) 
VM46 (nM) 
______________________________________ 
paclitaxel 1.3-3.5 244-403 
Ia 1.2 30.5 
Ib 1.3-3.0 2.8-13.9 
Ic 0.6 12.3 
Id 1.3 3.3 
______________________________________ 
The compounds of the instant invention have tumor inhibiting activities in 
mammals. Thus, another aspect of the instant invention concerns with a 
method for inhibiting mammalian tumors sensitive to a compound of formula 
I. 
The present invention also provides pharmaceutical formulations 
(compositions) containing a compound of formula I in combination with one 
or more pharmaceutically acceptable, inert or physiologically active, 
carriers, excipients, diluents or adjuvants. Examples of formulating 
paclitaxel or its related derivatives (including a possible dosage) are 
described in numerous literatures, for example in U.S. Pat. Nos. 4,960,790 
and 4,814,470, and such examples may be followed to formulate the 
compounds of this invention. For example, the new compounds are 
administrable in the form of tablets, pills, powder mixtures, capsules, 
injectables, solutions, suppositories, emulsions, dispersions, food 
premix, and in other suitable forms. The pharmaceutical preparation which 
contains the compound is conveniently admixed with a nontoxic 
pharmaceutical organic carrier or a nontoxic pharmaceutical inorganic 
carrier, usually about 0.01 mg up to 2500 mg, or higher per dosage unit, 
preferably 50-500 mg. Typical of pharmaceutically acceptable carriers are, 
for example, manitol, urea, dextrans, lactose, potato and maize starches, 
magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl 
cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, 
isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium 
carbonate, silicic acid, and other conventionally employed acceptable 
carriers. The pharmaceutical preparation may also contain nontoxic 
auxiliary substances such as emulsifying, preserving, wetting agents, and 
the like as for example, sorbitan monolaurate, triethanolamine oleate, 
polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium 
sulfosuccinate, and the like. 
The compounds of the invention can also be freeze dried and, if desired, 
combined with other pharmaceutically acceptable excipients to prepare 
formulations suitable for parenteral, injectable administration. For such 
administration, the formulation can be reconstituted in water (normal, 
saline), or a mixture of water and an organic solvent, such as propylene 
glycol, ethanol, and the like. 
The compounds of present invention can be used as paclitaxel for treating 
mammalian tumors. The mode, dosage and schedule of administration of 
paclitaxel in human cancer patients have been extensively studied. See, 
for example Ann. Int. Med., 111, pp 273-279 (1989). For the compounds of 
this invention, the dose to be administered, whether a single dose, 
multiple dose, or a daily dose, will of course vary with the particular 
compound employed because of the varying potency of the compound, the 
chosen route of administration, the size of the recipient and the nature 
of the patient's condition. The dosage to be administered is not subject 
to definite bounds, but it will usually be an effective amount, or the 
equivalent on a molar basis of the pharmacologically active free form 
produced from a dosage formulation upon the metabolic release of the 
active drug to achieve its desired pharmacological and physiological 
effects. The dosage to be administered will be generally in the range of 
0.8 to 8 mg/kg of body weight or about 50-275 mg/m.sup.2 of the patient. 
An oncologist skilled in the art of cancer treatment will be able to 
ascertain, without undue experimentation, appropriate protocols for 
effective administration of the compounds of this present invention such 
as by referring to the earlier studies of paclitaxel and its derivatives.