IL103191A - Semi-synthesis of taxane derivatives using metal alkoxides and beta-lactams and intermediates thereof - Google Patents

Abstract

A process for the preparation of a taxane derivative comprising: providing a metal alkoxide having the bi-, tri-or tetracyclic taxane nucleus, reacting the metal alkoxide with a b-lactam wherein the b-lactam has the formula: wherein R1 is -OR6, -SR7, or -NR8R9; R2 is hydrogen, alkyl, alkenyl, alkynl, aryl, or heteroaryl; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl; R5 is -COR10, -COOR10, -COSR10, -CONR8R10, -SO2R11, or -POR12R13, R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, 1598 ד' באב התשס" א - July 24, 2001 R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R9 is an amino protecting group; R10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R11 is alkyl, alkenyl, aryl, heteroaryl, OR10, or -NR8R14, R12 and R13 are indepdnently alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NR8R14, R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and converting said intermediate to the taxane derivative. Claimed as novel is the intermediate b-lactam of the formula wherein R1 is -OR6, -SR7, or -NR8R9; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl, and that heteroaryl is other than pyridyl; R5 is -COR10, -COOR10, -COSR10, -CONR8R10, -SO2R11, or -POR12R13, R6 is a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R9 is an amino protecting gorup; R10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NR8R14, R12 and R13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl or -NR8R14.

Description

-SYNTHESIS OF TAXANE DERIVATIVES USING METAL ALKOXIDES AND BETA-LACTAMS , o "P0 i fc_ «rto>» Tin ι ορο nnbin v nToa>o-»no o>oopl» «n»ai o»nanD SEMI-SYNTHESIS OF TAXANE DERIVATIVES USING METAL ALKOXIDES AND B-LACTAMS ABSTRACT OF THE DISCLOSURE A process for preparing a taxane derivative by providing a metal alkoxide having the bi-, tri- or tetracyclic taxane nucleus, reacting the metal alkoxide with a β-lactam to form an intermediate, and converting the intermediate to a taxol. 103191/2 1 SEMI-SYNTHESIS OF TAXANE DERIVATIVES USING METAL ALKOXIDES AND β-LACTAMS BACKGROUND OF THE INVENTION The present invention is directed to a semi-synthesis for the preparation of taxane derivatives such as taxol, taxotere and other biologically active derivatives involving the use of metal alkoxides and β-lactams .

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 the following structure: (I) wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.

The supply of taxol for these clinical trials is presently being provided by the bark from Taxus brevifollia (Western Yew) . However, taxol is found only in minute 2 quantities in the bark of these slow growing evergreens, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently/ chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxol. So far, the results have not been entirely satisfactory.

One synthetic route that has been proposed is directed to the synthesis of the tetracyclic taxane nucleus from commodity chemicals. A synthesis of the taxol congener taxusin has been reported by Holton, et al. in JACS 110 , 6558 (1988). Despite the progress made in this approach, the final total synthesis of taxol is, nevertheless, likely to be a multi-step, tedious, and costly process.

A semi-synthetic approach to the preparation of taxol has been described by Greene, et al. in JACS 110. 5917 (1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure of formula II shown below: 10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the needles of Taxus baccata . According to the method "of Greene et al., 10-deacetyl baccatin III is converted to taxol by attachment of the C-10 acetyl group and by attachment of the C-13 fl-amido ester side chain through the esterification of the C-13 alcohol with a fl-amido 3 carboxylic acid unit. Although this approach requires relatively few steps, the synthesis of the β-amido carboxylic acid unit is a multi-step process which proceeds in low yield, and the coupling reaction is tedious and also proceeds in low yield. However, this coupling reaction is a key step which is required in every contemplated synthesis of taxol or biologically active derivative of taxol, since it has been shown by Wani, et al. in JACS 93. 2325 (1971) that the presence of the fl-amido ester side chain at C13 is required for anti-tumor activity.

More recently, it has been reported in Colin et al. U.S. Patent No. 4,814,470 that taxol derivatives of the formula III below, have an activity significantly greater than that of taxol (I).

OCOCeHg R ' represents hydrogen or acetyl and one of R" and R" ' represents hydroxy and the other represents tert-butoxycarbonylamino and their stereoisomeric forms, and mixtures thereof.

According to Colin et al., U.S. Patent 4,418,470, the products of general formula (III) are obtained by the action of the sodium salt of tert-butyl N-chlorocarbamate on a product of general formula: 4 ococHg in which R ' denotes an acetyl or 2 , 2 , 2-trichloroethoxycarbonyl radical, followed by the replacement of the 2 , 2 , 2-trichloroethoxycarbonyl group or groups by hydrogen. It is reported by Denis et al. in U.S. Patent No. 4,924,011, however, that this process leads to a mixture of isomers which has to be separated and, as a result, not all the baccatin III or 10-deactylbaccatin III employed for the preparation of the product of general formula (IV) can be converted to a product of general formula (III).

In an effort to improve upon the Colin et al. process, Denis et al. disclose a different process for preparing derivatives of baccatin III or of 10-deactylbaccatin III of general formula 5 in which R' denotes hydrogen or acetyl wherein an acid of general formula: in which R^ is a hydroxy-protecting group, is condensed with a taxane derivative of general formula: OCOCeHg in which R2 is an acetyl hydroxy-protecting group and R3 is a hydroxy-protecting group, and the protecting groups R]_, R3 and, where appropriate, R2 are then replaced by hydrogen. However, this method employs relatively harsh conditions, proceeds with poor conversion, and provides less than optimal yields.

A major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of a readily available method for easy attachment, to the C-13 oxygen, of the chemical unit which provides the β-amido ester side chain. Development of such a process for its attachment in high yield would facilitate the synthesis of taxol as well as related anti-tumor agents having a 6 modified set of nuclear substituents or a modified C-13 side chain. This need has been fulfilled by the discovery of a new, efficient process for attachment, to the C-13 oxygen, of the chemical unit which provides the β-amido ester side chain.

Another major difficulty encountered in the synthesis of taxol is that known processes for the attachment of the β-amido ester side chain at C-13 are generally not sufficiently diastereoselect ive . Therefore the side chain precursor must be prepared in optically active form to obtain the desired diastereomer during attachment. The process of this invention, however, is highly diastereoselective, thus . permitting the use of a racemic mixture of side chain precursor, eliminating the need for the expensive, time-consuming process of separating the precursor into its respective enantiomeric forms. The reaction additionally proceeds at a faster rate than previous processes, thus permitting the use of less side-chain precursor than has been required by such previous processes.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation ofa taxane derivative comprising: providing a metal alkoxide having the bi-, tri- or tetracyclic taxane nucleus, reacting the metal alkoxide with a β-lactam wherein the β-lactam has the formula: wherein R1 is -0R6, -SR7, or -NRgRg ; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl ; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl; R5 is -COR10, -COOR10, -COSR10, -CONR8R10, R6 is a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R9 is an amino protecting group; R10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, R1]L is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NR8R1 , R12 and R13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10' or -NR8R14' R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and converting said intermediate to the taxane derivative .

Passages which are not in the ambit of the claims do not belong to the invention. The scope of protection is as defined in the claims, and as stipulated in the Patent Law (1968).

Among the objects of the present invention, therefore, is the provision of a side chain precursor for the synthesis of taxane derivatives; the provision of a process for the attachment of the side chain precursor in relatively high yield to provide an intermediate which is readily converted to the desired taxane derivative; and the provision of such a process which is highly diastereo-selective.

In accordance with the present invention, a process is provided for preparing taxol, taxotere and other biologically active taxane derivatives having the following structural formula: 7 wherein R^ is -ORg, -SR7, or - RgRg; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl; R5 is -GOR10' -COOR10, -COSR10' -CONR8R10' Rg is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative, R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; Rg is an amino protecting group; R10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl , Rn is alkyl, alkenyl, alkynyl, aryl, heteroaryl, R12 and R13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NR8R14, 103191/2 8 R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl ; R1S and R16 are independently hydrogen, hydroxy, lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy or R15 and R16 together form an oxo; R17 and R18 are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R17 and R18 together form an oxo; R19 and R20 are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; R21 and R22 are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R21 and R22 together form an oxo? R23 is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or R24 is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or R23 and R2 together form an oxo or methylene or R23 and R24 together with the carbon atom to which they are attached form an oxirane ring or R23 and R22 together with the carbon atom to which they are attached form an oxetane ring; R25 is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R26 is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or R26 and R25 taken together form an oxo; and R27 is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy.

Briefly, therefore, the present invention is directed to a process for the preparation of a taxane derivative in which β-lactam (2) is reacted with a metal alkoxide having the bi-, tri- or tetracyclic taxane nucleus to form a β-amido ester intermediate. The intermediate is then converted to the taxane derivative. β-lactam (2) has the general formula: 9 wherein - R5 are as previously defined. The metal alkoxide preferably has the tricyclic taxane nucleus corresponding to the general formula: wherein is a metal, and R15-R27 are as Previously defined. Most preferably, the metal alkoxide has the tetracyclic taxane nucleus corresponding to metal alkoxide (3) wherein R22 an<^ R23 together form an oxetane ring.

Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.

DETAILED DESCRIPTION The present invention is directed to a process for preparing taxol, taxotere and other taxane derivatives which are biologically active using β-lactam (2), the structure of which is depicted hereinbelow: 10 wherein Rlt R2, R3, R and R5 are as previously defined.

In accordance with the present invention, R5 of β-lactam (2) is preferably -COR^ with R^Q with R^g being aryl, p-substituted phenyl, or lower alkoxy, and most preferably phenyl, methoxy, ethoxy, tert-butoxy ("tBuO"; (CH3)3CO->, or wherein X is CI, Br, F, CH3O-, or N02-. Preferably R2 R4 are hydrogen or lower alkyl. R3 is preferably a most preferably, naphthyl, phenyl, wherein X is as previously defined, Me is methyl and Ph is phenyl. Preferably, Rx is selected from -0R6, -SR7 or -NR8R9 wherein R*6, R7 and R9, are hydroxy, sulfhydryl, and amine protecting groups, respectively, and R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl . Most preferably, Rj is -0R6 wherein R6 is triethylsilyl ("TES"), 1-ethoxyethyl ("EE") or 2 , 2 , 2-trichloroethoxymethyl .

The β-lactam alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl, and the like.

The β-lactam alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms . They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

The β-lactam alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in 103191/2 12 the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

The β-lactam aryl moieties described, either alone or with various substituents , contain from 6 to 15 carbon atoms and include phenyl, a-naphthyl or β-naphthyl, etc. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.

As noted above, Rt of β-lactam (2) may be -OR6 with R6 being alkyl, acyl, ethoxyethyl ("EE"), triethylsilyl ("TES"), 2 , 2 , 2-trichloroethoxymethyl, or other hydroxyl protecting group such as acetals and ethers, i.e., methoxymethyl ("MOM"), benzyloxymethyl ; esters, such as acetates; carbonates, such as methyl carbonates; and alkyl and aryl silyl such as triethylsilyl, trimethylsilyl , dimethyl-t-butylsilyl , dimethylarylsilyl , dimethyl-heteroarylsilyl, and triisopropylsilyl, and the like. A variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981. The hydroxyl protecting group selected should be easily removed under conditions that are sufficiently mild, e.g., in 48% HF, acetonitrile, pyridine, or 0.5% HCl/water/ethanol, and/or zinc/acetic acid so as not to disturb the ester linkage or other substituents of the taxol intermediate. However, R6 is preferably triethylsilyl, 1-ethoxyethyl or 2 , 2 , 2-trichloroethoxymethyl, and most preferably triethylsilyl.

Also as noted previously, R7 may be a sulfhydryl protecting group and R9 may be an amine protecting group. Sulfhydryl protecting groups include hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates . Amine protecting groups include 13 carbamates, for example, 2 , 2 , 2-trichloroethylcarbamate or tertbutylcarbamate . A variety of sulfhydryl and amine protecting groups may be found in the above-identified text by T. W. Greene.

Since β-lactam (2) has several asymmetric carbons, it is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in diastereomeric , racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers , racemic mixtures, and other mixtures thereof. β-lactam (2) can be prepared from readily available materials, as is illustrated in schemes A and B below: Scheme A 1 03191 /2 14 Scheme B reagents: (a) triethylamine, CH2C12, 25°C, 18h; (b) 4 equiv eerie ammonium nitrate, CH3CN, -10°C, 10 min; (c) KOH, THF, H20, 0°C, 30 min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), 0°C, 1.5h; (e) n-butyllithium, ether, -78°C, 10 min; benzoyl chloride, -78°C, lh; (f) lithium diisopropyl amide, THF -78°C to -50<>C; (g) lithium hexamethyldisilazide, THF -78°C to 0°C; (h) THF, -78oc to 25°C, 12h.

The starting materials are readily available. In scheme A, a-acetoxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give l-p-methoxyphenyl-3-acyloxy-4- arylazetidin-2-ones . The p-methoxyphenyl group can be readily removed through oxidation with eerie ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones . The 3 -hydroxy1 group is protected with 1-ethoxyethyl , but may be protected with variety of standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) 103191/2 15 silyl groups. In Scheme B, ethyl-a-triethylsilyloxyacetate is readily prepared from glycolic acid.

The racemic β-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 β-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 3- (1-ethoxyethoxy) -4-phenylazetidin-2-one of scheme A and the 3- ( 1-triethylsilyloxy) -4-phenylazetidin-2-one of scheme B can be converted to i5-lactam (2), by treatment with a base, preferably n-butyllithium, and an acyl chloride, alkylchloroformate, sulfonyl chloride, phosphinyl chloride or phosphoryl chloride at -78 oc or below.

As noted above, the metal alkoxides used in the process of the present invention have the bi-, tri- or tetracyclic taxane nucleus. As used herein, a metal alkoxide having the bicyclic taxane nucleus corresponds to a compound containing rings A and B of metal alkoxide (3) : 16 wherein M and R15-R27 are as previously defined. A metal alkoxide having the tricyclic taxane nucleus corresponds to a compound containing rings A, B and C of metal alkoxide (3). A metal alkoxide having the tetracyclic taxane nucleus corresponds to a compound containing rings A, B and C of metal alkoxide (3) and in which R22 an( R23 together form an oxetane ring.

Preferably, the metal alkoxide used in the process of the present invention is metal alkoxide (3). Most preferably, R15 is -OT2 or -OCOCH3; R16 is hydrogen; R17 and R18 together form an oxo; R19 is -ΟΊ^; R2u and R2i are hydrogen; R22 an^ R23 together form an oxetane ring; R2 is CH3COO-; R25 is PhCOO-; R26 is hydrogen; R27 is hydroxy; and and T2 are independently hydrogen or hydroxy protecting group.

Metal substituent, M, of metal alkoxide (3) is a Group IA, IIA, IIIA, lanthanide or actinide element or a 17 103191/2 transition, Group IIIA, IVA, VA or VIA metal. Preferably, it is a Group IA, IIA or transition metal, and most preferably, it is lithium, magnesium, sodium, potassium or titantium.

The metal alkoxide alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 10 carbon atoms.

They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl, and the like.

The metal alkoxide alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon . atoms in the principal chain and up to 10 carbon atoms.

They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

The metal alkoxide alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms.

They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.

Exemplary alkanoyloxy include acetate, propionate, butyrate, valerate, isobutyrate and the like. The more preferred alkanoyloxy is acetate.

The metal alkoxide aryl moieties, either alone or with various substituents contain from 6 to 10 carbon atoms and include phenyl, a-naphthyl or β-naphthyl, etc.

Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy,' nitro, amino, amido, etc.

Phenyl is the more preferred aryl.

Metal alkoxides (3) are prepared by reacting an alcohol having two to four rings of the taxane nucleus and 18 103191/2 a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Preferably, the alcohol is a derivative of baccatin III or 10-deacetyl baccatin III having the structure wherein Ta is a hydroxy protecting group, and Z is -OT2 wherein T2 is acyl, preferably acetyl, or other hydroxy protecting group. Most preferably, the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al. in JACS 110, 5917 (1988) or by other routes) or 7 , 10-bis-O-triethylsilyl baccatin III.

As reported in Greene et al . , 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-lO-deacetyl baccatin III according to the following reaction scheme: (5) (6a) 19 103191/2 Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2H5)3SiCl at 23°C under an argon atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-lO-deacetyl baccatin III (6a) as a reaction product in 84-86% yield after purification. The reaction product is then acetylated with 5 equivalents of CH3C0C1 and 25 mL of pyridine/mmol of (6a) at 0 °C under an argon atmosphere for 48 hours to provide 86% yield of 7^0-tri-ethylsilyl baccatin III (6b). Greene, et al. in JACS 110 , 5917 at 5918 (1988) .

Al ernatively, 7 -triethylsilyl-10-deacetyl baccatin III (6a) can be protected at C-10 oxygen with an acid labile hydroxy1 protecting group. For example, treatment of (6a) with n-butyllithium in THF followed by triethylsilyl chloride (1.1 mol equiv.) at 0°C gives 7 , 10-bis-O-triethylsilyl baccatin III (6c) in 95% yield. Also, (6a) can be converted to 7-O-triethylsilyl-lO- (1-ethoxyethyl) baccatin III (6d) in 90% yield by treatment with excess ethyl vinyl ether and a catalytic amount of methane sulfonic acid. These preparations are illustrated in the reaction scheme below. 103191/2 20 (6b) (6a) OCOCBH5 (6c) 0C0C6H5 (6d) 7-O-triethylsilyl baccatin III (6b), 7, 10-bis-O-triethylsilyl baccatin III (6c), or 7-O-triethylsilyl- 10- ( 1-ethoxyethyl ) baccatin III (6d) is reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF) , to form the metal alkoxide 13-0-lithium-7-0-triethylsilyl 21 103191 /2 baccatin III (7b) 13-0-lithium-7 , 10-bis-O-triethylsilyl baccatin III (7c), or 13-O-lithium-7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (7d) as shown in the following reaction scheme: T HF (7b) z = -OCOCH3 (7c) z = -OSi(C2H5)3 (7d) z = -OEE As illustrated in the following reaction scheme, a suitable metal alkoxide of the present invention such as 13-0-lithium-7-0-triethylsilyl baccatin III derivative. (7b, 7c, or 7d) reacts with a β-lactam of the present invention to provide an intermediate (8b, 8c, or 8d) in which the C-7 hydroxyl group is protected with a triethylsilyl or 1-ethoxyethyl group. 22 b-d Intermediate compound (8b) readily converts to taxol when R is -ORg, 2 and R3 are hydrogen, R4 is phenyl, R5 is benzoyl and R6 is a hydroxy protecting group such as r iethylsi lyl . Intermediate compound (8c) readily converts to taxotere when R is -OR g, R2 and R3 are hydrogen, R4 is phenyl, R5 is tertbutoxyca rbony1 and R6 is a hydroxy protecting group such as t riethyIs i ly1.

Intermediate compound (8d) readily converts to 10-deacetyl taxol when. R1 is -OR6, R2 and R3 are hydrogen, R is phenyl, R5 is benzoyl, and R6 is a hydroxy protecting group such as t riethyls i lyl . Intermediate compounds (8b, 8c and 8d) may be converted to the indicated compounds by hydrolyzing the triethylsi lyl and 1-ethoxyethy 1 groups under mild conditions so as not to disturb the ester linkage or the taxane derivative substituents.

HF, CcHcN, CHoCN 8b — > TAXOL HF, CcHcN, CH^CN- 8c ^—^ > TAXOTERE 0.1% HC1, EtOH 8d > 10-DEACETYL TAXOL 23 Other taxane derivatives may readily be prepared by selection of the proper substituents R^ - R5 of β-lactam (2) or R"L5 - R27 of metal alkoxide (3). The preparation of such other compounds is illustrated in the examples which follow.

Both the conversion of the alcohol to the metal alkoxide and the ultimate synthesis of the taxol can take place in the same reaction vessel. Preferably, the β-lactam is added to the reaction vessel after formation therein of the metal alkoxide.

The organometa 11 ic compound n-butyl lithium is preferably used to convert the alcohol to the corresponding metal alkoxide, but other sources of metallic substituent such as lithium diisopropyl amide, other lithium or magnesium amides, ethylmagnes ium bromide, methylmagnesium bromide, other organolithium compounds, other organomagnesium compounds, organosodium, organotitanium or organopotassiuni may also be used. Organometallic compounds are readily available, or may be prepared by available methods including reduction of organic halides with metal. For example, butyl bromide can be reacted with lithium metal in diethyl ether to give a solution of n-butyllithium in the following manner: - i o°c CH3CH2CH3CH-. Br + 2 Li ► CBjCHjCHjC^ Li ♦ Li Br Et -O Although THF is the preferred solvent for the reaction mixture, other ethereal solvents, such as dimethoxyethane, or aromatic solvents may also be suitable. Certain solvents, including some halogenated solvents and some straight-chain hydrocarbons in which the reactants are too poorly soluble, are not suitable. Other 103191/2 24 solvents are not appropriate for other reasons. For example, esters are not appropriate for use with certain organoirtetallic compounds such as n-butyllithium due to incompatibility therewith.

Although the reaction scheme disclosed herein is directed to the synthesis of certain taxol derivatives, it can be used with modifications in either the β-lactam or the tetracyclic metal alkoxide. Therefore metal alkoxides other than 13-0-lithium-7-0-triethylsilyl baccatin III may be used to form a taxol intermediate according to- the method of this invention. The β-lactam and the tetracyclic metal alkoxide can be derived from natural or unnatural sources, to prepare other synthetic taxols, taxol derivatives, 10-deacetyltaxols , and the enantiomers and diastereomers thereof contemplated within the present invention .

The process of the invention also has the important advantage of being highly diastereoselective. Therefore racemic mixtures of the side chain precursors may be used. Substantial cost savings may be realized because there is no need to resolve racemic β-lactams into their pure enantiomers. Additional cost savings may be realized because less side chain precursor, e.g., 60-70% less, is required relative to prior processes.

The water solubility of compounds of formula (1) may be improved if is -OR6 and R19 is -OTj, and R6 and/or Ti are a functional group which increases solubility, such as -COGCOR1 wherein: G is ethylene, propylene, CHCH, 1,2-cyclo-hexylene, or 1 , 2-phenylene; R1 = OH base, NR2R3, OR3, SR3, OCH2CONR4R5, or OH; R2 = hydrogen or methyl ; R3 = (CH2)nNR6R7 or (CH2) -.N^R^X^; n = 1 to 3 ; 103191/2 25 R4 = hydrogen or lower alkyl containing 1 to 4 carbons ; R5 = hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl , CH2C02H, or dimethylarninoethyl ; R6 and R7 = lower alkyl containing 1 or 2 carbons or benzyl, or R6 and R7 together with the nitrogen atom of NR6R7 forms one of the following rings R8 = lower alkyl containing 1 or 2 carbons or benzyl ; Xje = halide; and base = NH3, (HOC2H4)3N, N(CH3)3, CH3N (C2H4OH) 2 , NH2 (CH2) 6NH2, N-methylglucamine, NaOH, or KOH.

The preparation of compounds in which R6 or j. is -COGCOR1 is set forth in Hangwitz U.S. Patent 4,942,184 which is incorporated herein by reference.

The following examples illustrate the invention.

EXAMPLE 1 Preparation of 2 ' -ethoxyethyl-7-triethylsilyl taxol, and subsequently taxol, from racemic β-lactam: To a solution of 7-triethylsilyl baccatin III (20mg, 0.028 mmol) in 1 ml of THF at -78°C was added dropwise 0.17 ml of a 0.164M solution of nBuLi in hexane. After 30 min at -78°C, a solution of cis-l-benzoyl-3- (1-ethoxyethoxy) -4-phenylazetidin-2-one (47.5 mg, 0.14 26 mmol) in 1 ml of THF was added dropwise to the mixture. The solution was allowed to slowly warm (over 1.5 h) to 0°C and was then stirred at 0°C for 1 h and 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 flash chromatography to give 23 mg (80%) of (2'R, 3 ' S) -2 · -ethoxyethyl-7-triethylsilyl taxol and 3.5 mg (13%) of 2 ' , 3 ' -epi (2 ' S, 3 'R)-2 ' -ethoxyethyl-7-triethylsilyl taxol.

A 5 mg sample of (2'R, 3 ' S)-2 * -ethoxyethyl-7-triethylsilyl taxol was dissolved in 2 ml of ethanol, and 0.5 ml of 0.5% aqueous HC1 solution was added. The mixture was stirred at 0°.C for 30 h and diluted with 50 ml of ethyl acetate. The solution was extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to provide 4.5 mg (ca.90%) taxol, which was identical with an authentic sample in all respects.

A 5 mg sample of 2 ' , 3 ' -epi (2 · S, 3 'R)-2 ' -ethoxy-ethyl-7-triethylsilyl taxol was dissolved in 2 ml of ethanol and 0.5 ml of 0.5% aqueous HC1 solution was added. The mixture was stirred at 0°C for 30 h and diluted with 50 ml of ethyl acetate. The solution was extracted with 20 ml of saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography to provide 4.5 mg (ca.90%) of 2 ' , 3 ' -epitaxol . 27 EXAMPLE 2 Preparation of 2 ' , 7-(bis) triethylsi lyl taxol, and subsequently taxol, from racemic fl-lactam: To a solution of 7-triethylsi lyl baccatin III (lOOmg, 0.143 mmol) in 1 ml of THF at -45°C was added dropwise 0.087 ml of a 1.63M solution of nBuLi in hexane. After 1 h at -45°C, a solution of cis-l-benzoyl-3-triethylsilyloxy)-4-phenylazetidin-2-one (274 mg , 0.715 mmol) in 1 ml of THF was added dropwise to the mixture.

The solution was allowed to warm to 0°C and held at 0°C for 1 h. One ml of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCC>3 and 60/40 ethyl acetate/hexane . Evaporation of the organic layer gave a residue which was purified by flash chromatography followed by recrystallization to give 131 mg (85%) of (2'R, 3*S)-2' ,7-(bis)triethylsilyl taxol and 15 mg (10%) of 2· ,3'-epi(2,S/3,R)-2' , 7-(bis) triethylsilyl taxol.

To a solution of 121.3 mg (0.112 mmol) of (2'R, 3 ' S) -2 7-(bis) triethylsilyl taxol in 6 ml of acetonitrile and 0.3 ml of pyridine at 0°C was added 0.9 ml of 48% aqueous HF. The mixture was stirred at 0°C for 8 h, then at 25°C for 6 h. The mixture was 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 and recrystallization to give 94 mg (98%) taxol, which was identical with an authentic sample in all respects.

To a solution of 5 mg of (2*R, 3 ' S) -2 ' , 7- (bis ) triethylsilyl taxol in 0.5 ml of acetonitrile and 0.03 ml of pyridine at 0°C was added 0.09 ml of 48% aqueous HF. The mixture was stirred at 0°C for 8 h, then at 25°C for 6 h. The mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 5 mg of material which was 28 purified by flash chromatography and recrystallization to give 4.6 mg (ca. 95%) of 2 ' , 3 ' -epitaxol .

EXAMPLE 3 Preparation of 2 ', 7-(bis) triethylsilyl taxol, and subsequently taxol, from optically active β-lactam: To a solution of 7-triethylsilyl baccatin III (lOOmg, 0.143 mmol) in 1 ml of THF at -45°C was added dropwise 0.087 ml of a 1.63M solution of nBuLi in hexane. After 1 h at -45°C, a solution of (+) -cis-l-benzoyl-3-triethylsilyloxy-4-phenylazetidin-2-one (82 mg, 0.215 mmol) in 1 ml of THF was added dropwise to the mixture. The solution was allowed to warm to 0°C and held at 0°C for 2 hours. One 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 flash chromatography followed by recrystallization to give 145 mg (94%) of (2'R, 3'S)-2' ,7-(bis)triethylsilyl taxol.

To a solution of 121.3 mg (0.112 mmol) of (2*R, 3 ' S)-2 7-(bis) triethylsilyl taxol in 6 ml of acetonitrile and 0.3 ml of pyridine at 0°C was added 0.9 ml of 48% aqueous HF. The mixture was stirred at 0°C for 8 h, then at 25°C for 6 h. The mixture was 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 and recrystallization to give 94 mg (98%) taxol, which was identical with an authentic sample in all respects. 29 EXAMPLE 4 Preparation of taxotere.

To a solution of 7, 10-bis-triethylsilyl baccatin III (200 mg, 0.248 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- (tert-butoxycarbonyl) -3-triethylsilyloxy-4-phenylazetidin-2-one (467 mg, 1.24 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 280 mg of crude 2 ' , 7, 10-tris-triethylsilyl taxotere.

To a solution of 280 mg of the crude product 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 215 mg of material which was purified by flash chromatography to give 190 mg (95%) of taxotere, which was recrystallized from methanol/water . All analytical and spectral data were identical with that reported for taxotere in U. S. Patent 4, 814, 470.

EXAMPLE 5 wherein p2 is Preparation of 3 '-desphenyl-S'- (2-naphthyl) taxol.

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 rtunol) in 2 mL of THP at -45 °C waa added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -Ί5 °C, a solution of cis-l-benxoyl-3-triethylailyloxy-4- (2-naphthyl) azetidin-2-οηβ (620 mg, 1.43 mtnol) in 2 mL of THF wns 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 partition d between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 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 waa added 2.8 mL of 48% aqueous HP. 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 '-deaphenyl 3 *-· (2-naphthyl) taxol, which was recrystalllzed from 31 methanol/water. m.p 164-165 °C [a] «N4 -52.6° (c 0.005, CHClj) . lH NMR (CDC13, 300 MHz) 68.14 (d, J - 7.3 Hz, 2H, benzoate artho) , 7.96 (m, 1H, aromatic), 7.90 (m, 1H, aromatic), 7.35 (m, 2H, aromatic), 7.76 (m, 2H, aromatic), 7.60 (m, 3H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 2H, aromatic), 7,01 (d, J - 8.8 Hz, 1H, NH) , 6.27 (s, 1H, H10) , 6.26 (dd, J- 9.2, 9.2 Hz, 1H, H13), 5.97 (dd, J - 8.8, 2.5 Hz, 1H, Η3·), 5.68 (d, J - 7.1 Hz, 1H, Η2β), 4.93 (m, 1H, H5) , 4.92 (m, 1H, H2 · ) , 4.39 (m, 1H, H7), 4.30 (d, J - 8.5 Hz, 1H, Η20α) , 4.20 (d, J - 8.5 Hz, 1H, Η20β), 3.81 EXAMPLE 5A 32 Preparation of 3'-de3phenyl-3'-(l-naphthyl) taxol.

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C waa added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -4!> °C, a solution of cis-l-benzoyl-3-triethylsilyloxy-4- (1- naphthyl) azetidin-2-one (620 mg, 1.43 mmol) in 2 mL of THF wen 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)triethylsi3yl- 3'-desphenyl-3'-(l-naphthyl) taxol and a small amount of the (2'S,3'ft) isomer.

To a solution of 325 mg (0.287 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrlle and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous Hi'. 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 166 mg (64%) of 3'-(l-naphthyl) taxol, which was recrystallized from methanol/water. 33 m.p. 164-165 °C; [α] »ΜΛ -52.6° (c 0.005, CHC13) .

JH NMR (CDClj, 300 MHz) δ 8.11 (d, J - 7.1 Hz, 2H, bemoate artho) , 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, H2fJ), 4.85 (dd, J - 7.6, 2.2 Hz, 1H, H5) , 4.97 (dd, J ~ 1.6 Hz, 1H, H2»), 4.39 (m, 1H, H7), 4.24 (d, J - 8.5 Hz, 1H, H20CX), 4.17 (d, J - 8.5 Hz, 1H, Η20β) , 3.80 (d, J - 7.1 Hz, 1H, H3), 3.65 (br, 1H, 2 *OH) , 2.55 (m, 1H, H6 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 -15 °C, a solution of cis-l-benzoyl-3-triethylailyloxy-4- (4-methoxyphenyl) a2etidin-2-one (590 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 NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to givo 320 mg of a mixture containing (2,R,3lS)-2l/7-(bis)triethylsily -3 '-desphenyl-S1- (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 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 fox 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 Clash chromatography to give 172 mg (68%) of 3 · -desphen l-3 · -(4-methoxyphenyl) taxol, which was reerystallized from 35 mechanol/water . m.p. 174-176 °C; [aj",,. -43.86° (c 0.05, CHC13) . lH NMR (CDC13, 300 MHz ) 58.12 (d, J - 7.1 Hz, 2H, benzoate orlho) , 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 (a, 1H, H10) , 6.21 (dd, J - 9.3, 9.3 Hz, 1H, H13), 5.70 (dd, J - 8.8, 2.7 Hz, 1H, H3 · ) , 5.66 (d, J m 6.8 Hz, 1H, H20), 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, Η20α) , 4.18 (d, J- 8.Θ Hz, 1H, Η20β) , 3.78 (d, J- 6.3 H¾, 1H, H3), 3.78 (s, 3H, ArQMft) , 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 (3, 3H, lOAc) , 1.84 (m, 1H, Η6β) , 1.79 (br 3, 3H, Mel8), 1.79 (8, 1H, 10H> , 1.67 (3, 3H, Mel9), 1.22 (3, 3H, Mel7), 1.13 (3, 3H, Mel6) . 36 103191/2 EXAMPLE 6A 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-l-benzoyl-3-tri-ethylsilyloxy-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 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-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 37 methanol/water . m.p. 173-175 °C [a] »„. -50.3° (c 0.01, CHC13) . >H NMR (CDClj, 300 MHz) 58.13 (d, J - 7.1 Hz, 2H, benzoate ortfto) , 7.72 (d, J » 8.2 Hz, 2H, benzamide ortho), 7.65-7,35 (m, 10H, aromatic), 6.97 (d, J - 8.8 Hz, 1H, NH) , 5.27 (a, ]H, 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, Η2β) , 4.95 (dd, J »■ 8.8, 2.2 Hz, 1H, H5) , 4.77 (br 9, 1H, H2»), 4.40 (m, 1H, H7) , 4.31 (d, J - 8.2 H2, 1H, H20CX), 4.19 (d, J - 8.2 Hz, 1H, H20p) , 3.80 (d, J - 7.1 Hz, 1H, H3) , 3.61 (br a, 1H, 2*OH), 2.54 (m, 1H, H60) , 2.38 (3/ 3H, 4Ac) , 2.32 To a solution of 7-triethylsilyl baccatin III (200 mg, 0.2Θ6 mmol) in 2 mL of THF at -45 °C was added dropwise 0.1*74 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cia-l-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 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)triethy..silyl-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 acetonltrilc and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueou.t 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 265 mg of material which was purified by flash chromatography to give 186 mg (64%) of 3 ' -desphenyl-3 ' -(4-bromophenyl) taxol, which was recrystalli2ed from 39 methanol/water . m.p. 170-172 °C/ [CX] »N, -50.94n (c 0.01, CHC13) .

H NMR (CDC1 300 MHz) δ 8.12 EXAMPLE 8 Preparation of 3 '-desphenyl-3 \- (3, 4-methylenedioxyphenyl) taxol.

To a solution of 7-triethylailyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwiee 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of ois-l-benzoyl-3-triethylsilyloMy-4- (3, 4-methylenedioxyphenyl) 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 mi. 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)triethylsiJ.yl-3' -desphenyl-3' -<3, 4-methylenedioxyphenyl) taxol and a small amount of the (2'3,3'R) isomer.

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 2.6 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 41 (3, 4-methylenedioxyphenyl) taxol, which was recrystallized frora me hanol/water . m.p. 178-180 °C [O] -46.6° (C 0.005, CIIClj) .

:H NMR (CDClj, 300 MHz) δ 8.14 (d, J - 7.2 Hz, 2H, benzoate ortho) , 7.72 (m, 2H, aromatic), 7.15 (m, 1H, aromatic), 7.50 (m, 2H, aromatic), 7.38 (m, 2H, aromatic), 7.0 (m, 1H, aromatic), 6.94 (m, 2H, aromatic), 6.88 (d, J ■ 9.1 Hz, 1H, NH), 6.83 (m, 1H, aromatic), 6.28 (3, 1H, H10) , 6.23 (dd, J ·■ 9.1, 9.1 Hz, 1H, H13), 5.97 (3, 2H, methylene), 5.69 (dd, J n 9.1, 2.5 HZ, 1H, H3'), 5.68 (d, J- 6.9 Hz, 1H, Η2β) , 4.95 (dd, J - 9.6, 2.2 H , 1H, H5), 4.72 (dd, J - 2.5 H2, 1H, H2 · ) , 4.41 (m, 1H, H7) 4.31 - (d, J - 8.4 Hz, 1H, Η20α) , 4.20 (d, J» 8.4 Hz, 1H, H20|J), 3.81 (d, J - 6.9 He, 1H, H3), 3.60 (br, 1H, 2 ' OH) , 2.56 (m, 1H, H6a) , 2.43 (d, J m 4.1 Hz, 1H, 70H) , 2.39 (3, 3H, 4Ac), 2.31 (m, 2H, H14), 2.24 (a, 3H, lOAc) , 1.88 (m, 1H, H63), Χ.Θ2 (br 3, 3H, Me.18), 1.69 (3, 1H, 10H), 1.68 (s, 3H, Mel9), 1.24 (s, 3H, Mel7), 1.15 (s, 3H, Mel6) . 42 EXAMPLE 9 Preparation of 3 '-deephenyl-3 (3, 4-dimethoxyphenyl) taxol .

To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THP 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 cia-l-benzoyl-3-triethylailyloxy-4- (3, -dimethoxyphenyl) azetidin-2-one (630 m 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 NaflC03 and 60/40 ethyl acctate/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 (2'3,3'R) isomer.

To a solution of 330 mg (0.2Θ6 mmol) of the mixture obtained from the previous reaction in 16 mL of acetonitrlle 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 aC 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 '-desphen l-3'- 43 (3, 4-dimethoxyphenyl) taxol, which was recrystallizod from ir.ethanol/water , m.p. 165-167 °C [a] "N, -42.0° (c 0.0C5, CHCl3) .

H MMR (CDClj, 300 MHz) δ 8.12 (d, J « 8.3 Hz, 211, benzoate ortho) , 7.73 (d, J - 8.2 Hz, 2H, benzamide ortho), 7.65-7.35 (m, 6H, aromatic), 7.1-7.0 (m, 2H, aromatic), 6.94 (d, J m 8.8 Hz, 1H, NH), 6.88 (d, J- 8.3 Hz, 2H, aromatic), 6.27 (3, 1H, H10), 6.21 (dd, J " 9.3, 9.3 H2, 1H, H13), 5.69 (m, 2H, H3, Η2β), 4.94 (dd, H¾, J - 9.9, 2.2 Hz, 1H, H5) , 4.77 (d, J - 2.8 Hz, 1H, H2'), 4.39 (dd, J- 11.0, 6.6 Hz, 1H, H7), 4.30 (d, J - 8.5 Hz, 1H, H20CX), 4.19 (d, J- Θ.5 Hz, 1H, H2O0) , 3.88 (3, 3H, ArOMft), 3.87 (s, 3H, X OMft) , 3.80 (d, J - 7.1 Hz, 1H, H3), 3.59 (d, J - 4.4 Hz, 1H, 2' OH), 2.54 (m, 1H, H60C) , 2.38 (9, 3H, 4AO, 2.36 (m, 2H, H14tt, H14") , 2.23 (e, 3H, lOAc) , 1.86 (m, 1H, H6(3), 1.80 .

Preparation of W-debenzoyl-tf-ethoxycarbonyl taxol.

To a solution of 7-triethylsilyl baccatin III (155 mg, 0.221 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.136 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of ci5-l-ethoxycarbonyl-3-triethylsilyloxy-4-phenylazetidin-2-one (386 mg, 1.11 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 252 mg of a mixture containing (2 ' , 3 ' S) -2 · , 7- (bis) triethylsilyl-W-debenzoyl-W-ethoxycarbonyl taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 252 mg (0.112 mmol) 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 216 mg of material which was purified by flash chromatography to give 155 mg (85%) of tf-debenzoyl-W-ethoxycarbonyl taxol, which was recrystallized from methanol/water . 45 m.p. 161.5-162.5 °C [ "-H NMR (CDC13, 300 MHz) δ 8.12 (d, J - 7.7 Hz, 2H, benzoate ortho) , 7.65-7.3 (m, 8H, aromatic), 6.28 (m, 1H, H10) 6.2 (m, 1H, H13), 5.67 (d, J = 7.1 Hz, 1H, Η2β) , 5.53 (d, J =» 9.3 Hz, lH, H3'), 5.29 (d, J = 9.3 Hz, 1H, NH) , 4.94 (dd, J = 9.3, 2.2 Hz, 1H, H5), 4.64 (dd, J = 5.0, 2.8 Hz, 1H, H2 ' ) , 4.41 (m, 1H, H7), 4.29 (d, J - 8.5 Hz, 1H, H20 3.9 Hz 1H, 70H) , 2.36 (s, 3H, 4Ac),2.24 (s, 3H, lOAc) , 2.22 (m, 2H, H140C, Η14β) , 1.87 (m, 1H, H6(X) , 1.83 (br s, 3H, Mel8), 1.77 (s, 1H, 10H), 1.68 (s, 3H, Mel9) , 1.27 (3, 3H, Mel7), 1.15 (s, 3H, Mel6), 1.14 (t, J =» 7.1 Hz, 2H, COOCH2£a3) . 46 EXAMPLE 11 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 TH? at -45 °C wae added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at - 5 WC, a solution of cij-l-benzoyl-3-triethylsllyloxy-4- (4-nitrophenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 ml. of ?HF 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 aqueou9 NaHCOj 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) triethylsJiy -a'-desphenyl-S'-^-nitrophenyl) 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 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 wae purified by flash chromatography to give 147 mg (57%) of 3· -desphenyl-3 ' -(4-nitrophenyl) taxol, which was reorystallized from 47 methanol/water . m.p. 188-190 °C; [CX] »M, -63.7° (c 0.01, CHCl3) .

*R NM (CDClj, 300 MHz) 68.26 (d, J - 8.8 Hz, 2H, benzoate ort o) , 8.20 (m, 2H, aromatic), 7.73 (m, 4H, aromatic), 7.60 (m, 1H, aromatic), 7.52 (m, 4H, aromatic), 7.41 To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.087 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-l-benzoyl-3-triethylsilyloxy-4- (2-furyl) azetidin-2-one (266 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 3C 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 143 mg of a mixture containing (2 'R, 3 ' S) -2 · , 7- (bis) triethylsilyl-3 ' -desphenyl-3 ' - (2-furyl) taxol and a small amount of the (2'S,3'R) isomer.

To a solution of 143 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile- and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 115 mg of material which was purified by flash chromatography to give 98 mg (81%) of 3 '-desphenyl-3 (2-furyl) taxol, which was recrystallized from methanol/water . 49 .ο. 174-176 aC; [α]»!,, -47.3° (c 0.045, CHC13) .

'-H MMR (CDC13, 300 MHz) δ 8.14 (d, J = 7.0 Hz, 2H, benzoate ortho) , 7.74 (m, 2H, aromatic), 7.51 (m, 7H, aromatic), 6.86 (d, J = 9.2 Hz, 1H, NH) , 6.40 (d, J => 1.2 Hz, 2H, furyl) , 6.29 (s, 1H, H10), 6.24 (dd, J = 9.2, 9.2 Hz, 1H, H13) , 5.89 (dd, J = 9.2, 2.4 Hz, 1H, H3 ' ) , 5.69 (d, J = 7.0 Hz, 1H, Η2β) , 4.96 (dd, J - 9.5, 1.8 Hz, 1H, H5) , 4.83 (d, J = 2.4 Hz, 1H, H2 · ) , 4.42 (dd, J = 10.7, 6.7 Hz, 1H, H7), 4.31 (d, J - 8.6 Hz, 1H, Η20α) , 4.20 (d, J" - 8.6 Hz, 1H, Η20β) , 3.83 (d, J - 7.0 Hz, 1H, H3), 2.56 (m, 1H, H60C) , 2.43 (s, 3H, 4Ac) , 2.35 (m, 2H, H14) , 2.24 (s, 3H, lOAc) , 1.89 (m, 1H, Η6β) , 1..87 (br s, 3H, Mel8) , 1.87 (s, 1H, 10H) , 1.69 (s, 3H, Mel9),. 1.25 (s, 3H, Mel7) , 1.15 (s, 3H, Mel6) . 50 EXAMPLE 13 Preparation of. S'-desphenyl-S'-'^-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 0.17Ί mL of a 1.63M solution of nBuLi in hexane. After 0 . 5 h at -45 °C, a solution of ci*-l-benaoyl-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 UC 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 NaHCOa and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 2lb mg of a mixture containing ( 2 ' # 3 ' S) -2 · , 7- (bis) triethylsilyJ-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 recrystalliied from 51 methanol/water . m. .371-173 °C; [a] »„, -49.0° (c 0.005, CHC13) . l NM (CDClj, 300 MHz) δ 8.13 , 3.57 (d, J - 4.8 Hz, 1H, 2 ΌΗ) , 2.58 (m, 1H, H6a), 2.43 (d, J · 4.3 Hi, 1H, 70H) , 2.38 (a, 3H, 4Ac) , 2.30 (m, 2H, ΗΓ4), 2.24 (a, 3H, lOAc) , 1.85 (m, 1H, Η6β) , 1.80 (br a, 3H, Mel8) , 1.69 (s, 1H, 10H) , 1.55 (s, 3H, Mel9), 1.23 (9, 3H, el7), 1.14 (3, 3H, Mel6) .

EXAMPLE 14 Preparation of 3 * -Desphenyl-3 ' - (2-thienyl) taxol .

To a solution of 7-triethylsilyl baccatin III (100 mg, 0.143 mmol) in 1 mL of THF at -45 °C was added dropwise 0.087 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis-1- (4-benzoyl) -3-triethylsilyloxy-4- (2-thienyl) azetidin-2-one (277 mg, 0.715 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous 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 169 mg of a mixture containing (2 'R, 3 · S) -21 , 7- (bis ) triethylsilyl-31 -desphenyl-3 (2-thienyl) taxol and a small amount of the <2'S,3'R) isomer.

To a solution of 169 mg of the mixture obtained from the previous reaction in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 140 mg of material which was purified by flash chromatography to give 93 mg (76%) of 3 · -desphenyl-3 (2-thienyl) taxol, which was recrystallized from methanol/water. 53 .·?..?. 172-175 3C Γα] »4 -42.1° (c 0.515, CHCI3) . -3 M?.

Claims (10)

• 103191/4 54 ) WHAT I CLAIM IS:

1. A process for the preparation of a taxane derivative comprising: providing a metal alkoxide having the bi-, tri- 5 or tetracyclic taxane nucleus, reacting the metal alkoxide with a β-lactam wherein the β-lactam has the formula : wherein R is -OR6, -SR7, or -NRgRg; 10 R2 s hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; ' R3 and R4 are independently hydrogen, alkyl-, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R^ are not both acyl . and provided that when 15 one of R3 or R_, is hydrogen the other is not alkyl, alkeny alkynyl or aryl: R5 is -COR10, -COOR10 < -COSR1Q / -CONRgR10 -S02R1;L, or -POR12R13' 20 R6 is a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, provided that when R2 is hydrogen and R, is ORF, RFT is not a hydroxy protecting group; R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, - or sulfhydryl protecting group, Rg is hydrogen, alkyl, alkenyl, alkynyl, aryl, or 25 heteroaryl; Rg is an amino protecting group; R10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, provided that when R5 is CORK,. R|(> is not alkyl. alkenyl, alkynyl or aryl; 55 Rn is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -O 1Q/ or -NR8R14, R12 and R13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NRgR14, R1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and converting said intermediate to the taxane derivative .

2. The process of claim 1 wherein R2 and R4 are hydrogen or lower alkyl, R3 is aryl, and R^ is selected from the group consisting of -ORg, -SR7, and -NRgRg wherein R6, R7 and R9 are hydroxy, sulfhydryl, and amine protecting groups, respectively and Rg is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl.

3. The process of claim 2 wherein R3 is phenyl and RjL is -ORg wherein g is triethylsilyl , ethoxyethyl, or 2,2, 2-trichloroethoxymethyl .

4. The process of claim 1 wherein the metal alkoxide is a metal alkoxide of 7-protected baccatin III.

5. The process of claim 1 wherein the metal alkoxide has the following formula: 1 031 91 56 wherein t is a hydroxy protecting group, Z is -OCOCH3 or -OT2 wherein T2 is ■- a hydroxy protecting group and M is selected from the group comprising Li, Mg, Na, K and Ti .

6. The process of claim 5 wherein the β-lactam has the formula : C or wherein R6 is a hydroxy protecting group selected from the group consisting of triethylsilyl, ethoxyethyl, 2 , 2 , 2 -trichloroethoxymethyl , trimethylsilyl , dimethyl-t-butylsilyl , dimethylarylsilyl , dimethyl-heteroarylsilyl , and triisopropylsilyl . 57

7. A process for the preparation of a taxane derivative comprising: providing a metal alkoxide having the bi-, trior tetracyclic taxane nucleus, reacting the metal alkoxide with a β-lactam to form an intermediate, wherein the β-lactam has the formula: wherein R-L is -ORg, with Rg being alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl ; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl, Rj is -COR^Q, with Rin being alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy or heteroaryloxy and converting said intermediate to the taxane derivative. 103191/2 58

8. The process of claim 7 wherein the β-lactam has the formula: or CCHgD wherein R6 is a hydroxy protecting group

9. The process of claim 7 wherein the metal alkoxide is derived from an alcohol having the formula: wherein rT1 is a hydroxy protecting group, Z is -OT2, and T2 is acetyl or hydroxy protecting group. 103191/4 59

10. A β-lactam of the formula wherein Rl is -OR6, -SR7, or -NRgRg ; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heterparyl; R3 and 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl , and that heteroaryl is other than pyridyl; R5 is -COR10' -COOR10' -COSR1Q, -CONRgR10 •S02 i]_/ or -POR12R13' 6 is a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or a hydroxy protecting group, ' R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group, RQ is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; Rg is an amino protecting group; R^Q is alkyl, alkenyl, alkynyl, aryl, or heteroaryl , R^ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OR10, or -NR8RL4, are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl or -NRgR14, 103191/3 60 R14 is hydrogen, alkyl, alkenyl, aikynyl, aryl, or heteroaryl; provided, however, if R5 is -CORi0, at least one of the following conditions shall exist: (a) Rj shall have a value other than -OR6, (b) R2 shall be other than hydrogen, ,(c) R3 and R4 shall be other than hydrogen, (d) at least one of R3 and R4 shall be acyl , or (e) Rl 0 is other than alkyl, alkenyl, aikyny l or aryl. C:\2main\D61\61736.DOC