MXPA99007770A - Process for preparing pharmaceutical compounds - Google Patents

Abstract

Cryptophycin compounds may be prepared utilizing an epoxidation step early in the synthetic process under the conditions set forth herein. This invention also relates to novel intermediates generated by this early epoxidation process.

Description

PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOUNDS BACKGROUND OF THE INVENTION Neoplastic diseases, characterized by the proliferation of cells not subject to normal control of cell development, are a leading cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has shown that new and more effective drugs are desirable to treat these diseases. Such clinical experience has also shown that drugs that disrupt the microtubule system of the cytoskeleton may be effective in inhibiting the proliferation of neoplastic cells. Cryptophycin compounds can now be prepared using a total synthetic process; however, many of the useful cryptophycin compounds contain an acid labile epoxide group. Barro, R.A. et al., J. Am. Chem. Soc. 117, 2479 (1995). Applicants have discovered that beta-epoxide can be particularly desired. However, in the REF .: 30997 synthesis of Barrow and collaborators of some cryptophycin compounds of the formula (I) shown below, the epoxidation is carried out in the last step which provides only a selectivity of 2: 1 for the desired epoxide. In addition, diastereoisomers are difficult to separate at this stage. While it may be desirable to epoxidize an intermediate early in the process, the epoxides are sensitive for a number of reaction conditions. The present invention provides a much more desired novel and efficient method for the preparation of cryptophycin compounds having an epoxide functional group. The epoxidation takes place at an early step in the total synthesis process that allows the easier separation of diastereoisomers for the highest selectivity. In addition, epoxidation at an early stage increases the overall efficiency of the process by preserving materials, reducing costs and improving performance.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of the compound of the formula: (I wherein G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; RJ is alkyl of 1 to 6 carbon atoms; RA and R "are each hydrogen, or R4 and R5 taken together form a second bond between carbon 13 and carbon 14, R7 and R6 are each independently hydrogen or alkyl of 1 to 6 carbon atoms, or R7 and R8 taken together they form a cyclopropyl or cyclobutyl ring, R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl 3 to 5 carbon atoms) or benzyl, where m is the integer one to three, R10 is hydrogen or alkyl of 1 to 6 carbon atoms, R ?: is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl, R14 is hydrogen, or alkyl of 1 to 6 carbon atoms, R50 is hydrogen or (= 0), and is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms, R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl 3 to 8 carbon atoms substituted, a substituted heteroaromatic or heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R6a, R6b, and Rc independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR18; R 15 R 16 and R I 1 V 'are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR 16, O-aryl, NH 2, NR 18 R 19, N 0 2, OP 0 4 H 2, (C 1 -C 6 alkoxy) phenyl, S -benzyl, C0NH2, C0; H, P03H2, S02R2J or Z '; R18 and R1Q are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH;) p- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1, or 2; and is a substituted aromatic aromatic group; or a pharmaceutically acceptable salt thereof; which comprises deprotecting a compound of the formula (10) wherein G, R3, R5, R6, R, R8, R9, R10, R11, R14, R50 and Y are as defined above; q is a whole number 1 or 2; R81 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; and R82 is a base-labile protecting group, with a deprotection agent to form a compound of the formula (10a) wherein G, R3, R5, R6, R7, R8, R °, R1C0 R11, R14, R50, Y, q and R81 are as defined above; optionally contacting the compound of the formula (9c) a cyclization agent to form a compound of the formula (I); and optionally forming a pharmaceutically acceptable salt thereof. In addition, the present invention relates to a process for the preparation of a compound of the formula (I) comprising the steps of: (a) epoxidation of a compound of the formula 2) wherein G, R3, R4 and R5 are as defined above; R2a is hydrogen or tri (alkyl of 1 to 6 carbon atoms) silyl; and R is hydrogen or an activatable, suitable carboxyl protecting group; with an epoxidation agent to form a compound of the formula (3 wherein G, R3, R, R5, R2a and Rp are as defined above, with the proviso that R2a and Rp are not both hydrogen; (b) coupling the compound of the formula (3) with an amino acid of the formula (4) wherein R and R are as defined above and Rpl is hydrogen or alkyl of 1 to 6 carbon atoms; also in the presence of a silylating agent when R14 and Rpl are hydrogen; to produce a compound of the formula (5: wherein G, R% R4, R5, R a, Rpl, Rb and R14 are as defined above; c) deprotection of the compound of the formula (5) with an appropriate alkoxy deprotection agent, and further deprotection of the carboxyl of the compound of the formula (5) when Rpl is alkyl of 1 to 6 carbon atoms, with a adequate base to form a compound of the formula 6) wherein G, R3, R, R5, R6 and R14 are as defined above and M + is a cation; (d) contacting a compound of the formula (6) with a thioester forming agent, to form a compound of the formula wherein G, R3, R4, R5, R6, R14 and R81 are as defined above; (e) coupling a compound of the formula (7) with a compound of the formula wherein R7, R8, R9, R10, R11, R50 and R82 are as defined above, to form a compound of the formula where G, R3, R4, R5, R6, R, R8, R9, R, R11, R14, R50, R81, R82 and Y are as defined above; (f) oxidation of a compound of the formula (9) with an oxidizing agent to form a compound of the formula wherein G, R3, R4, R5, R6, R7, R8, R9, R10, R11, R14, R5C, R81 and R82, Y and q are as defined above; (g) deprotection of a compound of the formula (10) with a suitable deprotecting agent to form a compound of the formula (10a: where G, R3, R5, R6, R7, R8, R9, R10, R11, R "4, R50, Y and R81 are as defined above, and optionally contacting a compound of the formula (10) with a cyclization agent to form a compound of the formula (I), and (h) forming optionally a pharmaceutically acceptable salt of a compound of the formula (I).

In addition, the present invention relates to the compound of the formula wherein G, R3, R4, R5, R6, R, R8, R9, R10, R11, R14, R50, R81 and R82, Y and q are as defined above; or a pharmaceutically acceptable salt thereof; useful as an intermediary for the preparation of anti-neoplastic and / or anti-fungal agents. In addition, the present invention relates to a compound of the formula: (10a) wherein G, R3, R4, R5, R6, R7, R8, R ?, R1C, R11, R14, R50, Y and RB1 are as defined above, or a pharmaceutically acceptable salt thereof; useful as an intermediary for the preparation of anti-neoplastic and / or anti-fungal agents. In addition, the present invention relates to a compound of the formula wherein G, R3, R4, R5, R6, R7, R8, R9, R10, R11, R14, R50, R81, R82 and Y are as defined above; or a pharmaceutically acceptable salt thereof; useful as an intermediary for the preparation of anti-neoplastic and / or anti-fungal agents. In addition, the present invention relates to a compound of the formula where G, R3, R4, R5, R2a and Rp are as defined above, with the proviso that R "a u RF are not both hydrogen; useful as an intermediary for the preparation of antineoplastic and / or anti-fungal agents. In addition, the present invention relates to a compound of the formula wherein G, R3, R4, R5, R2a and Rpl, R6 and R14 are as defined above; useful as an intermediary for the preparation of antineoplastic and / or anti-fungal agents.

In addition, the present invention relates to a compound of the formula wherein G, R, R4, R, R and 14 are as defined above, and M + is a cation; useful as an intermediary for the preparation of anti-neoplastic and / or anti-fungal agents. In addition, the invention relates to a process for the preparation of a compound of the formula (I) which comprises deprotection of a compound of the formula (9) with a deprotection agent to form a compound of the formula 9ci G, R3, R \ R5, R6, R7, R8, R9, R: or, R11, R14, R50 and Y are as defined above; optionally contacting a compound of the formula (9c) with a cyclizing agent to form a compound of the formula (I), and optionally forming a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION As used in the request: (a) the designation * ^ m-m "refers to a link projecting forward from the page plane; (b) the designation * un ....-» refers to a link projecting backward from the page plane; and (c) the designation *? ** - * refers to a link for which the stereochemistry is not designated.As used herein, the term "Pharmaceutically acceptable salt" refers to either the acid addition salts or the base addition salts The term 'pharmaceutically acceptable acid addition salt' is intended to apply to any salt by the addition of non-organic or inorganic acid. toxic, of the compounds of the formula I or any of their intermediates. Illustrative inorganic acids which form the suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acid and the acid metal salts such as sodium monoacid orthophosphate and potassium acid sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymelic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2- phenoxybenzoic, and sulphonic, such as p-toluenesulfonic acid, methanesulfonic acid, and 2-hydroxyethane sulfonic acid. Such salts may exist in either hydrated or substantially anhydrous form. The term 'pharmaceutically acceptable base addition salts' is intended to apply to any non-toxic organic or inorganic base addition salts of the compounds of formula I, or any of its intermediaries.

Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonia and aliphatic, cyclic or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, isopropyldiethylamine, pyridine and picoline. As used herein, the term "alkyl of 1 to 12 carbon atoms" refers to a straight or branched chain hydrocarbon group, saturated from one to twelve carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl. , octyl, nonyl, decyl and the like. Included within the term is the term 'alkyl of 1 to 6 carbon atoms' which refers to a straight or branched chain hydrocarbon radical, unsaturated or saturated, of one to six carbon atoms, included within the scope of this term there are the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 2-methylbutyl, 3-methylbutyl, hexyl, and the like. from 1 to 12 carbon atoms "and" alkyl of 1 to 6 carbon atoms "are the terms" alkyl of 1 to 3 carbon atoms ", which refers to a straight or branched chain hydrocarbon radical, saturated, unsaturated , from one to three carbon atoms. Included within the scope of this term are the methyl, ethyl, isopropyl, and the like groups. "Substituted alkyl of 1 to 6 carbon atoms" refers to an alkyl group of one to six carbon atoms, which may include up to three (3) substituents containing one or more heteroatoms Examples of such substituents are OH, NH2 , CONH2, C02H, PO3H, PO3H2 and S02R21 wherein R2: is hydrogen, alkyl of 1 to 3 carbon atoms or aryl The term 'cycloalkyl of 3 to 8 carbon atoms' refers to a cycloalkyl group of 3 to 8 carbon atoms, saturated. Included within this group are the cyclopropyl, cyclobutyl, cyclohexyl, cyclooctyl and the like groups. A "substituted cycloalkyl group of 3 to 8 carbon atoms," refers to a cycloalkyl group of 3 to 8 carbon atoms, having up to three alkyl substituents of 1 to 3 carbon atoms, halo or OR21. bonded at any available carbon atom Cyclohexyl is an especially preferred cycloalkyl group The term '- (CH) m- (C 3 -C 5 cycloalkyl)', where m is a whole number one, two or three, refers to a cyclopropyl, cyclobutyl or cyclopentyl ring coupled to a methylidene, ethylidene or propylidene substituent. The term "alkenyl of 2 to 12 carbon atoms" refers to an unsaturated straight or branched chain hydrocarbon radical, having two to twelve carbon atoms and having one to three double bonds, included within the scope of this term, there are the ethenyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl, 2-methylbutenyl, 3-methylbutenyl, hexenyl, octenyl, nonenyl, decenyl and the like groups It is especially preferred that the alkenyl has only one double bond. alkynyl of 2 to 12 carbon atoms "refers to an unsaturated straight or branched chain hydrocarbon radical, having two to twelve carbon atoms, and having one to three triple bonds. Included within the scope of this term are ethynyl, propynyl, isopropynyl, 2-methylpropynyl, hexynyl, decynyl, and the like. It is particularly preferred that the alkynyl have only one triple bond. The term 'C 1 -C 6 alkoxy' refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy , pentoxy, 2-methylpentoxy, and the like The term "C 1 -C 6 -alkoxy" refers to a phenyl group substituted with an alkoxy group of 1 to 6 carbon atoms at any available carbon atom on the ring of phenyl. The term "halo" refers to chlorine, bromine, fluorine, or iodine The terms "aromatic group" and "heteroaromatic group" refer to common aromatic rings having 4n + 2 p-electrons in a monocyclic or bicyclic conjugate system. The term "aryl" refers to an aromatic group, and the term "aralkyl" refers to an aryl group (alkyl of 1 to 6 carbon atoms) Examples of aromatic groups are phenyl, benzyl and naphthyl. The heteroaromatic groups will contain one or more oxygen, nitrogen and / or sulfur atoms in the ring. Examples of heteroaromatic groups include furyl, pyrrolyl, thienyl, pyridyl, and the like. When the aromatic or heteroaromatic groups are substituted, they may have one to three substituents independently selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or halo. The aromatic groups can be further substituted with trifluoromethyl, COOR57 (wherein R57 is hydrogen or alkyl of 1 to 6 carbon atoms), P03H, SO3H, S02R57, N (R59) (R60) (wherein R59 is hydrogen or 1 to 6 carbon atoms and R °° is hydrogen, alkyl of 1 to 6 carbon atoms, BOC or FMOC), -CN, -NO3, -OR57, -CH2OC (O) (CH2) mNH2 (where m ' is an integer 1 to 6) or -CHz-O-Si (R57) (R58) (R59) (wherein R58 is hydrogen or alkyl of 1 to 6 carbon atoms). Especially preferred substituents for the aromatic groups include methyl, halo, N (R59) (R60), and -OR57. The substituents can be attached at any available carbon atom. Preferred substituted heterocyclic or heterocyclic groups include: wherein R20 is hydrogen or alkyl of 1 to 6 carbon atoms. The term "aryl" refers to an aromatic group of 6 to 12 carbon atoms, such as phenyl or naphthyl groups, wherein said groups are optionally substituted with one, two or three substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with halo, halogen or alkoxy of 1 to 4. The terms 'lower alkyl group' or 'alkoxy of 1 to 5 carbon atoms' refers to an alkyloxy radical constituted by an oxygen radical having a straight or branched chain saturated hydrocarbyl radical of from one to five carbon atoms and specifically includes methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy and the like Specifically included within the scope of the term 'aryl' are the phenyl, p-toluoyl, p-methoxyphenyl, p-chlorophenyl, naphthyl and the like groups. As used herein, the term "heteroaryl" refers to a substituted or unsubstituted heteroaromatic radical which contains one or more non-carbon substituents within the ring, said substituents being selected from oxygen, nitrogen or sulfur. of carbon atoms and atoms other than carbon in the ring is in the range of four to twelve atoms Specifically included within the scope of the term 'heteroaryl' are monocyclic conjugated systems such as furyl, pyrrolyl, thienyl, pyridyl and the like and conjugated bicyclic systems such as indole. As used herein, "epoxide ring" means a three-membered ring whose main chain consists of two carbon atoms and one oxygen atom.As used herein, "aziridine ring" means a three-membered ring whose main chain consists of two carbon atoms and one nitrogen atom. As used herein, "sulfide ring" means a three-membered ring whose main chain consists of two carbon atoms and one sulfur atom, as used herein "epilsulfide ring" means a three-membered ring whose Main chain consists of two carbon atoms and one sulfur atom. As used herein, "sulfate group" means a five-membered ring consisting of a carbon-carbon-oxygen-sulfur-oxygen backbone with two additional oxygen atoms connected to the sulfur atom. 'cyclopropyl ring' means a three-membered ring whose main chain consists of three carbon atoms. As used herein, "monoalkyl phosphate ring" means a five-membered ring consisting of a carbon-carbon-oxygen-phosphorus-oxygen backbone with two additional oxygen atoms, one of which has a lower alkyl group , connected to the phosphorus atom.

As used herein, the term '(= 0)' in combination with the carbon on the ring to which it is attached, refers to a carbonyl group of the formula The term "O-aryl" refers to an aryloxy or aryl group attached to an oxy moiety. As used herein, the term "TBS" refers to tert-butyldimethylsilyl represented by the formula As used herein, the term "NHS" refers to the N-hydroxysuccinimide represented by the formula As used herein, the term "Ph" refers to a phenyl portion As used herein, the term "amino protecting group labile to a base" refers to the amino protecting groups, common, the which are known to be labile to the bases. The person skilled in the art can consult common works such as Greene, T.W. Protecting Groups in Organic Synthesis, Wiley (New York, 1981) See particularly Greene Chapter 7. A particularly preferred base-labile amino protecting group is fluorenylmethoxycarbonyl (Fmoc). activatable carboxyl"suitable" refers to carboxyl protecting groups that contain activatable ester substituents and are known to one of ordinary skill in the art and are described by Greene, TW, supra.The suitable carboxyl protecting groups are those which are activatable by ester substituents including N-hydroxysuccinimide, N-hydroxysulfosuccinimide and salts thereof, 2-nitrophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, and the like .. An activatable carboxyl protecting group, especially preferred is N-hydroxysuccinimide ( NHS) A general synthetic procedure is described in Scheme A. In Scheme A, all substituents, unless otherwise indicated, are as previously defined.The reagents, techniques, and procedure used in the system A are well known and appreciated by someone of ordinary skill in the art.

E S BURN A SCHEME A (cont < 1) step 8 In Scheme A, step 1, an alkene of the formula (2) is epoxidized with an epoxidation agent to form an epoxide of the formula (3). The compound of the formula (2) can be non-selectively epoxidized using a suitable epoxidation agent. An "epoxidation or epoxidation" agent is an agent capable of converting the alkene analog of compound (2) to the epoxide of compound (3). Suitable epoxidizing agents include potassium peroxymonosulfate (Oxone) in combination with acetone, m-CPBA , methyltrioxorhene (VII), trifluoroperacetic acid, and magnesium monoperoxyphthalate, with Oxone in combination with acetone, or m-CPBA, which is preferred. Possible solvents for the epoxidation of a compound of the formula (2) include acetone, dimethylformamide, ethylene glycol monomethyl ether (glyme), dioxane, CH 3 CN, alcohols, tetrahydrofuran, ethyl acetate, halohydrocarbons, chlorobenzene, dichloromethane and toluene. The reaction optionally occurs in the presence of a suitable base such as sodium acid carbonate. The reaction temperatures may be in the range of about -30 ° C to about 50 ° C with about -10 ° C to about 25 ° C which is preferred. The epoxide of the formula (3) can be isolated and purified according to techniques and procedures well known in the art such as column chromatography. The a- and ß-epoxides of the formula (3) can also be separated by HPLC. It is preferred that the β-epoxide of the formula (3), the compound (3b), be separated from the α-epoxide of the formula (3), the compound (3a), and furthermore used in the remaining steps of the process of this invention for forming the β-epoxy of a compound of the formula (I). However, the epoxidation reaction of Scheme A, step 1 may also be used with the α-epoxide of the formula (3a) or with a mixture of the two epoxides.

The compound of the formula (2) wherein Rp is hydrogen can be epoxidized directly using m-CPBA. The epoxidation with m-CPBA can be carried out on a compound of the formula (2) to give a ß / a 1: 2: 1 diastereoisomeric mixture of the epoxides. The individual α- and β-diastereoisomers of (3) can be separated by high performance liquid chromatography (HPLC) high resolution liquid chromatography, as described above. This direct epoxidation is illustrated in Scheme B.

E S BURN B By eliminating the use of the N-hydroxysuccinimide ester, one step of the synthesis is eliminated. In addition, a compound of the formula (3c) can be prepared by deesterifying a compound (2b) according to Scheme Bl. In Scheme Bl, Ra is alkyl of 1 to 6 carbon atoms, while all remaining substituents are as previously defined.

SCHEME Bl In Scheme Bl, the alkyl ester of the formula (2b) is deesterified with a suitable deesterification agent to form the acid of the formula (3c). The term "suitable deesterification agent" encompasses any suitable means or conditions for removing the ester portion of Ra, while being inert to the epoxide.For example, a suitable base, such as potassium hydroxide, is added to a solution of the ester of alkyl of the formula (2b) in a suitable solvent, such as tetrahydrofuran The biphasic mixture is then allowed to stir at a temperature in the range of about 20 ° C to about 80 ° C, preferably 40 ° C and 65 ° C, a period of approximately 6 to 24 hours.

After cooling to room temperature, the aqueous layer is washed with an appropriate acid, such as IN hydrochloric acid, followed by brine. The mixture is dried, filtered and concentrated to provide the acid of (3c). The ester of the formula (2b) can be prepared by the epoxidation of the alkene derivative of Preparation 1, step 10, which is also known in the art. Barrow, R.A. and collaborators, J. Am. Ch em. Soc. 117, 2479 (1995). The compound of the formula (2) can also be stereoselectively epoxidized to form either the compound of the formula (3a) or (3b) using a chiral ketone with Oxone in the presence of a suitable base such as sodium acid carbonate using the methods analogous to those described by Tu, Y. et al., J. Am. Ch em. Soc. 118, 9806 (1996); Wang, Z-X et al., J. Org. Ch em. 62, 2328 (1997); Wang, Z-X et al., J. Am. Ch em. Soc. 119, 11224 (1997). Preferred compounds of the formula (2) for this reaction include those compounds where G is phenyl, R3 is methyl, R4 and R5 form a second bond and R is NHS. As used herein, the term "chiral ketone" refers to a ketone that contains the following general characteristics: 1) the stereogenic centers are close to the reaction center, and 2) the ketone has a fused ring and a quaternary center to a carbonyl group, and 3) one side of the ketone is sterically blocked.A particularly preferred chiral ketone is of the structure: This preferred chiral ketone can be prepared from D-fructose by ketalization and oxidation under routine conditions. For example, ketalization can be completed using acetone, HC104, and the process is conducted at approximately 0 ° C. For example, oxidation can be completed using pyridinium chlorochromate at room temperature. These reactions are known in the art; see, for example: Tu, Y. et al., supra, and Wang, Z-X et al., supra. The asymmetric epoxidation can be carried out at a pH in the range of about 7.0 to about 11.5 during the reaction. Although approximately 3 to 4 equivalents of the chiral ketone are required to obtain conversions greater than 95% with many cryptophycin intermediates at a pH of about 8.0, it is possible to use a less chiral ketone (approximately 1 to 2 equivalents) at a pH of approximately 9.0 or higher. Suitable solvents useful for the epoxidation step include water, dimethylformamide, diethylene glycol monomethyl ether (glyme), dioxane, CH3CN, alcohols, tetrahydrofuran, ethyl acetate, halohydrocarbons, chlorobenzene and toluene, with a combination of CH3CN / water solvents which is the preferred one. The reaction temperatures may be in the range of about -20 ° C to about 25 ° C, with about -10 ° C to about 10 ° C which is preferred. The individual isomers (3a) or (3b) of the raw product (3) can be isolated and purified by techniques well known in the art such as extraction, evaporation, chromatography and recrystallization. A preferred stereoselective epoxidation uses the chiral ketone of structure (2b) to provide a mixture of epoxides in the crude product (3) in the proportion of about: ß 1: 5. The compound of the formula (2) wherein Rp is hydrogen is known or is readily prepared by methods known or analogously known in the art; International Patent Publication No. WO96 / 07798, published March 6, 1997; International Patent Publication No. WO96 / 40184, published November 19, 1996; Barrow, R.A. and collaborators J. Am. Ch em. Soc. 117, 2479 (1995). The β-epoxide of the formula (3) is generally preferred and is used throughout the process of this invention. In Scheme A, step 2, the epoxide of formula (3) is coupled to the amino acid of formula (4), to produce a fragment compound A-B of formula (5). The amino acids of the formula (4) are commercially available or are readily prepared by methods known in the art. Particularly preferred amino acids of formula (4) include those where RB is a group of the formula (IA) and R6a is methoxy, R6b is chloro and Rbc is hydrogen; R14 is hydrogen; and RP1 is hydrogenated amino acids are described by PCT International Publication No. WO97 / 07798, published March 6, 1997, PCT International Publication No. WO96 / 40184, published December 9, 1996; Barrow, R.A. and collaborators, J. Am. Ch em. Soc. 117, 2479 (1995). The epoxide of the formula (3), where R ° is NHS is coupled to the amino acid of formula (4) according to coupling procedures that are inert to the epoxide functional group. For example, the epoxide of the formula (3) is contacted with about 1.5 to 3.5 equivalents of the amino acid (4), wherein Rpl and R14 are both hydrogen, and a suitable silylating agent in the presence of a suitable organic solvent. Suitable organic solvents include dimethylformamide, glime, dioxane, CH 3 CN, tetrahydrofuran, ethyl acetate, and halohydrocarbons, such as methylene chloride. The reaction is carried out at a temperature in the range of about -30 ° C to about 75 ° C, with a temperature in the range of about 20 ° C to about 60 ° C which is preferred. The compound of fragment A-B of formula (5) can be isolated and purified according to techniques and procedures well known in the art, such as extraction, evaporation, chromatography and recrystallization. As used herein, the tepain 'silylating agent' is selected from any reagent capable of coupling a silyl group to a silyl substituent.Sily-known silylating agents are employed See for example, Calvin, EW, 'Silicon Reagents in Organic Synthesis ", Academic Press, (London, 1988). Typical silylating agents in general include any reagent with a trialkylsilyl group such as trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, and t-butyldimethylsilyl, any reagent with an alkylarylsilyl group such as tribenzylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl, and tri-p-xylsilyl, and any reagent with a triarylsilyl group such as triphenylsilyl. The preferred silylating agent is a trimethyl silylating agent. Typical trimethyl silylating agents include N, O-bis (trimethylsilyl) acetamide, allytrimethylsilane, N, O-bis (trimethylsilyl) -carbamate, N, N-bis (trimethylsilyl) methylamine, bis (trimethylsilyl) sulfate, • N, 0-bis (trimethylsilyl) trifluoroacetamide, N, N-bis (trimethylsilyl) urea, (ethylthio) trimethylsilane, etyltrimethyl silylacetate, hexamethyldisilane, hexamethyldisilazane, hexamethyldisiloxane, hexamethyldisilyl, (isopropenyloxy) trimethylsilane, l-methoxy-2 -methyl-l-trimethyl-siloxy-propene, (methylthio) trimethylsilane, methyl 3-trimethylsilyoxy-2-butenoate, N-methyl-N-trimethylsilylacetamide, methyl trimethylsilylacetate, N-methyl-N-trimethylsilyl-hepta-fluorobutyramide, N-methyl-N-trimethylsilyl-trifluoroacetamide. , (phenylthio) trimethylsilane, trimethylsimethyl, trimethylchlorosilane, trimethyl ydosilane, 4-trimethylsiloxy-3-penten-2-one, N- (trimethylsilyl) acetamide, trimethylsilyl acetate, trimethylsilyl azide, trimethylsilyl benzenesulfonate, cyanide of trimethylsilyl, N-trimethylsilyldietylamine, N-trimethylsilyldimethylamine, trimethylsilyl N, -dimethylcarbamate, 1- (trimethylsilyl 1) imidazole, trimethylsilyl methanesulfonate, 4- (trimethylsilyl) morpholine, 3-trimethylsilyl-2-oxazolidinone. trimethylsilyl trichloroacetate, trimethylsilyl trifluoroacetate, and trimethylsilyl trifluoromethanesulfonate. Particularly useful silylating agents include the tri-lower alkyl silyl agents, the term of which contemplates triisopropylsilyl, trimethylsilyl and triethylsilyl, trimethylsilyl halides, silylated ureas such as bis (trimethylsilyl) urea (BSU) and silylated amides. as N, O-bis (trimethylsilyl) acetamide (BSA), Bis-N, O-trimethylsilylacetamide (BSA) is an especially preferred silylating agent, Alternatively, the desired β-epoxide (3c) can be coupled with (4), when Rpl is hydrogen, using a suitable coupling agent, preferably diphenylphosphinic chloride, and a silylating agent to give the AB (5) fragment.The suitable coupling agents are well known in the art, as described by Greene, TW ' Protecting Groups in Organic Synthesis ", Wiley (New York, 1981) and include N, O-diphenyl fos phynic chloride, diphenyl chlorophosphate, DCC, EDCI, chloroformates and 2-chloro-4,6-dimethoxy-1,3, 5-tr iazina. Diphenylphosphinic chloride is a preferred coupling agent. Suitable organic solvents described above, preferably methylene chloride, can be used. This procedure allows the elimination of the carboxyl protection step and allows the use of minor amounts of the amino acid (4). In Scheme A, step 3, the compound of fragment A-B of formula (5) is deprotected with a suitable alkoxy deprotection agent to form a compound of formula (6). A suitable alkoxy deprotection agent is one that removes the hydroxyl protecting group represented by the substituent R2a, while it is inert to the epoxide portion of the compound of the A-B fragment of the formula (5). Preferred deprotection agents include sources of basic fluoride such as tetrabutylammonium fluoride, pyridinium fluoride, triethylammonium fluoride, cesium fluoride, and the like, with tetrabutylammonium fluoride which is preferred. The deprotection reaction takes place in the presence of a suitable organic solvent such as tetrahydrofuran, optionally in the presence of a suitable base, such as sodium hydrogen carbonate (NaHCO 3). The reaction takes place in the range of about 0 ° C to about 80 ° C with about 20 ° C to about 70 ° C which is preferred. The reaction is run for a period of time in the range of about 3 to 24 hours. The crude product (6) can be used without further purification. Alternatively, the compound of the formula (6) can be isolated and purified according to procedures well known in the art, such as extraction, evaporation, chromatography and recrystallization. When Rpl for the compound of the formula (6) is hydrogen, the Rpl portion is effectively the cationic salt of the deprotection agent, for example, cesium, tetrabutylammonium, and the like. In Scheme A, step 4, the compound of the formula (6) is contacted with a thioester forming agent to form the ester of the formula (7). The term "thioester forming agent" encompasses any suitable means or conditions for the formation of the thioester portion of the formula (7). Included within this definition are the conditions described and / or analogously described in Ono, N. et al. , Bull, Chem. Soc. Jpn. 51 (8), 2401 (1978); Ho, Tse-Lok, Synth. Comm. 9 (4), 267-270 (1979); Narasaka, K. et al., J. Am. Chem. Soc. 106 (10), 2954-2960 (1984); L.G. Wade, Jr. and collaborators, Tetrahedron Lett. 731-732 (1978); Mora, N. et al., Tetrahedron Lett, 34 (15), 2461-2464 (1993); and Dossena, A. and collaborators JJ Chem. Soc. Perkin Trans. I, 2737 (1981). For example, the compound of the formula (6) can be treated with a sterically hindered alkyl halide, such as tertbutyl bromide, and a solvent of the formula (R81) (Me) SO, wherein R81 is as defined above , in the presence of a suitable base, such as sodium acid carbonate (NaHCO3). A preferred solvent for the reaction is dimethyl sulfoxide (DMSO). The sterically hindered alkyl halide and the suitable base are added in a molar excess of about 7.0 to 12.0 compared to the compound of the formula (6). The reaction takes place in the range of about 0 ° C to about 60 ° C with about 10 ° C to about 30 ° C which is preferred. The reaction is run for a period of time in the range of about 1 to 24 hours. The crude product (7) can be used without further purification. Alternatively, the ester of the formula (7) can be isolated and purified according to the procedures well known in the art such as extraction, evaporation, chromatography and recrystallization. In those cases when the substituent Rpl is a different portion of the hydrogen, the compound of the formula (6) must first be deprotected at the carboxyl. Deprotections at the carboxyl under basic conditions are known to those of ordinary skill in the art. For example, the compound of the formula (6) can be treated with a suitable base, such as lithium hydroxide (LiOH) for a period of time sufficient to remove the carboxyl protecting group, for example from about 1 to 24 hours. In Scheme A, step 5, the ester of the formula (7) is coupled with a carboxylic acid of the formula (8) to provide the compound of the formula ().

For example, the carboxylic acid of the formula (8) is dissolved in a suitable organic solvent, such as dimethylformamide, glime, dioxane, tetrahydrofuran, CH3CN, ethyl acetate, and halohydrocarbons, with dichloromethane being preferred. This solution is then treated with a coupling reagent. Possible coupling reagents include DCC, EDCI and similar reagents, such as DMAP which activate the carboxylic acids towards esterification with alcohols. This solution can then be optionally treated with a suitable base such as solid sodium acid carbonate, and then contacted with an ester of the formula (7). The concentration of (8) after these additions should be in the range of about 0.1 M to about 2.0 M. The reaction takes place in the range of about -30 ° C to about 60 ° C with about 10 ° C to about 30 ° C which is preferred. The reaction is run for a period of time in the range of about 0.5 to 12 hours. The final concentration of the crude product (9) can be used without further purification. Alternatively, the compound of formula (9) can be isolated and purified according to procedures well known in the art such as extraction, evaporation, chromatography and recrystallization. In Scheme A, step 6, the compound of the formula (9) is oxidized with a suitable oxidizing agent to provide the sulfone or the sulfoxide of the formula (10). A suitable oxidation agent is an agent capable of converting the sulfide of the formula (9) to the sulfone of the formula (10), while it is inert to the epoxide portion of the molecule. Suitable oxidizing agents include potassium peroxomonosulfate (Oxone), m-CPBA, methyltrioxorhenium (VII) and magnesium monoperoxyphthalate, with Oxone being preferred. For example, the sulfide of the formula (9) is treated with a suitable base, such as sodium acid carbonate followed by a suitable oxidizing agent, such as Oxone. The reaction is carried out in a suitable solvent, such as acetone, dimethylformamide, glime, dioxane, CH3CN, alcohols, tetrahydrofuran, ethyl acetate, halohydrocarbons, chlorobenzene, and toluene, with the acetone being preferred. In general, the reaction is carried out at temperatures from about -30 ° C to about 50 ° C with about -10 ° C to about 10 ° C which is preferred. In general, the reaction requires from about 15 minutes to about 5 hours. The crude sulfone or the sulfoxide (10) can be used without further purification. Alternatively, the sulfone or sulfoxide of the formula (10) can be isolated and purified according to procedures well known in the art such as extraction, evaporation, chromatography and recrystallization. In Scheme A, step 7, the sulfone or sulfoxide of the formula (10) is deprotected with a suitable deprotection agent to provide the amine of the formula (10a). A suitable deprotection agent is an agent capable of removing the base-laden R82 substituent on the compound of the formula (10), while it is inert to the epoxide portion of the molecule. Suitable deprotection agents include bases such as secondary and tertiary amines and inorganic bases for example, piperidine, morpholine, dicyclohexylamine, p-dimethylaminopyridine, diisopropylethylamine, and the like, with the piperidine being preferred. The reaction is carried out in a suitable solvent such as dimethylformamide, glime, dioxane, CH? CN, alcohols, tetrahydrofuran, ethyl acetate, halohydrocarbons, chlorobenzene, or toluene. In general, the reaction is carried out at a temperature in the range of about 0 ° C to about 120 ° C. In general, the reaction requires from about 1 to 72 hours. The compound of the formula (I) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization. Alternatively, the compound of the formula (10a) is isolated and can further be cyclized with a cyclization agent to provide a compound of the formula (I). Typically, once the compound of formula (10) is deprotected, it undergoes spontaneous cyclization. However, some particular compounds of the formula (10) may require an additional cyclization step. Also, for example, the sulfide of the formula (9), although much less active than its oxidized counterpart, after removal of the base-labile protecting group, can be cyclized with a suitable cyclization agent, such as 2-hydroxypyridine for forming a compound of the formula (I). For example, the sulfide of the formula (9), or alternatively a compound selected from the formula (10a), is heated in a suitable solvent, such as dimethylformamide at about 60 ° C for several days in the presence of piperidine and 2-hydroxypyridine. . The compound of the formula (I) is isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization. Optionally, on those compounds of the formula (I) which contain acidic or basic functional groups, the pharmaceutically acceptable salts of the compounds of the formula (I) can be formed using standard techniques. For example, the free base can be dissolved in aqueous or aqueous-alcoholic solution or other suitable solvent containing the appropriate acid, and the salt is isolated by evaporation of the solution. Alternatively, the free base can be reacted in an organic solvent containing the appropriate acid and the salt is isolated by evaporation of the solution. In addition, the free base can be reacted in an organic solvent in which case the salt is separated directly or can be obtained by concentrating the solution or in a solvent such as water which is then removed under vacuum or by lyophilization, or by cation exchange of an existing salt by another cation on a suitable ion exchange resin. A synthetic scheme for the preparation of the carboxylic acids of the formula (8) is described in Scheme C. The reagents and starting material are readily available to one of ordinary skill in the art. In Scheme C, all substituents, unless otherwise indicated, are as previously defined.

SCHEME C (11) (12) Protective Group Base Labile step 2 (B) In Scheme C, step 1, the Boc-protected amine of formula (11) is deprotected to provide the deprotected amine of formula (12). For example, the deprotection reaction involves the removal of an amino protecting group by techniques and procedures well known and appreciated by those of ordinary skill in the art. The selection, use and removal of protecting groups are described by Greene, T.W. Protecting Groups in Organic Synthesis, Wiley (New York, 1981) For example, the Boc-protected amine of formula (11) is dissolved in a suitable acid, such as trifluoroacetic acid or hydrochloric acid. it is carried out at a temperature in the range from about 0 ° C to about 60 ° C. In general, the reaction requires from about 1 to 24 hours.The deprotected amine of the formula (12) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization.The Boc-protected amine of formula (11) is described in Barrow, RA et al., JJ Am. Ch em. Soc. 117, 2479 (1995); International PCT Publication No. WO 96/40184, published December 19, 1996; and International PCT Publication No. WO 97/07798, published March 6, 1997. In Scheme C, step 2, the unprotected amine of Formula (12) is protected in group a with a protecting group of amino labile to the base, to provide the carboxylic acid of the formula (8). For example, the protection of an amino group with a base-labile amino protecting group, involves the addition of a labile amino protecting group to the base, by techniques and procedures well known and appreciated by one of ordinary skill in the art. The selection, use, and removal of base-labile amino protecting groups are as described by Greene, T.W. Protecting Groups in Organic Synthesis, Wiley (New York, 1981) A preferred protecting group of base-labile amino is Fmoc, for example, a solution of the deprotected amine of formula (12) in a suitable solvent , such as dioxane, is added to a suitable base, such as sodium bicarbonate, followed by a compound of the formula R82-C1 or R82-ONHS, such as Fmoc-Cl or Fmoc-ONHS-succinimide The mixture can optionally be diluted with a small amount of water and stirred for a period of time in the range of 12 to 48 hours at a temperature in the range from about 0 ° C to about 60 ° C. The mixture can be quenched with a suitable acid, such as hydrochloric acid The carboxylic acid of the formula (8) can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization.The pharmaceutically acceptable salts of a compound of the formula (I) can be in being optionally formed according to the procedures described in Scheme A. Some preferred features of this invention are as described in the following tabular form wherein features can be independently selected to provide preferred embodiments of this invention. The invention is by no means limited to the features described below: A) R8 is ethyl, propyl, isopropyl, butyl, isobutyl or isopentyl; B) R7 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl; C) R7 is hydrogen, R £ i is methyl, R3 is methyl; D) R3 is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl; E) R9 is methyl, ethyl, propyl, butyl, isobutyl, pentyl or isopentyl; F) R10 is methyl, ethyl, propyl, butyl, isobutyl, pentyl or isopentyl; G) Ar is phenyl optionally substituted with a substituent selected from the group consisting of hydrogen, halogen, -CH2OC (0) (CH2) m'NH2 and simple alkyl; H) a compound wherein Y is selected from the group consisting of O, NH, S, SO and S02; I) a compound wherein Y is CH, and R7, R8, R9 and R10 are each hydrogen; J) R7, R8 are each hydrogen; K) R7 and R8 are each selected from hydrogen or OH; L) R7 and R8 are each methyl; M) R7 and R8 together form a cyclopropyl group; N) Y is NH; O) R4 and Rb form a double bond; P) R6 is substituted benzyl wherein one substituent is a halogen and is an OR12 group wherein R12 is a lower alkyl; Q) the epoxidizing agent is Oxone; R) the epoxidation is selective; S) The chiral ketone is of the formula: T) Rp is NHS or hydrogen. The initial ester material can be prepared, for example, according to Scheme D. The reagents and the initial material are readily available to someone of ordinary skill in the art. In Scheme D, all substituents, unless otherwise indicated, are as previously defined. SCHEME D Step 9 KCN Step 10 DIBAL; HEW The scheme for the preparation of the ester is further explained by the Preparation Section herein, which provides a specific application of the scheme for the convenience of the person skilled in the art. Scheme D for the preparation of the ester is applicable to the Ar substituents claimed herein. The illustration of the scheme is not intended to limit the synthesis scheme only to the illustrated phenyl ring. Rather, the skilled person can widely apply this process to provide desired starting materials for use in the processes claimed herein. The necessary reaction time is related to the initial materials and the operating temperature. The optimal reaction time for a given process is, as always, a commitment that is determined by the consideration of the performance competition goals, which is favored by short reaction times, and maximum performance, which is favored by the extended reaction times. To further illustrate the invention, the following examples are provided. The scope of the invention is not considered in any way limited by the following examples.

Preparation 1 Step 1. 5-Phenylpent-2 (E) -methyl ester A solution of trimethyl phosphonoacetate (376 g, 417 ml, 2.07 mol) in 750 ml of tetrahydrofuran was stirred at 0 ° C in a 3-liter 3-neck round bottom flask equipped with a mechanical stirrer and inlet. nitrogen. To the cooled solution, pure tetramethylguanidine (239 g, 260 ml, 2.07 mol) was added dropwise via an addition funnel. The pale yellow, clear, cooled solution was stirred for 25 minutes at 0 ° C. A solution of hydrocinnamaldehyde (90%, 253 g, 248 ml, 1.9 mol) in tetrahydrofuran (125 ml) was added dropwise to the reaction solution slowly. After completion of the addition, the reaction was stirred for 10 hours raising the temperature to room temperature. GC indicated a 95: 5 ratio of the product to the initial material. 500 ml of water was added to the reaction vessel and the reaction was stirred overnight separating it into two layers. The organic layer was isolated and the aqueous layer was extracted with T-BuOMe. The organic layers were combined and dried over magnesium sulfate, then concentrated in vacuo to yield an orange oil. The crude product was distilled at 129 ° C / 0.3 mm Hg producing 360.5 g, 91.7% yield, of a slightly light yellow oil. EIMS m / z 190 (13; M +), 159 (410, 158 (39), 131 (90), 130 (62), 117 (22), 104 (12), 95 (57), 91 (100), 77 (21), 65 (59); HREIMS m / z 190.0998 (C? 2H1402 D -0.4 mnu); UV lmax (e) 210 (8400), 260 (230) n; IR n ax 3027, 2949, 1723, 1658, 1454, 1319, 1203, 978, 700 cm "1; XH-NMR d (CDC13) 7.15-7.3 (Ph-H5; bm), 7.00 (3-H, dt, 15.6 / 6.6), 5.84 (2-H; dt, 15.6 / 1.2), 3.70 (OMe; s), 2.76 (5-H2; t, 7.2), 2.51 (4-H2; bdt, 6.6 / 7.2); 13C NMR d (CDCI3 166.9 (1), 148.3 (3), 140.6 (pH-1 '), 128.4 / 128.2 (Ph2' / 3 '/ 5' 6 '), 126.1 (Ph 4'), 121.4 (2). 51.3 (OMe), 34.2 / 33.8 (4 /5) .

Step 2. 5-phenyl-pent-2-en-l-ol.

To a 12-liter, 4-neck, round bottom flask equipped with a thermocouple, mechanical stirrer and nitrogen inlet, an enolate ester solution of Preparation 1, step 1 (310.5 g, 1.5 mol) in tetrahydrofuran (1.5 liters) was charged and cooled to -71 ° C by means of a water bath. i-PrOH / C02. DIBAL (2.5 1, 1.5 M in toluene, 3.75 mol) was added dropwise to the reaction vessel at a rate or rate to keep the reaction temperature lower than -50 ° C. After the addition was complete, the reaction was stirred overnight with the reaction temperature lower than -50 ° C. TLC (3: 1 hexanes: ethyl acetate, Si02) indicated absence of initial material after 16 hours. The reaction temperature was allowed to rise to -15 ° C. The reaction was quenched slowly with 150 ml of IN hydrochloric acid. At this point the reaction became a gelatinous solid. A spatula was used to obtain the semi-solid and 200 ml of IN hydrochloric acid was added to make the mixture more fluid. 625 ml of concentrated hydrochloric acid was charged to form a two-phase system. The layers were separated and the product was extracted with t-BuOMe. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give a pale yellow, clear oil, 247.8 g. The crude product was distilled at 145 ° C / 0.25 mm Hg producing 209.7 g, 86.2%. EIMS m / z 162 (1: M +) 144 (16), 129 (7), 117 (9) 108 (6), 92 (17), 91 (100), 75 (5), 65 (12), HREIMS m / z 162, 1049 (CnHnO, D -0.4 miau); UV lmax (e) 206 (9900), 260 (360); IR nmax 3356, 2924, 1603, 1496, 1454, 970, 746, 700 cm "1; NMR lE d 7.15-7.3 (Ph-H5; m), 5.70 (3-H; dt, 15.6 / 6.0), 5.61 ( 2-H; dt, 15.6 / 4.8), 4.02 (1-H2; d 4.8), 2.68 (5-H2; t, 7.2), 2.40 (OH; bs), 2.36 (4-H2; dt, 6.0 / 7.2 ); 13 C NMR 141.6 (Phl '), 131.8 (3), 129.5 (2), 128.3 / 128.2 (Ph 2' Xi 'I' 1 '), 125.7 (Ph 4'), 63.3 (1), 35.4 / 33.8 (4/5).

Step 3. (2S, 3S) -2, 3-epoxy-5-phenyl-1-pentanol To a 1-liter 3-neck round bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet, 350 ml of methylene chloride was added, dried with 30 g of 4 Á molecular sieves, and added L- (+) -diethyl tartrate (7.62 g, 0.037 mol). The resulting mixture was cooled to -20 ° C and treated with Ti (0-i-Pr) 4 (9.2 ml, 0.031 mol), followed by the addition of t-butyl hydroperoxide (4.0 M in CH2C12, 182 ml, 0.78 mol) at a rate to maintain the temperature at -20 ° C. After completion of the addition, the reaction mixture was stirred for another 30 minutes, and then treated with an allyl alcohol solution of Preparation 1, step 2 (50 g, 0.31 mol) in 30 ml of methylene chloride at a speed to maintain the temperature at -20 ° C. The reaction was stirred at the same temperature for 5 hours, then filtered in a solution of 132 g of ferrous sulfate heptahydrate and 40 g of tartaric acid in 400 ml of water at 0 ° C. The mixture was stirred for 20 minutes, then transferred to a separatory funnel and extracted with two 200 ml portions of t-BuOMe. The combined organic phase was stirred with 30% sodium hydroxide solution containing sodium chloride, for 1 hour at 0 ° C. The layers were separated again, and the aqueous phase was extracted with t-BuOMe. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated to yield 52.8 g as an amber oil.

Step 4. (2R, 3R) -2-hydroxy-3-methyl-5-phenylpentan-1-ol.

To a 3-neck round bottom flask, liters, equipped with a mechanical stirrer, thermocouple and nitrogen inlet, added 1 liter of hexanes and cooled to 0 ° C. A 2.0 M solution of Me3Al in hexanes (800 mL, 1.6 mol) was added, followed by a solution of the epoxide of Preparation 1, step 3 (120 g, 0.677 mol) in 20 mL of hexanes / 50 mL of sodium chloride. methylene, keeping the temperature below 20 ° C. After the completion of the addition, the cloudy reaction mixture was stirred at 5 ° C for 35 minutes, after which 300 ml of a 10% hydrochloric acid solution was added dropwise, followed by the addition of 350 ml of concentrated hydrochloric acid. The layers were separated, and the organic phase was washed with brine and dried over magnesium sulfate. After removal of the volatile materials under vacuum, 122.1 grams of an oil was obtained.

Step 5. (2R, 3R) -2-Hydroxy-3-methyl-5-phenylpent-1-yl tosylate To a 2-liter 3-neck round bottom flask equipped with a mechanical stirrer and nitrogen inlet was added the diol of Preparation 1, step 4 (58 g, 0.30 mol), dibutyltin oxide (1.5 g, 0.006 mol, 2 mol%), toluenesulfonyl chloride (57.5 g, 0.30 mol), 580 ml of methylene chloride and triethylamine (42.0 ml, 0.30 mol). The resulting mixture was stirred at room temperature for 2 hours (although the reaction was completed within 1 hour), filtered, washed with water and dried over magnesium sulfate. Concentration of volatile materials in vacuo gave 104.1 g of a slightly amber oil.

Step 6. (2R, 3R) -2- [(tert-Butyldimethylsilyl) oxy] -3-methyl-5-phenylpent-1-yl tosylate A solution of the tosylate from Preparation 1, step 5 (100 g, 0.29 mol) and triethylamine (81.0 ml, 0.58 mol) in 1200 ml of methylene chloride was treated with pure TBS-OTf (99 ml, 0.43 mol) drop drop with continuous agitation for another 20 minutes. The reaction was washed twice with brine, dried over magnesium sulfate and concentrated to dryness. The oil was dissolved in a minimum amount of hexanes and filtered on a silica pad, eluting with hexanes: ethyl acetate (9: 1) to provide a slightly amber oil, 134 g.

Step 7. (2R, 3R, 5RS) -2- [(tert-Butyldimethylsilyl) oxy] -3-methyl-5-bromo-5-phenylpentyl tosylate.

To a 3-neck, 3-neck round-bottom flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet was added 1680 ml of carbon tetrachloride, the TBS Ts product of Preparation 1, step 6 (140 g , 0. 30 mol), NBS (65 g, 0.365 mol) and AIBN (16.5 g, 0.10 mol). The mixture was degassed by evacuation in complete vacuum by stirring, and re-gassing with nitrogen (3x). The reaction mixture was then heated to reflux, after which the color turned dark brown. After 15 minutes at vigorous reflux, the reaction mixture turned light yellow, and chromatographic analysis indicated that the reaction was complete. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated to dryness. The residue was redissolved in hexanes and filtered again, and concentrated to dryness to provide 170.3 grams as an amber oil.

Step 8. (2R, 3R) -2- [(tert-Butyldimethylsilyl) oxy] -3-methyl-5-phenylpent-4 (E) -en-1-yl tosylate.

To a 2-liter 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser, a solution of the bromide of Preparation 1, step 7 (100 g, 0.186 mol) in 700 ml of acetonitrile was added. DBU (83.6 ml, 0.557 mol) was added and the resulting dark brown solution was stirred at reflux for 15 minutes. After cooling to room temperature the solvent was removed in vacuo, and the residue was digested in 200 ml of methylene chloride and filtered through a pad of silica. The volatiles were again evaporated, and the residue was redissolved in ethyl acetate and washed with water, brine and dried over magnesium sulfate and concentrated to dryness. Preparative mplc chromatography (Prep 500) provided the desired unsaturated compound (50.3 g, 60% yield in 4 steps).

Step 9. (3S, 4R) -3- [(ter-but i ldimeti lsi li 1) oxy] -4-methyl-6-phenylhex-5- (E) -en-1-nitrile The tosylate from Preparation 1, step 8 (50 g, 0.11 mol) was dissolved in 1 liter of DMSO and treated with KCN (14.2 g, 0.22 mol) and 25 ml of water, and the resulting mixture was stirred at 60 °. C under nitrogen atmosphere for 18 hours. After cooling to room temperature, the reaction mixture was divided between 1 liter of ethyl acetate and 1 liter of water. The aqueous phase was extracted with 500 ml of ethyl acetate, and the combined organic phase was washed with brine and dried over sodium sulfate. Flash chromatography on silica with methylene chloride gave the desired nitrile in 92% yield.

Step 10. (5S, 6R) -5- [(tert-butyldimethylsilyl) oxy] -6-methyl-8-phenylocta-2- (E), 7 (E) -dienoate methyl.

The nitrile of Preparation 1, step 9 (14.67 g, 46.5 mmol) was dissolved in 200 ml of toluene and cooled to -78 ° C under nitrogen atmosphere. A 1.5 M solution of DIBAL in toluene (37.2 ml, 55.8 mol) was added dropwise with vigorous stirring. After completion of the addition, the cooling bath was removed and the reaction was stirred at room temperature for 1 hour. The reaction mixture was carefully poured into 1N hydrochloric acid and the mixture was stirred at room temperature for 30 minutes. The layers were separated, and the organic phase was washed with a saturated aqueous solution of sodium potassium tartrate (2x), brine and dried over sodium sulfate. The volatile materials were removed in vacuo, and the crude pale yellow oil was used directly in the subsequent condensation. The crude aldehyde from the previous step was dissolved in 90 ml of tetrahydrofuran and treated with trimethyl phosphonoacetate (9.03 ml, 55.8 mmol) and tetramethylguanidine (7.0 ml, 55.8 mol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 hours, then divided between 200 ml of ethyl acetate and 100 ml of water. The aqueous phase was again extracted with 100 ml of ethyl acetate, and the combined organic phase was washed with water, with brine and dried over sodium sulfate. The volatiles were removed in vacuo, and the crude yellow oil (17.0 g) was chromatographed on silica gel with methylene chloride: cyclohexane (1: 1 to 2: 1) to provide 13.67 grams of the desired ester, 78.5%.

Preparation 2 (5S, 6R) -5- [(tert-Butyldimethylsilyl) oxy] -6-methyl '8-phenylocta-2 (E), 7 (E) -dienoic acid.

The (5S, 6R) -5 - [(tert-butyldimethylsilyl) oxy] -6-methyl-8-phenylocta-2 (E), 7 (E) -dienoate methyl of Preparation 1, step 10 (1.00 g, 2673 mmol) was dissolved in 44 ml of acetone and then 26 ml of 1 N aqueous lithium hydroxide was added at room temperature. The cloudy mixture was further diluted with 20 ml of acetone and the resulting yellow mixture was stirred at room temperature for 23.5 hours. The reaction was diluted with 400 ml of diethyl ether and the organic materials were washed with 120 ml of 1 N hydrochloric acid, 200 ml of brine and 160 ml of water. The organic materials were dried over magnesium sulfate and concentrated in vacuo to leave a yellow oil which was purified by column chromatography (gradient elution: 5% AcOH + 20% -40% EtOAc / hexanes) to give the carboxylic acid as a yellow oil (960 mg, 100%). [a] D589 + 87.6 ° (c 10.5, CHC13; RMN lE (CDC13) d 7.38-7.19 (m, PhH5), 7.09 (ddd, J = 15.2, 7.6 and 7.9 Hz, 3-H), 6.38 (d, J = 16 Hz, 8-H), 6.16 (dd, J = 16 and 8 Hz, 7-H), 5.85 (d, J = 15.8 Hz, 2-H), 3.81-3.75 (m, 5-H) , 2.49-2.37 (m, 6-H, 4-HH '), 1.12 (d, J = 6.7 Hz, 6-Me), 0.91 (s, 9H, SiCMe3), 0.065 (s, SiMe), 0.068 (s) , SiMe) ppm; IR (CHC13) lmax 2957, 2930, 2858, 1697, 1258, 1098, 838 cm "1; MS (FD) 360.2 (M +, 100); Analysis calculated for C21H3203 requires: C, 69.95; H, 8.95% Found: C, 69.19; H, 8.39%.

Preparation 3 To a stirred solution of the carboxylic acid of Preparation 2 (720 mg, 2 mmol) in 5.50 ml of anhydrous dimethylformamide was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (459 mg, 2.4 mmol) and N-hydroxysuccinimide ( 299 mg, 2.6 mmol) at room temperature. The mixture was stirred for 28 hours and then diluted with 100 ml of ethyl acetate and washed with 2 50 ml portions of IN aqueous HCl, 75 ml of H 0, dried over magnesium sulfate, and concentrated in vacuo. to leave an oil. The crude product was purified by column chromatography (gradient elution: 5-30% ethyl acetate / hexanes) to give the active ester as a pale yellow oil (724 mg, 80%). [a] D589 + 71.3 ° (c 10.1, CHC13; 2H NMR (CDC13) d 7.36-7.20 (m, PhH5, 3-H), 6.38 (d, J = 16 Hz, 8-H), 6.14 (dd, J = 16.1 and 8.0 Hz, 7-H), 6.03 (d, J = 16 Hz, 2-H), 3.79 (q, J = 4.3 Hz, 5-H), 2.94 (broad, CH2CH2), 2.58-2.42 (m, 6-H, 4-HH '), 1.10 (d, J = 6.8 Hz, 6-Me), 0.90 (s, 9H, SiCMe3), 0.05 (s, 6H, SiMe) ppm, IR (CHC13) ? max 2957, 2931, 2858, 1772, 1741, 1648, 1364, 1254, 1092, 1069, 838 cm "1; MS (FD) 457 (M +, 100); Analysis calculated for C2; > H35N05 requires: C, 65.61; H, 7.71; N, 3.06% Found: C, 65.51; H, 7.56; N, 3.02%.

Preparation 4 To a stirred solution of active ester of Preparation 3 (2.50 g, 5.47 mmol) in 130 mL of CH3CN was added 15 mL of 48% aqueous HF, at 0 ° C. The solution was stirred at 0 ° C for 0.75 hours and then at room temperature for 4 hours. The reaction was diluted with 300 ml of diethyl ether and washed with water until the wash had a pH of about 7. The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give a yellow residue which was recrystallized from of Et20 to give the alcohol as white crystals (1.46 g, 78%). NMR lE (CDC13) d 7.41-7.20 (m, PhH5, 3-H), 6.48 (d, J = 16 Hz, 8-H), 6.15-6.07 (m, 7-H, 2-H), 3- 71-3.65 (m, 5-H), 2.83 (broad s, CH: CH2), 2.60-2.33 (m, 6-H, 4-CH2), 1.95 (broad s, 5-OH), 1.14 (d, J = 6.8 Hz, 6-Me) ppm: IR (KBr)? Ma 3457, 1804, 1773, 1735, 1724, 1209, 1099, 1067, 1049, 975, 744, 694 cm "1; UV (EtOH)? Max 250 (e = 20535) nm; MS (FD) 343.2 (M \ 100); [a] D -57.8 ° (c 10.56, CHC13); Analysis calculated for C? 9H2? N05S requires: C, 66.46; H, 6.16; N, 4.08%. Found: C, 66.49; H, 6.16; N, 4.07%.

Preparation 5 ml of acetone was added to a solution of the active ester of Preparation 3 (2.90 g, 6.35 mmol) in 20 ml of dichloromethane and the solution was cooled to 0 ° C. An aqueous solution of Oxone (11.7 g, 19 mmol) in 30 ml of water was then slowly added to the stirred solution of aqueous sodium hydrogen carbonate (5.3 g, 63.5 mmol) in 30 ml of water (evolution of gas) .

The resulting solution was added to the reaction mixture and stirred at 0 ° C for 7 hours (50% conversion by tic). An additional 6 g of Oxone and 15 ml of acetone were added and the mixture was stirred for 1.5 hours (all SM was consumed, by tic). The reaction mixture was diluted with water (5 volumes) and the product was extracted with 5 portions of 100 ml of methylene chloride. The combined organic extracts, dried with magnesium sulfate, were concentrated in vacuo to give the product as a yellow gummy solid (2.88 g). Tic and NMR: H indicated 90% of the desired epoxide product (a: ß = 1: 1.62): 10% SM. The crude product was purified by column chromatography (SiO;: gradient elution: ethyl acetate: hexanes 15% -25% to give the recovered styrene (389 mg, 13%) and the epoxide as a yellow oil (2.38 g, 80%) .The epoxides (2 g, a: ß = 1: 1.50) were separated by HPLC to give the β-epoxide as a white crystalline solid (1.17 g, 59%, 99.8% of) and the α-epoxide as a white crystalline solid (0.864 g, 43.2%, 99% ee).

Preparation 5A Alternative Preparation To a vigorously stirred solution of styrene (229 mg, 0.50 mmol) in 7.5 ml of acetonitrile, 5 ml of 0.1M aqueous Na EDTA and 0.1 ml of 0.1M aqueous tetra-n-butylammonium hydroxide, catalytic, at 0 ° were added. C. A mixture of Oxone and sodium bicarbonate (326 mg, 3.88 mmol) was sprayed and a portion of about 1/5 was added to the reaction mixture to bring the pH to approximately 7. After 5 minutes, the ketone was added ( 194 mg, 0.752 mmol) in portions over a period of 1 hour. Simultaneously, the remaining mixture of Oxone-sodium bicarbonate was added in a period of about 1 hour. After the additions were complete, the reaction was allowed to stir at 0 ° C for 4.5 hours (HPLC showed styrene: epoxide 50:50 and epoxide a: ß = 1: 5.6). An additional 380 mg of Oxone and an additional 170 mg of sodium bicarbonate were added in portions over a period of 1 hour and then the reaction was allowed to stir for an additional 3.5 hours, the reaction was diluted with 50 ml of ethyl acetate and washed with 50 ml of water. The organic extracts were dried over magnesium sulfate and concentrated in vacuo to give a crude product as an oil (140 mg).

HPLC: reversed phase C18 column, 70:30 CH3CN: H: 0, flow rate 1.0 ml / minute, 1 = 220 nm ß-epoxide Rt = 6.80 min (38.3%), a-epoxide Rt = 8.43 min (8.71 %), styrene Rt = 13.90 min (2.81%). a: ß epoxide = 1: 4.4 and styrene: epoxide = 6:94 Preparation 6 HPLC: C18 reverse phase, flow rate 1 ml / min, 60: 40-CH3CN: H2O,? Max = 254 nm, ß-epoxide Rt = 17.2 min (AUC 1.5); [a] D589 +77.36 (c 1.06, CH2C12); NMR XH (CDC13) d 7.35-7.24 (m, 6H, ArH5, 3-H), 6.08 (d, J = 15.8 Hz, 2-H), 3.91-3.88 (m, 5-H), 3.70 (s, 8- H), 2.97 (dd, J = 6 and 0.9 Hz, 7-H), 2.85 (s, 4H, CH2CH2), 2.56-2.51 (m, 4-HH '), 1.78-1.76 (m, 6-H) , 1.06 (d, J = 6.9 Hz, 6-Me), 0.86 (s, 6H, SiCMe3), 0.05 (s, SiMe), 0.01 (s, SiMe) ppm; IR (CHC13)? Ma? 2957, 2931, 1742, 1773, 1200, 1069, 839 cm "1; UV (EtOH)? Raax 217 (e = 21280) nm; MS (FD) m / z 474 (M +, 10), 416 ([M- CMe3] +, 100) Analysis calculated for C25H35NO6 requires: C, 63.40; H, 7.45; N, 2.96% Found: C, 63.45; H, 7.31; N, 3.21% Preparation 7 HPLC: C18 reverse phase, speed, flow rate 1 ml / min, 60: 40-CH3CN: H2O,? Max = 254 nm, a-epoxide Rt = 21.0 min (AUC 1.0); [a] D589 + 10.68 ° (c 1.03, CH2C12); NMR XH (CDC13 d 7.38-7.26, m.6H, ArH5, 3-H), 6.13 (d, . 7 Hz, 2-H), 3.94-3.89 (m, 5-H), 3.60 (s, 8-H), 2.99 (d, J = 7.3 and 1.3 Hz, 7-H), 2.85 (s, 4H, CH2CH2), 2.76-2.71 (, 4-H), 2.61-2.54 (m, 4-H '), 1.64 (dt, J = 7.2 and 2.8 Hz, 6-H), 1.03 (d, J = 7 Hz, 6-Me), 0.90 (s, 9H, SiMe3), 0.08 (s, SiMe), 0.05 (s, SiMe) ppm; IR (CHC13)? Raax 2957, 2931, 1741, 1773, 1649, 1254, 1200, 1125, 1095, 1069, 891, 839 cm "1; UV (EtOH)? Max 218 (e = 21727) nm; MS (FD) ) m / z 474 (M +, 10), 416 ([M-CMe3] 0 100); Analysis calculated for C25H35N06 requires: C, 63.40; H, 7.45; N, 2.96% Found: C, 63.20; H, 7.63; N, 3.07%.

Preparation Preparation of Fragment Acid A ß-epoxy (3c '). A solution of 2a '(1.91 g, 5.30 mmol) of the formula in 18 ml of methylene chloride was treated with m-chloroperbenzoic acid (0.96 g, 5.6 mmol) and the mixture was stirred for 4 hours before the volatiles were evaporated to give 2.88 g of a colorless oil. Preparative HPLC was used to separate the epoxides (1.2: 1 ß: a) to give the desired ß-epoxide as a colorless solid (42%). 1H NMR (500 MHz, CDC13) d 7.37-7.27 (m, 5H), 7.11 (ddd, ÍH, J = . 5, 7.6, 7.6 Hz), 5.92 (d, ÍH, J = 15.5 Hz), 3.90 (ddd, HH, J = 5.6, 5.6, 5.4 Hz), 3.70 (d, HH, J = 2.0 Hz), 3.00 (dd, HH, J = 6.6, 2.1 Hz), 2.51 (dd, 2H, J = 6.5 , 6.5 Hz), 1.77-1.73 (m, ÍH), 1.10 (d, 3H, J = 6.8 Hz), 0.89 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H). Ms (fd M / Z 377 (m + l, 43), 319 (M-57, 100).

Preparation 9 Alternative Preparation of Acid Fragment A of ß-epoxy. To a stirred solution of the 2a 'acid (100 mg, 0.277 mmol) in 3.7 ml of CH3CN at 0 ° C was added a solution of Na2EDTA (1X10"4 M in H20, 2.8 ml, 0.28 μmol) and tetrabutylammonium hydroxide (1). M in methanol, 28 μl, 28 μmol), then sodium hydrogen carbonate (23.3 mg, 0.277 mmol) was added, the pH adjusted to 8.0 with 2M sodium hydroxide and a mixture of Oxone (1.70 g, 2.77 mmol) was prepared. ) and sodium acid carbonate (722 mg, 8.59 mmol) A 100 mg portion of Oxone / sodium acid carbonate was added, followed by the ketone (2b) (143 mg, 0.554 mmol) The pH was immediately adjusted to 7.8-8.0 with 2M sodium hydroxide The rest of the Oxone / NaHC03 mixture was added in portions of 95 mg at 10 minute intervals and a solution of (2b) (143 mg, 0.554 mmol) in 500 μl was added. CH3CN to the mixture, during this period by means of a syringe pump.At the end of the experiment the pH was maintained at 7.8-8.0, with 2M sodium hydroxide and sulfuric acid IN. HPLC analysis (C18 reverse phase, detection at 220 nm, flow rate at 1 ml / min, CH3CN (0.05% TFA) / H2O (0.05% TFA) -% CH3CN: 80% to 90% in 10 minutes) 3 hours after the addition of Oxone it was revealed that the conversion was greater than 95% with an ß / a epoxide ratio of 5.0: 1. The mixture was filtered and the wet filter cake was washed with 15 ml of methylene chloride. The filtrate was washed with 15 ml of water and the aqueous phase was back extracted with 15 ml of methylene chloride. The combined organic phases were washed with 10 ml of 0.1 M HCl and 10 ml of water, dried over magnesium sulfate, and concentrated to give the crude product 4a as a yellow solid (104 mg, 100%).

Preparation 10 Preparation of the Methylester Ester of β-epoxy Fragment. The epoxidation of the methyl ester of Preparation 1, step 10 (104 mg, 0.278 mmol) was carried out in the same manner as described in Preparation 9, except that the pH was decreased to 3.3 with IN sulfuric acid, after added tetrabutylammonium hydroxide, before the addition of sodium bicarbonate. The HPLC analysis (same method that was used for the analysis of the product of Preparation 9 except% of CH3CN: 95%, isocratic) 2 hours after the addition of Oxone, revealed that the conversion was greater than 95% with a of epoxide ß / a of 4.9: 1. After 6 ml of methylene chloride was added, the mixture was filtered and the wet filter cake was washed with 14 ml of methylene chloride. The filtrate was washed with 10 ml of water and the aqueous phase was re-extracted with 2 20 ml portions of methylene chloride. The combined organic phases were dried over magnesium sulfate and concentrated to give the crude product as a yellow oil (123 mg, 113%). NMR JE (500 MHz, CDC13) d 7.38-7.26 (m, 5H), 6.99 (ddd, 1H, J = 15.8, 7.6, 7.6 Hz), 5.91 (d, ÍH, J = 15.8 Hz), 3.87 (ddd, ÍH, J 0 5.6, 5.6, 5.4 Hz), 3.75 (s, 3H), 3.70 (d, ÍH, J = 2.1 Hz), 3.00 (dd, ÍH, J = 6.8, 2.1 Hz), 2.49-2.45 (m , 2H), 1.75-1.69 (m, ÍH), 1.10 (d, 3H, J = 6.8 Hz), 0.88 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H), MS (FD) m / z 391 (M + l, 8), 333 (M-57, 100).

Preparation 11 Alternative Preparation of Fragment A of ß-epoxy. To a solution of the methyl ester of Preparation 10 (7.35 g, 18.8 mmol) in 35 ml of tetrahydrofuran was added 35 ml of 2N potassium hydroxide. The biphasic mixture was allowed to stir at 56 ° C for 14 hours.

After cooling to room temperature, the layers were separated and the aqueous layer was washed with t-butyl methyl ether (1 x 50 ml). The combined organic extracts were washed with IN hydrochloric acid (1 x 35 ml) followed by brine (1 x 35 ml). Drying with sodium sulfate with simultaneous treatment with Darco (20-40 mesh) followed by filtration and concentration in vacuo gave 7.85 g of the crude acid as a brown oil.

Example 1 To a solution of β-epoxide of Preparation 6 (473 mg, 1.0 mmol) in 6.7 ml of anhydrous dimethylformamide was added amino acid * B "(459 mg, 2.0 mmol), represented by the formula PCT International Publication No. WO 97/07798, published March 6, 1997; followed by N, 0-bis- (trimethylsilyl) acetamide (618 μl, 2.5 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to 55 ° C (a solution formed) for 8 hours, diluted with 250 ml of ethyl acetate and washed with 3 portions of 80 ml of IN aqueous hydrochloric acid, and with 100 ml of water. The combined organic extracts, dried over magnesium sulfate, were concentrated in vacuo to give a yellow foam (590 mg), which was further purified by column chromatography (Si02, gradient elution: methylene chloride - 5% -10% of methanol: methylene chloride) to give the silyl ether product as a white foam (489 mg, 89%). [a] 589 + 28.33 ° (c 1.06, MeOH); NMR aH (DMSO-d6) d Unit A: 7.33-7.17 (m, ArH5), 6.55-6.40 (m, 3-H), 6.03 (d, J = 15.3 Hz, 2-H), 3.83-3.76 (m, 5-H), 3.71 ( s, 8-H), 2.90 (d, J = 6.8 Hz, 7-H), 2.46-2.27 (m, 4-HH '), 1.50-1.44 (m, 6-H), 0.94 (d, J = 6.7 Hz, 6-Me), 0.74 (s, 9H, SiMe3), -0.54 (s, SiMe), -0.13 (s, SiMe); Unit B: 7.76 (d, J = 7.3, NH), 7.33-7.17 m, ArH), 7.04 (d, J - 8.5, ArH), 6.90 (d, J = 8.5, ArH), 4.27-4.23 (m, 2-H), 3.72 (s, 3H, OMe), 3.02 (dd, J = 13.3 and 4.3 Hz, 3-H), 2.78 (dd, J = 13.5 and 7.8 Hz, 3-H ') ppm; IR (KBr) u 2955, 2930, 2857, 1668, 1605, 1504, 1463, 1454, 1279, 1258, 1067, 1026, 837, 776 cm "1; UV (EtOH) lmax 278 (e = 2219) nm.

Example 2 Method A To a solution of the silyl ether of Example 1 (160 mg, 0.272 mmol) in 3.5 ml of anhydrous dimethylformamide, sodium bicarbonate (228 mg, 2.72 mmol) was added followed by solid hydrated solid tetrabutylammonium fluoride (TBAF) (358 mg. , 1.36 mmoles). The mixture was heated at 60 ° C for 17 hours and then additional TBAF (358 mg, 1.36 mmol) was added and heated for 9 hours and finally a solution of 1M TBAF in tetrahydrofuran (360 μL, 1.36 mmol) was added to make the mixture reaction of a brown color. The mixture was heated for 20 minutes and then the reaction was quenched in 100 ml of water and extracted with 3 50 ml portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, concentrated in vacuo to give a brown oily gum (248 mg). The crude carboxylate salt was used in the next step without further purification.

Example 3 Method B To a solution of the silyl ether of Example 1 (145 mg, 0.247 mmol) in 3.0 mL of anhydrous tetrahydrofuran, a 1M solution of tetrabutylammonium fluoride (800 μL, 0.8 mmol) was added under an atmosphere of anhydrous nitrogen. The resulting solution was heated at 60 ° C for 7 hours and then worked up as described above to give a brown residue (166 mg, 94%). The crude carboxylate salt was used in the next step without further purification.

Example 4 To an anhydrous solution of the crude carboxylate salt (0.272 mmole) in 3.5 ml of DMSO was added sodium bicarbonate (274 mg, 3.26 mmol) followed by the slow addition of a solution of t-butyl bromide (373 mg, 2.72 mmoles) in 1.5 DMSO in approximately 2 hours at room temperature and under nitrogen atmosphere. The mixture was stirred for an additional 21 hours and then quenched in 50 ml of brine and extracted with 3 30 ml portions of ethyl acetate. The organic extracts were washed with 50 ml of water, dried over sodium sulfate and concentrated in vacuo to give a crude ester as a gummy solid (117 mg, 81%). The crude alcohol A-B was used in the next step without further purification.

Example 5 Boc-a ina (1.69 g, 5.09 mmoles) of the formula PCT International Publication No. WO 97/07798, published March 6, 1997; was dissolved in 17 ml of trifluoroacetic acid and the solution was stirred at room temperature under an anhydrous nitrogen atmosphere for 4.75 hours and then concentrated in vacuo and dried under high vacuum for 24 hours to give the amine salt as a viscous oil yellow (1.76 g, 100%). [a] D589 -11.54 ° (c 1.04, MeOH); NMR XH (CDCl3) d Unit C: 7.43 (broad s, 3H, NH3 +), 3.34-3.28 (m, 3-H), 3.18-3.12 (m, 3-H '), 1.42 (s, 2-Me) , 1.36 (s, 2-Me); Unit D: 10.94 (broad s, C02H), 5.23-5.20 (m, 2-H), 1.92-1.77 (m, 3H, 3-HH ', 4-H), 1.10 (d, J = 5.8 Hz, 5 -H3), 0.98 (d, J = 5.8 Hz, 4-Me) ppm; IR (CHC13)? 2963, 1746, 1710, 1678, 1192, 1172 cm "1; MS (FAB) 232.2 ([M + 1] +, 100).

Example 6 To a stirred solution of the amine salt of Example 5 (5.09 mmole) in 20 ml of dioxane was added sodium bicarbonate (2.14 g, 25.5 mmole) followed by FmocCl (1.58 g, 6.11 mmole) at room temperature. The mixture was diluted with 4 ml of water and stirred for 19 hours. The reaction mixture was quenched in 150 ml of IN aqueous hydrochloric acid and extracted with 2 100 ml portions of ethyl acetate. The combined organic extracts were washed with 100 ml of water, dried over sodium sulfate and concentrated in vacuo to give a yellow gummy solid. The crude product was purified by column chromatography (Biotage-Si02: gradient elution; 10% -75% EtOAC: hexanes) to give Fmoc-amine as a pale yellow solid (850 mg, 37%). The product was contaminated with amino acid, which was removed by dissolving the product in ethyl acetate and stirring with IN aqueous hydrochloric acid for several hours. The organic materials were dried and concentrated to give the product (product: amino acid 85:15). [a] D589 -15.95 ° (c 0.50, CH2C12); XH NMR (CDC13) d Unit C: 7.59 (d, J = 7.4 Hz, ArH2), 7.67-7.61 (m, ArH2), 7.43 (t, J = 7.3 Hz, ArH2), 7.36-7.30 (m, ArH2) , 5.88 (t, J = 5.8 Hz, NH), 4.41-4.38 (m, 3'-HH '), 4.35-4.28 (, 4'-H), 3.42 (d, J = 6.5 Hz, 3-HH' ), 1.27 (s, 2Me), 1.26 (s, 2-Me); Unit D: 8.40 (broad s, C02H), 5.18-5.13 (, 2-H), 1.87-1.69 (m, 3H, 3HH ', 4-H), 0.97 (d, J = 5.8 Hz, 5-H3) , 0.93 (d, J = 6.1 Hz, 4-Me) ppm; IR (KBr)? 2959, 2937, 1730, 1540, 1471, 1451, 1307, 1268, 1145, 1128, 759, 741 cm "1; UV (EtOH)? Max 299 (e = 5851), 288 (e = 4773), 265 (e. = 18369), 227 (e-4813) nm; MS (FAB) 454 ([M + l] +, 26); Analysis calculated for C26H3? N05 requires: C, 68.86; H, 6.89; N, 3.09%. : C, 68.92; H, 7.01; N, 3.34%.

Example 7 To a stirred solution of the DC carboxylic acid of Example 6 (129 mg, 0.285 mmol) in 1.0 ml of anhydrous dichloromethane was added DMAP (5.4 mg, 0.044 mmol) and DCC (59 mg, 0.285 mmol) at room temperature under one atmosphere of anhydrous nitrogen. The solution was stirred for 0.5 hours and then solid sodium bicarbonate (37 mg, 0.44 mmol) was added followed by a solution of the crude alcohol A-B of Example 4 (117 mg, 0.22 mmol) in 1.2 ml of anhydrous dichloromethane. A precipitate formed within 10 minutes and the mixture was stirred for an additional 50 minutes. The crude reaction mixture was applied directly onto a silica column and purified (gradient elution: 10% -40% EtOAc: hexanes) to give the methyl sulfide product as a pale yellow solid (122 mg, 46% in 3 steps). 1H-NMR (CDC13) d Unit A: 7.43-7.20 (m, ArH5), 6.90-6.81 (, 2H, 3-H, ArH), 5.93 (d, J = 15.6 Hz, 2-H), 5.14-4.93 ( m, 5-H), 3.05 (dd, J = 14.5 and 8.3 Hz, 7-H), 2.65-2.63 (m, 4-HH '), 2.00-1.95 (m, 6-H), 1.17 (d, J = 7.0, 6-Me); Unit B: 7.43-7.20 (m, ArH), 7.06 (d, J = 8.1 Hz, ArH), 6.90-6.81 (m ArH), 6.44 (d, J = 7.7 Hz, NH), 5.19 (q, JAB = 11.8 Hz, l'-HH), 5.14-4.93 (m, 2-H), 3.87 (s, OMe), 3.20-3.10 (m, 3-HH '), 2.21 (s, SMe); Unit C: 7.79 (d, J = 7.4 Hz, ArH2), 7.67 (d, J = 6.9 Hz, ArH2), 7.43-7.20 (m, ArH4), 6.04 (d, J = 7.7 Hz, NH), 4.42- 4.34 (m, 3'-HH '), 4.30-4.25 (m, 4'-H, 3.42 (d, J = 6.2 Hz, 3-HH'), 1.27 (s, 2-Me), 1.20 (s, 2-Me), Unit D: 5.22-5.18 (m, 2-H), 1.82-1.58 (m, 3H, 3-HH ', 4-H), 0.96 (s, 5-H3), 0.94 (s, 4 -Me) ppm.

Example To a stirred solution of methyl sulfide from Example 7 (56 mg, 0.058 mmol) in 10 ml of acetone, sodium hydrogen carbonate (64 mg, 0.764 mmol) was added followed by an aqueous solution of Oxone (234 mg, 0.382 mmol). ) in 3.0 mL of water. The reaction mixture was stirred at room temperature for 20 minutes (SM is rapidly converted to a very polar component sulfoxide and then over time to the less polar sulfone product). The reaction was quenched in 40 mL of water and extracted with 3 x 20 mL of ethyl acetate. The organic extracts were washed with 30 mL of brine, dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude product was purified by column chromatography (Si02: gradient elution: 25% -60% ethyl acetate: exanos) to give the sulfone as a white foamy solid (43 mg, 74%).

NMR t (CDC13) d Unit A: 7.58-7.17 (, ArH5), 6.82-6.75 (m, 3-H), 5.87 (d, J = 16Hz, 2-H), 4.98-4.86 (m, 5-H) ), 3.70 (d, J = 1.1 Hz, 7-H), 2.92-2.89 (m, 7-H), 2-61-2.58 (m, 4-HH '), 1.94-1.89 (m, 6-H) ), 1.13 (d, J - 7.1 Hz, 6-Me); Unit B: 7.58-7.17 (m, ArH), 7.04 (d, J = 7.7 Hz, ArH), 6.81 (d, J = 8.1 Hz, ArH), 6.54 (d, J = 7.5 Hz, NH), 4.98- 4.86 (m, 2-H), 3.84 (s, 7-OMe), 3.17-2.98 (dq, JAB = 14 and 6.6 Hz, 2-HH '); Unit C: 7.75 (d, J = 7.4 Hz, ArH2), 7.62 (d, J = 6.8 Hz, ArH2), 7.62 (d, J = 6.8 Hz, ArH2), 7.58-7.17 (m, ArH4), 5.97 ( t, J = 5.5 Hz, NH), 5.00 (s, S02Me), 4.98-4.86 (m, 2H, l'-HH '), 4.38-4.33 (m, 3'-HH'), 4.25-4.20 (m , 4'-H), 3.40-3.36 (m, 3-HH '), 1.22 (s, 2-Me), 1.15 (s, 2-Me); Unit D: 5.19 (q, JAB = 5 Hz, 2-H), 1.80-1.61 (m, 2H, 3-H, 4-H), 1.57 '1.49 (m, 3-H'), 0.91 (s, 5-H3), 0.89 (s, 4-Me) ppm.

Example 9 Cryptophycin 52 To a stirred sulfone solution of Example 8 (18 mg, 17.98 mmol) in 2.0 mL of anhydrous dimethylformamide, pure piperidine (8.9 uL, 90 umoles) was added at room temperature and under nitrogen atmosphere. The resulting solution was stirred for 5 hours and then concentrated in vacuo to give the crude amine as a foam. The amine was dissolved in 3 mL of toluene and heated at 60 ° C under nitrogen atmosphere for 40 minutes. The reaction solution was purified directly by column chromatography (Si02; gradient elution; 20% -75% ethyl acetate: hexanes) to give cryptophycin 52 as white crystals (6.1 mg, 51% in 2 steps). XH NMR (CDC13) d Unit A: 7.45-7.38 (m, ArH3), 7.31-7.23 (m, ArH2), 6.85-6.76 (m, 3H), 5.76 (d, J = 15.6 Hz, 2-H), 5.27-5.23 (m, 5-H), 2.97 (dd, J = 7.5 and 1.7 Hz, 7-H), 2.66-2.44 (m, 4-HH '), 1-86-1.67 (d, J = 6.9 Hz, 6-Me); Unit B: 7.31-7.23 (m, ArH), 7.09 (dd, J = 8.3 and 2.0 Hz, ArH), 6.88 (d, J - 8.4 Hz, ArH), 5.50 (d, J = 7.8 Hz, NH), 4.79 (q, J = 6.4 Hz, 2-H), 3.92 (s, Ome); 3.73 (d, J = 1.5 Hz, 8-H), 3.17-3.11 (m, 3-HH '); Unit C: 3.47 (dd, J = 13.4 and 8.7 Hz, 3-H), 3.17-3.11 (m, 3'-H), 1.27 (s, 2-Me), 1.20 (s, 2-Me); Unit D: 4.87 (dd, J = 10 and 3.3 Hz, 2-H), 1.86 - 1.67 (m, 2H, 3-HH, 4-H), 1.40-1.30 (m, 3-H '), 0.88 ( app t, J = 6.3 Hz, 6H, 5-H3, 4-Me) ppm.

Example 10 Preparation of β-Epoxy Fragment A-B. To a solution of the product of Preparation 8 (60.4 mg, 0.160 mmol) and N, N-diisopropylacetylamine (56 μL, 0.32 mmol) in 330 μL of dimethylformamide, diphenylphosphinic chloride (32 μL, 0.17 mmol) was added. After the mixture was filtered for 1 h, it was added to a mixture of the amino acid * B ", represented by the formula (40.4 mg, 0.176 mmol) and N, O-bis- (trimethylsilyl) -acetamide (99 μL, 0.40 mmol) in 330 μL of dimethylformamide which had been prepared 20 minutes before. The reaction mixture was stirred for 2 h before it was diluted with 14 mL of ethyl acetate, and washed with 3 portions of 4.5 mL of 1 M hydrochloric acid and 4.5 mL of water. The organic phase was dried over magnesium sulfate and concentrated to give a yellow oil. Chromatography on silica gel with 5 to 10% methanol / methylene chloride gave the desired product as a colorless solid (83.2 mg, 88%).

Example 11 Alternative Preparation of Cryptophycin 52 After a mixture of the compound of Example 7 (325 mg, 0.335 mmol) and piperidine (166 μl, 1.68 mmol) in 34 mL of dimethylformamide was stirred for one hour at room temperature and 2 h at 60 ° C, the HPLC (phase Inverse C18, detection at 220 nm, flow rate at 1 mL / min, CH3CN (0.05% TFA) / H20 (0.05% TFA) -% CH3CN: 60% at 95% in 25 min) revealed that the protection of Fmoc had been removed and a mixture of free intermediate amine and cryptophycin 52 was now present. 2-Hydroxypyridine (63.7 mg, 0.670 mmol) was added and the reaction was allowed to stir for 18 h before it was checked again by HPLC. , which showed that the intermediary still remained. Additional piperidine (66 μL, 0.67 mmol) was added and the reaction was stirred for another 64 h, at which time HPLC showed that it had been carried out. The mixture was diluted with 90 mL of ethyl acetate and washed with 3 portions of 90 mL of water. The combined aqueous phases were back extracted with 30 mL of ethyl acetate and the combined organic phases were dried over magnesium sulfate, and concentrated to an orange oil. Chromatography on silica gel with ethyl acetate / hexane (1: 1 to 4: 1) gave cryptophycin 52 as a colorless solid (143 mg, 64% corrected to 58% due to contamination by N-formylpiperidine).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (71)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the preparation of a compound of the formula wherein G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or (= 0); Y is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R6a, R6b, and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR18; R15, R1, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, OP04H2, (C 1-6 alkoxy) phenyl, S-benzyl , C0NH2, C02H, P03H2, S02R23, or Z '; R18 and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH2) n- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1, or 2; and Z 'is a substituted aromatic or aromatic group; or a pharmaceutically acceptable salt thereof; which comprises deprotecting a compound of the formula wherein G, R3, R5, R6, R7, R8, R9, R10, R11, R14, R50 and Y are as defined above; q is a whole number 1 or 2; R81 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; and R82 is a base-labile protecting group, with a deprotection agent to form a compound of the formula (10a; where G, R3, R5, R6, R7, R8, R9, R10, R11, R14, R50, Y, q and R81 are as defined above; optionally contacting the compound of the formula (9c) a cyclization agent to form a compound of the formula (I); and optionally forming a pharmaceutically acceptable salt thereof.

2. A process according to claim 1, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R9 is alkyl of 1 to 6 carbon atoms RJ is hydrogen; R, 11 is hydrogen; R is hydrogen; R is (= 0); And it is 0; and R is a group of the formula (IA).

3. A process according to claim 1, characterized in that the deprotection agent is piperidine.

4. A process according to claim 2, characterized in that G is phenyl.

5. A process according to claim 1, characterized in that the compound of the formula (I) is cryptophycin 52.

6. A process for the preparation of a compound of the formula (I) wherein G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or an aromatic or substituted heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl , where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or (= 0); Y is CH, O, NR 12, S, SO, S 0 2, where R "is hydrogen or alkyl of 1 to 3 carbon atoms, R 6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted , cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R6a, R6t, and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR18; R15, R16, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, OP04H2, (C 1 -C 6 alkoxy) phenyl, S-benzyl , C0NH2, C0: H, P03H2, S02R 23, or Z '; R18 and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH 2) p- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1, or 2; and Z 'is a substituted aromatic or aromatic group; or a pharmaceutically acceptable salt thereof; characterized in that it comprises the steps of: (a) the epoxidation of a compound of the formula (2 wherein G, R3, R4 and R5 are as defined above; R 2a is hydrogen or tri (C 1-6 alkyl) silyl; and R p is hydrogen or an activatable, suitable carboxyl protecting group; with an epoxidation agent to form a compound of the formula (3 wherein G, R3, R4, R5, R2a and Rp are as defined above, with the proviso that R2a and Rp are not both hydrogen; (b) coupling the compound of the formula (3) with an amino acid of the formula wherein R6 and R14 are as defined above and Rpl is hydrogen or alkyl of 1 to 6 carbon atoms; also in the presence of a silylating agent when R14 and Rpl are hydrogen; to produce a compound of the formula (5) wherein G, R3, R4, R5, R2a, Rpl, R6 and R14 are as defined above; c) deprotection of the compound of the formula (5) with an appropriate alkoxy deprotection agent, and further deprotection of the carboxyl of the compound of the formula (5) when Rpl is alkyl of 1 to 6 carbon atoms, with a adequate base to form a compound of the formula M * 6) wherein G, RJ R, R, R and R are as defined above and M + is a cation; (d) contacting a compound of the formula (6) with a thioester forming agent, to form a compound of the formula wherein G, R3, R4, R5, R6 and R14 are as defined above and R81 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; (e) coupling a compound of the formula (7) with a compound of the formula (8) wherein R7, R8, R9, R10, R11 and R50 are as defined above and R82 is a base-labile protecting group, to form a compound of the formula (9 wherein G, R3, R4, R5, R6, R7, R8, R9, R10, R11, R14, R50, R81, R82 and Y are as defined above, (f) the oxidation of a compound of the formula (9) with an oxidizing agent to form a compound of the formula 10) wherein G, R3, R4, R5, R6, R7, R8, R9, R10, R11, R14, R50, R81 and R82, Y are as defined above and q is an integer of 1 or 2; (g) deprotection of a compound of the formula (10) with a suitable deprotecting agent to form a compound of the formula 10a) wherein G, R0 Rs, Rb, R ', Rt, Ra, Rl, R11, R14, R50, Y, q and R81 are as defined above; and optionally contacting a compound of the formula (10) with a cyclization agent to form a compound of the formula (I); and (h) optionally forming a pharmaceutically acceptable salt of a compound of the formula (I).

7. A process according to claim 6, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (0) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R9 is alkyl of 1 to 6 carbon atoms; R10 is hydrogen; R11 is hydrogen; R14 is hydrogen; R50 is (= 0); And it is 0; and R6 is a group of the formula (IA).

8. A process according to claim 6, characterized in that the deprotection agent is piperidine.

9. A process according to claim 6, characterized in that the oxidizing agent is Oxone.

10. A process according to claim 6, characterized in that R81 is methyl.

11. A process according to claim 6, characterized in that the epoxidizing agent is Oxone in the presence of acetone or m-CPBA.

12. A process according to claim 6, characterized in that the epoxidizing agent is Oxone in the presence of a chiral ketone.

13. A process according to claim 12, characterized in that the chiral ketone is a compound of the formula /---QuyOO..i-

14. A process according to claim 7, characterized in that the deprotective agent is piperidine; the oxidizing agent is Oxone; R8"is methyl, and wherein the epoxidizing agent is Oxone in the presence of acetone or m-CPBA.

15. A process according to claim 7, characterized in that the cyclization agent is piperidine; the oxidizing agent is Oxone; R81 is methyl; and wherein the epoxidizing agent is Oxone in the presence of a chiral ketone of the formula

16. A process according to claim 6, characterized in that the compound of the formula (I) is cryptophycin 52.

17. A process according to claim 6, characterized in that Rp is hydrogen and the epoxidizing agent is m-chlorobenzoic acid.

18. A process according to claim 14, characterized in that Rp is hydrogen and the epoxidizing agent is m-chlorobenzoic acid.

19. A process according to claim 18, characterized in that the compound of the formula (I) is cryptophycin 52.

20. A process for the preparation of the compound of the formula I) wherein G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or (= 0); Y is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R a, R 6b, and R independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR1 8R1 9 or 0Rl b; R15, R16, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, 0P04H2, (C 1 -C 6 alkoxy) phenyl, S-benzyl , CONH2, C02H, P03H2, S02R23, or Z '; Rl? and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH 2) p- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1, or 2; and Z 'is a substituted aromatic or aromatic group; or a pharmaceutically acceptable salt thereof; characterized in that it comprises deprotecting a compound of the formula where G, R3, R4, R5, R6, R7, R8, R9, R10, R11, R14, R50 and Y are as defined above; R81 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; and R82 is a base-labile protecting group, with a deprotection agent to form a compound of the formula (9c) where G, R3, R4, R5, R6, R7, R8, R9, R1, R11, R14, R50 and Y are as defined above; optionally contacting the compound of the formula (9c) a cyclization agent to form a compound of the formula (I); and optionally forming a pharmaceutically acceptable salt thereof, to form a compound of the formula (I) and optionally forming a pharmaceutically acceptable salt thereof.

21. A process according to claim 20, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) m > NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R9 is alkyl of 1 to 6 carbon atoms R1J0 is hydrogen; R, 11 is hydrogen; R14 is hydrogen; R50 is (= 0); And it is 0; and R * is a group of the formula (IA).

22. A process according to claim 20, characterized in that the deprotective agent is piperidine.

23. A process according to claim 20, characterized in that G is phenyl.

24. A process according to claim 20, characterized in that the compound of the formula (I) is cryptophycin 52.

25. A compound of the formula 10) wherein G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R is hydrogen or (= 0); Y is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R6a, R6b, and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR18; R15, R16, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, 0P04H2, (C 1-6 alkoxy) phenyl, S-benzyl , C0NH2, C02H, P03H2, S02R 2"3, or Z '; R18 and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; R 1 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; R82 is a base-labile protecting group; Z is - (CH2) n- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1, or 2; and q is an integer 1 or 2; and Z 'is a substituted aromatic or aromatic group; or a pharmaceutically acceptable salt thereof.

26. A compound according to claim 25, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m < NH2.

27. A compound according to claim 25, characterized in that R3 is methyl.

28. A compound according to claim 25, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R9 is alkyl of 1 to 6 carbon atoms; RJ is hydrogen; R, 11 is hydrogen; R14 is hydrogen; R50 is (= 0); And it is 0; and R6 is a group of the formula (IA); P81 is methyl; R82 is Fmoc and q is 1.

29. A compound according to claim 25, characterized in that the compound is represented by the formula

30. A compound of the formula characterized in that G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R 'and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or (= 0); Y is CH, O, NH, S, SO, S02 or alkylamino of 1 to 3 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R6a, R6D, and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR18; R15, R16, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, OP04H2, (C 1-6 alkoxy) phenyl, S-benzyl, C0NH2, C02H, P03H2, S02R23, or Z '; R18 and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH2) n- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1, OR 2; and Z 'is a substituted aromatic or aromatic group; R81 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; and R82 is a base-labile protecting group or a pharmaceutically acceptable salt thereof. of the formula

31. A compound according to claim 30, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) m, NH2.

32. A compound according to claim 30, characterized in that R3 is phenyl.

33. A compound according to claim 30, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R9 is alkyl of 1 to 6 carbon atoms; R10 is hydrogen; R11 is hydrogen; R14 is hydrogen; R50 is (= 0); Cast; and R6 is a group of the formula (IA); R81 is methyl; R82 is Fmoc.

34. A compound according to claim 30, characterized in that the compound is represented by the formula

35. A compound of the formula (3 characterized in that G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and Rb are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R 2a is tri- (C 1-6 alkyl) silyl; and R p is hydrogen or an activatable, suitable carboxyl protecting group, with the proviso that R 2a and R p are not both hydrogen; or a pharmaceutically acceptable salt thereof.

36. A compound according to claim 35, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) m-NH2.

37. A compound according to claim 35, characterized in that R3 is methyl.

38. A compound according to claim 35, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with CH2OC (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R is tert-butyldimethylsilyl; and Rp is N-hydroxysuccinimide or hydrogen.

39. A compound according to claim 35, characterized in that the compound is represented by the formula

40. A compound according to claim 35, characterized in that the compound is represented by the formula

41. A compound according to claim 35, characterized in that the compound is represented by the formula

42. A compound according to claim 35, characterized in that the compound is represented by the formula

43. A compound of the formula (5; characterized in that G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R14 is hydrogen or alkyl of 1 to 6 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group or a group of the formula (IA), (IB) or ( IC): R6a, R6b and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or 0R? E; R15, R16 and R17 independently are hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, OP04H2. (C 1-6 alkoxy) -phenyl, S-benzyl, CONH 2, C02H, P03H2, S02R23, or Z '; R18 and R19 independently are hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH2) n- or cycloalkyl of 3 to 5 carbon atoms; n is 0, 1 or 2; and Z 'is a substituted aromatic or aromatic group; Rpl is hydrogen or alkyl of 1 to 6 carbon atoms; and R2a is hydrogen or tri (C 1-6 alkyl) silyl; or a pharmaceutically acceptable salt thereof.

44. A compound according to claim 43, characterized in that G is phenyl, para-fluorophenyl, phenyl substituted with -CH2OC (0) (CH2) m-NH2.

45. A compound according to claim 43, characterized in that R ~ is methyl.

46. A compound according to claim 43, characterized in that G is phenyl para-fluorophenyl, or phenyl substituted with -CH20C (0) (CH2) m-NH2; R3 is methyl; R4 and R £ taken together form a second bond between carbon 13 and carbon 14; R2a is tert-butyldimethylsilyl; and Rp is N-hydroxysuccinimide or hydrogen.

47. A compound according to claim 43, characterized in that the compound is represented by the formula

48. A compound of the formula 6) characterized in that G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R 6 to R 6b R 6 c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR1 8R1 9 or OR1 8; R15, R16 and R, 17 'independently are hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, 0P04H2. (C 1-6 alkoxy) -phenyl, S-benzyl, CONH 2, C02H, P03H2, S02R23, or Z '; R18 and R19 independently are hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH2) n- or cycloalkyl of 3 to 5 carbon atoms; n is O, 1 or 2; and Z 'is a substituted aromatic or aromatic group; and M + is a cation, or a pharmaceutically acceptable salt thereof.

49. A compound according to claim 48, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) m < NH2.

50. A compound according to claim 48, characterized in that RJ is methyl.

51. A compound according to claim 48, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH20C (O) (CH2) ro-NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R14 is hydrogen; Rb is a group of the formula (IA); and Rpl is hydrogen or methyl.

52. A compound according to claim 48, characterized in that the compound is represented by the formula

53. A compound according to claim 48, characterized in that the compound is represented by the formula

54. A compound of the formula wherein G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and Rb are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or (= 0); Y is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): R6a, R6b, and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR18; R15, R16, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, OP04H2, (C 1-6 alkoxy) phenyl, S-benzyl, CONH2, C02H, P03H2, S02R23, or Z '; R18 and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; R81 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, phenyl or benzyl; Z is - (CH 2) n- or cycloalkyl of 3 to 5 carbon atoms, n is O, 1, O 2; and q is an integer 1 or 2; and Z 'is a substituted aromatic or aromatic group; or a pharmaceutically acceptable salt thereof.

55. A compound according to claim 54, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m-NH :.

56. A compound according to claim 54, characterized in that RJ is methyl.

57. A compound according to claim 54, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; Rp is NHS or hydrogen; and R 2a is tri (C 1-6 alkyl) silyl.

58. A compound according to claim 54, characterized in that it is represented by the formula

59. A compound of the formula (9c) characterized in that: G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R; they are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R14 is hydrogen, or alkyl of 1 to 6 carbon atoms; R50 is hydrogen or (= 0); Y is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms; R6 is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted, cycloalkyl of 3 to 8 carbon atoms, cycloalkyl of 3 to 8 carbon atoms substituted, a heteroaromatic or substituted heteroaromatic group, or a group of the formula (IA), (IB) or (IC): (IB) R6a, R6, and R6c independently are hydrogen, alkyl of 1 to 6 carbon atoms, halo, NR18R19 or OR16; R15, R16, and R17 are independently hydrogen, halo, alkyl of 1 to 6 carbon atoms, OR18, O-aryl, NH2, NR18R19, N02, OP04H2, (C 1-6 alkoxy) phenyl, S-benzyl, CONH2, C02H, P03H2, S02R23, or Z '; R18 and R19 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R23 is hydrogen or alkyl of 1 to 3 carbon atoms; Z is - (CH2) n- or cycloalkyl of 3 to 5 carbon atoms; n is 0, 1, or 2; and Z 'is a substituted aromatic or aromatic group; or a pharmaceutically acceptable salt thereof.

60. A compound according to claim 59, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m-NH2.

61. A compound according to claim 59, characterized in that R "is methyl.

62. A compound according to claim 54, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; Rp is NHS or hydrogen; and Ra is tri (alkyl of 1 to 6 carbon atoms) silyl.

63. A compound according to claim 59, characterized in that it is represented by the formula

64. A compound of the formula characterized in that G is alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, alkynyl of 2 to 12 carbon atoms, or Ar; Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group; R3 is alkyl of 1 to 6 carbon atoms; R4 and R5 are each hydrogen; or R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R2a is tri (alkyl of 1 to 6 carbon atoms) silyl; and Ra is alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

65. A compound according to claim 64, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (0) (CH2) m-NH2.

66. A compound according to claim 64, characterized in that R3 is methyl.

67. A compound according to claim 64, characterized in that G is phenyl, para-fluorophenyl, or phenyl substituted with -CH2OC (O) (CH2) m'NH2; R3 is methyl; R4 and R5 taken together form a second bond between carbon 13 and carbon 14; R2a is tert-butyldimethylsilyl; and Ra is methyl.

68. A compound according to claim 64, characterized in that the compound is represented by the formula

69. A compound of the formula characterized in that: R7 and R8 are each independently hydrogen or alkyl of 1 to 6 carbon atoms; or R7 and R8 taken together form a cyclopropyl or cyclobutyl ring; R9 is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, - (CH2) m- (cycloalkyl of 3 to 5 carbon atoms) or benzyl, where m is the whole number one to three; R10 is hydrogen or alkyl of 1 to 6 carbon atoms; R11 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or benzyl; R50 is hydrogen or (= 0); Y is CH, 0, NR12, S, SO, S02, wherein R12 is hydrogen or alkyl of 1 to 3 carbon atoms; R82 is a base-labile protecting group; or a pharmaceutically acceptable salt thereof.

70. A compound according to claim 69, characterized in that R9 is alkyl of 1 to 6 carbon atoms; R10 is hydrogen; R11 is hydrogen; R50 is (= 0); And it is 0; and R82 is Fmoc.

71. A compound according to claim 69, characterized in that the compound is represented by the formula