SYNTHESIS OF VINBLASTINE AND VINCRISTINE TYPE COMPOUNDS

Abstract: A new process for the stereospecific synthesis of alkaloids of the vinblastine and vincristine type including the synthesis of vinblastine and vincristine as well novel alkaloids which are active as anti-tumor agents.

Description: SYNTHESIS OF VINBLASTINE AND VINCRISTINE TYPE COMPOUNDS The indole-indoline alkaloids, the most important of which can be represented by the compound of formula I wherein R_ i, is acetoxy or hydroxy; R__> is formyl or methyl include vinblastine and vincristine, which are anti-tumor agents widely used in the treatment of cancer. These agents have been prepared from extracts of the Vinca rosea plant. As these alkaloids are present in the plant only in very small concentrations and since they must be separated from many other companion alkaloids, their synthetic generation becomes particularly valuable. Preparation of compounds of formula I, by a pathway quite different from that of the present invention, has already been described. Thus Potier and Kutney obtained products with the C18'S-C2*R absolute configuration, which is critical for antirumor activity, by a coupling reaction b . . . . . of the N -oxide of catharanthme, or its derivatives, with vindoline, in the presence of trifluoroacetic anhydride, followed by a reduction reaction. [See Potier et. al. J. Am. Chem. Soc. 9J3., 7017 (1976) and Kutney et. al. Helv. Chi . Acta. 5_9, 2858 (1976)]. The Potier and Kutney coupling process has disadvantages. The yields are not satisfactory except for the coupling of catharanthine N-oxide with vindoline and even there the preparative yield is low. While vindoline is the most abundant alkaloid of Vinca rosea and is thus readily available, the other possible components of the Potier-Kutney coupling process (catharanthine, allocatharanthine, voacangine.) are relatively inaccessible, costly, and they do not allow a wide range of structural variation of that component of the coupling process. In accor d ance with this invention it has been foun d that when compounds of the formula: wherein n is an integer of 0 to 1; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R is -CH_Y, for yl or a formyl protected by formation of an acetal group; R is lower alkyl and Y individually is a leaving group or a hydrolyzable ether group; X is halo and R 2 is amino protecting group; R5 is hydrogen or lower alkyl; and R is individually hydrogen, lower alkyl or taken together with Y forms lower alkylidenedioxy; are condensed with a compound containing the ring system of vindoline or salt thereof, a compound of the formula: wherein Z is the residue of a vindoline ring 1 2 5 6 system and n. A, B, R , R , R , R and R are as above or mixtures thereof with the corresponding 7R diastereomer having the opposite configuration at the 5-position, are formed. Unexpectedly, it has been found that this condensation produces the correct relative configuration of the asymmetric carbon atoms at C7 and C5 in the compound of formula III, to produce alkaloids of the formula I having the absolute configuration at the asymmetric carbon atoms 18' and 2' as shown. This absolute configuration is critical for antitu or activity. Through the process of this invention one can ultimately produce compounds of the formula wherein n. A, B, Z and R are as above; and R is hydrogen or lower alkyl; and 7 . R is hydrogen, hydroxy or lower alkyl; which have the "natural" con ormational structure i.e. that of the alkaloids isolated from, plants. It is these alkaloids of the "natural" configuration which are active as anti-tumor agents. In addition to these "natural type" alkaloids, the process of this inventions produces for the first time alkaloids of the formula where n. A, B, Z, R1, R5 and R7 are as above; which have a confor ational structure different from the "natural type" conformational structure. In accordance with ς this invention the compounds of formula I-B are intermediates for the "natural type" compounds of formula I-C and can be converted to the compounds of formula I-C by heating. While the compounds of formula I-B are not by themselves active as antifumor agents, they may be 10 administered as "pro-drugs" and activated by transformation into the compounds of formula I-C at the tumor site by heating or by micro waves or by ultrasonics or by infra-red radiation. 15 Through the stereospecific nature of the formation of the compound of formula III. one can produce the known antitumor agents; vinblastine- the compound of formula I where R_ is - 0 acetoxy, R is methyl, R is hydroxy, R is ethyl-; and vincristine- the compound of formula I where R is acetoxy, R is hydroxy, is ethyl, and R is 25 formyl. In addition, this synthesis provides a method for producing new vincristine and vinblastine type compounds which are active as anti-tumor agents, since i -provides the 30 correct relative and absolute configuration of the asymmetric carbon atoms at C18 ' and C2' respectively. Therefore, through the process of this invention not only 35 can the known vincristine and vinblastine alkaloids be synthesized, but also new anti-tumor compounds having the wherein n, B, and R are as above; R ' is hydrogen or lower alkyl; R ' is hydrogen or lower alkyl; and R is formyl or methyl. Among the compounds of Formula I-D where R is methyl, B is methylene and n is 1, the following are 5 preferred: Compound A = the compound of the formula I-D where R_ is methyl and R 4 is ethyl and R. is hydrogen. Q Compound B = the compound of formula I-D where R ς is methyl and R and R are hydrogen. Compound C = the compound of formula I-D where R e is formyl, and R. is ethyl and R. is hydrogen. 5 Compound D = the compound of formula I-D where R_ is I 5 formyl, and R_ and R. are hydrogen. The compounds of the formula I and I-C and I-D and their pharmaceutically acceptable salts are useful in inhibiting the growth of malignant tumors and may be utilized in this same manner as vinblastine and vincristine. However, the new analogues and con ormational isomers of vinblastine and vincristine produced through the claimed synthesis of this invention such as the compounds of I-D, in particular Compound A, B, C and D, do not have the high toxicity of vincristine and vinblastine as will be seen from the results of Table 1 below. The effect of Compounds A and B on intraperitoneally transplanted tumors and their reduced toxicity can be seen from the results of the P-388 leukemia test. In this test the compounds were administered in a saline solution. The P-388 leukemia test was performed on BDF hybrid mice. The tests were carried out on groups of six mice and 10 tumor cells/animal were transplanted intraperitoneally. Administration of the test compounds was started in the 24th hour after transplantation. Treatment was performed intraperitoneally and the body weight and state of animals was determined every day. The effect obtained on the treated animals is expressed in % of the mean length of life of the control group, given in days. This increase over the control is expressed in Table 1 as %T/C, i.e. Treated/Control. The figures in parenthesis represent repeat determinations two months after the first determination. TABLE I W . los s Com¬ Dose (Day 5 ) pound (mσ/kσ) Schedul e %T/C grams /Mous Compound A a) Free Base 2 Day 1 119 None 2.5 Days 1. 5, 9 118 None 4.0 Days 1, 5. 9 135 None 10.0 Days 1. 5. 9 207 0.4 b) HC1 salt 2 • Day 1 106 None 2 Days 1, 5. 9 115 None 5 Days 1, 5. 9 181 None Compound B 50 Days 3, 8 113 None 100 Days 3, 8 251 None Vincristine 1 Day 1 126(139) 2.2 positive control 1 Days 1, 5, 9 152(219) 1.3 The tumor inhibitory effect of the new compounds on P-388 mouse tumor is evident at doses ranging from 0.01 to 100 mg/kg/day dose and is equal to the effect of the known indole-indoline alkaloids. At the same time, the instant compounds are less toxic than these known alkaloid compounds For human treatment the compounds can best be employed intravenously or as infusions. In utilizing the novel compounds of formula I, I-C and I-D as anti-tumor agents in mammals, the parenteral route is ordinarily employed. Prior to administration, the drug is customarily mixed with a pharmaceutically suitable carrier. With parenteral administration, the intravenous route is preferred although, with smaller mammals such as mice, the intraperitoneal route may be used. For intravenous administration, isotonic solutions containing 1-10 mg/ml. of a salt of an alkaloid of the formula I or salts thereof are employed. The drug is administered at a dose of from 0.01 to 10 mg/kg and preferably from 0.05 to 1 mg/kg of human body weight once or twice a week or every two weeks depending on both the activity and the toxicity of the drug. An alternative method of arriving at a therapeutic dose is based on body surface area with a dose in the range 0.1 to 10 mg/meter squared of human body surface administered thrice weekly or every 7 or 17 days. As would be expected, the novel compounds encompassed within formula I or I-D differ in their anti-tumor spectrum from that of vinblastine and vincristine as the anti-tumor spectra of those compounds differ among themselves, one drug being more effective against certain tumors or classes of tumors and less effective against others. However, in utilizing these compounds clinically, an oncologist may administer them initially by the same route, in the same vehicle and against the same types of tumors as employed clinically with vincristine and vinblastine. Differences in dosage level would, of course, be based on relative oncolytic potency and toxicity. Tumors against which clinical trial candidates are screened include adenocarcinoma of the breast, adenocarcinoma of the colon, bronchogenic carcinoma, adenocarcinoma of the pancreas, ovarian cancer, malignant melanoma, acute myelocytic leukemia, acute lymphocytic leukemia, lymphomatous disease and malignant glioma. A compound of formula I would be tested clinically against one or more of these tumors as well as other tumors known to be susceptible to i.v. administration of vincristine and vinblastine. After its potency, nature and degree of side effects etc. had been established, the drug would be tried against tumors for which there is no therapy. After preliminary tests were concluded and the results published, the drug would be used against tumors susceptible to its action at relatively non-toxic dose levels. Useful non-toxic acids for forming acid addition salts with the bases of formula I include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobro iσ acid, hydroiodic acid, phosphorous acid and the like, as well as salts of non-toxic organic acids including aliphatic mono -and dicarboxylates, phenyl- substiruted alkanoates, hydroxy alkanoates and alkandioates, aromatic acids, alphatic and aromatic sulfonic acids, etc. Such pharmaceutically acceptable salts thus include the sulfate, bisulfate. sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate. dihydrogen-phosphate, metaphosphate. phosphite, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate. acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate. fumarate, maleate. butyne-1, -dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzene-sulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, 2-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propane-sulfonate, naphthalene-1-sul onate. naphthalene-2-sulfonate and the like salts. In carrying out the reaction to produce the compound of formula m the substituent A in the compound of formula II can be any group which when connected to the ring system of the compound of formula II forms an aromatic carbocyclic or heterocyclic ring. Any conventional aromatic carbocyclic or heterocyclic ring structure can be formed by A. The aromatic carbocyclic ring substrates formed by A include the carbocyclic aromatic monocyclic or polycyclic ring structures containing 6 to 12 carbon atoms in the ring, most preferably benzene and naphthalene. Where A, when connected to the remainder of the molecule in the compound of formula II forms an aromatic heterocyclic ring structure, any aromatic heterocyclic ring structure can be formed including those ring structures which contain from 1 to 3 nitrogen or sulfur atoms as the only hetero atoms in the ring structure. The heterocyclic ring structure is preferably monocyclic or bicyclic and can contain from 5 to 10 members in its ring. Among the aromatic heterocyclic ring structures formed by A are included pyridine, quinoline, pyrrole, thiophene etc. The ring structure formed by A can be unsubstituted or substituted with any conventional substituent. The use of these substituents does not affect the overall reaction to produce the compound of formula III with the stereoconfig- uration of vinblastine. If the ring formed by A is substituted, it can be substituted by any conventional substituent such as lower alkyl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, amino, nitro, lower alkylamino, halo, etc. In the process of this invention B can be any alkylene chain of from 1 to 4 carbon atoms such as methylene, ethylene, propylene, butylene. The lower alkylene chain can Q be unsubstituted or substituted with any conventional substituent including those substituents mentioned hereinbefore in connection with the ring defined by A. Among the most preferred substituents are included hydroxy, lower alkyl, lower alkoxy, etc. 5 The term lower alkylidenedioxy designates a lower alkylidenedioxy substituent where lower alkylidene contains from 1 -to 7 carbon atoms. Among the preferred lower alkylidenedioxy substituents are included isopropylidenedioxy. Where R is a formyl group protected through the formation of an acetal. the acetal can be formed with any conventional alcohol or glycol to produce an acetal which 10 upon hydrolysis yields R as formyl. Among the conventional alcohols used to produce the acetals are the mono-hydroxy alcohols such as methanol and ethanol as well as other lower alkanols and di ydroxy alcohols, or glycols which produce cyclic acetals such as lower alkylene glycols ,g including"ethylene glycol, etc and dihydroxy lower alkanes containing 2 to 7 carbon atoms such as 1,3-dihydroxypropane, 1,4-dihydroxy butane, etc. Where R is -CH.Y and Y taken together with its 2Q attached carbon atom forms a hydrolyzable ether group Y can be any ether protecting groups, which when subjected to cleavage form a hydroxy group. A suitable ether protecting group is. for example, the tetrahydropyranyl ether, or. 4-methyl-5,6-dihydro-2H-pyranyl ether. Others are 2 aryl ethyl ethers such as benzyl, benzylhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ether, for example, methoxymethyl. or tri(lower alkyl)silyl ethers such as trimethyl silyl ether or dimethyltert-butyl silyl ether. The preferred ethers which are removed by acid catalyzed 3 Q cleavage are t-butyl and tetrahydropyranyl and the tri(lower alkyl)silyl ethers, particularly dimethyl-tert-butyl silyl ether, which may be removed by reaction with a fluoride such as tetrabutyl ammonium fluoride. Acid catalyzed cleavage is carried out by treatment with a strong organic or inorganic 35 acid. Among the preferred inorganic acids are the mineral .-'acids such as sulfuric acid, hydrohalic acid, etc. Among the preferred organic acids are lower alkanoic acids such as acetic acid, para-toluene sulfonic acid, etc. The acid catalyzed cleavage can be carried out in an aqueous medium or in an organic solvent medium. Where an organic acid is utilized, the organic acid can be the solvent medium. In the case of t-butyl ethers, an organic acid is generally utilized with the acid forming the solvent medium. In the case of tetrahydropyranyl ethers, the cleavage is generally carried out in an aqueous medium. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. The leaving group designated by Y can be any 5 conventional leaving group. Among the conventional leaving groups which are preferred are tosyloxy, mesyloxy and halogen. With respect to R 2, which is an amino protecting group, any conventional amino protecting group which can be removed by hydrogenolysis or photochemical cleavage can be Q utilized in accordance with this invention. Among the preferred amino protecting groups are included trityl, o-nitrobenzyl. benzyl, and diphenyl ethyl, etc. As used throughout this application the term "lower 5 alkyl" designates monovalent saturated straight or branched chain alphatic hydrocarbon groups containing from 1 to 7 carbon atoms such as ethyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl. The term "lower alkylene" designates a divalent saturated aliphatic straight or branched chain Q hydrocarbon radical containing 1 to 4 carbon atoms such as methylene or ethylene. The term "halogen" or halide includes all four halogens or halides such as chlorine, bromine, fluorine and iodine with chlorine, bromine and iodine being preferred. The term "lower alkanoyl" 5 designates alkanoyl groups derived from alphatic monocarboxcylic acids containing from 1 to 7 carbon atoms such as acetyl, butyryl, pivaloyl. etc. In condensing the compound of formula II with a compound containing the ring system of vindoline, one produces the compound of formula III with the configurations as shown at the 5 and 7 positions, which are necessary for obtaining _ vinblastine type compounds. The compound of formula III with the configuration as shown can be produced as a mixture thereof with the corresponding diastereomer having the opposite stereo-configuration at the 5 and 7 positions from that shown, depending upon the stereo-configuration at the 5 1Q position of the compound of formula II. If the compound of formula II has a 5 configuration as shown, condensation of the compound of formula II with a compound containing the ring system of vinblastine will produce the compound of formula III with the configuration at the 5 and 7 positions .. as shown. On the other hand, if the compound of formula II contains a mixture of 5S and 5R isomers, the compound of formula III will be formed as a mixture of the 7 diastereomer as shown, with the corresponding diastereomer having the opposite configuration at both the 7 and 5 2 Q positions to that shown. Through the process of this invention, even with a mixture of enantiomers of formula II, one can produce the compound in formula III only as a mixture of the aforementioned diastereomers. This allows one to synthesize the vinblastine type compound of formula I 25 with the correct stereo-configuration. If one utilizes a 5R.S diastereomeric mixture of the compound of formula II, the compound of formula III is produced as a mixture of the 7S diastereomer as shown with the corresponding 7R diastereomer having the opposite configuration at the 3 Q 5-position to that shown. This diastereomeric mixture can be separated either at this stage or at some later stage in the reaction scheme utilizing conventional means such as chromatography. 35 In carrying out the condensation of the compound of formula II with a compound containing the ring system of - b - vindoline, any organic compound which contains the structure shown -in formula II can be utilized. It has been found that compound of formula II, when condensed with compounds containing the ring system of vindoline or salts thereof, produce the compound of formula III with the specific stereoconfiguration about the 5 and 7 position shown therein. Therefore, the substituents on A and B, as well as the substituent on the ring system of vindoline, are of no importance to the reaction of this invention. These substituents will be carried along to produce the compounds of formula III with stereo-configuration about the 5 and 7 position set forth above. In accordance with this invention any compound containing the ring system of vindoline can be co ' ndensed with the compounds of formula II to produce the compounds of formula III. Among the preferred compounds which contain the ring system of vindoline for use in this invention are vindoline, 16-demethoxy vindoline and 2,3-dihydro N methyl-tabersonine. The condensation of the compound of formula II with a vindoline ring system containing compound or salts thereof is carried out in the presence of an aprotic solvent. In carrying out this reaction any conventional aprotic solvent can be utilized. Among the conventional aprotic solvents are aldehydes and ketones such as acetone, methyl ethyl ketone, etc. Other aprotic solvents which are also preferred include ethers such as dioxane and diethyl ether. In accordance with a preferred embodiment of this invention, this reaction takes place in the presence of a protic acid or with a salt of a vindoline ring system contain compound with a protic acid. Any conventional protic acid can be used in carrying out this reaction. Among the preferred protic acids are hydrohalic acids such as HC1 and HBr.as well as acids such as HBF . In carrying out this reaction it is also generally preferred that condensation take place in the presence of a silver salt. Any conventional silver salt which reacts with halides can be utilized in carrying out this reaction. Among the preferred silver salts are silver nitrate, silver fluoroborate, silver perchlorate. In carrying out this reaction, temperature and pressure are not critical and this reaction can be carried out at room temperature and atmospheric pressure. On the hand higher or lower temperatures can be utilized. Generally it is preferred to carry out this reaction at a temperature of The compound of formula III can be converted to a compound of the formula wherein n, A, B, Z, R 10 and .10 are as above, This conversion is carried out by treating the compound of formula III with an alkali metal borohydride in an acid. Any conventional acid can be used in this conversion. Among the acids are included inorganic acids such as phosphoric acid, sulfuric acid as well as organic acids such as formic acid and acetic acid, with organic acids such as acetic acid being preferred. In carrying out this reaction, the organic acid can be utilized as the solvent. Furthermore, in carrying out this reaction, temperature and pressure are not - 17 - critical and this reaction can be carried out at room temperature and atmospheric pressure. On the other hand, if desired elevated or lower temperatures can be utilized. In accordance with another embodiment of this invention the compound of formula V can be produced by condensing a compound of the formula wherein n, X, B, Y, R " and R.10 are as above with a compound containing the ring system of vindoline. This reaction can be carried out utilizing the same conditions described hereinbefore in connection with the conversion of a compound of formula II to a compound of formula III. However, it is generally preferred to carry out this reaction, without the presence of a silver salt, simply in the presence of an inert solvent. Generally it is preferred to carry out this reaction in a protic solvent in the presence of an acid, or in an acid halide. In carrying out this reaction with an acid, any protic solvent such as a - 18 - lower alkanol i.e., methanol or ethanol can be utilized. The acids which are generally utilized are the' organic acids such as the lower alkanoic acids i.e. acetic acid. On the other hand mineral acids such as hydrochloric acid can be utilized as well. If this reaction is carried out in an acid halide, any conventional acid halide can be used such as lower alkanoic acid halides, i.e. acetyl chloride. In these procedures, temperature and pressure are not critical and room temperature can be utilized. In the next step of this process the compound of formula V wheerree RR iiss hhyyddrrooggeenn <or lower alkyl is converted to the compound of the formula where n, R 1, A, R5, Z, B, and R7 are as above, The compound of formula V where R ,1"0 is -CH 2 Y and Y is a leaving group can be converted to the compound of formula I-A by first subjecting the compound of formula V to hydrogenolysis or photochemical cleavage depending upon the 2 substituent R . In this manner the compound of formula V 2 . where R is hydrogen is produced. In carrying out this reaction any conventional method of hydrogenolysis or photochemical cleavage to remove an amino protecting group can be utilized. - 19 - In producing the compound of formula I-A, the compound of formula V where R 2 is hydrogen and R10 is -CH Y and Y is a leaving group, can be cyclized in an organic solvent to a temperature of 10 C to 100 C. In carrying out this reaction any conventional hydrocarbon or ether solvent can be utilized with aromatic solvents such as toluene or benzene being preferred. If elevated temperatures are required, lower boiling solvents can be utilized. With these lower boiling solvents the cyclization occurs by heating in a sealed tube. In accordance with an alternative embodiment the compound of the formula V where R .1 " 0 is -CH 2 Y and Y is a leaving group is converted to the compound of formula I-A via an intermediate of the formula w as above R s an anion, In producing the compound of formula VI, the compound of formula V where R is CH 2 Y and Y is a leaving group is heated in a organic solvent to a temperature of from 35°C o to 100 C. In carrying out this reaction, any conventional inert organic solvent can be utilized with aromatic hydrocarbons such as toluene and benzene or ether solvents being preferred. Among the solvents which can be utilized are solvents boiling above 35 C. However, lower boiling solvents can also be utilized if the reaction is carried out in a sealed tube. The leaving group Y in this reaction becomes the anion Y' upon formation of the quaternary salt. The compound of formula VI is converted to the compound of formula I-A by removal of the amino protection group as described above. The compound of formula V where R is -CH- Y and Y is a hydrolizable ether group can be converted to the compound of formula V where R 10 i.s a leaving group by 5 first removing the ether group by conventional ether hydrolysis to produce the compound of formula V where Y is -OH. This compound of formula V where Y is a hydroxy can be converted to the compound of formula V when Y is a leaving group such as mesyloxy, tosyloxy, or halogens such as chlorine or iodine by any conventional method of converting a hydroxy group to a leaving group. The compound of formula V where Y is a leaving group produced as above is converted to the compound of formula I-A as described above. 5 The compound of formula V where R is -CH, Y and Y and R form a lower alkylidenedioxy, particularly isopropylidenedioxy, can be converted to the compound of formula I-A by first converting this compound to the 2 corresponding compound of formula V where R is hydrogen. Q This conversion is carried out by removing the amino protecting group as described above. After the amino protecting group has been removed the lower alkylidenedioxy groups may be removed by hydrolysis to produce the compound of formula V where R 10 is -CH 2 OH. R2 is hydrogen and 5 R is hydroxy. On the other hand, this compound can be produced from the compound of formula V where R is -CH_ Y and Y and R c form lower alkylidenedioxy by first hydrolyzing the lower alkylidenedioxy groups to produce the 2 compound of formula V where R is an amino protecting 10 . 6 . group, R is -CH 2 OH and R is -OH and thereafter c removing the amino protecting group. The compound of formula V when R 2 i.s hydrogen. R10 -CH 2 OH and R6 i.s OH can be converted to the compound of formula I-A by cyclization with a cyclization agent such as methyl triphenoxyphosphoniu halide. Any of the conditions , Q conventionally used with these agents can be utilized in this conversion. In the compound of formula V where R is an acetalized formyl group, this compound can be converted to ,5 the compound of formula I-A by first hydrolyzing the acetal group, by conventional acetal hydrolysis, to produce the corresponding compound of formula V where R is formyl. This latter compound is next converted to the corresponding 2 compound of formula V where R- is formyl, and R is 2 Q hydrogen by removal of the amino protecting group in the manner described hereinabove. On the other hand this compound can be produced by first removing the amino protecting group and thereafter hydrolyzing the acetal 2 group. The compound of formula V where R is hydrogen and 10 . 25 R is formyl can be converted to the compound of formula I-A by first heating to a temperature of from 35 C to o 100 C m a lower alkanoic acid followed by reduction with sodium cyanoborohydride in a lower alkanoic acid at temperatures of from 20 C to 60°C. 30 35 The compound of formula V where R is hydrogen and .10 is formyl when subjected to heating in a lower alkanoic acid forms a compound of the formula and Y" is an anion of a lower alkanoic acid. In forming the compound of formula VII, any lower alkanoic acid can be utilized, with a acetic acid and formic acid being especially prefer.red. The compound of formula VII can be converted to the compound of formula I-A by reduction with sodium cyanoborohydride in a lower alkanoic acid at a temperature of from 20oC to 60oC. If the compound of formula V where R ,10 is formyl, at 5 7 least one of R and R is hydrogen, is heated to a temperature of 35 C to 100 C in a neutral or basic solvent the following compound is formed: - 23 - where n. A, Z, B and R are as above and R_ is hydrogen or lower alkyl On the other hand if the compound of formula V where R .10 is formyl. and both of R_ and R_ are lower alkyl. is heated to a temperature of 35 aC to 100 aC in a neutral or basic organic solvent then a compound of the formula where A , R J Z and B are as above, and R-" and R " are individually lower alkyl; is formed. The compounds of formula VII-A and VII-B can be converted to the corresponding compounds of formula I-A by reduction in the same manner as described in connection with the conversion of the compound of formula VII into the compound of formula I. In forming the compound of formula VII-A or VII-B, any conventional neutral or basic organic solvent can be used or. if desired, mixtures of neutral and basic solvents. Among the preferred neutral solvents which can be utilized are included toluene, benzene, trichloromethane, etc. Among the preferred basic solvents are included pyridine, triethylamine, etc. The compounds of formulae III, V, VI, VII, VII-A and VII-B and I-A can be formed as either the 7S-diastereomer with the C5 configuration as shown or as a mixture thereof with its corresponding 7R diastereomer where the configuration at C5 is opposite to that shown. The formation of the 7S-diastereomer or its mixture with the corresponding 7R-diastereomer depends upon enantiomeric purity of the compound of formula II or II-A at the tertiary carbon attached to the tertiary nitrogen group contained therein. If a mixture of the 7S-diastereomer with the corresponding 7R-diastereomer is formed these diastereomers can be separated at any stage of the process by means of chromatography. In each instance, the stereochemistry at C5 will correspond uniquely to the stereochemistry at C7 and have the priority antireflective relationship (PARF) found in vinblastine. The compound of formula I-A can "exist as one or the other or as a mixture of both of two conformational isomers, i.e. a compound of the formula I-B and I-C. The compound of formula I-C has the conformational structure of the natural product. In accordance with this invention we have found that when a compound of structure I-B is heated at a temperature of from 30 C to 150 C it is converted to a compound having the natural conformational structure, i.e. a compound of the formula I-C. In carrying out this reaction, any conventional inert organic solvent can be utilized but this conformational conversion of I-B to I-C can be obtained in any medium. In .fact heating the compound of formula I-B in solid form will accomplish this result. If a solvent is desired, the preferred solvents are the aliphatic or aromatic hydrocarbons boiling above 30 C. Among these solvents are included toluene and benzene. On the other hand, a mixture of compounds of formula I-B and I-C can be converted to the "natural" conformational isomer by heating in the manner described above. If it is desired to obtain the compound of formula I-B in pure form, the compound of formula I-B can be separated from its mixture with the compound of formula I-C. Any conventional method of separation can be used to separate the compound of formula I-B from this mixture of conformational isomers. The compound of formula II is prepared by reacting a compound of the formula wherein A and R are as above; and R is hydrogen or an amino protecting group with any one of the following compounds: „ 5 0=CH-CH_- ( B ) -C-CO- R ' XI I I -B -CHO XIII-C wherein n, R 5' R_ ' and B are as above; R 11 is hydrogen or lower alkyl; and R is lower alkylidenedioxy. The compound of formula XII where R is hydrogen can be reacted with the compound of formulaXIII -A where R_ is hydrogen or the compound of formula XIII-B or XIII-C to produce a compound of the formula where n. A, B, R J and R are as above; R is -CH 2 -R " or -CO. _ R13; _R8 i.s .hyd,rogen. or lower alkyl; R is hydroxy or taken together with R 8 forms lower alkylidenedioxy and R13 is 9 lower alkyl, with the proviso that when R is hydroxy, R 5 and R8 are hydrogen; The reaction of the compound of formula XII. with R 16 being hydrogen, with one of the compounds of formula XIII-A where R is hydrogen. XIII-B or XIII-C to form the compound of formula XIII is carried out by a Mannich reaction. Any of the conditions conventional in Mannich reactions can be utilized in carrying out this reaction to form the compound of formula XIII. The reaction of this compound of formula XII with the compound of formula XIII-A 5 8 produce the compound of formula XIII where R and R are hydrogen. R 15 i.s -CH 2 R_ and R9- is hydroxy. The reaction of the compound of formula XII with the compound of formula XIII-B produces the compound of formula XIII where 5 8 R is hydrogen or lower alkyl; R is hydrogen or lower alkyl and R is -C0 2 . The reaction of the compound of formula XII with the compound of formula XIII-C produces the compound of formula XIII where R is hydrogen or lower alkyl, R .15 is -CH. where R and R form lower alkylidenedioxy The compound of formula XIII is converted to the compound of formula II via the following intermediates - 28 - wherein n. Y' , A, B, R ' ΕL' R " R R and R are as above. The compound of formula XIII is converted to the compound of formula XIV by protecting the tertiary amine group. Any conventional method of protecting a tertiary amine group with any of the aforementioned tertiary amine protecting groups which can be removed by hydrogenolysis or by photochemical cleavage can be utilized to carry out the conversion of formula XIII to the compound of formula XIV. In the formation of the compound of formula XIV. generally the amino protecting reagent containing a leaving group such as halide is reacted with the compound of formula XIII. This leaving group becomes the anion Y~. The compound of formula XIV is converted to the compound of formula XV by treating the compound of formula XIV with a amine or inorganic base. Any conventional amine base, such as tri-lower alkylamine particularly triethylamine and diisopropylethylamine or an inorganic base such as sodium carbonate can be utilized. This reaction can be carried out in any conventional inert organic solvent. Among the preferred organic solvent are the alcohols, such as the lower alkanols including methanol. In carrying out this reaction, temperature and pressure are not critical. This reaction can be carried out at room temperature and atmospheric pressure. On the other hand, higher or lower temperatures can be utilized. Generally it is preferred to carry out this reaction at the reflux temperature of the solvent. On the other hand, when in the compound of formula XII, R is an amino protecting group, condensation via a Mannich reaction with- anyone of the compounds of formula XIII-A, XIII-B or XIII-C produces the compound of formula XVI directly. The compound of formula XV where R 15 i.s -CH R9 g . * and R is hydroxy can be converted to the compound of formula XVI where R is CH. Y where Y is a hydrolyzable ether group by conventional etherification procedures. Among the preferred ether groups are the tri(lower alkyl silyl)oxy groups particularly t-butyldimethylsilyloxy. The hydroxy group can also be converted into a leaving group, such as mesyloxy, tosyloxy or a halide. particularly a chloride, bromide or iodide group, to produce the compound of formula XVI where Y is a leaving group. Reactions conventional for converting primary alcohols into the aforementioned leaving groups can be utilized to affect this conversion to form the compound of formula XVI. Where R in the compound of formula XV is a -COOR this group can be converted to the compound of formula XVI 10 . . . where R is formyl by reduction. Any conventional reducing agents such as diisobutyl aluminium hydride, which are utilized to reduce esters to their corresponding aldehydes, can be utilized in this conversion. If it is desired to prepare the compound of formula XVI where R is formyl protected by formation of an acetal, the formyl group can be converted to an acetal by conventional means. The compound of formula XVI, which includes the compound of XV when R 8 and R9 form lower alkylidenedioxy, can be converted to the compound of formula II by treating the compound of formula XVI with a halogenating agent such as organic or inorganic hypohalite preferably calcium hypohalite, sodium hypohalite or t-butylhypohalite in the presence of a tertiary amine base. Any conventional tertiary amine base can be utilized in carrying out this reaction. Among the preferred tertiary amine bases are the tri-lower alkyl amines and the cyclic tertiary amines. Among the preferred cyclic tertiary amines included N-lower alkylpyrrolidine, N-lower alkylpiperidine, N,N-di-lower alkylaniline, pyridine, etc. In carrying out this reaction an inert organic solvent can be utilized. On the other hand, the amine base can act as the solvent medium. If it is desired to utilize a solvent generally aprotic solvents, such as halogenated hydrocarbons, ethers and dimethylformamide are preferred. In carrying out this halogenation, temperature and pressure are not critical and this reaction can be carried out at room temperature and aattmmoosspphheerriicc pprreessssuurree,, wwiittlh temperatures of -40 C to 30 C being generally preferred - 31 - The compounds of formula II-B can be prepared from compound of formula XVI via intermediates of the formula wherein n, R" R " A, B, and .10 are as above, The compound of formula XVI can be converted to the intermediate of the formula XIX by reduction with an alkali metal borohydride, preferrably sodium borohydride in an inorganic or organic acid. This reaction can be carried out in the same manner described hereinbefore in converting the compound of formula III to the compound of formula V except that temperature of a t least 40oC, preferably 70oC to o . . . . 100 C, are generally utilized for this conversion. The compound of formula XIX can be converted to the compound of formula II-B by chlorination with a hypohalite, such as t-butyl hypochlorite, sodium hypochlorite or calcium hypochlorite in the presence of a tertiary amine. This reaction is carried out in the same manner as described hereinbefore in connection with the formation of the compound of formula II. The compounds of formula I wherein the vindoline ring contains a methyl group at R_ , i.e. compounds of the vinblastine type, can be converted to the corresponding compounds where R_ is CHO, i.e. compounds of the vincristine type by oxidation procedures well known in the art. The following examples are illustrative but not limitative of the claimed invention. In the example, the ether is diethyl ether and Celite is diatomaceous earth. HPLC in the examples designates high pressure liquid chromatography. Examp l e 1 Methyl • 3-benzyl-1.2.3.3a,4,5-hexahvdro-4(3-hydroxypropyl)- 7H-pyrrolo(2,3-d)carbazole-6-carboxylate To methyl 1,2,3,4,5.6-hexahydroazepino(4,5- b)indole-5-carboxylate (5.0g, 20 mmol) stirring in methanol (25 mL) was added enough methanol saturated with HC1 to turn moist universal pH paper red. The methanol was evaporated at reduced pressure and to the residue was added H O (50 mL) and 2-hydroxytetrahydropyran (2.2g, 22 mmol) and the mixture was allowed to stir at 20°C overnight. TLC (SiO , 7.5% methanol/CH-Cl,, ) of the mixture showed the formation of two products which were methyl 1,2,4.6-tetrahydro-ll-|3(4-hydroxybutyl)-3,10b- methanoazepine (4,5-b)indole-5-carboxylate and methyl 1,2,4, 6-tetrahydro-ll-α (4-hydroxybutyl)-3,10b- methanoazepine (4.5-b)indole-5-carboxylate (R f 0.68 and 0.76, CAS, blue). The reaction mixture was basified (NH OH) , 10% (aq) and extracted three times with CH Ci The organic extracts were dried (Na SO ) and concentrated to a residue, which was immediately dissolved in THF (100 mL) . To the THF solution was added benzyl bromide (2.5 mL, 21 mmol) and then the solution- was heated to reflux and monitored by TLC until .conversion to the mixture of 3-benzyl 1.2.4.6-tetrahydro-ll-β(4- hydroxybutyl)-5-methoxycarbonyl-3, lOb-methanoazepino (4,5-b)indolium bromide and 3-benzyl-l,2.4, 6-tetrahydro-ll- α(4 '-hydroxybutyl)-5-methoxycarbonyl- , 10b- methanoazepino (4,5-b)indolium bromide (about 2h) was completed. At this point- the THF was evaporated and replaced with methanol (100 mL) and diisopropyl ethyl amine (5.3 mL) . Reflux was restarted until TLC showed complete disappearance of the above mixture of compounds. The methanol was evaporated and the residue chromatographed (SiO . 5% methanol/CH Cl ) to yield 5.7g (67%) of methyl 3-benzyl-l,2,3,3a,4,5-hexahydro-4(3- hydroxy-propyl)-7H-ρyrrolo(2,3-d)carbazole-6-carboxylate as a gum;TLC (SiO , 7.5% methanol/CH Cl ) R f 0.86 (CAS, blue). Example 2 Methyl 3-benzyl-1,2.3 ,3a. ,5-hexahydro-4(3-p.toluenesul- fonyloxypropyl)-7H-pyrrolo(2,3-d carbazole-6-carboxylate Methyl 3-benzyl-l,2,3,3a,4,5-hexahydro-4(3-hydroxy- propyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxylate (l.Og. 2.4 mmol) and p-toluenesulfonyl chloride (0.55g. 2.9 mmol) were stirred in pyridine (4 L) under a nitrogen atmosphere at 20°C overnight. The mixture, which had developed a precipitate, was diluted with CH 2 C1 2 , washed with 10% NH OH and brine, dried (Na SO ) and taken to dryness first at aspirator pressure and then high vacuum in order to avoid excess heating of the product. The residue was dissolved in methanol and allowed to crystallize overnight in the freezer; yield methyl 3-benzyl-1,2,3,3a,4,5-hexahydro- (3-p.toluenesulfonyloxy- propyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxyl e 0.59g (40%). An analytical sample was recrystallized from methanol, mp 158-159°C. TLC (SiO , 7.5% methanol/CH Cl ) R 0.91 (CAS, blue). Example 3 Methyl -benzyl-1,2.3 ,3a,4,5-hexahydro-4(3-p.toluenesul- fonyloxypropyl -7H-pyrrolo(2, -d)carbazole-6-carboxyla e A solution of methyl 3-ben∑yl-l,2,3,3a,4,5-hexahydro- 4(3-hydroxypropyl)-7H-pyrrolo(2,3-d)carbazole-6- carboxylate (1.95g, 4.66 mmol), and two small crystals of 4-dimethylaminopyridine in 8mL of anhydrous pyridine was cooled to 0°C and 0.890g (4.70 mmol) of p_ toluenesul- fonyl chloride added. The clear/red solution was stirred at 15°C for 15h, resulting in formation of a precipitate. The mixture was then poured into 20 mL of water and extracted with 25 mL of dichloromethane. The organic phase was washed with water, aqueous ammonium hydroxide, and brine and dried (Na 2 SO.). Concentration under vacuum and azeotropic removal of pyridine with toluene at 50°C at 15mm, followed by drying under high vacuum, gave a residue which was column chromatographed on silica, eluting with 4:6 ethyl acetate:hexane. The product methyl 3-benzyl-l,2,3,3a.4.5- hexahydro-4(3-p. oluenesulfonyloxypropyl)-7H-pyrrolo(2,3- d)carbazole-6-carboxylate (2.00g. 75% yield) matched the previously characterized sample, prepared in Example 2 in mp and speσtroscopic data. Example 4 5,7-priority anti-reflective (PARF) methyl 3-benzyl-l.2,3. 4,5.6,7, 8-octahydro-5(3-p. oluenesulfonyloxypropy1)azonino (6,7-b)indσle-7-(15-vindolinyl)-7-carboxylate A solution of methyl 3-benzyl-l,2,3 ,3a,4,5-hexahydro-4 (3-p.toluenesulfonyloxypropyl)-7H-pyrrolo(2,3-d)carbazole-6- carboxylate (0.740g, 1.30 mmol) in 10 mL of dichlorometh- ane and 0.18 mL (1.3 mmol) of triethyla ine was cooled to 0°C. Dropwise addition of 0.200 mL (1.69 mmol) of t_ butylhypochlorite and stirring for 10 min. gave a solution which, by TLC was free of starting compound (CAS, blue) and which contained a new less polar compound (CAS, brown) . The reaction mixture was washed with 2 x 10 mL of water, 10 mL of brine and dried (Na 2 S0 4 ). Concentration under vacuum gave 0.800g (1.30 mmol) of methyl 3-benzyl-6-chloro 1,2.3,3a,4,5-hexahydro-4(3- p-toluenesulfonyloxypropyl)-pyrrolo(2,3-d)carbazole-6- carboxylate as a white foam. To a solution of 0.800g of methyl 3-benzyl-6-chloro 1,2,3,3a,4.5-hexahydro-4(3- .toluenesulfonyloxypropy1)-pyrro lo(2.3-d) carbazole-6-carboxylate and vindoline 1.5 hydrochloride (0.456g, 0.895 mmol) in 15 mL of dry acetone was added a solution of 0.80g (4.0 mmol) of AgBF in 15 mL of dry acetone at room temperature. After 5 min. the heterogeneous gray reaction mixture contained no starting material. Addition of 10 mL of cone, ammonium hydroxide, 10 mL of water and 10 mL of brine, extraction with 3 x 20 m of dichloromethane, washing of the extracts with brine, drying (Na 2 SO ) and concentration gave 1.20g of the 6S and 6R isomers of 4.6-priority anti-reflective (PARF) methyl 3-benzyl-l,2, 3.3a,4,5-hexahydro-4-(3-p.toluenesul- fonyloxypropy1)-6-(15-vindolinyl)pyrrolo(2.3-d)carbazole-6- carboxylate. The 6S and 6R isomeric mixture of 4,6-priority anti- reflective (PARF) methyl 3-benzyl-l.2,3,3a,4,5-hexahydro- 4-(3-p.toluenesulfonyloxy-propy1)-6-(15-vindoliny1)pyrrolo- (2,3-d)carbazole-6-carboxylate was dissolved in 15 mL of acetic acid and, with stirring at room temperature, 0.54g (10 mmol) of sodium borohydride was added in six por¬ tions. After the final addition the reaction mixture was stirred for 10 min. and then poured onto ice. Adjustment of the pH to 9-10 with cone, ammonium hydroxide was fol¬ lowed by extraction with 60 mL of dichloromethane. The extract was washed with water (3 x 25 mL), brine (25 mL) , dried (Na SO ) and concentrated to 1.10g of«a yellow solid. Column chromatography on silica, eluting with ethyl acetate, gave 0.83g (91% yield based on 1 mmol of vindoline) of the mixture of 7S and 7R isomers of 5,7- priority anti-reflective (PARF) methyl 3-benzyl-l,2,3,4, 5,6,7,8-octahydro-5(3-p.toluenesulfonyloxypropyl)azonino (6.7-b)indole-7-(15-vindolinyl)-7-carboxylate as a white solid. R f 0.25 (Si0 2 , ethyl acetate, CAS brown). These diastereσmers showed slight separation on TLC using methanol-dichloromethane as solvent. A better separation of the 7S and 7R isomers was obtained with 1:1 hexane:acetone on silica, showing Rf 0.37 for the 7S compound and Rf 0.27 for the 7R compound. Thus, separation of 0.830g of the mixture on a 2mm centrifugal chromatography plate gave 0.374g of the 7S ' compound and 0.332g of the 7R compound. Example 5 Methyl 3-benzyl-1,2,3 ,4,5,6,7,3-octahydro- 5S( -p.toluenesulfonyloxypropyl) azoninα (6,7-b) indole-7 and 8-carboχylates Methyl 3-benzyl-1,2,3.3a,4,5-hexahydro-4(3-p-toluene¬ sulfonyloxypropyl)-7H-pyrrolo(2,3-d)carbazole-6-carboxyiate (O.lOg, 0.17 mmol) was dissolved in acetic acid (1 mL) and heated in a 90°C oil bath. Sodium borohydride (0.040g, 1.1 mmol) was added quickly in portions and the reaction was quenched by pouring onto ice. The aqueous phase was basified with NH OH (10% aq) and concentrated to a residue, which was chromatographed (SiO , 2% methanol/CH Cl ) to yield the 7α isomer of methyl 3-benzyl-1,2,3,4,5, 6,7,8-octahydro-5β(3-p.toluene¬ sulfonyloxypropyl) azonino (6,7-b) indole-7-carboxylate (0.055g, 55%) and the 70 isomer of methyl-3-benzyl- 1,2,3,4.5,6,7,8-octahydro-5β(3-p. oluene¬ sulfonyloxypropyl) azonino (6.7-b) indole-7-carboxylate (0.015g, 15%) as amorphous solids. These compounds tended to undergo, on standing, cyclization to the internal quaternary salt. Physical data for the 7α isomer of methyl 3-benzyl-1.2,3,4,5,6,7,8-octahydro-5β(3-p. oluene¬ sulfonyloxypropyl) azonino (6,7-b) indole-7-carboxylate: TLC (Si0 2 . i.5% methanol/CH 2 Cl ) R 0.74 (CAS, violet). Physical data for the 70 isomer of methyl 3-benzyl-1,2.3,4,5,6,7.8 octahydro-50(3-p.toluenesul- fonyloxypropyl) azonino (6,7-b) indole-7-carboxylate: TLC (SiO . 1.5% methanol/ CH Cl ) R 0.47 (CAS, violet) . Example 6 5,7-priority anti-reflective (PARF) methyl 3-benzyl-l,2,3,4,5,6,7,8-octahydro-5(3-p.toluenesulfonyl¬ oxypropy1)azonino (6,7-b)indole-7-(15-vindolinyl)-7- carboxylate A solution of the epimeriσ mixture of methyl 3-benzyl- 1.2,3.4.5,6,7,8-octahydro-50(3-hydroxypropyl)azonino(6,7-b) indole-7α and 0-carboxylates (0.574g, 1.00 mmol) and 0.18 mL (1.3 mmol) of triethylamine in 10 mL of dichloromethane was cooled to 0°C. Dropwise addition of 0.15 mL (1.3 mmol) of t-butylhypochlorite resulted in a clear yellow solution, which, after 15 min at 0-5°C, showed complete reaction of the starting epimers (CAS blue) and formation of the slightly less polar (TLC R f 0.8, 5% methanol in dichloromethane) methyl 3-benzyl-12b- chloro-1,2,3,4,5, 6-hexahydro-5(3-p.toluenesulfonyloxy¬ propyl)azonino (6,7-b)-2,3-dihydroindole-7-carboxylate (CAS orange). The reaction mixture was diluted with 20 mL of dichloromethane, washed with- water (2 x 50 mL) and brine (1 x 20 mL) , dried (MgSO ) and concentrated under vacuum to 0.61g (100%) of an orange foam. This material was used directly in the subsequent coupling reaction with vindoline. To a solution of the above indoline, i.e., methyl 3- benzyl-12b-chloro-l.2,3,4.5,6-hexahydro-5(3-p.toluene- sulfonyloxypropyl)azonino (6,7-b)-2,3-dihydroindole-7- . carboxylate (0.61g, 1.0 mmol) and vindoline 1.5 hydrochloride (0.365g, 0.715 mmol) in 7mL of dry methanol was added 5 mL of methanolic HCl (formed by- solution of 0.3 mL of acetyl chloride in 10 mL of methanol). The clear burgundy red reaction mixture was stirred at room temperature for 15 h. The mixture was then concentrated under vacuum, basified with ammonium hydroxide and extracted with 30 mL of dichloromethane. The extract was " washed with 2 x 50 mL of water, 1 x 20 mL of brine, dried (MgSO ) and concentrated under vacuum to 0.85g of a gummy residue. Chromatography on silica gel, eluting with ethyl acetate, gave 0.40g (48%) of the 5,7-priority anti-reflective (PARF) methyl 3-benzyl-l,2,3,4,5,6,7,8- octahydro-5(3-p.toluenesulfonyloxypropyl)azonino (6.7-b)indole-7-(15-vindolinyl)-7-carboxylate as a pale yellow solid. The product was identical by TLC, NMR and mass spectra to the above characterized product obtained in Example 4. Example 7 4' -Deethyl-4 '-deoxyvinblastine (2'S,18'S) and 4'-Deethyl- 4 '-deoxyvinblastine (2'R,13'R) a) The mixture of diastereomers 5,7-priority anti-reflective (PARF) methyl 3-benzyl-l.2, ,4, 5, 6,7,8- octahydro-5(3-p.toluenesulfonyloxypropyl)azonino (6,7-b)indole-7-(15-vindolinyl)-7-carboxyla e (0.258g. 0.250 mmol) was dissolved in 2.5 mL of dry toluene and heated at reflux, with stirring for 1.5 h. At that point the quaternary salts 6 ' -benzyl-4 ' -deethyl-4 ' -deoxyvin¬ blastinonium tosylate (2'S,18'S) and 6 ' -benzyl-4 ' -deethyl- '-deoxyvinblastinonium tosylate (2'R, 18'R), both in the form of their 1' -equatorial piperidine ring conforma- tional isomer, had precipitated as a brown gum and TLC indicated complete reaction of the starting material. The solvent was removed under vacuum and the residual solid 6'-benzyl- 4 ' -deethyl-4 '-deoxyvinblastinonium tosylate (2'S,18'S) and 6'-benzyl-4' -deethyl-4'-deoxyvinblastinonium tosylate (2'R. 18'R) (0.258 g. 100%) with R f (Si0 2 . 95:5 CH Cl : methanol, CAS pink) 0.05 was used directly in the following debenzylation. A solution of 0.206g (0.200 mmol) of the above solid in 5 mL of dry.methanol was stirred with 20 mg' of 10% palladium on charcoal under a hydrogen atmosphere at -5 to 0°C for 55 min. when 4.5 mL (0.20 mmol) of hydrogen had " been consumed. Filtration through Celite, concentration at 20°C and partioning of the residue between 30 mL of dichloromethane and 10% aq. ammonium hydroxide, followed by washing of the organic extracts with water and brine gave, on concentration, 150 mg (99%) of the two diastereomeric products 4' -deethyl-4'-deoxy¬ vinblastine (2'S,18 , S) and 4 '-deethyl-4 '-deoxyvinblastine (2'R,18'R) both in form of their 1'-equatorial piperidine ring conformational isomer. These two products in 5 L of toluene were heated at reflux for 2 h. TLC then showed " formation of the two diastereomeric products 4 '-deethyl-4'-deoxyvinblastine (2'S,18'S) and 4 '-deethyl-4' -deoxyvinblastine (2'R,18'R) both with the 1' axially substituted piperidine ring conformation. TLC (Si0 2 : 10% methanol in CH 2 C1 , CAS brown) 0.16 and 0.35. Concentration and centrifugal chro atography on a 2 mm Si0 2 plate, eluting with 5% methanol in CH_C1 2 . gave 32 mg of 20' -deethyl-20' -deoxyvinblastine (2'S, 18 'S) (R- 0.16), and 35 mg of its (2'R, 18'R) enantiomeric diastereomer (R. 0.35). Yield 47% for each diastereomer Alternatively, the separate 7S and 7R diastereomers of methyl 3-benzyl-l,2,3.4,5,6,7,8-octahydro-5(3-p.toluene¬ sulfonyloxypropyl) azonino (6;7-b) indole-7-(15- vindolinyl)-7-carboxylate. when subjected to the same reaction procedure of heating in toluene, followed by hydrogenolysis, gave respectively, prior to the final heating in toluene, the separate 2'S,18'S and the 2'R.18'R diastereomers of 4'-deethyl-4 ' -deoxyvinblastine, each as • the 1'-equatorial piperidine ring conformational isomer. The 2 , S,18S',1' equatorial compound had an HPLC retention of 63.3 min on a 250 x 4.6 mm C-18 reverse phase column with 1% triethylamine in 85:15 methanol.-water at a 0.5 mL/min flow rate. The above 1' -equatorial compound was conformationally inverted to the 2 , S,18 , S,1' axial 4'-deethyl-4'- deoxyvinblastine by heating in toluene at 95°C. This product had an HPLC retention of 8.8 min on the same column at the same flow rate. The 2'R,18'R.1' equatorial compound had HPLC retention of 35.1 min on a 250 x 4.6 mm C-18 reverse phase column with 1% triethylamine in 85:15 methanol:water at a 0.5 mL min flow rate. It was conformationally inverted to the Z'R.lB'R.l' axial 4' -deethyl-4 '-deoxyvinblastine by heating in toluene a: 100°C. This product had an HPLC retention of 5.4 min on the same column at the same flow rate. Example 3 4 ' -Deethyl-4 ' -deoxyvinblastine (2'S,18'S) and 4 ' -deethyl-4 ' -deoxyvinblastine (2'R, 18'R) The quaternary salts 6 ' -benzyl-4 ' -deethyl-4 '- deoxyvinblastinonium tosylate (2'S,18'S) and 6'-benzyl-4' - deethyl-4' -deoxyvinblastinonium tosylate (2'R, 18'R) were dissolved in methanol (5 mL) and the solution was purged with nitrogen. Palladium catalyst (10% Pd/C, O.lOg) was added, the flask fitted with a reflux condenser and heated in a 90°C oil bath. An excess of sodium borohydride (ca. 0.3g) was added through the top of the condenser as rapidly as possible, so that the vigorous reaction could be contained. TLC's were taken throughout this procedure to qualitatively determine if any starting material remained. The addition of the borohydride reagent took about 5 min. A short reaction time was necessary because a less polar side product seemed to form on longer reaction times. The hot solution was filtered and washed with hot methanol (ca. 50 mL) followed by CH Cl (ca. 10 mL) . The solution was partially concentrated and NH OH (10% aq) was added. The aqueous solution was extracted with CH Cl , the organic extracts were dried ' (Na SO ) and concentrated to a residue which was a 1:1 parts by weight mixture of the diastereomers 4 '-deethyl-4'-deoxyvinblastine (2'S,18'S) and '-deethyl-4 '-deoxyvinblastine (2'R,18'R). Yield 0.13g (70%). Physical data for the 2'R 18'R epimer: TLC ( si0 2 ; 10% methanol/CH 2 Cl 2 ) R f 0.37 (CAS. brown). Physical data for the 2'S, 18 'S epimer: TLC (SiO , 10% methanol/CH Cl ) R f 0.23 (CAS, brown). Example 9 4 i -Deethyl-4'-deoxyvinblastine and its 2'R,18'R epimer A solution of 5,7-priority anti-reflective (PARF) methyl 3-benzyl-1,2,3,4,5,6,7,8-octahydro-50(3- p.toluene-sulfonyloxypropyl)azonino(6,7-b) indole-7- (15-vindolinyl)-7-carboxylate(7 and 70) (0.100 g, 0.092 mmol), in 10 mL of acetic acid and 0.02 g of 10% Pd on charcoal was stirred under a hydrogen atmosphere for 3h. The reaction mixture was then filtered through Celite, made basic with ammonium hydroxide and extracted with 20mL of dichloromethane. The extract was washed with 2 x 20 mL of water, 1 x 20 mL of brine, dried (MgSO ) and concentrated under vacuum to 0.060 g of a yellow solid. TLC indicated that this product was 4'-deethyl-4 ' - deoxyvinblastine and its 2'R 18'R epimer with the "natural type" piperidine ring conformation and that none of the C16'-C14' PREF diastereomers (epimeriσ with the products at C16 ' ) were formed. Chro atographic separation .of the two products i.e. deethyl-4-deoxyvinblastine (2'S,18'S) and deethyl-4-deoxyvinblastine (2'R,18'R) as described in Example 7, and comparison of their NMR and mass spectra with those of- the products obtained from conformational inversion of the piperidine ring of the "unnatural" type piperidine conforms i.e. I 1 -equatorial piperidine ring conformational isomer of 2'R,18'R and 2'S, 18'S, 4'-deethyl-4'deoxyvinblastine, showed complete matching of spectra. Example 10 Methyl 2-Ethyl-5-hydroχyvalerate A solution of 30.Og (0.234 mol) of 2-ethylvalerolactone in 150 mL of dry methanol and 0.5 L of cone, sulfuric acid was stored under argon for 17 h at 20°C. Then 10.0 g of potassium carbonate was added and the mixture stirred for 20 min. After filtration, and concentration at 40°C under vacuum, the residue was dissolved in 100 mL of ether. The solution was washed with 200 L of satd. sodium carbonate, 100 mL of satd. brine, dried over MgSO , filtered, concentrated and the residue distilled to give 32.lg (86%) of methyl 2-ethyl-8-hydroxyvalerate, bp 58- ' 60°C (0.5 mm Hg) . Example 11 Methyl 2-Ethyl-5-Oxopentanoate To 50.46 g (0.234 mol) of pyridiniu chlorochromate, under argon, was added 100 mL of dichloromethane followed, with rapid stirring, by 25.0 g (0.156 mol) of methyl 2-ethyl-5-hydroxypentanoate in 20 mL of dichloromethane. After stirring at 20°C for 2.5 h. 15 g of silica gel was added followed by 200 mL of ether. Filtration through a 3.5 x 40 cm silica gel column (60-200 mesh), eluting with ether and concentration at 40°C under vacuum gave an oil, which was redissolved in 100 mL of dichlorometh¬ ane. Washing with 3 x 100 L of cold IN HCl, 3 x 100 mL of satd. NaHCO., drying over MgSO., filtration, con¬ centration at 40°C and distillation gave methyl 2-ethyl-5-oxopentanoate 14.64g (59%) product, b.p 104-105°C (16 mm Hg) . Example 12 Racemic methyl 1.2.4,6-tetrahydro-ll-(l-ethyl-4-methoχy- 4-oxobutyl)-3 ,10b-methanoazepino(4.5-b)indole-5-carboxylate To a solution of 6.00 g (24.6 mmol) of methyl 1,2,3,4,5,6-hexahydroazepino-[.4,5-b] indole-5-carboxylate in 50 mL of dry methanol, under argon, was added 4.00 g (25.3 mmol) of methyl 2-ethyl-5-oxopentanoate. After 12 h at 20°C the mixture was concentrated under vacuum at 40°C and the residue dissolved in dichloromethane. The solution was adsorbed on 20 g of SiO,, which was then placed on a 4 x 15 cm dry column of SiO . Elution with ethyl acetate, concentration, solution of the concentrated eluate in 100 mL of dichloromethane, drying over MgSO , filtration, and concentration gave an oily product from which two successive 100 mL portions of toluene were distilled at 40°C under vacuum. Drying at 20°C (0.05 mm) provided as a foam 7.70 g (82%) racemic methyl 1,2,4,6-tetrahydro-ll-(l-ethyl-4-methoxy-4-oxobutyl)- 3,10b-methanoazepino(4,5-b)indole-5-carboxylate. This product had UV (ethanol) λ 3V 228, 303, 330 nm absorption maxima. Example 13 4.2'-PREF and 4,2' -PARF Methyl 3-benzyl-l,2,3 ,3a,4 , 5- hexahydro-4f2-(hydrσxy ethyl)butyl1-7H-pyrrolo ' (2.3-d)carbazole-6-σarboxylate A solution of 6.182 g (16.08 mmol) of the methyl 1.2.4,6-tetrahydro-ll-(l-ethyl-4-methoxy-4-.oxobutyl)-3,10b- methanoazepino(4,5-b)indole-5-carboxylate and 2.750 g (16.08 mmol) of benzyl bromide in 100 mL of anhydrous ether was stirred for 48 h at 20°C under argon. Filtration, washing of the solids with 3 x 100 mL of ether and drying at 15 mm and 0.01 mm pressure gave 8.422 g (94%) of the quaternary salt 3-benzyl 1,2,4,6 tetrahydro-ll-(l-ethyl-4-methoxy-4-oxobutyl)-5-methoxycarbonyl- 3,lOb-methanazepino (4.5-b)indolium bromide. A solution of 4.000g (7.201 mmol) of the above quaternary salt in 40 mL of methanol and 1.100 g (10.80 mmol) of triethylamine was heated at reflux under argon for 5h. At 40°C (15 mm) the solution was then concentrated to a residual orange gum and the latter dissolved in 50 mL of dichloromethane. Washing with iced 15% ammonium hydroxide and satd. brine, with back extraction of the latter with 50 mL of dichloromethane, drying of the combined organic solutions (MgSO ) , filtration and concentration at 40°C (15 mm and 0.01 mm) gave a foam, which was chromatographed on a 3 x 15 cm SiO column, eluting with 1:4 ethyl acetate: pentane. The diastereomeric mixture of esters 4,2'-PREF and 4,2"-PARF-Methyl 3-benzyl-l.2.3,3a,4.5-hexahydro-4- [2-(methoxycarbonyl)butyl]-7H-pyrrolo-(2.3-d)carbazole- 6-carboxylate (2.737 g. 80% yield) showed almost no separation on TLC (Si0 2 ). Rf 0.61 (2:1 ether-hexane) ; Rf 0.43 (2% methanol in dichloromethane) ;' Rf 0.41 (1:4 ethyl acetate: pentane). This epimerte mixture could be separated by HPLC on a 22.1 mm x 50 cm 10 μm Silica column with ether: hexane 1:3 at flow rate of 8.0 mL/min, giving the PREF isomer with Rf 50 min and the PARF isomer with Rf 57 min in a 1.47:1.00 ratio. A solution of 2.147 g (4.526 mmol) of the diastereomeric mixture of 4,2 '-PREF and 4,2'- PARF-Methyl 3-benzyl-1,2,3,3a,4, 5-hexahydro-4-[2-(methoxycarbonyl)- butyl]-7H-pyrrolo(2,3-d)carbazole-6-carboxylate in 20 mL of dry tetrahydrofuran, under an argon atmosphere, was cooled to 0°C. With rapid stirring 5.40 mL of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (5.43 mmol) was added dropwise over 10 min. After stirring at 0°C for further 20 min., the reaction mixture was poured into 100 mL of iced 30% ammonium hydroxide and extracted with 3 x 50 mL of dichloromethane. The combined extracts were washed with 100 mL of cold satd. brine, dried (MgSO.) filtered and concentrated at 40°C (15 mm and 0.01 mm) to 1.744 g (86% yield) of 4.2 '-PREF and 4 ,2 ' -PARF methyl 3-benzyl- 1,2,3.3a,4.5-hexahydro-4-[2-(hydroxymethyl)butyl]-7H- pyrrolo(2.3-d)carbazole-6-carboxylate as a foam. TLC (Si0 2 . ether) Rf 0.50 (PREF isomer) -and 0.56 (PARF isomer). A 0.50 g portion of this product was subjected to centrifugal chromatography on a 2 mm SiO plate. Application in 5 mL of dichloromethane was followed by elution with 4:1 ether:hexane at 2.2 mL/min. and collection of 1 min. fractions. Fractions 5-30 and 52-90 contained the two nearly pure diastereomeric PARF and PREF isomers. Example 14 4.2 'PREF- and 4.2'PARF Methyl 3-benzyl-l,2,3 ,3a,4,5- hexahydro-4 [ ■ 2-(p.toluenesulfonyloxy ethyD-butyl1-7H- * pyrrolo(2,3-d) carbazole-6-carboxylate Under an argon atmosphere 0.980 g (2.19 mmol) of the 4.2' PREF and 4,2* PARF methyl 3-benzyl-l.2,3,3a. .5- hexahydro-4[2-(hydroxy ethyl)-butyl]-7H-pyrrolo(2,3-d) carbazole-6-carboxylate was combined with 0.460 g (2.41 mmol) of p-toluenesulfonyl chloride and 5 mg of 4-dimethylamino pyridine. At 0°C 10 mL of dry pyridine was added and the reaction mixture stirred at 0°C for 4 h and at 4°C for 24 h. The red solution was then poured into 50 mL of cold IN ammonium hydroxide and extracted with 3 x 50 mL of dichloromethane. The combined extracts were washed with 100 L of cold satd. brine, dried (MgSO ) . filtered and concentrated at 40°C (15 mm). Two 100 mL portions of toluene were then added and distilled at 40°C under vacuum, providing 0.991 g (75% yield) of the 4,2' PREF- and 4.2' PARF methyl 3-benzyl-1,2,3,3a,4, 5-hexa ydro-4[2-(p.toluene¬ sulfonyloxypropyl)-7H-pyrrolo(2,3-d) carbazole-δ-carboxy¬ late. TLC (SiO ) Rf 3.0 and 3.7, 1:4 ethyl acetaterpentane; Rf 4.6 and 5.1, 5% methanol in dichloromethane. The epimeric mixture of tosylates could be separated by centrifugal chromatography on a 4 mm SiO_ plate, with application in 10 mL of dichloromethane and elution with ethyl acetate: pentane (1:5). At 2.2 mL/min and with collection of 1 min fractions, the PREF isomer was- obtained in fractions 6-26 and the 4,2' PARF isomer in fractions 99-170. Rechromatography of central fractions (5x) gave final 0.420 g combined PREF isomer and 0.391 g combined PARF isomer (total 0.811 g, 61% yield). Alternatively, separation of the diastereomeric tosylates was accomplished by preparative high pressure liquid chromatography. For this, the crude reaction product was first passed through a 3 x 10 cm SiO_ * column, eluting with ethyl acetate: pentane (1:2). The concentrated eluates (200 mg) were then subjected to HPLC on a 22.1 mm x 50 cm 10 μm. Silica column, with ethyl acetate: pentane 1:4, 20 mL/min. Collecting 24 mL fractions gave in fractions 6-9 76 mg and in fractions 12-17 112 mg of the respective diastereomers (94% recovery) . Example 15 7S and 7R i somers of 5 . 7 PARF and 5 , 2 ' PARF Methyl 3 -benzyl 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8-octahydro-5 [ 2- ( p . toluenesul - fonyloxymethyD -butyπ azonino ( 6 , 7-b) indole 7- ( 15- vindo l inyl ) -7-car boxy late A solution of 6.36g (1.06 mmol) of the 4,2' PARF-methyl 3-benzyl-l,2,3 ,3a,4,5-hexahydro-4[2- (p.toluenesulfonyloxymethyl)-butyl]-7H-pyrrolo(2,3-d)- carbazole-6-carboxylate in 10 mL of dichloromethane and 0.118 g (0.162 μL, 1.16 mmol) of triethylamine was cooled to 0°C under argon. With vigorous stirring 135 μL (0.126g, 1.16 mmol) of tert. butyl hypochlorite was added. After 20 min at 0°C the yellow reaction mixture was poured into 20 mL of iced water and the mixture extracted with 3 x 10 mL of dichloromethane. The combined extracts were dried (MgSO ) , filtered and concentrated at 20°C at 15 mm and subsequently at 0.05 mm pressure to a tan foam which was methyl 3-benzyl-6-chloro 1,2.3,3a- 4,5-hexahydro 4-[2-(p.toluenesulfonyloxy- methyl)-butyl]-ρyrrolo(2,3-d) carbazole-6-carboxylate, 0.672g (100%). This chloroindolenine (0.636 ' g. 1.00 mmol) and 0.374 g (0.735 mmol) of vindoline 1.5 hydrochloride were placed under argon and 10 mL of dry acetone was added. After stirring for 5 min, 0.618 g (3.18 mmol) of silver tetrafluoroborate in 4 mL of dry acetone was added in one portion, with shielding from light. After stirring * in the dark for 20 min the brown suspension was poured into 50 mL of 10% ammonium hydroxide, saturated with sodium chloride, and the mixture was extracted with 3 x 25 mL of dichloromethane. The combined dried (MgSO ) extracts were filtered and concentrated at 40°C, 15 mm to a brown glass. TLC (SiO_, ethyl acetate) demonstrated the two i ines 4,5-PARF and 4,6-PREF methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-[2-(p.toluenesulfonyloxy¬ methyl)butyl]-6-(15-vindoliny1)-pyrrolo (2,3-d) carbazole-6-carboxylate (Rf 0.13 and 0.46) and the absence of vindoline (Rf 0.32). This imine mixture was dissolved • in 25 mL of acetic acid and 0.571g (10.6 mmol) of potassium borohydride was added in. ortions over 15 min. with rapid stirring. The reaction mixture was then poured into cold ammonium hydroxide solution and extracted with 3 x 50 mL of dichloromethane. The combined extracts were dried (MgSO ) filtered and concentrated at 40°C at 15 mm and subsequently at 0.05 mm Hg to give 0.660g (85% yield based on vindoline used) of the two amines, i.e. 7R and 7S 5,7 PARF -5,2' PARF methyl 3-benzyl-l,2,3,4,5,6,7,8- octahydro-5-[2-(p.toluenesulfonyloxymethyl)-butyl]-azonino (6,7-b)indole-7-(l5-vindolinyl)-7-carboxylate as a tan foam. TLC (Si0 2# ethyl acetate) Rf 0.37 and 0.49 (CAS grey-purple). Centrifugal chromatography on a 4 mm SiO plate, with application of the mixture in 10 mL of dichloromethane, followed by elution with 10 mL of dichloromethane and then 80% ethyl acetate in pentane at 2.1 mL/min and collection of fractions every minute gave the separated diastereomers. In fractions 3 to 30, the 7S isomer of 5,7 PARF and 5,2' PARF methyl 3-benzyl- 1,2.3,4,5,6,7,8-octahydro-5[2-(p.toluenesulfonyloxymethyl)- butyl]-azonino(6,7-b)indole-7-(15-vindoliny1)-7- carboxylate and in fractions 52 to 90 the corresponding 7R isomer. Rechromatography of the fractions 31-51 provided additional separated compounds, for a combined 0.300 g of ' the 7S isomer and 0.271g of the 7R isomer (66% total yield based on vindoline) . Example 16 4'-Deoxyvinblastine Under an argon atmosphere 0.180 g (0.170 mmol) of the 7S isomer of 5,7 PARF-5,2' PARF methyl 3-benzyl-l,2.3,4,5,6, 7,8-octahydro-5-[2-(p.toluenesulfonyloxymethyl)-butyl]- azonino(6,7-b)indole-7-(15-vindolinyl)-7-carboxylate in 25 mL of dry toluene was heated at reflux for 24 h with rapid stirring. At that point the starting amino tosylate had reacted completely. The cooled reaction mixture was concentrated under vacuum and the residual solid washed with three 50 mL portions of dry ether. The resulting quaternary salt, i.e. the 1' -equatorial piperidine ring conformational isomer of 6 '-benzyl-4'-deoxy-vinblas- tinonium tosylate (2'S,18'S) (0.172g, 96%), which was free of starting amine by TLC, (ethyl acetate: ethanol. 1:1). was dissolved in 6 mL of methanol. Addition of 0.015g of 10% Pd/charcoal and stirring under a hydrogen atmosphere at -20°C for 40 min resulted in an uptake of 4 mL of hydrogen. The reaction mixture was filtered through a 1 x 3 cm plug of Celite 545. with subsequent washing of the Celite with 30 mL of methanol. Concentra¬ tion at 20°C under vacuum and solution of the residue in 50 mL of dichloromethane, washing of the solution with 2 x 30 mL of 3% ammonium hydroxide and satd. brine, drying (MgSO ) filtration and concentration under vacuum gave 0.120 g of a mixture of 4' deoxyvinblastine and its bridged piperidine conformational isomer. This mixture was heated in 20 L of toluene, under argon, for 4 h. Concentration under vacuum and centrifugal chr matography on a 2 mm silica gel plate, eluting with 3:1 ethyl acetate: ethanol at a flow rate of 2 mL/min, gave 6mL of * solvent followed by 34 mL of solution containing 0.052g (41% yield) of the 1'-axial conformational isomer of 4 '-deoxyvinblastine. UV (ethanol)λ ax 225, 252, 288, 298 nm. The compound 4'-deoxyvinblastine (191mg) was converted to its methane sulfonate salt by first dissolving this compound in 10 ml of ether. To this solution was added 31μl of methane sulfonic acid. The resulting precipate was filtered and washed with 5ml of ether providing 212mg of the methane sulfonate salt of 4'deoxyvinblastine. Example 17 Methyl 3-benzyl-1,2,3 , 3a, 4,5-hexahydro-4(3-hvdroxypropyl)- 7H-pyrrolo(2,3-d) carbazole-6-carboxylate A mixture of methyl 3-benzyl-l,2,3,4,5,6-hexahydro- azepino (4,5-b) indole-5-carboxylate (1.336g, 4.0 mmol). 2-hydroxytetrahydropyran (0.980g. 8.2 mmol), toluene (30 mL) and ether saturated with HCl gas (10 drops) was heated under a nitrogen atmosphere at 110°C for 5 h. The reaction mixture was cooled, diluted with 15 mL of methanol and acidified with cone, hydrochloric acid. The reaction mixture was stirred for 12 h at 20°C, poured into 50 mL of water and made strongly basic with ammonium hydroxide. The toluene layer was separated and the aqueous portion extracted three times with 25 L of dichloromethane. The combined organic solutions were washed three times with 25 mL of saturated brine, dried over sodium sulfate and concentrated at 50°C under vacuum to provide 1.67g (100%) of methyl 3-benzyl- 1,2.3,3a.4,5-hexahydro-4-(3-hydroxypropyl)-7H-pyrrolo- (2,3-d)carbazole-6-carboxylate, identical in spectroscopic properties and TLC Rf value to the product obtained in Example 1. Example 18 4 '-Deoxyvincristine A solution of 4' -deoxyvinblastine methane sulfonate (21 mg, 0.023 mmol) in dichloromethane (2.5 mL) and acetic acid (320μL, 5.6 mmol) was cooled to -78°C and, with rapid stirring, a solution of potassium permanganate (8.2 mg, 0.052 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (17 mg, 64 mmol) in dichloromethane (1 mL) was added dropwise over 1 min. After 30 min at -78°C the reaction mixture was poured into 50 mL of 4.5% sodium bisulfite solution at 0°C and extracted with three 20 mL portions of cold dichloromethane. The combined organic extracts were washed with 50 ' mL of 8% sodium bicarbonate at 0°C, dried over magnesium sulfate and concentrated. Purification of the residue by high pressure liquid chromatography on a 50 x 2.5 cm lOμ SiO_ column with 2:1 ethyl acetate:ethanol at 12 mL/min gave 8.0 mg (50% yield) of '-deoxyvincristine with a retention time of 23 min and with TLC Rf 0.34 (SiO , 2:1 ethyl acetate:ethanol) , and mass spectroscopic m/z M + = 808.

Claims: CLAIMS : A process for producing a compound of the formula wherein n is an integer from 0 to 1; Z is the remaining portion of a vindoline ring system; R 1 is lower alkyl; R2 is an ammo pro 4t.ec«t.i • ng group; β R10 i • s -CH_ Y, formyl or formyl protected through the formation of an acetal; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of 1 to 4 carbon atoms; Y is individually a leaving group or a hydrolyzable ether group, R is hydrogen or lower alkyl, R is individually hydrogen or lower alkyl, or taken together with Y forms a lower alkylidenedioxy; or mixtures thereof with the corresponding 7R-diastereomer having the configuration at C-5 opposite to that shown above, comprising condensing a compound of the formula wh _.erei•n n, „R1, „R2, _R5, _R6, A_, _R10 and, B are as above and X is halogen; with a compound containing a vindoline ring system or a salt thereof. 2. The process of claim 1 wherein B is methylene and A forms a benzene ring. 3. The process of claim 1 wherein the condensation is carried out in the presence of a silver salt. 4. The process of claim 1 wherein the compound containing the vindoline ring system is • vindoline. A process for producing a compound of the formula: - 55 - wherein n, is an integer from 0 to 1; Z is the remaining portion of a vindoline ring system; R is lower alkyl; R is CH_ Y, formyl, or formyl protected through the formation of an acetal; 2 R is an amino protecting group; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an aklylene chain of 1 to 4 carbon atoms; Y is individually a leaving group or a hydrolyzable ether group, R is hydrogen or lower alkyl, R is individually hydrogen, or lower alkyl, or taken together with Y forms a lower alkylidenedioxy; or mixtures thereof with the corresponding 7R-diastereomer having a configuration at C-5 opposite to that shown, comprising condensing a compound of the formula wherein n, R , R , R . R , A, R and B are as above and X is halogen; - 56 - with a compound containing a vindoline ring system or a salt thereof. 6. ' The process of claim 5 wherein B is methylene and A forms a benzene ring. 7. The process of claim 5 wherein said condensation is carried out in the presence of a silver salt. 8. A compound of the formula wherein n is an integer from 0 to 1. R is lower al - > ,kyl-,; rR.2 i•s an amm• o pro_t.ecting group; „R10 i•s -CH- Y, formyl or formyl protected through the formation of an acetal; A is the remaining portion of an aromatic carboxylic, or heterocyclic ring; B is an alkylene chain of 1 to 4 carbon atoms, Y is individually a leaving group or a hydrolyzable ether group; X is halogen; R is hydrogen or lower alkyl; and R is individually hydrogen or taken together with Y forms a lower alkylidenedioxy, 9. The compound of claim 8 wherein B is methylene, and A forms a benzene ring. - 57 - 10. The compound of claim 8 wherein R_ is benzyl 11. The compound of claim 9 wherein R g taken together with Y forms lower alkylidenedioxy. 12. The compound of claim 9 wherein said compound is methyl 3-benzyl-6-chlor0-1,2.3.3a, , 5-hexahydro- (3-p- toluenesulfonyloxypropyl)-pyrrolo(2,3-d)carbazole-6- carboxylate. 13. A compound of the formula wherein n is an integer of from 0 to 1; R is 2 lower alkyl; R is an amino protecting group; R 10 i.s -CH 2 Y, formyl or formyl protected through the formation of an acetal; A is the remaining portion of an aromatic carboxylic, or heterocyclic ring; B is an alkylene chain of 1 to 4 carbon atoms; Y is individually a leaving group or a hydrolyzable ether group; X is halogen; R is hydrogen or lower alkyl; and R is individually hydrogen or lower alkyl or taken together with Y forms a lower alkylidenedioxy. 14. The compound of claim 13 wherein B is methylene and A forms a benzene ring. 15. The compound of claim 14 wherein said compound is methyl-3-benzyl-12b-chloro-l,2,3,4,5,6-hexahydro-5(3-ρ- toluenesulfonyloxypropyl) azonino (6,7-b)-2,3-dihydroindole- 7-carboxylate. 16. A compound of the formula wherein n is an integer from 0 to 1; Z is the remaining portion of a vindoline ring system; R 1 is lower alkyl; R2 is hydrogen or an amino protecting group; R is -CH_ Y, formyl or formyl protected through the formation of an acetal; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an aklylene chain of 1 to 4 carbon atoms; Y is individually hydroxyl, a leaving group, 5 or a hydrolyzable ether group; R is hydrogen or lower alkyl, R is individually hydrogen, lower alkyl, or taken together with Y forms lower alkylidenedioxy; - 59 - or mixtures thereof with the corresponding 7R diastereomer having the configuration at C-5 opposite to that shown above, 17. The compound of claim 16 wherein B is methylene and A forms a benzene ring. 18. The compound of claim 17 wher.ein said compound is 5,7-priority antireflective (PARF) methyl 3-benzyl- 1,2,3,4,5,6,7,8-octahydr0-5-(3-p-toluenesulfonyloxypropyl)- azonino (6,7-b) indole-7-(15-vindolinyl)-7-carboxylate. 19. A compound of the formula: wherein n is an integer of from 0 to 1; Z is the remaining portion of a vindoline ring system; R is lower 10 . alkyl; R is -CH Y, formyl, or formyl protected through the formation 2 of an acetal; R is an amino protecting group; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an aklylene chain of 1 to 4 carbon atoms; Y is individually a leaving group or a - 60 - hydrolyzable ether group, R is hydrogen or ethyl; R is individually hydrogen, or lower alkyl or taken together with Y forms a lower alkylidenedioxy; or mixtures thereof with the corresponding 7R diastereomer having the configuration at C-5 opposite to that shown. 20. The compound of claim 19 wherein B is methylene and A forms a benzene ring. 21. The compound of claim 20 wherein said compound is the 4,6-priority antireflective (PARF) methyl 3-benzyl 1,2,3,3a, ,5-hexahydro-4(3-p-toluenesulfonyloxypropyl)-6- (15-vindolinyl)pyrrolo(2,3-d)carbazole-6-carboxylate. 22. A compound of the formula wherein n is an interger of from 0 to 1; A is the remaining portion of an aromatic carboxylic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R is lower alkyl; R is -CH 2 Y. formyl or formyl protected through the formation of an acetal; Y individually forms a 2 leaving group or a hydrolyzable ether group; R is an amino protecting group; R is hydrogen or lower alkyl; R is individually hydrogen, lower alkyl or taken together with Y forms lower alkylidenedioxy. 23. The compound of claim 22 wherein Y is tosyloxy, and B is methylene. 24. The compound of claim 23 wherein said compound is methyl 3-benzyl-l,2,3,4,5,6,7,8-octahydro-5(3-p-toluene¬ sulfonyloxypropyDazonmo (6,7-b)indole-7-carboxylate. S 25. A compound of the formula: wherein n is an integer of from 0 to 1; A is the 0 remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R is lower alkyl; Y' is an 2 5 anion; R is an ammo protecting group; R is 7 . hydrogen or lower alkyl; R is hydrogen or lower 5 alkyl and Z is the remaining portion of a vindoline ring system; - 62 - or mixtures thereof with the corresponding 7R-diastereomer having the configuration at C-5 opposite to that shown above, 26. The compound of claim 25, wherein A form a benzene ring and B is methylene. 27. The compound of claim 26 wherein said compound is 6'-benzyl-4 '-deethyl-4' -deoxy-vinblastinonium tosylate. 10 28. The compound of claim 27, wherein said compound has the structure of a 1' equatorial piperidine ring conformational isomer. 29. The compound of claim 26 wherein said compound is ._ 6'-benzyl-4'-deoxy-vinblastonium tosylate. 30. The compound of claim 29 wherein said compound has the structure of a 1' equatorial piperidine ring conformational isomer. 20 31. A process of producing a compound of the formula: wherein n is an integer of from 0 to 1; Z is the 35 remaining portion of a vindoline ring system; R is lower alkyl; A is the remainder of an aromatic carbocyclic or heterocyclic ring, B is an alkylene chain of 1 to 4 carbon atoms; R is hydrogen or lower alkyl; 7 and R is lower alkyl, hydrogen or hydroxy; comprising isomerzing a compound of the formula: wherein n, R 1, R5, R7, A, B and Z are as above; by heating. 32. The process of claim 31 wherein said is heating carried out in a hydrocarbon solvent. 33. The process of claim 32 wherein the heating is carr:iieedd oouutt aatt aa tteemmppeerraattuur.e of from 30°C to the reflux temperature of the solvent. 34. A compound of the formula: - 64 - wherein n is an integer of from 0 to 1; Z is the remaining portion of a vindoline ring system; R is lower alkyl; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms, R is 7 hydrogen or lower alkyl; and R is hydrogen, hydroxy or lower alkyl; or pharmaceutically acceptable salts thereof. 35. The compound of claim 34 wherein Z is vindoline, A forms a benzene ring and B is methylene. 36. A compound of the formula: wherein n is an. integer of from 0 to 1; B is an alkylene chain of from 1 to 4 carbon atoms; R_ is lower alkyl; R is methyl or formyl; R * is hydrogen or lower alkyl; R ' is hydrogen or lower alkyl; or pharmaceutically acceptable salts thereof. 37. The compound of claim 36 wherein R is. methyl 38. The compound of claim 37 wherein n is 1. - 65 - 39. The compound of claim 38 wherein B is methylene, 40. The compound of claim 39 wherein R_ is methyl, R ' is hydrogen and R ' is hydrogen. 41. The compound of claim 39 wherein R_ is methyl, R ' is ethyl and R ' is hydrogen. 42. The compound of claim 36 wherein R ζ is formyl. 43. The compound of claim 42 wherein n is 1. 44. The compound of claim 43 wherein B is methylene, 45. The compound of claim 44 wherein R is methyl, R ' is ethyl and R * is hydrogen. 46. The compound of claim 43 wherein R is methyl, ' is hydrogen and R is hydrogen. 47. A compound of the formula - 66 - wherein n is an integer of from 0 to 1; Z is the remainder of a vindoline ring system; A is the remainder of an aromatic carbocyclic or heterocyclic ring; R is hydrogen or an amino protecting group; B is an alkylene chain of 1 to 4 carbon chains, R_ is hydrogen or lower alkyl or mixtures thereof with its corresponding 7R diastereomer having a configuration at C-5 opposite from that shown. ,- 48. The compound of claim 47 where B is methylene and A forms a benzene ring. 49. A compound of the formula 25 wherein n is an integer of from 0 to 1; A is the remaining portion of an aromatic carboxylic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R 1 i.s lower alkyl; R10 i.s -CH Y, formyl or formyl protected through the 30 formation of an acetal; Y individually forms a 2 leaving group or an etheπfied hydroxy group; R is an amino protecting group; R is hydrogen or lower alkyl; R is individually hydrogen or lower alkyl or taken together with Y forms lower 35 alkylidenedioxy; - 67 - 50. The compound ' of claim 49 wherein A forms a benzene ring and B is methylene. 51. A compound of the formula wherein n is an integer of from 0 to 1; R is -CH 2 -R 9 or -CO, R 13 ; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R is lower alkyl; R is hydrogen or g lower alkyl; R is hydrogen or lower alkyl; and R 9 is hydroxy or taken together with R3 forms lower alkylidenedioxy; and R is lower alkyl with the proviso, that when R 9 is hydroxy, R5 and R are hydrogen or compounds thereof where the tertiary nitrogen atom is protected with an amino protecting group. 52. The compound of claim 51 wherein A forms a benzene- ring, and B is methylene. - 68 - 53. A compound of the formula: wherein n is an integer of from 0 to 1; R 15 is -CH 2 -R- -CO_ 13 A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is -an 5 alkylene of from 1 to 4 carbon atoms; R is lower alkyl; R 2 is an amino protecting group; R9 is hydroxy or an etherified hydroxy group; and R 13 is lower alkyl. o 54. The compound of claim 53 wherein B is methylene and A forms a benzene ring. 55. A compound of the formula: wherein n is an integer of from 0 to 1; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R is lower alkyl; Y" is an 5 7 anion; R is hydrogen or lower alkyl; R is hydrogen or lower alkyl and Z is the remaining portion of a vindoline ring system; or mixtures thereof with the corresponding 7R-diastereomer having the configuration at C-5 opposite to that shown above, 56. The compound of claim 56, wherein A form a benzene ring and B is methylene. 57. A compound of the formula: wherein n is an integer of from 0 to 1; A is the remaining portion of an aromatic carbocyclic or heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R 1 i.s lower alkyl; R_' i.s hydrogen or lower alkyl and Z is the remaining portion of a vindoline ring system; or mixtures thereof with the corresponding 7R-diastereomer having the configuration at C-5 opposite to that shown above, - 70 - 58. The compound ' of claim 57, wherein A form a benzene ring and B is methylene. 59. A compound of the formula: wherein n is an integer of from 0 to 1; A is the remaining portion of an aromatic carbocyclic or - heterocyclic ring; B is an alkylene chain of from 1 to 4 carbon atoms; R is lower alkyl; R " and R " are lower alkyl and Z is the remaining portion of a vindoline ring system; or mixtures thereof with the corresponding 7R-diastereomer 5 having the configuration at C-5 opposite to that shown above, 60. The compound of claim 59, wherein A form a benzene ring and B is methylene. 0 61. The novel compounds, intermediates, formulations, processes, and methods substantially as described herein. 5

Inventors: KUEHNE MARTIN, KUEHNE, MARTIN
Applicants: UNIV VERMONT
Application year: 1986
Main classification: C07D519
IPC codes: A61K31, C07D471, C07D487, C07D519