PROCESS FOR PREPARING CERTAIN PYRROLO[3,4- b]QUINOLINES, CERTAIN 1H-PYRANO[3',4':6,7]INDOLIZINO[1,2-b]QUINOLIN-3,14(4H,12H)-DIONES, AND CERTAIN 8-METHYL-7-(OXOPROPYL)-INDOLIZINO[1,2-b]QUINOLIN-9(11H)-ONES

Abstract: The present invention provides a process for preparing certain pyrrolo(3,4-(b))quinolines, certain 1H-pyrano(3',4':6,7)indolizino(1,2-(b))quinolin-3,14(4H,12H)-diones, specifically camptothecin and its analogs, and certain 8-methyl-7-(oxopropyl)-indolizino(1,2-(b))quinolin-9(11H)-ones, specifically mappicine ketones and mappicines, said process comprising the step of intramolecular (4+2) cycloaddition of the N-arylimidate portion of a compound of formula (IV) where: X=OH, OAlCl2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H; R1=H, or OR, where R is an ester protecting group; R2=H, NO2, or a protected amine function; R3=H, C2H5, or a trialkylsilyl; R4=H or CH2COOEt; R5=COOMe or tosyl; or R4 and R5 are joined together to form a substituted pyridone (IVa): Y=H or Y,R1=-OCH2O-, formula in which A=H,COOR, or a functionnality for preparation of the hydroxymethyl (C-17) portion of an E ring lactone; B=H, OH, an appropriate leaving group such as halide or O(trifluoromethanesulfonate) or a functionality for preparation of C-(18-21) of the E ring lactone portion of camptothecin, with the unactivated acetylene portion of said compound.

Description: PROCESS FOR PREPARING CERTAIN PYRROLO[3,4-b]QUTNOLINES, CERTAIN lH-PYRANO[3',4':6,7]INDOLIZINO[l,2-b]QUINOLIN-3,14(4H,12H)- DIONES, AND CERTAIN 8-METHYL-7-(OXOPROPYL)-INDOLIZINO[l,2- b]QUINOLIN-9(l 1H)-0NES FIELD OF THE INVENTION The present invention relates to a process for preparing certain pyrrolo- [3,4-&]quinolines, certain lH-pyrano[3',4':6,7] indolizino[l,2-&]quinolin- 3,14(4H,12H)-diones, specifically camptothecin and its analogs, and certain 8- methyl-7-(oxopropyl)-indolizino[l,2-i>]quinolin-9(l lH)-ones, specifically mappicine ketones and mappicines. BACKGROUND OF THE INVENTION Certain lH-pyrano[3\4':6,7]indolizino[l,2- ?]quinolin-3,14(4H,12H)-diones are known to be phaπnaceutically useful. Several important examples of such compounds are shown in Formulae Ia-Ie. Referring to these formulae, note that R3 is substituted at the 7-position, R2 is substituted at the 9-position, and R j is substituted at the 10-position, and so forth. Each ring is designated by a letter A-E as shown. 4-Ethyl-4-hydroxy-lH-pyrano[3',4 , :6,7] indolizino[l,2-b]quinolin- 3,14(4H,12H)-dione, commonly known as camptothecin (Formula la, below), and certain of its close congeners are known to inhibit the growth of tumor cells both in vitro and in vivo. Formula No. (Compound Namr la (Camptothecin): R 1= R 2 =R 3 =H lb (Topotecan): Rl=OH, R2=-CH 2 N(CH 3 )2, R 3 =H Ic (irinotecan/CPT-11): R i =OC(0)-(4-piperidino)-piperidinyl, R 2 =H, R 3 =C 2 H 5 Id (9-aminocamptothecin): R!=H, R 2 =NH 2 , R 3 =H Ie(10,l 1-methylenedioxy camptothecin) : Y^!=-OCH 2 O-, R 2 =R 3 =H While camptothecin itself is known to be cytotoxic at levels which inhibit tumor growth, certain water-soluble camptothecin analogs which exhibit litde or no cytotoxicity are efficacious against solid tumor types normally refractory to known treatments. For instance, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy- lH-pyTano[3',4':6,7] indolizino[l,2- ?]quinolin-3,14(4H,12H)-dione, commonly known as topotecan (Formula lb), which is disclosed in U.S. Pat No.5,004,758, issued to Boehm et al. on April 2, 1991, is particularly useful in the treatment of a variety of cancerous tumors. As further disclosed in U.S. Ser. Nos.07/658,948, 07/658,936, and 07/658,937, filed by R. K. Johnson on February 21, 1991, and in U.S. Ser. No. 07/804,570, filed by R. K. Johnson on December 10, 1991, such tumors include, but are not limited to, ovarian, esophageal, non-small cell lung and colorectal carcinomas. As is further disclosed in U.S. Ser. No.07/793,041, filed by R. K. Johnson on November 15,1991, topotecan is also useful for the preparation of a combination chemotherapeutic pharmaceutical composition which also comprises a platinum coordination compound, most preferably cis-platin. The 4-(piperidino)- piperidinyl carbamate analogue of 7-ethyl-lO-hydroxycamptothecin, commonly known as irinotecan (or CPT- 11) (Formula Ic), has also been shown to be efficacious against certain tumors. Both compounds are presently undergoing human clinical testing in refractory tumor types. Additionally, the 9-amino and 10,11-methylenedioxy analogs: of camptothecin (Formula Id) have shown promising antitumor activity in preclinical testing. mappicine ketone mappicme Da lib Certain other modifications of the camptothecin molecule result in compounds possessing antiviral activity while exhibiting little or no cytotoxicity. Examples of such compounds include derivatives in which the E ring lactone has been replaced by some other functionality, i.e., two broad classes of compounds commonly called mappicine ketones and mappicines, of Formulas Ha and lib respectively. These compounds, which are useful in treating infections in humans and animals caused by a variety of viruses, (for example, Herpes simplex virus types 1 and 2, cytomegalovirus, and Varicella zoster virus) are disclosed in U.S. Ser. No. 07/606,216, filed by S. Petteway et al. on October 31,1990; U.S. Ser. No. 07/783,063, filed by H. S. Alaudeen on October 25, 1991; U.S. Ser. No. 07/870,649, filed by D. Berges et al. on April 17, 1992; and U.S. Ser. No. 07/868,824, filed by D. Berges et al. on April 14, 1992. Camptothecins have also been recently shown to possess antiretroviral activity, specifically the ability to inhibit the replication of Human Immunodeficiency Virus (HTV-1) at dosages non-cytotoxic to mammalian cells, and thus may be useful in the treatment of patients suffering from Acquired Immune Deficiency Syndrome (AIDS, see AIDS Res. Hum. Retr., 1991, 7, 65). The mode of action of these compounds is grounded in the inhibition of the eukaryotic cellular enzymes topoisomerase I and π. See Cancer Res. 1988, 48, 1722; Molec. Pharmacol. 1988, 34, 755. In order to utilize its genetic information as a template for DN A transcription and replication, certain topological features of cellular DNA must be temporarily altered. Specifically, the supercoiled DN A helix must undergo relaxation/uncoiling, with subsequent unwinding of its helical structure, before the process of transcription and replication can proceed. Topoisomerase I is a monomeric enzyme with a molecular weight of approximately 100,000. This enzyme undergoes covalent binding to DNA and introduces a transient single strand break, unwinds the double helix (or allows it to unwind) and subsequently reseals the break before dissociating from the DNA strand. There is evidence that this mechanism of action is selectively important for the replication of DNA in tumorigenic cells. Camptothecin is known to exert its antitumor activity by stabilization of the covalently bound topoisomerase I - DNA complex. As a result, progression of the DNA replication sequence proceeds only as far as induction of a single strand break. The ultimate result of this inhibition of the DNA transcription/replication process is cell death. Camptothecin and a few of its close congeners are the only agents in clinical drug development which inhibit topoisomerase I. Topoisomerase II consists of two identical subunits of molecular weight 170,000. Topoisomerase π induces transient breaks of both strands of the DNA helix and passes another double-stranded segment through the break. Several commercially important oncolytic agents (e.g., etoposide, doxorubicin and mitoxantrone) are inhibitors of topoisomerase II. Although camptothecin does not inhibit topoisomerase π, related derivatives in which the E ring lactone has been replaced by an alternate functionality, i.e,. mappicines and mappicine ketones, are known to inhibit topoisomerase IL As such these compounds are of interest both as potential antineoplastic and antiviral agents. A number of approaches to the preparation of camptothecin and its analogs are known. These include several semisynthetic approaches for the transformation of camptothecin into various related analogs, e.g. topotecan, which rely on naturally occurring camptothecin as the starting material. For example, our U.S. Ser. No. 07/589,848, filed on September 28, 1990 and allowed according to the Notice of Allowance and Issue Fee Due dated June 17, 1992, discloses a semisynthetic method of preparing certain 8-methyl-7-(-oxopropyl)indolizino[l,2-i>]quinolin-9(llH)-ones from camptothecin or derivitized camptothecins. U.S. Ser. No. 07/589,643, filed by P. Burk et al. on September 28, 1990, discloses a semisynthetic method of preparing certain water-soluble camptothecin analogs from camptothecin. At present, the only practical method for obtaining preparative- and commercial-scale quantities of camptothecin is by extraction of the tissues of the Camptotheca acuminata tree indigenous to the People's Republic of China or the Nothapodytes foetida shrub indigenous to India. However, as is well-known, reliance on such natural sources has certain inherent disadvantages, including very high starting material cost (about $28,000/kg) and lack of a dependable source. Camptothecin has also been prepared from readily available materials by various totally synthetic appx aches. Recently, a 4+1 radical annulation in which a radical N-propargylated intermediate is intramolecularly cyclized to form the B and C rings of what is formally a camptothecin precursor was disclosed in J. Am. Chem. Soc. 1992, 114, 5863-5864. However, generally the published strategies for the total synthesis of lH-pyrano[3\4':6,7]indolizino[l,2-b]quinolin-3,14(4H,12H)- diones, and specifically camptothecins, follow the two broad retrosynthetic outlines shown in Scheme 1. r β trosyπthβsis strategy A In strategy A, a tricyclic CDE ring system is prepared by known methods and is coupled with ort rø-aminobenzaldehyde via a Friedlander quinoline synthesis. As such, the critical bond disconnection strategy is shown by the dashed line labelled A. In strategy B, tricyclic ABC and bicyclic DE ring components are prepared separately by known methods and are coupled using a two-step, standard procedure to form the D ring pyridone. The critical bond disconnection strategy is shown by the dashed line labelled B. In many cases, the tricyclic ABC ring fragment for strategy B is ultimately prepared via a Friedlander quinoline synthesis requiring several steps. The Friedlander quinoline synthesis is therefore a basic component of many of the known approaches. However, such total syntheses are of limited value because they suffer from a variety of drawbacks: ortho- aminobenzaldehydes are difficult to prepare, are prone to polymerization, and require multi-step synthesis from commercially available starting materials for A- and B- ring analogs of camptothecin. Thus, many of these syntheses are troublesome to perform and result in very poor chemical yields of the desired analog. Other strategies which rely on multi-step elaborations of commercially available quinolines suffer from similar drawbacks. SUMMARY OF THE INVENTION The present invention provides an efficient general route for the facile synthesis of pyrrolo[3,4-Z>]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2- fc]quinolin-9(HH)-ones and lH-pyrano[3',4':6,7]indoUzmo[l,2-δ]qumoαn- 3,14(4H,12H)-diones, preferably camptothecin analogs. In a first aspect, the present invention provides a process for preparing pyrrolo[3,4- ?]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2-b]quinolin-9(llH)- ones; and lH-pyrano[3',4':6,7]indolizino[l,2- ?]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs , more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the step of intramolecular [4+2] cycloaddition of the N- arylimidate portion of a compound of Formula IV with the unactivated acetylene portion of said compound, the compound of Formula IV being generated from compounds of Formula IH (shown in Scheme 2 below and having the same substitutions as compounds of Formula IV), which are derived from generally available compounds. IV where: X= OH, OAICI2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H R-l = H, OH, or OR, where R is an ester protecting group; R2 = H, NO2, or a protected amine function; R3 = H, C2H5, or a trialkylsilyl; R4 = H or CH 2 COOEt; R5 = COOMe or tosyl; or R4 and R5 are joined together to form a substituted pyridone Ua: Y=H, or Y^ 1 = -OCH 2 0- B IVa where: A = H, COOR, or a functionality for preparation of the hydroxymethyl (C-17) portion of an E ring lactone; B = H, OH, an appropriate leaving group such as halide or O(trifluoromethanesulfonate) or a functionality for preparation of C-(18-21) of the E ring lactone portion of camptothecin. In a second aspect, the present invention also provides a process for the preparation of 7-(l,l-_tøs-alkoxycarbonyl)propyl-8-meΛoxycarbonyl-5,6- dihydroindolizino[ 1 ,2-6]quinolin-9( 1 lH)-ones, 8-methyl-7- (oxopropyl)indolizino[l,2-6]quinolin-9(l lH)-ones; and 1H- pyrano[3 , ,4 , :6,7]indolizino[l,2- >]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the step of coupling a vinyl triflate derived from a 7-hydroxy-5,6- dihydroindolizino[l,2-b]quinolin-9(llH)-one with a tertiary malonate anion to prepare a 7-(l,l-bw-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6- dihydroindolizino[l,2-b]quinolin-9(llH)-one. The resulting 7-( 1,1 -bis- alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-b]quinolin- 9(1 lH)-one may be conveniently elaborated into a 1H- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-3,14(4H,12H)-dione or a 8-methyl-7- (oxopropyl)indolizino[l,2-b]quinolin-9(llH)-one as disclosed elsewhere in the present application. In a third aspect, the present invention also provides a process for the preparation of pyrrolo[3,4-ό]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2- 6]quinolin-9(l lH)-ones; and lH-pyrano[3',4':6,7]indolizino[l,2-fc]quinolin- 3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water- soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, said process comprising the steps of: (a) intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV with the unactivated acetylene portion of said compound to give a pyrrolo[3,4-fc]quinoline substituted with an acetate ester at C-2; (b) cyclizing the 2-(acetate ester)-substituted pyrrolo[3,4-£)quinoline to form a 7-hydroxy-5,6-dihydroindottzino[l,2-6]quinolin-9(llH)-one; (c) coupling a 7-trifluoromethanesulfonate derivative of the 7-hydroxy-5,6- dihydroindolizino[l,2-fc]quinolin-9(llH)-one with a tertiary malonate anion to form a 5,6-dihydroindolizino[l,2-&]quinolin-9(llH)-one substituted at C-7 with an (alkyl)malonate diester, and (d) converting the 7-(l,l-bis-alkoxycarbonyl)propyl-5,6- dihydroindohzino[l,2-2>]quinolin-9(l lH)-one into the lactone E ring of a 1H- pyτano[3\4':6,7]indolizino[l,2-fc]quinolin-3,14(4H,12H)-dione, preferably a camptothecin analog. In a fourth aspect, the present invention also provides a process for the preparation of camptothecin analogs which lack the lactone E ring, preferably 8- methyl-7-(oxopropyl)-indolizino[l,2-fc]quinolin-9(l lH)-ones, most preferably mappicines and mappicine ketones, said process comprising the steps of: (a) intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV with the unactivated acetylene portion of said compound to give a pyrrolo[3,4-6]quinoline substituted with an acetate ester at C-2; (b) cyclizing the 2-substituted pyrrolo[3,4-b]quinoline to form a 7-hydroxy- 5,6-dihydroindolizino[ 1 ,2-b]quinolin-9( 1 lH)-one; (c) coupling a 7-trifluoromethanesulfonate derivative of the 7-hydroxy-5,6- dihydroindolizino[l,2-b]quinolm~9(llH)-one with a tertiary malonate anion to form a 5,6-dihydroindolizino[l,2-b]quinolin-9(l lH)-one substituted at C-7 with an (alkyl)malonate diester, (d) converting the 7-(l,l-bw-alkoxycarbonyl)propyl-8-methoxycarbonyl- 5,6-dihydroindolizino[l,2-b]quinolin-9(llH)-one into the lactone E ring of a 1H- pyrano[3',4':6,7]indolizino[l,2-6]quinolin-3,14(4H,12H)-dione, preferably a camptothecin analog; (e) opening the E ring of said camptothecin analog with extrusion of carbon dioxide to provide, depending upon choice of termination step, a camptothecin analog which lacks the lactone E ring, preferably a 8-methyl-7-(oxopropyl)- indolizino[l,2-&]quinolin-9(llH)-one, most preferably a mappicine ketone; and (f) reduction of mappicine ketone with a hydride source such as sodium borohydride to give a mappicine. In a fifth aspect, the present invention provides a process for the total synthesis of, depending upon choice of termination step, 4-ethyl-4-hydroxy-9- methoxy-lH-pyrano[3',4':6,7] indolizino[l,2-6]quinolin-3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl-4,9-dihydroxy-lH- indolizino[l,2-fe]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10-[(dimethylamino)methyl]-4- ethyl-4,9-dihydroxy-lH-pyrano[3',4 , :6,7]indoUzino[l,2-Z>]quinolin-3,14(4H,12H)- dione, more commonly known as topotecan, said process comprising the steps of: (a) heating a compound of Formula DI (e.g. VII) in a polar solvent, preferably methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone or N- methylpyrrolidinone, most preferably acetonitrile;at a temperature of about 20 - 85°C, preferably about 60 - 85°C, most preferably at about the reflux temperature of acetonitrile; in the presence of a strong alkylatmg agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide, most preferably trimethyloxonium tetrafluoroborate; to yield a pyrrolo[3,4- fc]quinoline substituted at C-2 by an acetate ester, (b) hydrolyzing the carbamate function of the C-2 substituted pyrrolo[3,4- £]quinoline resulting from step (a) with acetic acid saturated with HBr to give a tricyclic amine; (c) coupling said tricyclic amine with a monoalkyl malonyl chloride, preferably monomethyl malonyl chloride, to give the half-amide of a malonate diester, (d) subjecting said diester to a Dieckmann condensation in the presence of base to give a a tetracyclic enol; (e) forming a vinyl triflate of said tetracyclic enol, and coupling said triflate with a tertiary malonate anion to form a (1, l-di-rerr-butoxycarbonyl)propyl-8- methoxycarbonyl-5,6-dihydroindolizino[ 1 ,2-b]quinolin-9( 1 lH)-one; (f) 1,2- elimination of hydrogen at the 5,6 bond to give a 7-(l,l-W_y- alkoxycarbonyl)propyl-8-methoxycarbonyl-indolizino[l,2-ft]quinolin-9(llH)-one; (g) reduction of die 8-methoxycarbonyl group, followed by hydrolysis- decarboxylation of the diester group at C-7, and lactone formation to give a 1H- pyrano[3',4':6,7] indolizino[l,2-^]quinolin-3,14(4H,12H)-dione; (h) forming a tertiary alcohol α to the E ring carbonyl of said product to give 10-methoxycamptothecin; (i) cleaving the methyl ether of said 10-methoxycamptothecin to yield 10- hydroxycamptothecin; and (j) alkylating the 9-position of said 10-hydroxy camptothecin by reaction with N J f,N',N , -tetramethyldiaminomethane (BDAM) to give topotecan. DETAILED DESCRIPTION OF THE INVENTION Here and throughout this application, the term "a camptothecin" includes camptothecin and and any derivative thereof the structure of which is based on the lH-pyrano[3',4':6,7] indolizino-[l,2-6]quinolin-3,14(4H,12H)-dione ring system. The terms "pyrrolo[3,4-fc]quinoline", "indolizino[l,2-ft]quinolin-9(llH)-one" and lH-pyrano[3',4':6,7] indolizino-[l,2-fc]quinolin-3,14(4H,12H)-dione refer generally to compounds based on these ring systems. The term " camptothecin analog" includes camptothecins as defined above and also includes derivatives of camptothecin wherein the E ring has been replaced with another functionality. The term "ester protecting group" is defined to include C1-C6 alkyl groups as well as allyl, benzyl, phenyl and β,β,β-trichloroethyl. The term " amine protecting group" is defined to include alkyl and arylsulfonate esters, carbamates of common alkyl groups such as methyl, ethyl, β,β,β-trichloroethyl, allyl, re/T-butyl and phenyl, amides such as acetamido and propionamido, as well as common alkyl groups such as methyl and benzyl. The term "trialkylsilyl" is defined to include trimethyl, triethyl, triisopropyl and tripropylsilyl, as well as phenyldimethylsilyl and tert- butyldimethylsilyl. The present invention pre ides a process for preparing pyrrolo[3,4- £]quinolines, 8-methyl-7-(oxopropyl)indolizino[l,2-fc]quinolin-9(l lH)-ones; and lH-pyrano[3',4':6,7]indolizino[l,2-b]quinolin-3,14(4H,12H)-diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, most preferably topotecan, the process comprising the step of intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV, generated from a starting material of Formula III, with the unactivated acetylene portion of said compound. Scheme 2 illustrates one embodiment of the present process wherein R4 and R5 of the compound of Formula IV are a joined together to form a pyridone of Formula IVa. [4 + 2] addition ' ■ HX Scheme 2 X, Rl - R5 and Y are as defined for Formula IV; base, solvent Scheme 3 Table I illustrates representative compounds and intermediates made by the present process. Substrate Isolated Yield Product Table I The starting material of Formula HI is heated in a polar solvent, preferably methylene chloride, 1,1 ^ichloroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N- dimethylformamide, acetone or N-methylpyιτolidinone, most preferably acetonitrile; at a temperature of about 20 - 85 °C, preferably 60 - 85 °C, most preferably at the reflux temperature of acetonitrile; in the presence of a strong alkylatmg agent or such agent as is capable of producing either an O-alkylimidate or imidate ester, imidoyl halide, or such imide derivative as is capable of cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, 0-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide, most preferably trimethyloxonium tetrafluoroborate, thereby generating the compound of Formula IV which then undergoes [4 + 2] cycloaddition to yield a pyrrolo[3,4-6]quinoline. Compounds of Formula IV have not been isolated, but have been detected. The products of the present process are either pharmaceutically useful themselves, e.g. topotecan, or are intermediates, e.g. 10- methoxycamptothecin, useful for elaboration into pharmaceutically useful compounds, particularly camptothecin analogs. The present invention also provides a process for the preparation of 7-(l,l- 6w-alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2- 6]quinolin-9(l lH)-ones, 8-methyl-7-(oxopropyl)indolizino[l,2-Z>]quinolin-9(l 1H)- ones; andlH-pyrano [3',4': 6,7] indolizino [l,2-b] quinolin - 3,14 (4H, 12H - diones, preferably camptothecin analogs, more preferably water-soluble camptothecin analogs, yet more preferably topotecan and irinotecan, yet more preferably topotecan and irinotecan, most preferably topotecan, said process, referring to Scheme 3, comprising the step of coupling a vinyl triflate dervived from a 7- hydroxy-5,6-dihydroindolizino [1,2-6] quinolin-9(H )-one (V) with a tertiary malonate anion to prepare a 7-(l,l-6is)-alkoxycarbonyl)propyl-8-methoxycarbonyl- 5,6-dihydroindolizino [1,2-6] quinolin - 9(llM)-one (VI). The resulting 7-(l,l-6«- alkoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin- 9(1 lH)-one may be conveniently elaborated into a lH-pyrano[3 * ,4':6,7]indolizino- [l,2-6]quinolin-3,14(4H,12H)-dione or a 8-methyl-7-(oxopropyl)indolizino[l,2- 6]quinolin-9(llH)-one as disclosed elsewhere in die present application. In one preferred embodiment of the present invention, an exemplary illustration of which is shown in Scheme 4, the starting material (Vϋ) has the structure (referring to Formula HI in Scheme 2) wherein: R4 = H or CH2COOEt; R5 = COOMe, toluenesulfonyl, benzyl, COCH3; or COCH2CH3; and Y=M. As will be readily apparent to one of ordinary skill in the art, this embodiment of the present process may be conveniently used to provide a variety of useful intermediates (pyrrolo[3,4-b]quinolines, indolizino[l,2-b]quinolin-9(l lH)-ones and lH-pvrano[3\4':6,7]indolizino[l,2-b]quinolin-3,14(4H, 12H)-diones) and products, preferably camptothecin analogs, by the selection of appropriately substituted starting materials and of the appropriate terminating step. This process comprises the steps of: (a) intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV (exemplified by Formula IV, Scheme 2) with the unactivated acetylene portion of said compound to give a pyrrolo[3,4-b]quinoline substituted with an acetate ester at C-2 (exemplified by Formula VIII, Scheme 4); (b) cyclizing the 2-(acetate ester) substituted pyrrolo[3,4-6]quinoline to form a 7-hydroxy-5,6-dihydroindolizino[l,2-b]quinolin-9(l lH)-one (e.g. XII, Scheme 7). (c) coupling a 7-trifluoromethanesulfonate derivative of die 7-hydroxy-5,6- dihydroindolizino[l,2-6]quinolin-9(l lH)-one with a tertiary malonate anion to form a 5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one substituted at C-7 an (alkyl) malonate diester (e.g. XIII, Scheme 7); and (d) converting the 7-(l,l-6£s-alkoxycarbonyl) propyl-5,6- dihydroindolizino[l,2-6]quinolin-9(llH)-one into the lactone E ring of a 1H- pyrano[3',4':6,7]indolizino[l,2-6]quinolin-3,14(4H,12H)-dione, preferably a camptothecin analog (e.g. XVI, Scheme 7). MβaOBF acetonitrile, reflux (VII) Scheme 4 propargyiamine CICOO e, Et 3 N Scheme 5 Referring to the above embodiment, the compounds of Formula IV are readily prepared by known methods, for example as shown in Scheme 5 and Steps 1-3 of Scheme 7, below, and as is exemplified in me Example (Steps 1-3 ). In step (a), the amide starting material of Formula IV is reacted in a polar solvent such as methylene chloride, 1,2-dichlσroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N- dimemylformamide, acetonitrile, acetone or N-methylpyrrolidinone, but preferably acetonitrile; at a temperature of about 20 - 85 °C, preferably at 60 - 85 °C, most preferably at the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or an agent capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, or an imidoyl halide, e.g. trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O- benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide, preferably trimethyloxonium tetrafluoroborate, thereby generating a compound of Formula IV which then undergoes [4 + 2] cycloaddition to yield a substituted pyrrolo[3,4-6]quinoline. The choice of solvents, temperature ranges, and alkylating agents applies to all embodiments disclosed in the present application. In step (b), the substituted pyrrolo[3,4-b]quinoline resulting from step (a) is cyclized to a 7-hydroxy-5,6-dihydroindolizino[l,2-b]quinolin-9(l lH)-one as follows. The carbamate function protecting the C-ring nitrogen is hydrolytically cleaved, preferably with acetic acid saturated with HBr, to give the resulting tricyclic amine. The amine is then coupled at the C-ring nitrogen with a monoalkyl malonyl chloride, preferably monomethyl malonyl chloride, to give the resulting malonate half-amide. The D ring is formed when the malonate half-amide undergoes a Dieckmann condensation in the presence of base, preferably methoxide, to give a 7-hydroxy-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-b]quinolin- 9(llH)-one. When synthesis of an indolizino[l,2-6]quinolin-9(HH)-one is desired, the 7- hydroxy-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one is further reacted as follows. In step (c), the vinyl triflate of the 7-hydroxy-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin-9(HH)-one is coupled witii a tertiary malonate anion to form a 7-(l,l-di-rerr-butoxycarbonyl)propyl-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one. In step (d), the diester is cyclized to form the lactone E ring of an indolizino[l,2-6]quinolinone, preferably a camptothecin analog. More specifically, 1,2 elimination of the tertiary hydrogen to the quinolino nitrogen by oxidation in the presence of sodium nitrite or other oxidizing agents such as 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) gives the analogous indolizino[l,2-b]quinolin-9(llH)-one, followed by reduction of d e carbomethoxy group at C-8 to a hydroxymemyl function and hydrolysis/decarboxylation of the malonate diester to give the resulting 4-ethyl- 1H- pyrano[3\4':6,7] indolizino[l,2-6]quinolin-3,14(4H,12H)-dione. The 4-ethyl- 1H- pyrano[3',4':6,7] indolizino[l,2-6]quinolin-3,14(4H,12H)-dione may be further reacted to form a tertiary alcohol α to the E ring carbonyl by air-oxidation, thus giving a camptothecin. The camptothecin may be further elaborated to give a variety of camptothecin analogs. For instance, cleavage of the me oxy group of 4-edιyl-4- hydroxy-9-methoxy-lH-pyrano[3',4 , :6,7] indolizino[l,2-6]quinolin-3,14(4H,12H)- dione (10-methoxycamptothecin) with HBr yields 10-hydroxycamptothecin, which is itself pharmaceutically useful. 10-Hydroxycamptothecin may be conveniently converted to topotecan by reaction witii N.N.N'.N'-tetramethyldiaminomemane (BDAM). The camptothecin products of the present process may further be converted to camptothecin analogs in which the E ring has been replaced by some other functionality, e.g., mappicines and mappicine ketones, for instance by the process described in our recently allowed U.S. Ser. No. 07/589,848, which discloses a semisynthetic method of preparing certain 8-methyl-7-(-oxopropyl)indolizino[l,2- b]quinolin-9(l lH)-ones from camptothecin or derivitized camptothecins. In another preferrred embodiment of me present invention, which is illustrated retrosynthetically in Scheme 6, the starting material is a compound of Formula in wherein R4 and R5 are joined togetiier to form a substituted pyridone. Retrosynthetic Analysis of the approach to the total synthesis of camptothecins Scheme 6 In yet another preferred embodiment, the present invention provides a process for die preparation of camptothecin analogs which lack the lactone E ring, preferably 8-methyl-7-(oxopropyl)-indolizino [l,2-b]quinolin-9(HH)-ones, most preferably mappicines (lib) and mappicine ketone (11a), said process comprising the steps of: (a) intramolecular [4+2] cycloaddition of die N-arylimidate portion of a compound of Formula IV with the unactivated acetylene portion of said compound to give a pyrτolo[3,4-b]quinoline substituted witii an acetate ester at C-2; (b) cyclizing the 2-substituted pyrrolo[3,4-b]quinoline to form a 7-hydroxy- 5,6-dihydroindolizino[l,2-b]quinolin-9(l lH)-one; (c) coupling a 7-trifluoromethanesulfonate derivative of the 7-hydroxy-5,6- dihydroindolizino[l,2-6]quinolin-9(llH)-one with a tertiary malonate anion to form a 5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one substituted at C-7 widi an (alkyl)malonate diester, (d) converting the 7-(l,l-bw-alkoxycarbonyl)propyl-8-methoxycarbonyl- 5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one into the lactone E ring of a 1H- pyrano[3',4' :6,7]indolizino[ 1 ,2-6]quinolin-3, 14(4H, 12H)-dione, preferably a camptothecin analog; and (e) opening the E ring of said camptothecin analog with extrusion of, depending upon choice of termination step, carbon dioxide to provide a camptothecin analog which lacks the lactone E ring, preferably a 8-methyl-7- (oxopropyl)-indolizino[l,2-6]quinolin-9(llH)-one, most preferably a mappicine or mappicine ketone. Most preferably, the present invention provides a process, as shown in Scheme 7, for the total synthesis of, depending upon choice of termination step, 4- ethyl-4-hydroxy-9-memoxy-lH-pyrano[3',4':6,7] indolizino[l,2-6]quinolin- 3,14(4H, 12H)-dione, more commonly known as 10-methoxycamptothecin, 4-ethyl- 4,9-dihydroxy-lH-pyrano[3',4 , :6,7] indolizino[l,2-6]quinolin-3,14(4H,12H)-dione, more commonly known as 10-hydroxycamptothecin, as well as of 10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH-pyrano[3',4':6,7]indolizino[l,2- 6]quinolin-3,14(4H,12H)-dione, more commonly known as topotecan, said process comprising the steps of: (a) heating a compound of Formula in (e.g. VII) in a polar solvent, preferably methylene chloride, 1,2-dichloroethane, 1,2-dimethoxyethane tetrahydrofuran, N,N-dimetiιylformamide, acetonitrile, acetone or N- methylpyrrolidinone, most preferably acetonitrile;at a temperature of about 20 - 85°C, preferably about 60 - 85°C, most preferably at about the reflux temperature of acetonitrile; in the presence of a strong alkylating agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydration, preferably trifluoromethanesulfonic anhydride, dimetiiylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or rriphenylphosphine/carbon tetrabromide, most preferably trimethyloxonium tetrafluoroborate; to generate a compound of Formula IV which undergoes [4 + 2] cycloaddition to yield a pyrrolo[3,4- 6]quinoline substituted at C-2 by an acetate ester (VIII); (b) hydrolyzing die carbamate function of the C-2 substituted pyrrolo[3,4- frjquinoline from step (a) with acetic acid saturated widi HBr to give a tricyclic amine (X); (c) coupling said tricyclic amine with a monoalkyl malonyl chloride, preferably monomed yl malonyl chloride, to give me half-amide of a malonate diester (XI); (d) subjecting said malonate half-amide to a Dieckmann condensation in d e presence of an alkoxide to give a a tetracyclic enol (XII); (e) forming a vinyl triflate of said tetracyclic enol, and coupling said triflate with a tertiary malonate anion to form a 7-(l,l-di-te/τ-butoxycarbonyl)propyl-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one (XDI); (f) 1,2 elimination of hydrogen at the 5,6 bond of die 7-(l,l-di-rβrr- butoxycarbonyl)propyl-8-methoxycarbonyl-5,6-dihydroindolizino[l,2-6]quinolin- 9(llH)-one to give a 7-(l,l-di-rerr-butoxycarbonyl)propyl-8-methoxycarbonyl- indolizino[l,2-6]quinolin-9(l lH)-one (XTV); (g) reduction of the 8-methoxycarbonyl group of the 7-(l,l-di-rert- butoxyca_dκ>nyl)propyl-8-methoxycarbonyl-indolizino[l,2-6]quinolin-9(llH)-one, followed by hydrolysis-decarboxylation of the diester group at C-7, and lactone formation to give a 4-ethyl-9-methoxy-lH-pyrano[3',4':6,7] indolizino[l,2- 6]quinolin-3,14(4H,12H)-dione (XV); (h) forming a tertiary alcohol α to the E ring carbonyl of said 4-ethyl-9- methoxy-lH-pyrano[3',4':6,7] indolizino[l,2-6]quinolin-3,14(4H,12H)-dione to give 10-methoxycamptothecin (XVI); (i) cleaving the methyl ether of said 10-medιoxycamptothecin to yield 10- hydroxycamptothecin (XVII); and (j) alkylating the 9-position of said 10-hydroxycamptothecin by reaction with N,N,N\N'-tetramethyldiaminomethane (BDAM) to give topotecan (XVII). As may be seen in both Schemes 5 and 7, the starting material of Formula HI (e.g. Vπi) may be prepared from a variety of readily available starting materials using well-known methods. e, tBuOH (XIII) Scheme 7 11) 0 2 , CuCI, Mθ2- t MeO 100 % Total synthesis of topotecan; 13 steps, overall yield 5-6% Scheme 7 (con't) The most preferred process of the present invention, which provides for the total synthesis of topotecan, is further described in the Example below. EXAMPLE In the following synthetic Example, temperature is in degrees Centigrade (°C). Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. This Example is given merely to illustrate the present invention, and should not be construed as limiting the scope thereof in any way. Reference is made to the claims for what is reserved to the inventors hereunder. The following Example describes die most preferred process of the present invention for the total synthesis of topotecan, which process is outlined in Scheme 7. The steps in the Example correspond numerically with the steps oudined in Scheme 7. EXAMPLE 1 Step l To a stirred suspension of fumaric acid monoethyl ester (100 g, 95% purity; 0.66 mol) p-anisidine (90 g, 99% purity, 1.1 eq.) and 1-hydroxybenzotriazole (89 g, 1 eq.) in methylene chloride (3000 ml) was added dimethylaminopropyl ethyl cabodiimide (WSC, 125 g, leq.). The resulting mixture was stirred at 20 °C for 16 hours. Additional metiiylene chloride (2000 ml) was added and die mixture was successively washed wid dilute, aqueous, hydrochloric acid (10%, 1500 ml) and water (2 xl500 ml). The organic layer was evaporated to give a crude, greenish- yellow solid which was triturated widi 500 ml of diediyl ether and isolated by filtration to give 147 g of a yellow powder (89% yield) mp 144-145 °C. IR (KBr) 3400-3200, 1720, 1699, 1687, 1672, 1651, 1638, 1613, 1556, 1509, 1240, 1163, 843, 830 cm- 1 ; l H NMR (δ, CDCI3): 1.30 (t, J = 7.1 Hz, 3H, CH2CH3), 3.77 (s, 3H, OCH3), 4.25 (q, J = 7.1 Hz, 2H, CH2CH3), 6.85 (d, J = 8.8 Hz, 2H, aromatic), 6.91, 7.07 (AB, q, J = 15.3 Hz, 4H, olefin), 7.50 (d, J = 8.9 Hz, 2H, aromatic), 7.84 (br, IH, NH); *H NMR (δ, MeOD): 1.23 (t, J = 7.0 Hz, 3H, CH2CH3), 3.69 (s, 3H, OCH3), 4.16 (q, J = 7.1 Hz, 2H, CH2CH3), 6.71, 7.08 (AB, q, J = 15.3 Hz, 4H, olefin), 6.81 (d, J = 9.1 Hz, 2H, aromatic), 7.47 (d, J = 9.1 Hz, 2H, aromatic); MS m/z 250 (MH+), 204, 176, 127. Step 2 A mixture of fumaric acid mono p-memoxy phenyl amide mono etiiyl ester (50g, 0.2 mol) and propargyl amine (40 ml, 3 eq.) in tøuOH (700 ml) was stirred under reflux at 100 °C for 24 h. The reaction mixture was cooled to 20 °C and solvent was removed on a rotavapor. Ethyl acetate (1500 ml) was added to the remaining thick oil. The resulting solution was washed widi hydrochloric acid (10%, 3 x 500 ml). The aqueous phase was then made basic to a pH of approximately 8 by the slow addition of solid sodium bicarbonate. The resulting suspension was extracted with ethyl acetate (3 x 500 ml). The combined organic layers were washed with water (300 ml) dried and evaporated to give a black semisolid which was treated wid hexane:ethyl acetate (1:1) and filtered. The filtrate was concentrated using a rotary evaporator to give a brown oil which slowly formed a solid. The solid could be crystallized by trituration with t-butyl methyl ether to give white crystals, mp 66-67 °C (52.4g, 85.9% yield). IR (KBr) 3400-3200, 2048 1734, 1650, 1605, 1552, 1514, 1464, 1272, 1248, 1178, 1165, 833 cm- 1 ; iH NMR (δ, CDC13): 1.23 (t, J = 7.1 Hz, 3H, CH2CH3), 2.24 (t, J = 2.4 Hz, IH, al yne), 2.81, (AB, q, J = 16.6, 7.3Hz, IH, CH2COO), 2.94 (AB, q, J = 16.6, 4.2 Hz, IH, CH2COO), 3.45, 3.55 (AB, d,d, J = 17.0, 2.4 Hz, 2H, CH2NH), 3.65 (d,d, J = 7.3, 4.3 Hz, IH, OCCHNH), 3.76 (s, 3H, OCH3), 4.14 (q, J = 7.1 Hz, 2H, CH2CH3), 6.84 (d, J = 8.9 Hz, 2H, aromatic), 7.46 (d, J = 8.9 Hz, 2H, aromatic), 9.13 (br, 1H, NH); MS m/z 305 (MH+), 259, 217, 182, 154, 123. The white grey solid obtained as a byproduct from the initial filtration from hexane:ethyl acetate was N-propargyl aspartic N-p-methoxy phenyla ide, mp 165- 166 °C. NMR (δ, CDCI3): 2.30 (t, J = 2.4 Hz, IH, alkyne), 2.69, (AB, q, J = 17.9, 5.3Hz, IH, CH2CO2R), 3.09 (AB, q, J = 17.9, 8.3 Hz, IH, CH2CON), 3.46, 3.70 (AB, d,d, J = 17.4, 2.4 Hz, 2H, CH2NH), 3.80 (s, 3H, OCH3), 4.17 (d,d, J = 8.3, 5.2 Hz, IH, OCCHNH), 6.96 (d, J = 8.9 Hz, 2H, aromatic), 7.18 (d, J = 8.9 Hz, 2H, aromatic). Step 3 To a solution of starting amine (44.66g, 0.146 mol) and pyridine (15.1g, 1.3 eq.) in methylene chloride (150 ml) was added neat methyl chloroformate (14.9 ml, 1.3 eq.) drop wise with the internal temperature maintained at 0 °C with cooling. The resulting mixture was stirred at 0 °C for 30 min. Additional memylene chloride (400 ml) was added to the reaction mixture. The solution was successively washed widi aqueous hydrochloric acid (10%, 2 x 150 ml) and saturated sodium chloride solution (2 x 150 ml). The organic solvent was removed on a rotavapor to give a brown oil which was passed through a silica gel pad (200 g) widi ether as eluent. The filtrate was concentrated on a rotavapor to give the desired product (41.46g) in 78% yield, which was used as obtained. The product could be recrystallized in approximately 95% recovery by trituration with dietiiyl ether to give white crystals with mp 97-98 °C. IR (KBr) 3300, 2120, 1725, 1709, 1687, 1600, 1512, 1463, 1247, 1173, 830 cm" 1 ; !H NMR (δ, CDCI3): 1.25 (t, J = 7.1 Hz, 3H, CH2CH3), 2.30 (br, IH, alkyne), 2.89, 3.31 (br, 2H, CH2COO), 3.76 (s, 3H, OCH3),4.06, 4.22 (AB, d,d, J = 18, 2.3 Hz, 2H, CH2NH),4.56 - 4.98 (br, IH, OCCHNH), 6.82 (d, J = 8.9 Hz, 2H, aromatic), 7.36 (d, J = 8.9 Hz, 2H, aromatic), 7.90 - 8.03 (br, IH, NH); MS m/z 363 (MH+), 331, 317, 240, 212, 123. Step 4 A mixture of carbamate (27.7 g, 0.077 mol) and trimethyloxonium tetrafluoroborate (40g, 3.5 eq.) in acetonitrile (500 ml) was stirred under reflux for 2.5 h. After cooling to ambient temperature, saturated sodium chloride solution (200 ml) was added wid continued stirring. The organic layer was separated and the aqueous phase was extracted widi 3 x 300 ml of ethyl acetate. The combined organic phase was washed widi saturated sodium bicarbonate solution (3 x 100 ml) and saturated sodium chloride solution (100 ml) dried, and evaporated to give a yellow semisolid which was recrystallized from methanol to give 25.4 g of yellow solid, mp 132-134 °C. IR (KBr) 1728, 1701, 1623, 1577, 1504, 1451, 1228, 1122, 1029, 825, 769 cm" 1 ; l U NMR (δ, CDCI3): 1.06, 1.08 (t,t, J = 7.3 Hz, 3H, CH2CH3), 3.80 (br, 2H, CH2COO), 3.78, 3.80 (s,s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.78 - 4.95 (m, 2H, CH2NH), 5.29 (d, J = 14.1Hz, IH, OCCHNH), 7.05 (s, IH, aromatic), 7.31 (d,d, J = 9.2, 2.8 Hz, IH, aromatic), 7.84, 7.88 (s, s, IH, aromatic), 7.91 (d, J = 9.0 Hz, IH, aromatic); MS m/z 345 (MH+), 317, 299, 285, 271, 257. Step 5 To the tricyclic compound (25.4g) was added a solution of acetic acid saturated with hydrobromic acid (129 ml) and e mixture was stirred at ambient temperature for 24 h. The solvent was removed on a rotavapor and 300 ml of water was added to d e residue. The mixture was extracted with 2 x 200 ml of ethyl acetate and die organic extracts were discarded. The aqueous phase was made alkaline with solid sodium carbonate to a pH of >10. The resulting precipitated solid was collected by filtration and dried in oven (45 °C/740 mm) to give 8.98 g of product The aqueouse phase obtained after filtration was further extracted widi 3 x 400 ml of methylene chloride. This organic phase was dried and evaporated to give a black oil to which ethyl acetate (100 ml) was added. The resulting mixture was washed widi dilute, aqueous hydrochloric acid (3%, 3 x 100 ml). The aqueous phase was made basic by the addition of sodium bicarbonate to a pH > 8, then extracted widi me ylene chloride, dried, and evaporated to give 2.25 g of product which was combined wid die first isolated fraction, giving a total yield of 11.13 g of a yellow solid, m.p. 83-86 °C (51% total yield for 2 steps from the uncyclized carbamate). IR (KBr) 3350, 1723, 1622, 1502, 1236, 1183, 1026, 893, 842 cm" 1 ; NMR (δ, CDC13): 1.24 (t, J = 7.1 Hz, 3H, CH2CH3), 2.63 (d,d, J = 16.5, 9.8Hz, IH, CH2COO), 3.26 (d, d, J = 16.5, 2.9 Hz, IH, CH2COO), 3.89 (s, 3H, OCH3), 4.16 (q, d, J = 7.0, 1.3 Hz, 2H, CH2CH3), 4.36 (s, 2H, CH2NH), 4.84 (d, d, J = 9.8, 2.8Hz, IH, OCCHNH), 7.03 (d, J = 2.7Hz, IH, aromatic), 7.29 (d,d, J = 9.2, 2.8 Hz, IH, aromatic), 7.82 (s, IH, aromatic), 7.91 (d, J = 9.2 Hz, IH, aromatic); MS m/z 287 (MH+), 199. Step ό To a solution of die tricyclic amine (6.98g, 24.4 mmol) in methylene chloride (250 m l) was added pyridine (3.0g, 1 .56 eqoride (2.66 ml, 95% purity, 1.3 eq.) was then added dropwise, neat, at a rate so as to maintain the internal temperamre at 0 °C. The mixture was stirred at 0 °C for an additional 1 hour after addition was complete. Methylene chloride (350 ml) was added and die resulting solution was washed widi hydrochloric acid (10%, 2 x 100 ml) followed by saturated, aqueous, sodium bicarbonate solution and saturated, aqueous, sodium chloride solution. The organic layer was dried and evaporated to give 10.4 g of crude product as a heavy oil which was used in the next reaction without further purification. An analytical sample was obtained by recrystallization from 1:1 ethyl acetate:hexane to give a white powder, mp 1145-116 °C. IR (KBr) 1747, 1737, 1654, 1621, 1503, 1441, 1135, 900, 846 cm" 1 ; iH NMR (δ, CDCI3): 1.08 (t J = 7.3 Hz, 3H, CH2CH2), 3.24 (dd, J = 17.2, 3.3 Hz, IH, CH2COO), 3.55, 3.57 (2 x s, 2H, COCH2COO), 3.78 (s, 3H, COCCH^), 3.93 (q, J = 7.2 Hz, 2H, O^CH^), 3.93 (s, 3H, OO , 4.98, 5.07 (AB, d, J = 13.6 Hz, 2H CH2N), 5.47 (t, J = 3.8 Hz, IH, CHNH), 7.07 (d, J = 2.7 Hz, IH, aromatic), 7.35 (dd, J = 9.2, 2.8 Hz, IH, aromatic), 7.88 (s, IH, aromatic), 7.95 (d, J = 9.1 Hz, IH, aromatic) MS m/z 387 (MH+), 355, 313, 299, 285, 239, 199, 101 . Step 7 To a solution of starting material (10.4g) in mixed solvent (216 ml, methanohtoluene = 1: 5) was added sodium methoxide solution (7.4 ml of 25% solution in methanol, 1.2 eq.) dropwise at ambient temperature. The resulting mixture was stirred at 20 °C for 1 h. Water (250 ml) was added widi stirring and the layers were separated. The organic layer was extracted with water. The combined aqueous phases were acidified wid hydrochloric acid (10%) to a pH < 2. The precipitate was collected by filtration and washed wid water until neutral as indicated by pH paper. The white solid was dried under vacuum (60 °C/ 740 mm) to give 5.73g of product , mp 219 - 220 °C (69% yield for 2 steps). IR(KBr)3429, 1673, 1661, 1643, 1623, 1567, 1501, 1450, 1238, 1227, 1377, 1046, 1026,822cm" 1 ; NMR(δ,CDC13):2.86(d,d,J= 17, 13.6Hz, IH,CH2COO),3.31 (d,d,J= 17, 4.4Hz, IH,CH2COO),3.92(s,3H,OCH3),3.93 (s,3H,OCH3),4.75,5.13(AB, d, J = 17 Hz, 2H, CH2NH), 5.14 (d, d, J = 13.5, 4.5Hz, IH, OCCHNH), 7.07 (d, J = 2.7Hz, IH, aromatic), 7.36 (d,d, J = 9.2, 2.8 Hz, IH, aromatic), 7.94 (d, J = 9.3 Hz, IH, aromatic), 7.97 (s, IH, aromatic) 13.89 (s, IH, OH); MS m/z 341 (MH+), 337, 323, 309, 283, 265. Step 8 To a suspension of the tetracyclic enol (lg, 2.9 mmol) in methylene chloride (50 ml) was added triethylamine (0.5 ml, 1.2 eq.). The resulting brown solution was cooled to -78 °C using a dry ice-acetone batii. Trifluoromethanesulfonic anhydride (0.6 ml, 1.2 eq.) was added dropwise, neat. After me addition was complete, d e dry ice-acetone bath was replaced by an ice batii and d e reaction mixture was stirred at 0 °C for anotiier hour, then poured into ice water (100 ml). The mixture was extracted with 3 x 100 ml of methylene chloride. The combined organic phases were washed with water (100 ml) dried, and evaporated to give a brown solid which was used directly in the next reaction. l H NMR (δ, CDCI3): 2.75, 3.12 (AB, d,d, J = 15.9, 13.8Hz, IH, CH2COO), 3.25, 3.48 (AB, d, d, J = 17.3, 5.3 Hz, IH, CH2COO), 3.82, 3.92 (s, s, 3H, OCH3), 3.95, 3.96 (s, s, 3H, OCH3), 4.80, 5.14 (AB, d, J = 17.8 Hz, 2H, CH2NH), 5.39 (d, d, J = 15.0, 4.5Hz, IH, OCCHNH), 7.11 (d, J = 2.7Hz, IH, aromatic), 7.42 (d,d, d, J = 9.4, 2.9, 2.9 Hz, IH, aromatic), 7.99 (d, J = 9.2 Hz, IH, aromatic), 8.03, 8.04 (s, s, IH, aromatic). To a suspension of sodium hydride (132 mg, 80% in mineral oil, 1.3 eq.) in THF (10 ml) was added a solution of etiiyl, di-terr-butyl malonate (1.43g, 2eq.) in THF (10 ml) dropwise. The resulting mixture was stirred at 20 °C for 15 min. The mixture became a clear solution, to which the triflate obtained above in THF (50 ml) was added dropwise. The resulting dark green mixture was stirred at 20 °C for 1 h and poured into 150 ml of ice-cold water containing 2 ml of acetic acid. The mixture was extracted widi 3 x 150 ml of methylene chloride. The combined organic layers were dried over magnesium sulfate and evaporated to give a black semisolid which was purified by flash chromatography (2 :1 hexane:ethyl acetate as eluant) to give the desired product (680 mg) in 41% yield. The product was isolated as fluffy, tan crystals, mp 88-91 °C. IR (KBr) 1736, 1665, 1623, 1504, 1368, 1130, 1158, 1231, 1253, 832, 726 cm" 1 ; NMR (δ, CDCI3): 1.03 (t J = 7.3 Hz, 3H, CH2CH3), 1.48, 1.51 (s, s, 9H, CCH3), 2.05, 2.19 (q, d, J = 14.2, 7.3Hz, 2H, CH2CH3), 2.65 (d, d, J = 14.2, 14.2 Hz, IH, CH2COO), 3.21 (d, d, J = 16.4, 4.1 Hz, IH, CH2COO), 3.80 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.76, 5.14 (AB, d, J = 16.4 Hz, 2H, CH2NH), 5.13 (d, d, J = 13.9, 4.0Hz, IH, OCCHNH), 7.07 (d, J = 2.5Hz, IH, aromatic), 7.33 (d,d, J = 9.2, 2.6 Hz, IH, aromatic), 7.94 (d, J = 9.2 Hz, IH, aromatic), 7.95 (s, IH, aromatic); MS m/z 567 (MH+), 511, 479, 467, 411, 379, 323. Step 9 A mixture of the starting material (1.84g, 3.25 mmol) and sodium nitrite (1.15g, 95% purity, 5 eq.) in 39 ml of 10:3 acetic acid:water was stirred at 65 °C 8 h. The reaction mixture was cooled to ambient temperature and poured into 300 ml of ice-water. The mixture was extracted with 3 x 200 ml of methylene chloride and die organic layers were dried over magnesium sulfate. The organic layer was concentrated on a rotavapor to give 1.8 g of yellow solid (98% crude yield) which was pure enough to carry direcdy on to the next reaction. An analytical sample was obtained by recrystallization from methylene chloride:hexane, mp 198-200 °C. IR (KBr) 1742, 1730, 1649, 1623, 1605, 1510, 1370, 1254, 844, 834 cm" 1 ; J H NMR (δ, CDC13): 00 (t, J = 7.4 Hz, 3H, CH2CH3), 1.50 (s, 9H, CCH3), 2.38 (q, J = 7.4Hz, 2H, CH2CH3), 3.89 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 5.27(s, 2H, CH2NH), 7.15 (d, J = 2.7Hz, IH, aromatic), 7.25 (s, IH, aromatic), 7.45 (d,d, J = 9.3, 2.8 Hz, IH, aromatic), 8.09 (d, J = 9.4 Hz, IH, aromatic), 8.24 (s, IH, aromatic); MS m/z 565 (MH + ), 509, 493, 477, 465, 453, 409, 393, 377, 365, 333. Step 10 To a solution of starting material (1.24g, 2.2 mmol) in dimethoxyethane (50 ml) was added DIBAL (11 ml, 1.0M in hexane, 5 eq.) dropwise at 0 °C. The colour turned from yellow to blue and finally to dark brown. After the addition was complete, the mixture was stirred at 0 °C for lh and poured into a ice water (300 ml). The mixture was extracted witii 3 x 250 ml of mediylene chloride. The organic layers were dried and evaporated to give 1.18 g of yellow solid, to which was added a 50 ml of 3:2 methanokhydrochloric acid. Soduim borohydride (200 mg, 3 eq.) was added in small portions to this stirred solution and die resulting mixture was stirred for 15 minutes after addition was complete. The solvent was removed on a rotavapor and dilute hydrochloric acid (50 ml of 0.4% solution) was added to die residue. The mixture was extracted with 3 x 100 ml of methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated to give a dark solid to which trifluoroacetic acid (20 ml) was added. The mixture was stirred at ambient temperature for 1 h. Trifluoroacetic acid was removed on a rotavapor and water (50 ml) was added to the residue. The mixture was extracted widi 3 x 100 ml of methylene chloride.The combined organic layers were dried over magnesium sulfate and concentrated to give 774 mg of crude product (98% yield) which was carried directly on to the next reaction. An analytical sample was obtained by recrystallization from methylene chloride:hexane, mp 259-261 °C. IR(KBr) 1735, 1657, 1604, 1506, 1243, 825cm" 1 ; !H NMR (δ, CDC13): 1.09 (t J = 7.4 Hz, 3H, CH2CH3), 2.09 (m, 2H, CH2CH3), 3.61 (t, J = 6.5 Hz, IH, CHCOO), 3.98 (s, 3H, OCH3), 5.27 (s, 2H, CH2NH), 5.39, 5.56 (AB, d, J = 16.0 Hz, 2H, CH2OCO), 7.13 (s, IH, aromatic), 7.16 (d, J = 2.7 Hz, IH, aromatic), 7.47 (d, d, J = 19.3, 2.7Hz, IH, aromatic), 8.10 (d, J = 9.3 Hz, IH, aromatic), 8.25 (s, IH, aromatic); MS m/z 363 (MH+), 333, 319. Step 11 To a solution of starting material (665 mg, 1.84 mmol) in 60 ml of N,N- dimethylformamide was added piperidine (3.2 ml) and oxgen gas was bubbled dirough the solution for 6 h widi stirring. DMF was removed on a rotavapor to give 680 mg of brown solid, mp 278 -280 °C (100%). The crude product showed >95% total area response for the desired product as indicated by HPLC, and was carried on as obtained. IR (KBr) 3400, 1738, 1656, 1600, 1512, 1267, 1165, 1156, 1105, 825cm" 1 ; l H NMR (δ, CDC13): 1.05 (t, J = 7.1 Hz, 3H, CH2CH3), 1.91 (q, J = 7.1 Hz, 2H, CH2CH3), 3.70 (s, IH, OH), 3.99 (s, 3H, OCH3), 5.28 (s, 2H, CH2NH), 5.32, 5.76 (AB, d, J = 15.8 Hz, 2H, CH2OCO), 7.17 (s, IH, aromatic), 7.48 (d, J = 10.0 Hz, IH, aromatic), 7.62 (s, IH, aromatic), 8.13 (d, J = 9.3 Hz, IH, aromatic), 8.27 (s, IH, aromatic); MS m/z 379 (MH+), 335, 333. Step 12 A mixture of starting material (60 mg, 0.16 mmol) and HBr (48% solution, 3 ml) was refluxed at 155 °C for 2 h. The reaction mixture was cooled to ambient temperature. Water (50 ml) was added and the mixture was extracted wid methylene chloride:mcthanol. The organic layers were dried over magnesium sulfate and concentrated to give crude product which was purified by silica gel chromatography using a chromatotron to give the desired product (42 mg, 72% yield) widi mp 269 - 272 °C which was spectroscopically and chromatographically identical to a sample prepared independendy by semisynthesis from naturally- occurring camptothecin. *H NMR (δ, DMSO-d6): 0.87 (t, J = 7.3 Hz, 3H, CH2CH3), 1.85 ( hept, J = 7.3 Hz, 2H, CH2CH3), 5.22 (s, 2H, CH2N), 5.40 (s, 2H, CH2OCO), 7.25 (s, IH, aromatic), 7.28 (s, IH, aromatic), 7.41 (d, J = 9.1 Hz, IH, aromatic), 8.01 (d, J = 9.1 Hz, IH, aromatic), 8.45 (s, IH, aromatic); Step 13 To a solution of starting material (20 mg, 0.05 mmol) in 3 ml of 2:1 mediylene chloride: 1-propanol was added 0.05 ml (1.5 eq) of N,N,N\N'- tetramethyldiaminomethane (BDAM) and die mixture was stirred at ambient temperamre for 16 h. Hydrochloric acid (1 ml of 37% aqueous in 5 ml of 1-PrOH) was slowly added and the mixture was stirred at ambient temperature for another 5h. The solvent was removed in vacuo to give a hygroscopic, brown semisolid which was purified by reverse-phase HPLC (acetonitrile :wateπtrifluoroacetic acid; 16 : 84 : 1.5) to give racemic SK&F 104864 in approximately 88% yield from 10- hydroxycamptotiiecin. The identity of die product was confirmed by comparison of NMR and Mass spectra as well as chromatographic behavior with an authentic sample of die desired product. *H NMR (δ, DMSO-d6): 0.87 (t, J = 7.2 Hz, 3H, CH2CH3), 1.86 ( hept, J = 7.0 Hz, 2H, CH2CH3), 2.84 (s, 6 H, NCH3), 4.72 [s, 2H, CH2N(CH3)2], 5.28 (s, 2H, CH2N), 5.41 (s, 2H, CH2OCO), 6.50 (s, IH, OH), 7.28 (s, IH, aromatic), 7.64 (d, J = 9.2 Hz, IH, aromatic), 8.18 (d, J = 9.2 Hz, IH, aromatic), 8.91 (s, IH, aromatic); MS m/z 422 (MH+), 377, 307, 289, 220, 154, 136, 107, 77. The overall yield of topotecan for the total synthesis in 13 steps was about 5- 6%.

Claims: We claim: 1. A process for preparing a compound selected from the group consisting essentially of pyrrolo[3,4-b]quinolines, lH-pyrano[3',4':6,7]indolizino[l,2- b]quinolin-3,14(4H,12H)-diones, and 8-medιyl-7-(oxopropyl)-indolizino[l,2- b]quinolin-9(HH)-ones, said process comprising the step of intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV: IV where: X=OH, OAICI2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H ~~ l = H, OH, or OR, where R is an ester protecting group; R2 = H, NO2, or a protected amine function; R3 = H, C2H5, or a trialkylsilyl; R 4 = H or CH 2 COOEt; R5 = COOMe or tosyl; or R4 and R5 are joined together to form a substimted pyridone IVa: Y=H or Y,Rι = -OCH 2 O- IVa where: A = H, COOR, or a functionality for preparation of die hydroxymethyl (C-17) portion of an E ring lactone; B = H, OH, an appropriate leaving group such as halide or O(nifluoromethanesulfonate) or a functionality for preparation of C- (18-21) of the E ring lactone portion of camptothecin. with the unactivated acetylene portion of said compound. 2. A process according to Claim 1 wherein said step further comprises heating said compound of Formula IV, a compound Formula III, corresponding to in a polar solvent at a temperature of about 20-85°C in the presence of an agent selected from the group consisting essentially of a strong alkylating agent, such agent as is capable of producing either an O-alkylimidate or imidate ester, imidoyl halide, and such imide derivative as is capable of cyclodehydration. 3. A process according to Claim 2 wherein said polar solvent is selected from a group consisting essentially of mediylene chloride, 1,2-dichloroethane, 1,2- dimethoxyediane tetrahydrofuran, N,N-dimetiiylformamide, acetonittile, acetone and N-metiiylpyrrolidinone. 4. A process according to Claim 3 wherein said polar solvent is acetonitrile. 5. A process according to Claim 2 wherein said temperature is about 60-85°C. 6. A process according to Claim 5 wherein said temperature is about the reflux temperature of acetonitrile. 7. A process according to Claim 2 wherein said strong alkylating agent or such agent as is capable of producing eitiier an O-alkylimidate or imidate ester, imidoyl halide, or such imide derivative as is capable of cyclodehydration, is selected from a group consisting essentially of trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O-benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide 8. A process according to Claim 7 wherein said agent is trimethyloxonium tetrafluoroborate. 9. A process according to Claim 1 wherein said compound is a lH-pyrano[3',4':6,7]indolizino[l,2- 7]quinoUn-3,14(4H,12H)-dione. 10. A process according to Claim 9 wherein said 1H- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-3,14(4H,12H)-dione is a camptothecin analog. 11. A process according to Claim 10 wherein said camptothecin analog is a water-soluble camptothecin analog. 12. A process according to Claim 11 wherein said water-soluble camptotiiecin analog is selected from the group consisting essentially of topotecan and irinotecan. 13. A process according to Claim 12 wherein said water-soluble camptothecin analog is topotecan. 14. A process according to Claim 1 wherein said compound is a 8-methyl-7- (oxopropyl)-indolizino[l,2-&]quinolin-9(llH)-one. 15. A process according to Claim 14 wherein said 8-methyl-7-(oxopropyl)- indolizino[l,2-fc]quinolin-9(llH)-one is a mappicine. 16. A process according to Claim 14 wherein said 8-methyl-7-(oxopropyl)- indolizino[l,2-b]quinolin-9(llH)-one is a mappicine ketone. 17. A process for preparing a 7-(l,l-&w-alkoxycarbonyl)propyl-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-b]quinolin-9(l lH)-one, said process comprising the step of coupling a vinyl triflate derived from a 7-hydroxy-5,6- dihydroindolizino[l,2-b]quinolin-9(llH)-one with a tertiary malonate anion. 18. A process for preparing a 3,14(4H,12H)-dione, said process comprising the steps of: (a) intramolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV: IV where: X=OH, OAICI2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H Rj = H, OH, u OR, where R is an ester protecting group; R2 = H, NO2, or a protected amine function; R3 = H, C2H5, or a trialkylsilyl; R 4 = H or CH 2 COOEt; R5 = COOMe or tosyl; or R4 and R5 are joined together to form a substituted pyridone IV: Y=OH, OAICI2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H IVa where: A = H, COOR, or a functionality for preparation of die hydroxymethyl (C-17) portion of an E ring lactone; B = H, OH, an appropriate leaving group such as halide or O(trifluoromethanesulfonate) or a functionality for preparation of C- (18-21) of the E ring lactone portion of camptothecin. with the unactivated acetylene portion of said compound to form a 2-(acetate ester) substimted pyrrolo [3,4- ]quinoline; (b) cyclizing said 2-(acetate ester) substimted pyrrolo[3,4- >]quinoline to form a 5,6-dihydroindolizino[l,2-Z>]quinolin-9(llH)-one substimted at C-7 widi an (alkyl malonate) diester, (c) coupling a 7-substituted vinyl triflate of said 7-hydroxy-5,6- dihydroindolizino[l,2-Z>]quinolin-9(llH)-one with a tertiary malonate anion to form a 5,6-dihydroindolizino[l,2-fr]quinolin-9(l lH)-one substimted at C-7 an (alkyl malonate) diester, and (d) converting said 7-(l,l-6ύ-alkoxycarbonyl)propyl-5,6- dihydroindolizino[l,2- ?]quinolin-9(l lH)-one into the lactone E ring of a 1H- pyrano[3 , ,4':6,7]indolizino[l,2-b]quinolin-3,14(4H,12H)-dione. 19. A process according to Claim 18 wherein said step (a) further comprises heating a compound of Formula m, corresponding to said compound of Formula IV, in a polar solvent at a temperature of about 20-85°C in me presence of an agent selected from die group consisting essentially of a strong alkylating agent; such agent as is capable of producing eitiier an O-alkylimidate or imidate ester, imidoyl halide; and such imide derivative as is capable of cyclodehydration. 20. A process according to Claim 19 wherein said polar solvent is selected from a group consisting essentially of methylene chloride, 1,2-dichloroethane, 1,2- dimethoxyediane tetrahydrofuran, N,N-dimetiιylformamide, acetonitrile, acetone and N-mediylpyrrolidinone. 21. A process according to Claim 20 wherein said polar solvent is acetonitrile. 22. A process according to Claim 19 wherein said temperature is about 60-85°C. 23. A process according to Claim 22 wherein said temperature is about die reflux temperature of acetonitrile. 24. A process according to Claim 19 wherein said strong alkylating agent or such agent as is capable of producing eitiier an O-alkylimidate or imidate ester, imidoyl halide, or such imide derivative as is capable of cyclodehydration, is selected from a group consisting essentially of trifluoromethanesulfonic anhydride, dimethylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O- benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide. 25. A process according to Claim 19 wherein said agent is trimethyloxonium tetrafluoroborate. 26. A process according to Claim 18 wherein said compound is a camptothecin analog. 27. A process according to Claim 26 wherein said camptothecin analog is a water-soluble camptothecin analog. 28. A process according to Claim 27 wherein said water-soluble camptothecin analog is selected from the group consisting essentially of topotecan and irinotecan. 29. A process according to Claim 28 wherein said water-soluble camptotiiecin analog is topotecan. 30. A process according to Claim 1 wherein R4 and R5 of said compound of Formula IV are joined together to form a substimted pyridone. 31. A process for the total syndiesis of topotecan,, said process comprising the steps of: (a) intramolecular [4+2] cycloaddition of die N-arylimidate portion of a compound of Formula IV: IV where: X=OH, OAICI2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H Rj = OMe; R2 = H; R3 = H; R4 = O^COOEt; and R5 = COOMe; Y=H or Y,Rι = -OCH2θ- witii the unactivated acetylene portion of said compound by heating a compound of Formula HI, corresponding to compound of Formula IV, in a polar solvent at a temperature of about 20-85 °C in the presence of a strong alkylating agent or such agent as is capable of transforming an amide into its corresponding O-alkylimidate or imidate ester, imidoyl halide, or a strong acid (such as aluminum chloride) capable of initiating a cyclodehydretion to yield a pyrrolo[3,4-Z>]quinoline substimted at C-2 by an acetate ester, (b) hydrolyzing the carbamate function of the C-2 substimted pyrrolo[3,4- 6]quinoline from step (a) with acetic acid saturated widi HBr to give a tricyclic amine; (c) coupling said tricyclic amine with a monoalkyl malonyl chloride, preferably monomethyl malonyl chloride, to give the half-amide of a malinate diester, (d) subjecting said malonate half-amide to a Dieckmann condensation in die presence of an alkoxide to give a a tetracyclic enol; (e) forming a vinyl triflate of said tetracyclic enol, and coupling said triflate with a tertiary malonate anion to form a 7-(l,l-di-rerr-butoxycarbonyl)propyl-8- methoxycarbonyl-5,6-dihydroindolizino[l,2-Z)]quinolin-9(l lH)-one; (f) 1,2 elimination of hydrogen at die 5,6 bond to give 7-(l,l-di-re_f- butoxycarbony l)propyl- 8-methoxycarbonyl-indolizino[ 1 ,2-d]quinolin-9( 1 lH)-one; (g) reduction of die 8-metiιoxycarbonyl group of the 7-(l,l-di-ferr- butoxycarbonyl)propyl-8-methoxycarbonyl-indolizino[l,2- ?]quinolin-9(llH)-one, followed by hydrolysis-decarboxylation of die diester group at C-7, and lactone formation to give a 4-ethyl-9-medιoxy-lH-pyrano[3',4':6,7] indolizino[l,2- fc]quinolin-3,14(4H,12H)-dione; (h) forming a tertiary alcohol α to the E ring carbonyl of said 4-ethyl-9- methoxy-lH-pyrano[3',4':6,7] indolizino[l,2-&]quinolin-3,14(4H,12H)-dione to give 10-methoxycamptothecin; (i) cleaving the methyl ether of said 10-medιoxycamptothecin to yield 10- hydroxycamptotiiecin; and (j) alkylating die 9-position of said 10-hydroxycamptothecin by reaction widi N,N,N',N'-tetramethyldiaminomethane (BDAM) to give topotecan. 32. A process according to Claim 31 wherein said polar solvent is selected from a group consisting essentially of mediylene chloride, 1,2-dichloroethane, 1,2- dimethoxyetiiane tetrahydrofuran, N,N-dimethylformamide, acetonitrile, acetone and N-methylpyrrolidinone. 33. A process according to Claim 32 wherein said polar solvent is acetonitrile. 34. A process according to Claim 19 wherein said temperature is about 60-85°C. 35. A process according to Claim 34 wherein said temperature is about the reflux temperature of acetonitrile. 36. A process according to Claim 31 wherein said strong alkylating agent or such agent as is capable of producing either an O-alkylimidate or imidate ester, imidoyl halide, or such imide derivative as is capable of cyclodehydration, is selected from a group consisting essentially of trifluoromethanesulfonic anhydride, dimediylsulfate, alkyloxonium tetrafluoroborates, aluminum chloride, O- benzyltrichloroacetimidate, triphenylphosine/carbon tetrachloride, or triphenylphosphine/carbon tetrabromide 37. A process according to Claim 32 wherein said agent is trimethyloxonium tetrafluoroborate. 38. A process for the preparation of a camptothecin analog which lacks the lactone E ring, said process comprising the steps of: (a) inttamolecular [4+2] cycloaddition of the N-arylimidate portion of a compound of Formula IV: IV where: X=OH, OAICI2, Cl, Br, I, F, OR, OSO2CF3 or any good leaving group or H R\ = H, OH, or OR, where R is an ester protecting group; R2 = H, NO2, or a protected amine function; R3 = H, C2H5, or a trialkylsilyl; R4 = H or CH2COOEt; R5 = COOMe or tosyl; or R4 and R5 are joined together to form a substimted pyridone IV: Y=H or Y,Rι= -OCH 2 0- IVa where: A = H, COOR, or a functionality for preparation of the hydroxymethyl (C-17) portion of an E ring lactone; B = H, OH, an appropriate leaving group such as halide or O(trifluoromethanesulfonate) or a functionality for preparation of C- (18-21) of the E ring lactone portion of camptothecin; with die unactivated acetylene portion of said compound to give a pyrrolo[3,4- b]quinoline substimted witii an acetate ester at C-2; (b) cyclizing the 2-substituted pyπolo[3,4-fc]quinoline to form a 7-hydroxy- 5,6-dihydroindolizmo[l,2-6]quinolin-9(llH)-one; (c) coupling a 7-trifluoromedιanesulfonate derivative of die 7-hydroxy-5,6- dihydroindolizino[l,2-b]quinolin-9(l lH)-one with a tertiary malonate anion to form a 5,6-dihydroindolizino[l,2-6]quinolin-9(llH)-one substimted at C-7 widi an (alkyl)malonate diester, (d) converting the 7-(l,l-bis-alkoxycarbonyl)propyl-8-methoxycarbonyl- 5,6-dihydroindolizino[l,2-b]quinolin-9(llH)-one into the lactone E ring of a 1H- pyrano[3',4':6,7]indolizino[l,2-d]quinolin-3,14(4H,12H)-dione, preferably a camptothecin analog; and (e) opening the E ring of said camptothecin analog widi extrusion of, depending upon choice of termination step, carbon dioxide to provide a camptothecin analog which lacks the lactone E ring, preferably a mappicine or mappicine ketone. 39. A process according to Claim 38 wherein said camptothecin analog which lacks the lactone E ring is an 8-methyl-7-(oxopropyl)-indoliz o[l,2-£]quinolin- 9(llH)-one. 40. A process according to Claim 39 wherein said 8-methyl-7-(oxopropyl)- indolizino[l,2-£]quinolin-9(llH)-one is a mappicine. 41. A process according to Claim 39 wherein said 8-methyl-7-(oxopropyl)- indolizino[l,2-d]quinolin-9(llH)-one is a mappicine ketone.

Inventors: FORTUNAK JOSEPH M, ZHUANG ZHIPING, FORTUNAK, JOSEPH, M., ZHUANG, ZHIPING
Applicants: FORTUNAK JOSEPH M, SMITHKLINE BEECHAM CORP, ZHUANG ZHIPING, SMITHKLINE BEECHAM CORPORATION
Application year: 1993
Main classification: C07D491
IPC codes: C07D471, C07D491