WO2003099825A1 - Synthesis of polycyclic quinolines - Google Patents

Abstract

A method of synthesizing a polycyclie quinoline comprising the step of a cascade annulation wherein the precursor is reacted with an aryl isonitrile having the formula in the presence of a transition metalwherein X is chlorine, bromine, iodine or triflate; wherein R1, R2, R3 and R4 are independently the same or different and are hydrogen, -OR wherein R is H, an alkyl group, an aryl goup or a hydroxy protecting group, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, an acyloxy group, an acylamino group, a nitro group, a cyano group, -OC(O)ORa, wherein Ra is an alkyl group or an aryl group, -NRbRC wherein Rb and Rc are independently the same or different, H, an alkyl group, an aryl group or an amino protecting group, -OC(O)NRbRC, -C(O)Rd wherein Rd is H, an alkyl group, an aryl group, an alkoxy group, or -NRbRC, -SR, wherein Re is an alkyl group or an aryl group, -OSiRe3, or R1 and R2 or R2 and R3 together form a chain of three or four members selected from the group of CH, CH2, O, S, NH, of NRf, wherein Rf is an C1-C6 alkyl group; wherein R5 is cyano, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, -C(O)Rd wherein Rd is H, an alkyl group, an aryl group, an alkoxy group, -NRb RC, or -Si(RgRhRi)..or -(Rj)Si(RgRhRi), wherein Rj is an alkylene group, an alkenylene group, or an alkynylene group; and R6, Rh and Ri are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, or an aryl group; wherein R6 is H, F, Cl, a C1-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a C1-3 alkoxy group; and wherein R7 and R8 are independently the same or different and are H, F, Cl, an alkyl group, an aryl group, a hydroxyalkyl group, a dialkylamino alkyl group, or wherein R7 and R8 together form a chain of four or five members selected from the groups -C(Rk)(OR1)(CH2)ZC(O)OCH2- wherein z is an integer between 0 and 1, wherein Rk is H, an alkyl group, an allyl group, a propargyl group or a benzyl group, Rl is H, -C(O)Rd wherein Rd is H, an alkyl group, an aryl group, an alkoxy group, -NRbRc or -Si(RmRnRo) wherein Rm, Rn and Ro are independently a C1-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, or an aryl group..

Description

TITLE

SYNTHESIS OF POLYCYCLIC QULNOLLNES

Cross-reference to Related Application

This application claims benefit of U.S. Provisional Patent Application Serial No. 60/382,292, filed May 22, 2002, the disclosure of which is incorporated herein by reference.

Government Interest

This invention was made with government support under grant RO1 GM33372 awarded by the National Institutes of Health. The government has certain rights in this invention.

Background of the Invention

The present invention relates to the synthesis of polycyclic quinolines, and, particularly, to the synthesis of mappicines, camptothecins and homocamptothecins.

References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.

Polycyclic quinolines have shown utility in drug therapy. For example. certain lH-pyrano[3',4':6,7]indolizino[l,2-b]quinolinones, such as camptothecins an- homocamptothecins (sometimes referred to generally herein as camptothecins or th. camptothecin family) have been shown to have anticancer and antiviral activity.

Indeed, a number of camptothecins are in use as anticancer agents.

It has been shown, that substituted indolizino[l,2-b]quinolinones (and, in particular, mappicines) that lack the αr-hydroxylactone moiety of camptothecin are non-cytotoxic to mammalian cells, while exhibiting antiviral activity. In that regard, such substituted indolizino[l,2-b]quinolinones have been proposed for treating DNA viruses. See, for example, U.S. Patent No. 5,833,255; Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.; Kingsbury, W. D. "Synthesis and Anti-Hsv Activity of A-Ring-Deleted Mappicine Ketone Analog" J Org. Chem. 1994, 59, 2623-2625; Pendrak, I.; Wittrock, R.; Kingsbury, W. D. "Synthesis and anti-HSN activity of methylenedioxy mappicine ketone analogs" J. Org. Chem. 1995, 60, 2912-2915.

The structures of camptothecin 1, mappicine 2 and homocamptothecin 20 are illustrated in Figure 1. hi general, the core structure of the camptothecin class of molecules has five fused rings, A-E. Standard substituents include hydroxyl and ethyl at C20, and other positions of the camptothecin ring core can also be substituted. Homocamptothecin has the same A-D rings as camptothecin, but the E-ring contains an additional methylene group (C20a). The A-B ring system of the camptothecin and homocamptothecin is a quinoline, and this part of the ring system is especially important since substituents in the quinoline part of the molecule often impart useful properties, as detailed below.

7-Silyl camptothecins la and 7-silyl homocamptothecins 21a (sometimes referred to as silatecans and homosilatecans, respectively) as illustrated in Figure 1 are important classes of lipophilic camptothecin analogs, See, for example, a) Josien, H.; Bom, D.; Curran, D. P.; Zheng, Y.-H.; Chou, T.-C. Bioorg. Med. Chem. Lett., 7, 3189 (1997); b) Pollack, I. F.; Erff, M.; Bom, D.; Burke, T. G.; Strode, J. T.; Curran, D. P. Cancer Research, 59, 4898 (1999); Bom, D.; Du, W.; Garbarda, A.; Curran, D. P.; Chavan, A. j.; Kruszewski, S.; Zimmer, S. G.; Fraley, K. A.; Bingcang, A. L.; Wallace, N. P.; Tromberg, B. L; Burke, T. G. Clinical Cancer Research, 5, 560 (1999); Bom, D.; Curran, D. P.; Chavan, A. j.; Kruszewski, S.; Zimmer, S. G.; Fraley, K. A.; Burke, T. G. J. Med. Chem., 42, 3018 (1999). Many of the most interesting silatecans and homosilatecans contain one or more additional substituents (for example, hydroxy or amino) in the A and/or B rings, and the combination of these substituents can provide significant improvements over either of the corresponding the mono-substituted analogs. For example, 7-tert-butyldimethylsilyl-lO-hydroxy camptothecin 3 (DB-67), is currently in late stages of preclinical development. DB-67 and other silatecans and homosilatecans show a number of attractive features including high activity against a broad spectrum of solid tumors, low binding to blood proteins, resistance to lactone opening, high lipophilicity, and potential oral availability among others.

Isonitriles, which are isoelectronic to carbon monoxide, are useful intermediates in organic synthesis as one-carbon units. Isonitriles have, for example, been used in radical chemistry as geminal radical acceptor/radical precursor synthons. Ryu, I; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. Upon addition of a radical to the carbon end of an isonitrile, an imidoyl radical can be generated and subjected to subsequent transformations, such as atom/group transfer reactions, radical addition reactions, α-scissions and β-scissions. The synthetic potential of the radical chemistry of isonitriles has been widely recognized, as shown by their application in synthesis of imidoyl tellurium compounds, imidoyl iodides, quinolines, indoles, and cyano compounds, including complex natural products.

Polycyclic quinolines such as, mappicines, camptothecins, homocamptothecins, silatecans and homosilatecans have been prepared by total synthesis by using the cascade radical annulation route with aryl isonitriles. See, for example, U.S. Patent Application No 09/209,019, U.S. Patent Nos. 6,211,371, 6,150,343 and 6,136,978, Curran, D. P.; Ko, S. B.; Josien, H. Angew. Chem., Int. Ed. Eng., 34, 2683 (1995) and Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem. Eur. J., 4, 67 (1998), the disclosures of which are incorporated herein by reference, hi general, the tandem radical cyclization is the key step in such syntheses. That step involves a radical annulation between an aryl isonitrile and a propargylated halopyridone under photolysis conditions in the presence of stocliiometric amounts of hexamethylditin. The synthetic route is highly flexible and allows the preparation of a diverse array of polycyclic quinolines by both traditional and parallel routes. However, despite the generality and mild reaction conditions, the above tandem radical cyclization reactions to prepare polycyclic quinolines have potential limitations, for example, when applied to large-scale synthesis. In that regard, the use of toxic and expensive reagents such as hexamethylditm can make large-scale reactions unattractive, both environmentally and economically. Moreover, although satisfactory yields are obtained in small scale reactions, lower yields can be obtained when the photolysis reaction is performed on large-scale reactions.

It is thus desirable to develop improved synthetic routes for producing polycyclic quinolines.

Summary of the Invention

Generally, the present invention provides synthetic routes to polycyclic quinolines.

In one aspect, the present invention provides a method of synthesizing a polycyclic quinoline compound. Such polycyclic quinoline compounds can be represented by the following general formula

The method of synthesizing polycyclic quinoline compounds of the present invention comprises the step of a cascade annulation wherein the precursor

is reacted with an aryl isonitrile having the formula

in the presence of a metal catalyst suitable to promote the reaction;

wherein X is chlorine, bromine, iodine or triflate;

wherein R¹, R², R³and R⁴ are independently the same or different and are hydrogen, -OR wherein R is H, an alkyl group, an aryl goup or a hydroxy protecting group, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, an acyloxy group, an acylamino group, a nitro group, a cyano group, -OC(O)OR^a, wherein R^a is an alkyl group or an aryl group, -NR R^c wherein R^b and R^c are independently the same or different, H, an alkyl group, an aryl group or an amino protecting group, -OC(O)NR^bR^c, -C(O)R^d wherein R^d is H, an alkyl group, an aryl group, an alkoxy group, or -NR^bR^c, -SR^e, wherein R^e is an alkyl group or an aryl group, -OSiR^e ₃, or R¹ and R² or R² and R³ together form a chain of three or four members selected from the group of CH, CH₂, O, S, NH, of NR^f, wherein R^f is an Cι-C₆ alkyl group;

R⁵ is cyano, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, -C(O)R^d wherein R^d is H, an alkyl group, an aryl group, an alkoxy group, -NR R^c , or -Si(R⁸R^hR^I) or -(R^Si^^R¹), wherein R^j is an alkylene group, an alkenylene group, or an alkynylene group; and R^g, R^h and R¹ are independently a Cl-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, or an aryl group.

R⁶ is H, F, CI, a Cl-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a Cl-3 alkoxy group; and

R and R are independently the same or different and are H, F, CI, an alkyl group, an aryl group, a hydroxyalkyl group, a dialkylamino alkyl group, or wherein R⁷ and R⁸ together form a chain of four or five members selected from the groups -C(R )(OR¹)(CH₂)_zC(O)OCH₂- wherein z is 0 or 1, wherein R^k is H, an alkyl group, an allyl group, a propargyl group or a benzyl group, R¹ is H, -C(O)R^d wherein R^d is H, an alkyl group, an aryl group, an alkoxy group, -NR R^c, or -Si(R^mRⁿR°) wherein R^m, Rⁿ and R° are independently a Cl-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, or an aryl group.

The reaction with the aryl isonitrile can take place in the presence of or in the absence of a ligand such as a phosphine ligand or an arsine ligand (for example, a triarylphosphine or a triarylarsine). The metal catalyst can, for example, be a transition metal such as a group 10 transition metal. In one embodiment, the transition metal is palladium.

9 9

In one embodiment, R is not H. For example, R can be an electron donating group.

Preferably, the reaction with the aryl isonitrile takes place in the presence of a base. Examples of suitable bases include, but are not limited to, Et₃N, K₂CO₃, NaOAc, Na₃PO₄, Ag₂CO₃, AgOAc, and/or Ag₃PO₄.

h the case of camptothecins and homocamptothecins, respectively, R and R⁸ together form a chain of four or five members selected from the groups -C(R^k)(OR¹)(CH₂)_zC(O)OCH₂-. In the case of silatecans and homosilatecans, R⁵ is -Si(R^gR^hRⁱ) or -(R^j)Si(R⁸R^hRⁱ). R^g, R^h and R¹ can, for example, be independently (the same or different) a Ci-6 alkyl group, a phenyl group or a -(CH₂)_NR⁹ group, wherein N is an integer within the range of 1 through 6 and R⁹ is a hydroxyl group, alkoxy group an amino group, an alkylamino group a dialkylamino group, a halogen atom, a cyano group or a nitro group. In several preferred embodiments, R^k is an ethyl group; R¹ is H, and/or z = 0 or 1.

A wide variety of silatecans can be synthesized in the method of the present invention including, but not limited to, 7-trimethylsilyl camptothecin, 7-trimethylsilyl-lO-acetoxy camptothecin, 7-trimethylsilyl- 10-hydroxy camptothecin, 7-trimethylsilyl- 11-fluoro camptothecin, 7-trimethylsilyl-9-fluoro camptothecin, 7-trimethylsilyl- 10-fluoro camptothecin, 7-trimethylsilyl- 10-amino camptothecin, 7-trimethylsilyl- 11 -amino camptothecin, 7-trimethylsilyl-ll, 12-diflouro camptothecin, 7-trimethylsilyl-9, 10-diflouro camptothecin, 7-trimethylsilyl- 10-amino- 11-fluoro camptothecin, 7-tert-butyldimethylsilyl camptothecin, 7-tert-butyldimethylsilyl- 10-acetoxy camptothecin, 7-tert-butyldimethylsilyl- 10-hydroxy camptothecin, 7-dimethyl-3-cyanopropylsilyl camptothecin, 7-dimethyl- 3-halopropylsilyl camptothecin, 7-triphenylsilyl camptothecin, 7-triethylsilyl camptothecin, 7-dimethylnorpinylsilyl camptothecin.

Likewise, a wide variety of homosilatecans can be synthesized in the method of the present invention including, but not limited to, 7-trimethylsilyl homocamptothecin, 7-trimethylsilyl- 10-acetoxy homocamptothecin, 7-trimethylsilyl- 10-hydroxy homocamptothecin, 7-trimethylsilyl- 11-fluoro homocamptothecin, 7-trimethylsilyl-9-fluoro homocamptothecin, 7-trimethylsilyl- 10-fluoro homocamptothecin, 7-trimethylsilyl- 10-amino homocamptothecin, 7-trimethylsilyl- 11 -amino homocamptothecin, 7-trimethylsilyl-ll, 12-diflouro homocamptothecin, 7-trimethylsilyl-9, 10-diflouro homocamptothecin, 7-trimethylsilyl- 10-amino- 11-fluoro homocamptothecin, 7-tert-butyldimethylsilyl homocamptothecin, 7-tert-butyldimethylsilyl- 10-acetoxy homocamptothecin, 7-tert-butyldimethylsilyl- 10-hydroxy homocamptothecin, 7-dimethyl-3-cyanopropylsilyl homocamptothecin, 7-dimethyl-3-halopropylsilyl homocamptothecin, 7-triphenylsilyl homocamptothecin, 7-triethylsilyl homocamptothecin, 7-dimethyhιorpinylsilyl homocamptothecin.

h the case of certain mappicines, R is an alkyl group (for example a methyl group), and R⁷ is a hydroxyalkyl group (for example, -CH(OH)R^p, wherein R^p is an alkyl group such as -CH₂CH ). hi the case of mappicine ketones, R⁸ is an acyl group (that is, -C(O)R^d, wherein R^d is as described above (for example, an alkyl group such as -CH₂CH₃)).

Compared to the prior radical method of polycyclic quinoline synthesis, the transition metal promoted synthetic method of the present invention is more environmentally friendly (avoiding toxic and expensive tin reagent required in the radical method) and more economic (providing easier "scale up" than possible in the radical method). The synthetic method of the present invention is thus more practical, especially for large-scale synthesis. Substituents on the polycyclic quinolines synthesized under the methods of the present invention (for example, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸) can be substantially any substituents as known in the art. Examples of suitable substituents include, but are not limited to, those identified for R¹, R², R , R , R , R , R⁷, and R⁸ above.

A number of groups, such as amino groups, alkylamino groups and hydroxy groups, can be protected using protective groups as known in the art before, for example, the isonitrile reaction. Preferred protective groups for hydroxy groups include, but are not limited to, acetate, benzyl and trimethylsilyl groups. Preferred protective groups for amino groups include, but are not limited to, tert- butyloxycarbonyl, formyl, acetyl, benzyl, »-methoxybenzyloxycarbonyl, trityl. Other suitable protecting groups as known to those skilled in the art are disclosed in Greene, T., Wuts, P.G.M., Protective Groups in Organic Synthesis, Wiley (1991), the disclosure of which is incorporated herein by reference. Such protective groups can be removed to provide the desired substituent (for example, hydroxy group or an amino group) after synthesis using conditions known in the art. general, protecting groups used in the methods of the present invention are preferably chosen such that they can be selectively removed without affecting the other substituents on the polycyclic quinolines. In general, 7-silyl substituents on mappicines and camptothecins (including homocamptothecins) have been found to very stable under a variety of conditions. Wherein a product compound synthesized in the method of the present invention includes a substituent group for which a protective group is preferably used during synthesis, the method of the present invention preferably also includes the step of removing or converting the protective group to synthesize the product compound. In that regard, 7-tert-butyldimethylsilyl- 10-phenylmethoxy- camptothecin is readily converted to 7-tert-butyldimethylsilyl- 10-hydroxy- camptothecin in one representative example.

In general, compounds of the present invention (including, for example, the α-hydroxylactone group of camptothecins and silatecans or the β-hydroxylactone group of homocamptothecins and homosilatecans) can exist in racemic form, enantiomerically enriched form, or enantiomerically pure form. The formulas of such compounds as set forth herein cover and/or include each such form.

The terms "alkyl", "aryl" and other groups refer generally to both unsubstituted and substituted groups unless specified to the contrary. Unless otherwise specified, alkyl groups are hydrocarbon groups and are preferably Cι -Cι 5

(that is, having 1 to 15 carbon atoms) alkyl groups, and more preferably Cι-Cχo alkyl groups, and can be branched or unbranched, acyclic or cyclic. The above definition of an alkyl group and other definitions apply also when the group is a substituent on another group (for example, an alkyl group as a substituent of an alkylamino group or a dialkylamino group). The term "aryl" refers to phenyl or naphthyl. As used herein, the terms "halogen" or "halo" refer preferably to fluoro and chloro.

The term "alkoxy" refers to -OR^p, wherein R^p is an alkyl group. The term "aryloxy" refers to -OR^q, wherein R^q is an aryl group. The term acyl refers to -C(O)R^d. The term "alkenyl" refers to a straight or branched chain hydrocarbon group with at least one double bond, preferably with 2-15 carbon atoms, and more preferably with 2-10 carbon atoms (for example, -CH=CHR^r or -CH₂CH=CHR^r). The term "alkynyl" refers to a straight or branched chain hydrocarbon group with at least one triple bond, preferably with 2-15 carbon atoms, and more preferably with 2-10 carbon atoms (for example, -C≡CR^S or -CH₂-C≡CR^S). The terms "alkylene," "alkenylene" and "alkynylene" refer to bivalent forms of alkyl, alkenyl and alkynyl groups, respectively.

The groups set forth above can be substituted with a wide variety of substituents to synthesize camptothecin, homocamptothecin and mappicine analogs. For example, alkyl groups and aryl groups may preferably be substituted with a group or groups including, but not limited to, a benzyl group, a phenyl group, an alkoxy group, a hydroxy group, an amino group (including, for example, free amino groups, alkylamino, dialkylamino groups and arylamino groups), an alkenyl group, an alkynyl group and an acyloxy group. In the case of amino groups (-NR'R"), R^l and R^u are preferably independently hydrogen, an acyl group, an alkyl group, or an aryl group. Acyl groups may preferably be substituted with (that is, R^d is) an alkyl group, a haloalkyl group (for example, a perfiuoroalkyl group), an aryl group, an alkoxy group, an amino group and a hydroxy group. Alkynyl groups and alkenyl groups may preferably be substituted with (that is, R^r and R^s are preferably) a group or groups including, but not limited to, an alkyl group, an alkoxyalkyl group, an amino alkyl group and a benzyl group.

The term "acyloxy" as used herein refers to the group -OC(O)R^p.

The term "alkoxycarbonyloxy" as used herein refers to the group -OC(O)OR^p.

The term "carbamoyloxy" as used herein refers to the group -OC(O)NR^bR^c.

The present invention, along with the attributes and attendant advantages thereof, will best be appreciated and understood in view of the following detailed description taken in conjunction with the accompanying drawings.

Brief Description of the Drawings

Figure 1 illustrates the chemical structure of mappicine, camptothecin, homocamptothecin and several 7-silyl camptothecins and 7-silyl homocamptothecins.

Figure 2 illustrates a general reaction sequence for synthesis of polycyclic quinolines of the present invention.

Figure 3 illustrates synthesis of two drug candidates using the synthetic method of the present invention.

Detailed Description of the Invention

The general synthetic scheme for synthesis of polycyclic quinolines of the present invention is set forth in Figure 2. hi general, a precursor compound 16 (a halopyridone such as an iodopyridone) is reacted with an aryl isonitrile 17 in the presence of a metal catalyst such as a Group 10 transition metal (typically, in the form a compound, complex or a salt of the metal) to synthesize a polycyclic quinoline of the general formula 18 (wherein, ^R⁸ are, for example, as described above). hi addition to their use in radical chemistry described above, isonitriles are known for their insertion reactions, namely, insertion into a metal-carbon bond or a metal-heteroatom bond to form a new metal-imidoyl bond. Insertion of an isonitrile to a transition metal-carbon bond is particularly interesting for it provides a new C-C bond and a reactive transition metal intermediate which can undergo a broad range of reactions. Although the insertion reactions of isonitriles provide a chemistry equally rich to their counterpart radical reactions, their application to organic synthesis is limited. For example, isonitrile insertion to Sm-C, Ti-C, Ni-C, Pd-C bonds have been used to synthesize imine compounds that upon hydrolysis, gave carbonyl compounds. See, for example, Murakami, M.; Kawano, T. Ito, H.; Ito, Y. J. Org. Chem. 1993, 58, 1458; Murakami, M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. J. Org. Chem. 1991, 56, 1; Murakami, M.; Kawano, T.; Ito, Y. J. Am. Chem. Soc. 1990. 112, 2437; Berk, S. C; Grossman, R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 4912; Tamao, K.; Kobayashi, K.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 1286; Otsuka, S.; Nakamura, A.; Yashida, T. J. Am. Chem. Soc. 1969, 7196; Ohe, K.; Matsuda, H.; Ishihara, T.; Ogoshi, S.; Chatani, N. Murai, S. J. Org. Chem. 1993, 58, 1173; and Ishiyama, T.; Oh-e, T.; Miyaura, N.; Suzuki, A.; Tetrahedron Lett. 1992, 33, 4465. h each of the those cases, isonitriles were used merely as a synthetic equivalent for carbon monoxide.

Unlike carbon monoxide, however, an isonitrile can have a wide variety of substituents on its nitrogen end. Many of these substituents can be good substrates for transition metal catalyzed processes. This provides a good opportunity for new transition metal catalyzed cascade reactions that are not possible for carbon monoxide, for example, synthesis of nitrogen-containing heterocycles. Notwithstanding the current rapid development of transition metal chemistry, however, the synthetic potential of transition metal catalyzed isonitrile chemistry is largely ignored. There are only limited examples of synthesis of nitrogen containing heterocycles by transition metal catalyzed processes using isonitriles. For synthesis of indole from 2,6-dimethylphenyl isonitrile, see: Jones, W. D.; Kosar, W. P. J. Am. Chem. Soc. 1986, 108, 5640; and for synthesis of poly(2,3-quinoxaline), see: Ito, Y.; Ihara, E.; Murakami, M. J. Am. Chem. Soc. 1990, 112, 6446. As described above, there has long been interest in synthesis of polycyclic quinolines, and, in particular, camptothecins (including generally camptothecins, silatecans, homocamptothecins and homosilatecans) and mappicines via a radical annulation reaction using an aryl isonitrile reactant. The present inventors have discovered that polycyclic quinolines can be synthesized via a transition metal promoted cascade reaction which substantially overcomes the environmental and economical limitations of the radical annulation reaction.

Although a variety of transition metal-carbon bonds can be subject to isonitrile insertion in the present invention, the representative studies set forth herein focused on palladium (Pd) as a model catalyst. In general, Pd is known to catalyze a broad range of reactions. The studies of the present invention have shown that the synthetic method of the present invention has broad application in synthesis of polycyclic quinolines, including, for example, DB-67 (3), and other anticancer drug candidates of the camptothecin family.

It was envisioned that the substrates in isonitrile insertion and subsequent cascade transformations can be used in a transition metal catalyzed process. Increased electron density on isonitrile carbon terminus was postulated to be beneficial for coordination of an isonitrile to a transition metal such as palladium and its subsequent insertion reaction. In general, the electron density on an aryl isonitrile C-terminus can be influenced by the substituents in the phenyl ring para to isonitrile. See, Kim, M.; Euler, W. B.; Rosen, W. J. Org. Chem. 1997, 62, 3766. Thus we chose, _/p-methoxyphenyl isonitrile 4a which has a strong electron donating group, and iodopyridone 5a for model reactions as set forth in equation 1 below. Product (6a) from the model reaction contains an aromatic core that is very similar to that of drug candidate DB-67 (3).

Pd catalyst

conditions 4a 5a 6a (1)

We treated substrates 4a and 5a with 10% Pd(OAc)₂, 20% Ph₃P and Et N in MeCN at 80 °C. The reaction gave the desired product, by TLC comparison with authentic sample, but in low yields. A number of reaction conditions were subsequently studied, including different Pd catalysts, different ligands, different solvents, different temperatures, and different bases. A number of studies of various reaction conditions are summarized in Table 1 below.

Table 1

a: one equivalent of isonitrile was used when not specified; b: yields are determined by NMR when not specified; c: isolated yield.

In general, we found addition of phosphine ligand was not required for the reaction to proceed, hi that regard, product 6a was obtained when the substrates were treated with Pd catalyst and base alone. Isonitriles are known for their ability to act as a ligand in oranometallic chemistry. Thus, isonitrile 4a is believed to function as both ligand and reactant in the reactions of the present invention. Of the solvents tested, toluene was found to provide the best results.

Preferably, the reaction temperature is in the range of approximately 0°C to approximately 100°C. More preferably, the reaction temperature is in the range of approximately 10°C to approximately 50°C. Most preferably, the reaction temperature is approximately ambient or room temperature (for example, in the range of approximately 20°C to approximately 25°C.

Preferably, the reaction proceeds in the presence of a base. We found that the choice of base can play a role in the reaction of the present invention. A number of bases were tested. Preferred bases include, but are not limited to, Et₃N,

K₂CO₃, NaOAc, Na₃PO₄, and others. Of the bases tested, Ag₂CO₃ provided the best results.

The reaction did not proceed to completion under various conditions without recycle, h that regard, desired product 6a and unreacted 5a were obtained in different ratios under such conditions. The best results were obtained when 5a was mixed with 1.5 equiv of Ag₂CO , and 20% Pd(OAc)₂ in toluene, with 2 equiv of isonitrile 4a subsequently added slowly at room temperature. After stirring for 20 h, the reaction gave a mixture of product 6a and starting 5a in 3:1 ratio. Attempts to push the reaction to completion were generally unsuccessful. Although excess isonitrile was used, free isonitrile was not observed in NMR spectrum of crude product mixture, which was obtained after removing insoluble materials. Moreover, addition of additional isonitrile or Pd catalyst alone did not push the reaction to completion.

The reaction was completed, however, by recycling the unreacted starting iodopyridone 5a. In that regard, after filtration to remove insoluble precipitate, the crude reaction mixture was re-subjected to the same reaction conditions with reduced Pd catalyst loading (10%) and other reagents. After stirring for another 20 h, the reaction gave the desired polycyclic quinoline 6a in 83% isolated yield. The product obtained by this Pd reaction was identical to authentic sample prepared under photolysis conditions as described above.

The preferred reaction conditions set forth above were subsequently applied to various substrates, and the results of these studies are set forth in Table 2. The substituents on the phenyl ring of the aryl isonitrile influenced the reactivity of the isonitrile. In general, isonitriles with electron donating groups were found to gave better yields under the above reaction conditions. Various para-alkoxy and amino isonitriles gave excellent to moderate yields, while weak electron donating substituents, such as a methyl group (entry 6), gave lower yields (41%>) and unreacted starting material (40%). Phenylisonitrile and isonitriles with electron withdrawing groups gave lower yields.

The reaction showed good regioselectivity. For example, when 3,4- dimethoxyphenyl isonitrile was used, the reaction gave 6d as the only product.

Because of interest in silatecan (7-silylcamptothecins) as anticancer agents, we tested various silyl and alkyl substituents in substrate 5 and satisfactory results were obtained.

We tested using different halopyridones as substrate and found propargylated chloropyridone and bromopyridone to be less reactive than propargylated iodopyridones. After model reactions, the synthetic method of the present invention was applied to camptothecin and mappicine analogs. For example, isonitrile 4a was reacted with iodopyridone 5e to give camptothecin analog 6h in 53% yield, and isonitrile 4b reacted with iodopyridone 5f to give mappicine analog 6i in 62% yield.

Table 2. Polycyclic quinolines prepared by Pd promoted cascade reaction.

entry isonitriles iodopyridone Polycyclic quinoline yield

6f

6i this yield was determined by NMR, 40% unreacted starting 5 a remained.

In the absence of isonitrile 4a₃ iodopyridone 5a was stirred with 20%> Pd(OAc) and 1.5 equiv of Ag₂CO₃ in toluene at room temperature for 24 h. No reaction was observed and unreacted 5a was recovered. To make a comparison with photolysis conditions, 5a was mixed with stochiometric amount of hexamethylditm in toluene and was irradiated with UN light at room temperature. In the absence of isonitrile 4a, iodopyridone 5a was consumed under photolysis conditions to give a mixture of unidentified products. The above results indicate that the presence of a proper isonitrile is important to initiate the reaction.

As discussed above, drug candidates DB-67 (3) and its homo analog DB-91 (14) are of particular interest as anticancer agents. Bom, D.; Curran, D. P.; Chavan, A. J.; Kruszewski, S.; Zimmer, S. G.; Fraley, K. A.; Burke, T. G. J. Med. Chem. 1999, 42, 3018. Thus, isonitrile 4b reacted with iodopyridone 5e and 11 to give 12 and 13 in 70%o and 82% yield respectively. Compound 11 was prepared by propargylation of compound 15 set forth below.

15

Treatment of 12 and 13 with TFA and thioanisole removed benzyl ether protective group to give the desired product 3 and 14 in 75% and 61% yield. Compounds 3 and 14 were identical to authentic sample prepared before.

EXAMPLES

Experimental procedure, analytical data and NMR spectra for polycyclic quinolines reported in this paper.

General: Toluene, THF were freshly distilled from Na/benzophenone. Reagents were used as they were received from Aldrich. Isonitriles 4 were prepared according to reported procedure. Iodopyridone 5a-5d were prepared according to reported procedure. Iodopyridone 5e was prepared by known procedure. Compound 11 was prepared by propargylation of compound 15 whose synthesis will be reported later. H and ¹³C spectra were taken on an IBM model AF-300 (300 Hz) or an IBM Model AM- 500 (500 MHz) NMR spectrometer. Chemical shifts are reported in ppm. CDC1₃ was used as NMR solvent unless otherwise noted. In reporting spectral data, the following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplex-, dd = doublet. Coupling constants are reported in Hertz (Hz). Infrared spectra were taken on a Mattson genesis Series FTIR using thin film deposition on NaCl plate unless otherwise noted. Peaks were reported in wavenumbers (cm^" ). High resolution mass spectra were obtained on a VG 70/70 double focusing machine and were reported in units of m/e.

Example 1: General procedure for Pd promoted synthesis of polycyclic quinoline:

Iodopyridone 5 (0.027 mmol), Ag₂CO₃ (0.04 mmol, 1.5 eqiv) and Pd(OAc)₂ (0.005 mmol, 20%) were suspended in 0.5 mL of toluene. Then to this suspension was slowly added a solution of isonitrile 4 (0.05 mmol, 2 equiv) in toluene (1 mL) in 0.5 h. This reaction mixture was stirred at room temperature for 20 h and then filtered though celite. Solvent was removed, and the residue was mixed with Pd(OAc)₂ (0.0025 mmol, 10%o) and Ag₂CO₃ (0.02 mmol, 0.7 equiv) in 0.5 mL of toluene. Then a solution of isonitrile 4 (0.025 mmol, 1 equiv) in 0.5 mL of toluene was added. The mixture was stirred at room temperature for another 20 h. TLC showed that 5 disappeared. The reaction mixture was then filtered though celite, the filtrate was concentrated to give a crude product. Purification by chromatography on silica gel gave product 6 as yellow solid in 40-90%_> yield. Example 2 : 12-(tβrt-Butyl-dimethyl-silanyl)-2-methoxy-l lH-indolizino [1 ,2- b]quinolin-9-one (6a)

Using the general procedure, the title compound was prepared in 82%> yield as yellow solid: IR 2933, 2861, 1671, 1599, 1537, 1507, 1326, 1244, 1208, 1167, 1033,

847, 832, 801; 1H NMR (300 MHz, CDC1₃) δ 0.72 (s, 6H), 1.02 (s, 9H), 3.98 (s, 3H),

5.29 (s, 2H), 6.70 (d, J= 9.2 Hz, IH), 7.24 (d, J= 7.0 Hz, IH), 7.43 (dd, J= 9.2, 2.6

Hz, IH), 7.54 (d, J= 2.6 Hz, IH), 7.67 (dd, J= 9.2, 7.0 Hz, IH), 8.15 (d, J= 9.2 Hz,

IH); ¹³C NMR (CDC1₃, 75 MHz) δ -0.7, 19.6, 27.2, 52.3, 55.5, 100.0, 108.1, 119.5, 122.3, 131.7, 134.0, 136.7, 140.5, 143.8, 146.3, 149.0, 157.8, 161.4; HRMS (El) m/z calcd for C₂₂H₂₆N₂O₂Si 378.1764, found 378.1772, LRMS (El) m/z 378 (M⁺), 321, 307, 278.

Example 3: 2-Methoxy-12-(triethyl-silanyl)-llH-indolizino[l,2-b]quinolin-9-one (6b)

Using the general procedure, the title compound was prepared in 66%> yield as yellow solid: IR 2945, 1665, 1598, 1535, 1244, 1213, 1124, 1031, 844, 807, 734; 1H NMR (300 MHz, CDC1₃) δ 1.01 (t, J= 7.6 Hz, 9 H), 1.19 (q, J= 7.6 Hz, 6H), 3.99 (s, 3H), 5.29 (s, 2H), 6.70 (d, J= 8.7 Hz, IH), 7.24 (d, J= 7.0 Hz, IH), 7.45 (dd, J= 9.2, 1.9 Hz, IH), 7.54 (s, IH), 7.67 (t, J= 8.0 Hz, IH), 8.12 (d, J= 9.2 Hz, IH); ¹³C NMR (CDC1₃, 125 MHz) δ 4.9, 7.7, 52.1, 55.7, 100.0, 106.6, 119.6, 122.1, 132.2, 133.9, 136.7, 139.8, 140.6, 143.9, 146.6, 149.4, 158.2, 161.6; HRMS (El) m/z calcd for C₂₂H₂₆N₂O₂Si 378.1764, found 378.1762; LRMS (El) m/z 378 (M⁺), 351, 321, 293, 275, 231, 215, 149. Example 4: 2-Benzyloxy-12-(tert-Butyl-dimethyl-silanyl)-llH-indolizino[l-2- b]quinolin-9-one (6c)

Using the general procedure, the title compound was prepared in 92% yield as yellow solid: IR 2934, 2861, 1667, 1600, 1538, 1504, 1465, 1325, 1241, 1202, 1137, 1028, 837, 809, 736, 703; 1H NMR (300 MHz, CDC1₃) δ 0.64 (s, 6H), 0.95 (s, 9H), 5.23 (s, 2H), 5.27 (s, 2H), 6.69 (d, J= 9.4 Hz, IH), 7.24 (d, J= 7.2 Hz, IH), 7.3-7.6 (m, 7H), 7.67 (dd, J- 9.1, 7.0 Hz, IH), 8.12 (d, J= 9.0 Hz, IH); ¹³C NMR (CDC1₃, 75 MHz) δ -0.79, 19.4, 27.2, 52.4, 70.3, 99.9, 109.3, 119.5, 122.6, 127.2, 128.3, 128.8, 131.9, 134.0, 136.1, 136.7, 140.4, 144.1, 146.4, 149.3, 157.1, 161.4; HRMS (El) m/z calcd for C₂₈H₃₀N₂O₂Si 454.2077, found 454.2088; LRMS (El) m/z 454 (M⁺), 397, 363, 307, 277, 91.

Example 5 : 12-(tert-Butyl-dimethyl-silanyl)-2,3-dimethoxy-l lH-indolizino [1 ,2- b]quinolin-9-one (6d)

Using the general procedure, the title compound was prepared in 83% yield as yellow solid: IR 2957, 2930, 2860, 1667, 1598, 1507, 1475, 1432, 1330, 1250, 1164, 1014, 907, 849, 730; 1H NMR (300 MHz, CDC1₃) δ 0.71 (s, 6H), 1.01 (s, 9H), 4.05 (s, 3H), 4.08 (s, 3H), 5.26 (s, 2H), 6.69 (d, J- 9.2 Hz, IH), 7.22 (d, J- 6.7 Hz, IH), 7.51 (s, 2H), 7.66 (dd, J= 8.9, 7.1 Hz, IH), 8.12 (d, J= 9.0 Hz, IH); ¹³C NMR (CDC1₃, 75 MHz) δ -0.78, 19.6, 27.15, 27.23. 52.4, 56.0, 56.2, 99.7, 107.8, 108.3, 119.3, 129.0, 134.7, 140.4, 145.3, 146.5, 149.0, 149.7, 152.2, 161.4; HRMS (El) m/z calcd for C₂₃H₂₈N₂O₃Si 408.1869, found 408.1870; LRMS (El) m/z 408 (M⁺), 351, 335, 307, 149, 84.

Example 6: 2-Dimethylamino-12-(trimethyl-silanyl)-llH-indolizino[l,2- b]quinolin-9-one (6e)

Using the general procedure, the title compound was prepared in 67% yield as yellow solid: IR 1661, 1588, 1540, 1340, 1250, 1171, 821, 797; 1H NMR (300 MHz, CDC1₃) δ 0.63 (s, 9H), 3.15 (s, 6H), 5.24 (s, 2H), 6.64 (d, J = 8.9 Hz, IH), 7.15 (s, IH), 7.16 (d, J= 6 Hz, IH), 7.40 (dd, J= 9.3, 2.2 Hz, IH), 7.63 (dd, J= 8.6, 7.9 Hz, IH), 8.03 (d, J = 9.3 Hz, IH); ¹³C NMR (CDC1₃, 75 MHz) δ 1.2, 40.6, 51.8, 99.2, 106.1, 118.7, 119.0, 131.3, 133.6, 135.3, 139.2, 140.4, 141.6, 146.9, 147.3, 148.5, 161.6; HRMS (El) m/z calcd for C₂₀H₂₃N₃OSi 349.1610, found 349.1605; LRMS (El) m/z 349 (M⁺), 334, 305, 290.

Example 7: 7-tert-Butyldimethylsilyl-10-methoxy-camptothecin (6h)

Using the general procedure, the title compound was prepared in 53% yield as yellow solid: IR 3309, 2928, 2862, 1752, 1664, 1603, 1559, 1509, 1465, 1239, 1162, 1051, 845, 836; 1H NMR (300 MHz, CDC1₃) δ 0.72 (s, 6H), 1.02 (s, 9H), 1.05 (t, j = 7.4 Hz, 3H), 1.90 (m, 2H), 3.98 (s, 3H), 5.29 (s, 2H), 5.31 (d, J = 16.2 Hz, IH), 5.76 (d, j = 16.2 Hz, IH), 7.45 (dd, J = 9.3, 2.7 Hz, IH), 7.53 (d, j = 2.6 Hz, IH), 7.61 (s,

IH), 8.12 (d, J = 9.3 Hz, IH); ¹³C NMR (CDC1₃, 125 MHz) δ -0.66, 7.9, 19.7, 27.3, 31.7, 52.5, 55.7, 66.5, 72.9, 97.0, 108.2, 117.6, 122.5, 132.1, 134.3, 136.7, 140.6, 144.3, 146.9, 148.7, 150.3, 157.6, 158.2, 174.2; HRMS (El) m/z calcd for C₂₇H₃₂N₂O₅Si 492.2081, found 492.2073; LRMS (El) m/z 492 ( *), 448, 435, 391, 323, 261, 211, 165.

Example 8 : 2-Benzyloxy-l 2-(tert-butyl-dimethyl-silanyl)-7-(l-hydroxy-2,2- dimethyl-propyl)-8-methyl-l lH-indolizino [1 ,2-b] quinolin-9-one (6i)

Using the general procedure, the title compound was prepared in 62%o yield as yellow solid: IR 3351, 2955, 2865, 1656, 1627, 1582, 1509, 1463, 1294, 1226, 1017, 836,

808, 734; 1H NMR (300 MHz, CDC1₃) δ 0.70 (s, 3H), 0.75 (s, 3H), 0.87 (s, 9H), 1.00 (s, 9H), 2.13 (s, 3H), 4.23 (br s, IH), 4.71 (s, IH), 5.00 (d, J = 18.8 Hz, IH), 5.08 (s, 2H), 5.29 (d, J = 18.9 Hz, IH), 7.22-7.44 (m, 8 H), 7.72 (d, J = 8.9 Hz, IH); ¹³C NMR (CDC1₃, 125 MHz) δ -0.87, -0.25, 14.1, 19.5, 26.4, 27.1, 36.9, 52.4, 70.2, 76.1, 100.6, 108.6, 121.7, 126.0, 127.4, 128.3, 128.8, 131.4, 133.3, 136.2, 136.5, 139.7, 141.1, 143.3, 148.9, 152.7, 156.5, 161.2; HRMS (El) m/z calcd for C₃₄H₄₂N₂O₅Si 554.2965, found 554.2980; LRMS (El) m/z 554 (M÷), 536, 498, 463, 407, 350, 293, 91.

Example 9: 7-tert-Butyldimethylsilyl-10-phenylmethoxy-camptothecin (12)

Using the general procedure, the title compound was prepared in 70% yield.

IR 3395, 2931, 2863, 1751, 1662, 1604, 1509, 1461, 1235, 1161, 1050, 834; 1H NMR

(300 MHz, CDC1₃) δ 0.64 (s, 6H), 0.95 (s, 9H), 1.05 (t, J = 7.4 Hz, 3H), 1.90 (m, 2H), 5.24 (s, 2H), 5.28 (s, 2H), 5.31 (d, J = 16.2 Hz, IH), 5.76 (d, J = 16.2 Hz, IH), 7.35- 7.56 (m, 7H), 7.61 (s, IH), 8.14 (d, J = 10.0 Hz, IH); ¹³C NMR (CDC1₃) δ -0.82, 7.8, 19.5, 27.1, 31.6, 52.5, 66.4, 70.3, 72.8, 97.1, 109.2, 117.6, 123.0, 127.2, 128.3, 128.8, 132.0, 134.2, 136.0, 136.6, 140.8, 144.2, 146.7, 148.6, 150.2, 157.4, 157.5, 174.1; HRMS (El) m/z calcd for C₂₆H₃₀N₂O₅Si, found; LRMS (El) m/z 478 (W?), 434, 421, 393, 377, 347, 320, 291.

Example 10: 7-tert-Butyldimethylsilyl-10-hydroxy-camptothecin (3, DB-67)

Compound 12 (11 mg, 0.02 mmol) was dissolved in a mixture of TFA (1 mL) and thioanisole (0.1 mL). The reaction was heated at 55 °C for 10 h, then was diluted with EtOAc and washed with saturated NaHCO₃ and brine. The ester layer was collected and solvent was removed under reduced pressure. The crude product was purified by flash chromatography (10% acetone in dichloromethane) to give the title compound (6.8 mg) as yellow solid in 75% yield: IR 3373, 2931, 2862, 1751, 1656, 1592, 1557, 1508, 1463, 1235, 1155, 1051, 833; 1H NMR (300 MHz, CDC1₃ with a small amount of CD₃OD) δ 0.67 (s, 6H), 0.97 (s, 9H), 1.02 (t, J = 7.4 Hz, 3H), 1.88 (m, 2H), 5.25 (s, 2H), 5.28 (d, J = 16.2 Hz, IH), 5.71 (d, J = 16.2 Hz, IH), 7.38 (dd, J = 9.1, 2.1 Hz, IH), 7.55 (d, J = 2.5 Hz, IH), 7.61 (s, IH), 8.05 (d, J = 9.1 Hz, IH); ¹³C NMR (CDC1₃ with a small amount of CD₃OD, 125 MHz) δ -0.83, 7.8, 19.2, 27.1, 31.5, 52.6, 66.2, 72.9, 97.3, 111.4, 117.5, 122.3, 131.7, 134.6, 136.4, 140.5, 143.2, 146.7, 147.8, 150.8, 156.0, 157.7, 174.0; HRMS (El) m/z calcd for C₂₆H₃₀N₂O₅Si 478.1924, found 478.1924; LRMS (El) m/z 478 (M⁺), 434, 421, 393, 377, 347, 320, 291. Example 11 : 7-tert-Butyldimethylsilyl-l O-phenylmethoxy-homocamptothecin (13)

Using the general procedure, the title compound was prepared as yellow solid in 82% yield.

IR 3322, 2931, 2859, 1753, 1655, 1583, 1506, 1270, 1223, 1064, 833; 1H NMR (300 MHz, CDC1₃) δ 0.71 (s, 6H), 0.95 (m, 12H), 2.02 (m, 2H), 3.34 (d, J = 13.6 Hz, IH), 3.40 (d, J = 13.6 Hz, IH), 4.42 (s, IH), 5.04 (d, J - 19.0 Hz, IH), 5.18 (s, 2H), 5.37 (d, J = 15.8 Hz, IH), 5.44 (d, J = 19.0 Hz, IH), 5.65 (d, J = 15.8 Hz, IH), 7.24-7.56 (m, 9H); ¹³C NMR (CDC1₃) δ -0.96, -0.51, 8.1, 19.6, 27.1, 35.4, 42.6, 52.9, 62.2, 70.3, 73.6, 99.6, 108.8, 121.9, 122.1, 127.2, 128.3, 128.8, 131.4, 133.8, 136.0, 136.2, 140.4, 143.5, 145.2, 147.7, 156.6, 157.0, 159.8, 171.3; HRMS (El) m/z calcd for C₃₄H₃₈N₂O₅Si 582.2550, found 582.2575; LRMS (El) m/z 582 (M⁺), 564, 525, 483, 435, 375.

Example 12: 7-tert-Butyldimethylsilyl-10-hydroxy-homocamptothecin (14, DB- 91)

Using the procedure similar to compound 3, the title compound was prepared in 61 > yield: IR 3312, 2931, 2859, 1745, 1651, 1585, 1469, 1259, 1226, 1060, 834; 1H NMR (300 MHz, CDC1₃ with a small amount of CD₃OD) δ 0.64 (s, 3H), 0.66 (s, 3H), 0.95 (m, 12H), 1.97 (m, 2H), 3.21 (d, J = 13.6 Hz, IH), 3.38 (d, J = 13.6 Hz, IH), 5.09 (d, J = 19.0 Hz, IH), 5.22 (d, J = 19.0 Hz, IH), 5.36 (d, J - 15.3 Hz, IH), 5.61 (J = 15.3 Hz, IH), 7.25 (dd, J = 9.0, 2.3 Hz, IH), 7.40 9s, 1H0, 7.46 (d, J = 2.0 Hz, IH), 7.75 (d, J = 9.1 Hz, IH); ¹³C NMR (CDC1₃ with a small amount of CD₃OD, 125 MHz) δ - 0.95, -0.69, 8.2, 19.3, 27.2, 36.1, 42.5, 52.9, 62.3, 73.7, 100.0, 111.4, 121.7, 122.0, 131.1, 134.5, 136.3, 140.7, 142.7, 145.7, 147.4, 155.9, 156.8, 159.9, 172.5; HRMS (El) m/z calcd for C₂₇H₃₂N₂O₅Si 492.2081, found 492.2087; LRMS (El) m/z 492 (1st), 474, 445, 432, 417, 389, 375, 207, 91.

Although the present invention has been described in detail in connection with the above examples, it is to be understood that such detail is solely for that purpose and that variations can be made by those skilled in the art without departing from the spirit of the invention except as it may be limited by the following claims.

Claims

What is claimed is:

1. A method of synthesizing a polycyclic quinoline comprising the step of a cascade annulation wherein the precursor

is reacted with an aryl isonitrile having the formula

in the presence of a metal catalyst;

wherein X is chlorine, bromine, iodine or triflate;

wherein R¹, R², R³and R⁴ are independently the same or different and are hydrogen, -OR wherein R is H, an alkyl group, an aryl goup or a hydroxy protecting group, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, an acyloxy group, an acylamino group, a nitro group, a cyano group, -OC(O)OR , wherein R is an alkyl group or an aryl group, -NR R^c wherein R and R^c are independently the same or different, H, an alkyl group, an aryl group or an amino protecting group, -OC(O)NR R^c _! -C(O)R^d wherein R^d is H, an alkyl group, an aryl group, an alkoxy group, or -NR^bR^c, -SR^e, wherein R^e is an alkyl group or an aryl group, -OSiR^e ₃, or R¹ and R² or R² and R³ together form a chain of three or four members selected from the group of CH, CH , O, S, NH, of NR^f, wherein R^f is an Cι-C₆ alkyl group;

R⁵ is cyano, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, -C(O)R^d wherein R^d is H, an alkyl group, an aryl group, an alkoxy group, -NR^bR^c , or -Si(R^gR^hR¹) or -(R^SiCR^R¹), wherein " is an alkylene group, an alkenylene group, or an alkynylene group; and R^g, R^h and R¹ are independently a Cl-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, or an aryl group. R⁶ is H, F, CI, a Cl-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a Cl-3 alkoxy group; and

R⁷ and R⁸ are independently the same or different and are H, F, CI, an alkyl group, an

7 o aryl group, a hydroxyalkyl group, a dialkylamino alkyl group, or wherein R and R together form a chain of four or five members selected from the groups -C(R^k)(OR¹)(CH₂)_zC(O)OCH₂- wherein z is an integer between 0 and 1, wherein R^k is H, an alkyl group, an allyl group, a propargyl group or a benzyl group, R¹ is H, -C(O)R^d wherein R^d is H, an alkyl group, an aryl group, an alkoxy group, -NR^bR^c, or -Si(R^mRⁿR°) wherein R^m, Rⁿ and R° are independently a Cl-10 alkyl group, a C2-10 alkenyl group, a C2-10 alkynyl group, or an aryl group.

2. The method of Claim 1 wherein the reaction with the aryl isonitrile takes place in the presence of a phosphine ligand or an arsine ligand.

3. The method of Claim 1 wherein the metal catalyst is a group 10 transition metal.

4. The method of Claim 1 wherein the transition metal is palladium.

5. The method of Claim 1 wherein R² is not H.

The method of Claim 5 wherein R is an electron donating group.

7. The method of Claim 2 wherein the reaction with the aryl isonitrile takes place in the presence of a triarylphosphine or a triarylarsine.

8. The method of Claim 1 wherein the reaction with the aryl isonitrile takes place in the presence of a base.

9. The method of Claim 4 wherein the base is Et₃N, K₂CO , NaOAc, Na₃PO₄, Ag₂CO₃, AgOAc, or Ag₃PO₄.

10. The method of Claim 1 wherein R⁴ is H, F, a Cl-3 alkyl group, a C2-3 alkenyl group, a C2-3 alkynyl group, a trialkylsilyl group or a Cl-3 alkoxy group.

11. The method of Claim 10 wherein R⁴ is H.

7 R

12. The method of Claim 1 wherein R and R together form a chain of four or five members selected from the groups - C(R^k)(OR¹)(CH₂)_zC(O)OCH₂-.

13. The method of Claim 12 wherein R⁵ is -Si^^R¹) or -(R^j)Si(R^gR^hRⁱ).

14. The method of Claim 12, wherein R⁴ is H.

15. The method of Claim 13, wherein R^g, R^h and R¹ are independently the same or different and are a C\-β alkyl group, a phenyl group or a -(CH₂)_NR⁹ group, wherein N is an integer within the range of 1 through 6 and R⁹ is a hydroxyl group, alkoxy group an amino group, an alkylamino group a dialkylamino group, a halogen atom, a cyano group or a nitro group.

16. The method of Claim 13, wherein the compound synthesized is 7-trimethylsilyl camptothecin, 7-trimethylsilyl- 10-acetoxy camptothecin, 7-trimethylsilyl- 10-hydroxy camptothecin, 7-trimethylsilyl- 11-fluoro camptothecin, 7-trimethylsilyl-9-fluoro camptothecin, 7-trimethylsilyl- 10-fluoro camptothecin, 7-trimethylsilyl- 10-amino camptothecin, 7-trimethylsilyl- 11 -amino camptothecin, 7-trimethylsilyl-ll, 12-diflouro camptothecin, 7-trimethylsilyl-9, 10-diflouro camptothecin, 7-trimethylsilyl- 10-amino- 11-fluoro camptothecin, 7-tert-butyldimethylsilyl camptothecin, 7-tert-butyldimethylsilyl- 10-acetoxy camptothecin, 7-tert-butyldimethylsilyl- 10-hydroxy camptothecin, 7-dimethyl- 3-cyanopropylsilyl camptothecin, 7-dimethyl-3-halopropylsilyl camptothecin, 7-triphenylsilyl camptothecin, 7-triethylsilyl camptothecin, 7-dimethylnorpinylsilyl camptothecin.

17. The method of Claim 13, wherein the compound synthesized is 7-tert-butyldimethylsilyl- 10-hydroxy camptothecin.

18. The method of Claim 13, wherein the compound synthesized is 7-trimethylsilyl homocamptothecin, 7-trimethylsilyl- 10-acetoxy homocamptothecin, 7-trimethylsilyl- 10-hydroxy homocamptothecin, 7-trimethylsilyl- 11-fluoro homocamptothecin, 7-trimethylsilyl-9-fluoro homocamptothecin, 7-trimethylsilyl- 10-fluoro homocamptothecin, 7-trimethylsilyl- 10-amino homocamptothecin, 7-trimethylsilyl- 11 -amino homocamptothecin, 7-trimethylsilyl-ll, 12-difloιxro homocamptothecin, 7-trimethylsilyl-9, 10-diflouro homocamptothecin, 7-trimethylsilyl- 10-amino- 11-fluoro homocamptothecin, 7-tert-butyldimethylsilyl homocamptothecin, 7-tert-butyldimethylsilyl- 10-acetoxy homocamptothecin, 7-tert-butyldimethylsilyl- 10-hydroxy homocamptothecin, 7-dimethyl- 3-cyanopropylsilyl homocamptothecin, 7-dimethyl-3-halopropylsilyl homocamptothecin, 7-triphenylsilyl homocamptothecin, 7-triethylsilyl homocamptothecin, 7-dimethylnorpinylsilyl homocamptothecin.

19. The method of Claim 13, wherein the compound synthesized is 7-tert-butyldimethylsilyl- 10-hydroxy homocamptothecin.

20. The method of Claim 12, wherein R^k is an ethyl group, R¹ is H and Z is 0 or 1.

21^'. The method of Claim 1, wherein R⁸ is an alkyl group and R⁷ is a hydroxyalkyl group.

22. The method of Claim 1 , wherein R⁸ is -C(O)R^d.

23. The method of Claim 1 wherein at least one of R¹, R², R³and R⁴ is -OR, wherein R is other than H, the method further comprising the step of reacting the compound to convert R to H.

24. The method of Claim 1 wherein at least one of R¹, R², R³and R⁴ is -NR^bR^c, wherein at least one of R and R^c is other than H, the method further comprising the step of further the compound to convert at least one of R and R^c to H.