Catalytic method for dibenzocycloheptane synthesis and allocolchicinoid synthesis

Abstract

In a non-limiting embodiment, there is provided a compound of formula (I), which may permit for a method or use in treating or preventing a cancer, such as pancreatic cancer or leukemia. In one embodiment, there is also provide a method of preparing a compound of formula (Ia), the method including conducting a cyclization reaction of a compound of formula (III) to obtain a compound of formula (IV), wherein conducting the cyclization reaction comprises conducting a Michael reaction in the presence of a Lewis acid. ##STR00001##

Claims

1. A method of producing a compound of formula (Ia), or a salt or enantiomer thereof: ##STR00048## wherein: R.sup.1 and R.sup.2 are independently of each other H, OH, OR, C(O)OR, OP(O)(OH).sub.2 or a halogen atom, or R.sup.1 and R.sup.2 together with adjacent phenyl carbon atoms form a ring structure selected from the group consisting of cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl having one or more of N, O and S, aryl and heteroaryl having one or more of N, O and S, wherein the ring structure is optionally substituted; R.sup.3, R.sup.6 and R.sup.8 are independently of each other H, OH or OR, wherein at least one of R.sup.3 and R.sup.6 is OR; R.sup.4 and R.sup.5 are independently of each other H or R; R.sup.7 is R, NHR, O, OH, N.sub.3 or NHC(O)R; R is optionally substituted aryl, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; R is optionally substituted aryl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted acyl; and R is alkyl, the method comprising conducting a cyclization reaction of a compound of formula (III): ##STR00049## to obtain a compound of formula (IV): ##STR00050## wherein R.sup.1 to R.sup.6 and R.sup.8 are as defined for the compound of formula (Ia), and wherein said conducting the cyclization reaction comprises conducting a Michael reaction in the presence of a Lewis acid.

2. The method of claim 1, wherein said conducting the Michael reaction comprises preparing a mixture containing the compound of formula (III), the Lewis acid and one or more solvents selected from the group consisting of chloroform, dichloromethane, nitrobenzene, acetonitrile, benzene, hexane, cyclohexane, toluene, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide, and optionally refluxing the mixture.

3. The method of claim 1, wherein the Lewis acid comprises one or more of AlCl.sub.3, AuCl.sub.3, (CH.sub.3).sub.2SAuCl, AgBF.sub.4, FeCl.sub.3, InCl.sub.3, GaCl.sub.3, SnCl.sub.4, BF.sub.3O(CH.sub.2CH.sub.3).sub.2 and trimethylsilyl trifluoromethanesulfonate.

4. The method of claim 1, wherein R.sup.3 is OR and R.sup.6 is H, and wherein the Lewis acid comprises GaCl.sub.3 or AlCl.sub.3 in an amount between 1 mol % and 800 mol % with respect to an amount of the compound of formula (III).

5. The method of claim 1, wherein R.sup.3 is H, and R.sup.6 is OR, and wherein the Lewis acid comprises BF.sub.3O(CH.sub.2CH.sub.3).sub.2 in an amount between 1 mol % to 300 mol % with respect to an amount of the compound of formula (III).

6. The method of claim 1, wherein the compound of formula (III) is obtained by reacting a compound of formula (V) with vinylmagnesium halide: ##STR00051## to obtain a compound of formula (VI): ##STR00052## and oxidizing the compound of formula (VI) to obtain the compound of formula (III), wherein R.sup.1 to R.sup.6 and R.sup.8 are as defined in claim 1.

7. The method of claim 6, wherein said oxidizing the compound of formula (VI) is conducted in the presence of MnO.sub.2 or tetrapropylammonium perruthenate and N-Methylmorpholine N-oxide.

8. The method of claim 6, wherein the compound of formula (V) is obtained by conducting a Suzuki-Miyaura coupling reaction between compounds of formulas (VII) and (VIII): ##STR00053## wherein R.sup.1 to R.sup.6 and R.sup.8 are as defined in claim 6, and Y is a halogen atom.

9. The method of claim 1, the method further comprising reducing the compound of formula (IV) with 2-(3-nitrophenyl)-1,3,2-dioxaborolane-4R,5R-dicarboxylic acid to obtain a compound of formula (IX): ##STR00054## reacting the compound of formula (IX) with an azide compound to obtain a compound of formula (X): ##STR00055## reducing the compound of formula (X) with hydrogen and a Lindlar catalyst to obtain a compound of formula (XI): ##STR00056## and reacting the compound of formula (XI) with an acid anhydride compound to obtain the compound of formula (Ia), wherein R.sup.7 is NHC(O)R, and wherein R.sup.1 to R.sup.6 and R.sup.8 are as defined in claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows Scheme 1 for preparing compound 3;

(2) FIG. 2 shows Scheme 2 for preparing compound 7a from compound 4a;

(3) FIG. 3 shows Scheme 4 for preparing compound 10;

(4) FIG. 4 shows Scheme 4 for preparing compound 14 from compound 11;

(5) FIG. 5 shows Scheme 5 for preparing compound 3; and

(6) FIG. 6 shows Scheme 6 for preparing compounds 7b and 7c from compounds 4b and 4c, respectively.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(7) The present invention relates to the synthesis of various cycloheptane-containing compounds, and more particularly application of cycloheptyne-Co.sub.2(CO).sub.6 complexes, normally but not entirely derived by way of reactions of propargyl cation complexes. In this context, along with the methodology for ring synthesis, the applicant has proposed enantioselective syntheses of the known ()-allocolchicine (synonym: (5S)-5H-5-(acetylamino)-6,7-dihydro-9,10,11-trimethoxydibenzo[a,c]cyclo-heptene-3-carboxylic acid, methyl ester) itself; the known NSC 51046 (synonyms: (S)N-acetyl-O-methylcolchinol, NCME, N-[(5S)-6,7-dihydro-3,9,10,11-tetramethoxy-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide); as well as 8,9,10-trimethoxy-isomer N-[(5S)-6,7-dihydro-3,8,9,10-tetramethoxy-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide of Formula 1:

(8) ##STR00036##
Not only was the compound of Formula 1 (also known as GREEN1) unknown, but due to its completely synthetic origin, it is the first and to date only of the allocolchicinoids with the 8,9,10-trimethoxy-substitution pattern reported.

(9) It has been recognized that as a result of its novel substitution pattern compounds of Formula 1 may be promising for use in medicaments and/or antitumor agents. In particular, such compounds may not be cardiotoxic, and may provide a mechanism of action against pancreatic cancer and leukemia cell lines that is completely distinct from the conventional allocolicinoids. Further, without being bound by a particular theory, the mechanism for the compound of Formula 1 appears effective by way of pro-death autophagy.

(10) Given the promising biological activity of compounds of Formula 1, applicant has developed novel methods of preparing the dibenzocycloheptane ring system and allocolchicines, which is distinct from cobalt/Nicholas reaction based chemistry.

(11) Principal objects may be to at least partially achieve a critical seven membered-ring closure method which is catalytic in nature; which employs the cheapest possible reagents in the smallest possible amounts, and/or wherein other C ring substitution patterns would be possible.

(12) In one possible approach, the generation of a biaryl alkenone as a substrate for conjugate addition chemistry is used. For the rearranged allocolchicine of interest and in particular, the compound of Formula 1 below:

(13) ##STR00037##
the substrate was initially prepared from commercially available materials by way of Suzuki-Miyaura cross coupling (1) in accordance with the process of Scheme 1 shown in FIG. 1, followed by nucleophilic attack on the aldehyde by vinylmagnesium bromide, and oxidation of the resultant alcohol (2) to the ketone (3). The cross-coupling reaction product was first made in a cobalt mediated cyclization project based on known protocols. An addition reaction and subsequent oxidation reaction, however achieved new compounds and occurred as expected, and in good yield in accordance with the process of Scheme 1.

(14) With the substrate of Formula (3) (FIG. 1) in hand, a number of protocols were investigated for the central Michael reaction type cyclization towards the seven-membered ring. Two complementary types of Lewis acids were investigated, including -Lewis acids (Au.sup.I/III, Ag.sup.I) based and the more oxophilic Lewis acids. A complete list of results is included in Table 1.

(15) The general features are as follows. Gold (III) Lewis acids enable the complete consumption of compound 3 to occur, but with the isolation of desired 4 only in low yield (with gross decomposition as the only by-product). Gold (I) systems in conjunctions with Ag(I) salts are able to cause reaction with approximately the same efficiency, but subsequent experiments have demonstrated that it is likely the added Ag(I) salt accomplishing the transformation; while there is evidence that these are proceeding catalytically, the yields realized are not sufficient. Oxophilic Lewis acids also gave some success, with indium (III) based Lewis acids showing transformation but no catalytic turnover, and gallium (III) Lewis acids so vigorous as to cause gross decomposition of the starting material. While preliminary results for SnCl.sub.4 shows some hope that this could be optimized, there was greater early success with BF.sub.3OEt.sub.2. Stoichiometric amounts of this Lewis acid gave good yields of target dibenzosuberone compound 4a. With experimentation, it was possible to get efficient cyclization to occur with 10 mol % BF.sub.3OEt.sub.2 (see Table 1 below). Such an embodiment is believed to provide a commercially reasonable catalytic loading, and as BF.sub.3OEt.sub.2 is the least expensive of all the Lewis acids investigated, it is believed to be preferred from a commercial perspective.

(16) ##STR00038##

(17) TABLE-US-00001 TABLE 1 Optimization of Dibenzocycloheptanone 4a Formation Catalyst Yield Lewis acid loading Solvent Conditions (4a)/conversion AuCl.sub.3 10 mol % MeCN RT, 3 h 31% AuCl(SMe.sub.2) + 25 mol % CH.sub.2Cl.sub.2 RT, 24 h 28% AgBF.sub.4 AuCl(SMe.sub.2) + 5 mol % CH.sub.2Cl.sub.2 RT, 24 h 23% AgBF.sub.4 AgBF.sub.4 5 mol % CH.sub.2Cl.sub.2 RT, 24 h 25% FeCl.sub.3 45 mol % CH.sub.2Cl.sub.2 RT, 4 h 15% InCl.sub.3 25 mol % CH.sub.2Cl.sub.2 RT, 24 h 23% InCl.sub.3 10 mol % CH.sub.2Cl.sub.2 RT, 24 h 11% GaCl.sub.3 10 mol % CH.sub.2Cl.sub.2 RT, decomposition immediate SnCl.sub.4 50 mol % CH.sub.2Cl.sub.2 RT, 3 h 51% BF.sub.3OEt.sub.2 150 mol % CH.sub.2Cl.sub.2 RT, 24 h 75% BF.sub.3OEt.sub.2 50 mol % CH.sub.2Cl.sub.2 RT, 24 h 65% BF.sub.3OEt.sub.2 25 mol % CH.sub.2Cl.sub.2 RT, 24 h 78% BF.sub.3OEt.sub.2 10 mol % CH.sub.2Cl.sub.2 RT, 24 h 64% BF.sub.3OEt.sub.2 10 mol % CH.sub.2Cl.sub.2 78 C.-RT, 71% 3 h BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2 RT, 24 h 37% conversion
From compound 4a, the completion of the synthesis of Formula 1 is achieved from the applicant's previous cobalt-based work described in (a) Djurdjevic, S.; Yang, F.; Green, J. R. J. Org. Chem. 2010, 75, 8241. (b) Djurdjevic, S.; Green, J. R. Org. Lett. 2007, 9, 5505, the disclosure of which is incorporated herein by reference in its entirety. Upon repetition of the procedure, improvements in the enantioselectivity of the process were made. In particular, as shown Scheme 2 illustrated in FIG. 2, TARB-NO.sub.2 reduction afforded the alcohol 5 in highly enantiomerically enriched form. The Mitsunobu-type substitution by zinc azide gave the azide 6, whose reduction under Lindlar conditions, with subsequent N-acylation, gave 7a Formula 1. A single recrystallization afforded the material in >99% ee. As a result of this success delivery of 90 mg of 7a/Formula 1 has been achieved.

(18) It is worth highlighting that during the development of this process, synthesis of compound 7a/Formula 1 (FIG. 2) was shortened by five steps, from thirteen to eight from commercially available materials, making the synthesis much cheaper to carry out on a large scale.

(19) In a subsequent embodiment, synthesis NSC 51046 (also referred to as the compound of Formula 14) having more well-known allocolchicine ring systems was undertaken. The catalytic access to such systems has been recognized as important. As well, comparative biological testing also provides a rationale for obtaining further amounts of this material.

(20) Preparation of the cyclization precursor is directly analogous to that described with reference to FIG. 2 in achieving compound 7a/Formula 1. As shown in FIG. 3, in accordance with Scheme 3, biaryl 8 is obtained by Suzuki-Miyaura coupling and which has been made previously, is similarly subjected to reaction with vinylmagnesium bromide. The resultant alcohol (9) is then oxidized to ketone 10.

(21) With the critical substrate compound (10) in hand, a similar set of Lewis acid mediated Michael reaction protocols were investigated for the synthesis of dibenzocycloheptanone 11, bearing the 2,3,4-trimethoxyaryl substituent pattern of the conventionally known allocolchicines. While the complete list of results is summarized in Table 2, the salient features can be described as follows.

(22) While BF.sub.3OEt.sub.2 was found to be ideal for construction of the Formula 1 ring system, it is insufficient here. While the transformation occurs in reasonable yield with stoichiometric (full mole to mole equivalents) of BF.sub.3OEt.sub.2, catalytic turnover does not occur (Table 2). With both gold(III) and In(III) Lewis acids, the slightest amount of turnover appears to occur, but with 30 mol % causing incomplete conversion and the expensive nature of these reagents, this is not acceptable. Iron(III) is similarly not catalytic, but in this case the gallium(III) catalyst is promising. By continual variation of test conditions, the applicant has achieved commercially reasonable yields of compound 11 (62% yield) at an adequately low loading (20 mol %). Chemically, these results are of the expected trend, as the arrangement of the methoxy groups makes this trimethoxybenzene ring less electron rich at the site that attacks as a nucleophile, and therefore a more aggressive set of reaction conditions should be required. Aesthetically, it is considered to be a near-optimized, but capable of improvement, with a target of 10 mol % catalyst loading being a goal.

(23) ##STR00039##

(24) TABLE-US-00002 TABLE 2 Optimization of Dibenzocycloheptanone 11a Formation Catalyst Yield Lewis acid loading Solvent Conditions (11)/conversion AuCl.sub.3 30 mol % CH.sub.2Cl.sub.2 RT, 24 h (left 3 d) 50% conversion FeCl.sub.3 25 mol % CH.sub.2Cl.sub.2 RT, 24 h 29% conversion InCl.sub.3 30 mol % CH.sub.2Cl.sub.2 RT, 24 h (left 4 d) 45% conversion TMSOTf 40 mol % CH.sub.2Cl.sub.2 RT, 4 h Unknown byproduct BF.sub.3OEt.sub.2 100 mol % CH.sub.2Cl.sub.2 RT, 48 h 74% BF.sub.3OEt.sub.2 100 mol % CHCl.sub.3 RT-reflux, 48 h 66% BF.sub.3OEt.sub.2 20 mol % CH.sub.2Cl.sub.2 reflux, 24 h no conversion BF.sub.3OEt.sub.2 20 + 30 mol % CH.sub.2Cl.sub.2 reflux, 48 h 50% conversion GaCl.sub.3 50 mol % CH.sub.2Cl.sub.2 RT, 5 h 72% GaCl.sub.3 25 mol % 67% conversion GaCl.sub.3 20 mol % CH.sub.2Cl.sub.2 reflux, 2 d 100% conv, 62% GaCl.sub.3 20 mol % CH.sub.3CN reflux, 2 d No conversion

(25) The conversion of 11a to the compound of Formula 14 is understood involving the analogous steps to the compound 7a/Formula 1 synthesis. As a result, as shown in FIG. 4 (Scheme 4), it may be summarized that optimization has shorted the total synthesis of the compound of Formula 14 by five steps (from thirteen to eight), with experimental results achieving 150 mg of material at the 11a stage.

(26) With the Lewis acid catalyst mediated approach to the dibenzocycloheptanones and allocolchinoids worked out for Formula 1 and Formula 14, a generalized the methodology, particularly for the newer, 8,9,10-trimethoxy isomers may thus be understood. The precursors to these new A ring isomers of allocolchicines, (hereafter isoallocolchicines), are prepared by direct analogy to the successful chemistry of iso-NSC 51046 as follows:

(27) ##STR00040##

(28) As shown with reference to Scheme 5 in FIG. 5, as before, Suzuki-Miyaura coupling of 3,4,5-trimethoxyphenylbroronic acid with the appropriate 2-bromobenzaldehyde gave the biaryls (1). These in turn underwent vinyl Grignard reagent addition to the aldehyde function (giving compound 2) of FIG. 5, and oxidation to give ketones 3. Five new examples are summarized in the table below.

(29) TABLE-US-00003 TABLE 3 Preparation of Other Alkenone 3 Cyclization Precursors Entry R.sup.1 R.sup.2 Yield 1 Yield 2 Yield 3 b H H 1b, 86% 2b, 82% 3b, 57% c CO.sub.2Me H 1c, 76% 2c, 84% 3b, 62% d OCH.sub.2O 1d, 40% 2d, >95% 3d, 72% e F H 1e, 95% 2e, 90% 3e, 71% f H OMe 1f, 79% 2f, 80% 3f, 76% brsm.sup.a g OBn H 1g, 91% 2g, 80% 3g, 70%, 81% brsm .sup.abrsm = yield based on recovered starting material

(30) From the initial studies established in the iso-NSC 51046 (Formula 1) synthesis, conventional oxophilic Lewis acids (i.e., BF.sub.3OEt.sub.2) have been shown to be superior than Lewis acids selective for alkene or alkyne -systems; Consequently this approach is continued. For the targeted C ring system devoid of additional substitution (substrate 3b shown below), optimal yields of the cyclized compound 4b were realized with 5 mol % of BF.sub.3OEt.sub.2 Lewis acid, and substantial conversion was realized at even 3 mol % catalyst loading. These are even lower catalyst amounts than required for iso-NSC 51046 (Formula 1) (10 mol %)

(31) ##STR00041##

(32) TABLE-US-00004 TABLE 4 Optimization in the Synthesis of 4b Catalyst Yield (4)/ Lewis acid loading Solvent Conditions conversion BF.sub.3OEt.sub.2 10 mol % CH.sub.2Cl.sub.2 0-RT, 12 h 58% BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2 0-RT, 12 h 68% BF.sub.3OEt.sub.2 3 mol % CH.sub.2Cl.sub.2 0-RT, 12 h 90% conv., 65% yield

(33) The ester-substituted substrate 3c is the A ring isomer of allocolchicine itself (to be called isoallocolchicine itself), and with 10 mol % BF.sub.3OEt.sub.2 achieved good yields of cyclization as follows, much like iso-NSC 51046 (Formula 1). The 68% yield realized is quite respectable for this system.

(34) ##STR00042##

(35) TABLE-US-00005 TABLE 5 Optimization in the Synthesis of 4c Catalyst Yield (4)/ Lewis acid loading Solvent Conditions conversion BF.sub.3OEt.sub.2 25 mol % CH.sub.2Cl.sub.2 0-RT, 12 h 71% BF.sub.3OEt.sub.2 10 mol % CH.sub.2Cl.sub.2 0-RT, 48 h 68%

(36) Methylenedioxy-substituted 3d was also shown to behave very similarly to 3a and 3b, giving a reasonable yield of cyclization product 4d at 5 mol % BF.sub.3OEt.sub.2 as follows and shown in Table 6.

(37) ##STR00043##

(38) TABLE-US-00006 TABLE 6 Optimization in the Synthesis of 4d Catalyst Yield (4)/ Lewis acid loading Solvent Conditions conversion BF.sub.3OEt.sub.2 25 mol % CH.sub.2Cl.sub.2 RT, 12 h 55% BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2, 3 d 63% 1.8 10.sup.3M

(39) In a further embodiment, there is an interest in having at least one fluorine-substituted example of cyclization, given the omnipresence of fluorine-substituted drug candidates. Consequently the below illustrated reaction process 3e.fwdarw.4e, for example, may also prove commercially important. In the reaction shown, the yield of cyclization product was initially found to be low. As illustrated in Table 7, commercially reasonable yields of material were, however, obtained at the 5 mol % BF.sub.3OEt.sub.2 loading level, whilst maintaining high-dilution conditions.

(40) ##STR00044##

(41) TABLE-US-00007 TABLE 7 Optimization in the Synthesis of 4e Catalyst Yield (4)/ Lewis acid loading Solvent Conditions conversion BF.sub.3OEt.sub.2 10 mol % CH.sub.2Cl.sub.2 RT, 12 h 35% BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2 RT, 48 h 43% BF.sub.3OEt.sub.2 2.5 mol % CH.sub.2Cl.sub.2 RT, 48 h Incomplete conversion BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2, RT, 48 h 68% 1 10.sup.3M

(42) A substrate of the formula 3f with a C-5 substituted methoxy function, has also been found to provide a respectable yield of cyclization product with a 5 mol % BF.sub.3OEt.sub.2 loading level, according to the criteria indicated in Table 8 and the reaction process.

(43) ##STR00045##

(44) TABLE-US-00008 TABLE 8 Optimization in the Synthesis of 4f Catalyst Yield (4)/ Lewis acid loading Solvent Conditions conversion BF.sub.3OEt.sub.2 25 mol % CH.sub.2Cl.sub.2 RT, 2 10.sup.3M 58% BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2 RT, 2 10.sup.3M 54% BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2 RT, 1 10.sup.3M 70%

(45) In further experimental studies, the C-4 benzyloxy substituted compound of formula 3g underwent ready cyclization with a 10 mol % BF.sub.3OEt.sub.2 loading level, affording compound 4g in 83% yield. As shown below and overviewed in Table 9, the 5 mol % BF.sub.3OEt.sub.2 loading level, while giving slower transformation, results in nearly the same amount of product.

(46) ##STR00046##

(47) TABLE-US-00009 TABLE 9 Optimization in the Synthesis of 4g Catalyst Yield (4)/ Lewis acid loading Solvent Conditions conversion BF.sub.3OEt.sub.2 10 mol % CH.sub.2Cl.sub.2 [2.2 10.sup.3M] 0 C.-RT, 83% yield 12 h BF.sub.3OEt.sub.2 5 mol % CH.sub.2Cl.sub.2 [1.9 10.sup.3M] 0 C.-RT, 81% yield 48 h

(48) Two of the aforementioned cyclization products compounds of Formula 4b, 4c have been converted into their respective isoallocolchicines successfully, applying the protocol for iso-NSC 51046 (Formula 1) as shown according to Scheme 6 shown in FIG. 6. In individual reactions, material has been pushed forward to get the target isoallocolchicines at the expense of truly optimized yields. As a result, some adjustment of chemical yields may be required. In each case, enantioselective reduction of the compound of 4 by LiBH.sub.4/TARB-NO.sub.2 (i.e. as shown in FIG. 2Scheme 2) afforded the corresponding alcohols with excellent yield and enantioselectivity, see for example FIG. 6Scheme 6/compound 5b, 99%, 99% ee; 5c, 79%, 99% ee). Mitsunobu-type substitution with zinc azide afforded the corresponding organic azides 6b (53% yield) and 6c (75% yield). Reduction of the azides 6b and 6c with Lindlar hydrogenation conditions, and acetylation of the resultant amine afforded the target isoallocolchicines 7b (52% yield) and 7c (47% yield) in enantiomerically pure form. The resulting two compounds (Formula 15/7b, 3 mg; and Formula 16/7c, 4.6 mg), which are new isoallocolchicines, have been delivered for preliminary evaluation.

(49) An additional cyclization substrate bearing the 9,10,11-trimethoxyaryl substituent pattern of the conventionally known allocolchicines was demonstrated to be capable of cyclization to the corresponding dibenzocycloheptanone. In this case, according to the following reaction, and as shown in Table 10, from the compound of Formula (10b), greater than catalytic amounts of a Lewis acid (AlCl.sub.3) were necessary for obtaining 11b.

(50) ##STR00047##

(51) TABLE-US-00010 TABLE 10 Optimization in the Synthesis of 11b Catalyst Yield (11)/ Lewis acid loading Solvent Conditions conversion AlCl.sub.3/ excess, C.sub.6H.sub.6, 6 10.sup.3M Reflux, 12 h 52% nitrobenzene 6 equiv
Consequent, the use of catalytic amounts of Lewis acids on alkenone-substituted biaryls may be used as an efficient method for the synthesis of dibenzocycloheptanones with the 3,4,5-trimethoxy-substitution pattern, and also shows applicability to the 2,3,4-trimethoxy isomers. The resultant compounds have been demonstrated to be readily converted to the corresponding allocolchicnoids, of both the novel 3,4,5-trimethoxy- and conventional 2,3,4-trimethoxy-substitution patterns.

(52) While the invention has been described with reference to preferred embodiments, the invention is not or intended by the applicant to be so limited. A person skilled in the art would readily recognize and incorporate various modifications, additional elements and/or different combinations of the described components consistent with the scope of the invention as described herein.