GB2207670A - Indole derivatives - Google Patents

Abstract

Analogues of yuehchukene e.g. 2, 5'-dimethyl-yuehchukene, 2, 5'-dimethoxy-yuehchukene, N, N'-dimethoxy-yuehchukene, N, N'-dimethyl-yuehchukene, N'-methyl-yuehchukene, dihydro-yuehchukene, and 9, 10-dihydroxy-yuehchukene, monoindolyl compounds having the formula: <IMAGE> where R' and R'' each independently represents a hydrogen atom, a lower alkyl or lower alkoxy group, and R''' represents the group: <IMAGE> in the 2 or 3 position, 6, 6a - seco - yuehchukene and iso - seco - yuehchukene have activity: as female fertility regulating agents and/or are useful precursors of yuehcukene derivatives, yuehchukene being of the formula:- <IMAGE> Also, compounds containing a 9-methyl-6a, 7, 8, 10-tetrahydroindano [2, 1, b] indole nucleus: <IMAGE> are synthesised in a multistage process including the intermolecular Diels-Alder cyclization of an N-tosyl-3-(3-methylbuta-1,3-dienyl) indole, with a dienophile to form a 2-(3'-N-tosylindolyl)-4-methylcyclohex-3-enyl carboxylic acid, followed by a intramolecular acylation to form N-tosyl-9-methyl-6-oxo-6a-7,8, 10a-tetrahydroindano [2, 1, b] indole.

Description

Synthesis and Use of YuehchEkene Analogues This invention relates to the preparation and use of analogues and derivatives of yuehchukene.

Yuehchukene (1) is a potential female fertility regulating agent which has been isolated from the root of Murraya paniculation (L.). This forms the subject of European Patent Application No.84304243.3 Serial No.130 067. It has a unique structural feature of a tetracyclic tetrahydroindano [2,l,b] indole nucleus (2).

Yuehchukene has been synthesized by a biomimetic Diels-Alder dimerization of 3-dehydroprenylindole [3-MBDI] (3) as described in European Patent Application No.85309174.2 Serial No.185 538.

The present invention intone aspect relates to the development of a synthetic approach to compounds which contain the essential structural feature of yuehchukene, namely the 9-methyl-6a,7,8,10-tetrahydroindano [2,l,b] indole (4) nucleus:

This approach involves the intermolecular Diels-Alder cyclization of N-tosyl-3- (3-methylbuta-1, 3-dienyl) indole, [N-Ts-3-MBDI] with a dienophile (5) to form a 2-[3'-N-tosylindolyl)-4-methylcyclohex-3-enyl carboxylic acid, followed by a intramolecular acylation, e.g. thermally or with a Lewis acid catalyst, to form N-tosyl-9-methyl-6-oxo-6a,7,E,1Oa-tetrahydroindano [2,l,b1 indole, [N-Ts-TC-6-oxol, (7).

The present invention is illustrated by the synthesis of 7,7-bisnor-yuehchukene [7,7-bisnor-YCK] (8) as an example.

The synthetic sequence for 7,7-bisnor-YCK (8), intermolecular Diels-Alder adduct and the tetracyclic intermediate is below:

Commercially available indole-3-carbaldehyde (9) was protected as N-tosyl-indole-3-carbaldehyde, [N-Ts-ICA] (10).

Treatment of (10) with the Grignard reagent derived from 3-chloro-2-methylro-l-ene in tetrahydrofuran gave, after column chromatographic purification the alcohol N-Ts-3-HMBI (11).

Dehydration of alcohol (11) with methane sulphonyl chloride and triethylamine in tetrahydrofuran afforded the diene, N-Ts-3-MBDI, (12). The diene (12) when heated under reflux with acrylic acid in benzene, underwent intermolecular Diels Alder cyclization to give the adduct carboxylic acid cis-N Ts-IMCA, C13) as a white solid. Treatment of acid (13) with polyphosphate ester in refluxing chloroform gave, after appropriate work-up, a red oil which upon purification by column chromatography afforded the tetracyclic ketone N-Ts-TC-6-oxo (14), as a white solid. Reduction of ketone (14) with lithium trimethoxyalumino-hydride in tetrahydrofuran yielded the desired alcohol N-Ts-TC-6-OH (15) as a white solid.Conversion of the alcohol (15) to its benzoate derivative was achieved by treating the alcohol (15) with stoichiometric amount of triethylamine and 4-(dimethylamino)pyridine (DMAP) in chloroform whereby the benzoate derivative N-Ts-TC-6-OBz, (16) was obtained as a white solid. An X-ray analysis.on the crystal of benzoate (16) confirmed the structure and stereochemistry of this compound (figure 1). Treatment of benzoate (16) with indolyl-magnesium bromide in benzene at room temperature afforded the N-tosyl-7,7-bis-nor-yuehchukene, N-Ts-TC-6-In (17) on a white solid. Removal of N-tosyl group in (17) was achieved by treating (17) with sodium amalgam and sodium hydrogen phosphate in methanol at room temperature.

Purification of the crude product with column chromatography yielded the desired target molecule 7,7-bis-nor-yuehchukene (8) as a white solid.

figure 1. Crystal Structure of N-Ts-TC-6-OBz (16) The invention also relates to the 2,5'-di substituted yuehchukene analogues, such as 2,5'-dimethyl-yuehchukene, [2,5'-diMe-YCK] (18a) and 2,5' -dimethoxyl-yuehchukene [2,5' -diMeo-YCK] (18b) and their synthesis.

According to another aspect of the invention, therefore, there is provided a substituted yuehchukene of the general formula:

where R represents a lower alkyl or lower alkoxy group.

They can be synthesized by the following method:

Commercially available 5-substituted indole was converted to the corresponding indole-3-carb-aldehyde (20), by the method documented by Edwin H.P. Young, J. Chem. Soc.

1958, 3493 or by A.L. Mndzhoyan and G.L. Papayan, Chem.

Abst., 1963 (58), 4497d, with phosphorous oxychloride and dimethylformamide, followed by hydrolysis of the intermediate with aqueous alkali. N-Tosyl derivative of the indolecarboxaldehyde (21) was prepared by treating the appropriate aldehyde (30) with sodium hydride and then with -toluene-sulphonyl chloride. The N-tosyle derivative (21) was then allowed to react with the Grignard reagent which was prepared by the reaction of 3-chloro-2-methyl-propene in anhydrous tetrahydrofuran with magnesium ribbon, to yield a crude product as viscous oil, which upon purification by column chromatography gave the corresponding 5-substituted-N-tosyl-3-(1-hydrQxy- 3-methylbut-3-enyl) indole, [(22a), 5-Me-N-Ts-3-HMBI; (22b), 5-MeO-N-Ts-3-HMBI].Alcohol (22) was then detosylated and dehydrated in a one-pot alkaline catalysed reaction to afford the crude product of 5-substituted- 3-(3-methylbutadienyl) indole, [(23a), 5-Me-3-MBDI; (23b), 5-MeO-3-MBDI]. The crude diene (23) without further purification, was subjected to acid catalysed dimerization reaction whereby 2,5'-disubstituted yuehchukene analogues (18) was isolated pure.

Further the invention relates to other yuehchukene derivatives; these can be prepared from yuehchukene itself.

N,N'-Dimethylyuehchukene, N,N'-diMe-YCK, (24a) and N'-Methylyuehchukene, N'-Me-YCK(24b) were prepared by alkylating yuehchukene with methyl iodide and potassium hydride in tetrahydrofuran.

Dihydroyuehchukene, DiH-YCK (25) was prepared by catalytic hydrogenation of yuehchukene in the presence of Adam catalyst.

9,10-Dihydroxy-yuehchukene, 9,10-diOH-YCK (26) was prepared by hydroxylating yuehchukene with osmium tetroxide.

The invention also relates to yuehchukene related monoindolyl compounds, such as 3-(hydroxy3-methylbut-3-enyl) indole, (3-HMBI) (27), 2-(hydroxy-3methylbut-3-enyl) indole, (2-HMBI) (28), and N-methoxy-3 (hydroxy-3-methyl-but-3-enyl) indole (N-OMe-3-HMBI) (29) and their preparation. More generally those monoindolyl compounds have the general formula:

where R' and R" each independently represents a hydrogen atom, a lower alkyl or a lower alkoxy group, and R " ' represents the group

in the 2 or 3 position.

3-HMBI (27) was prepared by dehydration of N-tosyl-3-(l-hydroxy-3-methylbut-3-enyl) indole, N-Ts-3-HMBI (11).

2-HMBI.(28) was prepared-from indole-2-carboxaldehyde by reacting the latter with the Grignard reagent derived from 3-chloro-3-methylpropene in tetrahydrofuran.

N-OMe-3-HMBI 429) was prepared from N-methoxyindole-3-carboxaldehyde, see R.M. Acheson, G.N.

Aldridge, Michael C.K. Choi, J.O. Nwankwo, M.A. Ruscol, and John D. Wallis, J. Chem. Research (S), 1984, 101, by treating the latter with the Grignard reagent derived from 3 -chloro- 2 -methylpropene in tetrahydrofuran.

Certain of these compounds according to the various aspects of the invention are believed to have activity as female fertility regulating agents and so the invention extends to their use in this respect and in addition certain of these compounds are useful precursors of yuehchukene derivatives.

The invention also relates to the N,N'-di-substituted yuehchukene analogues, such as N,N'-dimethoxy-yuehchukene, (31), [N,N'-diMeO-YCK] and their synthesis.

According to another aspect of the invent.ion, therefore, there is provided a substituted yuehchukene of general formula:

where R represents an alkoxy group.

They can be synthesized by the following method as illustrated by the synthesis of N,N'-diMeO-YCK (31).

Alcohol N-OMe-3-HMBI (29) prepared from N-methoxyindole3-carbaldehyde was dehydrated with methanesulphonyl chloride and triethylamine in tetrahydrofuran to diene (30). The crude diene (30) without purification, was subjected to acid catalysed dimerization reaction whereby N,N'-dimethoxy-yueAchukene (31) was obtained.

Finally, the invention relates to the preparation of yuehchukene analogues with ring scission, namely 6,6a-seco-yuehchukene (32) and its isomer iso-seco-yuehchukene (33),

6,6a-Seco-yuehchukene (32) was synthesized by a sequence of reactions as outlined in tie scheme below:

Indole was first converted into its N-trimethylsilyl derivative (34). Friedal-Crafts acylation of (34) with the allylic alcohol (35) in ether in the presence of BF3.Et2O at low temperature (-90 to room temperature) gave, after removing the N-trimethylsilyl group during work-up, the 3-alkyl indole (37). The same 3-alkyl indole (37) was also obtainable by reaction of indole with the alcohol (35) in BF3.Et2O at OOC to room temperature.

Treatment of 3-alkyl indole (37) with indole-3-carbinol (39) in aqueous methanol gave 6,6a-seco-yuehchukene (32), Iso-seco-yuehchukene (33) was synthesized according to the following scheme:

Indole was first converted to its N-tosyl derivative (40).

Treatment of N-tosyl indole (40) with tert-butyl-lithium in THF generated a-lithio derivative (41) which was allowed to undergo ion exchange with CuI... The cuprate. (42) thus prepared was alkylated with allylic chloride (43) to afford compound (44). Detosylation of (44) with sodium amalgam in methanol gave 2-alkyl indole (45). The same -2-alkyl indole (45) was also obtainable from indole by refluxing indole with the allylic alcohol (35) in the presence of BF3.Et2O.

Condensation of 2-alkyl indole (45) with indole-3-carbinol (39) gave iso-seco-yuehchukene (33).

Preparation of N-tosyl-indole-3-carboxaldehyde, N-Ts-ICA (10)

To a suspension of sodium hydride (50% oil dispersion, 4 g, 0.083 mole, washed with anhydrous glyme) in anhydrous glyme (10 ml) was added dropwise a suspension of iiidole-3carboxaldehyde (10 g, 0.069 mole) in anhydrous glyme (60 ml) After evolution of hydrogen gas, the red solution was warmed at 60 0C for 30 minutes. The solution was cooled with an ice bath and a solution of p-tosyl cilloride (14.4 g, 0.076 mole) in allhydrous glyme (70 ml) was added dropwise.The resulting solution was warmed at 60 C for 1 iiour. The solution was cooled and filtered through Celite. The filtrate was poured into excess cold aqueous sodium hydrogen carbonate solution.

The pale yellow precipitate, formed was filtered, grinded into fine powder, washed with water aid petroleum ether, air dried and finally vacuum dried. The desired product was obtained as pale yellow solid, (19.5g, 95%) ; m.p. 145-6 C (recrystal. CHCl3 V (Nujol) 1665 s (C=O), 1596 (C=C), 1105, 1090, 980, 790 max.

and 760 cm-1, #H (90 MHz, CDCl3) 10.10 (1H, s, CHO), 8.3-7.1 (3H, m, In, Ph), and 2.30 (3H, s, Ph-CH3) ; m/z 299 (M+). Preparation of N-tosyl-3- (1-hydroxy-3-methylbut-3-enyl) indole, N-Ts-3-HMBI (11)

To a suspension of magnesium turnings (4.82 g, 0.2 mole) in anhydrous THF was added 3-chloro-2-methylpropene (0.2 ml) and a small piece of iodine. The resulting mixture was warmed until the iodine colour disappeared and exothermic Grignard reaction set in. A solution of N-Ts-ICA (10) (40 g, 0.134 mole) and 3chloro-2-methylpropene (19.6 ml, 0.20 mole) in anhydrous THF (500 ml) was added at such a rate so to maintain a gentle refluxing condition. The resulting solution was cooled and diethyl ether (500 ml) was added. Saturated aqueous ammonium chloride solution and dilute hydrochloric acid was added until the aqueous layer was acidic to litmus. The ether layer was washed with water and brine. Removal of ether yielded a brown viscous liquid which was purified by column chromatography (ether:petroleum ether = 1.1 v/v) to give the desired product (11) as a light yellow viscous liquid (33 g, 70%); ')max. (film) 3400 vbr (OH, H-bonded), 1650 (C=C), 1600 (C=C), 1230, 1100, 890 and 745 cm-1 ; #max. (EtOH) 221 and 249 nm ; #H (90 MHz, CDCl3) 7.0-8.0 (9H, m, In, Ph), 5.04 (1H, t, br, J 70 Hz, H-C-O), 4.89, 4.81 (2H, 2s, br, =CH2), 2.56 (2H, d, J 7.0 Hz, -CH2), 2.28 (4H, s, PhCH3, OH) and 1.76 (3H, s, CH3);; #C (22.5 MHz, CDCl3) 144.9, 141.9, 135.6, 135.5, 129.8, 129.0, 126.8, 125.4, 124.8, 123.1, 122.8,1 120.3, 114.0, 113.8, 65.4 (C-O) , 46.0, 22.4 (Me) and 21.5 (Ph-Me); m/z 355 (M+).

Preparation of N-tosyl-(E)-3-(3-methylbutacienyl)indole N-Ts-3-MBDI (12)

To solution of N-TS-3-HMBI (11) (24 g, 0.0676 mole) in anhydrous THF (270 ml) stirred under Argoli at -60 C was added triethylamine (28.4 ml, 0.203 mole) and mesyl chloride (7.8 ml, 0.101 mole). The resultiiig solutioii was warmed to room temperature ill 1@ hour and a wiiite solid was formed during this period. T!ie reactioii mixture was stirred at room temperature for further 30 minutes and heated under gentle reflux for 20 minutes. The precipitate was filtered aiid discarded.The filtrate was coiiceiitrated to give brow viscous liquid. The crude product was purified by coluiiui chromatography (dichloromethane : petroleum ether = 3:7 v/v) to give tlle desired dieiie (12) as Dale yellow viscous liquid (13.7 g, 60%) ; vmax. (film) 1598 (C=C), 1280, 1220, 1120, 970 and 810 cm-1 ; #max. (EtOH) 205, 229, 249, 268, 284 and 294 nm ; #H (90 MHz, CDCl3) 8.2-6.9 (9H, In, Ph), 6.79 (2H, Abg, J 16.2 Hz, -CH=CH-), 5.11 (2H, m, =CH2), 2.13 (3H, s, Ph-CH3) and 1.96 (3H, s, -CH3) ; #C (22.5 MHz, CDCl3) 144.9, 142.0, 135.7, 135.3, 133.0, 129.9, 129.2, 126.8, 125.0, 123.6, 123.5, 120.9, 120.3, 119.0, 117.1, 113.8, 21.4 (Ph-Me) aid 18.3 (Me), m/z 337 (M+) Preparation of (1S, 2S)-2-(3'-N-tosylindolyl) -4-methylcyclohex- 3-enylcarboxylic acid, cis-N-Ts-IMCA (13)

To a solution of freshly distilled acrylic acid (2.2 ml, 0.03 mole) in benzene (2 ml) heated under reflux was added dropwise a solution of N-Ts-3-MBDI (12) (5 g) in benzene (8 ml).

After all N-Ts-3-MBDI was used up (approximately 4 hours), the benzene solvent was removed under reduced pressure. Diethyl ether (100 ml) was added to the resulting red gum. Solid thus formed was scratched to fine powder. The precipitate was filtered and discarded. The ether filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and brine.

Removal of ether yielded the crude product as a deep yellow viscous liquid, which upon purification by column chromatography (ether : petroleum ether = 1:1 v/v) yielded cis-N-Ts-IMCA (13) (3.83 g, 63%) ; m.p. 158-9 C (recrystallized from ether - pet.

ether), v (KBr) 3360 br (OH, H-bonded), 1710 s (C=O), 1596 (C=C), 1280, 1180, 970 and 810 cm #max. (EtOH) 205, 215, 253, 282 sh and 290 nm sh; dH (90 MHz, CDCl3), 8.0-7.0 (10H, m, In, Ph, OH), 5.46 (1H, d, J 4.0 Hz, H-10), 4.01 (1H, t, br, H-lOa), 2.80 (1H, m, H-6a), 2.27 (3H, s, Ph-CH3), 1.85 (2H, m, -CH2) and-1.77 (5H, s, -CH3, -CH2-); J(H-10, H-lOa) 4.0 Hz; J(H-lOa, H-6a) 5.4 Hz.

Preparation of N-tosyl-9-methyl-t-oxo-6a,7,8,10a-tetrahydroindeno[2,1-blindole, N-Ts-TC-6-oxo (14)

To a solution of cis-N-Ts-IMCA (13) (4 g, 9.78 mmol) in ethanol-free anhydrous chloroform (30 ml) was added a solution of polyphosphate ester (8.4 g) in chloroform (10 ml). The resulting solution was heated under gentle reflux for 30 minutes.

The reaction mixture was poured into water and was extracted with diethyl ether. The organic extract was washed with water and brine. Removal of solvent yielded a red viscous liquid which was purified by column chromatography (ether : petroleum ether = 3:7 v/v) to give the desired ketone (14) as a white solid (2.29 g, 50%) ; m.p. 145-6 C (recrystal. ether pet.) ; # max.

(KBr) 1702 s (C=O), 1597 (C=C), 1160, 1110, 1000, 970, 720 and 650 cm ; Xmax. (EtOH) 202, 223, 242 and 292 nm; dH (90 MHz, CDC13) 8.4-7.15 (8H, m, In, Ph), 5.70 (1H, s, br, H-10), 3.92 (1H, s, br, H-lOa), 3.17 (1H, m, H-6a), 2.35 (3H, s, Ph-CH3), 1.83 (4H, m, -CH2-CH2-) and 1.62 (3H, s, -CH3); J(H-lOa, H-10) 1.5 Hz;J(H-lOa, H-61) 5.5 Hz; dC (75 MHz, CDC13 192.50 s, 155.62 s, 145.11 s, 137.59 s, 135.72 s, 129.96 s, 129.78 d, 129.17 d, 127.50 d, 124.40 s, 123.88 d, 121.90 d, 118.60 d, 115.75 d, 51.32 d, 34.42 d, 27.20 t, 24.13 t, 24.06 q and 21.60 q; m/z 391.1257 (M+, obs.) (calc. 391.1242 for C23H21NO3S). Preparation of N-tosyl-6-hydroxy-9-methyl-6a,7,8,10a-tetrahydroindeno[2,1-b]indole, N-Ts-TC-6-OH (15)

To a suspension of lithium aluminium hydride (0.76 g, 0.02 mole) in anhydrous THF (5 ml) cooled in ice bath was added dropwise a solution of anhydrous methanol (0.6 ml, 0.015 mole) in anhydrous THF (5 ml). A solution of N-Ts-TC-6-oxo (14) (2.0 g, 0.005 mole) in anhydrous THF (15 ml) was added dropwise to the freshly prepared solution of lithium trimethoxyaluminohydride.The reaction mixture was stirred at room temperature for 30 minutes. Dilute hydrochloric acid was added to quench the reaction. Diethyl ether was added to extract the product.

The ether extract was washed with water and brine. After removal of the ether solvent, the crude product was purified by column chromatography (ether : petroleum ether = 1:3 v/v) to give pure alcohol (15) as a white solid (1.5 g, 75%); m.p.

165-60C (recrystal. ether-pet.); '?max. (Nujol) 3590 s (OH), 1596 (C=C), 1070 and 790 cm ; max. (EtOH) 202, 220 and 257 nm; dH (90 MHz, CDC13) 8.0-7.0 (9H, m, In, Ph, OH), 5.76 (1H, s, br, H-10), 5.54 (1H, dd, J 7.0, 0.88 Hz, H-6), 3.55 (1H, s, br, H-lOa), 3.12 (1H, m, H-6a), 2.31 (3H, s, Ph-CH3), 2.02 (4H, m, -CH2-CH2-) and 1.69 (3H, s, -CH3); 6C (22.5 MHz, CDCl3) 144.9, 142.6, 140.1, 136.2, 135.3, 130.8, 129.9, 126.9, 124.5, 123.6, 120.1, 114.5, 72.2 (C-6), 44.8, 37.3, 28.8, 23.9, 21.5 and 21.4; m/z 393 (M+) Preparation of N-tosyl-6-benzoyloxy-9-methyl-6a,7,8,10a-tetrahydroindeno[2,1-b]indole, N-Ts-TC-6-OBz (16)

To a solution of N-Ts-TC-6-OH (15) (2.0 g, 5.09 mmol) in anhydrous chloroform (20 ml) was added dimethylaminopyridine (0.683 g, 5.6 mmol), triethylamine (0.785 ml, 5.6 mmol) and benzoyl chloride (0.65 ml, 5.6 mmol). The resulting solution was heated under gentle reflux for 30 minutes. The solution was poured into aqueous copper sulfate solution and was extracted with dichloroform. The organic layer was washed with water and brine.After removal of solvent, the crude product was purified by column chromatography (ether : petroleum = 1:4 v/v) to give the benzoate (16) as a white solid (2.15 g, 85%); m.p. 160-1 C (recrystallized from ether : pet. ether). #max. (Nujol) 1740 (C=O), 1597 (C=C), 1250, 1075, 895 and 680 cm1; Amax. (EtOH) 201, 222 and 258 nm; dH (90 MHz, CDCl3) 8.12-6.94 (13H, m, In, Ph), 7.04 (1H, d, J 3 Hz, H-6), 5.78 (1H, s, br, H-10), 3.63 (1H, s, br, H-lOa), 3.38 (1H, m, H-6a), 2.26 (3H, s, Ph-CH3), 1.88 (4H, m, 2 -CH2-) and 1.64 (3H, s, -CH3); J(H-lOa, H-6a) 7 Hz;J(H-6, H-6a) 3 Hz; dC (75 MHz, CDC13) 165.9 s, 144.6 s, 140.5 s, 138.1 s, 134.6 s, 133.6 s, 132.9 d, 130.1 s, 29.9 d, 129.8 d, 129.6 d, 128.3 d, 126.7 d, 125.6 s, 125.0 d, 123.4 d, 120.4 d, 120.0 d, 114.7 d, 74.0 d, 44.1 d, 37.0 d, 27.6 t, 24.0 q, 22.0 t and 21.4 q; m/z 497 (M+), 392.

Preparation of N-tosyl-6-(3' -indolyl) -9-m-thyl-6a,7 ,8,10a- tetrahydroindeno[2,1-b]indole, N-Ts-TC-6-In (17)

To a suspension of magnesium turnings (72.4 mg, 3.02 mmol) in anhydrous diethyl ether (3 ml) was added a solution of bromoethane (0.207 ml, 2.77 mmol) in anhydrous ether (1 ml).

After evolution of gas bubbles had ceased and most of the magnesium turnings had been reacted, a solution of indole (0.324 g, 2.77 mmol) in anhydrous benzene (6 ml) was added to the solution of ethylmagnesium bromide. Another portion of anhydrous benzene (3 ml) was added to the resulting solution after evolution of gas bubbles had stopped. All the diethyl ether and a further fraction of benzene (3 ml) was distilled off. The freshly prepared solution of indolyl magnesium bromide in benzene was added to a suspension of N-Ts-TC-.6-OBz (16) in anhydrous benzene (6 ml). The resulting solution after stirring at room temperature for 30 minutes, was poured into aqueous ammonium chloride solution; and extracted with diethyl ether. The ether extract was washed with water and brine.After removal of solvent under reduced pressure, the crude product was purified by flash column chromatography (ether : petroleum ether = 3:7 v/v) to the desired product (17) as a white solid.

(0.866 g, 70%); m.p. 900C (dec.) ; #max. (Nujol) 3440 s (NH) 1597 (C=C), 1230, 1210, 1090, 990, 890 and 785 cm-1 ; #max.

(EtOH) 203, 222 and 264 nm; dH (90 MHz, CDC13) 8.11-6.58 (12H, m, In, Ph), 7.85 (1H, s, br, NH), 6.59 (1H, d, J 2.2 Hz, H-2'), 5.58 (1H, s, br, H-10), 4.62 (1H, s, br, H-6), 3.83 (1H, s, br, H-10a) ; 2.88 (1H, m, H-6a), 2.18 (3H, s, Ph-CH3) 1.92 (4H, m, -CH2-CH2-) and 1.69 (3H, s, -CH3); J(H-10a, H-6a) 6.6 Hz; J(H-6, H-2') 2.2 Hz; #C (22.5 MHz, CDC13) 144.1, 143.8, 140.7, 136.7, 135.6, 129.2, 1270, 126.5, 123.6, 123.3, 121.8, 121.0, 120.4, 120.1, 119.5, 119.4, 117.8, 114.9, 111.2, 50.6 (C-6), 45.2 (C-6a), 38.2 (C-10a), 29.0, 27.6, 24.0 (9-Me) and 21.4 (Ph-Me) ; m/z 492 (M+), 375.

Preparation of 6-(3'-indolyl)-9-methyl-6a, ,8,10a-tetrahydroindeno[2,1-b]indole, 7,7-bis-nor-yuehchukene (8)

To a solution of N-Ts-TC-5-In (17) (0.6 g) in anhydrous diethyl ether (10 ml) and anhydrous methanol (20 ml) was added anhydrous disodium hydrogen phosphate (10 g) and sodium amalgam (5%, 10 g). The reaction mixture was stirred at room temperature until all the solid sodium amalgam became liquid mercury.

The progress of reaction was monitored with TLC. After the reaction had completed, water and diethyl ether was added to the reaction mixture. The ether extract was washed with water aiid brine. After removal of solvent uiider reduced pressure, the crude product was purified by flash column chromatography (ether : petroleum ether = 3:7 v/v) to give 7,7-bis-nor-YCK, (8) as a white ; solid (0.309 g, 75%) ; m.p. 121 C (dec.) ; #max. (Nujol) 3395 s (NH), 1070, 990 and 742 cm-1 s (NH) ; #max. (EtOH) 203, 224, 281 and 289 nm sh; #H (90 MHz, C6D6) 7.8-6.3 (8H, m, In), 6.34 (1H, d, J 2.6 Hz, H-2'), 5.95 (1H, s, br, H-10), 4.38 (1H, d, J 6.6 Hz, H-6), 3.94 (1H, s, br, H-10a), 3.17 (1H, m, H-6a), 1.89 (4H, m, -CH2-CH2-) and 1.64 (3H, s, -CH3), #C (22.5 MHz, C6D6) 144.2, 141.1, 137.1, 132.4, 127.5, 126.5, 125.2, 124.4, 122.4, 121.8, 121.0, 119.9, 119,7, 119.0, 117.5, 112.0, 111.5, 52.0 (c-6), 40.1 (C-6@), 38.8 (C-10a), 27.4, 25.2 and 24.2 ; m/z 338.1791 (M+, obs.) (cal.

338.17829 for C24H22N2).

Preparation of 5-methyl-N-tosyl-indole-3-carboxyaldehyde, 5-Me-N-Ts-3-ICA (21a)

5-Methylindole-3-carboxyaldehyde (20a) (5 g, 0.032 mol) in THF (50 ml) was added dropwise into a suspension of NaH (1.05 g, 0.0425 mol) while stirrinq under nitrogen at room temperature. After addition was completed, the mixture was then heated for 10 min at 60 C. The content was cooled in ice bath and to which p-toluene-sulphonyl-chloride (8.45 g, 0.042 mol) and imidazole (0.4 g) in THF (50 ml) were added. The mixture was heated to 60 C for 1 hour. Solution mixture was cooled and then was poured into chilled saturated solution of sodium bicarbonate (1 litre). The precipitate formed was filtered and dried to give a brown solid (9.5 g, 95% yield).

Recrystallization from ethanol yielded 5-Me-N-Ts-3-ICA (21a) as brown crystals; m.p. 167-1680C; Rf = 0.66, silica gel TLC, diethylethere : petroleum ether 7:3 v/v; vmax 3120(w), max.

3070(w) , 2920(w) , 2850 (w) , 2720(w) , 2320 (m) , 1673(s) , 1600(m) 1450(s), 1375(s), 1170(s), 820(s) cm-1, #H (90 MHz, CDCl3) 2.36 (3H, s, Ph-CH3), 2.43 (3H, s, Ph-CH3), 7.21-8.17 (8H, In, Ph), 10.06 (1H, s, CHO); m/z 313.0764 (M+, obs) (Calc. 313.0769 for C17H15NO3S).

Preparation of 5-Methoxy-N-tosyl-3-indole-3-carboxaldehyde, 5-MeO-N-Ts-3-ICA, (21b)

5-MeO-N-Ts-3-ICA (21b) was prepared from 5-methoxy-indole3-carboxaldehyde by method similar to the preparation of (21a).

Thus 5-MeO-N-Ts-3ICA (21) was obtained as a solid (80% yield); m.p. 128-129 C ; Rf = 0.448, silica gel TLC, ether:petroleum ether 4:7 v/v; #max. 3115(w), 2920(w), 2810(w), 1678(s), 1601(w), 1460(m), 1375(s), 1170(s), 820(s) cm ; dH (90 MHz, CDCl3) 2.37(3H, s, Ph-CH3) , 3.84(3H, s, -OCH3) , 6.98-8.17(8H, In, Ph), 10.06(1H, s, -.CHO); m/z 329.0719 (M+, obs) (Calc. 329.0718 for C Preparation of 5-Methyl-N-tosyl-3-(1-hydroxy-3-methyl-but-3enyl)indole, 5-Me-N-Ts-3-HMBI (22a)

To a reaction mixture of magnesium (0.6 g, 0.025 mol) and 3-chloro-2-methylpropene (0.1 ml) in THF (20 ml) added dropwise a solution of 5-Me-N-Ts-3-ICA (21a) (7 g, 0.022 mol) and 3chloro-2-methyl-1-propene (2.16 ml, 0.023 mol) in THF (50 ml).

The content of the flask was heated at 600C for 1 hour after addition was completed. The mixture was cooled and hydrolysed with saturated solution of ammonium chloride (200 ml). The organic layer separated was washed with water and then brine, dried with sodium sulphate. Removal of solvent under reduced pressure yielded a green viscous oil which upon purification by column chromatography (silica gel) eluted with diethylether: petroleum ether afforded 5-Me-N-Ts-3-HMBI (22a) as a light green viscous oil (3.86 g, 47.5% yield); Rf = 0.42, silica gel TLC, diethylether :petroleum ether 4:7 v/v; vmax 3550(s), 2920(s), 1600(m), 1450(s), 1370(s), 1170(s), 895(s), 810(s) cm-1 : #..

(250 MHz, CDC13) 1.81 (3H, s, Ph-CH3), 2.2 (1H, br, s, -OH), 2.35 (3H, s, -CH3), 2.41 (3H, s, Ph-CH3), 2.6 (2H, d, J 5.3 Hz, -CH2), 4.85, 4.94 (2H, 2s, =CH2), 5.14 (1H, t, J 5.3 Hz, OCH), 7.13-7.84 (8H, In, Ph); m/z 369.1390 (M+, obs.) (Calc. 369.1393 for C21H23NO3S).

Preparation of 5-Methoxy-N-tosyl-3- (1-hydroxy- 3-methylbut-3enyl) indole, 5-MeO-N-Ts-3-HMBI (22b)

5-MeO-N-Ts-3-HMBI (22b) was prepared from 5-MeO-N-Ts-3-ICA (21b) by method similar to the preparation (22a). Thus compound (22b) was obtained as an oil (50% yield); Rf = 0.466, silica gel TLC, hexane : ether 3:7 v/v ; #max. 3600-3800 (br. s), 2930 (s), 2320 (w), 1590 (s), 1370 (s), 895 (s), 810 (s) cm-1 ; # (90 MHz, CDCl3) 1.77 (3H, s, C-CH3), 2.30 (3H, s, Ph-CH3), 2.25 (1H, s, -OH), 2.56 (2H, d, J 6.6 Hz, -CH2) , 3.79 (3H, s, O-CH3) , 4.81-4.90 (3H, m, =CH2, O-CH-) , 6.90-7.85 (8H, In, Ph).

Prenaration of 5-Methyl-3-(3-methylbutadienyl)indole, 5-Me-3-MBDI (23a)

5-Me-N-Ts-3-HMBI (22a) (2.5g, 0.0068mol) was dissolved in absolute ethanol (lOml); to the stirring solution was added a 3N solution of KOH/water:ethanol (2:8) (100ml).

The content of the flask was heated at 600C for 2 hours then was cooled and diluted with ice water (250ml). The mixture was extracted with diethylether (2x50ml). The combined extracts-was washed with water (2x50ml) and dried over sodium sulphate Removal of solvent under reduced pressure gave a residue which upon purification by column chromatography (silica gel, 70-230 mesh, ether:petroleum ether 2:8 v/v) yielded the desired compound (.23a) (0.77 g, 59%); Rf = 0.57, silica gel TLC, diethyl ether:petroleum ether 3:7; m/z 197.1166 (M+, obs.) (Calc. 197.1201 for c? 14H15N).

Preparation of 5-Methoxy-3- (3-methylbutadienyl) indole, 5-MeO-3-MBDI (23b)

5-MeO-3-MBDI (23b) was prepared from 5-MeO-N-Ts-3-HBDI (22b) by method similar to the preparation of (23a). Thus compound (23b) was obtained in 50% yield; Rf = 0.6.3, silica gel TLC, hexane : ether 3:7 ; #H (90 MHz, C6D6) 1.98 (3H, s, CH3), 3.49(3H, s, OCH3), 5.02(lH, s, =CH2), 5.12(1H, s, 6.67-7.53(7H, m, In, Ph, -CH=CH-); m/z 213.1156 (M+, obs.) (Calc. 213.1150 for C14H15NO).

Preparation of 2,5'-dimethylyuehchukene, 2,5'-DiMe-YCK, (18a)

A suspension of silica gel (15 g) in benzene (50 ml) was stirred at room temperature under nitrogen; to which 5-Me-3 MBDI (23a) (1 g, 0.005 mol) was added. The flask was then placed in a pre-heated oil bath (X90 C). To the .mixture was added a solution of trifluoroacetic acid in benzene (0.0002 mol /ml; 0.8 ml). The content was kept at "'900C for 1 hour, then was cooled and filtered. The gel was washed with diethylether (2x50 ml).The benzene and ether extracts were combined, dried and evaporated to give a dark brown viscous oily residue which upon purification by a Lobar silica gel column (Si60, 40-60 um, eluted with diethylether:petroleum ether 4:7 v/v) yielded the 2,5'-dimethylyuehchukene (18a) as a white powder (0.05 g, 5%), m.p. 128-1320C;Rf = 0.5, silica gel TLC, diethylether:petroleum ether 4:7 v/v; ';max. 3410(s), 2950(m), 2920(m), 2860(m), 1590(m), 1425(s), 1100(m), 800(s) cm1; dH (250 MHz, CDC13), 0.84 (3H, s, 7-CH3), 1.11 (3H, s, 7-CH3), 1.57, 2.23 (2H, ABq. 2,8-H), 1.63 (3H, s, 9-CH3), 2.38 (3H, s, Ph-CH3), 2.43 (3H, s, Ph-CH3), 3.11 (1H, dd, J 8.1 Hz; 7 Hz, 6a-H), 3.98 (1H, m, 10a-H), 4.44 (1H, d, J 8.1 Hz, 6-H), 5.64 (1H, br. s, 10-H), 6.85-7.01 (4H, m), 7.21-7.35 (4H, m); m/z 394.2404 (M+, obs.) (Calc. 394.2402 for C28H30N2).

Preparation of 2,5'-dimethoxyyuehchukene, 2,5'-DiMeO-YCK, (18b)

2,5'-DiMeO-YCK (18b) was prepared from crude 5-MeO-3-MBDI (23b) by method similar to the preparation. of (18a). Thus compound (18b) was obtained as a solid (6% yield), m.p. 118 119 C ; Rf = 0.42, silica gel TLC, diethylether:petroleum ether 3:7 v/v ; #max. 3420 (s), 3320 (m), 2960-2840 (s ; b), 1610 (w), 1580 (m), 1480 (s), 1450 (s), 1430 (s), 1210 (s), 1180 (s) cm-1 dH (90 Mhz, C6D6) , 0.94 (3H, s, 7-CH3), 1.15 (3H, s, 7-CH3), 1.56, 2.51 (2H, ABq. 2,8-H), 1.65 (3H, s, 9-CH3), 3.39 (3H, s, O-CH3) , 3.59 (3H, s, O-CH3) , 3.16 (1H, t, J 7.9 Hz, 6a-H), 4.10 (1H, m, 10a-H), 4.50 (1H, d, J 7.9 Hz, 6-H), 5.85 (1H, br, s, 10-H), 6.46-7.23 (9H, m, In, Ph).

Preparation of N,N'-dimethylyuehchukene, N,N'-DiMe-YCK (24a)

Yuehchukene (183 mg) in tetrahydrofuran (5 ml) was added to potassium hydride (35% in oil dispersion, 80 mg) at room temperature. The whole was stirred until gas ceased to evolve.

Methiodide (300 mg) was added and the reaction mixture was stirred for 30 minutes. Water was then added and the aqueous solution was extracted with ether. Removal of solvent afforded the desired compound as pale yellow solid, m.p. 207-210 C ; #H (90 Mhz, CDC13), 7.63-6.89 (8H, m, Ar-H), 6.87 (1H, s, H-2'), 5.71 (1H, s, br, H-10), 4.57 (1H, d, J 8.75 Hz, H-6), 4.03 (1H, m, H-lOa), 3.74 (3H, s, NCH3), 3.10 (3H, s, NCH3), 3.04 (1H, m, H-6a), 2.22 (1H, d, J 7.66 Hz, H-8), 1.65 (3H, s, br, C9-CH3), 1.63 (1H, d, J 7.66 Hz, H-8), 1.08 (3H, s, C7-CH3), 0.83 (3H, s, C7-CH3); m/z 394 (M+).

Prenaration of Dihydroyuehchukene, DiH-YCK (25)

Yuehchukene (80 mg) in 10 ml of benzene saturated with water was hydrogenated over Adam catalyst at room temperature under 40 psi pressure for 40 hours. The mixture was filtered through a celite to remove platinum black.Removal of solvent afforded the desired product (25) as a brown oil (60 mg, 75%); # (90 MHz, CDCl3), 8.02 (1H, s, br, NH), 6.847.03 (10H, m, Ar-H, N-H), 4.46 (1H, d; J 10.06 Hz, H-6), 3.36 (1H, d, J 10.06 Hz, H-6a), 2.93 (1H, dd, J 6.12 Hz, 10.06 Hz, H-6a) , 0.97 (3H, s, quart. -CH3), 0.81 (3H, d, J 6.12, tert-CH3) , 0.70. (3H, s, quart-CH3) ; m/z 368 (M+) Preparation of 9,10-dihydroxy-yuehchukene, 9,10-diOH-YCK, (26)

To a solution of yuehchukene (0.225 g, 0.68 mmole) and pyridine (0.109 ml, 1.36 mmole) in anhydrous ether stirred at -50C was added dropwise osmium tetroxide (0.17 g, 0.68 mmole) in ether (5 ml). The whole was stirred for F hour.Yellow solid formed was collected by filtration and washed with small volume of ether. The solid was redissolved in dichloromethane (30 ml) and stirred at 0 C with addition of a solution of 10% mannitol and 5% aqueous NaOH (25 ml). The mixture was stirred at 0 C overnight. Organic layer was separated and the aqueous solution was extracted with dichloromethane (30 ml). The combined organic extract was dried and the solvent was removed under reduced pressure.Residue upon purification by flash column chromatography(silica gel 60, 70-230 mesh, hexane:ether 2:8 v/v) gave 9,10-diOH-YCK (26) as a yellowish powder (0.041 g, yield = 15%) m.p. = 159-1610C; ';max. 3420(s), 2960(m), 2920(m), 1620(w), 1580(w), 1460(s) cm ; dH (90 MHz, CDCl3) 0.80 (3H, s, 7-CH3), 1.14 (3H, s, 7-CH3), 1.36 (3H, s, 9-CH3), 1.55 (2H, m, 2,8-H), 1.73 (1H, br, -OH, replaceable by D2O), 1.94 (1H, br, -OH, replaceable by D2O), 2.97 (111, d, J 10.28 Hz, 6-H), 3.21 (1H, dd, J 10.06 Hz; 6.56 Hz, l0a-H), 3.62 (1H, dd, J 10.28 Hz; 6.45 Hz, 6a-H), 4.31 (1H, d, J 10.06 Hz, 10-H), 6.42-7.86 (llH, In, Ph); m/z 400.2146 (M+, obs.) (Calc. 400.2144 for C26H28N2O2).

Preparation of 3-(1-hydroxy-3-methylbut-3-enyl)indole, 3-HMBI, (27)

To a solution of N-Ts-3-HMBI (11) (0.5 g, 1.41 mmol) in anhydrous methanol (10 ml) was added disodium hydrogen phosphate (5 g) and sodium amalgam (5%, 5 g). The reaction mixture was stirred at room temperature and the progress of reaction was monitored with TLC. After all the starting material had been used up, diethyl ether (50 ml) was added and the ether extract was washed with water. After removal of solvent under redu.ced pressure, the crude product was purified by flash column chromatography (ether:petroleum ether = 3:2 v/v) to give the desired product as pale yellow viscous liquid (0.226 g, 80%); (film) 3360 s (NH), 3260 br (OH, H-bonded) and 750 cm S; max.

#H (90 MHz, CDC13) 8.22 (1H, s, br, NH), 7.7-6.8 (5H, m, In), 5.11 (1H, t, J 7.0 Hz, H-C-O-), 4.85 (2H, s, br, =CH2), 2.60 (2H, d, J 7.0 Hz, -CH2-), 2.34 (1H, s, br, OH) and 1.76 (3H, s, -CH3); dC (22.5 MHz, CDC13), 122.1, 121.8, 121.6, 121.3, 119.5, 119.1, 118.9, 113.4, 111.3, 111.1, 65.9 (C-O-), 46.4 and 22.4 (Me); m/z 201 (M+).

Preparation of 2-(hydroxy-3-methylbut-3-enyl)indole, 2-HMBI (28)

To a stirred mixture of magnesium turnings (5.1 g, 0.21 mole) and a small piece of iodine was added dropwise 3-chloro2-methylpropene (22.7 ml, 0.27 mole) in anhydrous THF (200 ml) under an anhydrous nitrogen atmosphere at such a rate that a gentle refluxing condition was maintained. When the Grignard formation reaction had ceased, a solution of indole-2-carbaldehyde (3.1 g, 0.021 mole) in anhydrous THF (100 ml) was added dropwise and the mixture was maintained at 50-600C for 2 hours.

To cooled resulting mixture was added ammonium chloride solution (11 g in 100 ml water). The aqueous layer was extracted with ether. The combined ether extract was washed with dilute sodium hydroxide, water and brine. Removal of ether afforded a residue which upon purifiçation by column chromatography (silica gel, ether:petroleum ether 6::4 v/v) yielded 2-HMBI (28) as a yellow solid (2.5 g, 59%); m.p. 73-740C; dH (90 MHz, CDC13) 8.43 (lH, s, NH), 7.33-7.67 (4H, m, Ar-H), 6.33 (1H, d, H-3), 4.80-5.10 (3H, m, =CH2, H-C-O), 2.63 (1H, s, OH), 2.46 (2H, d, -CH2), 1.77 (3H, s, CH3); #C (22.5 MHz, CDC13), 141.77 (s, C-2), 140.69 (s, C-3'), 135.87 (s, C-7a), 129.89 (d, C-6),128.44 (s, C-3a), 120.54 (d, C-4), 119.89 (d, C-6), 110.95 (d, C-7), 98.65 (t, =CH2), 66.09 (d, #CHOH), 46.32 (t, -CH2-), 22.43 (q, -CH3); m/z 201 (M+).

Preparation of l-methoxy-3-(1-hydroxy-3-methylbut-3-enyl)indole, N-OMe-HMBI, (29)

To a stirred mixture of magnesium turnings (0.386 g, 0.016 mol) in anhydrous tetrahydrofuran and a few crystal of iodine was added 3-chloro-2-methylpropene (ca. 0.3 ml) to initiate the reaction. As soon as iodine colour disappeared and the reaction (6) commenced, a solution of N-methoxyindole-3-carbaldehyde (N-OMe-ICA) (1.123 g, 0.0064 mole) and 3-chloro-2-methylpropene (1.57 ml, 0.016 mole) in anhydrous tetrahydrofuran (20 ml) was added dropwise to maintain a continuous refluxing. After complete addition, the resulting solution was stirred at room temperature for 2 hours, cooled and saturated ammonium chloride solution (ca. 20 ml) was added. The aqueous layer was extracted with ether.Removal of ether under reduced afforded a brown oil (1.76 g) which upon purification by column chromatography (silica gel, 70-230 mesh, ether:petroleum ether 1:1 v/v) yielded N-OMe-HMBI (29) as a brown viscous oil (1.348 g, 91%); v ax max.

(film) 3420 (OH, 3080 (=CH) , 2950, 1650 (C=C), 1445, 1080, 1040, 715 cm1; H (90 MHz, CDC13) 7.67 (1H, d, J 7.44 Hz, H-7), 6.98-7.62 (4H, m, Ar-H), 5.06 (1H, t, J 7 Hz, H-COH), 4.83 (2H, unresolved m, OH2) 3.94 (3H, s, OCH3), 2.57 (2H, d, J 7 Hz, -CH2-), 2.46 (1H, s, br., OH), 1.75 (3H, s, vinyl CH3); 6C (22.5 MHz, CDCl3), 142.64, 132.73, 122.54, 122.33, 120.21, 119.89 115.45, 113.22, 108.40, 65.82, 65.39, 46.48, 22.48; m/z 231 (M+) Preparation of 1-methoxy-3-(3-methylbutadienyl)indole, N-MeO-3-MBDI, (30)

To a solution of N-MeO-3-HMBI (29) in anyydrous THF stirred under nitrogen at -30 C was added triethylamine and mesyl chloride.The resulting solution was warmed to room temperature. The reaction mixture was extracted with ether, and removal of solvent afforded N-MeO-3-MBDI (30) as a crude oil, dH (90 MHz, CDC13), 1.96 (3H, s, vinyl CH3), 3.89 (3H, s, OCH3), 4.96 (1H, br.s, =CH2), 5.03 (1H, br.s, =CH2), 6.65 (1H, d, J 16.2 Hz, =CH), 6.87 (1H, d, J 16.2 Hz, =CH), 6.99-7.41 (4H, m, H-2, Ph), 7.84 (1H, m, H-7).

Preparation of N,N'-dimethoxy-yuehchukene, N,N'-diMeO-YCK, (31)

N,N'-diMeO-YCK (31) was prepared from crude N-MeO-3-MBDI (30) by method similar to the preparation of 2,5'-diMe-YCK (18a). Thus compound (31) was obtained as a solid, #H (90 MHz, CDC13), 0.84 (3H, s, 7-Me), 1.10 (3H, s, 7-Me), 1.64 (3H, s, 9-Me), 3.12 (1H, dd, J 7, 7 Hz, H-6a), 3.27 (3H, s, OMe), 3.81 (1H, m, H-10a), 4.03 (3H, s, OMe), 4.65 (1H, d, J 7 Hz, H-6), 5.69 (1H, m, H-10), 7.01-7.58 (9H, m, In, Ph).

Preparation of N'-methyl-yuehchukene, N'-Me-YCK, (24b)

To a suspension of NaH (2.5 mg, 0.1 mmol) in anhydrous THF (5 ml) was added dropwise a solution of yuehchukene (32 mg, 0.09 mmol) in THF (5 ml) at room temperature under nitrogen atmosphere after stirring the mixture for 0.5 h, methyliodide (13 mg, 0.09 mmol) was added. The mixture was stirred for another 0.5 h, poured into ice water (100 ml) and extracted with ether. The extract was dried over anhydrous sodium sulphate and evaporated to dryness. Chromatography on silica gel yielded N'-methylyuehchukene (24b) (8 mg, 24%) as a light brown powder, m.p. 127-129 C, (Found: M+, 380.2257.C27H28N2 requires M, 380.2246); #max. 3400(br.s), 2900(br.s), 1610(w), 1460(s) , 1450(s) , 1370(w) , 1365(w) , 1330(w) , 1250-(w) , 1150 (w), 1130(w), 1120(w), 1110(m), 740(s) cm ; dH (90 Mhz, CDC13), 0.84 (3H, s, 7-Me), 1.08 (3H, s, 7-Me),. 1.65 (3H, s, 9-Me), 2.17 (1H, br.s, H-8), 2.35 (1H, br.s, H-8), 3.10 (1H, dd, J 7.5, 8.3 Hz, H-6a), 3.68 (3H, s, N'-Me), 3.97 (1H, m, H-10a), 4.50 (1H, d, J 8.3 Hz, H-6), 5.68 (1H, br.s, H-10), 6.80-7.59 (10H, m, In, Ph).

Preparation of 3-(3,5,5-trimethyl-cyclohex-2-enyl)indole (37)

Method A: To a solution of indole (0.341 g,.91 mmol ), and 1,5,5-trimethyl-2-cyclohexen-1-ol (35) (0.408 g, 2.91 mmol) in anhydrous ether (55 ml) at 0 OC under an atmosphere of nitrogen was added boron-trifluoride etherate (0.35 ml, 2.85 mmol ). The mixture was allowed to stirred at room temperature for 7 hours during which the reaction mixture turned yellow. Ether (50 ml) was added and the ether layer was washed successively with saturated sodium bicarbonate solution (2 x 50 ml) and saturated brine (50. ml). The ether extract was dried over anhydrous MgSO4.Removal of solvent and purification of the crude product by flash chromatography- (petr. ether/ether 9:1) gave the alkylated product (37) as a yellow oil which upon scratching formed a light yellow solid (0.369 g, 53%) ; m.p. 103-106 OC; #max. (KBr) 3395, 3055, 2905, 1615, 1425, 1340, 1092, 925 and 747 cm-1 ; #max. (EtOH) 290, 283, 273, 222 and 199 nm; dH (90 Mz, CDC13) 7.80 (lH, s, br), 7.44- 7.72 (1H, m), 7.02-7.44 (3H, m), 6.94 (1H, d, J 2.19 Hz).

5.55 (1H, s, br), 3.68 (lli ni) , 1.72 (311, s), 1.04 (311, s) and 0.99 (3H, s) ; #C (22.5 MHz, CDCl3) 23.99 q, 25.45 q, 30.38 s, 31.79 d ; 31.95 q, 43.93 t, 44.36 t, 112.26 d, 119.06 d, 119.50 d, 120.42 d, 121.39 s, 121.83 d, 123.94 d, 126.87 s, 132.93 s and 136.72 s ; m/z 239 (M+) Method B : To a mixture of N-TMS indole (34) .(0.234 g, 1.42 llunol and 1,5,5-trimethyl-2-cyclohexen-1-ol (35) (0.173 g, 1.26 mmol) in anhydrous ether (20 ml) at -90 C under an atmosphere of nitrogen was added boron-trifluoride etherate (0.20 ml, 1.62 mmol) The mixture was allowed to reach room temperature and stirred overnight. Ether (50 ml) was added and the etheral solution was washed with saturated sodium bicarbonate (2 x 50 ml) followed by saturated brine. (50 ml). Tlie etlieral solution was dried over magnesium sulphate. Removal of solveiit at reduced pressure and purification of crude product by flash chromatography (pet. ether/ether 9:1 v/v) yielded the 3-alkyl indole (37) as a white solid (0.132 g, 45%).

Preparation of 3-(3,5,5-trimethyl-cyclohex-enyl)-2-(3indolylmethyl)indole, 6,6a-seco-yuehchukene (32)

To a solution of 3-alkyl indole (37) (1;65 g, 6.90 mmol-) and indole-3-carbinol (1.07 g, 7.28 mmol ) in anhydrous ether (120 ml) at 0 C under an atmosphere of nitrogen was added boron-trifluoride etherate (1.30 ml, 10 mmol-).

The mixture was stirred at 0 C for 45 minutes and subsequently at room temperature for 5 hours. Ether (200 ml) was added.

The etheral solution was washed successively with saturated sodium bicarbonate solution (3 x 100 ml) and saturated brine (100 ml). The etheral solution was dried over anhydrous magnesium sulphate. Removal of solvent under reduced pressure gave a gummy residue which was treated with pet. ether/ether (8.5:1.5). Insoluble material was discarded. The pet. ether ether solution was concentrated and subjected to flash chromatography 3 times eluted with pet. ether/ether 7:3, pet. ether/ether 8.5:1.5, and pet. ether/ether 9:1 successively.

,6a-Seco-yuehchukene (32) was isolated as a yellow solid (0.17 g, 7%); m.p. 57-60 OC; "max. (KBr) 3406, 3049, 2906, 1457, 1352, 1093, 1014 and 746 cm-1 : Xmax (EtOH) 289, 282, 224 and 201 nm; dH (90 MHz, CDCl3) 7.88 (1H, s, br), 6.807.68 (10H, m), 5.57 (1H, s, br), 4.24 (2H, s), 3.74 (1H, m), 1.76 (3H, s, br), 1.04 (3H, s) and 0.99 .(3H, s); #C (22.5 MHz, CDCl3) 22.37 t, 23.94 q, 25.24 q, 30.55 s, 31.57 d, 32.00 q, 43.55 t, 44.25 t, 110.61 d, 111.32 d, 113.05.s, 115.43 s, 118.85 d, 119.39 d, 119.77 d, 120.80 d, 122.31 d, 122.75 d, 124.43 d, 127.30 s, 128.11 s, 132.82 s, 133.15 s, 135.48 s and 136.45 s; m/z 368.2251 (M+, C26H28N2).

The desired product (44) thus obtained was a yellow viscous liquid (0.081 g, 37%); #max. (neat) 3048, 2928, 1599, 1490, 1363, 1073, 891, and 626 cm 1; #max. (EtOH) 215 and 253 nm; dH (90 MHz, CDCl3) 8.00-8.23 (1H, m), 6.92-7.76 (7H, m), 6.40 (1H, s), 5;.41 (1H, s, br), 4.16 (lH, m), 2.27 (3H, s), 1.71 (3H, s, br), 1.04 (3H, s) and 0.97 (3H, s); dC (22.5 MHz, CDC13) 21.40 q, 23.89 q, 25.08 q, 30.34 S, 31.58 d, 34.02 q, 44.15 t, 44.58 t, 108.51 d, 115.23 d, 120.10 s, 121.56 d, 123.45 d, 123.73 d, 126.12 d, 129.37 d, 129.64 d, 130.12 d, 134.19 s, 136.35 s, 137.44 s, 144.43 s and 147.68 s; m/z 393.

Preparation of 2-(3,5,5-trimethyl-2-cyclohexenyl)indole, (45)

Method A: From indole To boron-trifluoride etherate (20 ml, 0.16 mol.) under an atmosphere of nitrogen was added a solution of indole (0.359 g, 3.07 mmol.) and 1,5,5-trimethyl-2-cyclohexen-1-ol (35) (0.430 g, 0.16 mol.) in anhydrous ether (10 ml). The mixture was refluxed 'for 30 minutes. The mixture was slowly poured into NaOH solution (10 g NaOXI in 20 ml water). The aqueous mixture was extracted with ether (3 x 20 ml). The ether extract was washed with brine (20 ml) and dried over anhydrous magnesium sulphate. Removal of solvent at reduced pressure and preliminary purification by chromatography (pet.

ether/ether 8:2) and flash chromatography (pet. ether/ether 97:3) gave a gummy material. Purification by semi-preparative HPLC (pet. ether/ether 97:3, flow rate 1 ml min 1) desired product (45) was isolated as a yellow solid (0.269 g, 37%); #max. (KBr) 3413, 3038, 2928, 1537, 1329, 1003 and 695 cm-1 ; #max. (EtOH) 228, 275 and 220 nm ; #H (90 MHz, CDCl3) 7.86 (1H, s, br) , 7.40-7.68 (1H, m) , 6.88-7.40 (4H, m) , 6.26 (111, d, J 2.19 Hz), 5.48 (111, s, br), 3.54 (1H, m), 1.73 (3H, s, br) and 0.99 (6H, s);; dC (22.5 MHz, CDCl3) 23.94 q, 25.14 q, 30.17 s, 31.64 d, 34.35 q, 43.56 t, 44.10 t, 98.65 d, 110.35 d, 119.56 d, 119.94 d, 120.97 d,. 121.08 d, 128.88 s, 135.22 s, 135.92 s and 143.83 s.

Method B : From N-tosyl indole (44) To a solution of N-tosyl-2-(3',5',5'-trimethyl-2'- cyclohexenyl)indole (44) (0.0783 g, 0.l99mmol) in anhydrous methanol (3.2 ml) was added disodium hydrogen phosphate (0.187 g, 1.32 mmol). Sodium amalgam (50.%, 1.3 g) was added in small portions. The mixture was stirred for 6 hours.

Methanol (10 ml) was.added and the suspension was allowed to settle. The methano-lic content was transferred to water (100 ml). The mixture was extracted with ether (3 x 20 ml).

The ether extract was. washed with water (20 ml) and subsequently with saturated brine (20 ml) and dried over anhydrous magnesium sulphate. Removal of solvent under reduced pressure and purification of crude product by flash chromategraphy (pet.

ether/ether 95:5) yielded the desired product (45) as a yellow solid (0.0395 g, 83%).

Preparation of 3-(3-indolylmethyl)-2-(3,5,5-trimethylcyclohex2-enyl)indole, iso-seco-yuehchukene (33)

To a solution of 2-(3 ,5 ,5 -trilnetllyl-2 -cyclohexenyl)indole (45) (0.285 g, 1.19 mmol) in aqueous methanol (70%, 122 ml) with diluted llCl (2 H, 6 drops) was added dropwise indole-3carbinol (0.204 g, 1.39 mmol) in methanol (122 ml) over a period of 4 hours. The mixture was stirred at rooin temperature for 2 hours. The reaction mixture was poured into dilute NaOH solution. (1 g NaOH in 350 ml water). The agueous solution was extracted with ether (3 x 100 ml).The ether extract was washed successively with water (100 ml) and saturated brine (100 ml) After removal of solvent under reduced pressure, tlie crude product was purified by flash chromatography (pet. ether/ether 8:2) to give iso-seco-yuehchukene (33) as a white powder (0.123 g, 28%) ; m.p. 114-117 C; #max. 3415, 3051, 2908, 1448, 1267, 1067, 984 and 718 cm-1 ; #max. (EtOH) 283 and 227 nm ; #@ (90 Mflz, CDCl3) 8.08-7.52 (311, m), 7.52-6.76 (711, m) 6.65 (1H, s, br), 5.38 (1H, s, br), 4.19 (2H, d, J 1.31 Hz), 3.76 (115, m), 1.71 (311, s, br), 0.91 (311, s) aid 0.88 (311, s) ; #C (22.5 MHz, CDCl3) 19.77 t, 24.05 q, 24.81 q, 30.17 s, 31.64 q, 32.23 d, 43.18 t, 43.94 t, 109.32 s, 110.30 d, 111.00 d, 116.42 s, 118.86 d, 119.07 d, 120.86 d, 121.19 d, 121.79 d, 122.16 d, 127.52 s, 129.04 s, 135.32.s, 135.76 s, 136.46 s, and 139.28 s; m/z 368.2258 (M+, C26H28N2).

"The term "Lower" means a group which preferably has 1, 2, 3 or -4 carbon atoms.

Claims (39)

WHAT WE CLAIM IS:

1. A method of synthesising a 9-methyl-6a,7,8,10-tetrahydroindano [2,1,b) indole nucleus:

comprising the intermolecular Diels-Alder cyclization of an N-tosyl-3-(3-methylbuta-1,3-dienyl) indole, with a dienophile to form a 2- (3' -N-tosylindolyl) -4-methylcyclohex-3-enyl carboxylic acid, followed by a intramolecular acylation to form N-tosyl-9-methyl-6-oxo-6a,7,8,1Oa-tetrahydroindano [2,1,b] indole.

2. A method as claimed in Claim 1 in which the intra molecular acylation is achieved either thermally or with a Lewis acid catalyst.

3. An indolewhen made by a method as claimed in Claim 1 or Claim 2.

4. A substituted yuehchukene of the general formula:

where each R represents a lower alkyl or lower alkoxy group and where each R' represents a hydrogen atom or an alkoxy group.

5. 2,5 '-Dimethyl-yuehchukene.

6. 2,5' -Dimethoxyl-yuehchukene.

7. N,N' -Dimethoxy-yuehchukene.

8. A method of making a substituted yuehchukene as claimed in Claim 4 in which an indole having the general formula:

is dehydrated with methanesulphonyl chloride and triethylamine in tetra hydrofuran to give the corresponding diene which is then subjected to an acid catalysed dimerisation.

9. A substituted yuehchekene when made by a method as claimed in Claim 8.

10. N,N'-Dimethylyuehchukene.

11. N'-Methylyuehchukene.

12. A method of synthesising N,N'-dimethylyuehchukene or N'-methylyuehchukene comprising alkylating yuehchukene with methyl iodide and potassium hydride in tetrahydrofuran.

13. A yuehchukene derivative when made by a method as claimed in Claim 12.

14. Dihydroyuehchukene.

15. A method of preparing dihydroyuehchukenecomprising hydrogenating yuehchukene in the presence of Adam catalyst.

16. Dihydroyuehchukene when made by a method as claimed in Claim 15.

17. 9,10-Dihydroxy-yuehchukene.

18. A method of preparing 9,10-dihydroxy-yuehchukene comprising hydroxylating yuehchukene with osmium tetroxide.

19. 9,10-Dihydroxy-yuehchukene when made by a method as claimed in Claim 18.

20. A monoindolyl compound having the general formula:

where R'and R" each independently represents a hydrogen atom, a lower alkyl or lower alkoxy group, and R"' represents the group:

in the 2 or 3 position.

21. 3-(Hydroxy-3-methylbut-3-enyl) indole.

22. 2-(Hydroxy-3-methylbut-3-enyl) indole.

23. N-Methoxy-3-(hdroxy-3-methylbut-3-enyl) indole.

24. A method of preparing 3-(hydroxy-3-methylbut-3-enyl) indole comprising dehydrating N-tosyl-3-(l-hydroxy-3-methylbut-3-enyl) indole.

25. 3-(Hydroxy-3-methylbut-3-enyl) indole when made by a method as claimed in Claim 24.

26. A method of preparing 2-(hydroxy-3-methylbut-3-enyl) indole comprising reacting indole-2-carboxaldehyde with the Grignard reagent derived from 3-chloro-3-methylpropene in tetrahydrofuran.

27. 2-(Hydroxy-3-methylbut-3-enyl) indole when made by a method as claimed in Claim 26.

28. A method of preparing 3-methoxy-3-(hydroxy-3-methylbut-3-enyl) indole comprising treating N-methoxyindole-3-carboxaldehyde with the Grignard reagent derived from 3-chloro-2-methylpropene in tetrahydrofuran.

29. 3-Methoxy-3-(hydroxy-3-methylbut-3-enyl) indole when made by a method as claimed in Claim 28.

30. 6,6a-Seco-yuehchukene.

31. A method of making 6,6a-seco-yuehchukene comprising condensing the 3-alkyl indole having the formula:

with indole-3 carbinol.

32. 6,6a-Seco-yuehchukene when made by a method as claimed in Claim 31.

33. Iso-seco-yuehchukene.

34. A method of making iso-seco-yuehchukene comprising condensing the 3-alkyl indole having the formula:

with indole-3 carbinol.

35. A method as claimed in Claim 34 in which the 2-alkyl indole is prepared by refluxing indole with allylic alcohol, or by converting indole to its N-tosyl derivative, generation of the -lithio derivative, cupration and alkylation with allylic chloride.

36. Iso-seco-yuehchukene when made by a method as claimed in Claim 34 or Claim 35.

37. A female fertility regulating agent comprising a compound as claimed in any of claims 3 to 7, 9 to 11, 13, 14, 16, 17, 19 to 23,. 25, 27, 29, 30, 32, 33 and 36.

38. For use as an anti-implantation agent a compound as claimed in any of claims 3 to 7, 9 to 11, 13, 14, 16, 17, 19 to 23, 25, 27, 29, 30, 32,--33 and 36.

39. A pharmaceutical preparation comprising a compound as claimed in any of claims 3 to 7, 9 to 11, 13, 14, 16, 17, 19 to 23, 25, 27, 29, 30, 32, 33 and 36.