Synthesis of 3,4-bridged indoles by photocyclisation reactions. Part 1. Photocyclisation of halogenoacetyl tryptophan derivatives

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 Synthesis of 3,4-Bridged lndoles by Photocyclisation Reactions. Part I. Photocyclisation of Halogenoacetyl Tryptophan Derivatives Anthony L. Beckn8 Mark MascaV Christopher J. Alexandra M. Z. Slawin,a David J. Williams8 and William J. Coatesb a Department of Chemistry, Imperial College of Science, Technology and Medicine, London S W7 2A Y, UK SmithKline Beecham, The Frythe, Welwyn, Hertfordshire, AL6 9AR, UK Although irradiation of N-chloroacetyltryptophan results in a poor yield of photocyclisation to the indole 4-position due to competing cyclisation to C-2, the photocyclisation of (dichloroacety1)tryptophan derivatives gives, after addition of a nucleophile in work-up, 7-substituted pyrrolobenzazocines in good yield and with trans-stereospecificity.N-(Trichloroacety1)tryptophan derivatives also undergo photocyclisation to give 3,4-bridged indoles. The structures of the azocinoindoles 13, 21, 22 and 35, and the azepinoindole 15 were confirmed by X-ray crystallography. In one case the preparation of a cycloalkac,dindole was possible by the irradiation of the a-chloro amide of an indol-3-yl alkanoic acid. Of the naturally occurring indoles, those in which the indole carbonyl derivative of indole-3-propionyl chloride, compound 3-position is bridged to the 4-position (c,d-fused indoles) are 7 (n = 2), albeit in only 24 yield.6 Under the same conditions, among the most interesting in terms of biological activity. the cycloheptaindole 9 (n = 3) was obtained in 73 yield, whilst Examples include the well known lysergic acid 1,rsquo; as well as the 8-membered ring (n = 4) was not formed at all.More 4: Vand indolactam 3,3serotobenine2,2clavicipitic acid recently, the condensation of didehydrotryptophan methyl ester where the indole is bridged by 6-, 7-, 8-and 9-membe ed rings, respectively. HOZC lsquo;N H H 1 2 HO Me0 H H 3 4 In Nature, compounds such as 1 and 2 are invariably biosynthesized from tryptophan, with an isoprene unit being introduced in the indole 4-position by the enzyme dimethyl- allylpyrophosphate tryptophan dimethylallyl transferase. This direct functionalisation of the indole 4-position is extremely difficult to carry out in the laboratory although there are a few examples.Hence, treatment of the anhydride of N-acetylindole- 3-succinic acid, compound 5, with aluminium chloride to give the tetrahydrobenzc,dJindole6, a compound related to Uhlersquo;s ketone, has been described.rsquo; Subsequently it was shown that cyclisations of this sort generally took place at the indole 2- position unless it was blocked, and therefore the analogous indole 8 (n = 2) could only be derived from the 2-ethoxy- t Present address:Department of Chemistry, Loughborough University of Technology, Loughborough, Leics LE11 3TU. 10 with various aldehydes in the presence of camphorsulfonic acid (CSA) or boron trifiuoride-diethyl ether has been reported to yield the 4-cyclised products 11 (21-45).rsquo; However, despite the limited success of the above Friedel-Crafts-type cyclisations in indoles, it is still more common to carry out such cyclisations on indolines,rsquo; and then to oxidise the 5-membered ring at a later stage.The alternative, commonly used laboratory ap- proach involves the linking together of existing functionality in both the 3- and 4-position of the indole ring, such 3,4- disubstituted indoles often being prepared by a ring synthesis (of the 4-substituted compound) such as the Leimgruber- Batchko method,rsquo; followed by an electrophilic substitution to introduce the 3-substituent. ($0lsquo; N oQco2Hlsquo; N AC AC S 6 amp;:o:E:lsquo; I Oamp; CO2Et H H 7 8n=2 9n=3 H H 10 11 Reagents: i, AICl,; ii, RCHO, CSA or BF,*Et,O 798 We have now adapted a photochemically induced ring closure of simple tryptophan derivatives to the synthesis of 3,4-bridged indoles.The results described in full herein consti- tute a useful extension of classic tryptophan chemistry, which has long been used to prepare the well known 2,3-fused indoles such as P-carbolines, to the much more difficult 3,4-fused systems. O Results and Discussion Our photochemical approach is based on an attempted photoreduction of (chloroacetyl)tryptophan," which resulted in an unusual cyclisation to the indole 4-position to give, after esterification, compound 12. Although originally presented as something of a curiosity, the 'Witkop cyclisation' has sub- sequently been used on a number of indole-derived substrates,12 as well as various phenethylamine derivatives.' Such cyclis- ations are also relevant to the photochemistry of some tryptophan-containing pep tide^.'^ The mechanism is discussed in detail in the following paper.H ,C02Me MH 15 l2R=Co2M*L13 R=CH2OH iii 14 R = CHzOTBDPS Scheme 1 Reagents and conditions: i, hv, water; followed by CH,N,, Et,O-MeOH; ii, NaBH,, EtOH; iii, Bu'Ph,SiCl (TBDPSCI), imidazole, DMF Our own attempts to carry out the original photochemical cyclisation,' ' however, were disappointing. Thus, irradiation of W(chloroacety1)tryptophan at 254 nm in aqueous neutral solution, followed by esterification of the crude product with diazomethane, gave the desired pyrrolobenzazocine 12 in poor yield (10-25 over numerous runs), owing in part to competing formation of the 2,3-fused isomer 15, formed by cyclisation to the indole 2-position (Scheme 1).The structure of compound 15 was confirmed by X-ray crystallography (Fig. 1) as was that of the desired bridged product by an X-ray analysis of the Fig. 1 X-Ray molecular structure of methyl 1,2,3,4,5,6-hexahydro-4-oxoazepino4,5-bJindole-2-carboxylate15 showing crystallographic numbering J. CHEM. SOC. PERKIN TRANS. I 1992 Fig. 2 X-Ray molecular structure of 1,3,4,5,6,7-hexahydr0-4-hydroxy-methyl-6-oxopyrrolo4,3,2-fg3benzazocine 13 showing crystallo- graphic numbering crystalline alcohol 13 (Fig. 2) derived by sodium borohydride reduction. No mention was made of this alternative cyclisation product in the original paper, and it was only in the ensuing work 120 that such a possibility was acknowledged, even though in our hands it accounted for considerable quantities of cyclised material.Therefore in an attempt to increase the yield of the required cyclisation product 12 we investigated the effect of solvent, irradiation wavelength, and the nature of the halogen 'leaving group'. The combination of switching to an organic solvent (acetonitrile) and irradiating (254 nm) the methyl ester 16 in place of the acid resulted in a slight increase in yield of the cyclised product 12 (34). Irradiation at 350 nm led only to the recovery of starting material. The effect of 'leaving group' was briefly investigated by studying the irradiation of N-(bromo- acety1)- and -(iodoacetyl)-tryptophan 17 and 18 (Scheme 2).Monitoring of the reaction by HPLC showed that the chloro and bromo compounds reacted at a similar rate to give similar amounts of the desired product 12, although the alternative cyclisation product 15 was more prominent in the reaction mixture from the chloroacetyl precursor 16. The iodoacetyl compound, however, decomposed at a slower rate and gave rise to a number of additional, unidentified products. This may be attributed to the ease with which the carbon-iodine bond undergoes homolysis on irradiation. -12 H 16 X=CI 17 X=amp; 18 X=J Scheme 2 Reagents and conditions: i, hv, MeCN The disappointing yields of the desired 3,4-bridged indoles obtained from the above (halogenoacety1)tryptophan deriva-tives, coupled with the difficulties associated with functional- isation of the 7-position in the ester 12 or the protected alcohol 14 for further elaboration was a severe limitation.Therefore, the use of (dichloroacety1)tryptophan derivatives as precursors was investigated, where the additional halogen would provide built- in functionality for the new ring. Thus, irradiation of (-)-(dichloroacety1)tryptophan methyl ester 19 at 254 nm in acetonitrile gave, after chromatography, the 7-hydroxypyr- rolo4.3.2--g3benzazocine 20 (58) (Scheme 3), a major improvement in yield of photocyclised material. Alcohol 20 presumably arises by hydrolysis of the initially formed 7-chloro J. CHEM.SOC. PERKIN TRANS.1 1992 derivative during the work-up/chromatography. Indeed, when the photolysis reaction mixture was worked up in the presence of other nucleophiles such as methanol or hydroxylamine, the corresponding 7-substituted pyrrolobenzazocines 21 (63) and 22 (51) were formed (Scheme 3). In all cases the yields were better than those obtained from the monochloro derivative and no evidence of competing cyclisation to the indole 2-position was found. The increased yields observed with the dichloro amides may be attributable to the higher selectivity of the chloroacetamido radical as opposed to the unsubstituted acetamido radical. The stabilising effect of chloride is reflected both in the C-H bond energies (D",,,/kcal mol-') * of methane (105.l), chloromethane (100.9), and in the heats of formation (A~,,,,,/kcal mol-') of the methyl (35.1), dichloromethyl (24.1), and trichloromethyl(l9.0) radicals.' H H 20 X=OH 19 21 x=oMe 22 X=NHOH lii LObsol; N 20 H 23 Scheme 3 Reagents and conditions: i, hv, MeCN, then water (chromatography), MeOH, or NH,OH; ii, hv, aq. MeCN The reaction also exhibits a remarkable degree of asymmetric induction in that the 7-substituent is exclusively trans to the ester group at C-4, the structures 21 and 22being confirmed by X-ray crystallography (Figs. 3 and 4). We assume that the reaction proceeds with initial formation of a 7-chloro species with no stereochemical bias. This would be consistent with the observation that photocyclisation of AlaTrp gives a 1: 1 mixture of diastereoisomeric 7-methylpyrrolobenzazocines,'4band with our results for the irradiation of compound 19 in aqueous solution which gave a -1: 1 mixture of 7-hydroxy isomers, the cis-isomer spontaneously cyclising to give the lactone 23 (Scheme 3).In the absence of a nucleophile during the irradiation, the observed trans-stereochemistry must then originate from the addition of a nucleophile during work-up. One possible explanation is shown in Scheme 4, and involves participation of the ester oxygen. Thus of the two possible chlorides (presumably formed in 1:1 ratio), the trans-chloride is displaced in situ by internal attack of the ester oxygen, and the resulting intermediate as well as the remaining cis-chloride are displaced during work-up by the external nucleophile, to give exclusively the trans-isomer product.Evidence for the ease with which the internal displacement of the truns-chloride in these bridged indoles comes from the photocyclisation reaction of N-(dichloroacetyl)tryptophanol24 which gave, after work-up with aq. sodium azide, the bridged ether 25 together with the trans-azide 26 (Scheme 5) albeit in modest yield due to difficulties with their isolation. When the tryptophan01 hydroxy group was protected as its rert-butyl- * 1 cal = 4.184 J. CI 19 -+ H HIN"-HH Scheme 4 Fig. 3 X-Ray molecular structure of methyl 1,3,4,5,6,7-hexahydro- 7-methoxy-6-oxopyrrolo4,3,2-fg3benzazocine-4-carboxylate 21 showing crystallographic numbering U Fig.4 X-Ray molecular structure of methyl 1,3,4,5,6,7-hexahydro-7-hydroxyamino-6-oxopyrroloC4,3,2--~3benzazocine-4-carboxylate 22 showing crystallographic numbering dimethylsilyl (TBDMS) ether, no intramolecular reaction is possible and hence irradiation of the silyl ether 27 followed by addition of azide gave the truns-azide 28 in 36 yield. Deprotection of the silyl ether 28 gave the alcohol 26.These results are consistent with the proposed mechanism. Bearing in mind the previous discussion about the mechan- ism of the photocyclisation, and the effect of additional chloride 800 J. CHEM. SOC. PERKIN TRANS. 1 1992 H H H 25 ::iiL: ::1:BDMS iiici:i,,, Scheme 5 Reagents and conditions: i, hv, MeCN, then NaN,; ii, TBDMSCI, imidazole, DMF; iii, AcOH, aq.THF, heat atoms, the photocyclisation of N-(trichloroacety1)tryptophan derivatives was expected to give even better yields of 4-cyclised products. Indeed, irradiation of the trichloroacetyl methyl ester 29 in wet acetonitrile gave the cyclic keto amide 30 (Scheme 6) in high yield, apparently by way of 7,7-dichloro- and 7-chloro- 7-hydroxy intermediates, When the corresponding trypto-phanol31 was irradiated the cyclic chloro ether 32 was the only isolated product. Since one of two chlorine substituents in the first formed photocyclisation product is necessarily trans to the internal oxygen nucleophile it is readily displaced. Not surprisingly, the remaining chlorine could not be displaced for steric reasons.oa *,Me (fori29) -H bsol;N H 29 R=C02Me 30 31 R=CH20H 33 R=H (for 33) iii or iI c bsol; lgH H 34 X =OMe 32 35 xx=o Scheme 6 Reagents and conditions: i, hv, aq. MeCN; ii, hv, MeCN; iii, hv, MeCN, MeOH The simple photocyclisation of N-(trichloroacety1)trypto-phan methyl ester was also extended to the corresponding tryptamine derivative 33. When the irradiation was carried out in methanolic acetonitrile the major product (42) was the dimethoxyazocinoindole 34 together with 12 of the keto amide 35 (Scheme 6). When the photocyclisation was carried out in aqueous acetonitrile, keto amide 35 was the sole product (64). The structure of compound 35 was confirmed by X-ray crystallography (Fig. 5) which showed that the ketone carbonyl is twisted well out of the plane of the benzene ring.We have also shown that the reaction tolerates an alkyl group at the reaction centre, and have extended the method to the preparation of azocinoindoles 38/39 related to serotobenine 3. Acylation of tryptophan methyl ester with 2-chloro-3-phenylpropionyl chloride 36, prepared from hydrocinnamic acid, gave the chloro amide 37, irradiation of which gave a 1: 3 Fig. 5 X-Ray molecular structure of 1,3,4,5,6,7-hexahydro-6,7-di-oxoPYrroloC4,3,2~~lC3lbenzazocine35 showing crystallographic numbering mixture of the photocyclised products (47 total) with the frans-diastereoisomer39 predominating (Scheme 7)v The a-chloro amide is a key feature in all of the above photocyclisation reactions, and since these all derive from tryptophan the nitrogen of the amide necessarily forms part of the new ring.However, if the chloro amide were 'reversed,' then photocyclisation would lead to a carboxylic bridged indole pL9d OsMemCoc'i H 36 37 1 ii P h a OZMe PhL..@ 0 + / bsol; N bsol; N H H 39 38 Scheme 7 Reagents and conditions: i, TrpOMe, NaHCO,, aq. MeOH; ii, hv, MeCN bearing an amide substituent. This possibility was investigated by the synthesis of two such precursors, the a-chloro amides 44 and 47. The starting indole-3-alkanoic acids 40 and 45 were easily prepared by reaction of indole with the appropriate lactone in the presence of alkali,16 and subsequently converted into the corresponding dimethyl amides 41/46.In the case of the hexanamide 46 it was possible to chlorinate the dianion, formed by addition of lithium diisopropylamide (LDA) (2 mol equiv.) to give the desired a-chloro amide 47 directly. However, the dianion reaction on the pentanamide 41 proved troublesome and therefore the indole NH was protected as its tert-butoxycarbonyl (BOC) derivative 42. Formation of the anion and chlorination then proceeded smoothly to give compound 43, and the BOC group was cleaved in acid to give the required m-chloro amide 44 (Scheme 8). J. CHEM. SOC. PERKIN TRANS. 1 1992 H H 40 n =4 41 n=4 45 n =5 / 46 n =5 X Boc 43 n =3,X=Boc 42 44 n =3,X=H 47 n =4 Scheme 8 Reagents and conditions: i, Bu'O,CCl, Et,N, Me,NH; ii, LDA, THF, 0 "C,then CCl,; iii, (Boc),O, DMAP, MeCN; iv, LICA, THF, -78 "C,then CCI,; v, TFA, CH,Cl,.Irradiation of the exo-amide 47 did indeed result in the desired photocyclisation and the cyclo-octaindole 48 was formed, albeit in poor yield (13). The cyclised product was accompanied by the a,P-unsaturated amide 49, formed by photoelimination of HCl. Attempts to prepare the cyclohepta- indole analogue of compound 48 by photocyclisation of the chloroamide 44 were unsuccessful, with the elimination product 50being the only observed product (57 yield). H H 48 49 n =3 50 n =2 Thus a variety of functionalised tricyclic indoles, in which the 3- and 4-position are bridged by an 8-membered nitrogen- containing ring, can be prepared from tryptophan methyl ester in two simple steps-acylation, and photocyclisation with nucleophilic work-up.The extension of this reaction to tryp- tophol derivatives, and its application in the synthesis of the tumour-promoter indolactam V, are described in the following papers. Experimental General.-Commercially available solvents and reagents were used throughout without further purification, except for those detailed below which were purified as described. Light petroleum refers to the fraction boiling between 40 and 60 "C, and was distilled through a 36 cm Vigreux column before use. Ether refers to diethyl ether; this, together with benzene and toluene, was dried where necessary by storage over sodium wire for several days.Tetrahydrofuran (THF) was distilled from potassium benzophenone ketyl under nitrogen prior to use. Dichloromethane and tetrachloromethane were dried where necessary by distillation from phosphorus pentaoxide. Di- methyl sulfoxide (DMSO) and dimethylformamide (DMF) were stirred for 15 h over barium oxide, decanted, and distilled under reduced pressure before storage over activated 4A molecular sieves, under nitrogen. Pyridine, triethylamine, diisopropylamine, and N-isopropylcyclohexylamine were each distilled from, and stored over, potassium hydroxide pellets. 801 Acetonitrile for photolyses was purified as follows: The reagent- grade solvent was dried by being stirred for 15 h over finely ground calcium hydride, and was then distilled. Phosphorus pentaoxide (5 g dm-3) was added, and the mixture was stirred for a further 15 h before being redistilled through a 30 cm glass-packed column. Tryptophan in all cases refers to natural (9-(-)-tryptophan, which was purchased from the Aldrich Chemical Company and used without further purification. Photolyses were performed in a Rayonet type RS preparative photochemical reactor.Eight RUL 2537 A lamps were used, giving a total output of 120 W predominantly (99) at 254 nm. Solutions of the substrates were placed in a quartz vessel, and degassed by passage of a steady stream of dry nitrogen through the solution for at least 30 min prior to, and during, irradiation. The pH of mixtures was monitored using indicator paper.Analytical TLC was carried out on Merck Kieselgel 60 GF254 aluminium-backed plates.Visualisation was achieved by using UV light at 254 and 360 nm, iodine, and, in the case of indoles, by lightly spraying the plate with Ehrlich's reagent followed by gentle heating to produce a (usually) blue-purple colour. Ehrlich's reagent was prepared by addition of p-(di-methy1amino)benzaldehyde (1 g) to a 25 solution of conc. hydrochloric acid in absolute ethanol (100 cm3). Column chromatography refers to the flash method and was performed on Merck Kieselgel 60 H, under medium pressure provided by means of hand-bellows. The sample mixture was applied to the top of the column as a solution in a small amount of the column eluant, or by preadsorption onto silica.Optical rotations (alD) were measured in the solvent specified by using a Perkin-Elmer 141 polarimeter. Units for aID are in 10-' deg cm2 g-'. IR spectra were recorded on either a Perkin-Elmer model 1710 or 883 Fourier transform IR spectrometer, the samples being analysed as thin films, Nujol mulls, or in solution, as indicated. UV-visible spectra were obtained by using a Philips PU 8740 scanning spectrophoto- meter, the samples being dissolved in spectroscopic-grade methanol. Fourier transform 'H NMR spectra were recorded on either a Bruker WM 200 (200 MHz), a Bruker WM 250 (250 MHz), a JEOL GSX 270 (270 MHz), or a Bruker AM 500 (500 MHz) spectrometer. Chemical shifts are reported in parts per million downfield from SiMe, by reference to the residual protons of the respective solvents.Coupling constants (J) in Hertz are included where possible. 13C Spectra were recorded on either the JEOL GSX 270 (67.9 MHz) or the Bruker WM 250 (62.9 MHz) instrument, and are referenced to the solvent. Electron-impact ionisation mass spectra were performed at Imperial College in the Organic Mass Spectrometry Labora- tory, on an AEI MS 12 or a VG Micromass 7070 B mass spectrometer at an ionisation potential of 70 eV unless otherwise stated. N-(Chloroaceryl)tryptophan.-Tryptophan (1.00 g, 4.90 mmol) was dissolved in 1.0 mol dm-3 sodium hydroxide (4.9 cm3, 4.9 mmol) and the solution was cooled in an ice-bath. Chioroacetyl chloride (0.41 cm3, 0.58 g, 5.1 mmol) was added dropwise to the shaken mixture during 15 min while the pH was maintained at 10-11 by the simultaneous addition of 5 mol dmP3 sodium hydroxide (1.1 cm3, 5.5 mmol).The mixture was stirred at bath temperature for 10 min, then was transferred to a separatory funnel, where it was covered by a layer of ethyl acetate and acidified to pH 2 with 6 mol dm3 hydrochloric acid. The aqueous layer was extracted twice more and the pooled organic extracts were dried over magnesium sulfate. Evaporation left an oil which solidified to a brown mass, recrystallisation of which from water gave tan leaflets of the title compound (1.11 g, 81), m.p. 158-159 "C (lit.,17 159 "C); aID +29.5 (c 0.80 in EtOH) lit.," +32.9 (c 5.58 in EtOH); 802 J. CHEM. SOC. PERKIN TRANS.1 1992 Table 1 Crystal damp;a and data-collection parameters Compound Formula MW Crystal system Cr stal dimensions/mm K $4 I0 PI0 YI0 V/A~ Z Space group D,/g ~m-~ F(cw~(CU-KZ) 0 Range/" No unique reflections No. Observed reflections No. variables R RW gExtinction parameter, s 13 15 21 22 35 CI 3H14NzO2 230.3 C14H14N203 258.3 C15H16NZ04 288.3 C14Hl5N3O4 289.3 c12H1ON202 214.2 Orthorhomic Ort horhombic Monoclinic Orthorhombic Triclinic 0.12 x 0.23 x 0.27 0.27 x 0.33 x 0.47 0.15 x 0.27 x 0.67 0.17 x 0.23 x 0.33 0.10 x 0.17 x 0.67 8.549(2) 10.456(2) 12.230(3) 90 90 90 1093 6.297(2) 10.93 1 (3) 17.908(5) 90 90 90 1233 9.002(2) 7.5 1 O( 2) 10.710(3) 90 113.58(2) 90 664 8.258( 1) 9.326( 1) 14.302(1) 90 90 90 3599 8.605(2) 9.898(2) I2.878(2) 89.12(2) 82.88( 1) 68.59( 1) 1013 4 4 2 8 4 1.40p212121 p2 1 1.44 1.18" P22 2 P-I 1.40 488 544 306 1344 448 7 8 8 7 8 0-58 0-5 8 0-58 658 amp;58 88I 990 978 2757 2726 850 970 964 2229 2456 167 184 205 298 306 0.036 0.030 0.028 0.204 0.036 0.045 0.037 0.03 1 0.206 0.040 o.oO0 77 o.oO0 33 O.OO0 46 0.001 00 O.OO0 29 0.016( 3) 0.013(2) 0.04l(4) 0.013(2) " Compound 22 consisted of two independent molecules in the asymmetric unit, of which one was ordered, and one disordered, plus one molecule of acetone.This is taken into account in the density; the molecular weight given refers to one molecule of compound 22.w-' = a(F) + g2Fz. Table 2 Atom co-ordinates (x lo4) for compound 13 Atom x Y Z 1339(3) 2529(4) 3609(3)3023(3) 3550(3) 2709(4) 1316(4) 798(4) 1928(3) 2792(3) 2697(3) 1716(3) 123 l(3) 267(3) 245(3) -219(3) 7945(2) 8092(3) 7269(3) 6550(2) 5546(3) 5061(3) 5564(3) 6530(3) 1641(3) 5081(3) 66 12(4) 6964( 3) 6455(4) 7194(3) 1245( 3) 3431(3) 2670(3) 1626( 3) 12 19(3) 31 l(2) 7000(3)7158(3) 7318(2) 6545(2) 556 l(3) 5137(2) 5070(3) 6652(4) 8162(3) 1751(3) 2053(3) 1469( 3) 5025(2) 8440(3) 8W(2) 6,(250 MHz; 2H6acetone) 3.29 (1 H, dd, J 6.5 and 14.5, ArCH,), 3.39 (1 H, dd, J 5.3 and 14.5, ArCH,), 4.11 (2 H, s, COCH,CI), 4.80 (1 H, m, CHNHCO), 7.00 (1 H, t, J 7.4, 5-H), 7.08 (1 H, t, J 7.6, 6-H), 7.21 (1 H, S, 2-H), 7.36 (1 H, d, J 8.4, 7-H), 7.51 (1 H, br s, CHNHCO), 7.59 (1 H, d, J7.6,4-H) and 10.14 (1 H, br s, 1-H).Irradiation of N-(Chloroacety1)tryptophan.-A solution of N-chloroacetyltryptophan (245 g, 0.87 mmol) in water (100 cm3) was irradiated for 45 min. The resulting cloudy yellow solution was extracted with ethyl acetate and the extracts were evaporated to give a brown resin. The crude products of twelve such trials of this reaction were combined together (total of 2.93 g having thus been irradiated), dissolved in methanol, and treated with excess of ethereal diazomethane. The solvent was stripped off and the tarry residue was dissolved in the minimum volume of methanol. On storage, a solid precipitated and was collected on a filter and washed with a small amount of methanol.This chromatographically homogeneous, sparingly Table 3 Atom co-ordinates ( x lo4) for compound 15 Atom X Y Z 3 441(4) 1 509(2) 9 M(1) 2 182(4) 558(2) 9 187(1) 456(4) 1016(2) 8 808( 1) 615(4) 2 328(2) 8 846( 1) -640(5) 3 290(2) 8 590(1) -9(5) 4 483(3) 8 733( 1) 1880(5) 4 723(2) 9 112(2) 3 158(5) 3 794(2) 9 372(2) 2 517(5) 2 606(2) 9 243( 1) -1 275(4) 3 14(2) 8 430( 1) -899(4) -1 058(2) 8 422( 1) -756(3) -1 602(2) 9 170(1) 896(4) -1 477(2) 9 636( 1) 847(3) -1 939(2) 10 264(1) 2 776(4) -745(2) 9 369( 1) -2 709(4) -1 706(2) 8 016(1) -4 248(4) -1 213(2) 7 760(1) -2 392(3) -2 908(2) 7 991(1) -4 120(6) -3 631(2) 7 684(2) soluble tan powder was identified as methyl 1,3,4,5,6,7-hexa- hydro-6-oxopyrrolo4,3,2-fg3benzazocine-4-carboxylate 12 (644 mg, 24), a small portion of which was recrystallised, m.p.232-234 "C (from MeOH) (lit.,' ' 230-232 "C); -107 (c 0.35 in EtOH) lit.," -55 k 3 (c 0.35 in EtOH); v,,,-(CHCl,)/cm-' 3476 (indole NH), 3384 (amide NH), 3004,2956, 1744 (ester W), 1466, 1437, 1341, 1283, 1665 (amide W), 1160,1088, 1003,772 and 727; amp;,,,(MeOH)/nm 202 (log E 4.36), 223 (4.34) and 282 (3.76); 6,(250 MHz; 'HJacetone) 3.60 (2 H, d, J9.1, 3-H2), 3.70 (1 H, d, J 12.9, 7-H), 3.78 (3 H, s, C02Me), 4.15 (1 H,d, J 12.1,7-H),4.48 (1 H,m,4-H),6.42(1 H, br s, 5-H), 6.84 (1 H, d, J 7.2,8-H), 6.99 (1 H, t, J 7.6,9-H), 7.22 (1 H, S, 2-H), 7.26 (1 H), d, J8.3,10-H) and 10.19 (1 H, br s, 1-H); 6,(62.9 MHz off-resonance decoupled; C2H,DMSO) 28.4 (t, C-3), 41.4 (t, C-7), 52.0 (9, C02Me), 56.3 (d, C-4), 109.7 (s, C-2a), 110.2 (d, C-lo), 119.5(d,C-8), 121.0(d,C-9), 123.6(d,C-2), 125.7(s,C-7a), 127.7 (s, C-lob), 136.1 (s, C-lOa), 172.6 (s), and 172.9 (s); m/z 258 J.CHEM.SOC. PERKIN TRANS. I 1992 Table 4 Atom co-ordinates ( x lo4) for compound 21 Table 5 Atomic co-ordinates ( x lo4)for compound 22 Atom Y Y Atom x Y -1883(2) 2016(4) 9001(2) -2694( 2 1) 1786(10) 21 3(9) -748( 3) 902(4) 8869(2) -1905(15) 1223(11) 446(10) 55(2) 1729(4) 8189(2) -446( 14) 1369(8) 291(9) 1287(2) 940(4) 7739(2) -390(12) 2054(7) -55(8) 3057(2) 1576( 3) 8539(2) 791(16) 873(9) 429(7) 3310(2) 3429( 3) 8957( 2) 1824(15) 1 180(6) 925(7) 2690(2) 4994(3) 8325(2) 2 129( 16) 197 l(6) 922(6) 3210(2) 6416(3) 8892(2) 2595( 17) 2408(9) 493(5) 121 l(2) 497O(3) 6923(2) 3101(I 8) 3W7) 60x71 1206(2) 6502( 3) 6163(2) 223q 12) 2244(9) -220(6) -270( 2) 5005(4) 7273(2) 3233(20) 2585(9) -631(7) -1181(2) 652q4) 7133(2) 4616( 16) 223q9) -543( 7) -2456(3) 657q4) 7584(2) 723( 12) 247 1 (8) -307(8) -2794(3) 5 149(4) 821O(2) 386( 18) 31 lO(9) -607(10) -1854(3) 3625(4) 8392(2) -1176(17) 33 17( 12) -673( 15) -616(2) 3503(3) 7887(2) -2286(23) 2949(9) -443(10) -2(2) 976(3) 7775( 2) -1900(14) 2306(9) -96(9) 48 54( 2) -375(3) 8028(2) 3361(17) 802( 12) 863(9) 3965(2) 2089(3) 6784( 2) 4452( 17) 1054(9) 721(8) 4817(3) 1596(5) 5953(3) 3202( 17) 72(7) 982(9) 2464(3) 648 l(4) 5678(3) 447q32) -366(13) 983( 18) 5282(28) 4686( 13) 225q18) 3902(23) 4933( 16) 23 12( 18) 397q26) 5660( 17) 2529(25) 5530(26) 5787(11) 2494(15) 2825(40) 61 lO(17) 2837( 16) (M+,83), 199 (8,M -C02Me), 183 (3,171 (24), 170 (23), 154 (23), 144 (79), 143 (100, M -CONHCHC02Me), 115 (31, 2435(32) 677I( 13) 2434( 16) 3401(14) 7244(9) 2056(8)Ar'+) and 85 (17). 471 3( 14) 7451(9) 2158(7)The black filtrate was found by TLC to be a mixture of the 541 3( 16) 7 7 8 7( 7) 177q6)above product and a slightly less polar material.The two 5617(18) 7148( 8) 2732(7) compounds could not be completely separated chromato- 6739( 18) 7652(9) 2928(8) 6081(17) 8307(8) 3203(7)graphically, but crystals of the less polar product separated from enriched early fractions. This material was the alternative 6266(26) 6438(9) 259 I( 15) 7714(27) 6476( 18) 245q 16) cyclisa tion product, methyl 1,2,3,4,5,6-hexuhydro-4-oxouze-8558(50) 5781(20) 2397( 36) pino4,5-bindole-2-curboxylure15, m.p.238-240 "C (Found: 7944(23) 5 195(17) 2155( 15)C, 65.1;H, 5.5; N,10.8.C14H14N203requires C, 65.1;H, 5.5; N, 6417(23) 5166(12) 228q11) 10.9); ID-32.5 (c 1.00 in MeOH); v,,,(CHCl,)/cm-' 1337(50) 7245( 26) 2834(24) 3465 (indole NH), 3382 (amide NH), 3004, 1744 (ester GO), 1WW 6998(24) 29 14(22) 2W26) 76W( 1 1) 3024(11)1671 (amide C=O), 1461, 1434, 1383, 1329, 1314, 1277, 1206, 2648(29) 8396(11) 2925( 13) 1154, 1005 and 643; 1,,,(MeOH)/nm 200 (log E 4.39, 220 748(3 1) 7700( 14) 3304(12)(4.51), 281 (3.86) and 289 (3.80); SH(250 MHz; C2H6acetone) 539(58) 8293( 19) 3716(19)3.01(1 H,dd,J1l.Oand16.O,l-H),3.35(lH,dt,J2.5and16.0, 878(67) 8779(32) 1578(27) I-H), 3.54(1 H, d, J 16.0,5-H), 3.83 (3 H,s, CO,Me), 4.26 (1 H, -678( 56) 8863(24) 1674(22) d, J 17.0,5-H), 4.90 (1 H, m, 2-H), 6.68 (1 H, br s, 3-H), 7.00 -1804(39) 8922( 17) 1376(15) (1 H, t, J 7.0,9-H), 7.07 (1 H, t, J 7.0, 8-H), 7.31 (1 H, d, J 8.0, -1059(41) 8523(20) 2158(18) 7-H), 7.40 (1 H, d, J 7.5, 10-H) and 10.08 (1 H,br s, 6-H); m/z 258 (M+,53), 199 (5, M -C02Me), 170(loo), 144 (34), 143 (59,M -CONHCHCO,Me), 130 (9) and 115 (1 1, Ar").and 614; amp;,,,(MeOH)/nm 201 (log E 4.33), 224 (4.36, 283 1,3,4,5,6,7-Hexuhydro-4-hydroxymethyl-6-oxopyrrolo4,3,2-(3.78)and 290infl;SH(250MHz; C2H6acetone) 3.25 (1 H, dd, fg3benzuzocine 13.-To a suspension of ester 12 (500 mg, J9.2and 15.5,3-H), 3.64 (1 H,3.39(1 H, dd, J5.3 and 15.5,3-H),1.94 mmol) in (3:l) ethanol-water (20 cm3) was added a dd, J 6.3 and 10.8,CHHOH), 3.73 (1 H, dd, J 5.1 and 10.8, solution of sodium borohydride (366 mg, 9.68 mmol) in (3:l) CHHOH), 3.84(1 H, d, J 11.7, 7-H), 3.88 (1 H, m, 4-H), 4.01 ethanol-water (10cm3). Complete solution was effected within (1 H, d, J 12.0, 7-H), 6.14 (1 H, br s, 5-H), 6.82 (1 H, d, J7.0, 30 min, after which TLC revealed no remaining starting 8-H), 6.97(1 H, t, J7.4,9-H), 7.15 (1 H, S, 2-H), 7.25 (1 H, d, J material. The reaction mixture was acidified to pH 2 with dil.8.2, 10-H) and 10.14 (1 H, br s, 1-H);m/z230 (M', 26), 199 hydrochloric acid, saturated with sodium chloride, and (4,M -CHZOH), 171 (11, M -NHCHCHZOH), 149 (lo),extracted with ethyl acetate.The combined extracts were dried 144 (37), 143 (38, M -CONHCHCH,OH), 115 (13,Ar"), 45 over sodium sulfate and evaporated, to give a yellow solid, (60)and 31 (100,CH,OH'+). which was triturated with a small amount of methanol. The remaining microcrystalline powder was the analytically pure 4-(tert-Butyldiphenylsiloxymethy1)-1,3,4,5,6,7-hexuhydro-6-title compound 13 (197 mg), and another crop (77mg) of the oxopyrrofo4,3,2-fg~benzuzocine14.-To a solution of alcohol 13 was isolated from the filtrate by chromatography alcohol 13 (764 mg, 3.32 mmol) and imidazole (497mg, 7.30 (15 EtOH-CH2C12); total yield 274 mg (61), m.p. 246-mmol) in dry DMF (12 ml) was added tert-butylchlorodi- 248 "C (Found: C, 67.7;H, 6.1;N,12.1.CI3Hl4N2O2requires C, phenylsilane (0.95 cm3, 1.0 g, 3.65 mmol).After 15 h the 67.8;H, 6.1;N, 12.2); a,, -96.5 (c 0.0705 in MeOH); precipitated solid was filtered off from the reaction mixture and vmax(KBr)/cm-'3366, 3283br, 2927, 2890, 2851, 1625 (C--O), was washed with a small amount of methanol. The filtrate was 1464, 1432, 1341, 1324, 1272, 1146, 1111, 1059, 1040, 768, 703 evaporated, and triturated with methanol, to give more product Table 6 Atom co-ordinates ( x lo4) for compound 35 Atom Y F z 226( 2) 1 93 1 (2) 537( 1) lOlO(3) 1048(2) 1278(2) 2580(2) 1079(2) 1327(1) 3730(3) 106(2) 2038(2) 55 18(3) 39(2) 1907(2) 5662(2) 1360(2) 2303( 1) 5603(2) 2484(2) 1731(1) 552 l(2) 3673(2) 207 1 (1) 5628(2) 2364(2) 551(1) 6932(2) 2241(2) -3(1)4036(2) 2633(2) 132( 1) 3742( 3) 3561(2) -704( 1) 2244(3) 4001(2) --1135(2) 997(3) 35 17(2) -758(2) 1272(2) 2576( 2) 67(1)2767(2) 2095(2) 552( 1) -1817(2) 4026(2) 7080( 1 ) -1487(2) 5272(2) 7020( 1 ) 82(2) 5039(2) 6520( 1) 689(2) 6275(2) 63W(1 ) 2355(2) 591 l(2) 5623( 1) 3753(2) 5070( 1) 6175(1) 4438(2) 3644(2) 6128(1) 5544( 1 ) 2895( 1) 6643( 1 ) 3853(2) 28 32( 2) 5357( 1) 4810(2) 2308( 1) 4559( 1) 2322(2) 2521(2) 5684( 1 ) 2U6( 2) 1102(2) 5478(2) 1173(3) 599(2) 5833( 2) -285(3) 1501(2) 6394(2) -454(2) 2926(2) 6588( 1) 810(2) 3 504( 2) 624O(1 ) for a total yield of 1.19 g (76) of the analytically pure title compound 14 as a microcrystalline solid, m.p. 210 "C (Found: C, 74.1; H, 6.8; N, 5.9.C,,H,,N,O,Si requires C, 74.3; H, 6.9; N, 6.0); ID-26.0 (c 0.500 in MeOH); v,,,(CHCl,)/cm-' 3478 (indole NH), 3382 (amide NH), 3000, 2959, 2930, 2859, 1650 (C=O), 1463, 1428, 1339, 1204, 1111 (CH,OSi), 938, 824, 807, 695 and 614; /I,,,(MeOH)/nm 201 (log E 4.70), 218 (4.58) and 283 (3.77); SH(250 MHz; 'H,acetone) 1.10 (9 H, s, SiCMe,), 3.35 (1 H, dd, J 5.9 and 15.9, 3-H), 3.49 (1 H, dd, J 9.7 and 15.8, 3-H), 3.84 (1 H, 7-H), 3.85 (2 H, m, CH,OSi), 3.91 (1 H, m, 4-H), 4.11 (1 H, d, J 12.8, 7-H), 6.30 (1 H, br s, 5-H), 6.83 (1 H, d, J 7.1, 8-H), 6.98 (1 H, t, J 7.8, 9-H), 7.14 (1 H, S, 2-H), 7.25 (1 H, d, J8.2, 10-H), 7.45 (6 H, m, SiPh m-andp-H), 7.75 (4 H, m, SiPh o-H) and 10.13 (1 H, br s, 1-H); 6,(62.9 MHz; 'H,DMSO) 18.7 (SiCMe,), 26.6 (SiCMe,), 28.1 (C-3), 41.8 (C-7), 55.9 (C-4), 67.1 (CH,OSi), 110.2 (C-2a), 11 1.0 (C-lo), 119.5 (C-8), 120.9 (C-9), 123.5 (C-2), 125.7 (C-7a), 127.7 (SiPh C-ipso), 128.1 (C-lob), 129.7 (SiPh C-m), 132.7 (SiPh C-p), 135.0 (SiPh C-o), 136.3 (C-lOa) and 172.7 (C-6); m/z 468 (M', 773, 411 (100, M -CMe,), 333 (23), 240 (17), 199 (29, M -CH20SiR3), 183 (7), 171 (19, M -NHCHCH20SiR3), 162 (ll), 154 (6), 144 (50), 143 (20), 135 (12), 115 (12, Ar") and 77 (6).N-(Chluruacety1)tryptophanMethyl Ester 16.-A solution of N-(chloroacety1)tryptophan (1.00 g, 3.56 mmol) in methanol (10 cm3) was treated with excess of diazomethane in ether. The solvent was evaporated off and the resulting light yellow oil was purified by dry flash chromatography (light petrol- eum -,ether -,5 methanol-ether gradient) to give the title compound 16 (0.939 g, 89) as a glass which crystallised on storage, m.p.133-1 34 "C (from benzene) (Found: C, 57.1; H, 5.2; N, 9.5. C14HlsClN20, requires C, 57.1; H, 5.1; N, 9.5); a,,+ 11.0 (c 1.00 in MeOH); v,,,(CHCl,)/cm-' 3476 (indole NH), 3405 (amide NH), 3046, 2998, 2954, 1742 (ester C=O), 1675 J. CHEM. SOC. PERKIN TRANS. i 1992 (amide C=O), 1528,1457, 1439,1356, 1260,1181, 1092 and 805; ;1,,,(MeOH)/nm 219 (log E 4.52), 280 (3.75), and 289infl; 6,(250 MHz; 2H6acetone) 3.25 (1 H, dd, J 6.8 and 14.5, ArCHH), 3.33 (1 H, dd, J 5.6 and 14.5, ArCHH), 3.65 (3 H, s, C02Me), 4.10 (2 H, s, COCH,Cl), 4.77 (1 H, m,CHNHCO), 7.02 (1 H, t, J 7.3, 5-H), 7.09 (1 H, t, J 7.3, 6-H), 7.20 (1 H, S, 2-H), 7.37 (1 H, d, J 8.0, 7-H), 7.54 (1 H, d, J 7.5, 4-H), 7.61 (1 H, br s, CHNHCO) and 10.19 (1 H, br s, 1-H); m/z 294 (M', 7), 201 (13, M -H,NCOCH,Cl), 170 (2), 130 (100, ArCH,'+), 103 (4) and 77 (5).Irradiation of N-(chloroacety1)tryptophanMethyl Ester 16.-A solution of N-(chloroacety1)tryptophan methyl ester 16 (681 mg, 2.3 1 mmol) in acetonitrile (120 cm') was irradiated for 3.5 h. The solvent was evaporated off and the resulting dark brown resin was taken up in methanol and adsorbed onto the minimum amount of silica gel. This was applied to the top of a dry flash column through which increasingly polar eluents were passed, starting with light petroleum containing increasing proportions of ether and finishing with 22 methanol-ether.Those fractions enriched in the correct isomer were combined and evaporated and the residue was triturated with methanol, to give chromatographically homogeneous methyl 1,3,4,5,6,7- hexahydro-6-oxopyrrolo4,3,2-fg3 benzazocine-4-carboxyl-ate 12 (205 mg, 34). N-(Bromoacety1)tryptophan Methyl Ester 17.-The proced-ure was identical with that for the N-(chloroacety1)tryptophan 16, substituting bromoacetyl chloride (0.44cm', 0.85 g, 5.4 mmol) for chloroacetyl chloride. The product acid was dis- solved in methanol and treated with excess of diazomethane in ether. Evaporation of the solvent gave a light brown solid, which was chromatographed (20 Et20-CH2Cl,) to give the title compound 17 (1.30 g, 78) as crystals, m.p.141-142 "C (Found: C, 49.6; H, 4.4; N, 8.2. CI4H1 ,BrN,O3 requires C, 49.6; H, 4.5; N, 8.3); a,, + 17.3 (c 2.00 in MeOH); vmax-(CHCl,)/cm-' 3478 (indole NH), 3400 (amide NH), 301 1,2956, 1744 (ester c--O),1671 (amide GO),1523, 1458, 1441, 1421, 1360, 1093, 1012 and 988; I,,,(MeOH)/nm 218 (log E 4.54) and 279 (3.76); 6,(250 MHz; C2H6acetone) 3.23 (1 H, dd, J 6.7 and 14.4, ArCHH), 3.31 (1 H, dd, J5.6 and 14.4, ArCHH), 3.65 (3 H, s, CO,Me), 3.92 (2 H, s, COCH,Br), 4.76 (1 H, m, CHNHCO), 7.02 (1 H, t, J 7.2, 5-H), 7.09 (1 H, t, J 7.2, 6-H), 7.20 (1 H, S, 2-H), 7.37 (1 H, d, J 8.0, 7-H), 7.54 (1 H, d, J 7.8, 4-H), 7.67 (1 H, br s, CHNHCO) and 10.13 (1 H, br s, 1-H); m/z 338 (M', 273, 201 (11, M -H2NCOCH,Br), 170 (3), 149 (3) and 130 (100, ArCH,").N-(Ioduacety1)tryptophan Methyl Ester 18.--N-(Bromo-acety1)tryptophan methyl ester 17 (400 mg, 1.18 mmol) and sodium iodide (884 mg, 5.90 mmol) were introduced into a 25- cm3 round-bottomed flask with stirring bar. Stirring was initiated and acetone (4 cm3) was added to the solid mixture all at once. After 10 min the slurry was evaporated to dryness and the solid residue was partitioned between dichloromethane and water. The organic layer was separated, washed twice with water, and dried over magnesium sulfate. Evaporation of the solvent., and seeding with a minute crystal of the starting material, gave the analytically pure title compound 18 (440 mg, 97) in the form of a pale yellow crystalline powder, m.p.115- 116 "C (Found: C, 43.8; H, 3.9; N, 7.2. CI4Hl5IN2O3 requires C, 43.5; H, 3.9; N, 7.3); aID + 17.0 (c 2.00 in MeOH); v,,,,,(CHC1,)/cm-' 3478 (indole NH), 3412 (amide NH), 3010, 2955, 1742, (ester C--O),1673 (amide C=O), 1516, 1458, 1442, 1422, 1360, 1181, 1134, 1093, 1011 and 988; ;1,,,(MeOH)/nm 218 (log E 4.55) and 279 (3.80); SH(250 MHz; 'H,acetone) 3.21 (1 H, dd, J 6.7 and 14.7, ArCHH), 3.28 (1 H, dd, J 5.6 and 14.7, ArHCH), 3.65 (3 H, s, C02Me), 3.80 (2 H, s, COCH,I), J. CHEM. SOC. PERKIN TRANS. I 1992 4.76 (1 H, m, CHNHCO), 7.03 (1 H, t, J 7.4,5-H), 7.10 (1 H, t, J 7.5,6-H), 7.21 (1 H, S, 2-H), 7.38 (1 H, d, J7.8,7-H), 7.55 (1 H, d, J7.8, 4-H), 7.73 (1 H, br s, CHNHCO) and 10.15 (1 H, br s, 1-H); mi= 386 (M', 679,231 (2), 201 (18, M -H2NCOCH,I), I44 (7) and I30 (100, ArCH2'+).Quantitative Analysis and Rate Study of the Irradiation of N-Cltloroucet~~l(16)-, N-Bromoacetyl (17)-, and N-Iodoacetyl (18)-trjptophan Methyl Ester.-Solutions of N-chloroacetyl (I@-, N-bromoacetyl (17)-, and N-iodoacetyl (18)-tryptophan methyl ester in acetonitrile (2 mg per cm3) were irradiated and analysed at intervals oft = 1,5, 14,25,45, and, in the case of N- (iodoacety1)tryptophan methyl ester 18, 75 min. A quantitative analysis was performed by removal of an aliquot (1 cm3) at each interval, evaporation to dryness, and redissolution of the analyte in the chromatography solvent (40 water-methanol) (20 cm3). Of this, a portion (18 mm3) was taken and injected onto an ODS microanalytical HPLC column and eluted with the above mentioned solvent at the rate of 1.0 cm3 min- '.Peaks registered at 265 nm were integrated by the clip-and-weigh method and the area was expressed in terms of concentration by co-analysis of standard solutions of the product and start- ing materials to obtain conversion factors. First-order rate constants (k were calculated by substituting the data into eqn. (1) for the idealised equation A -B (below); the results of this investigation were discussed in the text. N-(Dic.hl~)r.oacet~l)tr~ptopliunMethjpl Ester 19.--A two-phase system of tryptophan methyl ester (3.50 g, 16.0 mmol) in dichloromethane (30 cm3) and sodium hydrogen carbonate (2.70 g, 32.1 mmol) in water (30 cm3) was stirred vigorously at 0 "C while a solution of dichloroacetyl chloride (2.60 g, 17.6 mmol) in dichloromethane (10 cm3) was added dropwise during 15 min.The reaction mixture was kept for an additional 1 h at O"C, then poured into water and extracted with dichloro- methane. The combined organic layer was dried over sodium sulfate and evaporated, to give the title compound 19 (5.18 g, 98) as an off-white solid, m.p. 115-122 "C. This material was chromatographically homogeneous and sufficiently pure for use, but recrystallisation of a small portion from ethyl acetate- light petroleum gave crystals, m.p. 124.5-125 "C (Found: C, 51.1; H, 4.2; N, 8.5. Cl4Hl4CI2N2O3 requires C, 51.1; H, 4.3; N; 8.50); ID +23.9 (c 1.625 in MeOH); v,,,(CHC~~)/C~-' 3476 (indole NH), 3403 (amide NH), 3006, 1742 (ester C=O), 1692 (amide C=O), 1522, 1457, 1441, 1364, 1250, 1183, 1092, 812, 776, 743 and 720; E,,,,(MeOH)/nm 219 (log E 4.59, 280 (3.76) and 289infl; 6,(250 MHz; C2H6acetone) 3.29 (1 H, dd, J6.6 and 14.9, ArCHH), 3.37 (1 H,dd, J5.6 and 14.9, ArCHH), 3.68 (3 H, s, CO,Me), 4.78 (1 H, m, CHNHCO), 6.43 (1 H, s, COCHCI,), 7.02 (1 H, t, J 7.3,5-H), 7.09 (1 H, t, J 7.6,6-H), 7.19 (1 H, S, 2-H), 7.37 (1 H, d, J 8.1, 7-H), 7.53 (1 H, d, J7.8,4-H), 7.93 (1 H, br s, CHNHCO) and 10.16 (1 H, br s, 1-H); m/z 328 (M', 4"/,), 269 (1, M -CO,Me), 245 (1, M -CHCl,), 201 (6, M -H2NCOCHC12), 170 (2), 158 (l), 130 (100, ArCH2"), 103 (3) and 77 (4).1,3,4,5,6,7-He.xahydro-7-hydroxy-6-o.uopyrrolo4,3,2-fg31-benzazocine-4-carboxylate 20.-A solution of N-(dichloro-acety1)tryptophan methyl ester 19 (256 mg, 0.778 mmol) in acetonitrile (100 cm3) was irradiated for 1 h.The solvent was evaporated off and the residue was chromatographed (30 EtOAc-Et20) to give the title compound 20 (123 mg, 58) as a light brown, amorphous powder (Found: M', 274.0958. CI4Hl4N2O4 requires M, 274.0954; amp;ID -96.4 (c 0.44 in MeOH); v,,,(CHC13)/cm-' 3477 (indole NH), 3386 (amide NH), 3027, 1746 (ester C=O), 1671 (amide C=O), 1461, 1438, 1419,1381, 1323,1282,1173,1112,1013,986,918,854 and 834; A,,,(MeOH)/nm 204 (log E 4.39), 222 (4.34) and 285 (3.78); SH(25O MHz; 2H6acetone) 3.60 (2 H, m, 3-H,), 3.78 (3 H, s, C02Me),4.31 (1 H, m,4-H),4.45 (1 H, br d, OH), 6.15 (1 H, br d, 7-H), 7.06 (1 H, t, J7.4, 9-Hj, 7.23 (1 H, d, J7.3, 8-H), 7.26 (1 H,s,2-H),7.27(1 H,d, J8.1, 10-H)and 10.20(1 H,brs, 1-H); m/z 274 (M', loo), 185 (32), 170 (56), 159 (54), 158 (68), 130 (77), 115 (24, Ar*+), 77 (22), 58 (24) and 43 (77).Methyl 1,3,4,5,6,7- Hexahydro-7-methoxy-6-oxopyrrolo4,3,2-fg3benzazocine-4-carboxyfate21.-A solution of N-(dichlo- roacety1)tryptophan methyl ester 19 (258 mg, 0.784 mmol) in acetonitrile (100 cm3) was irradiated for 1 h. The solvent was evaporated off and the residue was chromatographed (8 MeOH-CH2CI,) to give the title compound 21 (143 mg, 63) as a yellow resin. Slow evaporation of a solution of compound 21 in acetone caused light yellow crystals to separate, m.p.224- 229 "C after evolving gas at 190-191 "C (Found: M', 288.1 109. CI5Hl6N2O4requires M, 288.1110); aID -93.7 (c 0.413 in MeOH); v,,,(CHC13)/cm-' 3478 (indole NH), 3388 (amide NH), 3008, 2956, 2930, 2857, 1743 (ester C=O), 1677 (amide C=O), 1460,1438,1419,1347,1284,1171,1125,1086,1015,966, 838 and 816; A,,,(MeOH)/nm 202 (log E 4.39), 225 (4.28) and 286 (3.72); 6,(250 MHz; C2H6acetone) 3.56 (3 H, s, 7-OMe), 3.61 (2 H, m, 3-H,), 3.81 (3 H, s, C02Me),4.30(1 H, m, 4-H), 5.86 (1 H, s, 7-H), 6.71 (1 H, br d, 5-H), 7.03 (1 H, t, J7.5, 9-H), 7.18 (1 H,d, J7.2,8-H), 7.23 (1 H,s, 2-H), 7.25 (1 H, 10-H) and 10.23 (1 H, br s, 1-H); 6,(62.9 MHz modulated spin echo experiment; C2H6DMSO) 28.7 (C-3), 52.1 (CO,Me), 56.0 (C-4), 56.6 (7-OMe), 78.1 (C-7), 109.2 (C-2a), 110.5 (C-lo), 113.9 (C-8), 121.1 (C-9), 123.7 (C-2), 124.0 (C-lob), 130.1 (C-7a), 136.1 (C-lOa), 172.9, and 173.6; m/z 288 (M', loo), 273 (34, M -Me), 245 (6), 229 (20, M -CO,Me), 213 (20), 198 (14, M -OMe -CO,Me), 174 (52), 170 (40), 169 (46), 158 (50), 154 (46), 144 (22), 130 (46), 115 (30, Are+) and 47 (52).Methyl 1,3,4,5,6,7- Hexahydro-7-hydroxyamino-6-oxopyrrolo-4,3,2-fg3benzazocine-4-carboxylate22.-A solution of N-(dich1oroacetyl)tryptophan methyl ester 19 (303 mg, 0.920 mmol) in acetonitrile (100 cm3) was irradiated for 70 min. The resulting rust-coloured solution was evaporated to a volume of -10 cm3, and a solution of hydroxylamine, which was prepared from hydroxylamine hydrochloride (500 mg, 7.2 mmol) and potassium hydroxide (400 mg, 7.1 mmol) in water (2 cm3), was added to the shaken mixture.The reaction mixture could be decanted from the precipitated salts, which were then thoroughly washed with acetonitrile and discarded. The solvent was evaporated off and the residue was purified by chroma- tography (9 MeOHH,CI,) to give the tirle compound 22 (135 mg, 51) as a brown powder. Slow evaporation of solutions of compound 22 in acetone gave cubes, m.p. 130 "C with vigorous gas evolution (Found: M+, 289.1062. C14H15- N304 requires M, 289.1063); ED -41.2 (c 0.600 in MeOH); v,,,(CHC13)/cm-' 3478 (indole NH), 3264, 1742 (ester M), 1670 (amide C=O), 1603, 1559, 1541, 1522, 1508, 1459, 1436, 1420, 1340, 1285, 1173 and 992; 6,(250 MHz; C2H6acetone) 3.45-3.70 (2 H, br m, 3-H,), 3.74 (3 H, s, C02Me), 4.26 (1 H, m, 4-H), 5.57 (1 H, br s, 7-H), 6.86 (1 H, d, J7.1, 8-H), 7.01 (1 H, t, J 7.8, 9-H), 7.24 (1 H, s, 2-H), 7.26 (1 H, 10-H) and 10.18 (1 H, br s, 1-H); 6,(62.9 MHz modulated spin echo experiment; 2H6DMSO) 27.8 (C-3), 51.6 (C02Me), 55.9 (C-4), 64.0 (C-7), 109.0 (C-2a), 110 (C-lo), 114.0 (C-8), 120.8 (C-9), 123.3 (C-2), 124.4 (C-lob), 128.9 (C-7a), 135.7 (C-lOa), 172.1 and 174.4; m/z 289 (M', 273, 273 (12), 272 (lo), 271 (23, M -HZO), 258 (4 -OMe), 241 (4), 226 (ll), 212 (8), 195 (5), 184 (lo), 169 (31), 156 (42), 155 (loo), 142 (19), 130 (26), 115 (9, At"), 44 (86) and 31 (42).Irradiation of N-(Dichloroacety1)tryptophan Methyl Ester 19 in Aqueous Solution.-A solution of N-(dichloroacety1)trypto-phan methyl ester 19 (200 mg, 0.608 mmol) in (80:20) acetonitrile-water (100 cm3) was irradiated for 1 h.Most of the acetonitrile was stripped off under reduced pressure and the resulting cloudy solution was diluted with water (100 cm3) and extracted with dichloromethane. The extracts were dried over sodium sulfate and evaporated, and chromatography (6 MeOH-CH,Cl,) of the residue gave alcohol 20 (36 mg, 21) J. CHEM. SOC. PERKIN TRANS. 1 1992 3.28 (1 H, d, J 16.8,3-H), 3.55 (1 H, dd, J7.7 and 17.0,3-H),4.07 (3 H, m, 4-H and 12-H2), 5.05 (1 H, s, 7-H), 6.92 (1 H, d, J 7.2, 8-H), 6.97 (1 H, t, J7.4,9-H), 7.18 (1 H, s, 2-H) and 7.33 (1 H, dd, J 1.7 and 7.4, 10-H); m/z 228 (M+, loo), 199 (3), 185 (S), 170 (29), 158 (33), 149 (6), 143 (9), 130 (40), 115 (15, Are+), 103 (9), 77 (16) and 44 (33).Continued chromatography gave 7-azido-l,3,4,5,6,7-hexa-hydro-4-hydroxymethyl-6-oxopyrrolo4,3,2-fg31 benzazocine 26 (25 mg, 9), m.p. 215-218 "C with evolution of gas (Found: and 1,3,4,5,6,7-he.rahydro-6,12-dioxo-7,4-(epoxymethano)pyr-M+, 271.1071. CI3Hl3N5O2 requires M, 271.1069); MID rolo4,3,2-fg3benzazocine 23 (27 mg, 18), as a pale yellow -137.2 (c 0.634 in MeOH); v,,,(CHC13)/cm-' 3478 (indole "C (Found: C, 64.4; H, 4.2; N, 11.4. NH), 2113 (N3), 1668 (M),solid, m.p. ~300 1524, 1461, 1435, 1343, 1289 C,,H,,N,O, requires C, 64.5; H, 4.2; N, 11.6); aD +252 and 919; 6,(270 MHz; C2H6acetone) 3.20 (1 H, br d, 3-H), (c 0.190 in MeOH); v,,,(CHCl,)/cm-' 3475 (indole NH), 3.66 (1 H, br m, 3-H), 3.82 (2 H, br s, CH,OH), 4.49 (1 H, t, 3398 (amide NH), 3027, 1752 (ester C=O), 1701 (amide M),4-H), 6.43 (1 H, br s, 7-H), 6.58 (1 H, br s, 5-H), 7.07 (1 H, t, J 1437, 1399, 1366, 1322, 1 192, 1164, 11 11, 1032, 994 and 926; ;I,,,(MeOH)/nm 201 (log E 4.28), 224 (4.30) and 294 (3.75); 6,(250 MHz; C2H6acetone) 3.71 (2 H, m, 3-H,), 4.71 (1 H, m, 4-H), 5.68 (1 H, S, 7-H), 7.10(1 H, t, J7.5,9-H), 7.16 (1 H,dd, J 1.5and7.1,8-H),7.36(1 H,s,2-H),7.52(lH,dd,JlSand7.8, 10-H), 7.88 (1 H, br s, 5-H) and 10.72 (1 H, br s, 1-H); m/z 242 (Mf, loo), 198 (6, M -COZ), 170 (43, M -C02 -CO), 158 (32), 154 (13), 143 (12), 130 (28) and 115 (24, Are+).N-(Dichloroacety1)tryptophanol 24.-A solution of N-(di-chloroacety1)tryptophan methyl ester 19 (200 mg, 0.61 mmol) in ethanol (3 cm3) was added dropwise to a solution of sodium borohydride (1 15 mg, 3.0 mmol) in water (2 cm3) at 0 "C.After 24 h the reaction mixture was warmed to room temperature and methanol (1 cm3) was added to give a homogeneous solution, which was stored for 2 h before being evaporated to minimum volume. Water (50 cm3) was added and the solution was saturated with salt and extracted with ethyl acetate. The extracts were pooled and dried over magnesium sulfate, and evaporation of the solvent gave an off-white solid (172 mg), which was purified by chromatography (0.5 MeOH-Et,O) to yield the title compound 24 (130 mg, 71) in the form of a white crystalline mass, m.p. 118 "C (Found: C, 52.0; H, 4.7; N, 9.3.C13H14C12N202requires C, 51.8; H, 4.7; N, 9.3); aD -19.8 (c 2.00 in MeOH); v,,,(CHC13)/cm-' 3478 (indole NH), 3409 (amide NH), 3031,1688 (M),1522,1457,1337 and 1090; ;I,,,(MeOH)/nm 219 (log E 4.54) and 279 (3.81); 6,(250 MHz; C2H6acetone) 3.01 (1 H, dd, J 6.6 and 14.6, ArCHH), 3.09 (1 H, dd, J 7.4 and 14.8, ArCHH), 3.62 (2 H, m, CH,OH), 4.18 (1 H, m, CHNHCO), 6.36 (1 H, s,COCHCl,), 7.01 (1 H, t, J7.4, 5-H), 7.08 (1 H, t, J7.5,6-H), 7.18 (1 H, S, 2-H), 7.36 (1 H, d, J 8.0, 7-H), 7.64 (1 H, br s, CHNHCO), 7.70 (1 H, d, J 7.6, 4-H) and 10.07 (1 H, br s, 1-H); m/z 300 (M+, 673, 173 (24, M -H,NCOCHCl,), 149 (3,130 (100, ArCH,'+), 117 (7), 103 (5) and 77 (7). Irradiation of N-(Dichloroacety1)tryptophanol24 and Treat- ment with Sodium Azide.-A solution of N-(dichloroacety1)- tryptophan01 24 (301 mg, 1.00 mmol) in acetonitrile (100 cm3) was irradiated for 30 min.The resulting opaque, dark green reaction mixture was evaporated to -20 cm3 and saturated aq. sodium azide (1.0 cm3) was added to the vigorously stirred mixture. The mixture was evaporated to dryness and the residue was chromatographed (8 MeOH-CH,Cl,). The first of two compounds to elute was 1,3,4,5,6,7- hexahydro-6-0~0-7,4- (epoxymethano)pyrrolo4,3,2-fg3benzazocine25 (28 mg, 1273, which precipitated from early fractions as highly insoluble, hexagonal crystals, m.p. 300 "C (Found: M +, 228.0896. CI3Hl2N2O2 requires M, 228.0899); aD + 110.0 (c 0.100 in MeOH); v,,,(KBr)/cm-' 3403, 3229, 3114, 2929, 2878, 1677 (C=O), 1640, 1439, 1414, 1356, 1339, 1322, 1133, 11 17, 940, 793, 758, 731 and 625; 1,,,(MeOH)/nm 202 (log E 4.32), 227 (4.29) and 291 (3.81); 6,(250 MHz; C2H6acetone) 7.6, 9-H), 7.11 (1 H, d, J 7.1, 8-H), 7.20 (1 H, br d, 2-H), 7.30 (1 H, d, J 7.6, 10-H) and 10.13 (1 H, br s, 1-H); m/z 271 (M+, 31), 243 (100, M -N,), 230 (29), 228 (85), 225 (13), 200 (12), 197 (14), 185 (26), 170 (44),156 (31), 155 (31), 143 (42), 130 (26), 1 15 (23, Ar"), 102 (7), 77 (14) and 43 (22).a-(tert-Butyldimethylsiloxymethyl)-N-(dichloroacetyl)trypto-phamine 27.-A mixture of N-(dichloroacety1)tryptophanol 24 (200 mg, 0.66 mmol), TBDMSCl (100 mg, 0.73 mmol), and imidazole (100 mg, 1.5 mmol) in DMF (2 cm3) was stirred for 18 h at room temperature.Most of the solvent was removed under reduced pressure and the residue was chromatographed (ether) to yield the title compound 27 (233 mg, 84) as a clear resin (Found: C, 54.7; H, 6.8; N, 6.5. C19H,,Cl,N,0,Si requires c, 54.9; H, 6.8; N, 6.7); aD -27.5 (c 0.880 in MeOH); v,,,(CHCl,)/cm-' 3478 (indole NH), 3415 (amide NH), 3031, 2954,2929,2857,1688 (M),1518,1457,1254,1115 (CH,OSi), 1090, 836, 812 and 712; i,,,(MeOH)/nm 219 (log E 4.54) and 279 (3.76); 6,(250 MHz; 'H6acetone) 0.07 (3 H, s, SiMe), 0.08 (3 H, s, SiMe), 0.93 (9 H, s, SiCMe,), 2.99 (1 H,dd, J 6.8 and 14.6, ArCHH), 3.12 (1 H, dd, J7.1 and 14.6, ArCHH), 3.71 (2 H, d, J4.9, CH,OSi), 4.22 (1 H, m, CHNHCO), 6.33 (1 H, S, COCHCI,), 7.01 (1 H, t, J7.4, 5-H), 7.09 (1 H, t, J7.5, 6-H), 7.18 (1 H, s, 2-H), 7.37 (1 H, d, J8.1, 7-H), 7.58 (1 H, br s, CHNHCO), 7.67 (1 H, d, J 7.8, 4-H) and 10.10 (1 H, br s, 1-H); m/z 414 (M', 8), 380 (3), 357 (30, M -CMe,), 323 (9), 287 (28, M -HZNCOCHCI,), 230 (27), 186 (5), 184 (7), 156 (21), 130 (100, ArCH,") and 116 (7, Ar").7-Azido-4-(tert-butyldimethylsiloxymethyl)-1,3,4,5,6,7-hexa-hydro-6-oxopyrrolo4,3,2-fg3benzazocine28.-A solution of the N-(dichloroacety1)tryptophanol tert-butyldimethylsilyl de- rivative 27 (204 mg, 0.49 mmol) in acetonitrile (100 cm3) was irradiated for 45 min. The solution was evaporated to -20 cm3 and a solution of sodium azide (96 mg, 1.5 mmol) in water (2 cm3) was added to the shaken mixture. The reaction mixture was then diluted with dichloromethane (100 cm3) and dried with sodium sulfate.The solvent was evaporated off and the residue was chromatographed (5 MeOH-CH2C12) to give the title compound 28 (68 mg, 36) in the form of a light brown resin (Found: M -N,, 357.1872. CI9H,,N,O2Si requires m/z, 357.1873); aD -121.7 (c 0.235 in MeOH); v,,,(CHCl,)/cm~' 3477 (indole NH), 3384 (amide NH), 3029, 3009, 2955, 2931, 2885, 2859, 2112 (N,), 1668 (C=O), 1463, 1435, 1420, 1343, 1260,1112, (CH,OSi), 1015,944 and 838; I,,,(MeOH)/nrn 203 (log E 4.38) and 289 (3.79); 6,(250 MHz; 'H6acetone) 0.18 (6 H, s, SiMe,), 0.98 (9 H, s, SiCMe,), 3.19 (1 H, br d, 3-H), 3.68 (2 H, br m, 3- and 4-H), 3.92 (2 H, br s, CH,OSi), 6.29 (1 H, br s, 7-H),6.70(1H,brs,5-H),7.08(1 H,t,J7.6,9-H),7.15(1 H,d,J 7.1,8-H), 7.21 (1 H,s,2-H),7.31 (1 H,d, J7.7, 10-H)and 10.20(1 H, br s, 1-H); m/z 385 (M+,0.2),359 (3), 357 (4, M -N,), 344 (4), 328 (1, M -CMe,), 300 (5, M -N, -CMe,), 287 (3), 255 J.CHEM. SOC. PERKIN TRANS. I 1992 (2), 225 (21,212 (l), 184 (3), 182 (4), 174 (2), 171 (3), 169 (3), 156 (6), 149 (2), 143 (4), 132 (3,116 (4) and 75 (100). Desilylation of Compound 28.-A solution of silyloxy derivative 28 (60 mg, 0.16 mmol) in (3: 1 :1) acetic acid-THF- water (2 cm') was heated at 75 "C for 3.5 h. The reaction mixture was transferred to a separatory funnel containing 10 aq. sodium hydrogen carbonate (100 cm3) and was extracted with dichloromethane. The extracts were dried over sodium sulfate, then evaporated, and the residue was chromatographed (7 MeOH-CH2C12) to yield a product indistinguishable (TLC, NMR) from azido alcohol 26 (6.4 mg, 15).N-(Trichlor oace ty 1)tryptophan Me thy1 Ester 29.-A two-phase system of tryptophan methyl ester (300 mg, 1.4 mmol) in dichloromethane (5 cm3) and sodium carbonate (318 mg, 3.0 mmol) in water (3 cm3) was vigorously stirred at 0 "C while a solution of trichloroacetyl chloride (275 mg, 1.5 mmol) in dichloromethane (5 em3) was added dropwise. The reaction mixture was kept for an additional 1 h at 0 "C, during which the majority of the title compound 29 crystallised out of the reaction mixture. This product was collected on a filter and the filtrate was diluted with water and extracted with dichloro- methane, to provide an additional crop of compound 29, the whole of which was combined and recrystallised from methanol to give rod-shaped crystals (433 mg, 87), m.p.176-178 "C (Found: C, 46.3; H, 3.5; N, 7.7. C14Hl,C13N20, requires C, 46.2; H, 3.6; N, 7.7); aD -22.0 (C 1.00 in MeOH); vm,,(CHC13)/cm-' 3476 (indole NH), 3403 (amide NH), 3037, 3019, 2954, 1744 (ester C=O), 171 1 (amide GO), 1599, 151 1, 1457, 1441, 1360, 1237, 1092, 1011 and 822 (CCl,); A,,,-(MeOH)/nm 217 (log E 4.53) and 277 (3.76); 6,(250 MHz; C2H6acetone) 3.37 (1 H, dd, J 7.6 and 14.9, ArCHH), 3.46 (1 H, dd, J 5.2 and 14.9, ArCHH), 3.72 (3 H, s, C02Me), 4.76 (1 H, m, CHNHCO), 7.03 (1 H, t, J 7.3, 5-H), 7.10 (1 H, t, J 7.5, 6-H), 7.25 (1 H, S, 2-H), 7.38 (1 H, d, J 7.8, 7-H), 7.58 (1 H, d, J 7.8, 4-H), 8.18 (1 H, br s, CHNHCO) and 10.20 (1 H, br s, 1 -H); m/z 362 (Mf, 473, 328 (3), 303 (1, M -C02Me), 245 (3, M -CCI,), 201 (6 M -HzCOCCl,), 185 (l), 170 (2), 158 (l), 143 (l), 130 (100, ArCH,*+), 103 (3), 77 (3) and 36 (14).Methyl 1,3,4,5,6,7-Hexahydro-6,7-dioxopyrro104,3,2-fg3-henzazocine-4-carboxylate 30.-A solution of N-(trichloro-acety1)tryptophan methyl ester 29 (200 mg, 0.55 mmol) in (95: 5) acetonitrile-water (100 cm3) was irradiated for 1 h. The dark orange solution was evaporated and the residue was chroma- tographed (6 MeOH-CH,Cl,) to give the title compound 30 (123 mg), which coeluted with a dark red chromophore which was removed by rechromatography using a high silica-to- compound ratio.The final yield of compound 30 was 112 mg (75) as a fluorescent, dark yellow crystalline solid, m.p. 256- 258 "C with evolution of gas (Found: C, 61.5; H, 4.4; N, 10.1. C14H12N204 requires C, 61.8; H, 4.4; N, 10.3); aID -302 (c 0.500 in MeOH); v,,,(CHC13)/cm-' 3689, 3472 (indole NH), 1746 (ester C=O), 1679 (amide GO), 1648, 1603, 1437, 1343, 1287, 1233, 1123,998,805 and 710; L,,,(MeOH)/nm 205 (log E 4.39), 235 (4.03) and 360 (3.65); 6,(250 MHz; C2H6acetone) 3.42 (1 H, dd, J 12.2 and 16.7,3-H), 3.63 (1 H, d, J16.7,3-H),3.80(3H,s,CO,Me),4.90(1H,m,4-H),7.22(1H, t, J 7.7,9-H), 7.37 (1 H, br d, J 7.2, 8-H), 7.51 (1 H, s, 2-H), 7.72 (1 H, dd, J 1.2 and 8.0, 10-H), 7.80 (1 H, br d, 5-H) and 10.97 (1 H, br s, 1-H); m/z 272 (M', 6873, 244 (36, M -CO), 185 (52, M -CO -C02Me), 170 (53), 158 (91), 145 (18), 144 (22), 130 (84), 129 (loo), 43 (41) and 28 (78).N-( Trichloroacetyl )tryptophan01 31.-To a suspension of N- (trichloroacety1)tryptophan methyl ester 29 (300 mg, 0.83 mmol) in ethanol (12 cm3) at 0 "C was added a solution of sodium borohydride (1 56 mg, 4.1 mmol) in water (3 cm3). After 807 48 h the reduction was still incomplete but dehalogenation of the trichloromethyl group was beginning to predominate so the reaction was halted. The mixture was evaporated to a minimum volume, diluted with water, saturated with sodium chloride and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and evaporated and the residue was chromatographed (4 MeOH-CH,Cl,) to give the title compound 31 (48 mg, 17) as a resin (Found: M+, 334.0047.C13H1,C13N202 requires M, 334.0043); aD -26.2 (c 0.706 in MeOH); ~,,,,,(CHCl~)/crn-~ 3479 (indole NH), 341 7 (amide NH), 3025, 3011, 2934, 1708 (GO),1510, 1458, 1442, 1420, 1339, 1092, 1036, 1012, 900, 854 and 824 (CCl,); 6,(250 MHz; 2H6acetone) 3.07 (1 H, dd, J 6.5 and 14.6, ArCHH), 3.15 (1 H, dd, J 7.4 and 14.6, ArCHH), 3.70 (2 H, m, CH,OH), 4.21 (1 H, m, CHNHCO), 7.02 (1 H, t, J7.6,5-H), 7.09 (1 H, t, J 7.6, 6-H), 7.21 (1 H,s,2-H), 7.37 (1 H,d, J8.1, 7-H), 7.70(1 H, d, J 7.9,4-H), 7.87 (1 H, br s, CHNHCO) and 10.10 (1 H, br s, 1-H); m/z 334 (M', 473, 300 (l), 217 (1, M -CCl,), 216 (l), 197 (l), 173 (16, M -H,NCOCCl,), 130 (100, ArCH'+), 58 (19), 43 (54), 36 (1 6) and 3 1 (48).7-Chloro-1,3,4,5,6,7-hexahydro-6-oxo-7,4-(epoxymethmo)pyr-rolo4,3,2-fg3benzazocine 32.-A solution of N-(trichloro- acety1)tryptophanol 31 (86 mg, 0.26 mmol) in acetonitrile (50 cm3) was irradiated for 1 h. The resulting opaque, dark green solution was evaporated and the residue was chromatographed (8 MeOH-CH2C12) to give the title compound 32 (24 mg, 36) as an amorphous, highly insoluble tan solid (Found: M+, 262.0503. C13H1 ,ClN, requires M,262.0509); aID +67.1 (c 0.216 in MeOH); vm,(CHC13)/cm-' 1684 (C=O), 1640, 1450, 1417 and 1348; 6,(250 MHz; c2H6acetone) 3.27 (1 H, d, J 16.7, 3-H), 3.59 (1 H, dd, J 7.9 and 16.7, 3-H), 4.14 (2 H, d, 4- and 12-H),4.30(1H,d,12-H),7.07(lH,t,J7.7,9-H),7.22(1H, s, 2-H), 7.40 (1 H, d, J 7.9, 10-H), 7.47 (1 H, d, J 7.5, 8-H) and 7.81 (1 H, br s, 5-H); m/z 262 (M', 69), 227 (12, M -Cl), 219 (5, M -CONH), 199 (12), 192 (39), 184 (100, M -CONH -Cl), 169 (14), 164 (7), 156 (21), 154 (21), 129 (42), 115 (9, Ar"), 110 (4), 92 (13) and 77 (19).Trichloro-N-2'-(indol-3-yl)ethyl-Jacetamide33.-To a solu- tion of tryptamine (5.0 g, 31.2 mmol) and pyridine (2.5 cm3, 31.2 mmol) in dry dichloromethane (50 cm3) at 0deg;C was added dropwise trichloroacetyl chloride (3.8 cm3, 34.3 mmol). The brown solution was stirred at ambient temperature for 1 h, and then was evaporated to leave a yellow-brown solid. This was purified by chromatography (CH2Cl,) to give the title com- pound 33 (9.31 g, 98) as a crystalline solid, m.p.102-103 "C (Found: C, 47.1; H, 3.45; N, 9.0. Cl,HllC13N20 requires C, 47.2; H, 3.6; N, 9.2); v,,,(Nujol)/cm-l 3412 (indole NH), 3351 (amide NH), 1715 (C--O),1695, 1526, 1257, 1223, 1208, 825, 807 and 742; 6,(270 MHz; CDCl,) 3.09 (2 H, td, J 5.9 and 0.7, 1'-H2), 3.70 (2 H, dt, J 6.6 and 5.9, 2'-H,), 6.78 (1 H, br s, CH,NHCO), 7.08 (1 H, d, J2.4,2-H), 7.16 (1 H, td, J7.1and1.2,5-H),7.24(1H,td,J6.8and1.2,6-H),7.40(1H, d, J8.1,7-H), 7.64 (1 H, d, J7.8,4-H) and 8.09 (1 H, br s, 1-H); m/z304 (M', 373, 149 (6), 144 (91, 143 (38), 131 (ll), 130 (100, ArCH,*+), 84 (6) and 77 (8). Irradiation of Trichloro-N-2'-(indol-3-yl)ethyl-Jacetamide33 in Methanolic Acetonitrile.-A solution of trichloro-N-2'-(in- dol-3-y1)ethyllacetamide 33 (0.10 g, 0.327 mmol) in 20 methanol-acetonitrile (50 cm3) was irradiated for 30 min.The green-brown solution was evaporated, and the residue was purified by chromatography (5 MeOH-CH,CI,) to give, firstly, 1,3,4,5,6,7-hexahydro-7,7-dimethoxy-6-oxopyrrolo4,3,2-fg3benzazocine 34 (0.036 g, 42) as a yellow solid, m.p. 244- 246 "C (decomp.) (Found: M+, 260.1 161. C,,H,,N,O, re-quires M, 260.1 161); v,,,(CHC13)/cm-' 3479 (indole NH), 1660 (C=O), 1344, 1223, 1173, 1123, 1089, 666 and 559; i,,,(MeOH)/nm 297 (log E 3.76); 6,(270 MHz; CDCI,) 3.03-3.09 (1 H, m, 3-H), 3.19 (3 H, s, OMe), 3.21-3.29 (1 H, m, 3-H), 3.42-3.49 (1 H, m, 4-H), 3.56 (3 H, s, OMe), 4.08-4.17 (1 H, m, 4-H), 5.76 (1 H, br s, 5-H), 7.05 (1 H, d, J2.0,2-H), 7.20 J.CHEM. SOC. PERKIN TRANS. I 1992 prepared from the above acid (0.55 g, 3.0 mmol) and thionyl chloride (5 cm3); 70 "C; 45 min in dichloromethane (2.5 cm3) was added dropwise during 15 min to a vigorously stirred two- phase system of tryptophan methyl ester (0.65 g, 3.0 mmol) in dichloromethane (5 cm3) and sodium hydrogen carbonate (1 H,t,J7.7,9-H),7.35(1H,dd,J8.0and1.0,8-H),7.64(1H,(0.50 g, 6.0 mmol) in water (5 cm3) at 0 "C. The reaction mix- dd, J 7.5 and 1.O, 10-H) and 8.12 (1 H, br s, 1-H); m/z 260 (M +, 2273, 228 (65), 213 (44), 201 (44), 169 (96), 154 (44), 153 (100) and 129 (51). This was followed by 1,3,4,5,6,7-hexahydr0-6,7-dioxopyr-rolo4,3,2-fg3ben=a=ocine 35 (0.008 g, 1273, which was isolated as a golden yellow solid, m.p.274-278 "C (decomp.) (Found: C, 67.1; H, 4.8; N, 12.8. C,,H,,N,02 requires C, 67.3; H, 4.71; N, 13.1); v,,,(CHC13)/cm-' 3290 (indole NH), 1658 (amide and ketone C=O), 1607, 1345, 1251, 1033 and 743; i,,,(MeOH)/nm 237 (log E 3.50), 331infl and 353 (4.13); 6,(270 MHz; 'H6acetone) 3.10-3.16 (1 H, m, 3-H), 3.20- 3.32 (2 H, m, 3- and 4-H), 3.71-3.83 (1 H, m, 4-H), 7.20 (1 H, t, J 7.5, 9-H), 7.35 (1 H, dd, J 7.3 and 1.2, 8-H), 7.43 l H, s (with multiple fine splitting), 2-H, 7.45-7.54 (1 H, br s, 5-H), 7.69 (1 H, dd, J 8.1 and 1.2, 10-H) and 7.86 (1 H, br s, 1-H); mi; 214 (M', 3373, 186 (33), 158 (22), 157 (15), 143 (17), 130 (41), 129 (100)and 115(18). Irradiation of Trichloro-N-2'-(indol-3-yI)ethylacetumide33 in Aqueous A cetorzitri1e.-A solution of trichloro-N-2'-(indol-3-y1)ethyllacetamide 33 (0.20 g, 0.654 mmol) in 20 water- acetonitrile (100 cm3) was irradiated for 45 min.The green- brown solution was evaporated to -20 cm3 and then water (-50 cm3) was added. The green-brown suspension was thoroughly extracted with dichloromethane (4 x 100 cm3), the combined green-yellow extracts then being washed with brine (50 cm3) which removed much of the green colour to leave a golden yellow solution. The brine solution was then re-extracted with dichloromethane (3 x 30 cm3), and all the combined extracts were dried (MgS04) before evaporation to leave a golden brown solid. This was purified by chromato- graphy (5 MeOH-CH,CI,) to give 1,3,4,5,6,7-hexahydro-6,7-dioxopyrrolo4,3,2~fg3benzazocine 35 (0.089 g, 64) as a golden yellow solid, m.p. 275-278 "C (decomp.) data given above.2-Chloro-3-phenylpropionic Acid.-An LDA solution was prepared from diisopropylamine (1.0 cm', 0.74 g, 7.3 mmol) and butyllithium (4.7 cm3 of a 1.55 mol dm-3 solution in hexanes, 7.3 mmol) in THF (5 cm3) at -20 "C. To this was added a solution of 3-phenylpropionic acid (0.50 g, 3.3 mmol) in THF (2 cm3) at such a rate as not to allow the temperature to exceed 0 "C. When the addition was complete the mixture was stirred for 30 min at 0 "C, then taken to -78 "C, where dry tetra- chloromethane (0.35 cm3, 0.56 g, 3.7 mmol) in THF (1 cm3) was added dropwise during 5 min, during which the reaction mixture went from pale pink to green and finally dark brown.The reaction was allowed to come to room temperature and after 1 h was poured into 0.5 mol dm-, hydrochloric acid (40 cm3, 20 mmol) and extracted with ether. The combined organic layer was dried over sodium sulfate and evaporated and the residual crude product was purified by chromatography 1 AcOH-Et,O; visualisation with cerium(rv) sulfate spray re-agent to give the title compound (0.55 g, 89) as a brown oil used without further purification: v,,,(film)/cm-' 3000br (CO,H), 1724 (C=O), 1631, 1606, 1497, 1455, 1288, 1259, 1206, 1080, 1032, 954, 918, 832, 809, 747 and 700; 6,(60 MHz; CDCI3) 3.30 (2 H, IE,PhCH,), 4.53 (1 H, t, J 7.2, CICHCOZH), 7.33 (5 H, s, Ph) and 10.58 (1 H, br s, C0,H).N-(2-Clzloro-3-phenylpropionyl)tryptophan Methyl Ester 37.-A solution of 2-chloro