Enantioselective synthesis of 1-substituted

Enantioselective synthesis of l-substituted tetrahydroisoquinoline-1-carboxylicacids ZBIGNIEW CZARNOCKI Department of Chemi.stry, University of Warsaw, ul. L. Pasteura 1 , 01-093 Warsaw, Poland

DENNISSUHAND DAVIDB.

MACLEAN'

Depnrtrnent of Chemistry, McMaster University, Hamilton, Otzt., Cntzada L8S 4MI AND

PHILIPG. HULTINAND WALTERA.

SZAREK'

Departmzent of Chemistry, Queen's University, Kingston, Ont., Canada K7L 3N6

Received September 1 1, 1991

Can. J. Chem. Downloaded from www.nrcresearchpress.com by 58.11.21.22 on 08/27/15 For personal use only.

This paper is dedicated to Professor Zdenek (Denny) Valerzta on the occasion of his 65th birthday

ZBIGNIEW CZARNOCKI, DENNIS SUH,DAVID B. MACLEAN, PHILIP G. HULTIN, and WALTER A. SZAREK. Can. J. Chem. 70, 1555 (1992). The 3,4-dihydroisoquinoliniumsalt 1 and its enantiomer have been converted readily and stereoselectively into (+)and (-)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline-l-carboxylic acids. The synthetic route described should be applicable to the enantioselective synthesis of a variety of l-alkyl- or 1-aryl-l,2,3,4-tetrahydroisoquinoline-lcarboxylic acids. The absolute configuration of the amino acid hydrochloride 11 was established to be as depicted in Scheme 2.

ZBIGNIEW CZARNOCKI, DENNIS SUH,DAVID B. MACLEAN, PHILIP G. HULTIN et WALTER A. SZAREK. Can. J. Chem. 70, I555 (1992). Le sel de 3,4-dihydroisoquinolCinium ( I ) et son Cnantiomkre ont pu facilement et stCrCosClectivement Ctre transformCs en acides (+)- et (-)-I ,2,3,4-tttrahydro-6,7-dimethoxyI-mCthylisoquinolCine-l-carboxyliques.La voie de synthkse dCcrite devrait Ctre applicable 21 la synthkse Cnantioselective d'une variCtC d'acides I-alkyl- ou 1-aryl-1,2,3,4tCtrahydroisoquinolCine-1-carboxyliques.On a pu dCterminC que la configuration absolue du chlorhydrate de l'acide amink 11 est celle dCcrite dans le schCma 2. [Traduit par la rCdaction] Tetrahydroisoquinolines in which C-1 is a quaternary centre have been found in nature, and include a number of cactus alkaloids ( I ) , several mammalian alkaloids (2), and the spirobenzylisoquinoline alkaloids (3). Brossi and coworkers (4) have prepared enantiomeric l-alkyltetrahydroisoquinoline-l-carboxylicacids by resolution of racemic mixtures. Here we describe an enantioselective synthesis of (+)- and (-)-tetrahydro-6,7-dimethoxy-l-methylisoquinoline-l-carboxylic acids; the work is to our knowledge the first report of the enantioselective synthesis of this class of compounds. Domyei and Szantay (5) reported the preparation of 1 and showed that it undergoes stereoselective reduction with hydrides, or with hydrogen in the presence of a catalyst, to the corresponding tetrahydroisoquinoline 2. W e employed the enantiomer of 2 in the enantioselective synthesis of a number of tetrahydroisoquinoline alkaloids having the (S) configuration at C-1 of the tetrahydroisoquinoline system (6). Here we show that 1 and its enantiomer may be converted readily and stereoselectively into (+)- and (-)-tetrahydro-6,7dimethoxy- 1 -methylisoquinoline- 1-carboxylic acids. The synthesis of the target amino acids from 1 or its enantiomer requires alkylation at C-1 followed by transformation of the three-carbon side chain at C-l into a carboxylic acid group. In the first approach to the synthesis we proceeded through the nitrone 3 (Scheme 1). A variety of methods were investigated for the conversion of 1 into 3. The most satisfactory method proved to be an oxidation using hydrogen peroxide in the presence of sodium tungstate. This procedure was originally used for epoxidation of a,@-unsat' ~ u t h o r to s whom correspondence may be addressed.

urated acids (7). Organic peroxy acids have been used also to convert imines into a mixture of nitrones and oxaziranes (8), and a mixture of hydrogen peroxide and sodium tungstate has been used to convert primary arnines into oximes (9). In our case, the conversion of imine 1 into nitrone 3 proceeded in 87% yield. The nitrone was characterized through its spectroscopic properties. Alkylation of 3 was accomplished by treatment with a large excess of methyllithium, a reaction that afforded hydroxylamine 4 in 40% yield. Addition of methyllithium to the carbon-nitrogen double bond was accompanied by alkylation at the ester function to afford a tertiary alcohol. The structure of 4 was deduced from its 'H and I3cnmr spectra. The I H nmr spectrum had three singlets corresponding to C-Me groups, two singlets attributed to OMe groups, two signals attributed to adjacent CHOH groups, two signals corresponding to aromatic protons, and signals corresponding to the four protons associated with C-3 and C-4 of the tetrahydroisoquinoline system. The signals were assigned through the use of nuclear Overhauser enhancement (nOe) difference spectra and through ' H , ' ~ Cchemical-shift correlation experiments. The nOe experiments showed that irradiation of the C-Me signal at 6 1.59 enhanced the signals at 6.44 and 4.25, whereas irradiation of the C-Me signal at 6 1.13 enhanced the signals at 2.95 and 4.25. On this basis the signal at 1.59 was assigned to the methyl group at C-1 and that at 1.13 to one of the two methyl groups at C-3'. It follows that the signals at 6 2.95, 4.25, and 6.44 may be assigned to H-2', H- 1 ', and H-8, respectively. Using these data and the information derived from the 'H,"c chemical-shift correlation experiments it was possible to assign virtually all signals in the 'H and "C nmr spectra of 4.


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CAN. J. CHEM. VOL. 70. 1992

The oxidation of 4 with lead tetraacetate afforded an aldehyde in low yield (13%) as an unstable oil that decomposed rapidly at room temperature. Reduction of 4 with hydrogen over Adams' catalyst converted it in high yield into the secondary amine 5 , a stable compound, which appeared to be a suitable intermediate for elaboration to the target molecule. Thus, an alternative route to 5 was investigated in the hope that the compound might be obtained in higher overall yield. It was found that 1 upon treatment with an excess of methyllithium afforded 5 in 80% yield. This procedure provided a convenient route to 5 and established that the addition of methyllithium to the nitrone and to the imine proceeded in the same stereochemical sense; however, it was not possible at this stage to establish the configuration at C-1 of 4 o r 5 . 'The signals of the 'H and "C nmr spectra of 5 were assigned in a manner similar to that used for 4 through application of nOe difference spectra and 'H,"c chemical-shift correlation experiments. Irradiation of the C-Me signal at 6 1.55 enhanced the signals at 6 3.01, 4.07, and 6.45 whereas irradiation of the C-Me signal at 6 1.08 enhanced the signal at 2.98. Also, irradiation at 6 2.55 enhanced the signals at 6.57 and 3.01. Thus, the nOe experiments enabled the signals at 6 1.08, 1.55, 2.55, 2.98, 3.01, 4.07, 6.45, and 6.57 to be assigned, respectively, to a C-Me at C-3', the C-Me at C-l , an H at C-4, H-2', a hydrogen at C-3 or C-4, H-1 ' , H-8, and H-5. These data, together with ' H , ' ~ c chemical-shift correlation experiments, enabled us to assign the majority of signals in the 'H and "C spectra of 5. With the structure of 5 secure it now remained to oxidize the side chain at C-1 to a carboxylic acid (Scheme 2). The oxidation of the side chain was effected with sodium periodate. When the starting material had been consumed a large excess of sodium borohydride was added to the reaction mixture in order to reduce the aldehyde formed in the oxidation step to a primary alcohol. Upon completion of the

reduction reaction the alcohol 6 was isolated in 76% yield from the reaction mixture. Its spectroscopic properties were in agreement with the assigned structure. The amino alcohol 6 was converted into its 2-ethoxycarbonyl derivative 7 by treatment of 6 with sodium hydroxide and ethyl chloroformate under carefully controlled conditions in a two-phase system. If the reaction time were extended beyond the optimum, compound 7 was slowly 8; converted into the 3H-oxazolo[4,3-a]isoquinolin-3-one compound 8 was the major product when the reaction period was 2 h. Also, compound 8 was obtained when methyl chlorofonnate was substituted for ethyl chlorofonnate, under the conditions used to prepare 7. The oxidation of the primary alcohol group of 7 was now examined. Treatment of 7 with Jones' reagent or with a variety of other common oxidizing agents afforded the aldehyde 9, which was seemingly impervious to further oxidation. Eventually it was found that oxidation to the carboxylic acid 10 could be effected by treatment of 7 with ruthenium dioxide and sodium periodate (10). Compound 7 was converted, first, into 9 and then much more slowly into 10.The final step in the synthesis, the hydrolysis of the ethoxycarbonyl group, was effected with aqueous ethanolic hydrochloric acid. The overall yield in the five steps from 1 to 11 was 35%. The spectroscopic properties of compounds 6-11 were in accord with the assigned structures. The absolute configuration of the amino acid 11 was established in the following manner. Brossi and co-workers (4) performed a resolution of racemic salsoline-1-carboxylic acid (12)in the form of its methyl ester 12a according to the sequence outlined in Scheme 3. The critical step, the separation of the diastereomers 13 and 14,was accomplished by chromatography. The diastereomerically pure ureas, 13 and 14,were converted into the hydantoins, 15 and 16,respectively, and thence into the amino acid hydrochlorides, 17 and 18. The (+)-enantiomer 17 as its hydrobromide salt was shown by X-ray diffraction to have the (S) configuration (4).

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action sequence using D-(-)-tartaric acid ((S,S)-tartaric acid) a s starting material. T h e synthetic route described here should b e applicable to the enantioselective synthesis of a variety of I-alkyl- o r 1-aryl-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acids. Further application of the methodology will b e reported.


Experimental

It follows, therefore, that the ureas, 13 a n d 14, a n d hydantoins, 15 and 16, must have the configurations depicted in S c h e m e 3. W e prepared 13 and 14 by the procedure of Brossi and coworkers (4). Treatment of each isomer with diazomethane afforded the hydantoins, 19 a n d 20, respectively. In this reaction the phenolic hydroxyl group w a s 0-methylated and, surprisingly, the urea underwent cyclization to the hydantoin. Vigorous hydrolysis of the (R,R) isomer 20 yielded 22, the (R)-( - )-amino acid hydrochloride. By inference the (+)enantiomer 21 must have the (S) configuration. In o u r synthesis the (+)-enantiomer was derived f r o m 1, which o w e s its chirality to L-(+)-tartaric acid ((R,R)-tartaric acid). It is apparent that the methyl group is added from the top face of the molecule to the carbon-nitrogen double bond. T h e stereoselectivity of the addition reaction may be accounted for if o n e assumes that the C-I'oxygen and the imine nitrogen are coordinated with lithium in a five-membered ring. Under these circumstances the bottom face of the molecule is effectively shielded, from attack, by C-2'a n d C-3'and their associated groups (see Fig. 1). T h e enantiomeric amino acid 22 w a s obtained through the s a m e re-

The 'H nmr spectra were recorded on a Bruker AM400 or Bruker AM500 spectrometer at 400 or 500 MHz, or a Varian EM390 spectrometer at 90 MHz; CDCI, was the solvent and tetramethylsilane (TMS) was used as the internal standard, unless otherwise stated. Chemical shifts are reported in ppm (6) downfield from the signal of TMS. The symbols, s (singlet), d (doublet), t (triplet), q (quartet). m (multiplet), and br (broadened), are used to report the multiplicity and shape of signals. The "C nmr spectra were recorded at 125.76 MHz on a Bruker AM500 FT spectrometer or at 100.6 MHz on a Bruker AM400 spectrometer at ambient temperature. Nuclear Overhauser enhancement (nOe) difference spectra were obtained by subtraction of the off-resonance control FID from the on-resonance FID. The signal of interest was selectively saturated for 5.0 s and the decoupler was gated off during acquisition. This saturation period also served as the relaxation delay. Either 8 or 16 scans were acquired for each irradiation with the cycle of irradiations repeated 4-10 times. Free induction decays were processed using exponential multiplication (line broadening: 4-5 Hz) before Fourier transformation. Samples were not degassed. El mass spectra were recorded on a VG Micromass 7070F mass spectrometer at an ionizing voltage of 70 eV or on a VG Analytical ZAB-E mass spectrometer, and CI spectra were recorded using NH3 at - I Torr (1 Torr = 133.3 Pa) as reagent gas; data are given as m / z (% relative intensity.) The exact masses were determined under El conditions for those compounds which gave molecular ions in their EI spectra, and under CI conditions using methane as reagent gas for those compounds which did not have molecular ions in their El spectra. The high-resolution measurements were performed by peak matching using perfluorokerosene as a reference standard and at a resolution of -4000. Melting points were determined using a Gallenkamp or a FisherJohns apparatus and are uncorrected. Optical rotations were measured using a Perkin-Elmer 247MC or 241 polarimeter in a l-mL microcell that is 1 dm in length. Flash chromatography was performed on Kieselgel 60 (230-400 mesh). Preparative high-pressure liquid chromatography (HPLC) was performed using a Waters PrepLC System 500 instrument fitted with a PrepPAK 500 silica column. The homogeneity of the products was established on the basis of chromatographic and spectroscopic ('H nmr and mass spectral) examination. Preparatiotl oj'tt~etzitrot~e3

A stirred solution of 1 (5) (7.10 g) in water (25 mL) was cooled to O°C in an ice-salt bath and treated first with sodium tungstate dihydrate (6.10 g) and then with a saturated aqueous solution of sodium hydrogencarbonate (50 mL). To the resulting mixture hydrogen peroxide (30%, 10 mL) was added over a period of 10 min and the solution stirred for an additional 30 min. The solution was then treated with sodium chloride (10 g) and extracted four times with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and taken to dryness. The crystalline residue was recrystallized from chloroform-ether to afford 2 (5.83 g, 87%) as colorless crystals; mp 178-180°C (dec.); [a]: - 150.24 ( c 8.16, CHCI,); v,,,,,(KBr): 1600, 1615, 1735, 1755 cm-'; 'H nmr (90 MHz) 6: 2.96-3.23 (2H, m, C-4 H's), 3.76 (3H, s, CO,CH,), 3.93 and 3.98 (3H each, s , 2 X ArOCH,), 4.03-4.23 (2H, m, C-3 H's), 4.63 ( l H , d, J = 3.6 Hz, H-2'), 5.27 ( I H , d , J = 3.6 Hz, H - I t ) , 6.80 and 6.98 (1H each, s, H-5 and H-8), the OH protons appear as a broad signal in the


CAN. J . CHEM. VOL. 70, 1992

Me0 M O e% ;

I

I

LiO

\ ~ i

S = solvent

FIG. 1. Rationalization of the stereoselectivity of the addition of methyllithium to 1 . region 3.5-4.5; ms (El): 325 (M+) (lo), 308 (lo), 248 (1 l ) , 236 (loo), 219 (82), 204 (14); ms (CI, NH,): 326 (M + H)' (95), 308 (37), 292 (lo), 276 (15), 220 (100). Exact Mass calcd. for C15H19N07: 325.1161; found (hrms): 325.1159. Treatmetzt of tutrone 3 with methyllithiutn A solution of methyllithium in diethyl ether (1 5 M, 55 inL) was added slowly over a period of 20 min to a stlrred solutlon of 3 (3.00 g) in tetrahydrofuran (100 mL) at -70°C The nllxture was stirred at the same temperature for 40 mln, the cool~ngbath removed, and first methanol (20 mL), and then acetic acid (5 mL), were added slowly. The resulting mixture was evaporated to dryness and a saturated aqueous solution of sodlum chlor~de(30 mL) was added to the residue. The mixture was extracted three times with 30-mL portions of chloroform, and the extract was washed, dried, and evaporated to dryness. Chromatography of the residue on silica (Merck, 230-400 mesh) was effected w ~ t hchloroformmethanol (98:2, v/v) to afford 4 as a brown 011 that crystallized on standing. Recrystallization from a mixture of chloroforn~- dlethyl ether - petroleum ether gave 4 as long needles (40%), mp 158-160°C (dec.); [a]h5 + 170.9 (c 1.5, CHC1,); 'H nmr (500 MHz) 6 1.09 and 1 13 (3H each, s, CH,'s at C-37, 1.59 (3H, s, CH, at C-I), 2.62 ( I H , d, J = 15.0 Hz, H-4,,), 2.95 ( l H , s, H2'), 3 08 and 3.12 (2H, m, H-3,,, H-3,,), 3.15 (1H, m, H-4,,), 3.75 and 3.79 (3H each, s, 2 X ArOCH,), 4.25 ( l H , s, H-1'), 6.43 and 6 52 ( I H , each, s's, H-8 and H-5, resp.), the OH protons appear as 3 broad slgnals centered at 3.5 1, 5.35, and 7 SO; I3C nmr (CDCI?) 6: 17.5 (CH, at C-I), 24 9 and 27.4 (CH,'s at C-3'), 29.4 (C-4),

48.1 (C-3). 55.7 and 59.9 (OCH,), 67.9 (C- I), 74.0 (C-3'), 74.2 (C-2'), 78.0 (C-1'), 108.6 (C-8), 111.2 (C-5), 126.3 (C-8a), 130.2 (C-4a), 147.6 and 147.9 (C-6 and C-7); ms (CI, NH,): 342 ( M + H)' ( l o ) , 326 (12), 222 (50), 206 (loo), 190 (20). Exact Mass calcd. for C17H28N06(M + H)+: 342.1916; found (hrms): 342.1913. Reduction of hydro,ryla~nine4 to atnine 5 A sample of 4 (90 mg) was dissolved in methanol (30 mL) containing distilled water (10 mL) and acetic acid (4 drops), PtO, catalyst (20 mg) was added, and the stirred mixture was treated with hydrogen at atmospheric pressure for 4 h. The catalyst was removed, the volatile solvents evaporated, and the residual solution was made basic by addition of an aqueous solution of sodium carbonate (lo%, 10 mL) and then extracted with chloroform (3 x 15 mL). The extract was washed, dried, and evaporated to afford a residue that was purified by chromatography on silica (230-400 mesh). Residual starting material was eluted using chloroformmethanol (98 :2, v/v) and the product 5 using chloroform-methan01 (4: 1, v/v). Compound 5 was obtained as a colorless oil (71 mg, 83%); [a]? + 8 1.9 (c 2.83, CHCI,). (See below for spectroscopic data.) Preparatiot~of 5 by trentmet1t of 1 n~ithmethyllithium A suspension of 1 (4.50 g) in dry 1,2-dimethoxyethane (150 mL) at -10 to -5°C was treated with methyllithium in diethyl ether (1.5 M , 90 mL) over a period of 30 min under a nitrogen atmosphere. The mixture was stirred at the same temperature for 3 h and then treated with methanol (30 mL) to destroy the excess of reagent. The volatile solvents were removed by evaporation, water (45 mL) was added to the residue, and the mixture was extracted with chloroform (5 X 30 mL). The extract was washed, dried, and evaporated to afford a residue that was chromatographed on silica (70-230 mesh) using chloroform-methanol (98 :2, V/V)to remove nonpolar impurities. Further elution using chloroform-methanol (4: 1, v/v) gave 5 as a brownish oil (3.37 g, 80%); [a]k5 +80.5 ? 2 ( c 2.30, CHC1,) (the rotation was difficult to measure because of the dark solution); 'H nmr (500 MHz) 6: 1.08 and 1.18 (3H each, s's, C-CH3's at C-37, 1.55 (3H, s, CH, at C- I), 2.55 (lH, m, H-4,,), 2.98 ( l H , s, H-2'), 2.99 (IH, m, H - 4 4 , 3.01 and 3.10 (2H, m, H-3's), 3.77 and 3.82 (3H each, s's, 2 X OCHj), 4.07 ( I H , s. H-1'), 6.45 and 6.57 (1H each, s's, H-8 and H-5, resp.), OH and NH signals appear as a broad singlet at 4.50; "C nmr (CDCI,) 6: 24.1 and 27.6 (CH,'s at C-3'), 25.7 (CH, at C - l ) , 29.8 (C-4), 37.9 (C-3), 59.7 (C-I), 74.0 (C-3'), 74.6 (C-2'), 75.5



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(~)-1,2,3,4-Tetrahydr0-6-h)~droxy-7-metI1o~~y-lrnethoxycnrborzyl-1-methylisoquinoline(12a) (3-Hydroxy-4-methoxyphenyl)ethylamine hydrochloride (1.905 g, 9.35 mmol) was dissolved in aqueous ammonia (2.9 mL). Distilled pyruvic acid (1.24 g, 14 mmol) was added cautiously, with cooling to control the vigorous exothermic reaction. The pH of the solution was adjusted to 7 with concentrated hydrochloric acid, and the reaction mixture was stirred at 32°C for 18 h. The precipitated product was isolated by filtration, and was dried under vacuum at 50°C to afford the racemic amino acid 12 as pale yellow crystals (1.99 g , 89%). An analytical sample was obtained by recrystallization from water to afford white needles; mp 260°C (dec.) (lit. (1 1) mp 254°C (dec.)); 'H nmr (400 MHz, D 2 0 , K2CO3,sodium 3-(trimethylsily1)-1-propanesulfonateas internal standard) 6: 1.46 (3H, s , CH, at C- 1). 2.51-2.68 (3H, m, H-4 and H-47, 2.97 (2H, rn, H-3 and H-37, 3.65 (3H, s, OCH,), 6.32 ( I H, s, H-5), 6.80 (I H, S, H-8). Acid 12 was immediately esterified (see ref. 4). A suspension of the acid (1.99 g, 8.39 mmol) in dry methanol (20 mL) was cooled in an ice bath while thionyl chloride (4 niL, 5 0 mrnol) was slowly added. During the addition, the suspension cleared, and then became turbid again. The cooling was terminated, and the mixture was stirred at reflux temperature for 5 h and then at 20°C overnight. TLC (I-butanol-water - acetic acid (4: 1 : 1, v/v)) indicated that the reaction was incomplete; accordingly, the reaction mixture was heated at reflux temperature for an additional 1.5 h. The mixture was cooled, quenched with a saturated aqueous solution of sodium hydrogen carbonate (20 mL), and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated to give a solid. Recrystallization from dichloromethane-hexanes gave the ester 12n (1.16 g, 55%); mp 154156°C (lit. (4) mp 156-157°C); 'H nmr (400 MHz) 6: 1.62 (3H, s, CHI at C- 1), 2.50-2.61 ( I H , m, H-4), 2.68-2.80 (1 H, m, H-4'), 3.00-3.09 (2H, m, H-3 and H-3'). 3.70 (3H, s, ester OCH,), 3.85 (3H, s, ether OCH,), 6.60 (1 H, s, H-5), 6.87 (1 H, s, H-8). Acidification of the aqueous layer, concentration to dryness, and extraction of the solid residue with methanol allowed recovery of racemic 12 as its hydrochloride salt (0.522 g, 1.9 mmol). Taking this into account, the yield of 12~2was 7 1 %. (IS)-l,2,3,4-Tetrnhydro-6-h)~~Iro,~~~-7-~-11netlzo.~ycnrborz)~I-l-1neth~l-2[{(R)-1phenylethyl}carbnmo)~1~is~~qi~inolirie (13) arirl its (ZR) cliaster-eorner (14) The ester 12a (1.159 g, 4.6 1 mmol) was dissolved in dry chloroform (20 mL). The solution was cooled to O°C, and (R)-(+)-amethylbenzyl isocyanate (730 pL, 5.08 rnmol) was added dropwise (see ref. 4). The reaction was allowed to proceed at 0°C for 2 h and then the mixture was warmed to 20°C. Removal of solvent afforded a residue that solidified on standing under vacuum. The crude mixture of diastereomers (2.13 g) was resolved by preparative HPLC on silica using hexanes - ethyl acetate (3: 1, v/v) as eluant. The product fractions (500 mL) were identified by TLC; the plates were developed 6 times (hexanes - ethyl acetate (3: 1, v/v)) in order to separate the two diastereomers. The less-polar diastereomer 13 (757 mg, 41%) was obtained as a glassy foam, and the morepolar isomer 14 (702 mg, 38%) as crystals. Compound 13: [a];; +61.9 ( c 1.7, CHCI,) (lit. (4) [a]? +56.1 ( c 1.5, CHCI,)). According to ref, 4 compound 13 has the (S,R) configuration; 'H nmr (400 MHz) 6: 1.46 (3H, d, J = 7.0 Hz, CHCH,), 1.77 (3H, s, CH, at C-1), 2.75 ( l H , ddd, J, :,, = 5.0 Hz, J3eq,,cq = 6.0 HZ, JS,.,,l = 15.0 Hz, H-4,,), 2.90 ( I H , ddd, J ,,,,,~,, = 4.5 Hz, J,,,,,;,, 8.0 Hz, J,q,.,,, = 15.0 Hz, H-4,,,), 3.39 (3H, s, ester OCH,), 3.423.36 ( I H , m, H-3;,,), 3.56 ( l H , ddd, J,,,.,,, = 4.5 Hz, J,,,,,,,,, = 6.0 Hz, J,y,.,, = 12.0 Hz, H-3,,), 3.78 (3H, s, ether OCH,). 4.73 ( l H , d , J = 7 . 0 H z , N H ) , 4 . 9 8 ( l H , d q , J,,,.,, = 7,.0Hz, J,,,.,,, = 7.0 Hz, benzylic H), 5.63 ( I H! s, OH), 6.65 (IH. s, H-5 or H-8), 6.69 ( I H , s, H-5 or H-8), 7.17-7.34 (5H, m, phenyl H's). Compound 14: mp 138-140°C; [ a ] ? -36.5 (c 1.2, CHCI,) (lit.(4) mp 139-140°C; [a]: -34.3 (c 1.2, CHCI,)). According to ref. 4 con~pound14 has the (R,R) configuration; ' H nmr (400 MHz) 6:

1.47 (3H, d, J = 7.0 Hz, CHCH,), 1.74 (3H, s, CH, at C-I), 2.78 15.5 HZ, ( I H , ddd, J,,,,,,, = 3.5 HZ, J 3 = 5.5 HZ. J,v,.,,, H-4,,), 2.93 ( I H , ddd, J3,,.,,, = 4.0 HZ, J,,,.,,, = 9.0 HZ, J ,,, = 15.5 HZ, H-4,,), 3.32 ( I H, ddd, J,;,,, = 3.5 HZ, J3:,, ,,, 9.0 Hz, J,,.,,, = 12.0 Hz, H-3,,), 3.62 (3H, s, ester OCH,), 3.663.53 ( I H , In, H-3,,,), 3.80 (3H, s, ether OCH,), 4.69 ( I H , d, J t o h c n l y ~ i c t l = 7.2 Hz, NH), 5.03 ( I H , dq, J,,.,, = 7.2 Hz, Jt, = 7.0 Hz, benzylic H), 5.60 ( I H, s, OH), 6.66 (I H, s, H-5 or H-8), 6.72 (I H, s, H-5 or H-8), 7.20-7.40 (5H, m, phenyl H's).

,,,,,,

,,,

.I,,

(IObS)-6,I0b-Dihy~lro-8,Y-climethoxy-l0b-niethyI-2-[(R)-lpher~~le~/i~l]-5H-imidci~o[4,3-a]isor/ltinolir1e-l(2H),3 rliorie (19) The less-polar phenol 13 (620 mg, 1.56 mmol) was dissolved in methanol (5 mL), and the solution was cooled to O°C. A solution of diazomethane in ether (-10 mmol) was added gradually. The cooling was terminated, and the reaction mixture was stirred for 16 h at 23°C. The excess of diazomethane was evaporated under a stream of nitrogen, and the remaining solvent was evaporated. The resulting semi-solid was triturated with ether to afford 19 as white crystals (518 mg, 87%); mp 127-130°C; [a]? + 112.9 (c 1.15, CHCI,); ' H nnir (400 MHz) 6: 1.61 (3H, s, CH, at C-lob), 1.77 (3H, d, Jlo ,I, 1, = 7.3 HZ, CHCH,), 2.59 ( I H , dd, J5;!r.6~'~ = 4.0 Hz, J,v,.,,,= 16.3 Hz, H-6,,,), 2.95 ( l H , ddd, Jj,,,,,;,, = 6 . 0 Hz, J,,,,,,, = 12.7 HZ, J,,,,, = 16.3 Hz, H-6,,), 3.17 ( l H , ddd, Jjax.6cq = 4.0 HZ, JS;,x.~:nx = 12.7 Hz, J,,.,,, = 13.3 Hz, H-5;,,), 3.85 (3H, s, OCH, at C-9), 3.90 (3H, s, OCH, at C-8), 4.31 ( I H , dd, J S e q , G . i , = 6 . 0 HSo,, ~ , J= 1 3 . 3 H ~ , H - 5 , , , ) , 5 . 3 3 ( 1 H , q , J = 7 . 3 H Z , CHCH,), 6.56 ( l H , s, H-10). 7.24 ( 1 H, s , H-7), 7.22-7.46 (5H, tri-phenyl H's); ',c nmr (100.6 MHz, CDCl,) 6: 17.2(CHCH3),26.4 (CH, at C-lob), 27.5 (C-6), 35.4 (C-5), 50.5 (CHCH,), 55.8 (OCH,), 56.0 (OCH,), 60.8 (C-lob), 108.6 (C-7), 11 1.3 (C-lo), 124.8 (C-lOa), 125.8 (C-6a), 127.0 (0-phenyl C's), 127.5 (p-phenyl C), 128.4 (rn-phenyl C's), 140.1 (phenyl quaternary C), 147.9 (C8 or C-9), 148.6 (C-8 or C-9), 155.6 (C-3), 175.0 (C-I). Exact Mass calcd. for C,2H2,NI0,: 380.1737; Pound (hrms): 380.1733.

(1ObR)-6,106-Dihyrlro-8. Y-rlirnetho,r)'-10b-methyl-2-[(R)-l pIier1yletkyl]-5H-i~nid~1zo[4,3-a]isoqitiriolit~e-I(2H),3(4 diorie (20) The more-polar phenol 14 (640 mg, 1.61 mmol) was treated with diazornethane as described above. Trituration and filtration provided white crystals of 20 (612 mg, -100%). A sample was recrystallized from diisopropyl ether to afford colorless needles; mp 132°C; [a]? -72.9 (c 1.29, CHCI,); v,,,,,(KBr): 1760 (m), 1700 ( s ) , 1605. 1512, 1400, 1250cm-'; 'H nmr(400 MHz) 6: 1.67 (3H, s, CH, at C-lob), 1.80 (3H, d , J = 7.3 Hz, CHCH,), 2.61 (1 H, dd, J5 :,,, , = 4.0 Hz, J,v,.,,, = 16.5 Hz, H-6,,,), 2.98 ( l H , ddd, J s ~ ~ , . (= , : ,6.0 ~ HZ, J53x,0;,, = 12.0 HZ, Js'.,,, = 16.5 Hz, H-6,,,), 3. 16 ( l H , ddd, J, ;,,. = 4 . 0 Hz, J5 6:,x = 12.0 HZ, Jgr,), = 13.5 Hz, H-5,,), 3.85 (3H, s, OCH, at C-9), 3.91 (3H, s, OCH, at C-8), 4.28 ( I H , dd, J,,,,,,,,, = 6 . 0 Hz, J,v,., = 13.5 Hz, H - 5 4 , 5.36 (IH, q, J = 7.3 Hz, CHCH,), 6.57 (1 H, s, H-lo), 7.25 ( l H , s, H-7), 7.237.46 (5H, rn-phenyl H's); "C nmr (100 MHz, CDC1,) 6: 17.3 (CHCH,), 26.4 (CH, at C-lob), 27.4 (C-6), 35.3 (C-51, 50.3, (CHCH,), 55.8 (OCH,), 56.0 (OCH,), 61.1 (C-lob), 108.6 (C-71, 1 1 1.3 (C-lo), 124.9 (C-lOa), 125.8 (C-6a), 127.0 (0-phenyl C's), 127.6 (17-phenyl C), 128.4 (rn-phenyl C's) 140.0 (phenyl quaternary C), 147.8 (C-8 or C-9), 148.6 (C-8 or C-9), 155.5 (C-3), 175.3 (C-I). Exact Mass calcd. for C12H2,N20,: 380.1737; found (hrms): 380.1744.

,,,

(R)- 1.2,3,4-Tetrnhyclro-6,7-clirr1etho,~yI -ttlethylisocl~titiolit~e-1carbo.-\.lic acid A~clr.or~hloride (22) The (R,R)-hydantoin 20 (350 mg. 0.92 mmol) was dissolved in methyl cellosolve (3.5 mL). An aqueous 20% sodium hydroxide solution (3 rnL) was added, and the mixture was heated at reflux temperature for 3.5 h. The reaction mixture was cooled and acidified to pH 2 with concentrated hydrochloric acid. The mixture was filtered, the filtrate concentrated. and the residue taken up in 2-propanol. The mixture was filtered and the filtrate was concentrated to dryness. The residue was fractionated by column chro-

CZARNOCKI ET AL.

matography (I-butanol - acetic acid - methanol (5: 1 : 1, v/v)). Compound 22 was obtained as white crystals (78 mg, 31%) that were recrystallized from methanol - isopropyl ether; mp 255-262°C (dec.); [a12 -56.3 ( c 1.2, HzO). The ' H nmr spectrum (400 MHz, DzO) was identical with that obtained for compound 11.


Acknowledgements We thank the Natural Sciences and Engineering Research Council of Canada for financial support of this research in the form of grants to D.B.M. and W.A.S., and an International Scientific Exchange Award to Z.C. We thank also Dr. A. Brossi for reference samples. I. J. Lundstroni. In The alkaloids. Vol. 2 1. Edited by A. Brossi. Academic Press, New York, N.Y. 1983. pp. 255-327. 2. M. A. Collins. 111 The alkaloids. Vol. 2 1. Edited by A. Brossi. Academic Press, New York, N.Y. 1983. pp. 329-335.

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3. M. Shamma. The isoquinoline alkaloids. Academic Press, New York, N.Y. 1972. pp. 380-398. 4. M. Chrzanowska, B. Schonenbergcr, A. Brossi, and J . L. Flippen-Anderson. Helv. Chim. Acta. 70. 1721 (1987); B. Schonenberger and A. Brossi. Helv. Chim. Acta, 69. 1486 (1986); see also: Helv. Chim. Acta, 70, 271 (1987). 5. G . Dornyei and Cs. SzBntay. Acta Chim. Acad. Sci. Hung. 89, 161 (1976). 6. Z. Czarnocki, D. B. MacLean, and W. A. Szarek. J . Chem. Soc. Chem. Commun. 493 (1987); Can. J . Chem. 65, 2356 (1987). 7. G . B. Payne and P. H. Williams. J. Org. Chem. 24, 54 (1959). 8. Y. Ogata and Y. Sawaki. J . Am. Chem. Soc. 95, 4692 (1973). 9. K. Kahr and C. Berther. Chem. Ber. 93. 132 (1960). 10. D. G . Lee and M. Van Den Engh. In Oxidation in organic chemistry. Part B. Edited by W. S . Trahanovsky. Academic Press, New York, N.Y. 1973. p. 177. 1 1. G. Hahn and F. Rumpf. Chem. Ber. 71, 2141 (1938).