Synthesis of perhydro-1,4-ethano-1,5-naphthyridine and perhydro-4,7-ethanopyrrolo3,2-bpyridine derivatives: potential NK1-receptor antagonists. X-Ray molecular structures of (4aR,8S,8aR)-6-oxo-8-phenylperhydro-1,4-ethano-1,5-naphthyridine and (4aR,7R,8R,8aR)-7,8-diphenylperhydro-1,4-ethano-1,5-naphthyridine

摘要

J. CHEM. SOC. PERKIN TRANS. I 1995 Synthesis of Perhydro-l,4-ethano-l,5-naphthyridine and Perhydro-4,7- ethanopyrrolo3,2-bpyridine Derivatives: Potential NK,-receptor Antagonists. X-Ray Molecular Structures of (4aR",8S*,8aR*)-6-0xo-8-phenylperhydro-l,4-ethano-l,5-naphthyridine and (4aR*,7R",8R*,8aR")-7,8-Diphenylperhydro-l,4-ethano-l,5-naphthyridine Yevgeny Besidsky,e Kristina Luthman,*,e Alf Claesson,b Christopher J. Fowler,b lngeborg CsoreghC and Uli Hacksella a Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, S-751 23 Uppsala, Sweden Astra Pain Control AB, S-151 85 Sodertalje, Sweden Department of Structural Chemistry, Arrhenius laboratory, Stockholm University, S-7 06 91 Stockholm, Sweden Derivatives of perhydro-l.4-ethan0-1.5-naphthyridine and 4,7-ethanopyrrolo3,2-b pyridine were designed and synthesized as conformationally constrained analogues of the potent N K, -receptor antagonist CP-96,345.2-Benzylidenequinuclidin-3-one 1 was used as the common starting material: (i) heterocyclizations of compound 1 with N-(carbamoylmethy1)pyridinium chloride gave unsaturated pyridone derivatives which, after catalytic hydrogenation, afforded 1.5-naphthyridines, and (ii) functionalization of compound 1 by nucleophilic 1.4-addition reactions, followed by reductive cyclizations, gave quinuclidine derivatives with fused five- or six-membered rings. The cyclization reactions proceeded stereoselectively and the relative stereochemistries were determined by a combination of molecular mechanics calculations, X-ray crystallography, and N MR spectroscopy.The biological activities of the synthesized derivatives were evaluated by binding studies to human NK,-receptors in UC11 MG cells. The compounds had low to moderate affinity for the NK,-receptor. Substance P (SP) is a linear undecapeptide of the tachykinin family. It is known to be involved in several important physiological processes such as inflammation, pain transmis- sion, and regulation of dopamine levels in the brain.' SP exerts its action through NK,-receptor activation.' Recently, several selective non-peptide NK,-receptor antagonists have been discovered;3,4 e.g.,the quinuclidine derivative CP-96,345 (Fig.1) exhibits high affinity and high selectivity for both central and peripheral NK ,-receptor binding sites. Thus, CP-96,345 represents a valuable pharmacological tool in studies of SP CP-96,345 function.Early structure-activity relationship studies of CP-Fig. 1 The potent NK,-receptor antagonist CP-96,345 and the general 96,345-analogues indicated that three structural elements were structures of the compounds synthesized in this study required for high affinity to the NK,-receptor; 3c*3d the substituted 3-benzylamino group, the quinuclidine nitrogen, and the benzhydryl group. More recently it was shown that substantial structural changes did not necessarily lead to a decreased potency; e.g.,the 2-(3-chlorophenyl) analogue of CP- Ph 96,345 was equipotent to the parent compound.'j As part of an ongoing study on novel quinuclidine-based CP- 1 96,345 analogues we have produced compounds with the ring.Successful heterocyclizations using enone 1 or analoguesgeneral structures shown in Fig. 1, in which the important thereof have been reported previously."-' To promotesubstituents at C-2 and C-3 are incorporated in a fused ring. heterocyclization ofcompound 1we used W(carbamoylmethy1)- The new compounds, 7,8,10,22,23, Ma, 24b and 29, differ in pyridinium chloride t314which gave the desired naphthyridine the size of the fused ring, in the number of aryl groups, and in derivative 2 (Scheme 1). The use of BuOH as the solvent and the relative stereochemistry. The biological activities were addition of piperidinium acetate made it possible to synthesize evaluated by binding studies to 3H-Sar9,Met(02)' 'SP- compound 2 in 82 yield.Compound 2 had to be reduced in labelled human NK,-receptors in UCI IMG cells. order to give the desired saturated naphthyridine moiety. Since compound 2 was inert to reducing agents such as LiAIH, or Results and Discussion Et3SiH we attempted a catalytic hydrogenation as the first Syntheszs.-2-Benzylidenequinuclidin-3-one 1 was used as the key starting material in the syntheses. It contains a properly 7 The activating group of this reagent (the pyridinium cation) is not positioned phenyl substituent and exhibits a bifunctional transferred to the final product since it is an excellent leaving group. In reactivity at the electron-deficient C-3 and the vinylic P-carbon, contrast, reaction of compound 1with 2-cyanothioacetamide produces which could be utilized in the construction of a new heterocyclic a thiopyridone ring in which the cyano group is retained.I3 J.CHEM.SOC. PERKIN TRANS. 1 1995 reduction step. Both palladium on charcoal and freshly prepared Raney nickel failed to catalyse the hydrogenation. However, hydrogenation at 60 psi using the more active Adams catalyst (platinum oxide) in acetic acid (HOAc) efficiently reduced compound 2. Unfortunately, these conditions affected not only the pyridone ring but also the 8-phenyl substituent, which was reduced to a cyclohexyl group. When the reaction time was long enough (2-3 days) the lactam group in substrate 2 was also reduced, to give perhydronaphthyridine 6 in up to 18-20 yield (Scheme 1).Compound 2 was not reduced 2 7R= Ph SR=Ph 8R = C-CeHyy 6R=C-CeHjq Scheme 1 Reagenfs:i, H,, Pt; ii, LiAIH,; iii, 2-methoxybenzyl chloride when dissolved in MeOH and the use of HOAc as solvent produced mainly the cyclohexyl product 4.* However, the use of a MeOH-HOAc solvent mixture favoured the formation of the phenyl product 3 and gave a high yield of products 3 and 4 (85-90). Mixtures of compounds 3 and 4 were separated by a combination of column chromatography and recrystallization but the isolated yield of pure compound 3 was never higher than 30. Therefore we used the mixture in preparative experiments; reduction of compounds 3 and 4 with LiAIH, gave the amines 5 and 6,and a subsequent benzylation afforded the perhydronaph- thyridines 7 and 8, respectively (Scheme 1).Compounds 7 and 8 were readily separated by column chromatography. The 8-cyclohexyl-substituted lactam derivative 4 was also benzylated to give compound 9, which on reduction with LiAIH, afforded amine 10 (Scheme 2). All these derivatives had a cis-relation between 8-H and 8a-H according to NMR spectroscopy and X-ray crystallography (see below). A different synthetic strategy was used for the syntheses of the fused quinuclidine derivatives with trans-positioned * The same reaction conditions (PtO,/HOAc) applied to 6,8-diphenyl-3,4-dihydro-ZH-1,4-ethan0-1,5-naphthyridinelo resulted in formation of 6,8-dicyclohexyl-3,4-dihydro-2H-l,4-ethano-l,5-naphthyridine30as the main product (see the Experimental section).n 0 30 miHI 0 0 4 9 10 Scheme 2 Reagents: i, PhCH,CI, NaOMe; ii, LiAIH, hydrogens on C-8 and C-8a. Starting materials were produced by Michael-type 1,caddition reactions of enone 1 in alkaline media l6 (Scheme 3). The adducts 11-14 were produced in yields C02Me Ph 11 Ph Ph Ph 14 12 Ph 13 Scheme 3 Reagents: i, NCCH,CO,Me, NaOMe; ii, PhCH,CN, BuLi; iii, PhCH,N=CHPh, NaOH; iv, MeNO,, NaOMe varying from 25 when using methyl cyanoacetate to 70 when using phenylacetonitrile (Scheme 3). Hence, the yields appear to increase with increasing nucleophilicity (basicity) of the attacking anion. Compound 1 was not completely converted into the desired products even if an excess of the nucleophile was used in the 1,4-addition reactions.The moderate yields may be due to the relatively low reactivity at the electropositive benzylidene atom of substrate 1 and competing 1,2-addition reactions. This is exemplified by the formation of diester 15 as a by-product in the reaction of enone 1 with methyl cyanoacetate (Scheme 4) and FN CN Ph bh 15 16 Scheme 4 Reagent: HCI in the smooth conversion of enone 1 into the 3-(cyanomethyl)quinuclidin-3-ol derivative 17 on reaction with the anion of acetonitrile. Compound 15 was conveniently cyclized by treatment with acid to the polysubstituted benzene derivative 16 (Scheme 4). The reaction of enone 1 with benzylidenebenzylamine was J.CHEM. SOC. PERKIN TRANS. I 1995 the rate and the yield of the reaction. It is noteworthy that the highly basic quinuclidine nitrogen was not benzylated.* This is probably due to steric hindrance by the C-8 substituent. In contrast, the fused pyrrolidine derivative 26 was benzylated at Ph bh both nitrogens, to yield the salt 28, even when less than 1 mole 17 18 equivalent of 2-methoxybenzyl chloride was used (Scheme 6). A comparison of energy-minimized (MM2)t low-energy conform- ers of compounds 26 and 5, 6, 20 and 21 revealed less steric shielding of the quinuclidine nitrogen by the substituent in the qoMeU fused five-membered ring than in the corresponding six- uu membered ring analogues. The more labile N4-benzyl bond in Ph phlsquo;I 19R=H 20R=H 22R=H 12R=Ph 21R=Ph 23R=Ph Scheme 5 Reagents: i, H,/Ni(Ra); ii, 2-methoxybenzyl chloride accomplished using phase-transfer conditions which prevent solvolysis of the reagent. l8 However, some hydrolytic cleavage of the imino group occurred in the adduct 13.This was verified by the isolation of the by-product 18, which is formed by an intramolecular amination of C-3. All the Michael adducts derived from enone 1 gave mixtures of diastereoisomers. Typically, a 1 : 1 ratio of two isomers was observed. In contrast, all four isomers of cyanoacetate adduct 11 were observed by GLC, but these formed two diastereo- isomers after chromatography on silica gel. After work-up of nitrile 12 two diastereoisomers were observed but equilibration in methanolic sodium methoxide afforded only the thermody- namically more stable isomer.The epimeric mixtures of adducts 12-14, and 19 (Scheme 5; obtained by hydrolysis and decarboxylation of cyano ester 11 in refluxing 0.5 hydrochloric acid) were used directly in subsequent reductive cyclizations. 24aRt H,Rrsquo;= Ph 25aR = H, Rrsquo;= Ph 24bR= Ph, Rrsquo;= H 25bR = Ph, Rrsquo;= H y-Cyano ketones have been converted into piperidine derivatives by using catalytic hydrogenation on Pd,19 Pt,20 Raney Co2rsquo; or Ni,rdquo; or LiAIH, in gl~me.rsquo;~ Also, a nitro group has been selectively reduced in the presence of a carbonyl group by titanium() reagent^.'^ However, in our hands, the best selectivities and yields in the cyclization of compounds 12, 14 and 19 were achieved using freshly prepared Raney nickel in propan-2-01 (Scheme 5).25 The diastereoisomeric mixtures of 12, 14 and 19 surprisingly gave only one diastereoisomer of the cyclized products (21, 26 and 20, respectively).Compound 13 reacted slowly under the above reaction conditions but cyclized smoothly in the presence of sodium cyanoboranuide (NaCNBH,)2h to a mixture of two isomers, 24a and 24b, in a total yield of 84. These isomers were separated by column chromatography. Compound 18 was similarly reduced with NaCNBH, to a 1 : I mixture of the two C-2 isomers 25a and 25b. Benzylation of N-5 in the perhydronaphthyridines 5, 6 (Scheme I), 20 and 21 (Scheme 5), proceeded smoothly using an excess of 2-methoxybenzyl chloride in dichloromethane at ambient temperature.The addition of triethylamine increased the salt 28 could be selectively cleaved by treatment with piperidine at elevated temperature or catalytically (H2/Pd) to yield compound 29. Alternatively, compound 29 was synthesized via benzoylation of substrate 26, to afford the amide 27, which was subsequently reduced to amine 29 (Scheme 6). Me0 26 27 11 MeO, Me0 bsol; 28 29 Scheme6 Reagents: i, 2-methoxybenzoyl chloride; ii. 2-methoxybenzyl chloride; iii, LiAIH,; iv, HJPd or piperidine Stereochemical Assignments.-The relative stereochemistries of the final products were determined by a combination of molecular mechanics calculations, X-ray data, and NMR data using a modified Karplus equation.rdquo; The cyclizations involving a reductive amination were performed using diastereoisomeric mixtures as starting materials.However, the reactions produced only one diastereoisomer. Protons 4a-H and 8a-H (3a-H and 7a-H) were cis-related in all products regardless of whether a six- or five- membered ring was formed. This was demonstrated by NMR experiments showing nuclear Overhauser effects (NOES) between 4a-H and 8a-H (3a-H and 7a-H). Further, molecular mechanics calculations (MM2) gave a higher relative steric energy for the trans-as compared with the cis-derivatives (AE, 10 kJ mol-rsquo; in the perhydronaphthyridine series and AE, z 60 kJ mol-rsquo; for the perhydropyrrolopyridines). * Derivatives of CP-96,345 alkylated on the quinuclidine nitrogen have been synthesized, but prolonged reaction times in refluxing ethanol and an excess of the alkylating agent were needed.3k t The conformational analyses were performed using the MM2 force field as included in the MacMimic program (v.1.0.3).The MacMimic program can be obtained from InStar Software, IDEON Research Park, S-223 70 Lund, Sweden. 468 J. CHEM. SOC. PERKIN TRANS. I 1995 Fig. 2 Perspective view of compound 3 with the crystallographic labelling of the atoms Fig. 3 Perspective view of compound 21 with the crystallographic labelling of the atoms Table 1 Effects of compounds 23 and 29 upon the specific binding of 3H-Sarg,Met(0,)'1SP to the NK,-receptor in intact human UC1 IMG astrocytoma cells" Specific binding ( of control) at Compound 0.0 I pmol dm-3 0.I pmol dm-3 1 pmol dm-3 23.2HC1 98 ? 1 70 2 8 14 f 8 (N = 3)* 29*HCI(N = 4) 104 2 6 84 k 2 42 f 3 "Data are means + S.E.M; each compound was tested using a ligand concentration between 0.62-1 .I9 nmol dm-3. ( ? )-CP-96,345 was used as a positive control in each experiment (N = 7), and gave specific binding values ( of control) of 49 ? 6 and 24 + 3 at 1 and 3 nmol dm-3, respectively. N = number of experiments. The relative configurations at C-8 and C-8a in the piperidine moiety in compound 3 and at C-7, C-8 and C-8a in compound 21 were determined by X-ray crystallographic analysis (Figs. 2 and 3). This was especially important in compound 21 since it was impossible to assign the structure solely from coupling constants in 'H NMR spectra because several signals overlapped. In contrast, NOE experiments on lactam 3 showed that 4a-H, 8-H and 8a-H were positioned on the same face of the piperidone ring.In the X-ray analyses the observed bond distances and bond angles generally conformed to expected values. The piperidone ring of compound 3 adopts a flattened half-boat conformation with the phenyl group equatorially positioned. In compound 21, the piperidine ring adopts a 24. 24b Fig. 4 Observed NOE correlations used in the determination of the relative stereochemistries of epimers 24s and 24b strongly distorted half-chair conformation with the two phenyl groups pseudo equatorially positioned.A product structurally related to compound 5 was expected to be formed in the cyclization of nitrile 19 (Scheme 5). Since the product 20 gave (i) the same molecular ion as compound 5, (ii) similar, yet distinctly different, NMR spectra as compared with compound 5, and (iii) different physicochemical properties, it was formulated as a diastereoisomer in which 8-H and 8a-H adopt a trans-relationship. The trans-stereochemistry of 3-H and 3a-H in the ring homologue 26 was evident since no NOE was observed between these two protons. A complete assignment of the relative stereochemistries in the derivatives 24a and 24b was performed by a detailed investigation of NOES throughout the molecules (Fig. 4).The studies indicated a stereochemical difference only at C-2.Factors injuencing the Observed Stereoselectivities.-Cata-lytic hydrogenation of the highly substituted double bonds in naphthyridone 2 may be hampered by the presence of the C-8 phenyl group and the sterically rigid quinuclidine fragment. The cis-stereoselectivity observed in the reduction of the pyridone moiety is not unexpected since a heteroaromatic ring is believed to remain adsorbed on the catalyst surface until complete hydrogenation has occurred.'' Thus, a mixture of products 3 and 4 was obtained with the phenyl or cyclohexyl substituents assuming endo-positions. The use of diastereoisomeric mixtures as starting materials in the Raney nickel-catalysed cyclizations of substrates 12, 14 and 19 resulted in only one diastereoisomer of the product.The relatively high acidity of 2-H in compounds 12,14 and 19 might be responsible for a rapid epimerization on the alkaline surface of the catalyst. The corresponding proton exchange is not expected to be equally efficient in the intermediate cyclic imines due to the weaker electron-accepting ability of the imino group and the increased rigidity of the cyclic systems. Therefore, we suppose that the cyclization step in the stereospecific reactions affording products 20, 21 and 26 is kinetically controlled, favouring the epimer giving a cyclic product with the substituents at C-8 and C-8a (C-3 and C-3a) in a trans-orientation. Reduction of the imines resulted in a cis-relationship between 4a-H and 8a-H (3a-H and 7a-H) probably due to steric interactions between the catalyst and the quinuclidine nucleus.* The weaker electron-accepting ability of imines is also apparent in the cyclization of ketone 13 with NaCNBH, since it produced a C-2 diastereoisomeric mixture of products (24a and 24b). Test Results-The affinities for the human NK,-receptor were assessed by determining the effects of the compounds on the specific binding of 3H-Sarg,Met(0,)1'SP to intact human UCllMG astrocytoma cells, which have been shown * It is noteworthy that the related reductive cyclization of 24~-cyanobenzy1)cyclohexanone gives the cyclic perhydroindole with a trans-relationship between the corresponding hydrogens.2s J.CHEM. SOC. PERKIN TRANS. I 1995 previously to express high densities of NK ,-receptors coupled to the phosphoinositide signal transduction ~ystem.~~-,~ As a positive control, the potent antagonist (k)-CP-96,345' was in- cluded.The majority of the compounds tested had a low affinity for the NK,-receptor at the concentrations tested ( 20 inhibition at 1 Fmol dm ,). The only active compounds, 23 and 29, appeared to be moderately potent NK,-receptor antago- nists, producing 86 and 58 inhibition at 1 pmol dm-3, respectively (Table 1). However, these derivatives were considerably less active than ( k)-CP-96,345, which produced 51 and 76 inhibition at 1 and 3 nmol dm3, respectively, a finding in agreement with previous studies using this cell Iine.31,32 Conclusions.-We have synthesized conformationally con- strained analogues of CP-96,345 by efficient and stereoselective reactions.Although the new compounds did not show high NK,-receptor affinities, the synthetic methods presented herein should be useful in the development of other derivatives of potential interest as NK,-receptor antagonists. Experimental Chernisrrj'.-M.p.s were measured in open glass capillaries on a Thomas-Hoover apparatus and are uncorrected. The NMR spectra were run on a JEOL JNM-EX 270 hTMR spec- trometer for solutions in CDCI, (if not otherwise stated) and the chemical shifts were determined relative to tetramethyl- silane. J-Values are given in Hz. The numbering of the atoms of the naphthyridine derivatives is given in Scheme 1 and that of the pyrrolopyridines in Scheme 6.The IR spectra were recorded on a Perkin-Elmer 298 infrared spectrophotometer (KBr tablets). Mass spectral data together with GLC data were obtained with a combined Hewlett-Packard GC(5890)- MS(5791) unit. The reaction mixtures were monitored by TLC on aluminium sheets precoated with silica gel (60F,,,, E. Merck) or with alumina, using 10 or 2 MeOH in CHIC, as eluent, respectively. Elemental analyses were performed by MikroKemi AB, Uppsala, Sweden. Compound 1 was obtained from Astra Pain Control AB and 6,8-diphenyl- 1,2,3,4-tetra- hydro-I ,4-ethano-l,5-naphthyridinewas synthesized from com- pound I according to the method of Madhav." Extracts were dried over MgSO,. pH Values were measured with litmus paper.Receptor-binding Tests.-Methods and materials. UC 1 1MG cells were obtained from Dr. Carl Johnson, University of Cincinnati, and were used between passage numbers 7 and 10 after arrival at Astra (each time the cells are split into a new growth medium is called one passage). C3H-Sar9, Met(O,)"SP (specific activity 42 Ci mmol ') was obtained from NEN (Du Pont Scandinavia AB, Biotechnology Systems Division. Stockholm, Sweden). Physalaemin was obtained from Peninsula Laboratories Europe Ltd., St. Helens, UK, and was dissolved in 10 mmol dm-3 acetic acid to a stock solution of 1 mmol dm '. ( k)-CP-96,345 ( k)-cis-2-diphenylmethyl-3-(2-methoxybenzy1amine)quinuclidinedihydr~chloride~"was syn- thesized at Astra Pain Control AB and was dissolved in dis- tilled water to give a stock solution of 1 mmol drn-,.RPMI 1640 cell culture media, together with foetal calf serum and glutamine were obtained from Gibco, Paisley, UK. Penicillin G and streptomycin were obtained from Astra and the Sigma Chemical Co., respectively. The test compounds were dissolved in dimethyl sulfoxide at a stock solution of 10 mmol drn-,. 3H-Sar9,Met(0,)' JSP-binding assay. The binding of 3H-Sarq,Met(0,)' 'ISP to intact UCI IMG cells was undertaken as described previo~sly.~~~~~Briefly, UCI 1MG cells were cultured in 75 cmz flasks in RPMI 1640 medium supplemented with 10 foetal calf serum, 2-4-(2-hydroxyethy1)piperazin-1-ylethanesulfonic acid HEPES (10 mmol dm-3, pH 7.33, penicillin G (50 U cm-,) and strepto- mycin (50 pg ~m-~).The cells were plated out onto 24-well culture plates 2-4 days before assay at a cell density of 34 000-50 000 cells/well. Upon assay, the wells were rinsed with 0.5 cm3 ice-cold assay buffer (phosphate-buffered saline, 10 mg cm-, bovine serum albumin, 1.8 mmol dm-, CaCI, + 0.81 mmol dm-, MgSO,). Test compounds and radioligand (both dissolved in the assay buffer) were added to the wells and incubated at 4deg;C for 2 h. The assay volume was 0.5 cm3. Physalaemin (1 pmol drn-,) was used to define non-specific binding. After incubation, the wells were washed three times with 0.5 cm3 of ice-cold assay buffer. Bound r3H-Sarg,Met- (0,)"ISP was removed by addition of 0.2 mol dm-, NaOH (0.5 cm3) and incubation at 65-75 "C for 15 min.Aliquots were then counted (d.p.m.) by liquid scintillation spectroscopy. General Procedure for Reductive Cyclization with Raney Nickel.-Freshly prepared Raney nickel (3-S-fold molar excess) was added to a solution of the substrate (12, 14 or 19) in propan-2-01, The mixture was hydrogenated in a Parr apparatus at 60 psi for 48 h. The catalyst was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified on silica gel, using a gradient of 20-50 MeOH in CHCL, as eluent, or on alumina, using a gradient of 0-5 MeOH in EtOAc as eluent. Analytical samples were obtained by conversion of the oily bases into crystalline hydrochloride salts by addition of ethereal HCI.General Procedure for Benzylation with Benryl Chloride and 2-Mefhoxybenzyl Chloride.-The quinuclidine derivative (5,6,20, 21 or 26) (0.5 mmol), benzyl chloride (or 2-methoxybenzyl chloride) (1.0 mmol) and triethylamine (0.07 cm3, 0.5 mmol) were mixed in CH,Cl, (15 cm3) and kept at ambient temperature for 8-10 h. The clear solution was washed successively with 0.5 mol dm-3 NaOH (10 cm3) and water (15 cm3) and the organic phase was dried, filtered, and concentrated. The residue was purified by column chromatogra- phy on either silica gel, using a gradient of 5-10 MeOH in CHCI, as eluent, or on alumina, using a gradient of 30-60 EtOAc in hexane as eluent, to give the desired products as oily bases or crystalline hydrochlorides.6-0xo-8-phenyl-3,4,5,6-tetrahydro-2H-1.4-ethano- 1,5-naph- thyridine 2.-A stirred mixture of 2-benzylidenequinuclidin-3-one 1 (3.0 g, 14.1 mmol) and N-(carbamoylmethy1)pyridinium chloride (7.3 g, 42.3 mmol) in butan-1-01 (100 cm3) containing piperidine (5 cm3) and HOAc (3 cm3) was heated at 115-120 "C for 18 h. After cooling, the solution was concentrated under reduced pressure and the residue was partitioned between 5 MeOH in CHCI, (2 x 150 cm3) and water. The organic phase was concentrated to leave a crystalline residue, which was recrystallized from MeOH to give title compound 2 (2.91 g, 82); m.p. 285-287 "C; vmaX/cm-' 3000-2300 (NH) and 1640 (GO); BH 1.55-2.2 (5 H, m,3- and 9-H,, NH). 2.45-3.5 (5 H, m, 2- and 10-H, and 8-H), 6.47 (1 H, s, 7-H) and 7.38-7.6 (5 H, m, Ph); 6, 22.9, 29.3 ((2-3, -4, -9), 53.8 (C-2 and -lo), 116.2, 122.1, 127.8, 130.2, 130.4 and 132.2 (C-7 and -8, and Ph), 148.6 and 151.5 (C-4a, -8a) and 162.8 (C-6).An analytical sample was obtained by conversion of the base into the hydrochloride salt using ethereal HC1 (m.p. 241 "C) (Found: C, 66.3; H, 6.0; N, 9.7. Cl6HI6N20.HCJ requires C, 66.6; H, 5.9: N, 9.7). (4aR*,8S*,8aR*)-6-0xo-8-phenylperhydro-l,4-ethano-1,5-naphthyridine 3.-A mixture of compound 2 (0.10 g, 4.0 mmol) and platinum dioxide hydrate (79-84 Pt content) (70 mg) in 3 HOAc in MeOH (50 cm3) was hydrogenated in a Parr apparatus at 60 psi for 20 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure.GLC of the reaction mixture showed the presence of compounds 3 and 4 in a 2 : 1 ratio. Column chromatography using a gradient of 5-10 MeOH in CHCl, as eluent afforded compounds 3 (0.18 g, 18), 4 (0.11 g, 1 1) and a mixed fraction (0.46 g, 45). Since compound 3 showed less solubility in diethyl ether compared with compound 4 the mixed solid from the fraction was triturated several times with hot diethyl ether to give an additional amount of pure compound3 (0.1 1 g, 11); m.p. 227- 228 "C;S, 1.30-1.90(4H,m, 3-and9-HZ),2.00-2.04(1 H,m,4- H), 2.61-2.80 (4 H, m, 2- and 10-H,), 2.92-3.1 I (2 H, m, 7-H,), J CHEM. SOC PERKIN TRANS. I 1995 (4aR*,8SS,8aR*)-5-(2-Methoxybenzyl)-8-phenylperhydro-1,4-ethano-l,5-nuphthyridine7.-Compound 7 was synthesized from compound 5 (0.12 mg, 0.5 mmol) according to the general procedure in 72 yield (0.13 g); m.p.145-148 "C (monohydro- chloride); 6,(10 CsD6 in CDCI,) 1.10-1.25 and 1.52-1.71 (4 H, m, 3- and 9-HZ), 1.95-2.08 (2 H, m, 6- and 7-Ha), 2.13-2.27 (2 H, m, 4-H and 7-Hb), 2.50-2.61 (3 H, m, 4a-H and 10-H,), 2.62-2.73(1 H,m,2-Ha),2.79-2.84(1 H,m,8-H),2.96(1H,dd, J, 6.7, J27.1,8a-H), 3.06 (1 H, m, 6-Hb), 3.34 and 3.9 (2 H, 2 d, J -14.5, CH,Ph), 3.35-3.41 (1 H, m, 2-Hb), 3.7 (3 H, s, OMe) and 6.81-7.48 (9 H, m, ArH); ~3~21.0, 24.7, 26.8 and 28.2 (C-3, -4, -7 and C-9), 46.0, 46.1, 51.0, 51.7, 52.5, 54.9, 58.5 and 60.7 (C-2, -4a, -6, -8, -8a and -10, OMe and CH,Ph) and 110.1, 120.4, 3.23(1H,dd,J,6.1,J,8.8,8a-H),3.4(1H,m,8-H),3.81(1H, 125.8, 127.3, 127.4, 127.7, 127.8, 127.9, 128.1, 129.2, 144.2 and dd, J, 4.4, J, 8.8,4a-H), 7.04 (1 H, br s, NH) and 7.21-7.42 (5 H, m, Ph);S, 19.3,24.5 (C-3, -9), 28.6 (C-4), 33.6 (C-7), 41.2 (C- 8), 44.8 and 51.5 ((2-2, -lo), 53.3 (C-4a), 55.6 (C-8a), 126.7, 127.7, 128.3 and 140.5 (Ph) and 172.6 (C-6); m/z 256 (M+, 100) (Found: c, 73.0; H, 7.8; N, 10.5.C16H20N,0-$-120 requires C, 72.5; H, 7.9; N, 10.6). (4aR*,8S*,8aR*)-8-Cyclohexyl-6-oxoperhydro-1,4-ethnno-1,5-nuphthyridine 4.4ompound 4 was synthesized from compound 2 as described for compound 3 except that glacial HOAc (50cm3) was used as solvent and the reaction time was 8 h. Purification on silica gel gave pure title compound 4 (0.78 g, 75); m.p.201-202 "C; v,,,/cm-' 3200 (NH) and 1650 (M); SH 0.8amp;2.00 (1 7 H, m, 3- and 9-H,, 4- and 8-H, and cyclohexyl), 2.26(1 H, dd,J1 13.5,J -18.2, 7-H"), 2.56(1 H, dd,J, 6.0,Jz -18.2, 7-Hb), 2.70-2.90 (4 H, m, 2- and 10-H,), 3.11 (1 H, dd, J,5.9,JZ8.3,8a-H),3.66(lH,dd,J14.7,J28.3,4a-H)and6.75 (I H, br s, NH); S,(CDCI,) 19.4, 24.6, 25.9, 26.0, 26.5, 28.4, 30.5, 30.8, 32.5 and 37.9 (C-3, -4, -8, -9 and cyclohexyl), 40.6, 44.9, 50.9, 51.1 and 52.9 (C-2, -4a, -7, -8a and -10) and 172.9 (C-6); m/z 262 (M', 29) and 82 (100) (Found: C, 72.7; H, 9.9; N, 10.4. C,,H,,N,O requires C, 73.2; H, 10.0; N, 10.7). (4aR*,8S*,8aR*)-8-Phenylperhydro-l,4-ethuno-1,5-nuph-thyridine 5.4ompound 3 (0.20 g, 0.78 mmol) was added in portions to a stirred solution of LiAIH, (74 mg, 1.95 mmol) in tetrahydrofuran (THF) (20 cm'), kept under N,.The mixture was refluxed for 5 h. Water (20 ~m-~) was carefully added at 5 "C, and the layers were separated. The aqueous phase was extracted with diethyl ether (20 cm3) and the combined organic phases were dried, filtered, and concentrated under reduced pressure. Purification on alumina, using a gradient of 04 MeOH in EtOAc as eluent, gave pure amine 5 as an oil (0.14 g, 75);6, 1.20-2.20 (8 H, m, 3-, 7- and 9-H,, 4-H and NH), 2.50- 3.30 (9 H, m, 2-, 6- and 10-H, and 4a- 8-and 8a-H) and 7.15- 157.7 (Arc); mjz 362 (Mi, 63) and 241 (100) (Found: C, 69.0; H, 8.1; N, 6.8. C,,H,,N0.HCI.H20 requires C, 69.1; H, 7.9; N, 6.7). (4aR* ,8S*,8aR*)-8- Cyclohexyl-5-(2-methoxybenzyl)per-hydro-l,4-ethuno-l,5-nuphthyridine8.-Compound 8 was syn- thesized from substrate 6 (0.12 g, 0.50 mmol) according to the general procedure, in 68 yield (0.12 8); m.p.223- 225 "C (monohydrochloride); amp;(lo C6D, in CDCI,) 0.75-2.20 (18 H, m, 3-, 7- and 9-H,, 8-H and cyclohexyl), 2.27- 2.34 (1 H, m, 4-H), 2.35-2.42 (1 H, dd, J1 = J, = 5.6, 4a-H), 2.83-2.92 (1 H, m, 6-Ha), 3.03 (1 H, dd, J, = J, = 5.6, 8,-H), 3.08-3.22 (2 H, m, 6-Hb and 2-Ha), 3.18 and 3.71 (2 H, d, CH,Ar), 3.42-3.57 (3 H, m, 2-Hb and 10-H,), 3.61 (3 H, s, OMe), 6.80-7.35 (4 H, m, Ph) and 10.3 (1 H, br s, NH); amp;(lo C6D6 in CDCI,) 18.3, 21.3, 24.9, 25.0, 25.5, 25.8, 26.2, 30.9, 31.9 (C-3, -4, -7, -8, -9 and cyclohexyl), 36.0, 44.3, 46.7, 50.9, 52.6,SS.l and 58.3 (C-2, -4a, -6, -8a, -10, OMe and CH,Ar) and 110.5, 120.5, 125.0, 128.5, 129.9 and 157.7 (Arc); m/z368 (M', 66) and 247 (100) (Found: C, 69.8; H, 9.1; N, 6.8.C,,H,,- N,O-HCl-~H,O requires C, 69.6; H, 9.3; N, 6.8). (4aR*,8S*,8aR*)-5-Benzyl-8-cyc~ohexyl-6-oxoperh~dro-1,4-ethuno-l,5-nuphthyridine9.-A mixture of lactam 4 (0.20 g, 0.76 mmol), benzyl chloride (0.23 cm', 1.91 mmol) and sodium methoxide (82 mg, 1.52 mmol) in dry DMF (10 cm3) was stirred for 48 h at ambient temperature. Water (20 cm3) was added, and the solution was concentrated. The residue was partitioned between dichloromethane (2 x 30 cm3) and water (30 cm'). The organic layer was dried and filtered. After concentration under reduced pressure the residue was purified on silica gel, with a gradient of 30-50 EtOAc in hexane as eluent, to afford title compound 9 (0.1 1 g, 42); m.p.133-1 34 "C; v,,,/cm-' 1640 (C--o);6,0.81-1.91 (16H,rn,3-and9-H2, 8-Handcyclohexyl), 2.10-2.17 (1 H, m, 4-H), 2.38 (1 H, dd, J, 13.5,J, -17.7, 7-H"), 2.70-2.82 (4 H, m, 2-and 10-H,), 2.87-3.03 (1 H, rn,7-Hb), 3.08 7.38(5H,m,Ph);Sc20.8,25.5,28.7and29.3(C-3,-4,-7and-9),(1H,m,J,5.1,J29.2,4a-H),3.38(IH,ddd,J,1.1,J27.1,J,45.2,45.4, 45.8, 50.9, 54.4 and 57.3 (C-2, -4a, -6, -7, -8 and -8a) and 125.7, 127.1, 127.6, 127.8 and 129.2 (Ph); mlz 242 (M'. 54) and 97 (100) (Found: C, 55.9: H, 7.7; N, 8.3. C,,H,,N,-2 HC1.1.5 H20 requires C, 56.1; H, 7.9; N, 8.2). (4aR*,8S*,8aR*)-8-Cyclohexylperhydro-l,4-ethano-1,5-nuphthyridine 6.-Compound 6 was synthesized from lactam 4 (0.20 g, 0.76 mmol) as described above for the synthesis of amine 5.After chromatographic purification the product was recrystallized from water-ethanol (5: 1) to give pure title compound 6 (0.14 g, 72); m.p. 91-92 "C; S, 0.80-1.90 (20 H, m. 3-, 7- and 9-H,, 4-and 8-H, NH and cyclohexyl) and 2.51- 3.22 (8 H, m, 2-, 6- and 10-H,, and 4a- and 8a-H); 6,21.1,25.6, 26.0, 26.2, 26.8, 27.7, 28.4, 30.6, 31.3, 37.9 and 44.8 (C-3, -4, -7, -8, -9 and cyclohexyl) and 45.5, 45.6, 50.4, 53.5 and 54.4 (C-2, -4a, -6, -8a and -10); m/z 248 (M', 45) and 82 (100) (Found: C, 77.1; H, 11.6; N, 11.1. CI6Hl8N, requires C, 77.4; H, 11.3; N, 11.3). 9.2, 8a-H), 3.81 and 5.60 (2 H, 2 d, CH,Ph) and 7.20-7.40 (5 H, m, Ph); 6, 19.1, 24.8, 24.9, 26.0, 26.1, 26.5, 30.6, 30.8 and 33.5 (C-3, -7, -9 and cyclohexyl), 37.7 and 40.6 (C-4 and -8), 45.2 and 46.3 (C-2 and -10).51.4 (CH,Ph), 52.6 and 56.3 (C-4a and -8a), 127.3, 128.0, 128.6 and 137.1 (Ph) and 171.1 (C-6); m/z 352 (M', 40) and 91 (100) (Found: C, 78 3; H, 9.5; N, 8.2 C2,H,,N,0 requires C, 78.4; H, 9.2; N, 8.0). (4aR*,8S*,8aR*)-5-Benzyl-4-c),clolzexylperhydro-l,4-ethuno-1,5-nuphrhyridine 10.-Compound 10 was synthesized from lactam 9 (0.18 g, 0.5 mmol) as described above for the synthesis of compound 5, in 59 yield (0.10 g); S, 0.8-1.9 (1 8 H, m, 3-, 7-and 9-H,, 8-H and cyclohexyl), 2.0-2.1 1 (1 H, m, 6-Ha), 2.22- 2.28(1 H,m,4-H),2.36-2.42(1 H,m,4a-H),2.68-2.93(5H,m, 8a-H and 2-and 10-H,), 3.00 and 4.08 (2 H, 2 d, CH,Ph), 3.25- 3.35 (1 H, m, 6-Hb) and 7.20-7.40 (5 H, m, Ph); Sc 21.2, 25.0, 26.1,26.2.26.4,26.7,26.8,30.7,31.4and37.7(C-3, -4,-7, -9and J.CHEM. soc. PERKIN TRANS. I 1995 cyclohexyl), 45.3 (C-8), 46.2, 50.7, 51.6 and 59.0 (C-2, -6, -10 and CH2Ph), 54.6 and 61.7 (C-4a and -8a) and 126.5, 128.1, 128.5and 132.9(Ph);m/z338(Mt, 55)and247(100)(Found: C, 80.4; H, 10.3; N, 8.0. C,,H,,N2.:H20 requires C, 80.6; H, 10.1; N, 8.2). Methyl 2-Cyano-3-(3-oxoquinuclidin-2-yl)-3-phenylpropano-ate 11 and Methyl 2-Cyano-3-{ 3-cyano(methoxycarbonyl)-rnethylenequinuclidin-2-yl}-3-phenylpropanoate 15.-Methyl cyanoacetate (0.83 cm3, 9.4 mmol) was added to a solution of enone 1 (1 .OO g, 4.7 mmol) and sodium methoxide (0.25 g, 4.7 mmol) in MeOH (20 cm3).The mixture was stirred for 3 h at 5540deg;C and then cooled to room temperature, an equal volume of water was added, and the methanol was evaporated off under reduced pressure. The aqueous solution (50 cm3; pH 7-8) was extracted with CHCI, (3 x 50 cm3). The extract was dried and concentrated to give an oil, which was triturated with propan-2-01 for 20 h at 0deg;C. Concentration under reduced pressure and purification on silica gel, with a gradient of 24 MeOH in CHCI, as eluent, yielded keto ester 11 as a yellow oil (0.37 g, 25), contaminated with 4 of impurities according to 471 diastereoisomers in the ratio 2 : 1 and tricycle 18(0.18 g, 10) as a mixture of two diastereoisomers in the ratio 1.7: 1. Compound 13: S, 1.30-2.25 (4 H, m, quin 5-and 8-H2), 2.32- 2.37 (1 H, m, quin 4-H), 2.40-2.80, 3.00-3.30 and 3.50-3.60 (4 H, m, quin 6- and 7-H,), 3.61 and 3.82 (1 H, 2 d, J 10.0and 8.8, quin 2-H), 4.31 and 5.03 (1 H, 2 d, 1'-H), 4.67,4.8 (1 H, 2 app br s, 2'-H) and 7.05-7.65 (16 H, m, Ph and CH=N). Compound 18: 6, 1.8Cb2.10 (4 H, m, 6- and 8-Hz), 2.70-2.85 and 3.00-3.2 (4 H, m, 5- and 9-Hz), 2.93-2.96 and 3.02-3.05 (I H,m,7-H),3.30-3.42and3.90~.05(2H,m,3-and3a-H),5.01 and 5.42 (1 H, dd, J 1.8, J2 7.8 and 10.3, 2-H) and 6.70-7.30 (10 H, m, Ph); hC 188.0 and 190.6 (GN); m/z 302 (M+, 100).2-(2'-Nitro-1'-phenylethyl)quinuclidin-3-one14.-Compound 14 was synthesized from enone 1 (5.0 g, 23.5 mmol) nitromethane (2.55 cm3, 47 mmol) and sodium methoxide (1.30 g, 25.0 mmol) in MeOH (100 cm3) according to the procedure described for the synthesis of cyano ester 11.After trituration the resulting crystals were filtered off, and washed with cold propan-2-01 to give title product 14 consisting of an equimolar mixture of two diastereoisomers (4.18 g, 65); m.p. 8486 "C; m/z v,,,/cm-' 1725 (GO)GLC; v,,,/cm-' 2240 and 2200 (CN) and 1745-1725 (0); and 1460 and 1380 (NO,); dH 1.9-2.1 (4 284 and 284 (M' -CO, 100)and 225 (68);S,1.85-2.05 (4 H, m, quin 5-and 8-H,), 2.262.31 and 2.41-2.46 (1 H, m, quin 4-H), 2.50-3.05 (5 H, m, 3-H and quin 6- and 7-H2), 3.48 and 3.50 (3 H, 2 s, OMe), 4.05 and 4.37 (1 H, d, quin 2-H), 4.95 and 4.98 (1 H, 2 d, 2-H) and 7.20-7.35 (5 H, m, Ph). The crude solution was used without further purification.Continued elution of the column with a gradient of l@-l5 MeOH in CHCI, gave diester 15 (10-15) as a powder, consisting of mostly one epimer according to NMR analysis; 6, 1.3-1.8 (4 H, m, quin 5-and 8-H,), 2.28-2.33 (1 H, m, quin 4-H), 2.6-3.15 (4 H, m, quin 6- and 7-H,), 3.13 (1 H, m, 3-H), 3.16 and 3.54 (6 H, 2 s, OMe), 4.07 (1 H, d, J0.8, quin 2-H), 6.35 (I H, app br s, 2-H) and 7.1-7.27 (5 H, m, Ph). 3-(3-Oxoquinuclidin-2-yl)-1,2-diphenylpropanonitrile 12.-Compound 1 (2.13 g, 10 mmol) was added in portions to a stirred solution of r-lithiophenylacetonitrile prepared from BuLi in hexane (1.6 mol drn-,; 7.5 cm3, 12 mmol) and phenylacetonitrile (1.5 cm3, 13 mmol) at -78 "C in dry THF (100 cm3) at -40 "C under nitrogen.The mixture was allowed to warm slowly to 0 "C and was maintained at 0 "C for 2 h. After addition of an equal volume of water the organic layer was separated. The aqueous phase was extracted with CHCI, and the combined extract was dried (MgSO,) and concentrated to give nitrile 12 (2.31 g, 70); m.p. 160-162 "C (from MeOH); v,,,,'cm 2242 (CN), 1733 (M),and 1605 and 1500 (Ph); 6, H, m, quin 5- and 8-H,), 2.38-2.41 and 2.44-2.47 (1 H, m, quin 4-H), 2.6-3.1 (4 H, quin 6- and 7-H,), 3.36 and 3.46 (1 H, 2 d, J 10.1 and 10.7,quin2-H), 3.77-3.84(1 H,m, l'-H),4.62and4.67 (1H,m,2'-Ha),5.0and5.4(1H,2dd,J,4.9and5.4;J2 -12.8 and -13.2, 2'-Hb) and 7.2-7.4 (5 H, m, Ph); m/z 246 and 246 (M' -CO, 100) and 200 (100) (Found: C, 65.6; H, 6.7; N, 10.3.C,,H,BN20, requires C, 65.7; H, 6.6; N, 10.2). 5-Cyano-6-methoxy-8-phenyl-3,4-dihydro-2H-1,4-ethano-quinoline-7-carboxamide 16.-A solution of diester 15 (0.I0 g, 0.25 mmol) in 0.5 HCl in 80 HOAc (10 cm3) was heated at 90-100 "C for 4 h. After cooling, the solution was concentrated under reduced pressure and the residue was partitioned between CHCI, (2 x 50 cm3) and an aqueous alkaline solution (pH 9-10). The organic layer was dried and concentrated to leave an oil residue, which was purified on silica gel with a gradient of 50-75 EtOAc in hexane as eluent to afford title compound 16 (35 mg, 42); m.p. 219-221 "C (from acetone);BH 1.5-1.65 and 1.85-1.97 (4 H, m, 3- and 9-H2), 2.45- 2.60 and 2.97-3.12 (4 H, m, 2- and 10-H,), 3.32 (3 H, s, OMe), 3.463.51 (I H, m, 4-H), 5.65 (2 H, br s, NH2)and 7.13-7.42 (5 H, m, Ph); 6, 27.5 (C-3 and -9), 30.7 (C-4), 49.1 (C-2 and -lo), 51.6(OMe), 93.7 (CN), 113.4, 115.7, 127.4, 127.5, 128.3, 137.9, 138.3, 142.6, 147.9 and 152.9 (Arc) and 168.9 (C=O); m/: 333 (M+, 100) (Found: C, 72.2; H, 6.0; N, 12.9.C2,H,,N,02 requires C, 72.1; H, 5.7; N, 12.6). 4.7-ethanopyrro/o3,2-bpyridinelS.-Compound 1(1.28 g, 6.0 mmol) benzylidenebenzylamine (1.29 g, 6.6 mmol) and triethylbenzylammonium chloride (0.14 g, 0.6 mmol) were mixed in benzene (6 cm3), and 50 aq. NaOH (4.8 g, 60 mmol) was added. The heterogeneous mixture was stirred vigorously at room temperature for 5 h. Water (100 cm3) was added and the mixture was extracted with CH,C12 (100 cm3). The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified on silica gel with CHC13 as eluent to give imine 13 (1.34 g, 55) as a mixture of two 1.9-2.1 (4H,m,quin5-and8-H2),2.35-2.40,2.43-2.65(2H,m, quin 4-H and 7-Ha)), 2.9-3.04 and 3.15-3.3 (4 H, m, 3-H, and (2-Benzylidene-3-hydroxyquinuclidin-3-yi)acetonitrile17.-quin 6-H, and 7-Hb).3.73 and 3.83 (1 H, 2 d, J 10.7, quin 2-H), Compound 17 was synthesized from enone 1 (0.43 g, 2.0 mmol), 4.79 and 5.30 (1 H, 2 d, J4.9,2-H) and6.90-7.30 (10 H, m, Ph); cyanomethyllithium prepared from BuLi in hexane (1.6 mol mlz 302 and 302 (M' -CO, 58) and 186 (100) (Found: C, dm-3; 1.38 cm3, 2.2 mmol) and acetonitrile (0.12 cm3, 13 mmol) 79.9; H.6.7; N, 8.3. C22H22N,0 requires C, 80.0; H, 6.7; N, at -78 "C in dry THF (20 cm3) as described above for the 8.5). synthesis of compound 12 to afford the cyanohydrin 19 (0.32 g, 62); m.p. 143-145 "C (from diethyl ether): vma,/cm-' 3496 24 2'- Benzylideneamino- 1',2'-diphenylethyl)guinuclidin-3-one (OH) and 2245 (CN); BH 1.50-1.62, 1.64-1.85 and 1.90-2.08 (4 13 and (2RS,3R*,3aS*)-2,3-Diphenyl-2,3,3a,5,6,7-hexahydro-H, m, 5-and 8-H2), 2.23-2.28 (1 H, m, 4-H), 2.5 (1 H, br s, OH), 2.65-2.80 and 2.95-3.15 (4 H, m, 6- and 7-H,), 3.01 (2 H, app br s, CH,CN), 6.39 (1 H, s, CHPh), 7.40-7.55 (3 H, m, Ph) and 7.94-8.03 (2 H, m, Ph); aC21.3, 23.8, 29.7 and 33.6 (C-4, -5,-8 and CH,CN), 45.9 and 47.4 ((2-6 and -7), 71.6 (C-3). 117.3, 122.1, 127.6, 128.1, 129.7 and 134.9 (CHPh) and 152.2 (C-2) (Found: C, 75.9; H, 7.4; N, 11.4.CI6HlBN2O requires C, 75.6; H, 7.1; N, 11.0). 3-(3-Oxoquinuclidin-2-yl)-3-phenylpropanonitrile19.-Com-pound 11(0.50 g, 1.6mmol) was converted into the title product 19 according to the procedure described above for the synthesis of amide 16. Compound 19 was isolated as a viscous oil containing two diastereoisomers (0.22 g, 54); v,,,/crn-' 2225 (CN) and 1740 (C=O);BH 1.92-2.08 (4 H, m, quin 5- and 8-H,), 2.36and2.49(1 H,2appq,quin4-H),2.55-3.35(7H,m, 1-H,, 2-H, and quin 6- and 7-H,), 3.46 and 3.53 (1 H, 2 d, J 10.2, quin J. CHEM. SOC. PERKIN TRANS. 1 1995 24b.-Compound 13 (0.50 g, 1.22 mmol) was dissolved in MeOH (10 cm3) and acidified with HOAc to pH 3.5-4.5.Sodium cyanoboranuide (0.31 g, 4.9 mmol) was added in portions during 10 min at room temperature and the mixture was stirred for 6-8 h. Water (20 cm3) was added, and methanol was removed under reduced pressure. The aqueous phase was 2-H)and7.2-7.4(5H,m,Ph);Sc23.9,24.0,24.9,25.7,26.0andextracted with CHCI, (2 x 30 cm3) and the extract was dried, 26.9 (quin C-4, -5 and -8),40.4,40.8, 41.2,41.6,41.7, 41.8,49.0 and 49.1 (quin C-6 and -7, and C-1, -2), 70.0 and 70.6 (quin C-2), 118.3 and 118.5 (CN), 127.6, 127.7, 127.8, 127.9, 139.4 and 139.7 (Ph) and 218.0 and 221.0 (W);m/z 226 and 226 (M' -CO, 100). (4aR*,8R*,8aR*)-8-Phenylperhydro-l,4-ethano-1,5-naphthy-ridine 20.-Compound 20 was synthesized from nitrile 19 (0.50 g, 1.97 mmol) according to the general procedure, in 70 yield (0.32 g); 6, 1.40-2.40 (8 H, m, 3-, 7- and 9-H,, 4-H, and NH), 2.70-3.80 (9 H, m, 2-, 6- and 10-H,, 4a-H, 8-and 8a-H) and filtered, and concentrated. The residue was separated on silica gel with 5 MeOH in CHC13 as eluent to give the pure epimers 24a (higher R,, 0.24 g) and 24b (0.17 g) in 84 total yield.Isomer 24a: m.p. 143-145 OC; SH 1.2-1.6 and 2.10-2.25 (4 H, m, 6- and amp;HI), 1.5amp;1.54 (1 H, m, 7-H), 2.65-2.75, 2.9-3.05, 3.35-3.55 (4 H, m, 5-and 9-H,), 2.78 (1 H, dd, J, 3.2, 5,8.8, 7a-H), 3.27 (1 H, dd, J, = Jz = 8.8, 3-H), 3.37 (1 H, dd, J, = J2 = 8.8,3a-H),3.67(1H,d,J9.5,2-H),3.42and3.91(2H,2 d, J -13.2, CH,Ph) and 7.03-7.42 (15 H, m, Ph); Sc 20.3 and 24.1 (C-6 and 425.2 (C-7), 41.8 and 49.5 (C-5 and -9), 55.9 (C- 3), 56.5 (CH,Ph), 64.1 (C-7a), 67.7 (C-3a), 74.7 (C-2) and 126.3, 7.10-7.35(5H,m,Ph);SC 19.1,24.5,25.4and26.5(C-3,-4,-7126.8, 127.2, 127.7, 127.8, 128.2, 128.3, 129.4, 137.9, 140.8 and and -9), 36.0, 39.8,40.9,49.1, 55.0 and 61.0 (C-2, -4, -4a, -6, -8, -8a and -10) and 127.0, 127.2, 128.7 and 141.9 (Ph); mjz 242 (M', 65) and 97 (100) (Found: C, 67.1; H, 7.9; N, 10.0.C,6H,,N,.HCI.:H,0 requires C, 66.8; H, 8.4; N, 9.7). (4aR',7R*$R*,8aR*)-7amp;Diphenylperhydro-1,4-erhano-I ,5-nuphfh,vridine 21.-Compound 21 was synthesized from nitrile 12 (0.50 g, 1.52 mmol) according to the general procedure in 65 yield (0.31 g); m.p. 157-159 "C;SH 1.3-1.45, 1.53-1.75 and 1.92-2.04 (5 H, m, 3- and 9-H,, NH).1.77-1.82 (1 H, m, 4-H), 2.55-3.43 (10 H, m, 2-, 6- and 10-H,, 4a-, 7-, 8-and 8a-H) and 6.9-7.13 (10 H, m, Ph); Sc 20.2 and 26.5 ((2-3 and -9), 27.4 (C-4), 41.3, 49.7 and 51.7 ((2-2, -6 and -lo), 44.6 and 47.3 (C-7 and 4,55.9 and 63.4 (C-4a and -8a) and 125.7, 125.8, 127.8, 127.9, 128.0, 128.2, 142.7 and 145.4 (Ph); mjz 318 (M+, 100) (Found: C, 80.8; H, 8.2; N, 8.5. C,,H,,N,~~H,O requires C, 80.7; H, 8.3; N, 8.6). (4aR*,8R*,8aR*)-5-(2-Methoxybenzyl)-X-pheny~erhydro-1,4-ethano-l $naphthyridine 22.-Compound 22 was syn-thesized from compound 20 (0.12 g, 0.5 mmol) according to the general procedure (98 mg, 54); BH 1.22-2.20 (7 H, m, 3-, 7- and 9-H,, and 4-H), 2.50-3.42 (9 H, m, 2-, 6- and 10-H,, 4a-, 8a- and 8-H), 3.12 and 3.92 (2 H, 2 d, J -14.2, CH,Ph), 3.80 (3 H, s, OMe) and 6.81-7.55 (9 H, m, ArII); 6, 21.0, 24.4, 26.1 and 29.8 (C-3, -4, -7 and -9), 37.4, 41.6, 49.1, 49.9, 51.7, 55.2, 62.2 and 63 3 (C-2, -4a, -6, -8, -8a, -10, OMe, CH,Ph) and 110.2, 120.3, 126.0, 127,4, 127.5, 127.7, 128.4, 129.5, 145.8 and 157.6 (Arc); m,': 362 (M', 87) and 241 (100) (Found: C, 79.2; H, 8.5; N, 7.7.CZ4H,,N2O requires C, 79.5; H, 8.3; N, 7.7). (4aR*,7R*,8Rf,8aR*)-5-(2-Methoxybenzyl)-7,8-dipheny/-perhydro-1,4-ethano-l,5-naphthyridine23.-Compound 23 was synthesized from compound 21 (0.16 g, 0.5 mmol), according to the general procedure, in 65 yield (0.14 g); 6, 1.75-2.65 (4 H, m, 3- and 9-H,), 2.63-2.90 and 3.02-3.50 (9 H, m, 2-, 6- and 10- H,, 4-, 7- and 8-H), 2.97 (1 H, br d, 4a-H), 3.21 and 4.04 (2 H, 2 d, CH,Ph), 3.85 (3 H, s, OMe), 4.06 (1 H, m, 8a-H) and 6.67- 6.72,6.87-7.0and7.12-7.3(14H,m.ArH);Sc17.9(C-9),22.1 (C-3), 23.6 (C-4), 41.8 and 49.9 (C-2 and -lo), 46.1 (C-7), 46.3 (C-8), 52.1 (CH,Ph), 55.3 (OMe), 56.4 (C-6), 61.1 (C-4a), 62.8 (C-8a)and 110.4, 120.3, 125.2, 126.2, 127.1, 127.9, 128.1, 128.4, 131.2,137.1,144.6 and 157.8 (Arc); m/z438 (M', 56) and 317 (100) (Found: C, 75.5; H, 7.6; N, 5.8.C,oH3,N,0~HCl requires C, 75.9; H, 7.4; N, 5.9). (2R*,3S*,3aR*,7aR*)-1-Benzyl-2,3-diphenyIperhydro-4,7-ethanopyrro/o3,2-bpyridine24a and (2R*,3R*,3aS*,7aS*)-l- Benzyl-2,3-diphenylperhydro-4,7-ethanopyrrolo3,2-blpyridine 141.4 (Ph); m/z 394 (M', 75) and 303 (100) (Found: C, 85.1; H, 7.3; N, 7.0. C28H30N2 requires C, 85.3; H, 7.6; N, 7.1).isomer 24b: m.p. 201-203 "C:6, 1.20-1.95 (4 H, m, 6- and 8-H,), 2.00-2.04(1 H, m, 7-H), 2.35-2.5,2.65-2.8 and2.9-3.05 (4 H, m, 5-and 9-H,), 3.42 (1 H, m, 7a-H), 3.75-3.90 (4 H, m, 3- and 3a-H, and CH,Ph), 4.88 (1 H, app dt, J 6.5 and 8.7, 2-H) and7.05-7.65(15 H,m,Ph);dc21.2and25.1 (C-6 and-8), 24.1 (C-7), 42.4 and 49.9 (C-5 and -9), 50.6 (CH,Ph), 55.6 (C-3), 58.4 (C-7a), 63.1 (C-3a), 68.9 (C-2) and 125.8, 126.5, 127.5, 127.8, 127.9, 128.0, 128.4, 128.6, 138.4, 139.8 and 142.7 (Ph); m/z 394 (M', 68) and 303 (100) (Found: C, 85.4; H, 7.5; N, 7.0). (2R*,3S*,3aR*,7aR*)-2,3-Diphenylperhydro-4,7-ethano-pyrrolo3,2-bpyridine 25a and (2R*,3R*,3aS*,7aS*)-2,3-Diphenylperhydro-4,7-ethanopyrrolo3,2-bpyridine 25b.-A mixture of two diastereoisomers of imine 18(0.15 g, 0.5 mmol) was treated with sodium cyanoboranuide as described for the synthesis of compounds 24 to give the pure epimers 25a (higher R,,62 mg) and 25b (69 mg) in 87 total yield.Isomer 25a: m.p. 123-125deg;C; S, 1.36-1.58, 1.67-1.8 and 2.22-2.40 (4 H, m, 6- and 8-H2), 1.95-1.99 (1 H, m, 7-H), 2.70- 2.87, 2.98-3.12 and 3.35-3.52 (4 H, m, 5- and 9-H,), 3.17 (I H, dd, J, 7.1, J, 9.8, 3-H). 3.38-3.45 (2 H, m, 3a- and 7a-H), 4.23 (1 H, d, 2-H) and 7.10-7.35 (10 H, m, Ph); Sc 19.9 and 24.3 (C-6 and 4, 27.0 (C-7), 41.9 and 49.5 (C-5 and -9), 55.6 (C-3), 57.1 (C-7a), 68.1 (C-3a), 69.5 ((2-2) and 126.5, 126.8, 127.2, 128.1, 128.3, 128.4, 140.8 and 142.2 (Ph); m/z 304 (M', 100) (Found: C, 82.1; H, 7.6; N, 9.1.C21H24N2.iH20 requires C, 81.8; H, 7.9; N, 9.1). Isomer 25b: m.p. 125-126 "C; 6, 1.40-1.52, 1.561.67, 1.68- 1.82 and 2.05-2.20 (4 H, m, 6- and 8-H,), 1.93-1.97 (1 H, m, 7- H), 2.72-2.93, 3.0-3.13 and 3.28-3.43 (4 H, m, 5- and 9-Hz), 3.65 (1 H, dd, J, 6.0, J29.2, 3a-H), 3.70 (1 H, br s, NH), 3.75 (1 H,dd,J3.0and10.1,7a-H),3.91(lH,dd,J,J, = 7.2,3-H),= 4.90(1 H,d,2-H)and6.82-6.95and7.00-7.10(10H,m,Ph);6, 19.5 and 24.7 (C-6 and 4,28.2 (C-7), 42.4 and 49.8 (C-5 and -9), 52.1 (C-3), 58.0 (C-7a), 66.2 (C-3a and -2) and 126.2, 126.6, 127.2, 127.8, 127.9, 128.6, 139.9 and 142.2 (Ph); m/z 304 (M', 100) (Found: C, 82.5; H, 8.1; N, 9.0. C21H,4N, requires C, 82.9; H, 7.9; N, 9.2). (3R*,3aS*,7aS*)-3-Phenylperhydro-4,7-ethanopyrrolo3,2-b-pyridine 26.-Compound 26 was synthesized from compound 14 (0.50 g, 1.82 mmol) according to the general procedure, and was obtained as an oil (295 mg, 71); 8, 1.13-1.54, 1.62-1.74 and 1.87-2.0 (6 H, m, 6- and 8-H,, 7-H, and NH), 2.65-2.82, 2.863.08 and 3.10-3.58 (9 H, m, 2-, 5-and 9-Hz, 3-, 3a- and 7a- H) and 7.15-7.30 (5 H, m, Ph); 6, 19.4 and 24.7 (C-6 and -8), 26.1 (C-7), 41.4 (C-2), 46.6 (C-3), 49.4 and 52.5 (C-5 and -9), J CHEM SOC PERKIN TRANS.I 1995 58.7 and 68.7 (C-3a and -7a) and 126.3, 127.3, 128.4 and 142.0 (Ph); m/: 228 (Mt,100) (Found: C, 64.6; H, 7.7; N, 9.8. C,,H,,N,~HCI~~H,Orequires C, 64.7; H, 8.1; N, 10.1). (3R* ,3aS* ,7aS*)- 1-(2-Methoxyben,-oyl)-3-phenylperhydro-4,7-ethanopyrrolo3,2-bpyridine 27.-2-Methoxybenzoyl chloride (0.30 g, 1.76 mmol) was added to a solution of amine 26 (0.20 g, 0.88 mmol) in pyridine (10 cm3) at 5 OC.After 24 h at ambient temperature the mixture was quenched with water (20 cm3) and concentrated under reduced pressure. The residue was partitioned between 10 aq. Na2C0, (20 cm3) and CHCI, (2 x 20 cm3). The combined organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified on silica gel with a gradient of 5-10 MeOH in CHCI, as eluent to afford titleamide 27 (0.27 g, 86); m.p. 122-123 "C: d,(mixture of rotamers) 1.02-1.95 (4 H, m, 6- and 8-H2), 2.36 2.46 (I H, m, 7-H), 2.65-3.20, 3.35-3.61, 3.90415 and 4.30- 4.45 (9 H, m, 2-. 5-and 9-H, and 3-, 3a- and 7a-H), 3.80 and 3.91 (3 H, 2 s, OMe) and 7.08-7.40 (9 H, m, ArH) (Found: C, 76.6; H, 7.1; N, 7.7.C2,H2,N,0, requires C, 76.2; H, 7.2; N, 7.7). (3R*,3aSr,7aS*)-1,4-Bis(2-methoxybenzyl)-3-phenylper-hydro-4.7-ethanopyrrolo3,2-bpyridiniumChloride 28.-Com-pound 28 was synthesized from free amine 26 (0.11 g, 0.5 mmol) according to the general procedure. After the reaction had finished (TLC) the mixture was washed with water. The aqueous layer was extracted twice with CHCI, (50 cm3). The combined extract was dried, filtered, and concentrated, to give a residue, which was purified on silica gel to afford the salt 28 (0.21 g, 83); m.p. 140 "C (decomp.); 6, 1.50-2.62 (5 H, m, 6- and 8-H,. and 7-H), 2.80-2.96 (1 H, m, 5-Ha), 3.05-3.20 (I H, m.2-H"), 3.30-3.50 (2 H, m , 5-Hb and 7a-H), 3.43 and 3.90 (2 H, 2 d, CH,Ar), 3.75-3.97 (3 H, m, 3-H and 9-H,), 3.82 and 3.85 (6 H. 2 s, OMe), 4.06 and 4.41 (2 H, 2 d, CH,C,H,OMe), 4.44-4.58 (1 H. m, 2-Hb), 5.2 (1 H, dd, J, = J, = 8.3, 3a-H) and 6.85-7.0, 7.15-7.43 and 7.56-7.68 (13 H, m, ArH);6, 18.6, 22.2 and 13.3 (C-6, -7 and 4,45.3, 47.7, 51.0, 54.9, 55.2, 55.7, 59.2, 61.2, 64.1 and 74.3 (C-2, -3, -3a, -5, -7a, -9, OMe and CH,Ph) and 110.4, 111.1, 115.0, 120.2, 121.2, 125.3, 127.6, 128.1. 128.8, 129.2, 130.8, 132.3, 135.7, 138.3, 157.6 and 158.3 (Arc) (Found: C, 71.7; H, 7.5; N, 5.3. C3,H3,CIN202~~H20 Reduction of amide 27 with LiAIH, as described above for the synthesis of compound 5 produced amine 29 in 62 yield. 6,s-Dicyclohe.xyl-3,4-dihydro-2H-1,4-ethano-1,5-naphthyrid-ine 30.-Hydrogenation of 6,8-diphenyl-3,4-dihydro-2H-l,4-ethano-1,5-naphthyridinelo (0.20 g, 0.64 mmol) as described above for the synthesis of lactam 3 afforded title compound 30 (93 mg, 45); dH 1.20-2.05 (24 H, m, 3- and 9-Ha, and cyclohexyl), 2.51-2.75 (3 H, m, 2-Ha and 3-and 9-Hb), 3.05- 3.25 (3 H, m, 2-Hb and 10-H,), 3.25-3.31 (1 H, m, 4-H)and 6.90 (1 H,s,7-H);rn/z324(Mi,27)and269(100)(Found:C,81.7; H, 10.3; N, 8.6.C2,H3*N2 requires C, 81.5; H, 9.9; N, 8.6). Crystal-structure Determination-Data collection and pro- cessing. The intensities of 2434 and 3399 reflections were collected at room temperature from the selected single crystals of compounds 3 (0.09 x 0.190 x 0.38 mm) and 21 (0.26 x 0.38 x 0.07 mm), respectively, using Cu-Ka radiation (i= 1.541 83 A, Om,, = 70").Data reductions included corrections for background, decay, Lorentz and polarization effects, but the rather low absorption effects = 5.89 (3) and 5.06 cm-' (21) were ignored. The number of unique; non-zero observations was 2233 for 3 and 2704 for 21. The unit-cell parameters were refined against 0-values of 58 (30 28 50") (3) and 56 (23 28 47") reflections (21). Structural analysis and refinements. The structures were solved by application of direct methods (SHELXS) 33 and refined by full-matrix least-squares method based on IF' (SHELX).34 The non-hydrogen atoms were treated anisotropi- cally, whereas isotropic displacement parameters were refined for the hydrogens, either located from difference electron density (Ap)maps and held riding on their parent atoms during the subsequent calculations, or assumed in idealized positions with C-H = 1.00 A, which were recalculated after each refinement cycle using geometric evidence.Final refinements of 192 and 245 variables for compounds 3 and 21, respectively, yielded the final R-values listed below. In the last refinement calculation for structure 3, four strong low4 reflections with considerably lower Fobsthan Fcalc,probably due to extinction effects, were omitted. In case of structure 21, an empirical isotropic extinction parameter x F = (1 -0.0001~-F~/ sin 8)13' was also included in the final refinement calcul- requires C.71.9; H, 7.4; N, 5.4). (3R*,3aS*,7aS*)-1-(2-Methoxybenzyl)-3-pheny(perhydro-4,7-ethanop~rrolo3,2-bpyridine29.-Compound 28 (200 mg, 0.40 mmol) was dissolved in toluene (10 cm3) containing butan- 1-01) (I cm3) and piperidine (0.5 cm3). The solution was refluxed for 4-5 h, and was then cooled to room temperature. The residue obtained after concentration under reduced pressure was purified on alumina to give pure title product 29 (86mg. 62:/,); m.p. 233-235 "C (dihydrochloride); dH 1.40-1.90 (3 H, m. 6-Ha and S-H,). 1.95-2.02 (1 H, m, 7-H), 2.04-2.18 (1 ation; its value converged to x = 0.353. The weights of the structure factors were assumed 34 as w = a2(F)+ lg( F2-' with g = 0.000 25 and 0.000 50 for structures 3 and 21, respec- tively.* Crystal data.Compound 3: C,,H20N,0, M, = 256.347, triclinic (PT),a = 6.591(1), b = 10.731(1), c = 10.972(2) A, a: = 107.126(7), ,!? = 105.591(7), y = 103.081(7)0, V, = 673.8(2) A3, Z = 2, D, = 1.2634(4) g ~m.~,F(OO0) = 276. Final R = 0.047 and wR = 0.066 for 1573 reflections with I 3u(I). Compound 21: C22H2,N2, M, = 318.461, triclinic (Pi)? aH,rn,6-Hb),2.3(1H,dd,J,8.9,J210.9,2-Ha),2.51(1H,dd,J, = 6.102(1), b = 10.552(1), c = 13.982(1) A, z = 79.906(8), 4.0. J2 9.1. 7a-H), 2.63-2.76 (2 H, m, 5-H,), 2.94-3.08 (1 H, m, ,!?= 83.393(8),y = 80.366(9)", V, = 870.4(2)A3, Z = 2, D,= 9-H"), 3.21 (1 H, dd, J, = J2 = 9.1, 3a-H), 3.28-3.37 (2 H, m, 1.2151(3) g F(OO0) = 344. Final R = 0.040 and wR = 2- and 9-Hb).3.40-3.52 (1 H, m, 3-H), 3.48 and 3.91 (2 H, 2 d, 0.050 for 1821 reflections with l/a(r) 2.5. CH2Ar). 3.8 (3 H, s, OMe) and 6.85-6.97 and 7.15-7.40 (9 H, m, ArH):d,. 17.4,21.6and22.6(C-6,-7and-8),41.3,42.8,47.6, 51.4. 55.8. 59.1,62.4,64.2and 64.4(C-2, -3, -3a, -5, -7a, -9, OMe Acknowledgements and CH,Ar) and 111.0, 116.4, 121.5, 128.2, 128.8, 128.9, 132.4, Financial support was obtained from the Swedish National 133.5.134.1 and 158.1 (ArC);m/z348(M+,44)and227(100) (Found: C. 63.2; H, 7.2; N. 6.5. C23H,8N20.2 HCI.H,O requires C. 62.9; I-I, 7.3; N, 6.4). Compound 28 was also debenzylated by catalytic hydrogen- ation Pd(C)IMeOH in a Parr apparatus at 45-50 psi for 3 h. After the catalyst had been filtered off, purification as described above gave compound 29 in 35 yield.* Supplementarydara. Fractional atomic coordinates and the calculated bond distances and bond angles have been deposited as supplementary data at the Cambridge Crystallographic Data Centre (see Instructions for Authors, J. Chew Soc., Perkin Trans I, January issue). Lists of the atomic displacement parameters and of the observed and calculated structure factors are available directly from the authors (1. C.). Board for Industrial and Technical Development (NUTEK), Swedish Natural Science Research Council (NFR), and Astra Pain Control AB. We thank Gunilla Brannstrom for performing the biochemical assays. References 1 Review on SP pharmacology: B. Pernov, Pharmacol. Rev., 1983,35, 85. For SP in inflammation, see, e.g., M.Lotz, J. H. Vaughan and D. A. Carson, Science, 1988, 241, 1218; A. Perianin, R. Snyderman and B. Malfroy, Biochem. Biophys. Res. Commun., 1989,161,520. Review on SP in pain transmission: J. L. Vaught, Life Sci., 1988. 43, 1419. SP in dopamine regulation: P. Baruch, F. Artaud, G. Godeheu, L. Barbeito. J. Glowinski and A. Cheramy, Neuro-science, 1988, 25, 889. 2 S. Nakanishi, Annu. Rev. Neurosci., 1991,14,123. 3 CP-96.345and analogues: (a) R. M. Snider, J. W. Constantine, J. A. Lowe, II1,K. P. Longo, W. S. Lebel,H. A. Woody, S. E. 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