FACULTAD DE FARMACIA DEPARTAMENTO DE FARMACOLOGÍA Y QUÍMICA TERAPÉUTICA SÍNTESIS ESTEREOSELECTIVA DE cis-DECAHIDROQUINOLINAS: INTERMEDIOS AVANZADOS PARA EL ACCESO A LAS LEPADINAS MARISA MENA CERVIGÓN 2006 6. PUBLICACIONES 6.1 Model studies in the lepadin series: synthesis of enantiopure decahydroquinolines by aminocyclization of 2-(3aminoalkyl)cyclohexenones Marisa Mena y Josep Bonjoch Tetrahedron 2005, 61, 8264-8270. 93 Tetrahedron 61 (2005) 8264–8270 Model studies in the lepadin series: synthesis of enantiopure decahydroquinolines by aminocyclization of 2-(3-aminoalkyl)cyclohexenones Marisa Mena and Josep Bonjoch* ´ ` ` Laboratori de Quımica Organica, Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIIIs/n, 08029-Barcelona, Spain Received 2 May 2005; revised 3 June 2005; accepted 8 June 2005 Abstract—Syntheses of enantiopure 3-acetoxy-2-methyldecahydroquinolines are accomplished by coupling cyclohexenyllithium 3 with a-amino epoxides and an aminocyclization of 2-(3-aminoalkyl)cyclohexenones (i.e., 5 and 9) as the key steps. The procedure allows the incorporation of alkyl substituents at C(5) to give enantiopure 2,3,5-trisubstitued decahydroquinolines. q 2005 Elsevier Ltd. All rights reserved. 1. Introduction Lepadin alkaloids are structurally characterized by the presence of a 2,3,5-trisubstituted cis-fused decahydroquinoline ring. The substitution pattern, which has a methyl group at C(2), a hydroxyl group, free or acylated, at C(3), and an eight carbon side chain at C(5), shows a variety of stereochemical arrangements, as shown in Figure 1. Eight lepadins (A–H) have been isolated from marine sources since 1991,1–4 of which lepadins A–C have been found to possess significant in vitro cytotoxicity against several human cancer cell lines, whereas lepadins D–F have shown low cytotoxicity but significant and selective antiplasmodial and antitrypanosomal activity. methyldecahydroquinolines in these synthetic approaches involve the elaboration of a polyfunctionalized piperidine followed by carbocyclic ring closure through aldol processes5,6 or the construction of the piperidine ring from cyclohexanone derivatives either by an intramolecular enamine alkylation7 or using a xanthate-mediated radical cyclization8 (Scheme 1). In this work, we report our studies on a new synthetic entry to the azabicyclic core of lepadins, either those that show a cis or trans relationship between the respective methyl and hydroxyl substituents at C(2) and C(3) of the decahydroquinoline ring (see Fig. 1). In our approach, we envisaged enantiopure cyclohexenones of type I (R 0 ZH) as potential intermediates as they would bring about ring closure by forming the N–C(8a) bond. Here, we present the synthesis of these building blocks and the results obtained by their aminocyclization, either when R 0 ZH or R 0 Zalkyl. 2. Results and discussion Figure 1. 2.1. Synthetic aspects The required starting materials are 2-bromocyclohex-2enone ethylene acetal (1) and the (S) and (R) isomers of [(S)1 0 -(dibenzylamino)ethyl]oxirane (2a and 2b). The cyclohexenone derivative 1, reported by Smith,9 is a precursor of the a-ketovinyl anion equivalent 3, often used in the formation of C–C bonds, for example, in reactions with alkyl halides,9,10 ketones,11 ethyl chloroformate,9 and DMF.12 Moreover, this vinyllithium derivative has been Total enantioselective syntheses of lepadins A,5 B,5–7 C,5 D–E,7 and H,7 as well as a formal route to rac-lepadin B8 have been reported. The strategies described for the construction of 5-substituted 3-hydroxy-2Keywords: Lepadin alkaloids; Decahydroquinolines; Epoxides; Organolithiums; Nitrogen heterocycles. * Corresponding author. Tel.: C34 934024540; fax: C34 934024539; e-mail: josep.bonjoch@ub.edu 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.06.024 M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270 8265 Scheme 1. Synthetic approaches to lepadin alkaloids. transmetallated with copper,13 tin,14 and palladium15 reagents and then used in coupling processes. Finally, the lithium compound 3 reacts with TMSCl16 and sulfinates to give vinylsilane and vinylsulfoxide17 derivatives, respectively. To our knowledge, this versatile lithium derivative has not been used in reactions with epoxides, such as described in the present work. On the other hand, epoxides 218 have been described by Reetz,19 Barluenga and ´ Concellon20 and Beaulieu,21 but there are no examples of their reactions with organolithium derivatives.22 The vinyllithium 3 formed on treatment of bromoacetal 1 with n-BuLi in THF reacted with epoxide 2a20 in presence of BF3$Et2O (Ganem’s conditions)23,24 to give enantiopure alcohol 4a (Scheme 2). After protection of the hydroxyl group as an acetate and subsequent deprotection of the acetal, the resulting cyclohexenone 5a was submitted to a hydrogenation reaction, which involves a reduction of the double bond, a double debenzylation of the tertiary amine and an intramolecular reductive amination, to give the decahydroquinoline ring. In this process, in which two new stereogenic centers are formed, the bicyclic compounds 6a and 7a were isolated in a 2:1 ratio. We then carried out the same sequence of reactions but starting from epoxide 2b20 (Scheme 3). In this series, the aminocyclization step starting from cyclohexenone 5b gave a nearly equimolecular mixture of decahydroquinolines 6b and 7b. Thus, 5-dealkyllepadin derivatives with the same absolute configuration as lepadins D, E, and H (i.e., compound 6a), and lepadins A, B, and C (i.e., compound 6b) were achieved. Scheme 3. Scheme 2. At this point, we explored the usefulness of cyclohexenones 5 as precursors of 5-alkylsubstituted decahydroquinolines (Scheme 4). Treatment of 5a with n-BuLi gave a tertiary alcohol as an epimeric mixture, which was reacetylated upon the hydroxyl of the side chain, and the resulting 8a was oxidized25 to give the rearranged enone 9a. The multi-step tranformation of 9a under a hydrogen atmosphere (hydrogenation, debenzylation, and reductive aminocyclization) gave a mixture of trisubstituted decahydroquinolines 10a 8266 M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270 relationship between the hydrogen atoms of these stereocenters suggesting that the double bond underwent a trans hydrogenation, as has been reported in some tetrasubstituted alkenes,26 or, after a cis hydrogenation and formation of the subsequent imine, an epimerization took place at C(4a) through an enamine intermediate. Again, as occured in the 5-unsubstituted series, the ratio of trans decahydroquinolines (i.e., 11b) to the cis epimers was higher in compounds with a 3S rather than 3R configuration. 2.2. NMR studies of decahydroquinolines 6, 7, 10, and 11 (series a and b) The cis (6 and 10) and trans decahydroquinolines (7 and 11) are clearly differentiated by two NMR features: (i) the 1H NMR chemical shift of H-8a, which appears more deshieled (d 2.95) in the cis-than in the trans-derivatives (d 2.20); (ii) the 13C chemical shift of C(7) is more deshielded (w4– 5 ppm) in the trans than in the cis derivatives.27 In all cases, the preferred conformation of the cis decahydroquinolines has the H-8a axial with respect to the N-containing ring (Nendo conformer). The absolute configuration of 6a was deduced considering that: (a) the coupling constants for H-2 (dq, JZ10, 6.5 Hz) and H-3 (td, JZ10.5, 4.8 Hz) determined their axial location and hence, fixed the methyl at C(2) and the acetoxy at C(3) to an equatorial disposition; (b) the multiplicity of H-8a (br s) implied an equatorial relationship with respect to the cyclohexane ring, which discarded not only a trans junction of the decaline ring but also, taking into account the preferred conformation, implied an R configuration for C(8a). The 13C chemical shifts also agree with this elucidation since the value of d 20.3 for C(7) is diagnostic of a cis decahydroquinoline in a N-endo conformation. For trans compound 7a, the axial proton H-8a is strongly coupled to two adjacent axial protons and one equatorial proton. Hence, its resonance signal appears as a deceptively simple triplet (JZ10.4 Hz) of doublets (JZ3.2 Hz) centered at d 2.19. The NMR data for compounds 6b and 7b follow the same pattern of signals as that of their corresponding epimers at C(3), the major differences being in the chemical shift for H-3, which is now more deshielded since it is located in an equatorial arrangement, and in C-3 and C-4a, which resonate at a lower field, due to the axially Scheme 4. and 11a in a nearly equimolecular ratio (71% overall yield), in which three new stereogenic centers were formed. Working with the epimeric epoxide 5b, and following the same reaction sequence, decahydroquinolines 10b and 11b were formed in a 1:4 ratio (65% overall yield). In all the cyclization processes (5/6C7 and 9/10C11), both in series a (3R configuration) and series b (3S configuration), the isolated decahydroquinolines show an R configuration at C(8a) (see Fig. 2). The configuration at C(4a) is controlled by the configuration of C(3) as well as by the presence or absence of a substituent at C(5). From the b-unsubstituted cyclohexenones (i.e., compounds 5), the aminocyclization takes place with some diastereoselection if the acetoxy substituent can adopt a pseudo-equatorial disposition in the transition state leading to the reduced product, as occurs in 6a, whereas in the epimeric series no stereocontrol was observed in the formation of the C(4a) stereocenter. Since it has not been established if the course of the reaction follows a pathway through an enimine intermediate or if there is a reduction of the double bond prior to the cyclization step, a clear understanding of the stereochemical course is not possible at this stage. More intriguing is the pathway of the aminocyclization leading to 2,3,5-trisubstituted decahydroquinolines 10 and 11. The configuration at C(4a) and C(5) in all cases showed a trans Figure 2. Preferred conformation of decahydroquinolines 6, 7, 10, and 11. M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270 170.6/21.3 170.8/21.4 170.4/21.2 171.0/21.3 170.5/21.1 170.5/21.3 171.0/21.3 8267 located acetoxy group (Table 1). For trisubstituted cis decahydroquinoline 10a, the butyl substituent at C(5) controls the preferred conformation of the bicyclic ring, which agrees with the conformation showed for lepadins where the substituent at C(5) is always equatorially located. The stereochemistry at C(5) for the butyl substituted products (10 and 11) was determined considering that the equatorially located butyl side chain exerts a steric crowding on H-4eq, due to their 1,3-synperiplanar relationship, which is reflected in the 13C and 1H NMR spectra by an upfield chemical shift (w3 ppm) for C(4) and a downfield chemical shift (d 2.25G0.05) for H-4eq as compared to the NMR data for compounds 6 and 7. In summary, a new synthetic entry to enantiopure polysubstituted decahydroquinolines has been reported. Although the observed stereoselectivity does not allow lepadin-type stereochemistries to be achieved, further studies in aminocyclization processes, starting from cyclohexenones of type 5, are in progress with the aim of achieving the required stereochemistry of lepadin derivatives. Interestingly, the reported methodology could be applied to the synthesis of another type of natural decahydroquinolines, such as trans-195A,28 5-epi-trans243A,29 and related alkaloids isolated from dendrobatid frogs,27c which show the same pattern of relative configuration as compounds 11a and 11b in their four stereocenters. 3. Experimental All spectra were recorded at 100 MHz in CDCl3 and the assignments were aided by HSQC experiments. OAc C-4 0 C-3 0 C-2 0 C-1 0 C-8a C-8 C-9 31.9 32.6 32.6 33.2 32.7 33.1 33.4 54.3 54.6 60.9 61.4 55.5 60.8 61.1 18.9 18.2 18.5 18.3 18.8 18.7 18.2 — — — — 31.9 32.1 31.7 — — — — 28.1 28.5 28.4 — — — — 23.1 23.1 23.1 — — — — 14.1 14.1 14.1 3.1. General All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions. Analytical TLC was performed on SiO2 (silica gel 60F254, Merck) or Al2O3 (ALOX N/UV254, Polygram), and the spots were located with iodoplatinate reagent (compounds 4, 5, 8, and 9) or 1% aqueous KMnO4 (compounds 6, 7, 10, and 11). Chromatography refers to flash chromatography and was carried out on SiO2 (silica gel 60, SDS, 230–240 mesh ASTM) or Al2O3 (aluminium oxide 90, Merck). Drying of organic extracts during workup of reactions was performed over anhydrous Na2SO4. Optical rotations were recorded with a Perkin-Elmer 241 polarimeter. 1H and 13C NMR spectra were recorded with a Varian Gemini 200 or 300, or a Varian Mercury 400 instrument. Chemical shifts are reported in ppm downfield (d) from Me4Si. All new compounds were determined to be O95% pure by 1H NMR spectroscopy. 3.1.1. 2-[(2R,3S)-3-Dibenzylamino-2-hydroxybutyl] cyclohex-2-enone ethylene acetal (4a). A solution of 6-bromo-1,4-dioxaspiro[4.5]dec-6-ene (1, 1.04 g, 4.75 mmol) in THF (3 mL) was added to a solution of n-BuLi (1.6 M in hexanes, 3.2 mL, 5.11 mmol) in THF (7 mL) at K78 8C. The reaction mixture was stirred for 90 min, treated with a solution of (2S)-[1 0 (S)-(dibenzylamino)ethyl]oxirane (2a, 489 mg, 1.83 mmol) in THF (6 mL) and BF3$Et2O (0.64 mL, 5.11 mmol), and continuously stirred at K78 8C for 2 h prior to being quenched with saturated NaHCO3 solution (10 mL) and warmed to rt. The C NMR data for decahydroquinolines 6, 7, 10, and 11 C-4a C-4 C-3 C-2 Table 1. 13 6a 6b 7a 7b 10a 11a 11b 56.5 55.0 55.7 54.0 56.5 55.4 53.7 73.0 70.3 75.7 71.6 72.7 76.4 71.6 36.4 35.0 37.5 36.6 32.5 34.4 33.5 36.8 33.5 41.6 36.9 41.8 46.3 40.9 26.5 27.5 31.8 31.9 33.0 40.8 40.7 C-5 26.1 26.8 25.6 26.0 29.7 31.3 31.9 C-6 20.3 20.8 25.3 25.5 21.3 24.7 24.9 C-7 8268 M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270 product was extracted with Et2O (3!20 mL), the combined organic layers were dried, concentrated, and the residue was chromatographed (SiO2, elution with 9:1 hexane/EtOAc) to give 560 mg (75%) of 4a as a colorless oil: RfZ0.31 (SiO2, 8:2 hexane/EtOAc); [a]20 C10.0 (c 1.2 in CHCl3); 1H NMR D (300 MHz, CDCl3) 1.15 (d, JZ6.3 Hz, 3H), 1.60–1.80 (m, 5H), 1.95–2.05 (br, 2H), 2.52–2.61 (m, 1H), 2.85 (dm, JZ 14 Hz, 1H), 3.25 (br, 1H), 3.45 (d, JZ13.8 Hz, 2H), 3.66– 3.73 (m, 1H), 3.77 (d, JZ13.8 Hz, 2H), 3.84–3.90 (m, 2H), 3.91–3.97 (m, 2H), 5.76 (t, JZ3 Hz, 1H), 7.18–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3) 8.4 (CH3), 20.6 (CH2), 25.4 (CH2), 33.2 (CH2), 36.2 (CH2), 54.3 (CH2), 57.7 (CH), 64.6 (CH2), 64.7 (CH2), 74.1 (CH), 107.5 (C), 126.7 (CH), 128.1 (CH), 128.7 (CH), 133.6 (CH), 140.3 (C). HRFABMS calcd for C26H34NO3 (MCC1) 408.2539, found 408.2516. 3.1.2. 2-[(2S,3S)-3-Dibenzylamino-2-hydroxybutyl] cyclohex-2-enone ethylene acetal (4b). Operating as above, starting from 881 mg (4.02 mmol) of 1 and using (2R)-[1 0 (S)-(dibenzylamino)ethyl]oxirane (2b, 414 mg, 1.55 mmol), and after chromatography (SiO2, 9:1 hexane/ EtOAc) 4b (518 mg, 82%) was isolated as an oil: RfZ0.28 (SiO2, 9:1 hexane/EtOAc); 1H NMR (200 MHz, CDCl3) 1.05 (d, JZ6.6 Hz, 3H), 1.62–1.72 (m, 5H), 1.95–2.05 (br, 2H), 2.17–2.25 (m, 1H), 2.52–2.62 (m, 1H), 3.33 (d, JZ 13.6 Hz, 2H), 3.64–3.76 (m, 1H), 3.88 (d, JZ13.6 Hz, 2H), 3.90–3.98 (m, 4H), 5.93 (t, JZ2 Hz, 1H), 7.16–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3) 8.6 (CH3), 20.6 (CH2), 25.3 (CH2), 33.6 (CH2), 34.3 (CH2), 53.6 (CH2), 58.2 (CH), 64.7 (CH2), 64.8 (CH2), 70.8 (CH), 107.8 (C), 127.0 (CH), 128.3 (CH), 128.9 (CH), 131.5 (CH), 139.2 (C). 3.1.3. 2-[(2R,3S)-2-Acetoxy-3-(dibenzylamino)butyl] cyclohex-2-enone (5a). To a solution of 4a (101 mg, 0.25 mmol) in pyridine (0.8 mL) and Ac2O (0.24 mL, 2.5 mmol) was added DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred overnight at rt. A saturated NaHCO3 solution (15 mL) was added and the mixture was extracted with CH2Cl2 (3!10 mL). The dried organic extracts were concentrated to give the corresponding acetate, which was used directly in the following acetal hydrolysis step. The above crude acetal was dissolved in 1:1 H2O/THF (4 mL) and stirred at rt for 1 h. The reaction mixture was basified with saturated aqueous NaHCO3 (15 mL) and extracted with CH2Cl2 (3!10 mL), and the resulting organic extracts were dried and concentrated. The residue was purified by chromatography (SiO2, hexane/ EtOAc 8:2) to give 5a as an oil (80 mg, 83%): RfZ0.27 (SiO2, 8:2 hexane/EtOAc); [a]20 C7.8 (c 0.7 in CHCl3); 1H D NMR (300 MHz, CDCl3) 1.08 (d, JZ6.6 Hz, 3H), 1.75– 1.83 (m, 1H), 1.83–1.93 (m, 2H), 1.94 (s, 3H), 2.16–2.28 (m, 2H), 2.31–2.38 (m, 2H), 2.75 (quint, JZ6 Hz, 1H), 3.18 (dm, JZ14 Hz, 1H), 3.41 (d, JZ13.6 Hz, 2H), 3.78 (d, JZ 13.6 Hz, 2H), 5.17 (ddd, JZ9.6, 7.6, 3.4 Hz, 1H), 6.53 (t, JZ4 Hz, 1H), 7.17–7.41 (m, 10H); 13C NMR (50 MHz, CDCl3) 8.8 (CH3), 21.2 (CH3), 22.9 (CH2), 26.2 (CH2), 33.2 (CH2), 38.2 (CH2), 53.9 (CH2), 55.1 (CH), 74.3 (CH), 126.7 (CH), 128.1 (CH), 129.0 (CH), 136.4 (C), 139.9 (C), 146.4 (CH), 170.4 (C), 198.7 (C). Anal. Calcd for C26H31NO3: C, 77.00; H, 7.70; N, 3.45. Found C, 76.75; H, 7.85; N, 3.39. 3.1.4. 2-[(2S,3S)-2-Acetoxy-3-(dibenzylamino)butyl] cyclohex-2-enone ethylene acetal (5b). Operating as above, starting from 263 mg (0.64 mmol) of alcohol 4b, and after chromatography (SiO2, 8:2 hexane/EtOAc), acetate 5b (196 mg, 81%) was isolated as an oil: RfZ0.25 (SiO2, hexane/EtOAc, 8:2); [a]20 K32 (c 1.8 in CHCl3); 1H D NMR (300 MHz, CDCl3) 1.09 (d, JZ7.2 Hz, 3H), 1.86– 1.94 (m, 3H), 2.01 (s, 3H), 2.16–2.30 (m, 3H), 2.33–2.40 (m, 1H), 2.60 (dm, JZ14 Hz, 1H), 2.89 (quint, JZ7 Hz, 1H), 3.37 (d, JZ13.8 Hz, 2H), 3.87 (d, JZ13.8 Hz, 2H), 5.06 (ddd, JZ10.2, 6.2, 2.6 Hz, 1H), 6.60 (t, JZ4.2 Hz, 1H), 7.18–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3): 9.7 (CH3), 21.2 (CH3), 22.9 (CH2), 26.1 (CH2), 33.0 (CH2), 38.2 (CH2), 54.3 (CH2), 55.4 (CH), 74.7 (CH), 126.6 (CH), 128.1 (CH), 128.8 (CH), 136.3 (C), 140.3 (C), 146.3 (CH), 170.3 (C), 198.8 (C). HRFABMS calcd for C26H32NO3 (MCC1) 406.2382, found 406.2339. 3.1.5. Aminocyclization of 5a. A suspension of enone 5a (50 mg, 0.12 mmol) and activated30 Pd(OH)2 in EtOH (2 mL) was stirred overnight under hydrogen. The catalyst was removed by filtration through Celite, and the solvent was evaporated to give a residue, which was purified by chromatography (Al2O3, 9:1 hexane/EtOAc) to give 6a (13 mg, 54%) and 7a (9 mg, 36%), both as oils. (2S,3R,4aR,8aR)-3-Acetoxy-2-methyldecahydroquinoline (6a). RfZ0.51 (Al2O3, 8:2 hexane/EtOAc); [a]20 K20.7 (c D 1.3 in CHCl3); 1H NMR (400 MHz, CDCl3, COSY) 1.08 (d, JZ6.4 Hz, 3H, Me), 1.20 (m, H-5ax), 1.40 (m, 3H, H-6ax and H-7), 1.45 (m, H-4ax), 1.55 (m, H-8), 1.70 (m, H-8), 1.74 (m, 3H, H-4a, H-5eq, H-6eq), 1.87 (ddd, JZ11.0, 3.6, 1.2 Hz, H-4eq), 2.05 (s, 3H, OAc), 2.70 (dq, JZ10.0, 6.5 Hz, H-2ax), 2.95 (br s, H-8a), 4.58 (td, JZ10.5, 4.8 Hz, H-3ax); 13C NMR see Table 1. HRFABMS calcd for C12H22NO2 (MCC1) 212.1651, found 212.1646. (2S,3R,4aS,8aR)-3-Acetoxy-2-methyldecahydroquinoline (7a). 1H NMR (400 MHz, CDCl3, COSY) 1.02 (qd, JZ 10.4, 3.2 Hz, H-5ax), 1.10 (masked, H-4ax), 1.12 (d, JZ 6.4 Hz, 3H, Me), 1.20–1.30 (m, 2H, H-8ax and H-4a), 1.35 (m, 2H, H-6ax and H-7ax), 1.65 (m, 2H, H-7eq and H-5eq), 1.8 (m, 2H, H-8eq and H-6eq), 2.04 (s, 3H, OAc), 2.05 (masked, H-4eq), 2.19 (td, JZ10.4, 3.2 Hz, H-8a), 2.76 (dq, JZ10, 6.4 Hz, H-2ax), 4.45 (td, JZ10.4, 4.4 Hz, H-3ax); 13 C NMR see Table 1. 3.1.6. Aminocyclization of 5b. Operating as above, starting from 49 mg (0.12 mmol) of enone 5b, and after chromatography (Al2O3, from 9:1 to 7:3 hexane/EtOAc), 11 mg (43%) of 6b and 11 mg (43%) of 7b, both as colorless oils, were isolated. (2S,3S,4aR,8aR)-3-Acetoxy-2-methyldecahydroquinoline (6b). RfZ0.30 (Al2O3, 8:2 hexane/EtOAc); [a]20 C10.8 (c D 0.8 in CHCl3); 1H NMR (400 MHz, CDCl3, COSY) 1.08 (d, JZ6.6 Hz, 3H, Me), 1.20 (m, H-5ax), 1.40 (m, 3H, H-6ax, H-7), 1.50 (m, 2H, H-8ax, H-4ax), 1.72 (m, 4H, H-4a, H-5eq, H-6eq, H-8eq), 1.87 (ddd, JZ12, 3.6, 1.5 Hz, H-4eq), 2.09 (s, 3H, OAc), 2.90 (qd, JZ6.8, 2 Hz, H-2ax), 2.92 (br, H-8a), 4.75 (ddd, JZ3.2, 3.2, 1.6 Hz, H-3eq); 13C NMR see Table 1. HRFABMS calcd for C12H22NO2 (MCC 1) 212.1651, found 212.1648. (2S,3S,4aS,8aR)-3-Acetoxy-2-methyldecahydroquinoline M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270 8269 (7b). RfZ0.23 (Al2O3, 8:2 hexane/EtOAc); [a]20 C28.6 (c D 0.8 in CHCl3); 1H NMR (400 MHz, CDCl3, COSY) 0.94 (qd, JZ12, 3 Hz, H-5ax), 1.06 (dd, JZ6.8 Hz, 3H, Me), 1.21–1.34 (m, 5H, H-4ax, H-4a, H-6ax, H-7ax, H-8ax), 1.54 (dm, JZ12 Hz, H-5eq), 1.69 (dm, JZ12 Hz, H-6eq), 1.77 (dm, 2H, JZ12 Hz, H-7eq, H-8eq), 1.88 (dd, JZ10.8, 3.2 Hz, H-4eq), 2.12 (s, 3H, OAc), 2.22 (td, JZ10, 3.2 Hz, H-8a), 2.92 (qd, JZ6.4, 1.6 Hz, H-2ax), 4.88 (ddd, JZ3.2, 3.2, 1.6 Hz, H-3eq); 13C NMR see Table 1. HRFABMS calcd for C12H22NO2 (MCC1) 212.1651, found 212.1648. 3.1.7. 2-[(2R,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-1butylcyclohex-2-en-1-ol (8a). To a cooled (K78 8C) solution of 5a (105 mg, 0.258 mmol) in THF (3 mL) was added n-BuLi (1.6 M in hexanes, 0.8 mL, 1.29 mmol) and the reaction mixture was stirred for 4 h, the temperature slowly rising to rt. The reaction was quenched by addition of saturated aqueous NH4Cl (20 mL) and extracted with CH2Cl2 (3!20 mL). The dried organic extracts were concentrated and the residue was dissolved in pyridine (1 mL) and treated with Ac2O (0.25 mL, 2.58 mmol) and DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred overnight at rt, saturated aqueous NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (3! 15 mL). The dried organic extract was concentrated and purified by chromatography (SiO2, hexane/EtOAc 8:2) to give the epimeric alcohols 8a and 1-epi-8a (81 mg, 68%), in a 1:1 ratio according to the NMR spectrum, which were used directly in the next step.Compound 8a. RfZ0.82 (SiO2, 8:2 hexane/EtOAc); 1H NMR (200 MHz, CDCl3) 0.92 (t, JZ6.8 Hz, 3H), 1.11 (d, JZ7.0 Hz, 3H), 1.18–1.38 (m, 4H), 1.49–1.80 (m, 7H), 1.82–1.93 (m, 2H), 1.98 (s, 3H), 2.75 (quint, JZ7 Hz, 1H), 2.95 (dm, JZ12 Hz, 1H), 3.44 (d, JZ 13.6 Hz, 2H), 3.75 (d, JZ13.6 Hz, 2H), 5.29–5.40 (m, 2H), 7.18–7.40 (m, 10H). Compound 1-epi-8a. RfZ0.64 (SiO2, 8:2 hexane/EtOAc); 1H NMR (200 MHz, CDCl3) 0.89 (t, JZ6.6 Hz, 3H), 1.06 (d, JZ6.6 Hz, 3H), 1.18–1.38 (m, 4H), 1.40–1.70 (m, 7H), 1.74–1.88 (m, 2H), 2.00 (s, 3H), 2.44– 2.54 (m, 1H), 2.85 (quint, JZ7 Hz, 1H), 3.48 (d, JZ 13.6 Hz, 2H), 3.73 (d, JZ13.6 Hz, 2H), 5.30 (m, 1H), 5.39 (t, JZ3.9 Hz, 1H), 7.18–7.40 (m, 10H). 3.1.8. 2-[(2S,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-1butylcyclohex-2-enol (8b). Operating as above, starting from 147 mg (0.36 mmol) of cyclohexenone 5b, and after chromatography (SiO2, hexane/EtOAc 8:2), 85 mg (51%) of 8b was obtained: RfZ0.58 (SiO2, 8:2 hexane/EtOAc); 1H NMR (200 MHz, CDCl3) 0.91 (t, JZ6.8 Hz, 3H), 1.09 (d, JZ7 Hz, 3H), 1.20–1.40 (m, 5H), 1.42–1.78 (m, 6H), 1.84– 1.96 (m, 2H), 2.05 (s, 3H), 2.18–2.28 (m, 1H), 2.85 (quint, JZ7 Hz, 1H), 3.37 (d, JZ13.5 Hz, 2H), 3.90 (d, JZ 13.5 Hz, 2H), 5.13–5.22 (m, 1H), 5.45 (t, JZ3.7 Hz, 1H), 7.18–7.40 (m, 10H). 3.1.9. 2-[(2R,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-3butylcyclohex-2-enone (9a). To a solution of epimeric alcohols 8a (81 mg, 0.18 mmol) in CH2Cl2 (2 mL) were added PCC (57 mg, 0.26 mmol) and SiO2 (57 mg), and the mixture was stirred overnight at rt. The residue obtained after evaporation of the solvent was purified by chromatography (SiO2, hexane/EtOAc 9:1) to give 9a as a viscous oil (50 mg, 62%): RfZ0.36 (SiO2, 8:2 hexane/EtOAc); [a]20 D K5.3 (c 0.3 in CHCl3); 1H NMR (400 MHz, CDCl3) 0.91 (t, JZ6.8 Hz, 3H), 1.11 (d, JZ6.4 Hz, 3H), 1.20–1.50 (m, 4H), 1.70–1.8 (m, 2H), 1.92 (s, 3H), 1.98–2.33 (m, 6H), 2.34– 2.42 (m, 1H), 2.71 (quint, JZ6.8 Hz, 1H), 3.08 (dd, JZ 13.6, 4.4 Hz, 1H), 3.45 (d, JZ13.6 Hz, 2H), 3.75 (d, JZ 13.6 Hz, 2H), 5.20 (ddd, JZ8.8, 6.8, 5.2 Hz, 1H), 7.18–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3, HSQC) 8.9 (CH3), 14.1 (CH3), 21.2 (CH3), 22.4 (CH2), 22.9 (CH2), 28.3 (CH2), 30.1 (CH2), 30.8 (CH2), 34.7 (CH2), 37.7 (CH2), 54.0 (CH2), 55.2 (CH), 75.0 (CH), 126.7 (CH), 128.1 (CH), 128.9 (CH), 131.3 (C), 140.1 (C), 160.9 (C), 170.4 (C), 198.7 (C). Anal. Calcd for C30H39NO3$H2O: C, 75.12; H, 8.62; N, 2.92. Found C, 75.48; H, 9.02; N, 2.58. 3.1.10. 2-[(2S,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-3butylcyclohex-2-enone (9b). Operating as above, starting from 71 mg (0.15 mmol) of alcohol 8b and after chromatography (SiO2, 9:1 hexane/EtOAc), enone 9b (41 mg, 61%) was isolated as a viscous oil; 1H NMR (400 MHz, CDCl3) 0.89 (t, JZ7.2 Hz, 3H), 1.10 (d, JZ6.8 Hz, 3H), 1.20–1.32 (m, 2H), 1.32–1.44 (m, 2H), 1.81–1.88 (m, 2H), 1.96 (s, 3H), 1.96–2.03 (m, 2H), 2.16–2.42 (m, 6H), 2.34– 2.42 (m, 1H), 2.68 (dd, JZ13.8, 11.0 Hz), 2.89–2.96 (m, 1H), 3.39 (d, JZ13.6 Hz), 3.90 (d, JZ13.6 Hz), 5.08 (ddd, JZ11.0, 5.8, 2.4 Hz, 1H), 7.18–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3, HSQC) 9.7 (CH3), 14.1 (CH3), 21.1 (CH3), 22.4 (CH2), 23.0 (CH2), 28.4 (CH2), 30.1 (CH2), 30.9 (CH2), 34.8 (CH2), 37.8 (CH2), 54.5 (CH2), 55.8 (CH), 75.9 (CH), 126.7 (CH), 128.1 (CH), 128.7 (CH), 131.7 (C), 140.22 (C), 160.1 (C), 170.1 (C), 198.8 (C). 3.1.11. Aminocyclization of 9a. Following the above procedure for the aminocyclization of 5a using enone 9a (38 mg, 0.08 mmol) and carrying out the hydrogenation process for 36 h, the crude product was purified by chromatography (Al2O3, from 9:1 to 7:3 hexane/EtOAc) to give 7 mg (33%) of 10a and 8 mg (38%) of 11a, both as colorless oils. (2S,3R,4aS,5R,8aR)-3-Acetoxy-5-butyl-2-methyldecahydroquinoline (10a). RfZ0.59 (Al2O3, 8:2 hexane/ EtOAc); [a] 20 K34.5 (c 0.5 in CHCl3); 1H NMR D (400 MHz, CDCl3, COSY) 0.90 (m, 1H, H-1 0 ), 0.90 (t, JZ6.8 Hz, 3H, H-4 0 ), 1.10 (d, JZ6.4 Hz, Me), 1.12 (masked, H-8ax), 1.20 (m, 4H, H-6 and H-2 0 ), 1.25 (m, 2H, H-3 0 ), 1.30 (m, H-4ax), 1.40 (m, H-4a), 1.48 (m, 2H, H-7), 1.5 (m, H-8eq), 1.70 (m, 2H, H-5ax, H-1 0 ), 2.04 (s, 3H, OAc), 2.27 (ddd, JZ12.4, 3.6, 2.8 Hz, H-4eq), 2.76 (dq, JZ10, 6.5 Hz, H-2ax), 2.97 (br s, H-8a), 4.49 (td, JZ10.4, 4.4 Hz, H-3ax); 13C NMR see Table 1. HRFABMS calcd for C16H30NO2 (MCC1) 268.2198, found 268.2202. (2S,3R,4aR,5S,8aR)-3-Acetoxy-5-butyl-2-methyldecahydroquinoline (11a). RfZ0.28 (Al2O3, 8:2 hexane/ EtOAc); [a] 20 K4.3 (c 0.3 in CHCl 3 ); 1 H NMR D (400 MHz, CDCl3, COSY) 0.88 (t, JZ6.8 Hz, 3H, H-4 0 ), 0.90 (masked, 1H, H-6ax), 0.94 (m, 2H, H-4ax, H-4a), 1.05 (masked, 2H, H-5 and H-1 0 ), 1.07 (d, JZ6.4 Hz, 3H, Me), 1.15 (m, 1H, H-8ax), 1.25 (m, 4H, H-2 0 , H-3 0 ), 1.30 (m, 1H, H-7ax), 1.45 (m, 1H, H-1 0 ), 1.75 (m, 3H, H-6, H-7, H-8), 2.05 (s, 3H, OAc), 2.20 (ddd, JZ11, 9, 3 Hz, H-8a), 2.29 (dm, JZ12 Hz, H-4eq), 2.70 (dq, JZ10.4, 6.4 Hz, H-2ax), 4.41 (td, JZ10.4, 4.8 Hz, H-3ax); 13C NMR see Table 1. 8270 M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270 HRFABMS calcd for C16H30NO2 (MCC1) 268.2198, found 268.2203. 13. 3.1.12. Aminocyclization of 9b. Operating as in the cyclization of 9a, from enone 11 (22 mg, 0.05 mmol) was obtained 11b as an oil (6 mg, 52%) after chromatography (Al2O3, from 9:1 to 7:3 hexane/EtOAc).31 (2S,3S,4aR,5S,8aR)-3-Acetoxy-5-butyl-2-methyldecahydroquinoline (11b). RfZ0.13 (Al2O3, 8:2 hexane/ EtOAc); 1H NMR (400 MHz, CDCl3, COSY) 0.87 (t, JZ 6.8 Hz, 3H, H 0 -4), 0.98 (m, 4H, H-4a, H-5, H-6, H-1 0 ), 1.06 (d, JZ6.8 Hz, 3H, Me), 1.15 (m, 2H, H-4ax, H-8ax), 1.25 (m, 4H, H-2 0 and H-3 0 ), 1.30 (m, H-7ax), 1.45 (m, 1H, H-1 0 ), 1.77 (m, 3H, H-8eq, H-7eq, H-6eq), 2.11 (s, 3H, OAc), 2.20 (dt, JZ10, 3.2 Hz, H-4eq), 2.27 (td, JZ10, 3 Hz, H-8a), 2.90 (qd, JZ6.4, 1.6 Hz, H-2ax), 4.91 (ddd, JZ3.2, 3.2, 1.6 Hz, H-3eq); 13C NMR see Table 1. HRFABMS calcd for C16H30NO2 (MCC1) 268.2198, found 268.2194. 14. 15. 16. 17. 18. Acknowledgements This work was supported by the MEC, Spain (Project CTQ2004-04701). Thanks are also due to the DURSI, Catalonia, for Grant 2001SGR-00083. M. M. is a recipient of a fellowship (MCYT, Spain). 19. 20. 21. 22. 23. References and notes 24. 1. Lepadin, A.; Steffan, B. Tetrahedron 1991, 47, 8729–8732. 2. Lepadins, B.-C.; Kubanek, J.; Williams, D. E.; de Silva, E. D.; Allen, T.; Anderson, R. J. Tetrahedron Lett. 1995, 36, 6189–6192. ¨ 3. Lepadins, D.-F.; Wright, A. D.; Goclik, E.; Konig, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067–3072. 4. Lepadins, F.-H.; Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65, 454–457. 5. (a) Toyooka, N.; Okumura, M.; Takahatam, H. J. Org. Chem. 1999, 64, 2182–2183. (b) Toyooka, N.; Okumura, M.; Takahatam, H.; Nemoto, H. Tetrahedron 1999, 55, 10673–10684. 6. (a) Osawa, T.; Aoyagi, S.; Kobayashi, C. Org. Lett. 2000, 2, 2955–2958. (b) Osawa, T.; Aoyagi, S.; Kobayashi, C. J. Org. Chem. 2001, 66, 3338–3347. 7. Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222–4225. 8. Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun. 2002, 1430–1431. 9. Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J. Org. Chem. 1982, 47, 1855–1869. 10. (a) Tokoroyama, T.; Tsukamoto, M.; Iio, H. Tetrahedron Lett. 1984, 25, 5067–5070. (b) Baldwin, J. E.; Adlington, R. M.; Robertson, J. Tetrahedron 1989, 45, 909–922. (c) Laschat, S.; Narjes, F.; Overman, L. E. Tetrahedron 1994, 50, 347–358. (d) Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-Y.; Chang, R.-C.; Chang, S.-C. J. Org. Chem. 1986, 51, 1490–1494. (e) Anderson, J. C.; Pearson, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2023–2029. 11. (a) Paquette, L. A.; Su, Z.; Bailey, S.; Montgomery, F. J. J. Org. Chem. 1995, 60, 897–902. (b) Warrington, J. M.; Yap, G. P. A.; Barriault, L. Org. Lett. 2000, 2, 663–665. 12. (a) Bodwell, G. J.; Pi, Z. Tetrahedron Lett. 1997, 38, 309–312. 25. 26. 27. 28. 29. 30. 31. (b) Yadav, V. K.; Senthil, G.; Babu, K. G.; Parvez, M.; Reis, J. L. J. Org. Chem. 2002, 67, 1109–1117. (a) Majetich, G.; Leigh, A. J.; Condon, S. Tetrahedron Lett. 1991, 32, 605–608. (b) Molander, G. A.; Bibeau, C. T. Tetrahedron Lett. 2002, 43, 5385–5388. ¨ Scott, T. L.; Soderberg, B. C. G. Tetrahedron 2003, 59, 6323–6332. (a) Lee, J.; Snyder, J. K. J. Org. Chem. 1990, 55, 4995–5008. ¨ (b) Scott, T. L.; Soderberg, B. C. G. Tetrahedron Lett. 2002, 43, 1621–1624. Shih, C.; Fritzen, E. L.; Swenton, J. S. J. Org. Chem. 1980, 45, 4462–4471. (a) Posner, G. H.; Frye, L. L.; Hulce, M. Tetrahedron 1984, 40, 1401–1407. (b) Mase, N.; Watanabe, Y.; Ueno, Y.; Toru, T. J. Org. Chem. 1997, 62, 7794–7800. (S)-Epoxide 2a has been described from N,N-dibenzylalaninal by addition of sulfonium ylide CH2]SMe219 or a (halomethyl)lithium,20,21 but (R)-epoxide 2b has only been reported ´ by Barluenga and Concellon20 through addition of (chloromethyl)lithium upon the ethyl ester of N,N-dibenzylalanine followed by diastereoselective reduction of the resulting a 0 -chloro a-amino ketone and ring closure of the formed chlorohydrin. Reetz, M. T.; Binder, J. Tetrahedron Lett. 1989, 30, 5425–5428. ´ ˜ Barluenga, J.; Baragana, B.; Concellon, J.-M. J. Org. Chem. 1995, 60, 6696–6699. Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635–3645. For a recent study on the reactivity of epoxides 2, see: ´ ´ ´ ´ Concellon, J. M.; Suarez, J. R.; Garcıa-Granda, S.; Dıaz, M.-R. Org. Lett. 2005, 7, 247–250. Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106, 3693–3694. Ring opening of epoxides catalyzed by BF3$Et2O: Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J. Org. Chem. 1991, 56, 5161–5169. For the generation of oxiranyl anions and further olefin formation with alkylation by reaction of epoxides with alkyllithiums, see: Satoh, T. Chem. Rev. 1996, 96, 3303–3325. Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682–685. (a) McKenzie, T. C. J. Org. Chem. 1974, 39, 629–631. (b) Overman, L. E.; Tomasi, A. L. J. Am. Chem. Soc. 1998, 120, 4039–4040. For NMR studies of decahydroquinolines, see: (a) Eliel, E. L.; Vierhapper, F. W. J. Org. Chem. 1976, 41, 199–208. b Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1977, 42, 51–62. (c) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H. J. C.; Daly, J. W.; Fukumoto, S.; Imamura, K.; Torres, J. A.; Snelling, R. R.; Jones, T. H. J. Nat. Prod. 1999, 62, 5–21. ¨ Holub, N.; Neidhofer, J.; Blechert, S. Org. Lett. 2005, 7, 1227–1229. Tokuyama, T.; Tsujita, T.; Shimada, A.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron 1991, 47, 5401–5414. Yoshida, K.; Nakajima, S.; Wakamatsu, T.; Ban, Y.; Shibasaki, M. Heterocycles 1988, 27, 1167–1170. Minor signals (approximately in a 1:3 ratio with respect to the major compound isolated 11b) in the NMR of the crude reaction mixture at d 4.76 (ddd, JZ3.2, 3.2, 1.6 Hz, H-3eq), 2.96 (m, H-8a), 2.66 (qd, JZ6.4, 3.2 Hz, H-2ax), and 2.16 (dm, JZ12 Hz, H-4eq) were observed. They could be attributed to the isomer 10b, which cannot be isolated in pure form. The isolated decahydroquinoline 11b remains partially contaminated by this compound even after repeating the chromatography. 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 6.2 Ring expansion of Functionalized Octahydroindoles to Enantiopure cisdecahydroquinolines Marisa Mena y Josep Bonjoch Domingo Gomez-Pardo y Janine Cossy J. Org. Chem. 2006, 71, 0000. 139 140 Ring Expansion of Functionalized Octahydroindoles to Enantiopure cisDecahydroquinolines† Marisa Mena and Josep Bonjoch,* Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av Joan XXIII s/n, 08028-Barcelona, Spain Domingo Gomez Pardo and Janine Cossy Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France josep bonjoch@ub edu RECEIVED DATE TITLE RUNNING HEAD: Ring expansion of octahydroindoles to cis- decahydroquinolines 0 Table of Contents Graphic H For R = H H O O H N Bn R OH 1. MsCl, Et3N, -20 οC 2. AgOAc, rt O O H N Bn Me (54%) 1. TFAA, Et3N, rfx 2. NaOH, rt O O H H N Bn (77%) OAc OH For R = Me ABSTRACT A new synthetic entry to enantiopure cis-decahydroquinolines is reported Endo and exo derivatives of cis-1-benzyl-2-(hydroxymethyl)octahydroindol-6-one ethylene acetal undergo ring-enlargement upon treatment with TFAA and then Et3N (thermodynamic conditions) to give enantiopure 1-benzyl-3-hydroxydecahydroquinolin7-one derivatives in 77% and 82% yield, respectively For 2-(1-hydroxyethyl) analogs, the best synthetic result is obtained from the (2S,1'R) endo isomer, which under kinetic reaction conditions (MsCl, THF, -20 °C, then AgOAc at rt) gives the expanded product in 54% yield cis-Decahydroquinoline constitutes the azabicyclic skeleton of natural products such as lepadins1 and several amphibian alkaloids,2 as well as some pharmacologically interesting synthetic compounds 3 Moreover, this heterocyclic motif occurs as a subunit of other azapolycyclic natural products (e.g. gephyrotoxins,4 cylindricines,5 and pseudoaspidopermidine and pandoline alkaloids6) (Figure 1) The extensive occurrence of this azabicyclic ring has stimulated the implementation of new procedures to gain access to functionalized enantiopure cis-decahydroquinolines that can be used as advanced intermediates in the synthesis of compounds embodying this skeleton-type 7 1 R1 H OR2 N H Me H O H lepadin F N C6H13 CH2OH R1 = (CH2)4CHOH-CH2CH2CH3 R2 = COCH=CH(CH2)4CH3 H H H HO gephyrotoxin N cylindricine C OH H N H N H CO2Me Et pandoline FIGURE 1. Natural and synthetic compounds embodying the cis-decahydroquinoline framework In this paper we report the studies devoted to the ring-enlargement of cisoctahydroindole derivatives to cis-decahydroquinolines The diastereoselective ring expansion of monocyclic and amines (azetidines,8 amines pyrrolidines,9,10 pyrrolines,11 1- piperidines12) bicyclic (2-azabicyclo[3 3 0]octanes,13 indolines,16 azabicyclo[2 2 2]octanes,14 indolizidines,15 hexahydropyrrolo[3,4- d]isoxazoles17) with a hydroxymethyl substituent adjacent to the nitrogen atom is a well known process,18,19 but it is unprecedented in octahydroindole compounds Considering the precedents, we envisaged that the transformation (Scheme 1) would occur via aziridinium intermediates,20 once the hydroxyl group is converted into a good leaving group A ring opening at the fused carbon atom would then lead to a new heterocyclic derivative with an expanded ring If the leaving group were a chloride or trifluoroacetate, in absence of another nucleophile in the reaction medium, the process would be reversible and the ratio of the expanded and non-expanded compounds would reflect their thermodynamic stability On the contrary, if X were an acetate and the - 2 chloride ion were taken out of the reaction medium using silver acetate, the ring opening of the aziridinium ion would be irreversible and the ratio of the formed compounds would arise from a kinetic control SCHEME 1. The synthetic approach to enantiopure cis-decahydroquinolines O O N Bn OH R H or Me after conversion of hydroxyl group to a leaving group (OCOCF3, OMs, Cl) X O X O O N Bn R reversible when X = Cl or OCOCF3 irreversible when X = OAc O N Bn R Our study of the stereospecific rearrangement of 2-hydroxymethyl- and 2-(αhydroxyethyl)octahydroindoles to 3-substituted and 2,3-disubstituted decahydroquinolines began with the preparation of the rearrangement precursors (Scheme 2) The starting materials were the azabicyclic esters endo 1 and exo 2, which were available from O-methyltyrosine in three steps (Birch reduction, aminocyclization promoted by MeOH-HCl, and benzylation) 21 Both esters were protected to give acetals 3 and 4, which, in turn, were reduced with LiBH4 to the corresponding primary alcohols 5 and 6 in 80% overall yield in each series On the other hand, the preparation of the secondary alcohols was carried out as follows: esters 3 and 4 were transformed to methyl ketones 7 (endo) and 8 (exo), respectively, in a two-step sequence involving the formation of their corresponding Weinreb amides,22 followed by coupling with methylmagnesium bromide Then, ketones 7 and 8 were both reduced with NaBH4 to give a mixture of secondary alcohols 9a and 10a (55:45 ratio)23 in the endo series and 11a and 12a (63:37 ratio) in the exo series At this point, improving the 3 diastereoselectivity of the reduction was not a priority since the availability of all the diastereomers would help evaluate the scope and limitations of the enlargement process SCHEME 2. Synthesis of cis-2-hydroxymethyl- and 2-(αα hydroxyethyl)octahydroindole derivatives H (CH2OH)2 O 1 LiBH4 H N Bn CO2Me toluene,rfx O O 3 80%, two steps H O O H 5 H (CH2OH)2 O H 2 N Bn CO2Me toluene,rfx O O 4 LiBH4 81%, two steps H O O H 6 N Bn OH H N Bn CO2Me H i) Me(MeO)NH.HCl, i-PrMgCl ii) MeMgBr O O 8 NaBH4 (86% from 4) O O H N Bn 12a Me H H OH H N Bn O H O O H N Bn 11a + N Bn OH (83% from 3) H N Bn CO2Me H i) Me(MeO)NH.HCl, i-PrMgCl ii) MeMgBr H O O 7 NaBH4 (83% from 3) O O H N Bn 10a H H OH Me Me 9a + H H OH H N Bn O O O H N Bn Me H H OH Two 13C NMR features clearly differentiate the endo and exo series of cis-2-substituted octahydroindol-6-ones (Table 1, Supporting Information): (i) the chemical shift of the benzylic carbon resonates at a higher field in exo compounds (δ 51 5-54 0) than in the endo compounds (δ 59-63); (ii) the C-7 signal appears at lower values in the exo compounds (δ 29-32) than in the endo isomers (δ 37-39) It is worth noting that the stereochemistry at C-1' for alcohols 9a-12a was only unequivocally established after the stereochemical elucidation of the expanded decahydroquinolines (cf. vide infra) The conformationally mobile cis-octahydroindole system21 has two conformers (N-outside 4 and N-inside) in which H-7a is axial or equatorial, respectively, with respect to the carbocyclic ring NMR studies allowed us to assign the conformational preference of the described cis-2-substituted octahydroindol-6-one derivatives, in which the coupling constants H7-H7a (one of them of 11 Hz) are consistent with antiperiplanar couplings, indicating that the H-7a proton24 is axially located with respect to the carbocyclic ring (Figure 2) H H 5 CH2OH 3 O O C6H5 H H N H H N H 6 CH2OH H H 7 4 3a O O H 7a C6H5 H 5 FIGURE 2. Preferred conformation of endo and exo compounds 5 and 6 Treatment of 2-(hydroxymethyl)octahydroindole derivative 5 with TFAA in THF followed by the addition of triethylamine9 led to the ring-expanded product, which after a hydrolytic work-up (aqueous NaOH) allowed the isolation of decahydroquinoline 13 (Scheme 3) The NMR data (see below) of this compound proves that the configuration of C-3 in (-)-13 is R, which supports the mechanism depicted in Scheme 1 (stereocontrolled process during the nucleophilic attack at C-2 of the aziridinium intermediate) The same protocol (TFAA/Et3N/NaOH) was also applied to the exo isomer 6, decahydroquinoline (+)-14 being isolated as a single isomer in 82% yield Both decahydroquinolines show the same preferred conformation according to their NMR spectra Thus, the coupling constants of H-4a and H-8a in each diastereomer are in accordance with an axial and an equatorial relationship, respectively, with respect to the N-containing ring (N-exo conformation) 25 The 13C NMR data corroborate the above stereochemical elucidation since both 13 and 14 show a relative upfield for C-2 and C- 5 8, a characteristic feature of cis-decahydroquinolines in the N-exo conformation (see Figure 3) SCHEME 3 Synthesis of 3-hydroxydecahydroquinolines H O O H N Bn 5 H O O H 6 N Bn OH TFAA, Et3N, THF then NaOH (82%) 14 O O H N Bn OH (77%) 13 H OH TFAA, Et3N, THF then NaOH O O H N Bn H OH When we applied the same procedure (TFAA, THF, then Et3N) to the secondary alcohols 9a-12a, i e under thermodynamic reaction conditions, the results were disappointing since after long reaction times (4-5 days at reflux temperature) only the starting material and degradation products were obtained 26,27 The next attempt to expand the ring involved converting alcohols 9a-12a to the secondary chlorides 9b-12b, which were then heated in refluxing THF In all cases, the unexpanded 2-(αchloroethyl)octahydroindoles 9b-12b were isolated (Scheme 4) 28 Since the configuration at C-1' was retained, these results show that the process occurred through an aziridinium salt intermediate and that chlorides 9b-12b were either directly formed by opening of an aziridinium by the chloride ion or by a reversion process from an initially expanded product Thus, under thermodynamic reaction conditions, we were unable to achieve 2,3-disubstituted decahydroquinolines from octahydroindoles 9a12a 29 6 SCHEME 4. Attempted ring expansion under thermodynamic conditions O O 9a-12a H N Bn Me MsCl OH Et3N O O N Bn H Cl Me 9b-12b TFAA, Et3N; THF reflux X O O N Bn Me THF reflux X = OCOCF3 or Cl (see references 26 and 28) In order to have an irreversible ring opening of the aziridinium intermediate, the chlorides 9b-12b were treated with AgOAc in a THF solution at reflux temperature (Method A) Under these kinetic conditions, the ring expanded decahydroquinolines 1719 were formed in variable yields (Scheme 5), and 20 was only detected in the GC-MS analysis The non-enlarged acetates 9c-12c formed by the acetate attack on the carbon linked to the methyl group in the aziridinium intermediate, were also isolated 30 The best results from a synthetic point of view were obtained for the endo compound 9b, since it was only in this series that the decahydroquinoline derivative was isolated as the main product We then decided to carry out the process starting from alcohols 9a-12a, working at -20 °C to avoid the formation of the corresponding chlorides,10c and promoting the ring opening of the aziridinium with AgOAc at room temperature (Method B) This decrease in temperature led to a slight increase in the ratio of the thermodynamically unfavoured decahydroquinolines (see Scheme 5) Not unexpectedly, in the endo series of 2-(α-hydroxyethyl)octahydroindoles the best result was obtained from alcohol 9a, which was transformed into the decahydroquinoline 17 in 54-58% yield 31,32 The reason was that the aziridinium intermediate was formed and opened without generating steric repulsion due to the antiperiplanar relationship between the methyl group and the C(2)-C(3) bond On the contrary, the reason for the poor yields 7 observed in the ring-expanded compounds in the exo series (11a and 12a) is unclear, even taking into consideration that the transition states between 12a and decahydroquinoline 20 are likely to be the most sterically demanding of the four pathways leading to expanded compounds Figure 3 depicts the preferred conformation of all the synthesized 3-oxygenated cis-decahydroquinolines SCHEME 5. Ring expansion under kinetic conditions 9a (2S,1'R) H O O H N Bn 9c H OAc Me O O H N Bn 17 Me H OAc Method 9c / 17 A B 34% / 46% 24% / 54% 10a (2S,1'S) H O O H N Bn 10c 11a (2S,1'S) H O O H N Bn 11c 12a (2S,1'R) H O O H N Bn 12c H OAc Me O O H N Bn 20 Me OAc H OAc O O H N Bn 19 Me H H OAc O O H N Bn 18 Me H OAc Method 10c / 18 A B 52% / 18% 35% / 31% Me Method 11c / 19 OAc A B 68% / 12% 66% / 10% Me H Method 12c / 20 A B 56% / 4% 40% / --- Method A: (i) MsCl, Et3N, THF reflux, 4h (9b-12b formed); (ii) AgOAc, THF reflux, 4 h Method B: (i) MsCl, Et3N, THF, -20 °C; (ii) AgOAc, rt, 1h 8 O H O H H Bn 8 4a H 2 OR2 H H 4a 8a R1 2 H H R2 OR3 H 8a N Bn 8 R1 H H N H O O H 13 17 18 21 R1 = R2 = H; R3 = H R1 = H; R2 = Me; R3 = Ac R1 = Me; R2 = H; R3 = Ac R1 = H; R2 = Me; R3 = H 14 R1 = R2 = H 15 R1 = Me; R2 = H 19 R1 = Me; R2 = Ac FIGURE 3 Stereochemistry of cis-decahydroquinolines Finally, to obtain a better understanding of the ring enlargement process, decahydroquinoline 21 (obtained under kinetic conditions from 9a)31 was submitted to the thermodynamic conditions of the aziridinium ring formation and opening (TFAA, then Et3N followed by heating at reflux for 8 h, and ending with an aqueous NaOH treatment) Under these conditions, octahydroindole 9a was formed, albeit as the only product (Scheme 6) This result confirms that 2-(α-hydroxyethyl)octahydroindoles are more stable than 2-methyl-3-hydroxyquinolines in the series of compounds examined (9-12 vs 17-20) SCHEME 6 kinetic conditions (i) MsCl, Et3N (ii) CF3CO2Ag, THF -20 οC to rt (iii) NaOH N Bn OH Me (i) (CF3CO)2O (ii) Et3N, THF 0 οC to reflux (8 h) (iii) NaOH thermodynamic conditions O O H N Bn 21 Me H O O H H OH 9a 9 In summary, the study of the ring enlargement of cis-octahydroindole derivatives has given access to valuable functionalized enantiopure cis-decahydroquinolines (13 and 14, in excellent yields, and 17 in good yield), which could be used as building blocks in the synthesis of natural products Moreover, it has been shown that subtle stereochemical differences in the octahydroindoles studied can have a significant impact on the ringexpansion pathway when the process is carried out under thermodynamic or kinetic conditions Experimental Section (3R,4aS,8aS)-1-Benzyl-3-hydroxy-7-oxodecahydroquinoline ethylene acetal (13). To a solution of alcohol 5 (223 mg, 0 74 mmol) in THF (2 mL) cooled to -78 ºC was added TFAA (0 21 mL, 1 47 mmol, 2 equiv) and the reaction mixture was stirred for 3 h at this temperature Et3N (0 5 mL, 3 68 mmol, 5 equiv) was added and after 15 min, the reaction mixture was heated at reflux for 20 h The mixture was cooled to 25 ºC, and 2 5 N NaOH (15 mL, 50 equiv) was added After stirring for 3 h, the reaction mixture was extracted with CH2Cl2 (3x20 mL) The organic extracts were dried and concentrated to give an oil, which was purified by chromatography (SiO2, 1% to 5% MeOH in CH2Cl2) to give 173 mg (77%) of 13 as a colorless oil: Rf = 0 35 (SiO2, CH2Cl2/MeOH 95:5); [α]D20 - 44 (c 0 3, CHCl3); 1H NMR (500 MHz, gCOSY, CDCl3) 1 45 (dm, J = 10 5 Hz, 1H, H-5eq), 1 47 (m, 1H, H-6eq), 1 50 (q, J = 10 5 Hz, 1H, H-4ax), 1 55 (m, 1H, H6ax), 1 58 (m, 1H, H-4eq), 1 61 (ddd, J = 12 5, 4 5, 2 0 Hz, 1H, H-8eq), 1 73 (tt, J = 13 5, 5 0 Hz, 1H, H-5ax), 1 82 (t, J = 12 5 Hz, 1H, H-8ax), 1 97 (dm, J = 10 5 Hz, 1H, H-4a), 2 10 (t, J = 10 5 Hz, 1H, H-2ax), 2 62 (ddd, J = 10 5, 5 0, 1 5 Hz, 1H, H-2eq), 3 00 (dt, J = 12 5, 4 5 Hz, 1H, H-8a), 3 45 and 3 66 (2d, J = 12 5 Hz, 1H each, NCH2Ar), 3 68 (dddd, J = 10 5, 10 5, 5 0, 5 0, 1H, H-3ax), 3 80-3 90 (m, 4H, OCH2), 10 7 20-7 30 (m, 5H, ArH); 13C NMR (75 MHz, gHSQC) 26 9 (C-5), 27 0 (C-8), 29 9 (C6), 32 8 (C-4a), 33 1 (C-4), 52 0 (C-2), 57 0 (C-8a), 58 3 (NCH2), 64 1 and 64 2 (OCH2), 68 1 (C-3), 109 9 (C-7), 126 8, 128 1, 129 5, 139 3 (Ar) Anal Calcd for C18H25NO3: C 71 26, H 8 31, N 4 62 Found: C 70 86, H 8 03, N 4 38 (3R,4aR,8aR)-1-Benzyl-3-hydroxy-7-oxodecahydroquinoline ethylene acetal (14). Operating as above, alcohol 6 (464 mg, 1 53 mmol) in THF (4 mL) was treated with TFAA (0 43 mL, 3 04 mmol, 2 equiv), and then with Et3N (1 07 mL, 7 65 mmol, 5 equiv) After work-up, the crude material was purified by chromatography (SiO2, 1% to 5% MeOH in CH2Cl2) to give 14 (380 mg, 82%) as a white solid: Rf = 0 40 (SiO2, CH2Cl2/MeOH 95:5); mp 101-103 °C; [α]D20 + 39 (c 1 0, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1 47 (m, 1H, H-6eq), 1 52 (m, 1H, H-5eq), 1 55 (m, 1H, H-4), 1 60 (m, 1H, H-6ax), 1 68 (m, 2H, H-4, H-8eq), 1 80 (tt, J = 13 5, 5 0 Hz, 1H, H-5ax), 1 87 (t, J = 12 5 Hz, 1H, H-8ax), 2 31 (dm, J = 10 5 Hz, 1H, H-4a); 2 52 and 2 57 (2d, J = 12 0 Hz, 1H each, H-2), 3 15 (dt, J = 12 5, 4 5 Hz, 1H, H-8a), 3 48 and 3 71 (2d, J = 13 0 Hz, 1H each, NCH2Ar), 3 84 (br s, 1H, H-3eq), 3 90-3 95 (m, 4H, OCH2), 7 20-7 35 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, gHSQC), 25 6 (C-8), 26 6 (C-5), 29 8 (C-6), 28 8 (C-4a), 30-5 (C-4), 50 6 (C-2), 57 7 (C-8a), 58 5 (NCH2), 64 1 and 64 3 (OCH2), 65 4 (C-3), 109 8 (C-7), 127 2, 128 4, 128 7, 139 0 (Ar) Anal calcd for C18H25NO3: C 71 26, H 8 31, N, 4 62 Found: C 70 89, H 8 50, N 4 44 Ring expansion of alcohol 9a. A solution of alcohol 9a (50 mg, 0 16 mmol) in THF (1 mL) was treated with MsCl (16 µL, 0 19 mmol, 1 2 equiv) and Et3N (90 µL, 0 64 mmol, 4 equiv) under an argon atmosphere at – 20 ºC for 1 h AgOAc was added (80 mg, 0 48 mmol, 3 equiv) and the resulting mixture was warmed to rt over a period of 1 h The reaction mixture was filtered through a bed of Celite and diluted with CH2Cl2 The organic layer was washed with saturated NaHCO3 (10 mL), dried and concentrated 11 to give a mixture of acetates 9c and 17 Purification and separation of the compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1) to afford 14 mg (24%) of 9c (for analytical data, see Supporting Information) and 31 mg (54%) of 17 (2S,3aS,7aS)-1-Benzyl-2-[(1'R)-(1-acetoxyethyl)]octahydroindol-6-one ethylene acetal (9c): Colourless oil Rf = 0 38 (SiO2, CH2Cl2/EtOAc 8:2); [α]D20 - 10 7 (c 0 4, CHCl3); IR 1736 cm-1; 1H NMR (400 MHz, CDCl3, gCOSY) 1 23 (d, J = 6 4 Hz, 3H, CH3), 1 26 (m, 2H, H-5), 1 44 (d, J = 8 4 Hz, 2H, H-7), 1 60 (m, 2H, H-4), 1 76 (m, 2H, H-3), 2 07 (s, 3H, OAc), 2 20 (m, 1H, H-3a), 2 90 (q, J = 8 4 Hz, 1H, H-7a), 2 91 (ddd, J = 8 4, 8 0, 4 0 Hz, 1H, H-2), 3 63 and 3 86 (2d, J = 14 0 Hz, 1H each, NCH2Ar), 3 66-3 83 (m, 4H, OCH2), 5 05 (qd, J = 6 4, 4 0 Hz, 1H, H-1'), 7 20-7 35 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3), see Table 1 HRFABMS: calcd for C21H30NO4 360 2175 (MH+), found 360 2170 (2S,3R,4aS,8aS)-3-Acetoxy-1-benzyl-2-methyl-7-oxodecahydroquinoline ethylene acetal (17): Colourless oil Rf = 0 84 (SiO2, CH2Cl2/EtOAc 8:2) [α]D20 - 37 (c 1 0, CHCl3); IR 1734 cm-1; 1H NMR (400 MHz, CDCl3, gCOSY) 1 03 (d, J = 6 4 Hz, 3H, Me), 1 45-1 74 (m, 7H, H-4, H-5, H-6, and H-8eq), 1 91 (t, J = 12 4 Hz, 1H, H-8ax), 2 06 (s, 3H, OAc), 2 10 (dm, J = 12 0 Hz, 1H, H-4a), 2 84 (dq, J = 10 0, 6 0 Hz, 1H, H2ax), 2 93 (dt, J = 12 4, 4 4 Hz, 1H, H-8a), 3 63 and 3 90 (2d, J = 14 8 Hz, 1H each, NCH2Ar), 3 81-3 94 (m, 4H, OCH2), 4 60 (td, J = 11 0, 5 2 Hz, 1H, H-3ax), 7 18-7 35 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, DEPT, gHSQC) 16 8 (Me), 21 3 (OAc), 26 6 (C-5), 28 1 (C-8), 29 6 (C-4), 29 7 (C-6), 31 4 (C-4a), 52 6 (NCH2), 53 0 (C-2), 55 8 (C-8a), 64 0 and 64 1 (OCH2), 75 5 (C-3), 109 8 (C-7), 126 5, 127 7, 128 2, 141 2 (Ar), 170 6 (CO) HRFABMS: calcd for C21H30NO4 360 2175 (MH+), found 360 2171 Acknowledgment This research was supported by the MEC (Spain)-FEDER through project CTQ2004-04701/BQU Thanks are also due to the DURSI (Catalonia) for Grant 12 2005SGR-00442 and the Ministry of Education and Science (MEC, Spain) for a fellowship to M M I D R SERVIER (France) is greatly acknowledged for experiment with microwave conditions Supporting Information Available Experimental and NMR data for all compounds reported, including Tables of 13 C NMR chemical shifts of octahydroindoles and 1 decahydroquinolines reported Copies of H and 13 C NMR spectra of all new compounds as well as COSY and HSQC spectra when available This material is available free of charge via the Internet at http://pubs acs org REFERENCES † Dedicated to the memory of the late Professor Marcial Moreno Mañas 1 Pu, X ; Ma, D Angew. 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Lett. 2000, 2, 1661-1664 15 Verhelst, S H L ; Paez Martinez, B ; Timmer, M S M ; Lodder, G ; van der Marel, G A ; Overkleeft, H S ; van Boom, J H J. Org. Chem. 2003, 68, 95989603 16 Ori, M ; Toda, N ; Takami, K ; Tago, K ; Kogen, H Tetrahedron 2005, 61, 2075-2104 17 18 Deyine, A ; Delcroix, J -M ; Langlois, N Heterocycles 2004, 64, 207-214 For some applications in natural products synthesis, see: (a) Harding, K E ; Burks, S R J. Org. Chem. 1984, 49, 40-44 (b) Kuehne, M E ; Podhorez, D E J. Org. Chem. 1985, 50, 924-929 (c) Williams, D R ; Osterhout, M H ; McGill, J M Tetrahedron Lett. 1989, 30, 1331-1334 (d) Morimoto, Y ; Shirahama, H Tetrahedron 1996, 52, 10631-10652 (e) Cossy, J ; Mirguet, O ; Gomez Pardo, D Synlett 2001, 1575-1577 (f) Ori, M ; Toda, N ; Takami, K ; Tago, K ; Kogen, H Angew. Chem. Int. Ed. 2003, 42, 2540-2543 15 19 For some applications in therapeutical agent synthesis, see: (a) Cossy, J ; Dumas, C ; Gomez Pardo, D Bioorg. Med. Chem. Lett. 1997, 7, 1343-1346 (b) Cossy, J ; Mirguet, O ; Gomez Pardo, D ; Desmurs, J -R Tetrahedron Lett. 2001, 42, 5705-5707 (c) Cossy, J ; Mirguet, O ; Gomez Pardo, D ; Desmurs, J R Eur. J. Org. Chem. 2002, 3543-3551 (d) Déchamps, I ; Gomez Pardo, D ; Karoyan, P ; Cossy, J Synlett. 2005, 1170-1172 20 For a review on the synthesis of six-membered nitrogen-containing compounds via aziridinium intermediates, see: Cossy, J ; Gomez Pardo, D Chemtracts 2002, 15, 579-605 21 Valls, N ; López-Canet, M ; Vallribera, M ; Bonjoch, J Chem. Eur. J. 2001, 7, 3446-3460 22 For the preparation of N-methoxy-N-methylamides from esters using isopropylmagnesium chloride, see: Williams, J M ; Jobson, R B ; Yasuda, N ; Marchesini, G ; Dolling, U -H ; Grabowski, E J J Tetrahedron Lett 1995, 36, 5461-5464 23 Using LS-Selectride as the reducing agent, ketone 7 furnished stereoselectively alcohol 10a 24 The chemical shift of H-3a and H-7a appears more deshielded in the exoderivatives than in the endo compounds, due to the syn relationship of the nitrogen lone pair with both protons in the exo series (Figure 2) 25 For 13 C NMR studies in cis-decahydroquinolines, see: Spande, T F ; Jain, P ; Garraffo, H M ; Pannell, L K ; Yeh, H J C ; Daly, J W ; Fukumoto, S ; 16 Imamura, K ; Torres, J A ; Snelling, R R ; Jones, T H J. Nat. Prod. 1999, 62, 5-21 26 Decahydroquinoline 15 was isolated in one run working from alcohol 11a, although only in 5% yield For Information) H O O H 15 N Bn Me 13 C NMR data see Table 2 (Supporting OH 27 28 The use of microwave conditions did not give satisfactory results either Together with chloride 9b, the expanded product 16 was formed according to the 13 C NMR spectrum of the reaction mixture For NMR data of 9b-12b, see Supporting Information H O O H 16 N Bn Me Cl 29 There are scarcely any examples of ring enlargement via aziridinium ions from secondary alcohols and they are always of the benzylic type: see references 9b and 10b-c 30 It was confirmed in two series that the configuration at C-1' of the side chain was identical to that of the starting alcohol Treatment of 10a and 11a with acetic anhydride gave the same acetates 10c and 11c as those obtained through sequential treatment with MsCl and Et3N, then AgOAc 17 31 The use of silver trifluoroacetate instead of silver acetate slightly increased the yield of the expanded compound, which after a basic work-up gave alcohol 21 (58%), see Scheme 6 32 The use of tetrabutylammonium acetate did not improve the course of the reaction From 9a, a mixture of acetates 17 (38%) and 9c (34%) were isolated, whereas from 10a-12a more complex reaction mixtures were formed, the decahydroquinolines 18, 19, and 20 being obtained in a yield lower than 10% 18 Supporting Information Ring Expansion of Functionalized Octahydroindoles to Enantiopure cis-Decahydroquinolines Marisa Mena and Josep Bonjoch,* Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona , Av. Joan XXIII s/n, 08028-Barcelona, Spain Domingo Gomez Pardo and Janine Cossy Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France josep.bonjoch@ub.edu Contents - Table 1. 13C NMR Chemical shifts of octahydroindoles 3-12 - Table 2. 13C NMR Chemical shifts of decahydroquinolines 13-21 - Experimental and/or NMR data of compounds 3-21 - Copies of 1H NMR and 13C NMR spectra of all new compounds, including COSY and HSQC spectra for compounds 11c and 19, 13, 14, 17, 18, and 21 15-72 2-3 4 5-14 S1 Table 1. 13C NMR Chemical shifts of octahydroindoles 3-12a 3 4 5 6 7 8 9a 10a 11a C2 C3 C3a C4 C5 C6 C7 C7a NCH2 ips-Ar o-Ar m-Ar p-Ar C-1' Me OCH2 66.2 33.6 35.7 24.0 31.0 109.1 37.5 62.5 58.8 139.1 129.1 127.9 126.8 175.0 51.6 64.3 64.0 62.9 31.7 35.2 23.3 29.9 109.3 31.9 59.5 53.4 139.0 128.8 128.1 126.9 174.2 51.6 64.3 64.0 66.2 32.1 35.0 24.3 31.0 108.9 37.8 63.0 58.8 139.2 128.9 128.3 127.2 61.2 --64.1 63.9 61.7 30.5 35.6 22.8 28.9 109.4 30.6 59.3 51.7 139.3 128.4 128.3 127.0 62.4 --64.3 63.9 74.9 33.3 35.6 24.2 31.0 108.8 38.2 63.0 60.0 139.2 129.4 128.1 127.1 213.2 24.9 64.0 64.0 70.8 30.6 35.6 22.8 29.2 109.2 30.9 59.4 53.4 138.5 128.7 128.2 127.1 216.4 24.9 64.3 63.9 71.0 30.6 34.6 23.9 27.5 108.9 38.2 62.9 58.9 140.0 129.1 128.4 127.2 63.5 18.2 64.0 64.0 72.5 32.2 34.8 22.7 29.3 109.0 38.8 63.3 63.2 140.0 128.3 128.3 127.0 71.9 20.8 64.1 63.9 66.1 25.4 35.6 22.9 28.9 109.4 30.4 58.9 51.4 139.4 128.4 128.2 127.0 64.7 18.2 64.1 63.8 a Values for compounds 3, 5, 9a, 10a and 11a were assigned on the basis of gHSQC spectra. H O O H N Bn R 3 R = CO2Me 5 R = CH2OH 7 R = COCH3 9a R = (R)-CHOHCH3 10a R = (S)-CHOHCH3 H O O H N Bn R 4 R = CO2Me 6 R = CH2OH 8 R = COCH3 11a R = (S)-CHOHCH3 S2 Table 1 continued). 13C NMR Chemical shifts of octahydroindoles 3-12b 12a 9b 10b 11b 12b 9cc 10cc 11cc 12cc C2 C3 C3a C4 C5 C6 C7 C7a NCH2 ips-Ar o-Ar m-Ar p-Ar C-1' Me OCH2 66.5 30.3 35.3 22.7 29.0 109.4 31.2 58.8 53.9 139.5 128.2 127.8 126.7 71.1 20.6 64.2 63.8 72.1 29.7 34.5 23.0 29.5 109.2 39.2 62.5 61.4 140.6 128.3 128.1 126.6 63.4 22.9 64.1 63.8 71.6 30.4 34.5 23.3 29.9 109.1 39.1 63.7 61.3 140.7 128.6 128.2 126.8 60.6 19.8 64.0 63.9 66.7 28.2 34.6 22.8 29.7 109.5 31.0 58.9 52.2 139.9 128.2 128.2 126.7 60.9 22.3 64.2 63.9 66.4 27.1 35.0 22.8 29.0 109.4 30.9 58.3 52.7 139.8 128.2 128.1 126.8 59.8 17.7 64.3 63.9 69.1 30.1 34.4 23.3 29.8 109.2 39.1 62.2 60.4 139.2 129.4 128.1 127.1 71.1 17.1 63.9 63.8 68.8 31.0 34.6 23.2 29.7 109.1 39.3 63.8 61.8 141.2 128.2 128.0 126.5 75.2 16.5 64.0 63.8 64.4 27.7 34.8 22.9 29.1 109.5 30.2 58.2 52.0 139.8 128.1 128.0 126.6 70.7 16.7 64.1 63.8 62.9 27.4 35.2 22.8 29.0 109.5 30.6 58.4 52.5 140.0 128.1 128.0 126.6 72.3 14.5 64.2 63.9 b c Values for compounds 12a, 10b, 11b, 9c, 11c, and 12c were assigned on the basis of gHSQC spectra. OAc: 170.6 / 170.7 and 21.3 /21.5. H O O H N Bn H R Me 9b R = Cl (1'R) 10b R = Cl (1'S) 9c R = OAc (1'R) 10c R = OAc (1'S) H O O H N Bn Me H 12a 11b 12b 11c 12c R = OH (1'R) R = Cl (1'S) R = Cl (1'R) R = OAc (1'S) R = OAc (1'R) S3 Table 2. 13C NMR Chemical shifts of decahydroquinolines 13-21a 13 14 15 16b 17 18 19c 21 C2 C3 C4 C4a C5 C6 C7 C8 C8a Me NCH2 Ar 52.0 68.1 33.1 32.8 26.9 29.9 109.9 27.0 57.0 --58.3 126.8 128.1 129.5 139.3 50.6 65.4 30.5 28.8 26.6 29.8 109.8 25.6 57.7 --58.5 127.2 128.4 128.7 139.0 64.3 64.1 57.1 69.7 26.8 28.3 26.4 30.2 109.3 33.5 56.6 14.9 55.3 127.1 128.3 128.5 n.o. 63.9 64.2 56.0 61.4 33.1 35.5 26.7 32.4 109.6 28.9 56.2 18.4 52.7 126.5 127.6 128.1 141.1 64.0 63.7 53.0 75.5 29.6 31.4 26.6 29.7 109.8 28.1 55.8 16.8 52.6 126.5 127.7 128.2 141.2 64.1 64.0 170.6 21.3 51.9 73.2 27.0 33.6 25.0 30.2 109.4 34.1 56.1 11.5 55.7 126.9 128.2 128.2 139.8 64.2 63.9 170.4 21.3 53.2 73.1 24.2 28.4 26.8 30.0 109.3 34.7 56.9 15.7 55.9 140.2 128.3 127.9 126.6 64.2 63.9 170.7 21.4 55.7 73.6 33.3 32.0 26.9 29.9 109.9 27.6 56.5 16.9 52.8 126.5 127.9 128.1 140.6 64.1 64.0 OCH2 64.2 64.1 Other a Values for compounds 13, 17, 18, 19 and 21 were assigned on the basis of gHSQC spectra b Values taken from an NMR spectrum of a mixture of 9b and 16. c Values taken from an NMR spectrum of a mixture of 11c and 19. H O O H N Bn 13 14 OH O O H N Bn H OH O O H N Bn Me H OR O O H N Bn 16 R = Cl 17 R = OAc 21 R = OH Me H R O O H N Bn 18 Me H OAc 15 R = H 19 R = Ac S4 Experimental Section General: All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions. Analytical thin-layer chromatography was performed on SiO2 (silica gel 60 F254) or Al2O3 (ALOX N/UV254), and the products were located with iodoplatinate spray. Chromatography refers to flash chromatography and was carried out on SiO2 (silica gel 60, 230-240 mesh ASTM) or Al2O3 (aluminium oxide 90). Drying of organic extracts was performed over anhydrous Na2SO4. Evaporation of solvent was accomplished with a rotatory evaporator. Chemical shifts of 1H and 13C NMR spectra are reported in ppm downfield (δ) from Me4Si. Only noteworthy IR absorptions (cm-1) are listed. Methyl 2S,3aS,7aS)-1-Benzyl-6-oxooctahydroindole-2-carboxylate ethylene acetal 3). To a solution of ketone 1 (3.28 g, 11 mmol) in toluene (350 mL) were added a catalytic amount of TsOH and ethyleneglycol (1.84 mL, 33 mmol), and the reaction mixture was heated at reflux temperature for 4 h in a flask incorporating a Dean-Stark apparatus. The cooled solution was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 (100 mL). The organic phase was dried and concentrated to give 3.64 g of 3 as a yellowish oil, which was used in the next step without further purification. An analytical sample was obtained by chromatography (SiO2, 1% MeOH in CH2Cl2). Rf = 0.37 (SiO2, hexane/EtOAc 3:2); [α]D20 -41 (c = 0.9, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1.46-1.58 (m, 1H), 1.64-1.85 (m, 5H), 1.87-1.95 (m, 1H), 2.02-2.11 (m, 1H), 2.13 -2.26 (m, 1H), 2.99 (q, J = 7.5 Hz, 1H, H-7a), 3.41 (dd, J = 9.1, 7.7 Hz, 1H, H-2), 3.54 (s, 3H, OCH3), 3.74-3.92 (m, 6H), 7.18-7.40 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3, DEPT, gHSQC), see Table 1. Anal. Calcd for C19H25NO4: C 68.86, H 7.60, N 4.22. Found: C 68.48, H 7.55, N 4.20. Methyl 2S,3aR,7aR)-1-Benzyl-6-oxooctahydroindole-2-carboxylate ethylene acetal 4). Operating as above, from ketone 2 (1.03 g, 3.6 mmol), acetal 4 was obtained (1.12 g) as yellowish crystals and used in the next step without further purification. An analytical sample was obtained by chromatography (SiO2, 1% MeOH in CH2Cl2): Rf = 0.24 (SiO2, hexane/EtOAc 3:2); mp 64-66 °C; S5 [α]D20 -53 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3) 1.44-1.72 (m, 4H), 1.79-1.94 (m, 3H), 2.12 (dt, J = 12.9, 10.7 Hz, 1H), 2.46 -2.58 (m, 1H), 3.37 (dt, J = 10.5, 5.3 Hz, 1H, H-7a), 3.50 (dd, J = 10.2, 3.6 Hz, 1H, H-2), 3.55 (s, 3H, OCH3), 3.74 (d, J = 13.2 Hz, 1H), 3.81 (d, J = 13.2 Hz, 1H), 3.83 -3.96 (m, 4H), 7.18-7.40 (m, 5H, ArH). 13C NMR (75 MHz, CDCl3, DEPT), see Table 1. Anal. calcd for C19H25NO4: C 68.86, H 7.60, N 4.22. Found: C 68.56, H 7.85, N 4.24. 2S,3aS,7aS)-1-Benzyl-2-hydroxymethyl-6-oxooctahydroindole ethylene acetal 5). Ester 3 (603 mg, 1.82 mmol) was dissolved in THF (9 mL) and then cooled to 0 ºC. LiBH4 (2 M in THF, 2.8 mL, 5.46 mmol, 3 equiv) was slowly added, and the reaction mixture was stirred at rt for 24 h. The reaction was quenched by adding H2O (5 mL) and the organic layer was dried and concentrated to give a residue, which was purified by chromatography (SiO2, 1% MeOH in CH2Cl2) to afford 441 mg (80% from 1) of 5 as a colourless oil: Rf = 0.31 (SiO2, CH2Cl2/MeOH 95:5); [α]D20 -15 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1.49 (dddd, J = 12.0, 5.0, 5.0, 1.2 Hz, 1H, H5eq), 1.65 (m, 3H, H-5 and H-7), 1.75 (m, 3H, H-3 and H-4), 1.85 (dd, J = 12.4, 7.2 Hz, 1H, H-3), 2.20 (m, 1H, H-3a), 2.40 (brs, 1H, OH), 2.98 (dddd, J = 8.0, 7.5, 5.4, 1.8 Hz, 1H, H-2), 3.02 (q, J = 7.2 Hz, 1H, H-7a), 3.33 (dd, J = 11.0, 1.2 Hz, 1H, CH2OH), 3.42 (dd, J = 11.0, 3.6 Hz, 1H, CH2OH), 3.69-3.88 (m, 6H, OCH2 and NCH2), 7.26-7.32 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS calcd for C18H26NO3 304.1906 (MH+), found 304.1913. 2S,3aR,7aR)-1-Benzyl-2-hydroxymethyl-6-oxooctahydroindole ethylene acetal 6). Operating as above from ester 4 (627 mg, 1.89 mmol), alcohol 6 (464 mg, 81% from 2) was obtained after chromatography (SiO2, 1% MeOH in CH2Cl2), as white crystals: Rf = 0.40 (SiO2, CH2Cl2/MeOH 95:5); mp 72-74 °C; [α]D20 -72 (c 0.25, CHCl3); 1H NMR (400 MHz, COSY, CDCl3) 1.46 (t, J = 12.0 Hz, 1H, H-7ax), 1.52 (dq, J = 12.5, 2.5 Hz, 1H, H-4eq), 1.63 (dm, J = 12.0 Hz, 1H, H-5eq), 1.64 (td, J = 10.0, 3.2 Hz, 1H, H-5ax), 1.78 (m, 1H, H-4ax), 1.80 (m, 1H, H-3β), 1.83 (dd, J = 12.0, 5.5 Hz, 1H, H-7eq), 2.05 (q, J = 12.0 Hz, 1H, H-3α), 2.30 (m, 1H, H-3a), 2.99 (dt, J = 10.0, 3.2 Hz, 1H, H-2), 3.24 (ddd, J = 12.0, 5.5, 5.5 Hz, 1H, H-7a), 3.38 (dm J = 10.8 Hz, 1H, CH2OH), 3.55 (dd, J = 10.8, 3.2 Hz, 1H, CH2OH), 3.64 and 3.71 (2d, J = 13.6 Hz, 1H each, S6 NCH2), 3.77-3.93 (m, 4H, OCH2), 7.26-7.32 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3, DEPT), see Table 1. Anal. Calcd for C18H25NO3: C 71.26, H 8.31, N 4.62. Found: C 71.05, H 8.20, N 4.57. 2S,3aS,7aS)-2-Acetyl-1-benzyloctahydroindol-6-one ethylene acetal 7). To a solution of ester 3 (2.45 g, 7.4 mmol) in THF (140 mL) cooled to -20 ºC was added Me(MeO)NH.HCl (1.82 g, 18.5 mmol, 2.5 eq) and then over 30 min was added a solution of i-PrMgCl in THF (18.5 mL, 2.0 M, 5 equiv) maintaining the temperature at -10 °C. The mixture was stirred for 40 min and quenched with saturated aqueous NH4Cl solution (50 mL). The organic layer was dried and concentrated to afford 2.65 g of the corresponding Weinreb amide as a yellow oil, which was used without purification: Rf = 0.21 (SiO2, CH2Cl2/MeOH 96:4). To a solution of the aforementioned Weinreb amide (2.65 g, 7.4 mmol) in THF (95 mL) cooled to 0 ºC was added dropwise MeMgBr in Et2O (6.4 mL, 3 M, 19.24 mmol, 2.6 eq). The reaction mixture was stirred at 0 ºC for 1 h and quenched with saturated aqueous NH4Cl solution (50 mL). The organic layer was dried and concentrated to give ketone 7 (2.32 g) as an oil, which was used without further purification. Rf = 0.52 (SiO2, CH2Cl2/MeOH 95:5); 1H NMR (300 MHz, CDCl3) 1.53 (m, 1H), 1.61-1.85 (m, 6H), 2.02 (dt, J = 12.3, 7.2 Hz, 1H), 2.04 (s, 3H, CH3), 2.25 (m, 1H, H-3a), 3.02 (q, J = 6.9 Hz, 1H, H7a), 3.29 (dd, J = 9.3, 7.8 Hz, 1H, H-2), 3.63 and 3.83 (2d, J = 13.5 Hz, 1H each, NCH2Ar), 3.753.95 (m, 4H, OCH2), 7.20- 7.35 (m, 5H, Ar); 13C NMR (50 MHz, CDCl3, DEPT), see Table 1. 2S,3aR,7aR)-2-Acetyl-1-benzyloctahydroindol-6-one ethylene acetal 8). The above procedure was applied to ester 4 (1.12 g) to afford the corresponding Weinreb amide (1.30 g): Rf = 0.16 (SiO2, CH2Cl2/MeOH 95:5). The Weinreb amide was treated with MeMgBr in Et2O (3.12 mL, 3 M, 9.36 mmol, 2.6 eq) and operating as in the formation of ketone 7, 1.21 g of ketone 8 was isolated, which was used without further purification. Rf = 0.49 (SiO2, CH2Cl2/MeOH 95:5); 1H NMR (300 MHz, CDCl3) 1.40 (t, J = 12.0 Hz, 1H, H-5ax), 1.50-1.70 (m, 3H), 1.75-1.90 (m, 3H), 2.07 (s, 3H, CH3), 2.16 (dt, J = 13.5, 11.4 Hz, 1H), 2.50 (m, 1H, H-3a), 3.36 (ddd, J = 11.4, 5.7, 5.7 Hz, 1H, H-7a), 3.35 (dd, J = 11.0, 1.5 Hz, 1H, H-2), 3.57 and 3.71 (2d, J = 13.2 Hz, 1H each, CH2Ar), 3.75-3.94 (m, 4H, OCH2), 7.20- 7.35 (m, 5H, Ar); 13C NMR (50 MHz, CDCl3, DEPT), see Table 1. S7 Reduction of ketone 7. To a solution of amino ketone 7 (2.29 g, 7.25 mmol) in MeOH (85 mL) at -20 °C was added NaBH4 (571 mg, 14.5 mmol) in small portions. The resulting mixture was maintained at this temperature for 6 h. Then, water (25 mL) was added and the mixture was extracted with Et2O (3x50 mL). The organic extracts were washed with brine, dried, and concentrated. Purification of the residue by chromatography (SiO2, hexane to hexane/EtOAc 1:1) provided 1.05 g (46%) of alcohol 9a as a colourless oil and 862 mg (37%) of alcohol 10a as a colorless oil, after two succesive purifications. Overall yield for three steps (3 → 9a + 10a): 83%; 1.2:1 ratio of alcohols 9a:10a. 2S,3aS,7aS)-1-Benzyl-2-[ 1'R)- 1-hydroxyethyl)]octahydroindol-6-one ethylene acetal 9a): Rf = 0.30 (SiO2, CH2Cl2/MeOH 95:5); [α]D20 - 41 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1.09 (d, J = 6.6 Hz, 3H, CH3), 1.43-1.81 (m, 8H, H-3, H-4, H-5, and H-7), 2.20 (m, 1H, H3a), 2.80 (ddd, J = 9.3, 6.9, 3.3 Hz, 1H, H-2), 3.02 (q, J = 7.2 Hz, 1H, H-7a), 3.66-3.85 (m, 7H, H1', NCH2Ar, and OCH2), 7.26-7.32 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS: calcd for C19H28NO3 318.2069 (MH+), found 318.2070. 2S,3aS,7aS)-1-Benzyl-2-[ 1'S)- 1-hydroxyethyl)]octahydroindol-6-one ethylene acetal 10a): Rf = 0.30 (SiO2, CH2Cl2/MeOH 95:5); [α]D20 - 32 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1.16 (d, J = 6.4 Hz, 3H, CH3), 1.50 (m, 2H, H-5 and H-7), 1.60 (m, 2H, H-3 and H-5), 1.63 (t, J = 12.0 Hz, 1H, H-7ax), 1.77 (m, 2H, H-4), 1.88 (ddd, J = 12.0, 8.0, 7.0 Hz, 1H, H3), 2.34 (m, 1H, H-3a), 2.82 (q, J = 7.5 Hz, 1H, H-2), 2.97 (dt, J = 12.0, 6.0 Hz, 1H, H-7a), 3.54 (quint, J = 6.2 Hz, 1H, H-1'), 3.74-3.86 (m, 6H, OCH2, NCH2Ar), 7.20-7.40 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS: calcd for C19H28NO3 318.2069 (MH+), found 318.2074. Reduction of ketone 8. The above procedure was followed using ketone 8 (1.06 g, 3.36 mmol). Purification by chromatography (SiO2, hexane to hexane-EtOAc 1:1) afforded 622 mg (54%) of alcohol 11a as a white solid and then 365 mg (32%) of alcohol 12a as a white solid. Overall yield for three steps (4 → 11a + 12a): 86%; 1.7:1 ratio of alcohols 11a and 12a. S8 2S,3aR,7aR)-1-Benzyl-2-[ 1'S)- 1-hydroxyethyl)]octahydroindol-6-one ethylene acetal 11a): Rf = 0.22 (SiO2, CH2Cl2/MeOH 98:2); mp 73-75 °C; [α]D20 -100 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1.13 (d, J = 6.4 Hz, 3H, CH3), 1.41 (t, J = 12.0 Hz, 1H, H-7ax), 1.50 (dm, J = 12.0 Hz, 1H), 1.60-1.68 (m, 2H), 1.73-1.90 (m, 4H), 2.21 (m, 1H, H-3a), 2.76 (dq, J = 10.0, 2.4 Hz, 1H, H-2), 3.21 (ddd, J = 12.0, 5.5, 5.5 Hz, 1H, H-7a), 3.61 and 3.77 (2d, J = 14.0 Hz, 1H each, NCH2Ar), 3.78-3.93 (m, 5H, OCH2 and H-1'), 7.20-7.40 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS: calcd for C19H28NO3 318.2069 (MH+), found 318.2074. 2S,3aR,7aR)-1-Benzyl-2-[ 1'R)- 1-hydroxyethyl)]octahydroindol-6-one ethylene acetal 12a): Rf = 0.11 (SiO2, CH2Cl2/MeOH 98:2); mp 91-93 °C; [α]D20 - 36 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, gCOSY) 1.22 (d, J = 6.6 Hz, 3H, CH3), 1.43 (t, J = 12.0 Hz, 1H, H-7ax), 1.501.75 (m, 4H, H-3, H-4, H-5, H-7), 1.80 (m, 2H, H-4 and H-5), 2.15 (m, 1H, H-3), 2.32 (m, 1H, H3a), 2.88 (ddd, J = 9.8, 4.8, 2.2 Hz, 1H, H-2), 3.22 (ddd, J = 11.0, 5.4, 5.4 Hz, 1H, H-7a), 3.69 (m, 1H, H-1'), 3.73-3.92 (m, 6H, NCH2 and OCH2), 3.96 (br s, 1H, OH), 7.20-7.40 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS: calcd for C19H28NO3 318.2069 (MH+), found 318.2063. Conversion of alcohols 9a-12a to their corresponding chlorides 9b-12b. Compounds 9b-12b were prepared according to the following procedure: to a solution of alcohol (9a-12a, 50 mg, 0.16 mmol) in THF (1 mL) at 0 ºC was added MsCl (0.014 mL, 0.18 mmol, 1.1 equiv), followed by Et3N (0.09 mL, 0.64 mmol, 4.0 equiv). After 4 h at reflux, the reaction mixture was poured into an aqueous 2.5 M NaOH solution (1 mL). After extraction with CH2Cl2 (3 x 2 mL), the organic phase was dried and concentrated to afford compounds 9b-12b, which were used without further purification. 2S,3aS,7aS)-1-Benzyl-2-[ 1'R)- 1-chloroethyl)]octahydroindol-6-one ethylene acetal 9b). This compound was obtained together with the expanded chloride 16; 1H NMR (300 MHz, CDCl3) 1.53 (d, J = 6.6 Hz, 3H, CH3), 1.40-2.10 (m, 8H), 2.25 (m, 1H), 2.85-3.00 (m, 2H), 3.80-4.00 (m, S9 7H), 7.20-7.40 (m, 5H); 13 C NMR (75 MHz, CDCl3), see Table 1. HRFABMS calcd for C19H2735ClNO3 336.1730 (MH+), found 336.1731. 2S,3aS,7aS)-1-Benzyl-2-[ 1'S)- 1-chloroethyl)]octahydroindol-6-one ethylene acetal 10b): yellow oil; 1H NMR (400 MHz, CDCl3, gCOSY) 1.49 (d, J = 6.8 Hz, 3H, CH3), 1.55-1.65 (m, 4H, H-5 and H-7), 1.70-1.80 (m, 3H, H-3, H-4), 1.88 (ddd, J = 12.0, 8.0, 7.0 Hz, 1H, H-3), 2.25 (m, 1H, H-3a), 2.94 (dt, J = 10.5, 6.8 Hz, 1H, H-7a), 3.15 (dt, J = 9.2, 6.4 Hz, 1H, H-2), 3.73 and 3.87 (2d, J = 13.5 Hz, 1H each, NCH2Ar), 3.70-3.84 (m, 4H, OCH2), 3.95 (dq, J = 11.5, 6.4 Hz, 1H, H-1'), 7.20-7.38 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3, gHSQC), see Table 1) . HRFABMS calcd for C19H2735ClNO3 336.1730 (MH+), found 336.1727. 2S,3aR,7aR)-1-Benzyl-2-[ 1'S)- 1-chloroethyl)]octahydroindol-6-one ethylene acetal 11b): white solid; 1H NMR (400 MHz, CDCl3, gCOSY) 1.39 (t, J = 12.0 Hz, 1H, H-7ax), 1.44 (d, J = 6.8 Hz, 3H, CH3) 1.50-1.65 (m, 4H, H-3 and H-4), 1.75-1.95 (m, 3H, H-7eq and H-5), 2.42 (m, 1H, H3a), 2.96 (dt, J = 10.0, 3.0 Hz, 1H, H-2), 3.23 (ddd, J = 11.6, 5.6, 5.6 Hz, 1H, H-7a), 3.72 and 3.84 (2d, J =14 Hz, 1H each, NCH2), 3.78-3.90 (m, 4H, OCH2), 4.05 (qd, J = 6.8, 3.2 Hz, 1H, H-1'), 7.20-7.40 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS calcd for C19H2735ClNO3 336.1730 (MH+), found 336.1741. 2S,3aR,7aR)-1-Benzyl-2-[ 1'R)- 1-chloroethyl)]octahydroindol-6-one ethylene acetal 12b): yellow oil; 1H NMR (300 MHz, CDCl3) 1.48 (d, J = 6.6 Hz, CH3), 1.40-2.05 (m, 8H), 2.25 (m, 1H), 3.20 (m, 2H), 3.6-4.0 (m, 7H), 7.20-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3), see Table 1. Ring expansion of chlorides 9b-12b Method A. A solution of the appropriate chloride derivative 9b-12b (0.16 mmol) in THF (1 mL) was treated with AgOAc (0.48 mmol, 3 equiv) at reflux for 4 h. The reaction mixture was filtered through a bed of Celite and diluted with CH2Cl2. The organic layer was washed with saturated NaHCO3 (10 mL), dried and concentrated to afford the corresponding mixture of acetates 9c-12c and 17-20. (See Table 1 in the main paper for results in each series and below for the NMR data of formed acetates). S10 • From 9b, a mixture of acetates 9c and 17 was obtained (80% overall yield) in a 1:1.3 ratio according to the NMR spectrum. Purification and separation of the compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc; 9:1). • From 10b, a mixture of acetates 10c and 18 was obtained (70 % overall yield) in a 2.9:1 ratio according to the NMR spectrum. Purification and separation of the compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc; 9:1). • From 11b, a non-separable mixture of acetates 11c and 19 was obtained (80 % overall yield) in a 5.7:1 ratio according to the NMR spectrum and GC-MS analysis. Purification of the mixture of compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1). • From 12b, a non-separable mixture of acetates 12c and 20 was formed (60 % overall yield) in a 13:1 ratio according to the NMR spectrum. Purification of the mixture of compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1). Ring expansion of alcohols 9a-12a Method B. A solution of the appropriate alcohol derivative 9a – 12a (0.16 mmol) in THF (1 mL) was treated with MsCl (0.19 mmol, 1.2 equiv) and Et3N (0.64 mmol, 4 equiv) under an argon atmosphere at – 20 ºC for 1 h. AgOAc (0.48 mmol, 3 equiv) was added and the resulting mixture was warmed to rt over a period of 1 h. The reaction mixture was filtered through a bed of Celite and diluted with CH2Cl2. The organic layer was washed with a saturated aqueous NaHCO3 solution (10 mL), dried and concentrated to afford the corresponding mixture of acetates. From 9a. A mixture of acetates 9c and 17 was obtained in a 1:2.2 ratio according the NMR spectrum in 78 % yield. Purification and separation of the compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1). For analytical data of 9c and 17, see the main text and Tables 1 and 2. From 10a. A mixture of acetates 10c and 18 was obtained in a 1.1:1 ratio according the NMR spectrum in 66 % yield. Purification and separation of the compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1). S11 2S,3aS,7aS)-1-Benzyl-2-[ 1'S)- 1-acetoxyethyl)]octahydroindol-6-one ethylene acetal 10c): Colourless oil. Rf = 0.26 (SiO2, CH2Cl2/EtOAc 9:1). [α]D20 - 57 (c 0.2, CHCl3); IR 1732 cm-1; 1H NMR (400 MHz, CDCl3, gCOSY) 1.21 (d, J = 6.0 Hz, 3H, CH3), 1.50 (t, J = 11.0 Hz, 1H, H-5), 1.50-1.80 (m, 7H), 1.90 (s, 3H, OAc), 2.25 (m, 1H, H-3a), 2.85 (dt, J = 11.0, 6.4 Hz, 1H, H-7a), 3.00 (dt, J = 10.0, 7.0 Hz, 1H, H-2), 3.70 and 3.94 (2d , J = 14.0 Hz, 1H each, NCH2Ar), 3.74-3.86 (m, 4H, OCH2), 4.91 (quint, J = 6.2 Hz, 1H, H-1'), 7.20-7.35 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3), see Table 1. HRFABMS: calcd for C21H30NO4 360.2175 (MH+), found 360.2163. 2R,3R,4aS,8aS)-3-Acetoxy-1-benzyl-2-methyl-7-oxodecahydroquinoline ethylene acetal 18): Colourless oil. Rf = 0.58 (SiO2, CH2Cl2/EtOAc 9:1). [α]D20 - 24 (c 1.0, CHCl3); IR 1733 cm-1; 1H NMR (400 MHz, CDCl3, gCOSY) 1.10 (d, J = 7.0 Hz, 3H, CH3), 1.48 (m, 1H, H-5), 1.52 (m, 1H, H-4), 1.59 (m, 2H, H-6), 1.72 (t, J = 12.4 Hz, 1H, H-8ax), 1. 80 (m, 1H, H-5), 1.87 (brt, J = 13.0 Hz, 1H, H-4ax), 1.94 (dm, J = 12.4 Hz, 1H, H-8eq), 2.00 (s, 3H, OAc), 2.08 (m, 1H, H-4a), 3.00 (dt, J = 12.8, 4.4 Hz, 1H, H-8a), 3.20 (q, J = 6.5 Hz, 1H, H-2); 3.78 and 3.84 (2d, J = 14.4 Hz, 1H each, NCH2Ar), 3.86-3.95 (m, 4H, OCH2), 4.99 (ddd, J = 12.0, 5.6, 4.4 Hz, 1H, H-3), 7.20-7.35 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, gHSQC), see Table 2 HRFABMS: calcd for C21H30NO4 360.2175 (MH+), found 360.2171. From 11a. 11c and 19 were obtained in a 2.2:1 ratio according the NMR spectrum in 76 % yield as a unseparable mixture. Purification of the mixture of compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1). 2S,3aR,7aR)-1-Benzyl-2-[ 1'S)- 1-acetoxyethyl)]octahydroindol-6-one ethylene acetal 11c): Colourless oil. Rf = 0.31 (SiO2, CH2Cl2); 1H NMR (400 MHz, CDCl3, gCOSY) 1.23 (d, J = 6.4 Hz, 3H, CH3), 1.35 (t, J = 12.4 Hz, 1H, H-7ax), 1.45-2.05 (m, 7H), 2.07 (s, 3H, OAc), 2.25 (m, 1H, H3a), 2.89 (dt, J = 10.0, 2.8 Hz, 1H, H-2), 3.08 (dt, J = 12.0, 6.0 Hz, 1H, H-7a), 3.52 and 3.88 (2d, J = 13.6 Hz, 1H each, NCH2), 3.80-4.00 (m, 4H, OCH2), 5.14 (qd, J = 6.4, 2.4 Hz, 1H, H-1'), 7.157.35 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3, gHSQC), see Table 1. HRFABMS: calcd for C21H30NO4 360.2175 (MH+), found 360.2158. S12 2R,3R,4aR,8aR)-3-Acetoxy-1-benzyl-2-methyl-7-oxodecahydroquinoline ethylene acetal 19): Colourless oil. Rf = 0.31 (SiO2, CH2Cl2); 1H NMR (400 MHz, CDCl3) 1.04 (d, J = 7.2 Hz, 3H, CH3), 1.45-2.05 (m, 8H), 2.07 (s, 3H, OAc), 2.34 (m, 1H, H-4a), 2.89 (qd, J = 7.2, 1.2 Hz, 1H, H-2ax), 3.09 (dt, J = 11.5, 4.4 Hz, 1H, H-8a), 3.68-3.80 (m, 6H, NCH2Ar and OCH2), 4.82 (q, J = 2.8 Hz, 1H, H-3eq), 7.15-7.30 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3), see Table 2. HRFABMS: calcd for C21H30NO4 360.2175 (MH+), found 360.2158. From 12a. Acetate 12c and traces of 20 were formed in a 13:1 ratio, according the NMR spectrum and GC-MS analysis, in 40% yield as a unseparable mixture. Purification of the mixture of compounds was performed by chromatography (SiO2, CH2Cl2/EtOAc 9:1). 2S,3aR,7aR)-1-Benzyl-2-[ 1'R)- 1-acetoxyethyl)]octahydroindol-6-one ethylene acetal 12c): White Solid. Rf = 0.31 (SiO2, CH2Cl2); 1H NMR (400 MHz, CDCl3, gCOSY) 1.24 (d, J = 6.4 Hz, 3H, CH3), 1.37 (t, J = 12.0 Hz, 1H, H-7ax), 1.49 (dm, J = 12.0 Hz, 1H, H-5eq), 1.60-1.70 (m, 3H, H-5 and H-4), 1.75 (m, 1H, H-3),1.80-1.90 (m, 2H, H-3 and H-7eq), 1.96 (s, 3H, OAc), 2.28 (m, 1H, H-3a), 3.05 (ddd, J = 8.8, 6.4, 2.8 Hz, 1H, H-2), 3.15 (ddd, J = 11.2, 5.6, 5.6 Hz, 1H, H-7a), 3.69 and 3.88 (2d, J = 14.4 Hz, 1H each, NCH2Ar), 3.73-3.90 (m, 4H, OCH2), 4.95 (quint, J = 6.4 Hz, 1H, H-1'), 7.20-7.35 (m, 5H, ArH); 13 C NMR (100 MHz, CDCl3), see Table 1. HRFABMS: calcd for C21H30NO4 360.2175 (MH+), found 360.2163. Ring expansion of octahydroindole 9a using silver trifluoroacetate. A solution of alcohol 9a (62 mg, 0.2 mmol) in THF (1.4 mL) was treated with MsCl (0.019 mL, 0.24 mmol, 1.2 equiv) and Et3N (0.11 mL, 0.8 mmol, 4 equiv) under argon atmosphere at – 20 ºC for 1 h. CF3CO2Ag was added (221 mg, 1 mmol, 5 equiv) and the resulting mixture was warmed to room temperature over a period of 1 h. The mixture was treated with 2.5 N NaOH (1 mL) and stirred for 3 h. The reaction mixture was filtered through a bed of Celite and diluted with CH2Cl2. The organic layer was dried and concentrated to afford a mixture of 9a and 21, which was purified by chromatography (Al2O3, hexane/EtOAc 9:1) to give 16 mg (26%) of 9a and 36 mg (58%) of (2S,3R,4aS,8aS)-1-Benzyl-3hydroxy-2-methyl-7-oxodecahydroquinoline ethylene acetal (21): Colourless oil. Rf = 0.10 (Al2O3, S13 Hexane/EtOAc 8:2). [α]D20 +1.5 (c 0.6, CHCl3); 1H NMR (300 MHz, CDCl3, COSY) 1.17 (d, J = 6.0 Hz, 3H, CH3), 1.43-1.49 (m, 2H, H-5 and H-6), 1.55-1.74 (m, 5H, H-4, H-5, H-6, and H-8eq), 1.88 (t, J = 12.6 Hz, 1H, H-8ax), 2.04 (m, 1H, H-4a), 2.57 (dq, J = 9.0, 6.0 Hz, 1H, H-2ax), 2.93 (dt, J = 12.6, 4.5 Hz, 1H, H-8a), 3.36 (td, J = 9.0, 7.2 Hz, 1H, H-3ax), 3.57 and 3.90 (2d, J = 14.4 Hz each, NCH2Ar), 3.79-3.94 (m, 4H, OCH2), 7.18-7.35 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3, gHSQC), see Table 2. HRFABMS: calcd for C19H28NO3 318.2069 (MH+), found 318.2064. S14 S15 S16 S17 S18 S19 S20 S21 S22 S23 S24 S25 S26 S27 S28 S29 S30 S31 S32 S33 S34 S35 S36 S37 S38 S39 S40 S41 S42 S43 S44 S45 S46 S47 S48 S49 S50 S51 S52 S53 S54 S55 S56 S57 S58 S59 S60 S61 S62 S63 S64 S65 S66 S67 S68 S69 S70 S71 S72 6.3 Synthesis of enantiopure cis-decahydroquinolines from homotyramines by Birch reduction and aminocyclization Marisa Mena, Nativitat Valls, Mar Borregán y Josep Bonjoch Tetrahedron. 2006, remitido 233 234 Graphical Abstract Synthesis of enantiopure cis-decahydroquinolines from homotyramines by Birch reduction and aminocyclization Marisa Mena, Nativitat Valls, Mar Borregán and Josep Bonjoch* H OR MeO NBn2 Me O N H H 7b major, when R = H (43%) OR + Me O N H H 8b major, when R = Me (39%, after benzoylation) Me H OR 0 Synthesis of enantiopure cis-decahydroquinolines from homotyramines by Birch reduction and aminocyclization Marisa Mena, Nativitat Valls, Mar Borregán, and Josep Bonjoch∗ Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain Abstract –Birch reduction of homotyramines with a syn-β-amino alcohol unit followed by acid treatment of formed dihydroanisole derivatives gives polysubstituted enantiopure cis-decahydroquinolines. The stereoselectivity of the process differs if the hydroxyl group is free or protected. The procedure allows the synthesis of 7oxodecahydroquinolines embodying four stereogenic centers with the same relative configuration as that of lepadins F and G. 1. Introduction The use of (ω-aminoalkyl)methoxybenzene derivatives (e.g. tyrosine and tyramine compounds) as starting materials to elaborate azabicyclic compounds through a Birch reduction followed by an intramolecular cyclization of the resulting amino-tethered cyclohexenone (Scheme 1) is well-precedented in the literature. Following this methodology, octahydroindoles,1,2 azaspiroundecanes,3 6-azabicyclo[3.2.1]octanes,4 2azabicyclo[3.3.1]nonanes,,5 and decahydroquinolines6 have been prepared, but, apart from of our work on the synthesis of enantiopure octahydroindoles,2 all described processes lead to racemic compounds. n MeO NH2 O n NH2 O n N Scheme 1. The Birch reduction-aminocyclization process leading to azabicyclic compounds ∗ Keywords: Lepadin alkaloids; ecahydroquinolines; poxides; Conformational analysis; Nitrogen heterocycles * Corresponding author. Tel.: 34-934024540; fax: 34-934024539; e-mail: josep.bonjoch@ub.edu 1 In this paper, we describe the synthesis of enantiopure polysubstituted decahydroquinolines from homotyramine precursors following the aforementioned Birch reduction/aminocyclization sequence.7 The interest of this work, aside from the studying the stereocontrol of the process, lies in the possible usefulness of the resulting compounds in the synthesis of lepadin alkaloids. These natural products are structurally characterized by the presence of a 2,3,5-trisubstituted cis-fused decahydroquinoline ring. The substitution pattern, which has a methyl group at C(2), a hydroxyl group, free or protected, at C(3), and a functionalized side chain at C(5), shows a variety of stereochemical arrangements.8 Total enantioselective syntheses of lepadins A,9 B,9-11 C,9 - ,11 and H,11 as well as a formal route to rac-lepadin B12 have been reported. R' H H OR Me O N H H OR Me OR MeO Me N H H Lepadins A-C R' H H OR Me O N H H NH2 OR Me N H H Lepadins F,G (relative configuration) * absolute configuration unknown Scheme 2. Retrosynthetic approach to lepadin alkaloids We focused our attention on the synthesis of cis-decahydroquinolines incorporating a methyl at C(2) and a hydroxyl at C(3), with an S configuration at both stereogenic centers, as occurs in lepadins A, B, and C. In lepadins F and G both substituents also have a cis relationship, although their absolute configuration is unknown (see Scheme 2). The strategies described for the construction 9,10 of 3-hydroxy-2- methyldecahydroquinolines involve the elaboration of a polyfunctionalized piperidine followed by carbocyclic ring closure through aldol processes or the construction of the piperidine ring from cyclohexanone derivatives either by an intramolecular enamine alkylation11 or using a xanthate-mediated radical cyclization.12 In our approach, we envisaged enantiopure anisole derivatives of type I (R = H or Me) as potential intermediates for the aforementioned cis-decahydroquinolines, as they would bring about ring closure by forming the N-C(8a) bond.13 2 RESULTS AND DISCUSSION Synthetic aspects For the proposed studies of Birch reduction of homotyramines followed by an aminocyclization process to achieve cis-decahydroquinolines of interest in the lepadine field, α-methyl-β-aminoalcohol I was required. The synthesis of syn α-methyl-β-amino alcohols (II, Scheme 3) is well-precedented not only by the methodological studies of the reactivity of alanine derivatives but also by the presence of this structural motif in several natural products other than the aforementioned lepadins, such as various piperidine alkaloids14 (i.e. carpamic acid, azimic acid, julifloridine, and cassine inter alia). The most suitable procedures for syn amino alcohols of type II are the orgamometallic addition upon the Weinreb amide of N,N-dibenzylalanine15 followed by hydride reduction of the resulting α-amino ketone16 or the organometallic addition upon the N-Boc-alaninal.17,18 To our knowledge, none of these versatile approaches have been used in reactions involving p-methoxybenzylmagnesium bromide, as was required in the present work. We decided to use the protocol involving the Weinreb amide of N,Ndibenzylalanine and, in addition, introduced a new approach based on the ring-opening of a suitable epoxide with a lithium reagent is introduced to achieve aminoalcohol I. Me N OMe Me O Bn N Bn R R' N PG OH Me CHO H N Boc Me II (I, when R = 4-OMeC6H4CH2; R' = PG = H) Scheme 3. Synthesis of enantiopure syn-α-methyl-β-aminoalcohols Coupling of either the p-methoxybenzylmagnesium bromide with Weinreb amide 119,20 or the p-methoxyphenyllithium with the (R) isomer of [(S)-1'(dibenzylamino)ethyl]oxirane (3)21 in presence of BF3. t2O (Ganem's conditions)22,23 gave synthetic access to the required aminoalcohol 4a, a diastereoselective reduction of the initially formed β-amino ketone 2 being necessary in the former sequence (Scheme 4, * denotes that 10% of the epimer of 4a24 was additionally isolated in this route, see experimental part). This sequence (1 → 4a) seemed to result in some loss of enantiopurity25 as determined by optical rotations in comparison with the sample 3 obtained through enantiopure epoxide 3. Since the goal was to study the course of the aminocyclization of the dihydroanisole derivatives, optimizing the described protocol to minimize any racemization was not pursued at this stage. MgBr O + Me N OMe (87%) MeO 2 NBn2 O Me MeO Bn N Bn Me 1 NaBH4 (90%)* O Li + (69%) Bn N Bn 3 OH NH2 Me 5a H OH H Me MeO 4a NBn2 OH Me MeO H2, Pd(OH)2 Li, NH3, EtOH MeO NH2 6a OH Me MeO OH + O N H H 8a (17% from 4a) Me aq HCl O N H H 7a Me (43% from 4a) Scheme 4. Synthesis of cis-decahydroquinolines. ebenzylation of 4a gave the primary amine 5a, which was submitted to the Birch reduction conditions (Li/NH3) to allow the formation of dihydroanisole 6a. This was treated with a 2 N HCl solution at 75 ºC, and the decahydroquinoline ring was formed after enol ether hydrolysis, double bond isomerization, and an intramolecular 1,4addition of the amino group across the cyclohexenone intermediate. The process is stereoselective, with the exlusive formation of cis isomers of the decahydroquinoline ring. olysubstituted decahydroquinolines 7a (43%) and 8a (17%) were isolated in a 2.5:1 ratio and a overall yield of 60% from the sequence 4a → 7a + 8a. We then carried out the same sequence of reactions but starting from syn-amino ether 4b, which was obtained by O-methylation of aminoalcohol 4a (Scheme 5). In this series, the aminocyclization step starting from dihydroanisole 6b gave a 1:2.3 mixture 4 of decahydroquinolines 7b and 8b, which were only partially separated. However, when the reaction mixture was basified and treated with benzoyl chloride after aminocyclization, the corresponding amides 9b and 10b were isolated in 17% and 39% overall yield (four steps from 4b). Me i) MeI, NaH ii) H2, Pd(OH)2 4a (90%) MeO 4b iii) Li, NH3, N(Bn)2 OMe OMe MeO Me iv) HCl 5b EtOH NH2 6b H OMe + O N H H 7b H v) BzCl, K2CO3 O H COC6H5 9b (17% from 4b) N OMe + Me O Me O H OMe N H H 8b H OMe N H COC6H5 10b (39% from 4b) Me Me Scheme 5. In the cyclization processes (6 → 7 + 8), both in series a (3-OH) and series b (3-OMe), the isolated decahydroquinolines showed a cis-fused relationship. The major compound of series a (i.e. 7a) showed the same pattern of absolute configuration in its four stereocentres as lepadins A-C, while that of series b (i.e. 8b) matched the relative configuration of lepadins F and G, allowing them to be considered as advanced building blocks for elaborating the aforementioned alkaloids. The stereoselective cis-perhydroquinoline formation through a 6-exo process agreed with the stereochemical outcome observed in related cyclizations,6 and with both the steric and electronic preference for a pseudo axial addition of the nucleophilic species to the cyclohexenone moiety. Interestingly, the configuration of the new methine carbons (i.e. C-4a and C-8a) is controlled to some extent by the oxygenated function. Why does the decalin ring formation change diastereoselectivity if there is a free or protected 5 hydroxyl group?. Considering that the axial attack proceeds through a chair-like transition state, in the hydroxyl series perhaps a hydrogen bonding favours the formation of enone A with respect to the epimeric enone A', which could be in equilibrium by means of a tautomeric process through their corresponding dienol ether. On the contrary in series b, in which the hydroxyl group is protected as methyl ether, the steric factors (a 1,3-diaxial relationship between the C3-OMe and C4a-C5 bonds) prevent to some extent the formation of epimer B, the formation of B' being favoured (Scheme 6). Thus, the ratio of cis decahydroquinoline with an S configuration at the two new stereogenic centers formed in the aminocylization to the diastereoisomers with an R configuration was higher in compounds with a methoxy rather than hydroxyl substituent. H H Me NH2 OH vs O H NH2 H OH H Me O H Me NH2 OMe vs O H NH2 H OMe H Me O A A' B B' H H Me N H OH 7a O H H H O H H N H 8b H H H Me OMe H N H OMe H H H Me O conformational change Scheme 6. NMR studies of decahydroquinolines 7-10 (series a and b) The stereochemistry of the synthesized azabicyclic compounds was elucidated by 2 NMR spectra (COSY, HSQC). The N-inside (7a and 7b) and N-outside (8a and 8b) cisdecahydroquinoline isomers26 in the amino series are clearly differentiated by two NMR features: (i) the 1H NMR chemical shift of H-2, which appears more deshielded (δ 3.1) in the N-outside than in the N-inside derivatives (δ 2.8), due to the compression upon H2 of the C8-C8a bond, which has a 1,3-cis relationship, on the N-outside derivatives; (ii) the 13C chemical shift of C(2) is more upfielded (~ 10 ppm) in compounds with the Noutside conformation than those with the N-inside conformation; moreover the signals given by the carbon atoms at C-4, C-6, and C-8 also appear in a higher field in the Noutside derivatives. 6 The key evidence for the conformational elucidation of 7a was found in the 1H NMR coupling pattern for the methylene protons at C-8, which appear as dd (J =14.6 and 5.4 Hz). The relative configuration for methoxy derivative 7b is the same as that observed in 7a and their NMR data follows the same pattern of chemical shifts. (Scheme 2). The absolute configuration of 7a was deduced by considering that: a) the coupling constants for H-2 (qd, J = 6.6, 2 Hz) and H-3 (q, J = 2.4 Hz) determined their location and hence fixed the methyl at C(2) and the hydroxyl at C(3) to an equatorial and axial disposition, respectively; b) the multiplicity of H-8a (br s) implied an equatorial relationship with respect to the cyclohexane ring, which discarded not only a trans junction of the decaline ring but also, taking into account the preferred conformation, implied an R configuration for C(8a). For the major component in the methoxy series 8b, the axial proton H8a is strongly coupled to one adjacent axial. Hence, its resonance signal appears as a deceptively simple doublet (J = 10.4 Hz) of triplets (J = 4.8 Hz) centered at δ 3.43. In summary, the twin chair conformation with the nitrogen axially substituting the carbocyclic ring is the lowest energy conformation for 7a, whereas the twin chair conformation with the nitrogen equatorially substituting the carbocyclic ring is the lowest energy conformation for 8b. O H H HO H Me N H H H H H H H N H O 7a O H H MeO H Me N H H H H H H N H O 7b 8b N-outside conformation 8a Me OH H H H H H Me OMe N-inside conformation Figure 2. referred conformation of decahydroquinolines 7and 8. 7 Interestingly, the N-benzoyl derivatives 9a, prepared from amine 7a in quantitative yield, and 10b (Figure 3) showed a different preferred conformation to that of their precursors 7a and 8b, respectively, as has been observed in synthetic intermediates in lepadin synthesis9-11 when the amino group is converted to a carbamate or amide group. H H O N OH H Me H N H H 10b Bz H OMe H Me H Bz O 9a Figure 3. referred conformation of decahydroquinolines 9 and 10. In summary, a new synthetic to entry be to enantiopure polysubstituted studies cisusing decahydroquinolines has been reported. Since the observed stereoselectivity allows lepadin-type stereochemistries achieved, further decahydroquinolines 9a and 10b as advanced synthetic intermediates are in progress with the aim of achieving lepadins A-C and F-G, respectively. 3. Experimental 3.1. General. All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions. Analytical TLC was performed on SiO2 (silica gel 60 F254, Merck) or Al2O3 (ALOX N/UV254, olygram), and the spots were located with iodoplatinate reagent (compounds 1-8) or 1% aqueous KMnO4 (compounds 9 and 10). Chromatography refers to flash chromatography and was carried out on SiO2 (silica gel 60, S S, 230-240 mesh ASTM) or Al2O3 (aluminium oxide 90, Merck). rying of organic extracts during workup of reactions was performed over erkin- lmer 241 1 13 anhydrous Na2SO4. Optical rotations were recorded with a polarimeter. H and C NMR spectra were recorded with a Varian Gemini 200 or 300, or a Varian Mercury 400 instrument. Chemical shifts are reported in ppm downfield (δ) from Me4Si. All new compounds were determined to be >95% pure by 1H NMR spectroscopy. 8 3.1.1. (S)-(N,N-Dibenzyl)amino-N-methoxy-N-methylpropionamide (1). To a solution of benzyl (S)-2-(N,N-dibenzylamino)propionate (2.15 g, 6 mmol), which was prepared from L-alanine (BnBr, K2CO3, tOH) by the previously reported procedure,28 and HCl.HN(OMe)Me (3.0 g, 30 mmol) in THF (90 mL) at –20 ºC, i rMgCl 2 M in THF (30 mL, 60 mmol) was added dropwise over a period of 30 min. The reaction mixture was stirred for 2 h at this temperature and then warmed to rt for 2.5 h. NH4Cl (20 mL) was added and the product was extracted with CH2Cl2 (3 x 20 mL). The combined organic layer was dried and concentrated to an oil which contained 1 and BnOH. The latter was removed under vacuum to afford compound 1 (1.94 g), which was used without further purification. The 1H NMR data were identical to those previously reported.20 Rf = 0.1 (SiO2, 9:1 hexane/ tOAc); 13C NMR (50 MHz, C Cl3) 14.9 (CH3), 54.4 (CH2), 56.1 (CH), 60.1 (CH2), 126.8 (CH), 127.4 (CH), 127.6 (CH), 128.1 (CH), 128.3 (CH), 128.5 (CH), 139.8 (C), 173.9 (C). 3.1.2. (3S)-3-(N,N-Dibenzyl)amino-1-(4-methoxyphenyl)butan-2-one (2). To a solution of 1 (1.81 g, 5.8 mmol) in THF (50 mL) at 0 ºC, 2-methoxybenzylmagnesium chloride 0.25 M in THF (46 mL, 11.6 mmol) was added dropwise. The reaction mixture was stirred 1 h at 0 ºC and then quenched with NH4Cl. The organic layer was dried and concentrated to an oil, which was purified by chromatography (SiO2, 9:1 hexane/ tOAc) to give 2 as a colourless oil (2.17 g, 87%): Rf = 0.5 (SiO2, 9:1 hexane/AcO t); [α]25 -2.4 (c 1.0 , CHCl3); IR (KBr) 1715, 1611 cm–1; 1H NMR (300 MHz, C Cl3) 1.15 (d, J = 6.6 Hz, 3H), 3.47 (d, J = 13.2 Hz, 2H), 3.52 (q, J = 6.6 Hz, 1H), 3.72 (d, J = 15.0 Hz, 1H), 3.74 (d, J = 13.2 Hz, 2H), 3.76 (s, 3H), 3.88 (d, J = 15.3 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 7.20-7.40 (m, 10H); 13 C NMR (75 MHz, C Cl3) 7.1 (CH3), 45.3 (CH2), 54.6 (CH2), 55.2 (CH3), 60.6 (CH), 113.8 (CH), 126.5 (C), 127.2 (CH), 128.4 (CH), 128.9 (CH), 130.3 (CH), 139.2 (C), 158.3 (C). Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: 80.00; H, 7.29; N, 3.67. 3.1.3. (2S,3S)-3-(N,N-Dibenzyl)amino-1-(4-methoxyphenyl)butan-2-ol (4a) Method A (from ketone 2). To a solution of 2 (2.15 g, 5.75 mmol) in MeOH (68 mL) at -20 ºC NaBH4 (453 mg, 11.5 mmol) was added. The reaction mixture was stirred for 1 h at this temperature, and then quenched with brine (30 mL). The product was extracted with CH2Cl2 (3 x 30 mL), dried and concentrated to give a mixture of 9 alcohols 4a and epi-4a25 in a 9:1 ratio according to the NMR spectrum. urification by chromatography (SiO2, 9:1 hexane/ tOAc) gave 4a (1.94 g, 90 %) and epi-4a (216 mg, 10 %). 4a: colourless oil. Rf = 0.24 (SiO2, 9:1 hexane/AcO t); [α]25 -2.0 (c 0.4, CHCl3); IR (KBr) 3600-3100, 1611 cm–1; 1H NMR (300 MHz, C Cl3) 1.07 (d, J = 6.6 Hz, 3H), 2.38 (dd, J = 14.0, 7.8 Hz, 1H), 2.60 (dq, J = 9.3, 6.6 Hz, 1H), 2.78 (dd, J1 = 14.3, 3.0 Hz, 1H), 3.30 (d, J = 13.5 Hz, 2H), 3.68 (m, 1 H), 3.77 (s, 3H), 3.82 (d, J = 13.5 Hz, 2H), 6.77 (d, J = 9 Hz, 2H), 7.11 (d, J = 9 Hz, 2H), 7.20-7.40 (m, 10H); 13C NMR (75 MHz, C Cl3) 8.3 (CH3), 39.1 (CH2), 53.2 (CH2), 55.2 (CH3), 57.7 (CH), 71.9 (CH), 113.5 (CH), 127.1 (CH), 128.4 (CH), 128.9 (CH), 130.1 (CH), 131.0 (C), 138.7 (C), 157.8 (C). Anal. Calcd for C25H29NO2.1/2H2O: C, 78.12; H, 7.81; N, 3.64. Found : C, 77.84; H, 8.16; N, 3.34. epi-4a: colourless oil. Rf = 0.14 (SiO2, 9:1 hexane/AcO t); IR (KBr) 3600-3100, 1611 cm –1; 1H NMR (300 MHz, C Cl3) 1.17 (d, J = 6.6 Hz, 3H), 2.30 (dd, J = 13.8, 9.6 Hz, 1H), 2.75 (quint, J = 6.9 Hz, 1H), 3.21 (dd, J = 13.8, 3.0 Hz, 1H), 3.50 (J = 13.8 Hz, 2H), 3.73-3.81 (m, 1H), 3.80 (d, J = 14.1 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 7.20-7.40 (m, 10H); 13 C NMR (75 MHz, C Cl3) 8.6 (CH3), 40.6 (CH2), 54.7 (CH2), 55.3 (CH3), 57.2 (CH), 74.7 (CH), 113.9 (CH), 126.8 (CH), 128.2 (CH), 128.8 (CH), 130.2 (CH), 131.0 (C), 140.0 (C), 158.1 (C). Method B (from epoxide 3). To a solution of n-BuLi (1.6 M in hexanes, 1.05 mL, 1.68 mmol) in THF (3.5 mL) at -78 ºC was added 4-bromoanisole (0.2 mL, 1.56 mmol). The reaction mixture was stirred for 90 min, treated with a solution of (2R)-[1’(S)(dibenzylamino)ethyl]oxirane21 (162 mg, 0.6 mmol) in THF (2 mL) and BF3. t2O (0.21 mL, 1.68 mmol), and continuously stirred at -78 ºC for 2 h prior to being quenched with saturated NH4Cl (4 mL) and warmed to rt. The product was extracted with CH2Cl2 (3 X 10 mL), and the organic layer was dried and concentrated to give an oil, which was purified by chromatography (SiO2, 9:1 hexane/AcO t) to give 4a as a colourless oil (153 mg, 69 %). The spectroscopic data were identical with the product obtained by method A, but its rotatory power was higher: [α]25 = -5.6 (c 1.4, CHCl3). 3.1.4. (2S,3S)-N,N-Dibenzyl-3-methoxy-4-(4-methoxyphenyl)-2-butanamine (4b). To a suspension of NaH (195 mg, 4.89 mmol) in dry THF (2 mL) at 0 ºC under argon atmosphere a solution of 4a (1.22 g, 3.26 mmol) in dry THF was transferred (1 mL + 1 10 mL). The reaction mixture was warmed over 20 min to rt and then MeI (2 mL, 32.6 mmol) was added. The reaction was sealed and stirred for 48 h. NH4Cl was added (10 mL) and the product was extracted with CH2Cl2 (3 X 20 mL). The resulting organic layer was washed with H2O (15 mL), brine (15 mL), dried, and concentrated to give an oil, which was purified by chromatography (SiO2, 9:1 hexane/AcO t) to give 4b as a colourless oil. (1.14 g, 90%): Rf = 0.42 (SiO2, 9:1 hexane/AcO t); [α]25 –4.6 (c 1.0, CHCl3); IR (KBr) 1611 cm–1; 1H NMR (300 MHz, C Cl3) 1.13 (d, J = 6.9 Hz, 3H), 2.74-2.88 (m, 3H), 3.13 (s, 3H), 3.22 (dt, J = 7.2, 4.8 Hz, 1H), 3.43 (d, J = 13.5 Hz, 2H), 3.77 (s, 3H), 4.01 (d, J = 13.5 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.20-7.32 (m, 6H), 7.39-7.41 (m, 4H); 13 C NMR (75 MHz, C Cl3) 10.1 (CH3), 37.4 (CH2), 55.1 (CH), 55.2 (CH2), 55.2 (CH3), 59.2 (CH3), 88.1 (CH), 113.5 (CH), 126.6 (CH), 128.1 (CH), 128.9 (CH), 130.2 (CH), 132.3 (C), 140.9 (C), 157.7 (C). Anal. Calcd for C26H31NO2: C, 80.17; H, 8.02; N, 3.60. Found: C, 80.07; H, 8.31; N, 3.40. 3.1.5. (2S,3S)-3-Amino-1-(4-methoxyphenyl)butan-2-ol (5a). A suspension of 4a (2.16 g, 5.75 mmol) and d(OH)2/C (20%, 210 mg) in tOH (110 mL) was stirred at rt under hydrogen atmosphere overnight. The catalyst was removed by filtration through Celite and the filtrate was concentrated to give 5a as an oil (1.12 g), which was used directly in the next step. An analytical sample was obtained by chromatography (Al2O3, CH2Cl2 saturated with NH3); [α]25 -15.5 (c 0.7, CHCl3); 1 H NMR (300 MHz, C Cl3) 1.12 (d, J = 6.6 Hz, 3H), 2.56 (dd, J = 14.0, 8.6 Hz, 1H), 2.74-2.86 (m, 2H), 3.40-3.46 (m, 1H), 3.78 (s, 3H), 6.84 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H); 13C NMR (75 MHz, C Cl3) 20.5 (CH3), 39.6 (CH2), 50.3 (CH), 54.7 (CH2), 55.2 (CH3), 76.4 (CH), 113.7 (CH), 130.1 (C), 130.2 (CH), 158.0 (C). 3.1.6. (2S,3S)-3-Methoxy-4-(4-methoxyphenyl)-2-butanamine (5b). Operating as above, starting from 4b (1.14 g, 2.92 mmol), 5b was obtained (615 mg) as an oil which was used directly in the next step; 1H NMR (200 MHz, C Cl3) 1.11 (d, J = 6.3 Hz, 3H), 2.56 (dd, J = 14.3, 6.5 Hz, 1H), 2.90-2.81 (m, 2H), 3.07, dt, J = 6.6, 5.4 Hz, 1H), 3.30 (s, 3H), 3.79 (s, 3H), 6.84 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H); 13C NMR (50 MHz, C Cl3) 20.1 (CH3), 35.8 (CH2), 49.2 (CH), 55.2 (CH3), 58.8 (CH3), 87.6 (CH), 113.7 (CH), 130.4 (CH), 130.8 (C), 158.0 (C). 11 3.1.7. (2S,3S)-3-Amino-1-(4-methoxy-2,5-dihydrophenyl)butan-2-ol (6a). To a solution of 5a (1.12 g, 5.75 mmol) in tOH (6 mL) at -78 ºC, ammonia (46 mL) was added. Small chips of lithium (280 mg, 40 mmol) were added until the solution was a persistent deep blue for 1.5 h. The cooling bath was removed, the ammonia was allowed to evaporate overnight, and the reaction mixture was evaporated. The dried extract was dissolved in brine (15 mL) and the product was extracted with CH2Cl2 (3 X 15 mL), dried with Na2SO4 and concentrated to give 6a (1.112 g) as an oil which was used directly in the next step; 1H NMR (200 MHz, C Cl3) 1.11 (d, J = 6.3 Hz, 3H), 2.08 (dd, J = 14.1, 9.0 Hz, 1H), 2.21 (dd, J = 13.5, 3.3 Hz, 1H), 2.69-2.84 (m, 6H), 3.33-3.40 (m, 1H), 3.55 (s, 3H), 4.63 (m, 1H), 5.51 (m, 1H); (CH), 90.2 (CH), 120.2 (CH), 132.4 (C), 152.6 (C). 3.1.8. (2S,3S)-3-Methoxy-4-(4-methoxy-2,5-dihydrophenyl)-2-butanamine (6b). 13 C NMR (75 MHz, C Cl3) 20.2 (CH3), 29.1 (CH2), 29.4 (CH2), 41.6 (CH2), 50.8 (CH), 53.7 (CH3), 73.1 Operating as above, starting from 5b (611 mg, 2.92 mmol), 6b was obtained (620 mg) as an oil which was used directly in the next step; 1H NMR (200 MHz, C Cl3) 1.09 (d, J = 6.6 Hz, 3H), 2.14-2.29 (m, 2H), 2.74-2.84 (m, 3H), 2.87-2.96 (m, 1H), 3.02-3.07 (m, 1H), 3.40 (s, 3H), 3.55 (s, 3H), 4.62 (m, 1H), 5.49 (m, 1H); (CH3), 84.7 (CH), 90.4 (CH), 120.1 (CH), 132.6 (C), 152.9 (C). 3.1.9. Aminocyclization of 6a. A solution of 6a (95 mg, 0.48 mmol) in 2 N HCl (1.6 mL) was stirred for 3.5 h at 70 ºC. The mixture was basified with NaOH (1N, 10 mL) and the solution was extracted with CH2Cl2 (4 x 10 mL) and CHCl3/MeOH (4 x 10 mL), dried, and concentrated to give a brown oil. urification by chromatography (Al2O3, CH2Cl2 saturated with NH3) gave a partially separated 2.5:1 mixture of 7a (37 mg, 43%) and 8a (15 mg, 17%). (2S,3S,4aR,8aR)-3-Hydroxy-2-methyloctahydroquinolin-7-one (7a): white solid; mp 112-114 ºC. Rf = 0.17 (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH); 1H NMR (400 MHz, C Cl3, gCOSY) 1.11 (d, J = 6.8 Hz, 3H, Me), 1.81 (ddd, J = 14.8, 5.6, 3.6 Hz, H-4eq), 1.87 (dm, J = 14 Hz, H-5eq), 1.95 (dt, J = 14.4, 2 Hz, H-4ax), 2.05 (m, H-4a), 2.24 (dt, J = 14.4, 2 Hz, H-6eq), 2.29 (dd, J = 14.4, 5.6 Hz, H-8ax), 2.32 (m, H-6ax), 2.50 (qd, J = 13.6, 4.8 Hz, H-5ax), 2.65 (ddd, J = 14.8, 4.8, 0.8 Hz, H-8eq), 2.80 (qd, J 12 13 C NMR (50 MHz, C Cl3) 20.1 (CH3), 29.2 (CH2), 30.0 (CH2), 37.9 (CH2), 49.3 (CH), 53.9 (CH3), 58.4 = 6.6, 2 Hz, H-2ax), 3.35 (brs, H-8a), 3.58 (q, J = 2.4 Hz, H-3eq); 13C NMR (100 MHz, C Cl3, gHSQC) 18.1 (Me), 28.8 (C-5), 33.5 (C-4a), 36.4 (C-4), 41.6 (C-6), 47.5 (C-8), 56.8 (C-8a), 59.3 (C-2), 68.2 (C-3), 210.8 (C-7). HRMS ( SI-TOF) calcd for C10H18NO2 (M++1) 184.1332, found 184.1337. (2S,3S,4aS,8aS)- 3-Hydroxy-2-methyloctahydroquinolin-7-one (8a): Colourless oil. Rf = 0.14 (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH); 1H NMR (300 MHz, C Cl3) 1.10 (d, J = 6.6 Hz, 3H, Me), 1.72-1.98 (m, 4H), 2.15-2.44 (m, 4H), 2.93 (t, J = 12.6, H-8ax), 3.06 (qd, J = 6.5, 1,8 Hz, H-2ax), 3.39 (dt, J = 11.7, 4.8 Hz, H-8a), 3.76 (brs, H-3eq;13C NMR (75 MHz, C Cl3, T) 17.7 (Me), 28.0 (C-5), 28.1 (C-4a), 31.9 (C-4), 36.6 (C-6), 42.6 (C-8), 47.5 (C-2), 55.9 (C-8a), 68.2 (C-3), 210.9 (C-7). HRMS ( SI-TOF) calcd for C10H18NO2 (M++1) 184.1332, found 184.1331. 3.1.10. Aminocyclization of 6b. Following the above procedure for the aminocyclization of 6a using methoxy derivative 6b (225 mg, 1.07 mmol), heating at 70 ºC for 3 h, and purifying by chromatography (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH), a partially separated mixture of 7b (36 mg, 17%) and 8b (50 mg, 22%) was obtained. (2S,3S,4aR,8aR)-3-Methoxy-2-methyldecahydroquinolin-7-one (7b): white solid, mp 45-47 ºC; Rf = 0.25 (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH); [α]25 +14.6 (c 0.7, CHCl3); 1H NMR (400 MHz, C Cl3, gCOSY) 1.12 (d, J = 6.8 Hz, 3H, Me), 1.62 (ddd, J = 14.8, 5.6, 3.2 Hz, H-4eq), 1.74 (m, H-5eq), 2.00 (dm, J = 12 Hz, H-4a), 2.13 (dt, J = 14.8, 2.2 Hz, H-4ax), 2.23 (td, J = 14, 6 Hz, H-6ax), 2.26 (dm, J = 14.8 Hz, H-8), 2.32 (dddd, J = 14, 4.8, 2.4, 2.4 Hz, H-6eq), 2.61 (dd, J = 14.8, 5.6 Hz, H-8), 2.63 (qd, J = 14, 4.2 Hz, H-5ax), 2.78 (qd, J = 6.5, 2.4 Hz, H-2ax), 3.05 (q, J = 2.7 Hz, H-3eq), 3.30 (masked, H-8a), 3.31 (s, 3H, OMe); 13 C NMR (100 MHz, C Cl3, gHSQC) 18.1 (Me), 26.9 (C-5), 30.9 (C-4), 33.4 (C-4a), 41.4 (C-6), 47.6 (C-8), 56.3 (C-2), 56.9 (OMe), 58.7 (C-8a), 76.9 (C-3), 210.6 (C-7). HRMS ( SI-TOF) calcd for C11H20NO2 (M++1) 198.1489, found 198.1487. (2S,3S,4aS,8aS)-3-Methoxy-2-methyldecahydroquinolin-7-one (8b): colourless oil, Rf = 0.19 (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH); 1H NMR (400 MHz, C Cl3, gCOSY) 1.11 (d, J = 6.8 Hz, 3H, Me), 1.75-2.00 (m, 4H, H-4 and H-5), 2.20-2.30 (m, 3H, H-4a, H-6), 2.39 (ddd, J = 14.4, 4.4, 1.5 Hz, H-8eq), 2.62 (dd, J = 14.4, 10 Hz, H8ax), 3.13 (qd, J = 6.5, 3.2 Hz, H-2ax), 3.34 (masked, H-3eq), 3.36 (s, 3H, OMe), 3.43 (ddd, J = 10, 4.8, 4.8 Hz, H-8a); 13C NMR (100 MHz, C Cl3, gHSQC) 16.0 (Me), 27.6 13 (C-5), 27.8 (C-4), 29.6 (C-4a), 37.7 (C-6), 43.7 (C-8), 48.1 (C-2), 53.3 (C-8a), 56.7 (OMe), 76.4 (C-3), 210.9 (C-7). HRMS ( SI-TOF) calcd for C11H20NO2 (M++1) 198.1489, found 198.1487. 3.1.11. (2S,3S,4aR,8aR)-1-Benzoyl-3-hydroxy-2-methyloctahydroquinolin-7-one (9a). A solution of 7a (12 mg, 0.07 mmol) was dissolved in THF (0.2 mL) and H2O (0.2 mL) was added. Then, K2CO3 (39 mg, 0.28 mmol) and BzCl (8.4 µL, 0.074 mmol) were added. The reaction mixture was stirred for 2 h at rt, extracted with CH2Cl2 (4 x 15 mL), dried, and concentrated to give a brown oil. urification by column chromatography (Al2O3, from CH2Cl2 saturated with NH3 to 98:2 CH2Cl2 saturated with NH3/MeOH) gave 9a (19 mg, 99%): Rf = 0.44 (Al2O3, 98:2 CH2Cl2 saturated with NH3); 1H NMR (300 MHz, C Cl3, mixture of rotamers) 1.20 and 1.30 (2 brd, CH3), 1.70-2.20 (m, 6H), 2.34 (br, 1H), 2.75 (m, 1H), 3.85-4.15 (br, 2H), 5.07 (br, 1H), 7.257.45 (m, 5H, ArH); 13 C NMR (75 MHz, C Cl3) 14.1 and 15.7 (CH3), 27.5 and 28.6 (C.4), 29.7 (C-5), 31.9 (C-4a), 36.2 (C-6), 49.1 (C-8), 53.4 (C-2), 55.3 (C-8a), 74.6 (C3), 125.9, 128.8, 129.5, 136.5 (Ar), 171.6 and 172.2 (NCO), 208.0 (C-7). HRMS ( SITOF) calcd for C17H22NO3 (M++1) 288.1594, found 288.1585. 3.1.12. (2S,3S,4aR,8aR)-1-Benzoyl-3-methoxy-2-methyloctahydroquinolin-7-one (9b). Operating as above, starting from 7b (16 mg, 0.08 mmol) and after purification by chromatography (Al2O3, CH2Cl2 saturated with NH3), amide 9b (24 mg, 99%) was obtained as a white solid: mp 100-102 ºC; Rf = 0.52 (Al2O3, CH2Cl2 saturated with NH3); 1H NMR (300 MHz, C Cl3, mixture of rotamers) 1.05 and 1.25 (2 brd, CH3), 1.70-2.20 (m, 6H), 2.35 (br, 1H), 2.75 (m, 1H), 3.20 and 3.40 (2s, 3H, OCH3), 3.253.45 (masked, 2H), 3.95 (br, 0.5H), 4.15 (br, 0.5 H), 5.0 (br, 0.5H), 5.20 (br, 0.5H), 7.20-7.65 (m, 4H, ArH), 8.20 (d, J = 7.5 Hz, 1H, ArH); 13C NMR (75 MHz, C Cl3) 15.0 and 16.0 (CH3), 25.3 and 25.7 (C-4), 27.6 (C-5), 32.6 and 33.5 (C-4a), 36.0 and 36.4 (C-6), 43.6 and 45.2 (C-8), 45.4, 49.4, 51.2, and 56.2 (C-2 and C-8a), 55.6 and 56.6 (OCH3), 77.9 and 78.4 (C-3), 125.7, 128.7, 129.4, 136.6 (Ar), 171.6 (NCO), 207.4 and 207.9 (C-7). HRMS ( SI-TOF) calcd for C18H24NO3 (M++1) 302.1751, found 302.1752. 3.1.13. (2S,3S,4aR,8aR)and (2S,3S,4aS,8aS)-1-Benzoyl-3-methoxy-2- methyloctahydro-quinolin-7-one (9b and 10b). A solution of 6b (90 mg, 0.42 mmol) 14 in HCl 2 N (2 mL) was stirred for 3 h at 75 ºC. The mixture was basified with K2CO3 (464 mg, 3.36 mmol) and BzCl (0.06 ml, 0.5 mmol) in THF (2 mL) was added. The reaction mixture was stirred for 2 h at rt, concentrated and extracted with CH2Cl2 (4 x 20 mL). The dried organic layers were concentrated to give a brown oil, which was purified by chromatography (SiO2, from Hexane/AcO t 7:3 to AcO t) to give a 1:2.3 mixture of 9b (22 mg, 17% from 4b) and 10b (50 mg, 39% from 4b). For data of 9a, see above. Compound 10b: Colourless oil. Rf = 0.14 (SiO2, 1:1 Hexane/AcO t); [α]25 +16 (c 0.9, CHCl3); 1H NMR (400 MHz, C Cl3, gCOSY) 1.25 (d, J = 6.8 Hz, 3H, Me), 1.80 (m, H-5), 1.87 (m, H-4), 1.99 (dt, J = 14, 5.2 Hz, H-4eq), 2.11 (dddd, J = 12, 11, 9.4, 4.4 Hz, H-5ax), 2.25 (ddd, J = 15.4, 10, 5.4 Hz, H-6ax), 2.36 (m, H-4a), 2.64 (masked, 1H, H-6), 2.59 and 2.67 (2dd, J = 16.8, 5.6 Hz, 1H each, H-8), 3.20 (s, 3H, OMe), 3.51 (ddd, J = 10.8, 5.4, 5.4 Hz, H-3ax), 4.12 (ddd, J = 5.6, 5.6, 2.8 Hz, H-8a), 4.24 (quint, J = 6.4 Hz, H-2eq), 7.40 (s, 5H, ArH); 13C NMR (100 MHz, C Cl3, gHSQC) 12.5 (Me), 26.5 (C-5), 28.5 (C-4), 33.3 (C-4a), 38.5 (C-6), 43.0 (C-8), 51.9 (C-8a), 52.8 (C-2), 56.2 (OMe), 75.0 (C-3), 126.8, 128.6, 130.0, 136.6 (Ar), 173.2 (NCO), 205.4 (C-7). HRMS ( SI-TOF) calcd for C18H24NO3 (M++1) 302.1751, found 302.1750. Acknowledgments This research was supported by the M C (Spain)-F 04701/BQU. 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