Iterative Synthetic Strategy for Azaphenalene Alkaloids. Total

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Cite This: J. Org. Chem. 2018, 83, 5052−5057

Iterative Synthetic Strategy for Azaphenalene Alkaloids. Total Synthesis of (−)-9aepi-Hippocasine Sílvia Alujas-Burgos,† Cristina Oliveras-González,† Á ngel Á lvarez-Larena,‡ Pau Bayón,*,† and Marta Figueredo*,† †

Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain Servei de Difracció de Raigs X, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain

‡

S Supporting Information *

ABSTRACT: A new strategy for the stereoselective synthesis of alkaloids with perhydro-9b-azaphenalene skeleton has been developed. The starting material is the substituted glutarimide derivative 1, readily available in either enantiomeric form through the palladium-catalyzed asymmetric allylic alkylation of glutarimide. The strategy relies on an iterative methodology encompassing two nucleophilic allylations and two ring closing metathesis processes. The approach has been used in the first synthesis of (−)-9a-epi-hippocasine.

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INTRODUCTION The Coccinellidae family is comprised of more than 5000 species worldwide of small coleopteran insects, commonly named ladybugs, ladybirds, or lady beetles.1 Most of these species are carnivorous, eating aphids, mites, and other harvestdamaging insects. For this reason, some coccinellids have played an important role in biological pest control.2 Ladybugs usually present bright red, orange, or yellow color with black spots (or the opposite way). This bright coloration, along with their strong smell and bitter taste, are deterrent to their potential predators (such as birds and ants). The main defense mechanism of coccinellids is reflex bleeding, consisting in the secretion of an orange fluid (hemolymph) when they feel attacked.3 The aposematism of coccinellids is associated with the presence of specific alkaloids in their hemolymph.1,4 Among the different defense alkaloids secreted by ladybugs, we centered our attention on the azaphenalene family, which confer the bitter taste to these insects.5 Up to now, nine different monomeric alkaloids with perhydro-9b-azaphenalene skeleton have been isolated (Figure 1), which differ in their relative stereochemistry, the oxidation state of the nitrogen atom, and the presence and location of an endocyclic carbon− carbon double bond. Precoccinelline (and its N-oxide, coccinelline) and myrrhine are meso compounds, but the rest of the members of this family are chiral. In the hippodamine/ convergine couple, the reflection symmetry is broken by the trans relationship between the hydrogen atoms at positions 3a and 9a and, in the rest, it is lost due to the existence of a double bond. Propyleine and isopropyleine are in equilibrium and have not been independently isolated. In addition, several dimeric alkaloids containing at least one perhydro-9b-azaphenalene unit have also been discovered.6 Most reported syntheses of the simple azaphenalene alkaloids involve symmetrical precursors and, hence, end up © 2018 American Chemical Society

Figure 1. Monomeric azaphenalene alkaloids.

with achiral or racemic products.4,7 Recently, three enantioselective approaches have been also described.8 In two of them the stereodiscrimination was induced by a chiral auxiliary in the starting material,8a,c while in the third a chiral pool precursor was used.8b Herein we report an unprecedented synthetic design for azaphenalenes, making use of an iterative methodology, where the stereochemistry is established by enantioselective catalysis.

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RESULTS AND DISCUSSION In connection with a project devoted to the synthesis of other polycyclic alkaloids, we adapted the palladium-catalyzed asymmetric allylic alkylation (AAA) of phthalimide developed Received: February 9, 2018 Published: April 12, 2018 5052

DOI: 10.1021/acs.joc.8b00390 J. Org. Chem. 2018, 83, 5052−5057

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The Journal of Organic Chemistry by Trost and co-workers9 to the preparation of the Nsubstituted glutarimide 1 (Scheme 1) in excellent yield and

without isolation of the intermediate acetate 9, the reaction mixture was cooled to −78 °C and allylsilane 10 and a catalytic amount of trimethylsilyl triflate were added11 (Scheme 3). After

Scheme 1. Iterative Synthetic Strategy for Azaphenalene Alkaloids

Scheme 3. Synthesis of Bicyclic Alcohol 13

enantiomeric excess.10 We envisaged that glutarimide 1 would be ideally suited to act as a template for the asymmetric construction of the 9b-azaphenalene skeleton through an iterative synthetic approach: the two carbonyl functionalities were amenable to nucleophilic allylation and two ring closing metathesis (RCM) reactions to provide the two additional rings. The detailed synthetic plan (Scheme 2) uses a strategy to generate the N-acyliminium ion 2, with a specific configuration 4 h of reaction, the allylation product 11 was isolated in 97% yield, after chromatographic purification, as a mixture of diastereomers in a 10:1 ratio. From previous investigations, we knew that it was necessary to acetylate the hydroxyl group of the aminal 8 to 9 before generating the corresponding Nacyliminium ion, in order to circumvent the competitive elimination reaction leading to the formation of an enamide.10,11a The mixture of dienes 11 was then heated in refluxing dichloromethane in the presence of 3 mol % of secondgeneration Grubbs catalyst (G-II) for 48 h, affording, after chromatographic purification, the expected bicycle 12 in 91% yield as a single diastereomer.12 No evidence of a minor diastereomer of 12 was found. Desilylation of 12 furnished the corresponding alcohol 13, isolated as a single isomer in 94% yield by crystallization in hexane/ethyl acetate. The relative configuration of 13 was established as 3aS,9aS13 by X-ray diffraction analysis (Figure 2). Oxidation of alcohol 13 by treatment with Dess−Martin periodinane (DMPI) furnished the corresponding aldehyde, which slowly decomposed to furnish unidentified products.

Scheme 2. Synthetic Plan for Azaphenalene Alkaloids

of its stereogenic center, in the presence of an allylating reagent. This operation should furnish a diene containing a second stereogenic center (3). Then, a RCM reaction would provide the second ring (4). Next, the masked alcohol would be used to install an alkene (5) and a second reduction−allylation process to introduce the other alkene moiety and the third stereogenic center (6). Finally, a second RCM should deliver the tricyclic skeleton (7). Depending on the stereoselectivity observed and the targeted alkaloid, the methyl group could be introduced in the first or in the second nucleophilic allylation. Moreover, a hydrogenation could be performed after the first RCM or, alternatively, the two carbon−carbon double bonds could be hydrogenated at the end of the sequence. According to the plan, the known acylaminal (1′S)-8, readily available from (1′S)-1 by silylation and then reduction with LiEt3BH (90% yield from glutarimide),10 was treated with acetic anhydride, dimethylaminopyridine (DMAP), and trimethylamine in dichloromethane at room temperature and,

Figure 2. X-ray structure of alcohol 13. 5053


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The Journal of Organic Chemistry Hence, the crude aldehyde was immediately submitted to the next alkenylation step (Scheme 4). Attempts to introduce a Scheme 4. Synthesis of the Intermediate Trienes 15

Figure 3. Selective NOE and MM2 optimized geometry of (Z)-15.

the allylic chain attached to C-6a in an axial orientation. This preferential conformation led us to foresee that the following RCM reaction to form the tricycle would be more kinetically demanding than the previous one, since the involved alkene residues were pointing in opposite directions. At this point, we were unable to determine the stereochemical identity of the minor isomer, but considering that the precursor lactam 14 was a 6:1 mixture of Z and E isomers, we assumed that the amine 15 was also a mixture of the two Z and E diastereomers. The tentative stereochemical assignments of both isomers 15 were confirmed later on after the subsequent RCM step (vide infra). As anticipated, in order to achieve a good conversion, it was necessary to heat the mixture of trienes 15 in refluxing dichloromethane in the presence of 10 mol % of G-II catalyst for 14 h (Scheme 5). The expected tricyclic diene 19 was

methylene group resulted in poor yields of the expected terminal alkene, but fortunately, the reaction with ethyltriphenylphosphonium bromide and butyllithium in tetrahydrofuran at room temperature delivered a synthetically inconsequent Z/E mixture of the bicyclic dienes 14 in a 6:1 ratio and 77% overall yield. The next endeavor was the reduction of the lactam to hemiaminal, in order to generate an iminium ion, suitable for the second nucleophilic allylation. The reduction was investigated using a variety of hydride donors, including LiBEt3H, LiAlH4, DIBAL-H, NaBH4, BH3·THF, and Red-Al, under different conditions of solvent, temperature, and time, while allylmagnesium bromide was always used as the nucleophilic allylating agent. Two possibilities were explored: (i) a one-pot protocol, where the reduction was performed in the presence of the allylating reagent, and (ii) a two-step protocol with or without isolation of the intermediate hemiaminal.14 However, all attempts to isolate the intermediate hemiaminal led to the isolation of enamine 17 as the only reaction product. Hence, the extension of the reduction was evaluated by monitoring the signals of 17 in the 1H NMR of the crude products at different reaction times (see Figure S13 in the Supporting Information). After extensive experimentation, we found that treating the amide 14 with Red-Al (1:1 molar ratio) in THF at −55 °C for 3 h and then raising the temperature to 0 °C, adding 10 equiv of allylmagnesium bromide to the reaction medium, and extending the reaction time for an additional 1 h allowed the isolation of the expected triene 15, as a 5:1 mixture of diastereomers in 83% overall yield, after chromatographic purification. Other reducing agents showed poor chemoselectivity, leading to over-reduction that furnished amine 16, even when the conversion of the starting lactam was incomplete. Occasionally, trace amounts of the diallylated product 18 were detected. A selective NOE experiment irradiating H-9a (Figure S12) allowed us to tentatively assign the S configuration to the new stereogenic center of the major isomer of triene 15. Hence, the observed NOEs were consistent with the MM2 optimized geometry of (3aS,6aS,9aS)-15 (Figure 3), which presents a trans fusion of the azabicycle with protons H-3a and H-9a and

Scheme 5. Completion of the Synthesis of (−)-9a-epiHippocasine ((−)-20)

isolated as a single isomer in 83% yield. Its relative configuration was confirmed by NOE experiments (Figure S20), which evidenced the trans−trans−cis relationship among H-3a, H-6a, and H-9a. Considering that full hydrogenation of 19 would provide a meso compound, our efforts were devoted to the partial hydrogenation of the diene. This endeavor was accomplished by treatment of 19 with hydrogen (2 atm) in the presence of Pd/C and acetic acid in methanol as the solvent for 48 h. After column chromatography over silica gel, (−)-9a-epihippocasine (20) was isolated in 65% yield. The specific rotation of (−)-20 ([α] −0.71 (c 0.27, CHCl3)) is in agreement with the low values observed for related azaphenalene alkaloids.15 Although compound 20 had been previously prepared as a racemate and converted into the meso alkaloids precoccinelline and coccinelline,16 full characterization data have not been described. Hence, the completion of the synthesis of (−)-20 not only validates our strategy but also provides useful information for future investigations in the field. 5054


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HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C29H39NO2SiNa] 484.2648, found 484.2652. (6S,9aRS)-6-[(tert-Butyldiphenylsilyloxy)methyl]-8-methyl1,2,3,6,9,9a-hexahydroquinolizin-4(4H)-one (12). Compound 11 (10:1, diastereomeric mixture, 1.245 g, 2.70 mmol) was dissolved in anhydrous degassed DCM (300 mL). Then, second-generation Grubbs catalyst (68 mg, 0.08 mmol) was added portionwise and the resulting solution was heated at reflux for 48 h. After this time, the solution was cooled to room temperature and filtered through a pad of silica gel with Et2O as eluent. The solvent was then removed under vacuum and the oily brown residue was purified by flash column chromatography (hexane:Et2O, from 7:3 to 1:1) to furnish a yellowish oil identified as the bicyclic compound 12 (1.06 g, 2.44 mmol, 91%), which was a single isomer: Rf = 0.56 (Al2O3, Et2O:hexane, 3:1); 1H NMR (360 MHz, CDCl3) δ 7.64 (m, 4H), 7.37 (m, 6H), 5.62 (m, 1H), 4.60 (m, 1H), 3.93 (dd, J = 9.4, 5.2 Hz, 1H), 3.78 (dd, J = 9.4, 2.9 Hz, 1H), 3.33 (tt, J = 11.1, 2.9 Hz, 1H), 2.49−2.31 (m, 2H), 2.24 (m, 1H), 1.95−1.65 (m, 4H), 1.83 (s, 3H), 1.49 (m, 1H), 1.04 (s, 9H); 13 C NMR (91 MHz, CDCl3) δ 171.0, 135.7, 135.4, 133.9, 129.6, 127.6, 127.6, 121.2, 65.3, 54.9, 54.0, 37.0, 32.9, 31.0, 26.9, 23.3, 20.9, 19.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C27H35NO2SiNa] 456.2335, found 456.2337. (6S,9aS)-6-Hydroxymethyl-8-methyl-1,2,3,6,9,9a-hexahydroquinolizin-4(4H)-one (13). Compound 12 (1.03 g, 2.37 mmol) was dissolved in anhydrous THF (30.4 mL). The resulting clear solution was treated with Et3N·3HF (2.3 mL, 14.2 mmol) under reflux overnight. After this time, DCM (20 mL) was added and the solution was left to cool to room temperature. Then, the mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (3 × 50 mL). The organic extracts were dried over anhydrous Na2SO4 ,and the solvent was removed under vacuum to give a whitish solid. This solid was purified by flash column chromatography (from hexane:AcOEt, 1:5, to AcOEt) to give a white solid identified as 13 (434 mg, 2.22 mmol, 94%): Rf = 0.19 (AcOEt); [α]D +33.5 (c 0.01, DCM); IR (ATR) 3366, 2928, 2873, 1610, 1407, 1286, 1047 cm−1; 1H NMR (250 MHz, CDCl3) δ 5.43 (m, 1H), 4.60 (m, 1H), 4.27 (bs, 1H), 3.73 (dd, J = 11.5, 2.5 Hz, 1H), 3.49 (dd, J = 11.5, 6.5 Hz, 1H), 3.37 (tt, J = 11.3, 3.0 Hz, 1H), 2.52 (m, 2H), 2.19 (m, 1H), 1.99−1.50 (m, 5H), 1.75 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 173.4, 135.61, 120.0, 68.1, 57.2, 55.7, 36.5, 32.7, 30.6, 23.1, 20.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C11H17NO2Na] 218.1157, found 218.1152. (6R,9aS)-8-Methyl-6-(prop-1-en-1-yl)-1,2,3,6,9,9a-hexahydroquinolizin-4(4H)-one (14). Oxidation of 13 to the Aldehyde. To a solution of alcohol 13 (655 mg, 3.36 mmol) in anhydrous DCM (61 mL) was added a solution of Dess−Martin periodinane (15% in DCM, 8.4 mL, 4.03 mmol). The resulting clear solution was stirred at room temperature for 2 h. After this time, the reaction mixture was quenched with 60 mL of a solution prepared by addition of Na2S2O3 (17 g) to saturated aqueous NaHCO3 (90 mL) and stirred for 30 min. The solution was then extracted with DCM (3 × 60 mL), and the organic layer was dried over anhydrous Na2SO4. After solvent removal under vacuum, the expected aldehyde was obtained as a yellowish oil, which was immediately used in the next step without further purification: 1H NMR (250 MHz, CDCl3) δ 8.93 (d, J = 3.6 Hz, 1H), 5.18 (m, 1H), 4.47 (m, 1H), 3.40 (m, 1H), 2.51 (m, 1H), 2.26− 1.44 (m, 9H). Alkenylation. Next, Ph3PCH2CH3Br (1.5 g, 4.03 mmol) was dissolved in anhydrous THF (33 mL), the resulting solution was cooled to 0 °C, and BuLi (1.6 M solution in hexane, 2.5 mL, 4.03 mmol) was added to form the corresponding ylide. A solution of the previous crude aldehyde in anhydrous THF (61 mL) was treated with the solution of ylide at room temperature overnight. Then, Et2O (60 mL) was added, the solid was filtered through Celite, and the clear solution was concentrated under vacuum to furnish a yellowish crude material, which was purified by flash column chromatography over silica gel (hexane:Et2O, from 7:3 to 1:1). Lactam 14 (530 mg, 2.58 mmol, 77%) was obtained as a yellowish oil (Z:E 6:1): Rf = 0.50 (AcOEt); [α]D −72.1 (c 2.14, CHCl3); IR (ATR) 3458, 3015, 2916, 2854, 1643 cm−1; 1H NMR (400 MHz, CDCl3) major Z isomer δ 5.32 (dqm, J = 10.4, 6.9 Hz, 1H), 5.23 (m, 1H), 4.98 (m, 1H), 4.88 (ddq, J

CONCLUSIONS In summary, a new strategy for the stereoselective synthesis of the defensive coccinellid alkaloids with a perhydro-9bazaphenalene skeleton has been developed. The key first stereogenic center was formed in a palladium-catalyzed AAA of glutarimide, and the strategy relies on an iterative methodology encompassing two nucleophilic allylations and two ring closing metathesis processes. The approach has been used in the first synthesis of (−)-9a-epi-hippocasine (20) in only 11 steps from glutarimide with 26% total yield, which is the highest total yield so far described for an enantioselective synthesis of any alkaloid of the azaphenalene family. Work is in progress to extend the synthetic design to other azaphenalene alkaloids.

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EXPERIMENTAL SECTION

General Methods. Commercially available reagents were used as received. The solvents were dried by distillation over the appropriate drying agents. All reactions were performed avoiding moisture by standard procedures and under a nitrogen atmosphere. Thin-layer chromatography (TLC) was performed on 0.25 mm silica gel precoated aluminum plates (60 F254) and was visualized using a 254 nm UV lamp or developing with a KMnO4/NaOH aqueous solution or ethanol solution of molybdenum ammonium and cerium sulfate. Flash chromatography was performed in silica gel (230−400 mesh). 1H NMR and 13C NMR spectra were recorded at 250 and 62.5 MHz, 360 and 90 MHz, or 400 and 101 MHz. Proton and carbon chemical shifts are reported in ppm (δ) (CDCl3, δ 7.26 for 1H; CDCl3, δ 77.2 for 13C). NMR signals were assigned with the help of COSY, DEPT135, HSQC, HMBC, NOESY, and selective NOE experiments. All spectra have been registered at 298 K. Melting points were determined on a hot stage and are uncorrected. Optical rotations were measured at 22 ± 2 °C. (6RS)-1-[(S)-1-(tert-Butyldiphenylsilyloxy)but-3-en-2-yl]-6-(2methylallyl)piperidin-2-one (11). A 16:1 diastereomeric mixture of aminal 8 (2.89 g, 6.81 mmol) was dissolved in anhydrous DCM (36 mL). The solution was cooled to 0 °C, and DMAP (493 mg, 4.03 mmol), Ac2O (1.67 mL, 17.7 mmol) and anhydrous Et3N (2.5 mL, 17.7 mmol) were added. The resulting solution was warmed to room temperature and stirred for 14 h. Then, the resulting mixture was treated with saturated aqueous NaHCO3 (24 mL) and diluted in water (24 mL). The layers were separated, and the aqueous layer was extracted with additional DCM (3 × 20 mL). The whole organic layers were dried over anhydrous Na2SO4, and after solvent removal, the intermediate acetate 9 was obtained as a yellowish oil. This crude material was then dissolved in anhydrous DCM (36 mL), and the resulting clear solution was cooled to −78 °C. Silane 10 (2.4 mL, 13.6 mmol) and TMSOTf (1.85 mL, 10.2 mmol) were then subsequently added dropwise, and the mixture was stirred for 3.5 h. Next, saturated aqueous NaHCO3 (24 mL) was added, the resulting mixture was warmed to room temperature, and additional water was added (24 mL). The mixture was extracted with DCM (3 × 20 mL), the combined organic layers were dried over anhydrous Na2SO4, and after solvent removal an oily residue was obtained. This crude material was purified by flash column chromatography on silica gel (hexane:Et2O, from 7:3 to 1:1), yielding 3.05 g (6.61 mmol, 97%) of an oil identified as a 10:1 diastereomeric mixture of methylallylamide 11: Rf = 0.67 (Et2O:hexane, 3:1); IR (ATR) 3071, 2931, 2867, 1639, 1470, 1427, 1415, 1111 cm−1; 1H NMR (250 MHz, CDCl3) major diastereomer δ 7.66 (m, 4H), 7.40 (m, 6H), 6.20 (ddd, J = 17.3, 10.6, 6.8 Hz, 1H), 5.15−4.99 (m, 2H), 4.82 (bs, 1H), 4.72 (bs, 1H), 4.31 (m, 1H), 3.95− 3.76 (m, 2H), 3.60 (m, 1H), 2.49−2.13 (m, 4H), 1.88−1.60 (m, 2H), 1.70 (s, 3H), 1.06 (s, 9H); minor diastereomer (significant signals) δ 6.09 (m, 1H), 4.04 (dd, J = 15.5, 6.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) major isomer δ 169.8, 141.9, 135.7, 135.6, 135.3, 129.7, 127.7, 117.0, 113.5, 66.1, 64.2, 57.4, 41.4, 32.5, 26.9, 25.2, 22.2, 19.2, 16.0, minor diastereomer (significant signals) δ 170.1, 142.0, 134.8, 133.6, 133.5, 133.4, 117.5, 113.3, 64.5, 62.9, 54.2, 41.8, 32.0, 22.1, 19.3, 15.9; 5055


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(ATR) 2924, 2854, 1735, 1638, 1446, 633 cm−1; 1H NMR (250 MHz, CDCl3) δ 5.66 (m, 2H), 5.22 (dq, J = 3.2, 1.5 Hz, 1H), 4.02 (m, 1H), 3.28 (dddd, J = 11.5, 4.7, 2.3 Hz, 1H), 2.67 (m, 1H), 2.50−2.25 (m, 2H), 2.09−1.22 (m, 8H), 1.67 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 130.6, 128.3, 123.4, 121.4, 56.7, 53.5, 45.2, 34.6, 33.9, 30.0, 27.6, 23.3, 19.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C13H20N] 190.1596, found 190.1583. (3aS,6aS,9aR)-8-Methyl-1,2,3,3a,4,5,6,6a,7,9adecahydropyrido[2,1,6-de]quinolizine ((−)-9a-epi-Hippocasine, 20). Acetic acid (3 drops) and Pd/C (10%, 4 mg) were added to a solution of the tricyclic amine 19 (40.5 mg, 0.21 mmol) in methanol (1.5 mL), and the mixture was treated with hydrogen (2 atm) for 48 h. After that time, the mixture was filtered through Celite and eluted with DCM and the solution washed with saturated aqueous NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography in neutral alumina (from hexane to hexane:Et2O, 1:1, + Et3N, 3 drops/10 mL of eluent) to furnish (−)-9a-epi-hippodamine (26.6 mg, 0.14 mmol, 65% yield): Rf = 0.45 (Et2O + Et3N, 3 drops/10 mL of eluent); [α]D −0.71 (c 0.27, CHCl3); IR: 2926, 2854, 2363, 2344, 1686, 1199, 1129, 631 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C13H22N] 192.1752, found 192.1747. A 0.3 M solution of amine 20 CDCl3 (600 μL) was treated with TFA (100 μL) in order to obtain the corresponding salt, which was fully characterized by NMR: 1 H NMR (400 MHz, CDCl3) δ 5.23 (m, 1H), 4.26 (m, 1H), 3.84 (m, 1H), 3.15 (m, 1H), 2.49 (m, 1H), 2.25−2.00 (m, 3H), 1.95−1.55 (m, 11H), 1.85 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 134.4, 118.5, 56.9, 56.0, 52.7, 30.4, 30.3, 28.7, 28.5, 26.8, 22.6, 17.8, 17.2.

= 10.4, 8.7, 1.0 Hz, 1H), 3.26 (m, 1H), 2.31 (m, 2H), 2.03 (m, 1H), 1.92−1.72 (m, 3H), 1.72−1.55 (m, 6H), 1.55−1.37 (m, 2H), minor E isomer (significant signals) δ 5.41 (dqm, J = 15.2, 5.6 Hz, 1H), 4.76 (m, 1H); 13C NMR (101 MHz, CDCl3) major Z isomer δ 170.3, 132.2, 131.2, 122.7, 121.1, 54.7, 50.4, 36.8, 32.9, 31.1, 22.9, 20.5, 12.7, minor E isomer δ 170.1, 133.2, 130.9, 124.3, 122.1, 54.9, 53.7, 36.4, 32.6, 30.9, 22.8, 20.5, 17.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for [C13H19NONa] 228.1364, found 228.1363. (4S,6R,9aS)-4-Allyl-8-methyl-6-(prop-1-en-1-yl)-1,3,4,6,9,9ahexahydro-2H-quinolizine (15). A Z:E (6:1) mixture of lactam 14 (370.4 mg, 1.8 mmol) was dissolved in THF (25.7 mL). The clear solution was cooled to −55 °C, and Red-Al (65% solution in THF, 0.66 mL, 2.16 mmol) was added. The resulting mixture was stirred for 3 h at the same temperature. Then, allylmagnesium bromide (1 M solution in THF, 18 mL, 18 mmol) was added and the resulting mixture was left to warm to 0 °C and stirred for 3 h. Finally, aqueous saturated NaHCO3 (30 mL) was added and the whole mixture was extracted with DCM (3 × 30 mL). The organic layers were dried over anhydrous Na2SO4, and the solvent was removed under vacuum to give a yellow oil. This crude material was purified by flash column chromatography on silica gel (from hexane to hexane:AcOEt, 7:3, + Et3N, 3 drops/10 mL of eluent) to furnish a yellow oil identified as 15 (Z/E = 5/1, 345 mg, 1.49 mmol, 83%): Rf = 0.56 (DCM:MeOH, 9:1, + Et3N, 3 drops/10 mL of eluent); IR (ATR) 3074, 3016, 2921, 2854, 1638, 1446 cm−1; 1H NMR (400 MHz, CDCl3) major Z isomer δ 5.67 (dddd, J = 16.3, 10.2, 8.4, 6.2 Hz, 1H), 5.54 (dqm, J = 10.9, 6.9 Hz, 1H), 5.25 (ddd, J = 10.9, 2.0 Hz, 1H), 5.14−4.93 (m, 3H), 4.07 (m, 1H), 3.09 (m, 1H), 2.66 (m, 1H), 2.42−2.13 (m, 2H), 1.70 (dd, J = 6.9, 1.7 Hz, 3H), 1.64 (bs, J = 7.4 Hz, 3H), 1.93−1.38 (m, 8H); 13C NMR (101 MHz, CDCl3) major Z isomer δ 137.5, 133.8, 131.2, 124.9, 122.7, 115.9, 54.3, 53.6, 49.3, 39.4, 34.8, 28.1, 26.7, 22.8, 18.2, 13.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for [C16H26N] 232.2065, found 232.2059. Eventually, during the study of the allylation of amide 14, variable amounts of byproducts 16−18 were detected. (6R,9aS)-8-Methyl-6-(prop-1-en-1-yl)-1,3,4,6,9,9a-hexahydro-2H-quinolizine (16): 1H NMR (250 MHz, CDCl3) significant signals δ 5.58 (dq, J = 13.3 Hz, 6.8 Hz, 1H), 5.32 (m, 1H), 5.03 (bs, 1H), 3.45 (m, 1H), 3.19 (m, 1H), 1.66 (d, J = 7.0 Hz, 3H), 1.64 (d, J = 6.8 Hz, 3H). (6R,9aS)-8-Methyl-6-(prop-1-en-1-yl)-1,6,9,9a-tetrahydro2H-quinolizine (17): 1H NMR (250 MHz, CDCl3) significant signals δ 5.96 (dd, J = 6.0, 1.5 Hz, 1H), 5.64 (ddq, J = 10.8, 6.9, 0.9 Hz, 1H), 5.24 (ddq, J = 10.8, 9.3, 1.7 Hz, 1H), 5.05 (m, 1H), 4.60 (m, 1H), 4.0 (m, 1H), 2.8 (tt, J = 10.5, 3.57 Hz, 1H), 1.69 (m, 3H), 1.55 (bs, 3H). (6R,9aS)-4,4-Diallyl-8-methyl-6-(prop-1-en-1-yl)-1,3,4,6,9,9ahexahydro-2H-quinolizine (18): Rf = 0.4 (DCM:MeOH, 9:1, + Et3N, 3 drops/10 mL of eluent); [α]D −8.0 (c 0.01, CHCl3); IR (ATR) 3015, 2928, 2859, 2365, 2331, 1673, 1640, 1563, 1443 cm−1; 1 H NMR (400 MHz, CDCl3) δ 5.84 (dddd, J = 17.8, 11.3, 7.5, 0.9 Hz, 2H), 5.53 (ddq, J = 10.8, 6.9, 1.2 Hz, 1H), 5.30 (ddq, J = 10.8, 8.9, 1.7 Hz, 1H), 5.14 (m, 5H), 4.24 (m, 1H), 2.79 (m, 1H), 2.23 (m, 4H), 1.92−1.65 (m, 6H), 1.70 (d, J = 1.8 Hz, 3H), 1.68 (d, J = 1.8, 3H), 1.45 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 133.9, 133.4, 133.2, 126.2, 125.4, 123.8, 118.8, 118.7, 73.5, 53.2, 52.4, 43.9, 43.8, 39.2, 37.3, 36.9, 23.4, 19.7, 13.3; HRMS (ESI-TOF) m/z [(M·H2O) + H]+ calcd for [C19H32NO] 290.2484, found 290.2478. (3aS,6aR,9aS)-5-Methyl-1,2,3,3a,4,6a,9,9a-octahydropyrido[2,1,6-de]quinolizine (19). A Z:E (5:1) mixture of amine 15 (121 mg, 0.53 mmol) was dissolved in anhydrous and degassed DCM (70 mL). Then, second-generation Grubbs catalyst (44 mg, 0.05 mmol) was added in one portion. The resulting clear solution was heated at reflux for 14 h. After this time, the mixture was cooled to room temperature and filtered through a plug of silica gel that was then washed with Et2O. The solvent was removed under vacuum, and the resulting crude product was purified by flash column chromatography on neutral alumina (from hexane to hexane:AcOEt, 9:1, + Et3N, 3 drops/10 mL of eluent). A yellow oil was isolated and identified as amine 19 (86 mg, 0.44 mmol, 83%): Rf = 0.51 (DCM:MeOH, 9:1, + Et3N, 3 drops/10 mL of eluent); [α]D −52.1 (c 1.14, CHCl3); IR

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00390. NMR spectra of compounds 14−20, selective NOE spectra of compounds 15 and 19, X-ray structure determination of compound 13, and 1H NMR study of the reduction of compound 14 (PDF) Crystallographic data for compound 13 (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail for P.B.: [email protected]. *E-mail for M.F.: marta.fi[email protected]. ORCID

Marta Figueredo: 0000-0002-8278-7534 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the Spanish Dirección General de Investigación for financial support (projects CTQ2010-15380 and CTQ2013-41161-R). We are grateful for a grant from Universitat Autònoma de Barcelona (to S. A.-B.).

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REFERENCES

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Iterative Synthetic Strategy for Azaphenalene Alkaloids. Total

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