9a-epi-Hippocasine

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Iterative Synthetic Strategy for Azaphenalene Alkaloids. Total Synthesis of (-)-9a-epi-Hippocasine Sílvia Alujas-Burgos, Cristina Oliveras-González, Angel Alvarez-Larena, Pau Bayón, and Marta Figueredo J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00390 • Publication Date (Web): 12 Apr 2018 Downloaded from http://pubs.acs.org on April 12, 2018

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The Journal of Organic Chemistry

Iterative Synthetic Strategy for Azaphenalene Alkaloids. Total Synthesis of (−)-9a-epi-Hippocasine Sílvia Alujas-Burgos,† Cristina Oliveras-González,† Ángel Álvarez-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

[email protected]; [email protected]

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 relays on an iterative methodology encompassing two nucleophilic allylations

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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and two ring closing metathesis processes. The approach has been materialized in the first synthesis of (−)-9a-epi-hippocasine.

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 harvest-damaging insects. For this reason, some coccinellids have played an important role in biological pest control.2 Ladybugs usually present bright red, orange or yellow colors 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 to 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 this family members 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


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The Journal of Organic Chemistry H

9b 3a

H

H

H

N 6a

H

H N

N

9a 1

H Precoccineline H

H O

N

H Myrrhine

H N

H

H

H O

H Hippocasine N-oxide

H N

H O

H Coccineline

H

H Hippodamine

H Hippocasine

H N

Propyleine

N

H Convergine

H

H N

Isopropyleine

Figure 1. Monomeric azaphenalene alkaloids.

Most reported synthesis of the simple azaphenalene alkaloids involve symmetrical precursors and, hence, end up with achiral or racemic products.4,7 Recently, three enantioselective approaches have been also described.8 In two of them the stereo-discrimination was induced by a chiral auxiliary in the starting material,8a,c while in the third one 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.

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 by Trost and coworkers,9 to the preparation of the N-subtituted glutarimide 1 (Scheme 1) in excellent yield and enantiomeric excess.10 We envisaged that glutarimide 1 was 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 of nucleophilic allylation and two ring closing metathesis (RCM) reactions to provide the two additional rings.



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Scheme 1. Iterative synthetic strategy for azaphenalene alkaloids.

The detailed synthetic plan, Scheme 2, uses a strategy to generate the N-acyliminium ion 2, with a specific configuration 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 nucleophilic allylation or in the second one. 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. Scheme 2. Synthetic plan for azaphenalene alkaloids.


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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 glutarmide),10 was treated with acetic anhydride, dimethylaminopyridine (DMAP) and trimethylamine in dichloromethane at room temperature and, without isolation of the intermediate acetate 9, the reaction mixture was cooled to −78ºC and allylsilane 10 and a catalytic amount of trimethylsilyl triflate were added11 (Scheme 3). After 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 N-acyliminium ion, in order to circumvent the competitive elimination reaction leading to the formation of an enamide.10,11a Scheme 3. Synthesis of bicyclic alcohol 13.

The mixture of dienes 11 was then heated in refluxing dichloromethane in the presence of 3 mol% second generation Grubbs catalyst (G-II) for 48 h, affording, after chromatographic purification, the expected bicycle 12 in 91% yield as a single diastereomer.12 No evidences of a minor diastereomer of 12 were 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,9aS)13 by X ray diffraction analysis (Figure 2). 5 Environment ACS Paragon Plus


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Figure 2. X-ray structure of alcohol 13. Oxidation of alcohol 13 by treatment with Dess-Martin periodinane (DMPI) furnished the corresponding aldehyde, which slowly decomposed to furnish unidentified products. Hence, the crude aldehyde was immediately submitted to the next alkenylation step (Scheme 4). Attempts to introduce a 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 Supporting Information Figure S13). After extensive experimentation, we found that treating the amide 14 with Red-Al (1:1 molar ratio) in THF at −55ºC for 3 h, then raising the temperature to 0ºC, 6 Environment ACS Paragon Plus

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adding 10 equivalents of allylmagnesium bromide to the reaction medium, and extending the reaction time for 1 additional hour, 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 to tentatively assign the S configuration to the new stereogenic center of the major isomer of triene 15. Hence, the observed nOe’s 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, H-9a and the allylic chain attached to C-6a in 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/E isomers, we assumed that the amine 15 was also a mixture the two Z/E diastereomers. The tentative stereochemical assignments of both isomers 15 were later on confirmed after the subsequent RCM step (vide infra). Scheme 4. Synthesis of the intermediate trienes 15.



H N

O OH

i) DMPI, CH2Cl 2, rt ii) Ph3 PCH2CH3, BuLi, THF, rt

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H N

O

77%

H 13

H 14 Z/E = 6:1

i) Red-Al, THF, -55ºC ii) MgBr, 0ºC

H

6a 3a

N 9a

83%

H

H 15 Z/E = 5:1

H

H

N

N

N

H

H

H

16

17

18

Figure 3. Selective nOe and MM2 optimized geometry of (Z)-15. 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% G-II catalyst for 14 h (Scheme 5). The expected tricyclic diene 19 was 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 between 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-epi-hippocasine, 20, was isolated in 65% 8 Environment ACS Paragon Plus

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yield. The specific rotation of (−)-20 ([α] −0.71 (c 0.27, CHCl3)) is in agreement with the low values observed 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. Scheme 5. Completion of the synthesis of (−)-9a-epi-hippocasine, (−)-20.

Conclusions In summary, a new strategy for the stereoselective synthesis of the defensive coccinellid alkaloids with a perhydro-9b-azaphenalene skeleton has been developed. The key first stereogenic center was formed in a palladium-catalyzed AAA of glutarimide and the strategy relays on an iterative methodology encompassing two nucleophilic allylations and two ring closing metathesis processes. The approach has been materialized in the first synthesis of (−)-9a-epi-hippocasine, 20, in only eleven steps from glutarimide and 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. 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



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by standard procedures and under nitrogen atmosphere. Thin-layer chromatography (TLC) were performed on 0.25 mm silica gel pre-coated aluminum plates (60 F254) and they were visualized using a 254 nm UV lamp or developing with KMnO4/NaOH aqueous solution or ethanol solution of molybdenum ammonium and cerium sulfate. Flash chromatography were performed in silica gel (230-400 mesh).1H NMR and

13

C 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

13

C). NMR signals

were assigned with the help of COSY, DEPT135, HSQC, HMBC, NOESY and selective n.O.e. experiments. All spectra have been registered at 298 K. Melting points were determined on 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-(2-methylallyl)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 down to 0ºC 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 up to rt 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 one extracted with additional DCM (3 x 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 down to −78 ºC. 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 left to warm up to room temperature, and additional water was added (24 mL). The mixture was extracted with DCM (3 x 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 10 Environment ACS Paragon Plus

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(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), 2.492.13 (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);

13

C 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; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for [C29H39NO2SiNa]: 484.2648; Found: 484.2652. (6S,9aRS)-6-[(tert-Butyldiphenylsilyloxy)methyl]-8-methyl-1,2,3,6,9,9a-hexahydroquinolizin4(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 portion-wise and the resulting solution was heated at reflux for 48 h. After this time, the solution was cooled down to room temperature and filtered through a pad of silica gel employing 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); 1

H-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 down to room temperature. Then, the mixture was quenched with 11 Environment ACS Paragon Plus


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saturated aqueous NaHCO3 and extracted with DCM (3 x 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).

i)

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 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 x 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 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). ii) Alkenylation. Next, Ph3PCH2CH3Br (1.5 g, 4.03 mmol) was dissolved in anhydrous THF (33 mL), the resulting solution was cooled down to 0ºC 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, 12 Environment ACS Paragon Plus

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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 = 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)-1,3,4,6,9,9a-hexahydro-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 down to -55ºC 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 (1M solution in THF, 18 mL, 18 mmol) was added and the resulting mixture was left to warm up to 0ºC and stirred for 3 h. Finally, aqueous saturated NaHCO3 (30 mL) was added and the whole mixture was extracted with DCM (3 x 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); 13CNMR (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, 17, and 18 were detected. 13 Environment ACS Paragon Plus


Page 14 of 18

(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-tetrahydro-2H-quinolizine

(17):

1

H-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)-1,3,4,6,9,9a-hexahydro-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; 1H-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);

13

C-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 (ESITOF) 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, 2nd 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 down to room temperature and filtered through a plug of silica gel washing 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 (ATR): 2924, 2854, 1735, 1638, 1446, 633 cm1 1

; H-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 14 Environment ACS Paragon Plus

Page 15 of 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(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,7,9a-decahydropyrido[2,1,6-de]quinolizine, (−)-9a-epiHippocasine, (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®, eluting 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-epihippodamine (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: 1H-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);

13

C-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.

Supporting information Copies of NMR spectra of compounds 14-20. Selective nOe spectra of compounds 15 and 19. Xray structure determination of compound 13. 1H-NMR study of the reduction of compound 14. This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgements 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.). 15 Environment ACS Paragon Plus


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References (1) Daloze, D.; Braekman, J. C.; Pasteels, J. M. Ladybird Defense Alkaloids: Structural, Chemotaxonomic and Biosynthetic Aspects (Col.: Coccinellidae) Chemoecology 1994/1995, 5/6, 173-183.

(2) See for instance: Caltagirone, L. E.; R. L. Doutt, R. L. The History of the Vedalia Beetle Importation to California and its Impact on the Development of Biological Control. Annu. Rev. Entomol. 1989, 34, 1-16. (3) Happ, G. M.; Eisner, T. Hemorrhage in a Coccinellid Beetle and its Repellent Effect on Ants. Science 1961, 134, 329-331. (4) King, A. G.; Meinwald, J. Review of the Defensive Chemistry of Cocchinellids. Chem. Rev. 1996, 96, 1105-1122. (5) Tursch, B., Daloze, D., Dupont, M., Pasteels, J. M., Tricot, M.-C. A Defense Alkaloid in a Carnivorous Beetle. Experientia 1971, 27, 1380-1381. (6) (a) Timmermans, M.; Braekman, J.-C.; Daloze, D.; Pasteels, J. M.; Merlin, J.; Declercq, J.-P. Exochomine, a Dimeric Ladybird Alkaloid, Isolated from Exochomus Quadripustulatus (Coleoptera: Coccinellidae). Tetrahedron Lett. 1992, 33, 1281-1284. (b) McCormick, K. D.; Attygalle, A. B.; Xu, S.C.; Svatos, A.; Meinwald, J.; Houck, M. A.; Blankespoor, C. L.; Eisner, T. Chilocorine: Heptacyclic Alkaloid from a Coccinellid Beetle. Tetrahedron 1994, 50, 2365-2372. (c) Shi, X.; Attygalle, A. B.; Meinwald, J.; Houck, M. A.; Eisner, T. Defense Mechanisms of Arthropods. 131. Spirocyclic Defensive Alkaloid from a Coccinellid Beetle. Tetrahedron 1995, 51, 8711-8718. (d) Schröder, F. C.; Tolasch, T. Psylloborine A, a New Dimeric Alkaloid from a Ladybird Beetle. Tetrahedron, 1998, 54, 12243-12248. (e) Lebrun, B.; Braekman, J.-C.; Daloze, D.; Kalushkov, P.; Pasteels, J. M. Isopsylloborine A, a New Dimeric Azaphenalene Alkaloid from Ladybird Beetles (Coleoptera: Coccinellidae). Tetrahedron Lett. 1999, 40, 8115-8116. (7) For recent syntheses of racemic and achiral azaphenalene alkaloids see: (a) Rejzek, M.; Stockman, R. A.; Hughes, D. L. Combining Two-directional Synthesis and Tandem Reactions: An 16 Environment ACS Paragon Plus

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Efficient Strategy for the Total Syntheses of (±)-Hippodamine and (±)-epi-Hippodamine. Org. Biomol. Chem. 2005, 3, 73-83. (b) Gerasyuto, A. I.; Hsung, R. P. Stereodivergent Total Syntheses of Precoccinelline, Hippodamine, Coccinelline, and Convergine Org. Lett. 2006, 8, 4899-4902. (c) Gerasyuto, A. I.; Hsung, R. P. An Intramolecular aza-[3 + 3] Annulation Approach to Azaphenalene Alkaloids. Total Synthesis of Myrrhine. J. Org. Chem. 2007, 72, 2476-2484. (d) Díaz-Gavilán, M.; Galloway, W. R. J. D.; O’Connell, K. M. G.; Hodkingson, J. T.; Spring, D. R. Diversity-oriented Synthesis of Bicyclic and Tricyclic Alkaloids. Chem. Commun. 2010, 46, 776-778. (e) Kuznetsov, N. Y.; Lyubimov, S. E.; Godovikov, I. A.; Bubnov, Y. N. New Strategy for the Synthesis of Ladybird Beetle Azaphenalene Alkaloids Using a Combination of Allylboration and Intramolecular Metathesis. Total Synthesis of (±)-Hippocasine and (±)-epi-Hippodamine. Russ. Chem. Bull. 2014, 63, 529-537. (8) For enantioselective syntheses of azaphenalene alkaloids see: (a) Fujita, S.; Sakaguchi, T.; Kobayashi, T.; Tsuchikawa, H.; Katsumura, S. Total Synthesis of (-)-Hippodamine by Stereocontrolled Construction of Azaphenalene Skeleton Based on Extended One-Pot Asymmetric Azaelectrocyclization. Org. Lett. 2013, 15, 2758-2761. (b) Sherwood, T. C.; Trotta, A. H.; Snyder, S. A. A Strategy for Complex Dimer Formation. When Biomimicry Fails: Total Synthesis of Ten Coccinellid Alkaloids. J. Am. Chem. Soc. 2014, 136, 9743-9753. (c) Guerola, M.; Sánchez-Rosselló, M.; Mulet, C.; del Pozo, C.; Fustero, S. Asymmetric Intramolecular Aza-Michael Reaction in Desymmetrization Processes. Total Synthesis of Hippodamine and epi-Hippodamine. Org. Lett. 2015, 17, 960-963. (9) For review articles on asymmetric allylic alkylation see: (a) Trost, B. M.; Van Vranken, D. L. Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem. Rev. 1996, 96, 395-422. (b) Trost, B. M. Designing a Receptor for Molecular Recognition in a Catalytic Synthetic Reaction: Allylic Alkylation. Acc. Chem. Res. 1996, 29, 355-364. (c) Milhau, L.; Guiry, P. J. Palladium-Catalyzed Enantioselective Allylic Substitution. Top. Organomet. Chem. 2012, 38, 95-154. For articles closely related to this work see: (d) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. Dynamic Kinetic Asymmetric Transformation of Diene Monoepoxides: A Practical Asymmetric Synthesis of Vinylglycinol, Vigabatrin, and Ethambutol. J. Am. Chem. Soc. 2000, 122, 5968-5976. (e) Trost, B. M.; Horne, D. B.; Woltering, M. J. Palladium-catalyzed DYKAT of Butadiene Mono-epoxide: Enantioselective Total Synthesis of (+)-DMDP, (-)-Bulgecinine, and (+)-Broussonetine G. Chem. Eur. J. 2006, 12, 6607-6620. (10) González-Gálvez, D.; García-García, E.; Alibés, R.; Bayón, P.; de March, P.; Figueredo M.; Font, J. Enantioselective Approach to Securinega Alkaloids. Total Synthesis of Securinine and (-)Norsecurinine. J. Org. Chem. 2009, 74, 6199-6211. 17 Environment ACS Paragon Plus


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(11) For a closely related precedent see: (a) Lu, Y.; Alujas-Burgos, S.; Oliveras-González, C.; Vázquez-Jiménez, L.; Rojo, P.; Álvarez-Larena, A.; Bayón, P.; Figueredo, M. Enantioselective Approach to Indolizidine and Quinolizidine Scaffolds. Application to the Synthesis of Peptide Mimics. Tetrahedron 2018, 74, 104-116. For other nucleophilic allylations of acylaminals

with

allyltrimethylsilane see: (b) Girandinà, A.; Mecozzi, T.; Petrini, M. Acyclic Stereoselection in the Reaction of Nucleophilic Reagents with Chiral N-Acyliminium Ions Generated from N-[1(Phenylsulfonyl)alkyl]imidazolidin-2-ones. J. Org. Chem. 2000, 65, 8277-8282. (c) Klitzke, C. F.; Pilli, R. A. Enhanced trans Diastereoselection in the Allylation of Cyclic Chiral N-Acyliminium Ions. Synthesis of Hydroxylated Indolizidines. Tetrahedron Lett. 2001, 42, 5605-5608. (d) Pin, F.; Comesse, S.; Garrigues, B.; Marchalín, S.; Daïch, A. Intermolecular and Intramolecular alpha-Amidoalkylation Reactions Using Bismuth Triflate as the Catalyst. J. Org. Chem. 2007, 72, 1181-1191. (12) For examples of RCM reaction leading to quinolizidine frameworks see: (a) Jacek G. Sośnicki, Convenient

Approach

to

tetrahydro-Quinolizin-4-ones by Sequential

Addition

of

Lithium

Allyldibutylmagnesate to N-Allylpyridin-2-ones and Ring-Closing Metathesis Reactions. Tetrahedron Lett. 2006, 47, 6809-6812. (b) Bissember, A. C.; Banwell, M. G. Preparation of Some Angularly Substituted and Highly Functionalized Quinolizidines as Building Blocks for the Synthesis of Various Alkaloids and Related Scaffolds of Medicinal Interest. Tetrahedron 2009, 65, 8222-8230. (c) Pepe, A.; Pamment, A.; Georg, G. I.; Malhotra, S. V. Synthesis of Fused Bicyclic Systems with Nitrogen Atom at the Bridgehead, Including Indolizidines and Quinolizidines. J. Org. Chem. 2011, 76, 3527-3530. (13) Atom numbering refers to the position in the targeted alkaloids. (14) For a study on the reductive alkylation of lactams see: Xiao, K.-J.; Wang, Y.; Huang, Y.-H.; Wang, X.-G.; Huang, P.-Q. A Direct and General Method for the Reductive Alkylation of Tertiary Lactams/Amides: Application to the Step Economical Synthesis of Alkaloid (-)-Morusimic Acid D. J. Org. Chem. 2013, 78, 8305-8311. (15) Tursch, B.; Daloze, D.; Braekman, J. C.; Hootele, C.; Cravador, A.; Losman, D.; Karlsson, R. Chemical Ecology of Arthropods. IX. Structure and Absolute Configuration of Hippodamine and Convergine, Two Novel Alkaloids from the American Ladybug Hippodamia Convergens (ColeopteraCoccinellidae). Tetrahedron Lett. 1974, 15, 409-412. (16) (a) Ayer, W. A.; Furuichi, K. The Total Synthesis of Coccinelline and Precoccinelline. Can. J. Chem. 1976, 54, 1494-1495. (b) Mueller, R. H.; Thompson, M. E. Stereoselective Total Synthesis of the Ladybug Defensive Agents Coccinellin and Precoccinellin. Tetrahedron Lett. 1979, 20, 1991-1994. 18 Environment ACS Paragon Plus

9a-epi-Hippocasine

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