141
Les sujets de cette thèse ont exploré la structure de différents composés de la nature et synthétique. L’intérêt était particulièrement le développement de méthodes de synthèse organique et la compréhension d’auxiliaires chiraux.
Au chapitre II, nous visions une compréhension avancée du transfert de chiralité par un modificateur naturel hautement performant en étudiant des modèles plus simples qui interagissent avec le substrat sur la surface catalytique. Un de ces modificateurs, soit le diastéréoisomère performant (R,S)-PNEA, a vu sa structure absolue être corrigée via l’utilisation de méthodes solides de chimie organique.
L’autre modificateur chiral qui a été étudié est le modificateur sans azote NED. L’absence de cet élément est très révélatrice quant à la compréhension mécanistique du transfert de chiralité. Cette absence démontre que le design de modificateur ne nécessite pas nécessaire ce type d’atomes dans sa structure. Cette compréhension ouvre la porte au développement de nouveaux modificateurs de catalyse hétérogène, qui eux, pourraient agrandir le champ d’action et ainsi espérer que ce type chimie très robuste puisse s’appliquer dans de multiples cas.
Au chapitre III, on a présenté la première synthèse de l’antrocinnamomin D, incluant une méthode verte. C’est un produit naturel issu d’une médecine traditionnelle ayant des effets hépatiques bénéfiques. L’antrocinnamomin D est membre d’une famille incluant des composés d’anhydrides maléiques et dérivés maléimides issu d’un champignon appelé
Niuchangchih. La méthodologie de synthèse employée permet aussi d’obtenir deux autres
membres de la famille, soit les antrodins A et B. L’antrocinnamomin D, l’antrodin A et B ont été obtenus en 6-8 étapes avec des rendements globaux de 51%, 46% et 43% respectivement.
142
Cette synthèse inclut un couplage qui s’est démontré très efficace. Ce couplage fait intervenir comme catalyseur métallique un composé à base de fer, un élément peu toxique et dispendieux, qui a su rivaliser les catalyseurs de métaux nobles habituels.
Au chapitre IV, on y retrouve une méthode de synthèse permettant d’accéder à une famille de composés naturels, dont un composé ayant une structure très intéressante sans azote actif comme antagoniste antidépresseur. Ce produit a été isolé d’un champignon de sol appelé Aspergillus parvulus. Son antagoniste se situe au récepteur 2C de la sérotonine. Ce récepteur est associé aux troubles liés à la dépression et les agents antagonistes ont démontré des effets bénéfiques pour les patients atteints de ce problème de santé. Cette antagoniste naturelle appelée (+)-O-méthylasparvenone fait partie d’une famille de composés naturels appelée 4-hydroxy-1-tetralone. Leur structure simpliste cache une complexité exprimée par la rareté de synthèse énantiosélective de ces composés. La synthèse asymétrique d’un ces membres, un composé trisubstitué, a été accomplie avec un excès d’énantiomère de 94% en 8 étapes avec un rendement global de 22%.
143
Finalement au chapitre V : il y a une synthèse totale unie et régiosélective de deux produits naturels d’une famille de buténolide. Ces composés sont de la famille des rubrolides, soit les membres R et S. Ces deux composés sont issus du champignon Aspergillus terreus OUCMDZ-1925. Le rubrolide R a été décrit comme un antioxydant et le rubrolide S a démontré des activités anti-influenza A(H1N1). Les deux approches de synthèse font intervenir à la fois une condensation de type aldol vinylogue avec un contrôle régiosélectif et un couplage de Suzuki comme étapes clés. Ce projet inclut à la fois l’accès rapide au rubrolide S par une voie de synthèse en 4 étapes avec un rendement de 22% qui peut être amélioré à 27% en rajoutant une étape, mais aussi au rubrolide R en 6 étapes par une voie de synthèse similaire avec un rendement de 8,9% qui permet d’obtenir le rubrolide S avec une étape supplémentaire pour un rendement global de 8,5%.
144
145
Les spectres des composés synthétisés du chapitre II au chapitre IV peuvent être trouvés dans les articles publiés par nos groupes de recherche.
Chapitre IIA : ACS Catal. 2013, 3, 2677.
Chapitre IIB : Surf. Sci. 2016, 646, 13.
Chapitre III : Tetrahedron 2012, 68, 9592.
146
Matériel et méthodes générales
KPL (pureté 97%), (R)-MNEA (pureté 97%), (R)-NEA (pureté 99%) et autres produits commerciaux ont été acheté de Sigma-Aldrich et Silicyle.
Tous les substrats du STM ont été ensuite purifiés par pompage et cycle de gèle- dégèle dans la tubulure à vide précédant le dosage sur la surface à température pièce. Le cristal de Pt(111), acheté de MaTeck Gmbh, a été nettoyé par bombardement par Ar+ (1.0 X 10-5 Torr) à 600 K et par traitement à oxygène (2 X 10-7 Torr) à 900 K suivi d’un recuit à 1000 K dans une chambre sous ultra haut vide (UHV).
Les images STM ont été acquises utilisant un microscope SPECS Aarhus STM-150 avec l’échantillon à température pièce. Toutes les images ont été mesurées à une tension de polarisation dans une gamme de 1.0-1.25 V et un courant tunnel dans une gamme de 0.29- 0.32 nA. Le logiciel de traitement d’images WSxM a été utilisé pour ajuster la brillance et le contraste.
147
General methods
Unless otherwise indicated, all moisture-sensitive reactions were carried out under an argon atmosphere in glassware that had been flame-dried with stirrer under a stream of the same inert gas. New syringes and stainless steel needles or dry cannulæ were used to transfer moisture-sensitive liquids. Solvents were distilled or dried before use. CH2Cl2 was distilled from calcium hydride, THF from sodium/acetophenone and Et2O was dried on molecular sieves. Commercial reagents were used as received except for trifluoroacetic anhydride that was freshly distilled before use. Thin layer chromatography (TLC) was carried out using Silicyle 0.2 mm silica gel 60 F254 aluminum-backed plates. These plates were visualized by UV light and either cerium ammonium molybdate (CAM) or a potassium permanganate solution was used as developing agent. Flash column chromatography was performed using Silicycle silica gel P60 (230–400 mesh) and on a Teledyne Isco CombiFlash Rf 200 UV-Vis system. Optical rotation was measured with the digital polarimeter Jasco Dip-360, with a sodium lamp (589 nm) as light source. Enantiomer ratios were measured using an Agilent technologies HPLC instrument equipped with the specified chiral column. NMR spectra were recorded at room temperature on either an Agilent DDR spectrometer operating at 500 MHz for 1H and 125 MHz for 13C nuclei, or a Varian Inova spectrometer operating at 400 MHz for 1H and 100 MHz for 13C nuclei; 1H and 13C spectra are reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (1H NMR δ H 7.260, 13C NMR δ C 77.16 both in CDCl3). Melting points were recorded on a Barnstead Thermolyne Mel Temp Electrothermal apparatus, electrospray ionization (ESI) high- resolution mass spectra were recorded on an Agilent 6210 TOF LC/MS instrument. Infra-red spectra were recorded on a Bomem Arid Zone MB-series FTIR instrument, with samples prepared on single NaCl plates, as either a pure film if in liquid form, or a neat layer if solid.
148
Chapitre II partie A
Synthesis of PNEA 1 and epi-PNEA 2
According to the literature procedure, (R)-NEA (1.29 mL, 8 mmol) and KPL (1.28 g, 10 mmol) were dissolved in titanium (IV) isopropoxide (4 mL), and the viscous mixture was stirred at rt under argon. After 20 min, this became a more homogeneous yellow solution. After 4 h, NaBH3CN (340 mg, 5.4 mmol) and EtOH (12 mL) were added. The reaction was stirred overnight. Then again, NaBH3CN (340 mg, 5.4 mmol) and 3−4 few drops of acetic acid were added. The following day, the reaction was quenched with water, and the resulting precipitate was filtered over Celite and washed with ethanol. The filtrate was concentrated in vacuum, dissolved in ethyl acetate, and filtered over Celite again. The filtrate was concentrated, and the crude mixture was purified by flash chromatography (7% ethyl acetate/hexanes) over silica using a Teledyne Combiflash Rf system. The two diastereomers PNEA 1 and epi-PNEA 2 eluted in that order and were isolated in 24% and 9% yield, respectively. PNEA 1 was a viscous colorless oil that eventually solidified after significant drying, and epi-PNEA 2 formed as an off-white solid that was recrystallized in ether/pentane to provide white rhombic crystals for X-ray diffraction studies.
149 PNEA Rf = 0.38 (7% EtOAc/hexanes); mp: 48-50 °C; [α]D20 = -35.5° (c 1.25, CHCl3). IR (NaCl, film): 3336, 3049, 2964, 2895, 1770, 1463, 1141, 1010, 780 cm−1. 1H NMR (400 MHz, CDCl3): δ 1.04 (s, 3H), 1.11 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H), 1.57 (s, 2H), 2.16 (br s, 1H), 3.23 (br s, 1H), 3.71 (d, J = 8.8 Hz, 1H), 3.89 (d, J = 8.8 Hz, 1H), 4.88 (q, J = 7.9 Hz, 1H), 7.47−7.56 (m, 3H), 7.64 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.9, 140.0, 134.0, 131.4, 129.0, 127.5, 126.1, 125.7, 125.5, 122.6, 122.4, 76.4, 63.3, 51.8, 41.0, 23.9, 23.8, 20.1. ESI HRMS: m/z for C18H21NO2: [M+H] + calcd, 284.1645; found, 284.1644.
150 epi-PNEA Rf = 0.35 (7% EtOAc/hexanes); mp: 56−57.5 °C; [α] D20 = +171.1° (c 1.26, CHCl3). IR (NaCl, film): 3336, 3049, 2964, 2896, 1770, 1463, 1141, 1011, 780 cm−1. 1H NMR (400 MHz, CDCl3): δ 1.04 (s, 3H), 1.11 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H), 1.57 (s, 2H), 2.16 (br s, 1H), 3.23 (br s, 1H), 3.71 (d, J = 8.8 Hz, 1H), 3.89 (d, J = 8.8 Hz, 1H), 4.88 (q, J = 7.9 Hz, 1H), 7.47−7.56 (m, 3H), 7.64 (d, J = 6.1 Hz, 1H), 7.77 (d, J = 6.1 Hz, 1H), 7.88 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 6.1 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 179.4, 140.6, 134.2, 131.8, 129.1, 127.8, 126.1, 125.7, 125.7, 124.3, 123.5, 76.9, 64.4, 52.7, 40.6, 24.8, 23.1, 20.0. ESI HRMS: m/z for C18H21NO2: [M+H] + calcd, 284.1645; found, 284.1639.
151
(S)- (+)-amino-4, 4-diméthyldihydrofuran-2-one
AF
PNEA (123 mg) was dissolved in 5 mL of methanol in a high-pressure reaction flask, 32 mg of palladium on carbon (10%) was added, and the mixture was stirred under 10 bar hydrogen pressure for 14 h. The mixture was then filtered over Celite, washed with dichloromethane, and evaporated down to a yellow residue. This was purified by flash column chromatography over silica gel (CH2Cl2/MeOH/NH4OH, 40: 1: 0.1) to furnish (S)- (AF) as a white solid (50.8 mg, 91% yield). Rf = 0.34 (10% MeOH/CH2Cl2); mp: 61 °C; [α]D20 = +4.96° (c 0.88, CHCl3), +16.8° (c 0.91, MeOH). IR (NaCl, film): 3388 (br), 3329 (br), 2963, 2897, 1779, 1465, 1118, 1008 cm−1. 1H NMR (400 MHz, CDCl3): δ 3.95 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 8.8 Hz, 1H), 3.28 (s, 1H), 1.48 (br s, 2H), 1.14 (s, 3H), 0.96 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 178.6, 76.7, 60.2, 40.3, 23.0, 18.9. ESI-HRMS: m/z for C6H11NO2 [M+H]+ calcd, 130.0863; found, 284.1644.
152
(S)-(+)-N-Boc-amino-4, 4-diméthyldihydrofuran-2-one
Boc-AF
(S)-AF (25.0 mg) was dissolved in 1.5 mL of anhydrous THF, along with 18.2 mg of di-tert-butyl carbonate (1.2 equiv) and 40 μL of triethylamine. After overnight stirring at rt, the reaction mixture was concentrated in vacuo and partioned between ethyl acetate and aqueous saturated sodium bicarbonate. The combined organic layers were washed with 5% aqueous potassium hydrogen sulfate, and brine; dried over sodium sulfate; and concentrated in vacuo to give a white solid. Flash column chromatography on silica gel (20% ethyl acetate/ hexanes) furnished 29.3 mg of (S)-N-Boc-AF as a white powder (66%). mp: 141−142 °C (lit.: 11 138− 140 °C); [α]D20 = +53.7° (c 0.87, CHCl3). Lit.: [α]D = +63° (c 1, CHCl3). IR (NaCl, film): 3310 (br), 3280, 2983, 2925, 2853, 1779, 1701, 1678, 1550, 1367, 1142 cm−1. 1H NMR (400 MHz, CDCl3): δ 0.99 (s, 3H), 1.23 (s, 3H), 1.46 (s, 9H), 3.98−4.03 (m, 2H), 4.36 (d, J = 7.6 Hz, 1H), 4.85 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 175.3, 155.8, 80.5, 76.7, 59.6, 41.1, 28.2, 23.3, 19.8. ESI-HRMS: m/z for C11H19NO4 [M + H]+ calcd, 230.1387; found, 230.1360.
153
Formation of (S)-AF under Hydrogenation Conditions Using PNEA-Modified Pt/Al2O3. The 5 wt % Pt/Al2O3 catalyst (Sigma Aldrich) was pretreated at 400 °C in flowing nitrogen for 1 h, then 1 h with 10% hydrogen in argon and cooled to room temperature under flowing nitrogen for 2 h. The hydrogenation was carried out in a Teflon-lined Berghof BR- 25 reactor. The reaction mixture was magnetically stirred at 250 rpm. PNEA (53.0 mg) was dissolved in 5 mL of acetic acid, 53.1 mg of catalyst was added, and the mixture was stirred under 10 bar hydrogen pressure for 24 h. The mixture was then filtered over Celite, washed with dichloromethane; the solvent was quenched with aqueous saturated NaHCO3; and the organic layer was extracted and dried with sodium sulfate, filtered, and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography over silica gel (CH2Cl2/MeOH/NH4OH, 40: 1: 0.1) to give (S)-amino-4,4-dimethyldihydrofuran- 2-one (7.6 mg, 31% yield). [α]D 20 = +17.7° (c 0.32, MeOH), whose 1H and 13C NMR spectra were identical to those described above.
154
Chapitre II partie B
155
Chapitre III
methyl 4-prenyloxyphenylacetate
A mixture of methyl 4-hydroxyphenylacetate (6.83 g, 41.1 mmol, 1.0 equiv) and potassium carbonate (8.86 g, 64.1 mmol, 1.6 equiv) was stirred in freshly distilled acetone (62 mL) for 5 min, and prenyl bromide (7.96 g, 6.17 mL, 53.8 mmol, 1.3 equiv) was added dropwise over the course of 10 min. The resulting mixture was refluxed for 17 h. Once TLC had indicated complete disappearance of starting material, the solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (3 X 100 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to leave a brown oil, which was purified by flash column chromatography (15% EtOAc/hexanes) to yield the ester 5 as a colorless oil (9.37 g, 97% yield). Rf 0.40 (20% EtOAc/hexanes); IR (NaCl, film) ν 2975, 2952, 2873, 1733, 1612, 1512, 1435, 1239, 1157, 1004, 818 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.19 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 5.50 (t, J = 6.6 Hz, 1H), 4.49 (d, J = 6.6 Hz, 2H), 3.67 (s, 3H), 3.56 (s, 2H), 1.80 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 172.2, 157.9, 137.8, 130.1, 125.8, 119.7, 114.6, 64.6, 51.8, 40.1, 25.7, 18.0; HRMS (ESI): m/z calcd for C14H18O3: 234.1256; found: 234.126
156
4-hydroxy-3-(4-prenyloxyphenyl)-furan-2(5H)-one
To a solution of the ester 5 (4.00 g, 17.1 mmol, 1.0 equiv) and methyl glycolate (1.60 mL, 1.87 g, 20.7 mmol, 1.2 equiv) in 80 mL of anhydrous DMF was slowly added 40 mL of a THF solution of potassium tert-butoxide (1 M, 40.0 mmol, 2.3 equiv). The resulting light yellow suspension was stirred under argon at rt for 50 h. The reaction mixture was then poured in one portion into 200 mL of ice cold aq 1 M HCl. The resulting suspension was subsequently kept in an ice bath for 20 min, filtered, and the filter cake washed with ice cold aq 1 M HCl. The filter cake was then dissolved in ethyl acetate and washed with water then brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting beige crystals of the tetronic acid 6 (4.44 g, 99% yield) were pure enough for utilization in the next step. mp 121-122.5 °C; Rf 0.38 (10% MeOH/CH2Cl2 + 0.2% AcOH); IR (NaCl, film): ν 2925, 2871, 2696, 1695, 1652, 1608, 1425, 1394, 1293, 1253, 1172, 1052, 1003, 834, 738 cm-1; 1H NMR (400 MHz, acetone-d6): δ 7.90 (d, J = 9.2 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.44 (t, J = 7.2 Hz, 1H) 4.73 (s, 2H), 4.54 (d, J = 6.8 Hz, 2H), 1.74 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz, acetone-d6): δ 172.8, 171.4, 158.0, 137.0, 128.4, 123.0, 120.5, 114.3, 99.5, 65.9, 64.6, 25.1, 17.5; HRMS (ESI): m/z calcd for C15H16O4: 260.1049; found: 260.1059.
157
3-(4-prenyloxyphenyl)-4-trifluoromethanesulfonyl-furan-2(5H)-one
Tetronic acid 6 (30.7 mg, 0.118 mmol, 1.0 equiv) was dissolved in 2 mL of anhydrous dichloromethane and cooled to -40 °C, at which point 41.1 mL of DIPEA (30.5 mg, 0.236 mmol, 2.0 equiv) was added, followed by a slow dropwise addition of 25.9 mL of trifluoromethanesulfonic anhydride (43.4 mg, 0.154 mmol, 1.3 equiv). After 40 min at this same temperature, TLC indicated complete disappearance of starting material, at which point 5 mL of water was added and the temperature allowed to rise to rt. Once the water had melted the organic layer was separated and the aqueous layer extracted with dichloromethane (3 X 10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a brown oil. Purification by flash column chromatography (10% EtOAc/hexanes) yielded the triflate 7 as a bright orange oil, which solidified when stored in the freezer (43.8 mg, 94% yield). mp 44 °C; Rf 0.35 (5% EtOAc/hexanes); IR (NaCl, film): ν 3356, 2975, 2918, 1780, 1609, 1513, 1436, 1248, 1224, 1142, 1002, 951, 836, 810, 764 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 5.49 (t, J = 6.8 Hz, 1H), 5.06 (s, 2H), 4.56 (d, J = 6.8 Hz, 2H), 1.81 (s, 3H),1.76 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 168.9, 160.5, 157.6, 139.0, 130.0, 119.3, 118.5 (q, JC-F = 319.7 Hz), 117.9, 117.2, 115.3, 66.1, 65.1, 26.1, 18.5; HRMS (ESI): m/z calcd for C16H15O6SF3: 392.0541; found: 392.0546.
158
4-isobutyl-3-(4-prenyloxyphenyl)-furan-2(5H)-one
A solution of isobutylmagnesium bromide 7 (2 M in THF, 300 mL, 0.154 mmol, 1.2 equiv) was rapidly added to a solution of triflate (50 mg, 0.128 mmol, 1.0 equiv) and Fe(acac)3 (2.1 mg, 0.0064 mmol, 0.05 equiv) in THF (2 mL) and 1-methyl-2- pyrrolidinone (NMP, 0.1 mL) at -30 °C. There was an immediate color change from orange-red to brown/black. The mixture was left stirring for 15 min at that temperature before it was quenched with aq saturated ammonium chloride (1 mL). The mixture was partitioned between water (15 mL) and diethyl ether (15 mL) and was repeatedly extracted with diethyl ether (3 X 15 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a brown residue. Purification by flash column chromatography on silica gel (25% EtOAc/hexanes) gave the butenolide 8 as a yellow oil (25.5 mg, 67% yield). Rf 0.30 (15% EtOAc/hexanes); IR (NaCl, film): ν 2958, 2927, 2870, 1752, 1608, 1511, 1465, 1385, 1290, 1242, 1178, 1127, 1037, 986, 955, 834, 780, 628 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.8 Hz, 2H), 6.97 (d, J =9.0 Hz, 2H), 5.51 (t, J = 6.8 Hz, 1H), 4.80 (s, 2H), 4.54 (d, J = 6.8 Hz, 2H), 2.49 (d, J = 7.6 Hz, 2H), 1.91-1.84 (m, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 0.93 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 174.2, 160.3, 159.2, 138.7,130.5,127.4,122.5,119.7,114.9, 71.6, 65.0, 36.9, 27.8, 26.1, 22.9, 18.5. HRMS (ESI): m/z calcd for C19H24O3: 300.1725; found: 300.1727.
159
Method B: In a screw-cap sealed tube, a suspension of isobutylboronic acid (78.0 mg, 0.765 mmol, 1.5 equiv), the triflate (200 mg, 0.510 mmol, 1.0 equiv), Pd(dppf)Cl2 (41.7 mg, 0.051 mmol, 0.1 equiv), powdered potassium carbonate (211.5 mg, 1.530 mmol, 3.0 equiv), and Ag2O (295.5 mg, 1.275 mmol, 2.5 equiv) in THF (8 mL) was degassed with a flow of bubbling argon, sealed, and then stirred under argon at 80 °C. After 16 h, the mixture was cooled to rt, then concentrated in vacuum and purified by flash column chromatography (10% EtOAc/hexanes) to afford the butenolide as a yellow oil (84.8 mg, 55% yield), whose 1H and 13C NMR data were identical to those just described (method A).
160
4-isobutyl-3-(4-prenyloxyphenyl)-2- triisopropylsilyloxyfuran
To a solution of the butenolide 8 (61.9 mg, 0.206 mmol, 1.0 equiv) in anhydrous dichloromethane (4 mL) that had been cooled to 0 °C, were added sequentially triethylamine (37.3 mL, 27.1 mg, 0.268 mmol, 1.3 equiv) and triisopropylsilyl trifluoromethanesulfonate (66.5 mL, 75.7 mg, 0.247 mmol, 1.2 equiv). After 1 h, the mixture was poured into aq 10% sodium bicarbonate (10 mL). The aqueous layer was extracted twice using dichloromethane (2 X 15 mL) and the combined organic layers were dried with magnesium sulfate. The mixture was concentrated in vacuo and purified by flash column chromatography on neutralized silica gel (100% hexanes), furnishing the siloxyfuran 9 as a colorless oil (80.5 mg, 86% yield). Rf 0.65 (100% hexanes); IR (NaCl, film): ν 2946, 2868, 1651, 1609, 1575, 1516, 1464, 1404, 1289, 1238, 1174, 1035, 991, 883, 831, 688 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 9.0 Hz,2H), 6.90(d, J = 8.8 Hz, 2H), 6.65 (s,1H), 5.52 (t, J = 6.8 Hz,1H), 4.52 (d, J = 7.0 Hz, 2H), 2.31 (d, J = 6.8 Hz, 2H), 1.81 (s, 3H), 1.76 (s, 3H), 1.69- 1.62 (m, 1H), 1.23-1.14 (m, 3H), 1.02 (d, J = 8.0 Hz, 18H), 0.84 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 157.0, 153.1, 138.2, 129.9, 128.3, 126.1, 125.0, 120.1, 114.5, 99.1, 64.9, 34.6, 27.8, 26.1, 22.8, 18.4, 17.8, 12.5; HRMS (ESI): m/z calcd for C28H44O3Si: 456.3060; found: 456.3063.
161
antrocinnamomin D
The furan 9 (80.5 mg, 0.176 mmol, 1.0 equiv) was dissolved in anhydrous dichloromethane (1 mL) and cooled to -78 °C, whereupon dimethyldioxirane in acetone (6.5 mL, ca. 0.05-0.07 M) was added dropwise. After 30 min, the mixture was allowed to warm to ca. -20 °C, at which point TLC (on silica plates pre-neutralized with 10% triethylamine in hexanes, elution with hexanes) showed that all starting material was consumed. The volatiles were removed under reduced pressure at ca. -20 °C and the residue was dissolved in acetone (3 mL), to which 10 drops of water were added along with 15 mg of Amberlyst 15. After stirring for 30 min at rt, the solution was concentrated under reduced pressure and diethyl ether (25 mL) was added. After drying with MgSO4, filtration and removal of the volatiles under reduced pressure, purification by flash chromatography (30% EtOAc/hexanes) gave antrocinnamomin D as a white solid (54.4 mg, 98% yield). mp 66-68 °C; Rf 0.25 (30% EtOAc/hexanes); IR (NaCl, film): ν 3393, 2958, 2870, 1761, 1733, 1608, 1512, 1464, 1291, 1243, 1178, 1115, 994, 835 cm-1; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 6.08 (s, 1H), 5.50 (t, J = 6.4 Hz, 1H), 4.54 (d, J = 6.8 Hz, 2H), 4.33 (br s, 1H), 2.49 (d, J = 7.6 Hz, 2H), 2.03-1.96 (m, 1H), 1.81 (s, 3H), 1.76 (s, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.9, 159.5, 159.1, 138.8, 130.6, 129.7, 121.7, 119.6, 114.9, 97.3, 65.0, 35.6, 27.3, 26.1, 23.6, 22.5, 18.5. HRMS (ESI): m/z calcd for C19H24O4: 316.1675; found: 316.1694.
162 antrodin A
Antrocinnamomin D (37.3 mg, 0.118 mmol, 1.0 equiv) was stirred in a glass screw- cap vial in dichloromethane (1.5 mL) at rt. Dess-Martin periodinane (0.3 M in THF, 0.472 mL, 0.142 mmol, 1.2 equiv) was added and the reaction was monitored by TLC. After 1 h, the mixture was partitioned between a saturated solution of sodium sulfite (15 mL) and dichloromethane (20 mL). The organic layer was then washed successively with aq saturated sodium bicarbonate (15 mL), then brine (15 mL) and was dried with magnesium sulfate. The mixture was concentrated in vacuo and the residue subjected to flash column chromatography (8% EtOAc/hexanes) to give antrodin A as a fluorescent yellow oil (33.2 mg, 90% yield). Rf 0.50 (20% EtOAc/hexanes); IR (NaCl, film): ν 2959, 2917, 2872, 1838, 1764, 1605, 1506, 1422, 1350, 1233, 1170, 994, 926, 901, 838, 824, 752, 616 cm-1; 1H NMR(400 MHz, CDCl3): δ 7.62 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 9.2 Hz, 2H), 5.50 (t, J = 6.8 Hz, 1H), 4.56 (d, J = 7.0 Hz, 2H), 2.60 (d, J = 7.2 Hz, 2H), 2.18-2.08 (m, 1H), 1.82 (s, 3H), 1.77 (s, 3H), 0.95 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 166.6, 165.7, 161.2, 140.4, 140.0, 139.3, 131.3, 120.1, 119.1, 115.4, 65.2, 33.8, 28.2, 26.1, 22.9,18.5; HRMS (ESI): m/z calcd for C19H22O4: 314.1518; found: 314.1527.
163 antrodin B
A solution of antrodin A (23.6 mg, 0.075 mmol, 1.0 equiv) in DMF (0.6 mL) was treated with methanol (16 mL, 12.7 mg, 0.395 mmol, 5.3 equiv) and hexamethyldisilazane (158 mL, 122.3 mg, 0.758 mmol, 10.1 equiv). After 16 h at rt, the mixture was poured into water (50 mL) and extracted with ethyl acetate (2 X 30 mL). The combined extracts were washed with water (25 mL) and dried with magnesium sulfate. After filtration and concentration in vacuo, the residue was purified by flash column chromatography (15% EtOAc/hexanes), to furnish antrodin B as bright yellow crystals (21.9 mg, 93% yield) that fluoresced under a UV lamp. mp 104-105 °C (lit. 110-111 °C, lit. 104.5-105 °C). Rf 0.21 (15% EtOAc/hexanes); IR (NaCl, film): ν 3287 (br), 2959, 2926, 1770, 1709, 1605, 1511, 1349, 1247, 1176, 988, 837 cm-1; 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 8.7 Hz, 2H), 7.37 (br s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 5.51 (t, J = 6.6 Hz, 1H), 4.56 (d, J = 6.6 Hz, 2H), 2.53 (d, J = 7.3 Hz, 2H), 2.02-2.10 (m, 1H), 1.82 (s, 3H), 1.77 (s, 3H), 0.91 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 171.9,171.2,160.2,139.3, 138.9, 138.8, 131.1,121.3, 119.3,115.0, 65.0, 33.0, 29.9, 28.2, 26.0, 22.9, 18.4; HRMS (ESI): m/z calcd for C19H23NO3: 313.1678; found: 313.1689.
164
Chapitre IV
4-ethyl-3,5-dimethoxybenzaldehyde
Freshly cut sodium metal in small particles (0.58 g, 25.4 mmol, 3.1 equiv) was put in dry THF (50 mL). The mixture was cooled to 0 °C and a solution of commercially available 3, 4, 5-trimethoxybenzaldehyde dimethyl acetal (2.00 g, 8.25 mmol, 1.0 equiv) in dry THF (20 mL) was added dropwise. The reaction mixture was stirred at room temperature for 24 h, then cooled again to 0 °C, and a solution of EtI (1.37 mL, 17.0 mmol, 2.1 equiv) in dry THF (5 mL) was added dropwise. After stirring for 48 h at room temperature, the reaction mixture was dissolved in THF/1 N HCl (1: 1, 50 mL) and stirred at the same temperature for 5 min. The mixture was extracted with Et2O (3 X 20 mL). The combined organic phases were washed with H2O (2 X 20 mL), aq. 10% sodium thiosulfate (2 X 20 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography to afford the aldehyde 13 as a white solid (1.10 g, 69%): mp 68–72 °C, (lit. 68 °C); Rf 0.35 (hexanes/EtOAc; 9: 1); IR (NaCl film) ν 2942, 1688, 1585, 1461, 1142 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.06 (s, 2H), 3.89 (s, 6H), 2.71 (q, J = 7.4 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.1, 158.5, 135.3, 128.7, 105.0, 56.0, 17.0, 13.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C11H15O3 196.1016, found 196.1014.
165
(R)-methyl 4-(4-ethyl-3, 5-dimethoxyphenyl)-4-hydroxybut-2-ynoate
To a mixture of (S)-BINOL (246.8 mg, 0.86 mmol, 0.7 equiv), 1-methylimidazole (20 μL, 0.25 mmol, 0.2 equiv) and methyl propiolate (0.43 mL, 4.8 mmol, 4.0 equiv) in dry Et2O (12 mL) was slowly added ZnEt2 (1 M in hexanes, 5 mL, 5.0 mmol, 4.0 equiv). After the solution was stirred at room temperature for 16 h, Ti(i-PrO)4 (0.37 mL, 1.25 mmol, 1.0 equiv) was added and the stirring was continued for 1 h. Then, the aldehyde 13 (233.3 mg, 1.20 mmol, 1.0 equiv) was added and stirring continued at room temperature for 24 h. Saturated aq NH4Cl (1 X 10 mL) was added, and the mixture was extracted with CH2Cl2 (3 X 10 mL). The combined organic phases were washed with H2O (2 X 10 mL), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography to give the propargyl alcohol 14 as a yellow solid (193.3 mg, 58%): mp 107–111 °C; Rf 0.13 (hexanes/EtOAc; 9: 1); [α]20 D +4.9 (c 0.98, CHCl3); 94% ee [HPLC CHIRALCEL OJ-H; n-hexane–i-PrOH 9: 1; 1 mL min−1; tR = 13.11 (minor), 20.09 (major) min]; IR (NaCl film) ν 3410, 2963, 2238, 1717, 1605, 1256, 1137 cm−1; 1H NMR (500 MHz, CDCl3) δ 6.68 (s, 2H), 5.51 (d, J = 5.6 Hz, 1H), 3.83 (s, 6H), 3.79 (s, 3H), 2.64 (q, J = 7.4 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.4, 153.9, 137.1, 121.7, 102.2, 86.8, 77.5, 64.8, 55.9, 53.0, 16.4, 13.7; HRMS (ESI-TOF) m/z [(M + H) + (–H2O)]+ calcd for C15H17O4 263.1179, found 263.1191.
166
(R)-methyl 4-((tert-butyldiphenylsilyl) oxy)-4-(4-ethyl-3, 5-dimethoxyphenyl) but-2-ynoate
To the propargyl alcohol 14 (496.2 mg, 1.78 mmol, 1.0 equiv) in CH2Cl2 (10 mL), imidazole (267.3 mg, 3.92 mmol, 2.2 equiv) was added, followed by tert-butyldiphenylsilyl chloride (538.7 mg, 1.96 mmol, 1.1 equiv), at room temperature and the mixture was stirred 16 h. The volatiles were evaporated under reduced pressure and the residue was purified by flash chromatography to give the alkyne 15 as a colorless oil (873.2 mg, 95%): Rf 0.42 (hexanes/EtOAc; 9: 1); [α]20 D +24.9 (c 0.96, CHCl3); IR (NaCl film) ν 2959, 2237, 1719, 1590, 1139 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.80-7.32 (m, 10H), 6.53 (s, 2H), 5.41 (s, 1H), 3.75 (s, 9H), 2.64 (q, J = 7.4 Hz, 2H), 1.12 (s, 9H), 1.09 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 158.1, 154.0, 138.0, 136.1, 136.0, 135.3, 134.9, 132.7, 130.1, 130.0, 129.8, 127.8, 127.7, 120.9, 102.1, 87.8, 77.0, 65.9, 55.8, 52.8, 26.9, 26.7, 19.5, 19.2, 16.4, 13.9; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C31H37O5Si 516.2436, found 516.2462.
167
(S)-methyl 4-((tert-butyldiphenylsilyl) oxy)-4-(4-ethyl- 3, 5-dimethoxyphenyl) butanoate
The alkyne 15 (363.3 mg, 0.7 mmol, 1.0 equiv) was dissolved in EtOAc (3 mL) and 10% Pd/C (99.3 mg) was added and the mixture was put in Berghof high pressure reactor BR-25 hydrogenation system at 50 psi of H2 and stirred 17 h at room temperature. The mixture was filtered over Celite, washed with EtOAc and the solvent was evaporated. The residue was purified by flash chromatography to afford the ester 16 as a colorless oil (359.9 mg, 98%): Rf 0.45 (hexanes/EtOAc; 9: 1); [α]20 D -23.6 (c 0.86, CHCl3); IR (NaCl film) ν 2958, 1738, 1588, 1361, 1231, 1112 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.67-7.22 (m, 10H), 6.35 (s, 2H), 4.73 (t, J = 5.7 Hz, 1H), 3.70 (s, 6H), 3.58 (s, 3H), 2.61 (q, J = 7.7 Hz, 2H), 2.27 (m, 2H), 2.05 (m, 2H), 1.08 (s, 9H), 1.07 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.1, 157.7, 142.4, 136.0, 135.9, 134.0, 133.7, 129.7, 129.6, 127.6, 127.4, 119.4, 102.0, 75.2, 55.7, 51.6, 34.9, 29.7, 27.1, 19.6, 16.4, 14.0; HRMS (ESI-TOF) m/z [M]+ calcd for C31H40O5Si 520.2640, found 520.2611.
168
(S)-4-((tert-butyldiphenylsilyl) oxy)-4-(4-ethyl- 3, 5-dimethoxyphenyl) butanoic acid
The ester 16 (120.6 mg, 0.23 mmol, 1.0 equiv) was dissolved in methanol (5 mL) and lithium hydroxide (1 M aq solution, 2.5 mL, 2.5 mmol, 10.9 equiv) was added dropwise. The reaction mixture was heated at 65 °C for 1 h. The mixture was cooled to room temperature, the pH was adjusted to 3 using a dilute citric acid solution and the cloudy aqueous mixture was extracted with Et2O (2 X 20 mL). The ethereal layers were combined, dried (Na2SO4), filtered, evaporated and the residue subjected to flash column chromatography on silica gel to give the acid 17 as a colorless oil (111.8 mg, 95%): Rf 0.26 (hexanes/EtOAc; 9: 1); [α]20 D -19.8 (c 0.75, CHCl3); IR (NaCl film) ν 3403, 2960, 1708, 1588, 1453, 1426, 1231, 1139 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.65-7.20 (m, 10H), 6.33 (s, 2H), 4.72 (t, J = 5.6 Hz, 1H), 3.69 (s, 6H), 2.59 (q, J = 7.7 Hz, 2H), 2.27 (m, 2H), 2.02 (m, 2H), 1.07 (s, 9H), 1.05 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.5, 157.8, 142.2, 136.0, 135.9, 134.0, 133.7, 129.8, 129.6, 127.7, 127.4, 119.5, 102.0, 75.0, 55.7, 34.6, 29.5, 27.1, 19.5, 16.4, 14.0; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C30H38NaO5Si 529.2381, found 529.2411.
169
(S)-4-((tert-butyldiphenylsilyl) oxy)-7-ethyl-6, 8-dimethoxy-3, 4-dihydronaphthalen-1(2H)- one
The acid 17 (27.9 mg, 0.055 mmol, 1.0 equiv) was dissolved in CH2Cl2 (1 mL) and cooled to 0 °C. Freshly-distilled trifluoroacetic anhydride (10 μL, 0.071 mmol, 1.3 equiv) was added dropwise and the reaction was stirred at 0 °C for 2 h. The volatiles were evaporated and the residue was purified by flash chromatography on silica gel to give the tetralone 18 as a colorless oil (22.3 mg, 83%): Rf 0.32 (hexanes/EtOAc; 9: 1); [α]20D -23.2 (c 0.97, CHCl3); IR (NaCl film) ν 2961, 1678, 1589, 1462, 1254, 1141 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.74–7.32 (m, 10H), 6.58 (s, 1H), 4.87 (dd, J = 7.6, 3.4 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 2.86 (m, 1H), 2.63 (q, J = 7.4 Hz, 2H), 2.38 (m, 1H), 2.12 (m, 1H), 2.04 (m, 1H), 1.11 (s, 9H), 1.08 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 162.1, 159.9, 147.2, 136.0, 135.9, 133.8, 133.5, 130.1, 129.9, 127.9, 127.8, 126.9, 118.3, 105.1, 70.6, 62.2, 55.6, 36.4, 31.9, 27.1, 19.6, 16.7, 14.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H37O4Si 489.2456, found 489.2441.
170
(S)-4-((tert-butyldiphenylsilyl) oxy)-7-ethyl-8-hydroxy-6-methoxy- 3, 4- dihydronaphthalen-1(2H)-one
To a solution of tetralone 18 (48.7 mg, 0.10 mmol, 1.0 equiv) in CH2Cl2 (1 mL) at room temperature was added BCl3 (1 M in CH2Cl2, 160 μL, 0.16 mmol, 1.6 equiv). After stirring for 20 min, TLC showed complete consumption of the substrate. The reaction was quenched with NaHCO3 (1 mL), poured into water (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give the phenol 19 as a colorless oil (42.3 mg, 89%): Rf 0.51 (hexanes/EtOAc; 9: 1); [α]20 D -11.3 (c 0.48, CHCl3); IR (NaCl film) ν 3456, 2960, 1725, 1625, 1427, 1362, 1280, 1111 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.87 (s, 1H) 7.78-7.35 (m, 10H), 6.34 (s, 1H), 4.91 (dd, J = 7.25, 3.2 Hz, 1H), 3.63 (s, 3H), 2.96 (m, 1H), 2.64 (q, J = 7.4 Hz, 2H), 2.47 (m, 1H), 2.17 (m, 1H), 2.09 (m, 1H), 1.12 (s, 9H), 1.10 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.6, 163.3, 162.0, 145.4, 136.0, 135.9, 133.7, 136.0, 135.9, 133.8, 133.4, 130.1, 130.0, 127.9, 127.7, 118.7, 110.1, 101.6, 69.9, 55.6, 34.6, 32.0, 27.1, 19.6, 15.7, 13.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H35O4Si 475.2299, found 475.2310.
171
(+)-O-methylasparvenone
To a solution of the phenol 19 (10.2 mg, 0.0215 mmol, 1.0 equiv) in THF (0.7 mL),