Total Synthesis of Lycoposerramine-R

Abstract

A total synthesis of lycoposerramine-R was accomplished. The synthesis featured a Claisen–Ireland rearrangement to install a two-carbon unit, and a hetero-Diels–Alder reaction to form a cyclic enol ether that reacted with an ethynyl group to construct a cis-hydrindane core containing a quaternary carbon. A 2-pyridone synthesis using 2-(phenylsulfinyl)acetamide was used to complete the synthesis.

Key words

alkaloids - Diels–Alder reaction - total synthesis - gold catalysis - alkaloids - rearrangement

• References and Notes

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• 13 (3aS,6R,7aS)-3a-(3,3-Dimethoxypropyl)-2-hydroxy-6-methyl-3-methylenehexahydro-4H-inden-4-one (22) To a solution of the propargylic alcohol 21 (173 mg, 0.591 mmol) in MeOH (6.0 mL) was added the supernatant of a 0.059 M suspension of (Ph₃P)AuCl and AgSbF₆ in MeOH (1.0 mL, 0.059 mmol) at 0 °C, and the mixture was stirred for 11 h. The reaction was then quenched with sat. aq NaHCO₃, and the mixture was extracted with EtOAc (3 × 9 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified by flash column chromatography [silica gel, hexane–EtOAc (1:1)] to give a pale-yellow oil; yield: 113 mg (0.400 mmol, 67%); [α]_D ²¹ +39.4 (c 0.97, CHCl₃). This material was obtained as a 3:2 mixture of two diastereomers, containing small amounts of impurities. IR (film): 3445, 2955, 2359, 2249, 1698, 1456, 1383, 1191, 1128, 1053, 910 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.47 [d, J = 1.4 Hz, (³/₅)1 H], 5.45 [d, J = 2.3 Hz, (²/₅)1 H], 5.13 (m, 1 H), 4.56 [m, (³/₅)1 H], 4.40 [m, (²/₅)1 H], 4.33 (m, 1 H), 3.32 [s, (³/₅)3 H], 3.31 [s, (²/₅)3 H], 3.30 [s, (³/₅)3 H], 3.30 [s, (²/₅)3 H], 2.69 [m, (³/₅)1 H], 2.50–2.02 [m, 3 H + (²/₃)1 H], 1.93–1.46 [m, 8 H + (³/₅)1 H], 1.41 [m, (²/₅)1 H], 1.00 [d, J = 6.4 Hz, (²/₅)3 H], 0.98 [d, J = 6.4 Hz, (³/₅)3 H]. ¹³C NMR (100 MHz, CDCl₃): δ = 211.8, 211.4 (C), 155.2, 154.4 (C), 113.8, 112.2 (CH₂), 104.5, 104.5 (CH), 73.7, 73.4 (CH), 61.0, 60.4 (C), 53.0, 52.8 (CH₃), 46.8, 46.6 (CH₂), 40.2, 40.1 (CH), 38.7, 38.1 (CH₂), 33.6, 33.2 (CH₂), 30.5, 30.4 (CH₂), 28.7, 28.7 (CH), 28.1, 27.9 (CH₂), 21.8, 21.1 (CH₃). HRMS (ESI+): m/z calcd for C₁₆H₂₆NaO₄: 305.1729l; found: 305.1731.
• 14 Dess DB. Martin JC. J. Org. Chem. 1983; 48: 4155
• 15 (4aS,6R,7aS,12bS)-4-Benzyl-6-methyl-1,2,3,4,4a,5,6,7,7a,8-decahydropyrido[2′,3′:4,5]cyclopenta[1,2-e]quinolin-10(9H)-one (26) DBU (0.13 mL, 0.88 mmol) was added to a solution of enone 25 (27.4 mg, 0.088 mmol), LiCl (37.5 mg, 0.885 mmol), and 2-(phenylsulfinyl)acetamide (5, 64.5 mg, 0.354 mmol) in MeCN (1.0 mL) at r.t. The mixture was warmed up to 60 °C, stirred for 3 h, and then cooled to r.t. A 5–10% solution of HCl in MeOH (2.0 mL) was added, and the mixture was warmed to 80 °C and stirred for 42 h. The reaction was quenched with sat. aq NaHCO₃, and the mixture was extracted with EtOAc (3 × 3 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure, and the crude product was purified by preparative TLC (CH₂Cl₂–MeOH, 19:1) to give a white solid; yield: 11.8 mg (0.034 mmol, 39%); [α]_D ²¹ –23.7 (c 0.59, CHCl₃). IR (film): 2926, 2859, 2790, 1652, 1604, 1551, 1467, 1093, 832 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.38 (d, J = 9.2 Hz, 1 H), 7.38–7.23 (m, 5 H), 6.38 (d, J = 9.2 Hz, 1 H), 4.18 (d, J = 13.0 Hz, 1 H), 3.32 (dd, J = 17.4, 7.3 Hz, 1 H), 2.91 (m, 1 H), 2.81 (d, J = 13.0 Hz, 1 H), 2.52 (dd, J = 11.6, 5.2 Hz, 1 H), 2.42 (d, J = 17.4 Hz, 1 H), 2.29 (m, 1 H), 1.88 (ddd, J = 12.0, 12.0, 3.2 Hz, 1 H), 1.71–1.32 (m, 8 H), 1.23 (m, 1 H). 0.92 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.1 (C), 150.1 (C), 143.1 (CH), 140.3 (C), 128.9 (CH), 128.3 (CH), 126.7 (CH), 125.1 (C), 114.9 (CH), 62.6 (CH), 58.0 (CH₂), 54.1 (CH₂), 49.2 (C), 43.3 (CH), 39.1 (CH₂), 36.8 (CH₂), 36.0 (CH₂), 33.1 (CH₂), 24.6 (CH), 22.1 (CH₃), 21.8 (CH₂). HRMS (ESI+): m/z calcd for C₂₃H₂₈N₂NaO: 371.2099; found: 371.2099.
• 16 Lycoposerramine-R (1) 20% Pd(OH)₂/C (47.5 mg, 0.033 mmol) was added to a solution of 26 (11.8 mg, 0.033 mmol) in i-PrOH (1.0 mL) at r.t., and the mixture was stirred for 4.5 h at r.t. under 1.0 atm H₂. The mixture was then filtered through a pad of NH₂-silica gel. The solvent was removed under reduced pressure and the crude product was purified by preparative TLC (CH₂Cl₂–MeOH, 19:1) to give a white solid; yield: 8.6 mg (0.033 mmol, quant); [α]_D ²¹ –28.6 (c 0.43, CHCl₃). IR (film): 2925, 2851, 2801, 1650, 1600, 1550, 1466, 1437, 1093, 832, 753 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.32 (d, J = 9.2 Hz, 1 H), 6.34 (d, J = 9.2 Hz, 1 H), 3.21 (dd, J = 16.8, 6.4 Hz, 1 H), 3.17 (m, 1 H), 2.90 (dd, J = 12.0, 4.8 Hz, 1 H), 2.79 (ddd, J = 11.6, 11.6, 3.2 Hz, 1 H), 2.33 (d, J = 16.8 Hz, 1 H), 2.19 (ddd, J = 6.9, 6.9, 6.9 Hz, 1 H), 1.78 (m, 1 H), 1.68 (m, 1 H), 1.60 (m, 1 H), 1.52 (m, 1 H), 1.46 (m, 1 H), 1.45 (m, 2 H), 1.43 (m, 1 H), 1.24 (m, 1 H), 1.18 (m, 1 H), 0.97 (d, J = 7.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.1 (C), 150.3 (C), 143.3 (CH), 124.5 (C), 114.7 (CH), 57.1 (CH), 49.3 (C), 48.0 (CH₂), 41.7 (CH), 38.1 (CH₂), 36.1 (CH₂), 36.0 (CH₂), 34.8 (CH₂), 25.6 (CH), 22.9 (CH₂), 20.5 (CH₃). HRMS (ESI+): m/z calcd for C₁₆H₂₂N₂NaO: 281.1629; found: 281.1623.