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Synlett 2018; 29(18): 2377-2380
DOI: 10.1055/s-0037-1611024
letter
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of Lycoposerramine-R

Shinya Watanabe
,
Masatsugu Ishikawa
,
Toshimune Nomura
,
Tohru Fukuyama
,
Satoshi Yokoshima  *
Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan   Email: yokosima@ps.nagoya-u.ac.jp
› Author AffiliationsThis work was financially supported by JSPS KAKENHI (Grant Numbers 16H01141 and 17H01523), by JSPS A3 Foresight Program, and by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18am0101099.
Further Information

Publication History

Received: 31 August 2018

Accepted: 25 September 2018

Publication Date:
16 October 2018 (online)

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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1611024.
  • Supporting Information
 

  • 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.
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  • 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.