Synlett 2021; 32(07): 674-678
DOI: 10.1055/a-1334-6100
letter

Synthetic Studies on Cyclocitrinol: Construction of the ABC Ring System Based on Epoxy–Nitrile Cyclization

Kazuto Sato
a  Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
,
b  Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
› Author Affiliations
This work was supported by the Japan Society for the Promotion of Science (JSPS KAKENHI, Grant Numbers JP15H05842 in Middle Molecular Strategy and JP18H01970). This work was partially supported by the of Hokkaido University (Photo-Excitonix Project).


Abstract

The stereoselective synthesis of a model compound containing the ABC ring system of cyclocitrinol was accomplished. After connecting a C ring allyltitanium segment with an A ring bi­cyclo[4.1.0]heptanone segment, the seven-membered B ring moiety was constructed by an intramolecular cyclization reaction of an epoxy nitrile. The enone moiety was introduced through an oxidative decyanation reaction, and the bicyclo[4.4.1]undecane skeleton with the highly strained olefin moiety was formed through a ring-opening reaction of the bicyclo[4.1.0]heptane substructure.

Supporting Information



Publication History

Received: 11 November 2020

Accepted after revision: 10 December 2020

Publication Date:
10 December 2020 (online)

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • 20 The stereochemistry of cyclopropane ring-opening product was determined by NOE experiment of 24 converted from 20. Transformation of 24 into 5 was also achieved in three steps as follows, indicating that the configuration of compound 5 corresponds to that of the ABC ring system of natural product (Scheme 5).
  • 21 Synthesis of Compound 6 (Coupling Reaction of Ketone 10) To a cooled (–78 °C) suspension of Cp2TiCl2 (1.50 g, 6.0 mmol) in THF (8.0 mL) was added n-BuLi (2.67 M in hexane, 4.5 mL, 12.0 mmol). After being stirred for 1 h, a THF solution (1.0 mL) of S3 (490 mg, 2.4 mmol, see the Supporting Information) was added, and stirring was continued for 10 min at the same temperature and then at 0 °C for 1 h. After cooling to –78 °C, ketone 10 (300 mg, 2.0 mmol) in THF (1.0 mL) was added. After being stirred for 1 h, a 1 M aqueous NaOH solution was added, and the mixture was filtered through a pad of Celite. The insoluble materials were washed with EtOAc, and the filtrate was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 75:15) to afford 9 as a yellow oil (370 mg, 1.5 mmol, 75%, single isomer). IR (neat): ν = 2926, 2853, 2360, 2341, 1638, 1447, 1420, 1386, 1113, 1059, 995, 984, 953, 891 cm–1. 1H NMR (500 MHz, CDCl3): δ = 4.90 (1 H, s), 4.83 (1 H, s), 2.33 (1 H, dd, J = 9.0, 6.0 Hz), 2.26 (1 H, q, J = 6.5 Hz), 2.21 (1 H, t, J = 4.6 Hz), 2.11 (1 H, dd, J = 12.6, 4.0 Hz), 2.04 (2 H, d, J = 5.2 Hz), 1.87 (1 H, d, J = 10.3 Hz), 1.82–1.74 (3 H, m), 1.53–1.40 (4 H, m), 1.31–1.23 (4 H, m), 0.55 (2 H, dt, J = 17.9, 6.3 Hz). 13C NMR (125 MHz, CDCl3): δ = 149.33, 118.37, 108.47, 71.97, 56.65, 38.97, 38.11, 29.41, 29.00, 28.94, 26.15, 24.38, 21.12, 13.79, 5.83. HRMS (FI): m/z calcd for C16H23NO [M]+: 245.1780; found: 245.1773. Synthesis of Compound 7 (Cyclization Reaction of Epoxy Nitrile) To a cooled (–78 °C) solution of LTMP, which was freshly prepared from tetramethylpiperidine (250 μL, 1.45 mmol) in THF (6.3 mL) and n-BuLi (2.67 M in hexane, 540 μL, 1.45 mmol), was added a solution of 8 (200 mg, 0.727 mmol) in THF (1.0 mL). After being stirred for 30 min, the reaction mixture was slowly warmed up to room temperature. After being stirred for 1 h, the reaction was quenched with a saturated aqueous NH4Cl solution. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 75:15) to afford 7 as a white solid (146 mg, 0.531 mmol, single isomer); mp 207–209 °C. IR (neat): ν = 3381, 2960, 2939, 2919, 2872, 2359, 2225, 1496, 1296, 1237, 1061, 1036, 1004, 978 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.39 (1 H, dd, J = 10.9, 7.4 Hz), 3.17 (3 H, s), 2.36 (1 H, dd, J = 14.0, 12.3 Hz), 2.12–2.08 (2 H, m), 2.01 (2 H, t, J = 14.9 Hz), 1.90 (1 H, q, J = 4.4 Hz), 1.83 (1 H, dd, 12.0, 6.3 Hz) 1.75–1.66 (2 H, m), 1.58 (2 H, m), 1.47 (1 H, s), 1.41 (1 H, dt, J = 14.1, 3.9 Hz), 1.33–1.22 (4 H, m), 1.17 (1 H, dd, J = 15.2, 8.9 Hz), 1.03 (1 H, td, J = 8.9, 4.6 Hz), 0.85 (1 H, d, J = 14.3 Hz), 0.29 (1 H, q, J = 5.5 Hz). 13C NMR (125 MHz, CDCl3): δ = 124.41, 74.74, 72.16, 50.72, 47.09, 46.26, 36.05, 34.52, 31.38, 30.97, 27.75, 25.69, 23.90, 23.39, 18.87, 13.91, 12.66. HRMS (FI): m/z calcd for C17H25NO2 [M]+: 275.1885; found: 275.1884. Synthesis of Compound 5 (Cleavage of the Cyclopropane Moiety Followed by Saponification) To a cooled (0 °C) mixture of 6 (40 mg, 0.162 mmol) and AcOH (200 μL) in CH2Cl2 (400 μL) was added BF3·OEt2 (2.0 μL, 0.016 mmol). The reaction mixture was warmed up to room temperature and was stirred for 1 h. After cooling to 0 °C, a saturated aqueous NaHCO3 solution was added, and the mixture was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 9:1) to afford 23 as a yellow oil (34 mg, 0.123 mmol, 76%). IR (CHCl3): ν = 2931, 2856, 2365, 2342, 1656, 1617, 1460, 1437, 1363, 1326, 1162, 1108, 1085, 1020, 970, 888, 867, 850, 751 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.76 (1 H, s), 5.61 (1 H, t, J = 7.4 Hz), 4.52–4.48 (1 H, m), 2.87–2.80 (2 H, m), 2.74 (1 H, d, J = 5.2 Hz), 2.65 (1 H, q, J = 6.7 Hz), 2.54–2.43 (2 H, m), 2.33–2.29 (2 H, m), 2.18 (1 H, dd, J = 14.9, 12.6 Hz), 2.01 (3 H, s), 1.91–1.77 (3 H, m), 1.80 (1 H, td, J = 12.2, 4.4 Hz), 1.73 (1 H, d, J = 12.6 Hz), 1.43 (2 H, dtd, J = 47.7, 15.3, 8.6 Hz). 13C NMR (125 MHz, CDCl3): δ = 204.20, 169.97, 156.94, 146.84, 125.82, 121.11, 67.48, 53.75, 48.32, 37.62, 37.36, 32.65, 31.13, 27.32, 27.15, 25.22, 21.38. HRMS (FI): m/z calcd for C17H22O3 [M]+: 274.1569; found: 274.1572. A mixture of 23 (33 mg, 0.123 mmol) and K2CO3 (50 mg, 0.362 mmol) in MeOH (500 μL) was stirred at room temperature for 3 h. To this was added EtOAc and brine. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 2:1) to afford 5 as a white solid (27.0 mg, 0.118 mmol, 96%); mp 114–117 °C. IR (neat): ν = 3298 (br), 2927, 2853, 2366, 2358, 2342, 1655, 1614, 1031 cm–1. 1H NMR (500 MHz, CDCl3): δ = 5.75 (1 H, s), 5.57 (1 H, t, J = 7.4 Hz), 3.50 (1 H, t, J = 11.2 Hz), 2.86 (2 H, m), 2.71 (1 H, t, J = 6.0 Hz), 2.64 (1 H, q, J = 6.7 Hz), 2.49 (2 H, dt, J = 17.2, 8.3 Hz), 2.33–2.16 (3 H, m), 1.88 (2 H, t, J = 16.3 Hz), 1.70 (2 H, m), 1.50–1.37 (2 H, m). 13C NMR (125 MHz, CDCl3): δ = 205.01, 157.10, 146.37, 125.82, 121.62, 64.68, 53.84, 48.58, 41.71, 37.34, 35.66, 31.11, 27.31, 27.30, 25.23. HRMS (FD): m/z calcd for C15H20O2 [M]+: 232.1463; found: 232.1458.