An Asymmetric Total Synthesis of Picrotoxinin through a Mizoroki–Heck Reaction

Abstract

An asymmetric total synthesis of picrotoxinin was performed by using a Mizoroki–Heck reaction of an enantioenriched tricyclic lactone with isopropenyl bromide as a key transformation, permitting the highly diastereoselective introduction of the requisite C4-isopropenyl group. After functional-group manipulations, including carbonylation, bromoetherification, epoxidation, and dihydroxylation, picrotoxinin was obtained in a moderate to good yield.

Key words

total synthesis - picrotoxane sesquiterpenoids - Mizoroki–Heck reaction - carbonylation - hexahydroindanes

Publication History

Received: 01 November 2022

Accepted after revision: 17 November 2022

Accepted Manuscript online:
17 November 2022

Article published online:
10 January 2023

• References and Notes


For total and formal syntheses of 1, see:
• 1a Corey EJ, Pearce HL. J. Am. Chem. Soc. 1979; 101: 5841
• 1b Niwa H, Wakamatsu K, Hida T, Niiyama K, Kigoshi H, Yamada M, Nagase H, Suzuki M, Yamada K. J. Am. Chem. Soc. 1984; 106: 4547
• 1c Miyashita M, Suzuki T, Yoshikoshi A. J. Am. Chem. Soc. 1989; 111: 3728
• 1d Trost BM, Krische MJ. J. Am. Chem. Soc. 1996; 118: 233
• 1e Trost BM, Haffner CD, Jebaratnam DJ, Krische MJ, Thomas AP. J. Am. Chem. Soc. 1999; 121: 6183
• 1f Trost B, Krische MJ. J. Am. Chem. Soc. 1999; 121: 6131
• 1g Crossley SW. M, Tong G, Lambrecht MJ, Burge HE, Shenvi RA. J. Am. Chem. Soc. 2020; 142: 11376
• 2a Porter LA. Chem. Rev. 1967; 67: 441
• 2b Gössinger E. Prog. Chem. Org. Nat. Prod. 2010; 93: 71
• 2c Shenvi RA. Nat. Prod. Rep. 2016; 33: 535
• 2d Shi Q.-Q, Tang J.-J, Gao J.-M. Nat. Prod. Rep. 2022; 39: 2096
• 3 Freeman GM. Jr, Nakajima M, Ueda HR, Herzog ED. J. Neurophysiol. 2013; 110: 103
• 4a Wijnen H, Young MW. Annu. Rev. Genet. 2006; 40: 409
• 4b Takahashi JS. Nat. Rev. Genet. 2017; 18: 164
• 5a Watanabe S, Nishikawa T, Nakazaki A. Org. Lett. 2019; 21: 7410
• 5b Watanabe S, Nishikawa T, Nakazaki A. J. Org. Chem. 2021; 86: 3605

For the synthesis of estrogenic steroids based on a related Mizoroki–Heck approach, see:
• 5c Nakazaki A, Hashimoto K, Ikeda A, Shibata T, Nishikawa T. J. Org. Chem. 2017; 82: 9097
• 5d Nakazaki A, Kawai M, Nishikawa T. Org. Biomol. Chem. 2022; 20: 6432
• 6 The enantioenriched tricyclic lactone 2 (98% ee) was synthesized by optical resolution of the corresponding alcohol (73% ee), prepared according to refs. 5b and 5c, with Lipase MY-30, followed by benzoylation. See the Supporting Information for details.
• 7 It has been reported that the Mizoroki–Heck reaction of sterically hindered alkenes proceeded when Cy₂NMe was employed; see: Gürtler C, Buchwald SL. Chem. Eur. J. 1999; 5: 3107
• 8 Mizoroki–Heck Reaction of Benzoate 2 Pd₂(dba)₃·CHCl₃ (196 mg, 0.189 mmol), Cy₂NMe (2.50 mL, 11.5 mmol), and isopropenyl bromide (0.84 mL, 9.6 mmol) were added to a solution of benzoate 2 (600 mg, 1.92 mmol) in AcNMe₂ (9.6 mL) in a sealed tube. The resulting mixture was ultrasonicated for 5 min, purged with argon, and vigorously stirred at 120 °C for 22 h; this reaction was conducted in five batches. The resulting mixtures from the five batches were combined and diluted with Et₂O (100 mL). The mixture was washed with a 1 N aq HCl (3 × 50 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, hexane → hexane–Et₂O (10:1 to 5:1 to 3:1 to 1:1 to 1:3)] to afford an inseparable mixture of the desired Mizoroki–Heck product 3 and 4 as a yellow oil {yield: 1.42 g [42%; 3/4 = 92:8 (¹H NMR analysis)]}, together with regioisomer 10 as a yellow crystalline solid [yield: 664 mg (20%)] and recovered 2 as a yellow solid; yield: 856 mg (29%). 3 and 4: ¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 7 Hz, 2 H, Aryl-c), 7.58 (t, J = 7 Hz, 1 H, Aryl-a), 7.46 (t, J = 7 Hz, 2 H, Aryl-b), 6.46 (d, J = 10.5 Hz, 0.08 H, CH=CHCH), 5.89 (dd, J = 10, 2.5 Hz, 0.92 H, CH=CHCH), 5.76 (d, J = 10.5 Hz, 0.08 H, CH=CHCH), 5.63 (dd, J = 10, 1.5 Hz, 0.92 H, CH=CHCH), 5.32 (t, J = 8.5 Hz, 1 H, CHOBz), 4.90 (s, 0.92 H, CH_A H_B=C), 4.82 (s, 0.92 H, CH_A H_B =C), 3.10 (m, 0.08 H, CHCH₂COO), 2.92 [br d, J = 10.5 Hz, 0.92 H, CH(CH₃)C=CH₂], 2.75 (dd, J = 16, 14 Hz, 0.08 H, CHCH_A H_BCOO), 2.51–2.10 (m, 4.84 H), 1.87 (s, 0.24 H, CH₃ C=C), 1.85 (s, 0.24 H, CH₃ C=C), 1.80–1.69 (m, 3.76 H), 1.56 (dddd, J = 13.0, 11.0, 8.5, 7.0 Hz, 1 H, CH_A H_BCHOBz), 1.23 (s, 3 H, CH₃ CCH=CH). ¹³C NMR (100 MHz, CDCl₃): δ = 175.5, 166.1, 144.7, 133.23, 133.18, 133.1, 130.93, 130.85, 130.3, 129.7, 128.6, 127.6, 127.4, 126.1, 113.2, 93.8, 92.8, 80.8, 80.0, 49.6, 49.5, 47.2, 41.9, 40.6, 34.7, 32.6, 29.0, 28.4, 27.2, 26.9, 21.6, 20.0, 18.1, 17.5. 10: mp 153–155 °C. [α]_D ²⁷ +248 (c 1.02, CHCl₃). IR (KBr): υ_max = 1750, 1718, 1274, 1255, 1113 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 7 Hz, 2 H, Aryl-c), 7.58 (t, J = 7 Hz, 1 H, Aryl-a), 7.45 (d, J = 7 Hz, 2 H, Aryl-b), 5.84 (d, J = 2 Hz, 1 H, CH=C), 5.31 (dd, J = 8, 6 Hz, 1 H, CHOBz), 4.82 (s, 1 H, C=CH_A H_B), 4.78 (s, 1 H, C=CH_A H_B ), 3.00 (dd, J = 15.5, 5.0 Hz, 1 H, CH=CCH_A H_B), 2.84 [m, 1 H, CH(CH₃)C=CH₂], 2.75 (ddd, J = 15.5, 8, 2 Hz, 1 H, CH=CCH_A H_B ), 2.59 (ddd, J = 17, 14, 8 Hz, 1 H, CH_A H_BCHOBz), 2.47 (dt, J = 14, 9 Hz, 1 H, CH_A H_BCH₂CHOBz), 2.02–1.87 (m, 3 H), 1.81–1.70 (m, 4 H), 1.02 (s, 3 H, CH₃ CCHOBz). ¹³C NMR (100 MHz, CDCl₃): δ = 172.2, 170.1, 166.1, 147.1, 133.3, 130.3, 129.7, 128.6, 115.9, 111.3, 95.7, 84.0, 52.5, 39.7, 33.9, 32.9, 29.3, 28.7, 21.9, 19.3. HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₂H₂₄NaO₄: 375.1567; found: 375.1572.
• 9 CCDC 2211601and 2211602 contain the supplementary crystallographic data for compounds 10 and 21, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 10 Vedejs E, Engler DA, Telschow JE. J. Org. Chem. 1978; 43: 188
• 11 Griffith WP, Ley SV, Whitcombe GP, White AD. J. Chem. Soc., Chem. Commun. 1987; 1625
• 12 Barton DH. R, O’Brien RE, Sternhell S. J. Chem. Soc. 1962; 470
• 13 Beaubien S, Deslongchamps P. Can. J. Chem. 2006; 84: 29