Chiron Approach for the Total Synthesis of Brevipolide M

Abstract

An efficient stereoselective synthesis of brevipolide M was established in 13 linear steps and 17.8% overall yields based on chiron approach. The key steps of our synthesis involved tandem Wittig olefination–tetrahydrofuran cyclization and sequential ring-closing metathesis (RCM)–double-bond migration in one-pot processes.

Key words

brevipolide M - 5,6-dihydro-α-pyrone - total synthesis - d-mannofuranose diacetonide - chiron approach

Publication History

Received: 23 November 2021

Accepted after revision: 04 January 2022

Accepted Manuscript online:
04 January 2022

Article published online:
07 February 2022

• References and Notes

• 1 Pereda-Miranda R. In Phytochemistry of Medicinal Plants . Arnason JT, Mata R, Romeo JT. Plenum; New York: 1995: 83
• 2 Falomir E, Murga J, Ruiz P, Carda M, Marco JA, Pereda-Miranda R, Fragoso-Serrano M, Cerda-García-Rojas CM. J. Org. Chem. 2003; 68: 5672
• 3 Sedano-Partida MD, dos Santos KP, Sala-Carvalho WR, Silva-Luz CL, Furlan CM. Braz. J. Bot. 2020; 43: 213
• 4 Hegde VR, Pu H, Patel M, Das PR, Strizki J, Gullo VP, Chou C.-C, Buevich AV, Chan T.-M. Bioorg. Med. Chem. Lett. 2004; 14: 5339
• 5 Deng Y, Balunas MJ, Kim J.-A, Lantvit DD, Chin Y.-W, Chai H, Sugiarso S, Kardono LB. S, Fong HH. S, Pezzuto JM, Swanson SM, Carcache de Blanco EJ, Kinghorn AD. J. Nat. Prod. 2009; 72: 1165
• 6 Suárez-Ortiz GA, Cerda-García-Rojas CM, Hernández-Rojas A, Pereda-Miranda R. J. Nat. Prod. 2013; 76: 72
• 7 Suárez-Ortiz GA, Cerda-García-Rojas CM, Fragoso-Serrano M, Pereda-Miranda R. J. Nat. Prod. 2017; 80: 181
• 8 Lin J.-W, Kurniawan YD, Chang W.-J, Leu W.-J, Chan S.-H, Hou D.-R. Org. Lett. 2014; 16: 5328
• 9 Chen C.-N, Hou D.-R. Org. Biomol. Chem. 2016; 14: 6762
• 10 Kumaraswamy G, Jayaprakash N, Rambabu D, Ganguly A, Banerjee R. Org. Biomol. Chem. 2014; 12: 1793
• 11 Mohapatra DK, Kanikarapu S, Naidu PR, Yadav JS. Tetrahedron Lett. 2015; 56: 1041
• 12 Sheng Y.-H, Leu W.-J, Chen C.-N, Hsu J.-L, Liu Y.-T, Hsu L.-C, Hou D.-R, Guh J.-H. Molecules 2020; 25: 2929
• 13 Kurniawan YD, Rosyidah A. Beilstein J. Org. Chem. 2021; 17: 2399
• 14 Shiva Raju K, Sabitha G. Org. Biomol. Chem. 2017; 15: 6393
• 15 Raju KS, Sabitha G. Tetrahedron Lett. 2018; 59: 4213
• 16 Liu YX, Liu J, Zhao CF, Du YG. Org. Lett. 2021; 23: 3264
• 17 Yu S, Liu YX, Shang CX, Du YG, Liu J. Tetrahedron Lett. 2021; 70: 153072
• 18 Shang CX, Zhao CF, Nie PP, Liu J, Du YG. Tetrahedron 2021; 88: 132216
• 19 Chang CZ, Geng JL, Liu YX, Du YG, Liu J, Dong ZB. Synthesis 2020; 52: 1576
• 20 Lv QW, Chang CZ, Li Y, Du YG, Liu J. Tetrahedron 2020; 76: 131290
• 21 Zhao ZY, Lv QW, Geng JL, Liu Y, Hu C, Du YG, Liu J. Synthesis 2021; 53 in press; DOI:
• 22 The anti-allylic alcohol 9 was prepared on gram scale in 2 steps and 74% overall yield from l-ethyl lactate following protection with TBSCl, reduction of the ester with DIBAL-H, and subsequent treatment of the resulting aldehyde with vinylmagnesium chloride in one-pot. See ref. 21 and: Liu J, Gao YG, Wang LL, Du YG. Tetrahedron 2017; 73: 6443
• 23 Ovaa H, Codée JD. C, Lastdrager B, Overkleeft HS, Van der Marel GA, Van Boom JH. Tetrahedron Lett. 1998; 39: 7987
• 24 Chang CZ, Geng JL, Du YG, Lv QW, Dong ZB, Liu J. Tetrahedron 2019; 75: 3933
• 25 Chatterjee AK, Choi TL, Sanders DP, Grubbs RH. J. Am. Chem. Soc. 2003; 125: 11360
• 26 Synthesis of (3R,4S)-4-[(tert-butyldimethylsilyl)oxy]-1-{(3aS,4R,6aS)-6-hydroxy-2, 2-dimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl}pentan-3-yl methanesulfonate (8) and tert-butyl-((S)-1-{(2S,5R)-5-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]tetrahydrofuran-2-yl}ethoxy)dimethylsilane (7) To a stirred solution of 17 (0.79 g, 1.42 mmol) in MeOH (25 mL) was added MeONa solution to adjust the pH to 9–10. The mixture was stirred at room temperature for 1–2 h. After completion of the reaction, to the mixture was added IR-120 H⁺ resin to adjust the pH to 7. The mixture was filtered through a plug of silica gel and concentrated to afford crude hemiacetal 8 as a colorless oil. The crude 8 could be used for the next step without further purification. To a stirred solution of above 8 (ca. 1.42 mmol) in anhydrous THF (40 mL) was added LiHMDS (1.5 mL, 1 M in THF) under N₂ atmosphere. To a stirred solution of CH₃ ⁺PPh₃Br^– (1.43 g, 4 mmol) in anhydrous THF (25 mL) was added dropwise LHMDS (4.0 mL, 1 M in THF) at 0 °C under N₂ atmosphere. After stirring for 30 min at 0 °C, the mixture of above 8 (ca. 1.42 mmol) in anhydrous THF (4 mL) was added dropwise to the reaction. The reaction was refluxed at 65 ° C for 1 h and quenched with saturated aqueous NH₄Cl (40 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 40 mL). The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude residue was purified by flash column chromatography with PE/EtOAc (8:1, R_f = 0.35) to give 7 (358 mg, 71% for 2 steps) as a colorless oil. [α]_D ²⁰ +4.8 (c 0.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 5.88 (ddd, J = 8.8, 7.2, 1.2 Hz, 1 H), 5.32–5.19 (m, 2 H), 4.44 (dd, J = 8.5, 6.4 Hz, 1 H), 4.08 (dd, J = 8.1, 6.4 Hz, 1 H), 3.95–3.92 (m, 2 H), 3.82 (dd, J = 8.4, 5.9 Hz, 1 H), 1.93–1.85 (m, 1 H), 1.85–1.77 (m, 2 H), 1.52 (s, 3 H), 1.50–1.41 (m, 1 H), 1.38 (s, 3 H), 1.09 (d, J = 6.4 Hz, 3 H), 0.87 (s, 9 H), 0.04 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 134.8, 118.8, 109.3, 82.7, 81.5, 79.1, 78.2, 69.6, 28.0, 27.8, 25.9, 25.8, 25.5, 18.2, 18.1, –4.7, –4.8. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₉H₃₆NaO₄Si: 379.2281; found: 379.2273.
• 27 Neises B, Steglich W. Angew. Chem., Int. Ed. Engl. 1978; 17: 522
• 28 Gao YG, Shan QL, Liu J, Wang LL, Du YG. Org. Biomol. Chem. 2014; 12: 2071
• 29 Synthesis of Brevipolide M (3) To a stirred solution of 6 (22 mg, 0.051 mmol) in anhydrous DCM (80 mL) was added a catalytic amount of Grubbs second-generation catalyst (5.0 mg, 0.005 mmol). The reaction was refluxed at 50 °C for 1 h. After completion of the RCM reaction, the mixture was cooled to room temperature and DBU (7.6 mg, 0.05 mmol) was added to the solution. The reaction was allowed to stir 4 h at room temperature and concentrated under reduced pressure. The crude residue was purified by flash column chromatography with PE/EtOAc (2:1, R_f = 0.15) to give brevipolide M (3, 18 mg, 89%) as colorless oil. [α]_D ²⁰ +10.6 (c 0.01, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (d, J = 16.0 Hz, 1 H), 7.48 (d, J = 8.8 Hz, 2 H), 6.92–6.88 (m, 3 H), 6.31 (d, J = 16.0 Hz, 1 H), 5.96 (ddd, J = 9.6, 5.6 1.6 Hz, 1 H), 5.03 (dq, J = 6.8, 6.4 Hz, 1 H), 4.39–4.33 (m, 2 H), 4.00 (ddd, J = 8.4, 7.2, 5.6 Hz, 1 H), 3.84 (s, 3 H), 3.57–3.53 (m + br s, 2 H), 2.68 (ddd, J = 18.8, 5.2, 4.4 Hz, 1 H), 2.49 (ddd, J = 18.8, 11.2, 2.4 Hz, 1 H), 2.10–1.94 (m, 3 H), 1.78–1.75 (m, 1 H), 1.29 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.0, 163.8, 161.7, 145.5, 145.3, 129.9, 126.9, 121.1, 115.4, 114.3, 113.3, 82.3, 78.2, 78.0, 73.0, 72.7, 55.4, 28.4, 27.3, 26.5, 17.2. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₂H₂₆NaO₇: 425.1571; found: 425.1555.
• 30 See the Supporting Information for the detailed comparisons of ¹H and ¹³C NMR of natural and synthetic brevipolide M.