Organocatalyzed Regioselective α,γ-Difunctionalization of Deconjugated Butenolides: Synthesis of Butyrolactone–Butyrolactam Hybrid Molecules

On the occasion of Prof. H. Yamamoto’s 80th birthday

Abstract

A highly regioselective α,γ-difunctionalization of deconjugated butenolides that allows access to hybrid molecular frameworks composed of unsaturated butyrolactone and butyrolactam motifs is reported. The reaction is catalyzed by inexpensive quinidine, and products are isolated in high yields as a single diastereomer. The γ-selective monofunctionalization was also accomplished through substrate modification.

Key words

butenolides - γ-lactams - organocatalysis - hybrid molecules

Publication History

Received: 25 April 2023

Accepted after revision: 30 May 2023

Accepted Manuscript online:
30 May 2023

Article published online:
14 July 2023

• References and Notes

• 1a Wasserman HH, Precopio MF, Liu CT. J. Am. Chem. Soc. 1952; 74: 4093
• 1b Rodriguez AD. Tetrahedron 1995; 51: 4571
• 1c Negishi E, Kotora M. Tetrahedron 1997; 53: 6707
• 1d Alali FQ, Liu X, Mclaughlin JL. J. Nat. Prod. 1999; 62: 504
• 1e Bryskier A. Antimicrobial Agents . ASM Press; Washington: 2005
• 1f Cornut D, Lemoine H, Kanishchev O, Okada E, Albrieux F, Beavogui AH, Bienvenu A.-L, Picot S, Bouillon J.-P, Médebielle M. J. Med. Chem. 2013; 56: 73
• 1g Caruano J, Muccioli GG, Robiette R. Org. Biomol. Chem. 2016; 14: 10134
• 2a Murakami T, Sasaki A, Fukushi E, Kawabata J, Hashimoto M, Okuno T. Bioorg. Med. Chem. Lett. 2005; 15: 2587
• 2b Shen YC, Cheng Y.-B, Kobayashi J, Kubota T, Takahashi Y, Mikami Y, Ito J, Lin Y.-S. J. Nat. Prod. 2007; 70: 1961
• 2c Pilli RA, Rosso GB, De Oliveira MD. C. F. Nat. Prod. Rep. 2010; 27: 1908
• 2d Rosso GB, Paz BM, Pilli RA. Eur. J. Org. Chem. 2022; e202200585

For reviews, see:
• 3a Mao B, Fañanás-Mastral M, Feringa BL. Chem. Rev. 2017; 117: 10502
• 3b Choudhury AR, Mukherjee S. Chem. Soc. Rev. 2020; 49: 6755
• 3c Chatterjee S, Sahoo R, Nanda S. Org. Biomol. Chem. 2021; 19: 7298

For selected examples, see:
• 3d Jefford CW, Jaggi D, Boukouvalas J. J. Chem. Soc., Chem. Commun. 1988; 1595
• 3e Simlandy AK, Mukherjee S. Org. Biomol. Chem. 2016; 14: 5659
• 3f Roy SJ. S, Mukherjee S. Org. Biomol. Chem. 2017; 15: 6921
• 3g Griswold JA, Horwitz MA, Leiva LV, Johnson JS. J. Org. Chem. 2017; 82: 2276
• 3h Ji J, Lin L, Tang Q, Kang T, Liu X, Feng X. ACS Catal. 2017; 7: 3763
• 4a Li X, Lu M, Dong Y, Wu W, Qian Q, Ye J, Dixon DJ. Nat. Commun. 2014; 5: 4479
• 4b Ishii D, Hirashima SI, Nakashima K, Akutsu H, Sakai T, Matsushima Y, Kawada M, Miura T. Org. Lett. 2021; 23: 480
• 4c Li S, Chen Q, Yang J, Zhang J. Angew. Chem. Int. Ed. 2022; 61: e202202046
• 4d Romaniszyn M, Sieroń L, Albrecht Ł. J. Org. Chem. 2022; 87: 5296
• 4e You ZH, Zou S, Song YL, Song XQ. Org. Lett. 2022; 24: 7183
• 5 Mallik S, Bhajammanavar V, Baidya M. Org. Lett. 2020; 22: 1437
• 6 Yang M, Chen C, Yi X, Li Y, Wu X, Li Q, Ban S. Org. Biomol. Chem. 2019; 17: 2883

For selected examples, see:
• 7a Hu X, Zhou Y, Lu Y, Zou S, Lin L, Liu X, Feng X. J. Org. Chem. 2018; 83: 8679
• 7b Zhang Y, Lu X, Wang Y, Xu H, Zhan R, Chen W, Huang H. Org. Lett. 2019; 21: 10069
• 7c Lu X, Zhang Y, Wang Y, Chen Y, Chen W, Zhan R, Zhao JC. G, Huang H. Adv. Synth. Catal. 2019; 361: 3234
• 7d Wang Y, Chen Y, Li X, Mao Y, Chen W, Zhan R, Huang H. Org. Biomol. Chem. 2019; 17: 3945
• 8 Attempts were also unsuccessful with chiral thiourea and squaramide based organocatalysts.
• 9 Typical Procedures: α,γ-Difunctionalization of Deconjugated Butyrolactone: A 16×100 mm oven-dried reaction tube equipped with a magnetic stir was charged with α-amide enone 1a (110.8 mg, 2.0 equiv, 0.40 mmol), deconjugated butyrolactone 2a (34.0 mg, 1.0 equiv, 0.20 mmol), and quinidine (13 mg, 20 mol%). The reaction tube was capped with a rubber septum, evacuated, and backfilled with nitrogen gas. Anhydrous toluene (4 mL) was then added via syringe, and the reaction mixture was stirred for 36 h at room temperature. After completion of the reaction (TLC monitored), the reaction mixture was filtered and residue was subsequently washed with toluene to give pure product 3a (0.15 mmol, 79%, 109 mg) as white solid; mp 124–126 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.88 (s, 1 H), 8.12 (s, 1 H), 7.38–7.32 (m, 6 H), 7.28–7.24 (m, 4 H), 7.19 (br s, 3 H), 7.07–7.01 (m, 5 H), 6.85 (br s, 2 H), 5.67 (s, 1 H), 5.03 (s, 1 H), 4.68–4.54 (m, 4 H), 4.31–4.23 (m, 3 H), 3.91 (d, J = 18.6 Hz, 1 H), 3.50–3.38 (m, 2 H), 1.74 (s, 3 H), 1.31 (t, J = 6.8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.0, 167.2, 167.0, 161.7, 153.1, 145.1, 144.3, 138.4, 136.9, 136.8, 136.62, 136.56, 129.0, 128.9, 128.8, 128.7 (2×C), 128.2, 128.0, 127.90 (2×C), 127.87, 127.5, 127.1, 118.3, 117.5, 90.2, 62.4, 49.4, 48.7, 47.9, 47.0, 46.95, 37.3, 23.5, 14.0. HRMS (ESI/TOF-Q): m/z [M + Na]⁺ calcd for C₄₄H₄₀N₂O₈Na⁺: 747.2677; found: 747.2695. γ-Functionalization of Deconjugated Butyrolactone: A 16×100 mm oven-dried reaction tube equipped with a magnetic stir was charged with α-amide enone 1a (66.5 mg, 1.2 equiv, 0.24 mmol), deconjugated butyrolactone 4a (20 mg, 1.0 equiv, 0.20 mmol), and quinidine (13 mg, 20 mol%). The reaction tube was capped with a rubber septum, evacuated, and backfilled with nitrogen gas. Anhydrous toluene (2 mL) was then added via syringe and the reaction mixture was stirred for 24 h at room temperature. After completion of the reaction (TLC monitored), volatiles were removed under reduced pressure and the crude product was purified by column chromatography (25% ethyl acetate/hexane) to provide pure product 5a (0.15 mmol, 80%, 60 mg) as a white solid; mp 158–160 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.29 (m, 4 H), 7.23–7.20 (m, 5 H), 7.16–7.14 (m, 2 H), 5.71 (d, J = 5.6 Hz, 1 H), 4.69–4.59 (q, 2 H), 4.40 (s, 1 H), 4.20 (d, J = 18.7 Hz, 1 H), 3.86 (d, J = 18.6 Hz, 1 H), 1.52 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 172.6, 167.2, 160.4, 144.4, 137.0, 136.4, 129.1 (d, J = 5.8 Hz), 129.0, 128.5, 128.0, 127.8, 121.0, 118.9, 90.5, 49.32, 49.25, 47.1, 23.7. HRMS (TOF MS ES+): m/z [M + Na]⁺ calcd for C₂₃H₂₁NO₄ + Na⁺: 398.1363; found: 398.1365.