Synthesis of Dehydromuscone by an Alkene Metathesis Macrocyclization Reaction at 0.2 M Concentration

Abstract

The industrial fragrance compound dehydromuscone was synthesized in five linear steps and 19% overall yield. The synthesis features a highly efficient nondiluted ring-closing metathesis macrocyclization reaction as a key step that proceeds at a 0.2 M concentration in the presence of 0.1 mol% Nitro-Grela catalyst. The synthesis employs commercially available linear starting materials and is shorter by at least two steps than the current industrial synthesis route.

Key words

macrocyclization - dehydromuscone - Grela’s catalyst - fragrances - ring-closing metathesis - macrocycles

• References and Notes

• 1a Felix D, Schreiber J, Ohloff G, Eschenmoser A. Helv. Chim. Acta 1971; 54: 2896
• 1b Fehr C, Galindo J, Etter O. Eur. J. Org. Chem. 2004; 1953
• 1c Knopff O, Kuhne J, Fehr C. Angew. Chem. Int. Ed. 2007; 46: 1307
• 1d Lehr K, Fürstner A. Tetrahedron 2012; 68: 7695
• 1e Brenna E, Crotti M, De Pieri M, Gatti FG, Manenti G, Monti D. Adv. Synth. Catal. 2018; 360: 3677
• 2 Bru Roig M, Ruedenauer S. WO 2018011386, 2017
• 3a Jägel J, Maier ME. Synthesis 2009; 2881
• 3b Wei X, Shu C, Haddad N, Zeng X, Patel ND, Tan Z, Liu J, Lee H, Shen S, Campbell S, Varsolona RV, Busacca CA, Hossain A, Yee NK, Senanayake CH. Org. Lett. 2013; 15: 1016
• 3c Jover J, Spuhler P, Zhao L, McArdle C, Maseras F. Catal. Sci. Technol. 2014; 4: 4200
• 3d Raymond M, Holtz-Mulholland M, Collins SK. Chem. Eur. J. 2014; 20: 12763
• 3e Do J.-L, Mottillo C, Tan D, Štrukil V, Friščić T. J. Am. Chem. Soc. 2015; 137: 2476
• 3f Sytniczuk A, Dąbrowski M, Banach Ł, Urban M, Czarnocka-Śniadała S, Milewski M, Kajetanowicz A, Grela K. J. Am. Chem. Soc. 2018; 140: 8895
• 3g Seemann A, Panten J, Kirschning A. J. Org. Chem. 2021; 86: 13924
• 3h Hwang J, Mercado BQ, Miller SJ. Proc. Natl. Acad. Sci. U.S.A. 2021; 118: e2113122118
• 4 Fujimoto S, Yoshikawa K, Itoh M, Kitahara T. Biosci., Biotechnol., Biochem. 2002; 66: 1389
• 5a Villemin D. Tetrahedron Lett. 1980; 21: 1715
• 5b Monfette S, Fogg DE. Chem. Rev. 2009; 109: 3783
• 5c Crane EA, Scheidt KA. Angew. Chem. Int. Ed. 2010; 49: 8316
• 5d Girvin ZC, Andrews MK, Liu X, Gellman SH. Science 2019; 366: 1528
• 5e Sytniczuk A, Milewski M, Kajetanowicz A, Grela K. Russ. Chem. Rev. 2020; 89: 469
• 6a Felix D, Schreiber J, Ohloff G, Eschenmoser A. Helv. Chim. Acta 1971; 54: 2896
• 6b Trost BM, Warner RW. J. Am. Chem. Soc. 1982; 104: 6112
• 6c Hamtil R, Žilková N, Balcar H, Čejka J. Appl. Catal., A 2006; 302: 193
• 7a Shu C, Zeng X, Hao M.-H, Wei X, Yee NK, Busacca CA, Han Z, Farina V, Senanayake CH. Org. Lett. 2008; 10: 1303
• 7b Farina V, Shu C, Zeng X, Wei X, Han Z, Yee NK, Senanayake CH. Org. Process Res. Dev. 2009; 13: 250
• 7c Tracz A, Matczak M, Urbaniak K, Skowerski K. Beilstein J. Org. Chem. 2015; 11: 1823
• 8 Shen X, Nguyen TT, Koh MJ, Xu D, Speed AW. H, Schrock RR, Hoveyda AH. Nature 2017; 541: 380
• 9 9–Methylheptadeca-1,16-diene-7,11-dione (4) A 100 mL flask was dried and, after carrying out nitrogen gas substitution, Mg pieces (147.5 mg, 5.5 mmol) were added and activated by using a small amount of EtBr/THF. The supernatant was removed and a solution of 6-chlorohex-1-ene (7; 652.5 mg, 5.5 mmol) in 2:1 THF–toluene (5 mL) was added dropwise with stirring over 30 min at 40–50 °C. The mixture was then allowed to stand for 1 h to give the black-colored Grignard reagent 8. Under N₂, this reagent was added dropwise to a dry flask containing a solution of 6a or 6b (5 mmol) in THF (5 mL) at –30 °C, and the mixture was allowed to react for 8 h. 1 M aq HCl (10 mL) was then added and the mixture was extracted with EtOAc (×3), washed successively with H₂O (10 mL) and brine (10 mL), then dried (MgSO₄). The resulting mixture was purified by flash chromatography [silica gel, hexane–EtOAc (30:1)] to give a transparent oil; yield: 974 mg (70%). ¹H NMR (401 MHz, CDCl₃): δ = 5.71 (ddtd, J = 13.3, 10.2, 6.7, 1.0 Hz, 2 H), 4.98–4.84 (m, 4 H), 2.51–2.15 (m, 8 H), 2.05–1.92 (m, 5 H), 5 H), 1.56–1.44 (m, 4 H), 1.30 (dt, J = 14.9, 7.4 Hz, 4 H), 0.85 (d, J = 6.6 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃) δ = 210.41 (s), 138.44 (s), 114.62 (s), 49.18 (s), 42.92 (s), 33.48 (s), 28.39 (s), 25.43 (s), 23.15 (s), 20.22 (s). GC/MS: m/z = 278.2 (C₁₈H₃₀O₂). 3-Methylcyclopentadec-10-ene-1,5-dione (3) The appropriate catalyst (1.0 or 0.1 mol%) was added to a stirred solution of diketone 4 in degassed anhyd toluene (0.1 or 0.2 M), and the resulting solution was magnetically stirred for 16 h at 110 °C, to give a transparent oil; yield: 40–60%. ¹H NMR (401 MHz, CDCl₃): δ = 5.38–5.27 (m, 2 H), 2.44–2.23 (m, 9 H), 2.12–1.94 (m, 4 H), 1.56–1.47 (m, 4 H), 1.47–1.34 (m, 4 H), 1.08 (d, J = 6.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 211.50 (s), 131.17 (s), 48.56 (s), 42.73 (s), 31.58 (s), 27.92 (s), 26.72 (s), 23.40 (s), 20.89 (s). GC/MS: m/z = 250.2 (C₁₆H₂₆O₂). 3-Methylcyclopentadecane-1,5-dione (2) A 6 mL vial containing a magnetic stirrer bar was charged with 3 (17 mg, 0.0678 mmol), i-PrOH (1 mL), and 10 wt% Pd/C (4.2 mg, 5.9 mol%, 0.002 mmol). The vial was inserted into an autoclave and charged with H₂ at 10 atm pressure, and the mixture was then stirred for 16 h at r.t. When the reaction was complete, the hydrogen was released and the mixture was filtered and analyzed by GC, showing that diketone 2 was obtained in 99% yield. ¹H NMR (300 MHz, CDCl₃): δ = 2.51–2.33 (m, 9 H), 1.70–1.57 (m, 6 H), 1.37–1.14 (m, 10 H), 1.03 (d, J = 6.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 211.06 (s), 48.86 (s), 41.65 (s), 27.76 (s), 26.82 (s), 26.45 (s), 25.81 (s), 22.65 (s), 21.02 (s). GC/MS: m/z = 252.2 (C₁₆H₂₈O₂).
• 10 Patel BH, Heath SF. A, Mason AM, Barrett AG. M. Tetrahedron Lett. 2011; 52: 2258
• 11 Masilamani D, Rogic MM. J. Org. Chem. 1981; 46: 4486
• 12 Sato F, Inoue M, Oguro K, Sato M. Tetrahedron Lett. 1979; 20: 4303
• 13 Kotera Y, Ogawa K, Oba M, Shimomura K, Yonemura M, Ueno A, Todo N. Stud. Surf. Sci. Catal. 1976; 1: 575
• 14a Yide X, Jiasheng H, Zhiying L, Xiexian G. J. Mol. Catal. 1991; 65: 275
• 14b Balcar H, Hamtil R, Žilková N, Čejka J. Catal. Lett. 2004; 97: 25
• 15a Garnes-Portolés F, Rivero-Crespo M. Á, Leyva-Pérez A. J. Catal. 2020; 392: 21
• 15b Rivero-Crespo M. Á, Tejeda-Serrano M, Pérez-Sánchez H, Cerón-Carrasco JP, Leyva-Pérez A. Angew. Chem. Int. Ed. 2020; 59: 3846
• 15c Garnes-Portolés F, Greco R, Oliver-Meseguer J, Castellanos-Soriano J, Jiménez MC, López-Haro M, Hernández-Garrido JC, Boronat M, Pérez-Ruiz R, Leyva-Pérez A. Nat. Catal. 2021; 4: 293
• 16a Matsuda H, Tanaka S. US 7479574, 2004
• 16b Yamamoto K, Yagi M, Matsuda H, Maruyama K. US 2011313201, 2004
• 16c Fraile JM, García JI, Herrerías CI, Pires E. Synthesis 2017; 49: 1444
• 17 Collins JC, James K. Med. Chem. Commun. 2012; 3: 1489
• 18 Chen HS, Liu XF, Xu HS. Chin. Chem. Lett. 1997; 1: 17
• 19 Sanz-Navarro S, Garnes-Portolés F, López-Cruz C, Espinós-Ferri E, Corma A, Leyva-Pérez A. Appl. Catal., A 2021; 613: 118021
• 20 Kent RE, McElvain SM. Org. Synth. 1943; 23: 60
• 21 Sanz-Navarro S, Mon M, Doménech-Carbó A, Greco R, Sánchez-Quesada J, Espinós-Ferri E, Leyva-Pérez A. Nat. Commun. 2022; 13: n. 2831