Total Synthesis of (+)-Cryptocaryanone A

Abstract

The first total synthesis of (+)-cryptocaryanone A is described. The synthesis features a Mukaiyama aldol reaction, one-pot saponification/lactonization sequences, and TsOH-assisted dihydropyrone formation as key steps.

Key words

total synthesis - natural products - aldol reaction - saponification - lactonization

• References and Notes

• 1a Spencer JP. E. Br. J. Nutr. 2008; 99 (01) ES60
• 1b Cushnie TP. T, Lamb AJ. Int. J. Antimicrob. Agents 2005; 26: 343
• 1c Cushnie TP. T, Lamb AJ. Int. J. Antimicrob. Agents 2011; 38: 99
• 2 Dumontet V, Gaspard C, Van Hung N, Fahy J, Tchertanov L, Sévenet T, Guéritte F. Tetrahedron 2001; 57: 6189
• 3 Chou TH, Chen JJ, Lee SJ, Chiang MY, Yang CW, Chen IS. J. Nat. Prod. 2010; 73: 1470
• 4 Audia JE, Boisvert L, Patten AD, Villalobos A, Danishefsky SJ. J. Org. Chem. 1989; 54: 3738
• 5 Jeroncic LO, Cabal MP, Danishefsky SJ, Shulte GM. J. Org. Chem. 1991; 56: 387
• 6 Zhang W, Baranczak A, Sulikowski GA. Org. Lett. 2008; 10: 1939
• 7a Davey AE, Parsons AF, Taylor RJ. K. J. Chem. Soc., Perkin Trans. 1 1989; 1853
• 7b Stossel D, Chan TH. J. Org. Chem. 1988; 53: 4901
• 8a Dunn TB, Ellis JM, Kofink CC, Manning JR, Overman LE. Org. Lett. 2009; 11: 5658
• 8b Imoto S, Haruta Y, Watanabe K, Sasaki S. Bioorg. Med. Chem. Lett. 2004; 14: 4855
• 8c Danishefsky SJ, Selnick HG, Zelle RE, DeNinno MP. J. Am. Chem. Soc. 1988; 110: 4368
• 9 Cuthbertson JD, Godfrey AA, Taylor RJ. K. Org. Lett. 2011; 13: 3976
• 10a Jin M, Taylor RE. Org. Lett. 2005; 7: 1303
• 10b Crossman JS, Perkins MV. J. Org. Chem. 2006; 71: 117
• 11a Hayashi Y, Urushima T, Shin M, Shoji M. Tetrahedron 2005; 61: 11393
• 11b Hon Y.-S, Liu Y.-W, Hsieh C.-H. Tetrahedron 2004; 60: 4837
• 12 7-epi-Cryptochinone F (16): [α] _d ²⁰ +40 (c = 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 2.35 (dd, J = 18.0, 5.2 Hz, 1 H), 2.50 (dd, J = 18.4, 5.6 Hz, 1 H), 2.71 (dd, J = 17.0, 3.4 Hz, 1 H), 2.76 (dd, J = 19.8, 3.8 Hz, 1 H), 2.92 (dd, J = 16.8, 13.6 Hz, 1 H), 3.03 (dd, J = 18.2, 8.6 Hz, 1 H), 3.47 (s, 3 H), 3.61 (br dd, J = 14.4, 6.4 Hz, 1 H), 3.83 (br dd, J = 10.6, 5.4 Hz, 1 H), 4.67 (t, J = 6.6 Hz, 1 H), 5.48 (dd, J = 13.2, 3.6 Hz, 1 H), 7.37–7.43 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 30.24, 32.05, 34.89, 43.01, 58.18, 74.75, 78.26, 80.94, 110.75, 126.27, 129.11, 129.24, 137.88, 167.88, 176.16, 190.80. IR (KBr): 2985, 2547, 2256, 1739, 1374, 1245, 915, 734 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₉O₅ ⁺: 315.1227; found: 315.1223
• 13 Cryptochinone F was isolated from the evergreen tree Cryptocarya chinensis by Chou et al. (see ref. 3)
• 14 Cryptocaryanone A (1): To a solution of diketone 17 (9 mg, 0.022 mmol) in CH₂Cl₂ (5 mL) at r.t., was added TsOH·H₂O (41 mg, 0.22 mmol). The reaction mixture was stirred for 3 days, then quenched with sat. aq NaHCO₃ (2 mL). The layers were separated and the aqueous phase was extracted with CH₂Cl₂ (3 × 5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. Flash chromatography (hexanes–EtOAc, 3:1) afforded cryptocaryanone A (1; 3 mg, 49%) as a white powder. [α] _d ²⁰ +217 (c = 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ = 2.41 (dd, J = 17.9, 10.5 Hz, 1 H), 2.73 (dd, J = 16.8, 3.6 Hz, 1 H), 2.94 (dd, J = 17.2, 14.0 Hz, 1 H), 2.99 (dd, J = 18.0, 9.2 Hz, 1 H), 3.88 (dd, J = 19.8, 10.4 Hz, 1 H), 5.46–5.50 (m, 2 H), 6.10 (dd, J = 10.1, 1.8 Hz, 1 H), 6.29 (dd, J = 10.1, 2.7 Hz, 1 H), 7.41–7.45 (m, 5 H); ¹³C NMR (100 MHz, CDCl₃): δ = 30.75, 33.34, 42.94, 76.70, 81.08, 109.00, 124.30, 126.36, 129.13, 129.34, 134.87, 137.71, 162.77, 175.58, 190.47. IR (KBr): 2923, 2253, 1782, 1652, 1589, 1428, 910 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₉O₅ ⁺: 283.0965; found: 283.0959