Total Synthesis of Ascospiroketal B

Abstract

An enantioselective total synthesis of the marine tricyclic polyketide ascospiroketal B, previously isolated from the marine-derived fungus Ascochyta salicorniae, was accomplished in 21 steps by using an improved route. The intriguing 5,5-spiroketal-cis-fused-γ-lactone core was constructed through rearrangement of an epoxide, in conjunction with an acid-mediated spiroketalization.

Key words

ascospiroketal B - polyketides - spiroketals - rearrangement - total synthesis

• References and Notes

• 1 Seibert SF, Krick A, Eguereva E, Kehraus S, König GM. Org. Lett. 2007; 9: 239
• 2a Chang S, Hur S, Britton R. Angew. Chem. Int. Ed. 2015; 54: 211
• 2b Chang S, Hur S, Britton R. Chem. Eur. J. 2015; 21: 16646
• 3 Wang J, Tong R. Org. Lett. 2016; 18: 1936
• 4 Kim JW, Lee HW, Lee D.-H. Bull. Korean Chem. Soc. 2011; 32: 2877
• 5 Hara Y, Honda T, Arakawa K, Ota K, Kamaike K, Miyaoka H. J. Org. Chem. 2018; 83: 1976
• 6 Shiina I, Ibuka R, Kubota M. Chem. Lett. 2002; 286
• 7a Kosugi M, Sasazawa K, Shimizu Y, Migita T. Chem. Lett. 1977; 301
• 7b Milstein D, Stille JK. J. Am. Chem. Soc. 1978; 100: 3636
• 8 Li L.-S, Wu Y, Hu Y.-J, Xia L.-J, Wu Y.-L. Tetrahedron: Asymmetry 1998; 9: 2271
• 9 Sharpless KB, Amberg W, Bennani YL, Crispino GA, Hartung J, Jeong K.-S, Kwong H.-L, Morikawa K, Wang Z.-M, Xu D, Zhang X.-L. J. Org. Chem. 1992; 57: 2768
• 10 Ema T, Tanida D, Sakai T. Org. Lett. 2006; 8: 3773
• 11a Katsuki T, Sharpless KB. J. Am. Chem. Soc. 1980; 102: 5974
• 11b Hanson RM, Sharpless KB. J. Org. Chem. 1986; 51: 1922
• 11c Gao Y, Klunder JM, Hanson RM, Masamune H, Ko SY, Sharpless KB. J. Am. Chem. Soc. 1987; 109: 5765
• 12a Maruoka K, Ooi T, Nagahara S, Yamamoto H. Tetrahedron 1991; 47: 6983
• 12b Maruoka K, Murase N, Bureau R, Ooi T, Yamamoto H. Tetrahedron 1994; 50: 3663
• 13a Kraus GA, Roth B. J. Org. Chem. 1980; 45: 4825
• 13b Bal BS, Childers WE, Pinnick HW. Tetrahedron 1981; 37: 2091
• 14 CCDC 1997764 contains the supplementary crystallographic data for compound 8. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 15 Tungen JE, Aursnes M, Dalli J, Arnardottir H, Serhan CN, Hansen TV. Chem. Eur. J. 2014; 20: 14575
• 16a Hart DW, Schwartz J. J. Am. Chem. Soc. 1974; 96: 8115
• 16b Wipf P, Jahn H. Tetrahedron 1996; 52: 12853
• 17 Spiroketals 19 and 20 A solution of ketone 18 (58.4 mg, 62.3 μmol) in MeOH (300 μL) and THF (900 μL) was added to 2.0 M aq HCl (10.0 μL) at 30 °C, and the mixture was stirred for 3 h. The reaction was quenched with 2.0 M aq NaOH, and the mixture was diluted with Et₂O. The organic layer was washed with H₂O and brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, hexane–EtOAc (3:2)] to afford spiroketals 19 and 20. Spiroketal 19 Colorless oil; yield: 12.4 mg (35%); Rf = 0.15 (hexane–EtOAc, 2:1); [α]_D ²⁵ +18.6 (c 1.32, CHCl₃). IR (neat): 3435, 2959, 2933, 2588, 1776 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.58 (m, 4 H), 7.47–7.36 (m, 6 H), 6.54 (ddt, J = 1.0, 11.2, 15.0 Hz, 1 H), 6.16 (t, J = 11.2 Hz, 1 H), 5.69 (dd, J = 7.4, 15.0 Hz, 1 H), 5.52 (dt, J = 8.0, 11.0 Hz, 1 H), 5.22 (ddd, J = 2.2, 4.6, 6.9 Hz, 1 H), 4.68 (d, J = 4.5 Hz, 1 H), 4.59 (q, J = 7.1 Hz, 1 H), 3.88 (sextet, J = 6.2 Hz, 1 H), 3.77 (d, J = 9.7 Hz, 1 H), 3.62 (d, J = 9.7 Hz, 1 H), 2.65 (dd, J = 7.0, 15.0 Hz, 1 H), 2.40–2.04 (m, 6 H), 1.69 (m, 1 H), 1.26 (br s, 1 H), 1.23 (d, J = 6.2 Hz, 3 H), 1.03 (s, 3 H), 0.96 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 180.2 (C), 135.7 (CH × 2), 135.4 (CH × 2), 133.7 (CH), 132.6 (C), 131.7 (C), 130.5 (CH), 130.0 (CH), 129.9 (CH), 128.3 (CH), 127.9 (CH × 4), 126.8 (CH), 115.1 (C), 83.7 (CH), 82.0 (CH), 79.2 (CH), 69.4 (CH₂), 67.6 (CH), 51.0 (C), 42.4 (CH₂), 37.5 (CH₂), 35.1 (CH₂), 31.1 (CH₂), 26.7 (CH₃ × 3), 22.9 (CH₃), 19.1 (C), 13.6 (CH₃). HRMS (ESI–TOF): m/z [M + Na]⁺ calcd for C₃₄H₄₄NaO₆Si: 599.2805; found: 599.2808. Spiroketal 20 Colorless oil; yield: 12.8 mg (36%); R_f  = 0.10 (hexane–EtOAc, 2:1); [α]_D ²⁵ –5.04 (c 1.16, CHCl₃). IR (neat): 3435, 2963, 2933, 2858, 1773 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.64–7.58 (m, 4 H), 7.47–7.36 (m, 6 H), 6.49 (ddt, J = 1.2, 11.2, 15.2 Hz, 1 H), 6.16 (t, J = 11.1 Hz, 1 H), 5.69 (dd, J = 5.2, 15.2 Hz, 1 H), 5.45 (m, 1 H), 5.14 (t, J = 5.1 Hz, 1 H), 4.68 (d, J = 5.0 Hz, 1 H), 4.52 (quint, J = 7.1 Hz, 1 H), 3.88–3.75 (m, 2 H), 3.57 (d, J = 9.7 Hz, 1 H), 2.55–2.44 (m, 2 H), 2.28–2.02 (m, 5 H), 1.83 (m, 1 H), 1.62 (br s, 1 H), 1.22 (d, J = 6.2 Hz, 3 H), 1.13 (s, 3 H), 1.04 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 180.3 (C), 135.6 (CH × 2), 135.5 (CH × 2), 133.3 (CH), 132.8 (C), 131.9 (C), 130.3 (CH), 130.0 (CH), 129.9 (CH), 128.1 (CH), 127.89 (CH × 2), 127.86 (CH × 2), 126.0 (CH), 115.1 (C), 85.3 (CH), 81.8 (CH), 81.0 (CH), 70.1 (CH₂), 68.0 (CH), 51.3 (C), 41.7 (CH₂), 37.8 (CH₂), 36.2 (CH₂), 31.3 (CH₂), 26.8 (CH₃ × 3), 22.6 (CH₃), 19.2 (C), 14.1 (CH₃). LRMS (ESI–TOF): m/z (%) = 599 (100) [M + Na]⁺. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₃₄H₄₄NaO₆Si: 599.2805; found: 599.2808.