Total Synthesis and Structural Revision of Cephalosporolide J

Abstract

Herein, we report the first total synthesis of cephalosporolide J, which is a deep sea sediment derived polyketide harboring a unique bicyclo[3.3.0]furanolactone moiety. The adopted synthetic strategy consisted of the alkynylation of γ-lactone with lithium alkynyltrifluoroborate followed by a spiroketalization triggered by hydrogenation of the triple bond. Through this synthesis, the correct structure of cephalosporolide J is shown to be that of the 9-epi stereoisomer of the structure originally proposed.

Key words

cephalosporolide J - polyketide - bicyclo[3.3.0]furanolactone - total synthesis - structural revision

• References and Notes

• 1 Fang XP, Anderson JE, Chang CJ, Fanwick PE, McLaughlin JL. J. Chem. Soc., Perkin Trans. 1 1990; 1655
• 2 Chianese G, Yu HB, Yang F, Sirignano C, Luciano P, Han BN, Khan S, Lin HW, Taglialatela-Scafati O. J. Org. Chem. 2016; 81: 5135
• 3 Li X, Yao YH, Zheng YA, Sattler I, Lin WH. Arch. Pharm. Res. 2007; 30: 812
• 4 Seibert SF, Krick A, Eguereva E, Kehraus S, König GM. Org. Lett. 2007; 9: 239
• 5a Blázquez MA, Bermejo A, Zafra-Polo MC, Cortes D. Phytochem. Anal. 1999; 10: 161
• 5b Mereyala HB, Joe M. Curr. Med. Chem. Anticancer Agents 2001; 1: 293
• 5c de Fatima A, Modolo LV, Conegero LS, Pilli RA, Ferreira CV, Kohn LK, de Carvalho JE. Curr. Med. Chem. 2006; 13: 3371
• 5d Benedeković G, Francuz J, Kovačević I, Popsavin M, Zelenović BS, Kojić V, Bogdanović G, Divjaković V, Popsavin V. Eur. J. Med. Chem. 2014; 82: 449

Goniofufurone:
• 6a Shing TK. M, Tsui HC. J. Chem. Soc., Chem. Commun. 1992; 432
• 6b Yi XH, Meng Y, Li CJ. Chem. Commun. 1998; 449
• 6c Ruiz P, Murga J, Carda M, Marco JA. J. Org. Chem. 2005; 70: 713
• 6d Ralph M, Ng S, Booker-Milburn KI. Org. Lett. 2016; 18: 968

Cephalosporolide I:
• 6e Li J, Zhao C, Liu J, Du Y. Tetrahedron 2015; 71: 3885
• 6f Wang J, Tong R. J. Org. Chem. 2016; 81: 4325

Ascospiroketal B:
• 6g Wang J, Tong R. Org. Lett. 2016; 18: 1936
• 7 Okazaki S, Senda K, Tokuta A, Inagaki M, Kamaike K, Ota K, Miyaoka H. Org. Biomol. Chem. 2022; 20: 6771
• 8a Hara Y, Honda T, Arakawa K, Ota K, Kamaike K, Miyaoka H. J. Org. Chem. 2018; 83: 1976
• 8b Hara Y, Kamaike K, Ota K, Miyaoka H. Synlett 2020; 31: 1730
• 9 Niu S, Fan Z, Tang X, Liu Q, Shao Z, Liu G, Yang X.-W. Tetrahedron Lett. 2018; 59: 375
• 10a The compound called ‘cephalosporolide J’ was isolated and structurally determined from the wood decay fungus Armillaria tabescens by Nanayakkara et al. in 2013.^10b However, in 2014, Tong and colleagues synthesized the proposed structure and confirmed that the proposed structure was incorrect.^10c Moreover, they also confirmed that the compound reported by Nanayakkara’s group is identical to ‘cephalosporolide C’ discovered by Hanson et al. in 1985.^10d Later, Yang and colleagues named their new spirocyclic compound, ‘cephalosporolide J’ in 2018.⁹
• 10b Herath HM. T. B, Jacob M, Wilson AD, Abbas HK, Nanayakkara NP. D. Nat. Prod. Res. 2013; 27: 1562
• 10c Song L, Lee KH, Lin Z, Tong R. J. Org. Chem. 2014; 79: 1493
• 10d Ackland MJ, Hanson JR, Hitchcock PB, Ratcliffe AH. J. Chem. Soc., Perkin Trans. 1 1985; 843
• 11a Ramana CV, Suryawanshi SB, Gonnade RG. J. Org. Chem. 2009; 74: 2842
• 11b Fernandes RA, Ingle AB. Synlett 2010; 158
• 11c Brimble MA, Finch OC, Heapy AM, Fraser JD, Furkert DP, O’Connor PD. Tetrahedron 2011; 67: 995
• 11d Tlais SF, Dudley GB. Beilstein J. Org. Chem. 2012; 8: 1287
• 11e Chang S, Britton R. Org. Lett. 2012; 14: 5844
• 11f Cortezano-Arellano O, Quintero L, Sartillo-Piscil F. J. Org. Chem. 2015; 80: 2601
• 11g Chaudhari DA, Kattanguru P, Fernandes RA. RSC Adv. 2015; 5: 42131
• 11h Tlais SF, Dudley GB. Org. Lett. 2010; 12: 4698
• 11i Fernandes RA, Halle MB. Asian J. Org. Chem. 2013; 2: 593
• 11j Li J, Zhao C, Liu J, Du Y. Tetrahedron 2015; 71: 3885
• 12 Kona CN, Ramana CV. Tetrahedron 2014; 70: 3653
• 13 Finch OC, Furkert DP, Brimble MA. Tetrahedron 2014; 70: 590
• 14 Li W, Lin Z, Chen L, Tian X, Wang Y, Huang SH, Hong R. Tetrahedron Lett. 2016; 57: 603
• 15 Kawa K, Hara A, Ishikawa Y, Nishiyama S. Molecules 2011; 16: 5422
• 16 Ramakrishna GV, Fernandes RA. J. Org. Chem. 2019; 84: 14127
• 17 Kiddle JJ, Green DL. C, Thompson CM. Tetrahedron 1995; 51: 2851
• 18a Yamanaka H, Yokoyama M, Sakamoto T, Shiraishi T, Sagi M, Mizugaki M. Heterocycles 1983; 20: 1541
• 18b Harcken C, Brückner R. New J. Chem. 2001; 25: 40
• 19a Sharpless KB, Amberg W, Bennani YL, Crispino GA, Hartung J, Jeong KS, Kwong HL, Morikawa K, Wang ZM, Xu D, Zhang XL. J. Org. Chem. 1992; 57: 2768
• 19b Kolb HC, VanNieuwenhze MS, Sharpless KB. Chem. Rev. 1994; 94: 2483
• 20a Brown HC, Racherla US, Singh SM, Wetherill RB. Tetrahedron Lett. 1984; 25: 2411
• 20b Doubský J, Streinz L, Lešetický L, Koutek B. Synlett 2003; 937
• 21 Procedure for the Synthesis of α,β-Unsaturated Ynone 8 BuLi (2.40 mL, 1.59 M in hexane, 3.76 mmol) was added slowly at –78 °C under argon to a solution of benzyl ether (+)-4 (1.71 g, 3.99 mmol) in THF (8.40 mL). The reaction mixture was stirred for 45 min at the same temperature, after which BF₃·OEt₂ (0.487 mL, 3.88 mmol) was added dropwise. Stirring was continued for 15 min, and then γ-lactone 7 (269 mg, 1.14 mmol) in THF (3.00 mL) was added. The resulting mixture was warmed to room temperature and stirred for 1 h, after which a solution of saturated aqueous NH₄Cl solution/aqueous NH₃ solution (1:8, v/v, 4.0 mL) was added. The mixture was allowed to warm to room temperature and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 3:1 to 1:1) to give α,β-unsaturated ynone 8 (545 mg, 72% yield) as a colorless oil; R_f = 0.55 (hexane/EtOAc = 1:1); [α]_D ²⁵ +38.5 (c 2.16, CHCl₃). IR (neat): ν_max = 3434, 3069, 3031, 2929, 2857, 2209, 1756, 1676, 1112 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.60 (m, 4 H), 7.43–7.28 (m, 16 H), 4.78 (d, J = 11.6 Hz, 1 H), 4.61 (dd, J = 5.7, 7.9 Hz, 1 H), 4.53 (s, 2 H), 4.50 (d, J = 11.6 Hz, 1 H), 4.07 (m, 1 H), 3.86 (ddd, J = 4.7, 7.6, 10.5 Hz, 1 H), 3.79–3.66 (m, 4 H), 3.13 (d, J = 4.2 Hz, 1 H), 2.90 (d, J = 5.5 Hz, 1 H), 2.87 (dd, J = 8.3, 17.2 Hz, 1 H), 2.80 (dd, J = 4.2, 17.2 Hz, 1 H), 2.13–1.87 (m, 3 H), 1.78 (m, 1 H), 1.04–0.99 (m, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 186.2 (C), 137.6 (C), 137.2 (C), 135.5 (CH) × 4, 133.42 (C), 133.40 (C), 129.7 (CH), 129.6 (CH), 128.5 (CH) × 2, 128.4 (CH) × 2, 127.92 (CH) × 2, 127.87 (CH), 127.8 (CH), 127.70 (CH) × 2, 127.68 (CH) × 2, 127.66 (CH) × 2, 91.8 (C), 84.8 (C), 73.4 (CH₂), 72.6 (CH), 71.4 (CH₂), 69.8 (CH), 68.3 (CH₂), 65.3 (CH), 59.3 (CH₂), 49.0 (CH₂), 38.0 (CH₂), 32.9 (CH₂), 26.8 (CH₃) × 3, 19.1 (C). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₄₁H₄₈O₆SiNa: 687.3118; found: 687.3119.
• 22 The relative configuration of the C6 spirocenter of the synthesized tricyclic lactones 9, 10, 12, and 13 is also supported by comparison of their NMR spectra with cephalosporolide E and F,¹² whose structures have been determined by X-ray crystallography (see the Supporting Information).
• 23 Raghavan S, Samanta PK. Synlett 2013; 24: 1983