New Dephenylated Analogues of (–)-Goniofufurone: Optimization of Synthesis from l-Xylose

Abstract

Natural products containing highly oxygenated furanofuranone fragments are known for their potent biological activity, but also for their challenging total synthesis. In this study, the synthesis of five novel dephenylated (–)-goniofufurone analogues was completed and their cytotoxic activity against eight malignant and one normal human cell line was evaluated. Compared with previous syntheses of similar analogues, the synthesis was carried out starting from l-xylose, resulting in improved yields and a reduced number of synthetic steps for three divergent intermediates.

Key words

goniofufurone - lactones - bicycles - cytotoxicity - Meldrum’s acid

Publication History

Received: 05 June 2024

Accepted after revision: 25 June 2024

Accepted Manuscript online:
25 June 2024

Article published online:
18 July 2024

• References and Notes

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• 16 3,6-Anhydro-7-O-benzyl-2-deoxy-5-O-methyl-l-ido-heptono-1,4-lactone (5) and 3,6-Anhydro-2-deoxy-5,7-di-O-benzyl-l-ido-heptono-1,4-lactone (7) BnTCAI (0.19 mmol, 1.2 equiv for 7, 0.09 mmol, 1.1 equiv for 5) and a 1% solution of TfOH in CH₂Cl₂ (0.15 equiv) were added to a stirred solution of 2 (0.16 mmol) or 4 (0.08 mmol, 1 equiv) in 1:1 CH₂Cl₂–hexane, and the mixture was stirred at rt for 1.5 h. For compound 5, the reaction was stopped at this step, whereas for compound 7, an additional portion of BnTCAI (0.18 mmol, 1.1 equiv) was added, and stirring was continued for an additional 1.5 h at rt. When the reaction was complete, the mixture was neutralized with NaHCO₃ (1 equiv), concentrated, and purified by flash column chromatography [silica gel, CHCl₃–acetone (49:1)]. 5 White needle-like crystals; yield: 89%; mp 58–60 °C; [α]_D –5.4 (c 0.50, CHCl₃); R_f = 0.13 (light petroleum–Et₂O, 1:1). IR (KBr): 1773 (C=O). ¹H NMR (400 MHz, CDCl₃): δ = 2.70 (dd, J _2a,_2b = 19.0, J _2a,₃ = 2.1 Hz, 1 H, H-2a), 2.75 (dd, J _2a,_2b = 18.8, J _2b,₃ = 4.9 Hz, 1 H, H-2b), 3.45 (s, 3 H, –OCH₃), 3.65 (dd, J _7a,_7b = 10.2, J ₆,_7a = 6.4 Hz, 1 H, H-7a), 3.71 (dd, J _7a,_7b = 10.2, J ₆,_7b = 4.7 Hz, 1 H, H-7b), 4.00 (d, J ₅,₆ = 4.2 Hz, 1 H, H-5), 4.30 (dt, J ₆,_7a = 6.4, J ₆,_7b = 4.4, J ₅,₆ = 4.4 Hz, 1 H, H-6), 4.54 and 4.64 (2 × d, J _gem = 12.1 Hz, 2 × 1 H, CH ₂Ph), 4.93 (dd, J ₃,₄ = 4.8, J ₄,₅ = 0.7 Hz, 1 H, H-4), 4.96 (td, J ₃,₄ = 4.8, J _2b,₃ = 4.9, J _2a,₃ = 2.1 Hz, 1 H, H-3), 7.27–7.40 (m, 5 H, CH₂ Ph). ¹³C NMR (100 MHz, CDCl₃): δ = 35.99 (C-2), 58.54 (OCH₃), 67.88 (C-7), 73.54 (CH₂Ph), 76.79 (C-3), 79.59 (C-6), 83.85 (C-5), 84.84 (C-4), 127.75, 128.02, 128.44, 128.92, 128.99 (5 CH from Ph-group) and 137.95 (Cq from Ph-group), 175.36 (C-1). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₈NaO₅: 301.10464; found: 301.1047. 7 White crystals; yield: 43%; mp 76–78 °C; [α]_D –11.6 (c 0.50, CHCl₃); R_f = 0.32 (CHCl₃–Me₂CO, 49:1). IR (CHCl₃): 1787 (C=O). ¹H NMR (400 MHz, CDCl₃): δ = 2.69 (dd, J _2a,₃ = 2.6, J _2a,_2b = 19.4 Hz, 1 H, H-2a), 2.75 (dd, J _2b,₃ = 5.1, J _2a,_2b = 19.4 Hz, 1 H, H-2b), 3.72 (d, J ₆,₇ = 5.5 Hz, 2 H, 2 × H-7), 4.23 (d, J ₅,₆ = 4.1 Hz, 1 H, H-5), 4.31 (m, J ₅,₆ = 4.2, J ₆,₇ = 5.5 Hz, 1 H, H-6), 4.54 and 4.70 (2 × d, J _gem = 11.9 Hz, 2 H, CH ₂Ph on C-5), 4.59 and 4.62 (2 × d, J _gem = 12.3 Hz, 2 H, CH ₂Ph on C-7), 4.94 (dd, J ₃,₄ = 4.7, J ₄,₅ = 0.6 Hz, 1 H, H-4), 5.00 (td, J ₃,₄ = 4.8, J _2b,₃ = 4.8, J _2a,₃ = 2.7 Hz, 1 H, H-3), 7.27–7.40 (m, Ar-H, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 36.02 (C-2), 68.09 (C-7), 72.78 (CH₂Ph), 73.60 (CH₂Ph), 76.86 (C-3), 79.67 (C-6), 81.55 (C-5), 85.51 (C-4), 127.76, 127.78, 128.17, 128.44, 128.60, 137.11 and 137.89 (Ar-C), 175.30 (C=O). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₂NaO₅: 377.13589; found: 377.13589
• 17 3,6-Anhydro-7-O-benzoyl-2-deoxy-5-O-methyl-l-ido-heptono-1,4-lactone (6) and 3,6-Anhydro-7-O-benzoyl-5-O-benzyl-2-deoxy-l-ido-heptono-1,4-lactone (9)A 10% solution of BzCl in CH₂Cl₂ (0.37 mmol, 2.2 equiv for 6 or 0.21 mmol, 2.1 equiv for 9) was added to a solution of compound 4 (0.17 mmol) or 8 (0.10 mmol, 1 equiv) in 1:1 anhyd CH₂Cl₂–pyridine. The mixture was stirred at rt for 4 h, then transferred to a separatory funnel and washed with 10% aq NaHCO₃. The organic layer was dried (Na₂SO₄) and concentrated, and the residue was purified by flash column chromatography [silica gel, light petroleum–Et₂O (1:1)]. 6 White needle-like crystals; yield: 93%; mp 115–116 °C; [α]_D –15.0 (c 0.50, CHCl₃); R_f = 0.22 (PE–Et₂O, 1:1). IR (CHCl₃): 1770 (C=O). ¹H NMR (400 MHz, CDCl₃): δ = 2.71 (br d, J _2a,₃ = 1.4, J _2a,_2b = 18.8 Hz, 1 H, H-2a), 2.78 (dd, J _2b,₃ = 5.4, J _2a,_2b = 18.8 Hz, 1 H, H-2b), 3.50 (s, 3 H, OMe), 4.11 (d, J ₅,₆ = 3.3 Hz, 1 H, H- 5), 4.45–4.55 (m, 3 H, H-6, H-7a and H-7b), 4.98 (d, J ₃,₄ = 4.7 Hz, 1 H, H-4), 5.01 (m, J _2a,₃ = 1.3, J _2b,₃ = 5.4, J ₃,₄ = 4.4 Hz, 1 H, H-3). 7.42–8.08 (m, 5 H, Ar-H, Bz). ¹³C NMR (100 MHz, CDCl₃): δ = 35.99 (C-2), 58.68 (OMe), 62.67 (C-7), 77.01 (C-3), 78.67 (C-6), 83.91 (C-5), 84.72 (C-4), 128.45, 129.67, 129.79, 133.19 (Ar-C from Bz), 166.29 (C=O from Bz), 175.11 (C=O). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₆NaO₆: 315.0839; found: 315.08499. 9 White crystals; yield: 80%; mp 169–171 °C; [α]_D –9.0 (c 0.50, CHCl₃), R _f = 0.22 (1:1 light petroleum/Et₂O). IR (CHCl₃): ν_max 1770 (C=O), 1722 (C=O from Bz). ¹H NMR spectrum (400 MHz, CDCl₃): δ = 2.72 (dd,, J _2a,₃ = 1.9, J _2a,_2b = 18.8 Hz 1 H, H-2a), 2.78 (dd, J _2b,₃ = 5.2, J _2a,_2b = 18.8 Hz, 1 H, H-2b), 4.33 (d, J ₅,₆ = 4.2 Hz, 1 H, H-5), 4.47 (m, J ₅,₆ = 4.2, J ₆,₇ = 5.4 Hz, 1 H, H-6), 4.57 (d, J ₆,₇ = 5.7 Hz, 2 H, H-7), 4.63 and 4.74 (2 × d, J _gem = 11.9 Hz, 2 H, CH ₂Ph), 4.98 (d, J ₃,₄ = 4.5 Hz, 1 H, H-4), 5.04 (td, J _2a,₃ = 1.9, J _2b,₃ = 4.9, J ₃,₄ = 4.8 Hz, 1 H, H-3), 7.25–7.37 (m, Ar-H, 5 H, Bn), 7.42–8.06 (m, Ar-H, 5 H, Bz). ¹³C NMR spectrum (100 MHz, CDCl₃): δ = 36.00 (C-2), 62.60 (C-7), 72.82 (CH₂Ph), 77.07 (C-3), 78.68 (C-6), 81.26 (C-5), 85.23 (C-4), 127.94, 128.34, 128.44 (Ph from Bn), 128.70, 129.70, 133.19 (Ph from Bz), 129.76 (Cq from Bn), 136.72 (Cq from Bz), 166.25 (C=O from Bz), 175.08 (C=O). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₀NaO₆: 391.11521; found: 391.11698
• 18 Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seniff D, Boyd MR. Cancer Res. 1988; 48: 4827