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Synlett 2023; 34(14): 1699-1703
DOI: 10.1055/s-0042-1751400
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Published as part of the Special Section 13th EuCheMS Organic Division Young Investigator Workshop

New Synthetic Approach to Protulactone A and Structural Analogues

Jovana Francuz  ∗
a   University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
,
Sanja Djokić
a   University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
,
Mirjana Popsavin
a   University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
,
Marko V. Rodić
a   University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
,
Vesna Kojić
b   University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Put Dr. Goldmana 4, 21204 Sremska Kamenica, Serbia
,
Biljana Krüger
c   University of Innsbruck, Institute of Mineralogy and Petrography, Innrain 52, 6020 Innsbruck, Austria
,
Velimir Popsavin
a   University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
d   Serbian Academy of Sciences and Arts, Kneza Mihaila 35, 11000 Belgrade, Serbia
› Author AffiliationsThis work has received funding from the Ministry of Education, Science and Technological Development of the Republic of Serbia (contract No. 451-03-68/2022-14/200125), as well as the Serbian Academy of Sciences and Arts (Grant No. F-130). This work has also received funding from the Ministry of Education, Sciences and Technological Development of the Republic of Serbia and the Austrian Federal Ministry of Education, Science and Research (project No. 451-03-02141/2017-09/14; WTZ project No. SRB 14/2018).
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Abstract

A new synthetic approach to protulactone A and several of its structural analogues, starting from d-galactose, has been developed. In a preliminary bioassay, all the compounds showed potent cytotoxicities. A structure–activity relationship analysis identified structural segments that are important for antiproliferative activity.

Key words

protulactone A - natural products - bicyclic lactones - medicinal chemistry - structure–activity relationship

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0042-1751400.
  • Supporting Information


Publication History

Received: 16 November 2022

Accepted after revision: 30 November 2022

Article published online:
21 December 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

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  • 11 CCDC 2218800, 2218801, and 2218802 contain the supplementary crystallographic data for compounds 3, 4, and 7, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/
  • 12 Compounds 5 and 6 Compound 3 or 4 (1 equiv) was dissolved in 90% TFA (0.3 M), and the resulting solution was stirred at rt until the starting material was consumed (TLC, 1.5 h). The mixture was concentrated by co-distillation with toluene, and the residue was purified by flash column chromatography [silica gel, EtOAc–EtOH (9:1)]. A stirred solution of compound 3a or 4a (1 equiv) in anhyd DMF (0.3 M) was treated with Meldrum′s acid (3.0 equiv) and dry Et3N (3.0 equiv), and the mixture was stirred at 46–48 °C until the starting material was consumed (TLC, 72 h). The residue was evaporated and purified by flash column chromatography [silica gel, Et2O–PE (4:1) for 5; CH2Cl2–EtOAc (17:3) for 6]. For analytical data for compounds 5 (3,6-anhydro-5-O-benzyl-2,8-dideoxy-l-glycero-l-gluco-octono-1,4-lactone) and 6 (3,6-anhydro-5-O-benzyl-2,8-dideoxy-d-glycero-l-gluco-octono-1,4-lactone), see ref. 7.
  • 13 Analogues 7 and 8 A solution of 5 or 6 (1 equiv) in MeOH (0.04 M) was hydrogenated over 10% Pd/C (0.04–0.05 g; the catalyst contained 50% of water) at rt for 18 h. The mixture was filtered through a Celite pad, and the catalyst was washed with EtOAc. The combined organic solutions were evaporated, and the residue was purified by flash chromatography [silica gel, EtOAc–CH2Cl2 (7:3) for 7, EtOAc–CH2Cl2 (7:3) → EtOAc for 8]. 3,6-Anhydro-2,8-dideoxy-l-glycero-l-gluco-octono-1,4-lactone (7) Colorless prisms; yield: 92%; mp 123–124 °C (EtOAc–hexane); [α]D +63.8 (c 0.50, acetone); Rf = 0.23 (EtOAc–CH2Cl2, 4:1). IR (KBr): 3315, 3396, 3493 cm–1. 1H NMR (400 MHz, acetone-d 6 + D2O): δ = 1.14 (d, J 7,8 = 6.4 Hz, 3 H, H-8, CH3 ), 2.50 (d, J 2a,2b = 17.8 Hz, 1 H, H-2a), 2.82–2.89 (m, H-2b, 1 H), 3.63 (dd, J 5,6 = 4.5, J 6,7 = 5.7 Hz, 1 H, H-6), 3.73 (m, J 7,8 = 6.4, J 6,7 = 6.0 Hz, 1 H, H-7), 4.37 (d, J 5,6 = 4.5 Hz, 1 H, H-5), 4.81–4.84 (m, 2 H, H-3 and H-4). 13C NMR (100 MHz, acetone-d 6): δ = 19.9 (C-8), 36.6 (C-2), 67.5 (C-7), 76.5 (C-5), 78.4 (C-3), 91.4 (C-4), 91.8 (C-6), 175.7 (C-1). HRMS (ESI): m/z [M + Na]+ calcd for C8H12NaO5: 211.0577; found: 211.0583. 3,6-Anhydro-2,8-dideoxy-d-glycero-l-gluco-octono-1,4-lactone (8) Thin transparent needles; yield: 90%; mp 124–126 °C (EtOAc–hexane); [α]D +42.8 (c 0.50, Me2CO); Rf = 0.23 (EtOAc–CH2Cl2, 4:1). IR (KBr): 3317, 3476 cm–1. 1H NMR (400 MHz, acetone-d 6 + D2O): δ = 1.17 (d, J 7,8 = 6.5 Hz, 3 H, H-8, CH3 ), 2.54 (d, J 2a,2b = 18.5 Hz, 1 H, H-2a), 2.84 (dd, J 2a,2b = 18.3, J 2b,3 = 5.5 Hz, 1 H, H-2b), 3.61 (t, J 5,6 = 5.6, J 6,7 = 5.6 Hz, 1 H, H-6), 3.75 (m, J 7,8 = 6.4, J 6,7 = 5.7 Hz, 1 H, H-7), 4.18 (br d, J 5,6 = 5.5 Hz, 1 H, H-5), 4.80 (dd, J 3,4 = 4.5, J 2b,3 = 5.3 Hz, 1 H, H-3), 4.84 (dd, J 3,4 = 4.4, J 4,5 = 0.9 Hz, 1 H, H-4). 13C NMR (100 MHz, acetone-d 6): δ = 19.7 (C-8), 36.4 (C-2), 67.6 (C-7), 77.2 (C-5), 78.1 (C-3), 91.4 (C-6), 91.6 (C-4), 175.8 (C-1). HRMS (ESI): m/z [M + Na]+ calcd for C8H12NaO5: 211.0577; found: 211.0583.
  • 14 Acetyl analogues 9, 10, and 13 AcCl (5.0 equiv) and DMAP (4.6–5.0 equiv) were added to a stirred solution of 7, 8, or 12 (1 equiv) in dry MeCN (0.1 M), and the mixture was stirred at rt until the starting material was consumed (TLC, 17–24 h). The mixture was then poured into 10% NaCl and extracted with CH2Cl2 (×2) and EtOAc (×2). The combined organic solutions were dried and concentrated, and the crude residue was purified by flash column chromatography [silica gel, CH2Cl2–EtOAc (19:1 for 9, 23:2 for 10, 47:3 for 13)]. 5,7-Di-O-acetyl-3,6-anhydro-2,8-dideoxy-l-glycero-l-gluco-octono-1,4-lactone (9) Long transparent needles; yield: 92%; mp 107–109 °C (CH2Cl2–hexane); [α]D +54.60 (c 0.50, CHCl3); Rf = 0.50 (CH2Cl2–EtOAc, 9:1). IR (KBr): 1742, 1790 cm–1. 1H NMR (400 MHz, acetone-d 6): δ = 1.21 (d, J 7,8 = 6.5 Hz, 3 H, H-8, CH3 ), 1.97 (s, 3 H, COCH3 from C-7), 2.07 (s, COCH3 from C-5, 3 H), 2.53 (br d, J 2a,2b = 18.1 Hz, 1 H, H-2a), 2.89 (dd, J 2a,2b = 18.1, J 2b,3 = 5.1 Hz, 1 H, H-2b), 4.01 (t, J 5,6 = 4.6, J 6,7 = 4.6 Hz, 1 H, H-6), 4.89 (br dd, J 3,4 = 4.0, J 2b,3 = 5.1, 1 H, H-3), 4.95 (d, J 3,4 = 4.0, H-4, 1 H), 5.06 (quad, J 7,8 = 6.5, J 6,7 = 4.4 Hz, 1 H, H-7), 5.29 (d, J 5,6 = 4.7 Hz, 1 H, H-5). 13C NMR (100 MHz, acetone-d 6): δ = 16.2 (C-8), 20.7 (COCH3 from C-5), 20.9 (COCH3 from C-7), 36.3 (C-2), 69.6 (C-7), 77.4 (C-5), 79.2 (C-3), 87.1 (C-6), 88.2 (C-4), 170.1 (COCH3 from C-5), 170.2 (COCH3 from C-7), 175.0 (C-1, C=O). HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO7: 295.0788; found: 295.0784. 5,7-Di-O-acetyl-3,6-anhydro-2,8-dideoxy-d-glycero-l-gluco-octono-1,4-lactone (10) Thin transparent needles; yield: 91%; mp 84–85 °C (CH2Cl2–hexane); [α]D +74.80 (c 0.50, CHCl3); Rf = 0.37 (CH2Cl2–EtOAc, 9:1). IR (KBr): 1739, 1790 cm–1. 1H NMR (400 MHz, acetone-d 6): δ = 1.23 (d, J 7,8 = 6.5 Hz, 3 H, H-8, CH3 ), 2.00 (s, 3 H, COCH3 from C-7), 2.10 (s, 3 H, COCH3 from C-5), 2.57 (d, J 2a,2b = 18.2 Hz, 1 H, H-2a), 2.89 (dd, J 2a,2b = 18.2, J 2b,3 = 5.4 Hz, 1 H, H-2b), 4.05 (t, J 5,6 = 4.0, J 6,7 = 4.0 Hz, 1 H, H-6), 4.93 (br dd, J 3,4 = 4.4, J 2b,3 = 5.1 Hz, 1 H, H-3), 4.98 (d, J 3,4 = 4.3 Hz, 1 H, H-4), 5.08–5.16 (m, J 7,8 = 6.5, J 6,7 = 3.9, J 5,6 = 4.2 Hz, 2 H, H-7 and H-5). 13C NMR (100 MHz, acetone-d 6): δ = 16.6 (C-8), 20.6 (COCH3 from C-7), 20.8 (COCH3 from C-5), 36.5 (C-2), 69.7 (C-7), 78.6 (C-5), 79.3 (C-3), 87.4 (C-6), 87.9 (C-4), 170.3 (COCH3 from C-5), 170.5 (COCH3 from C-7), 175.1 (C-1, C=O). HRMS (ESI): m/z [M + Na]+ calcd for C12H16NaO7: 295.0788; found: 295.0785. 5,7-Di-O-acetyl-3,6-anhydro-2-deoxy-l-gluco-heptono-1,4-lactone (13) Colorless oil; yield: 97%; [α]D + 70.4 (c 1.0, CHCl3); Lit.14 [α]D +86 (c 1.0, CHCl3); Rf = 0.47 (CH2Cl2–EtOAc, 9:1). IR (film): 1743, 1790 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.08 (s, 3 H, COCH3 from C-7), 2.12 (s, 3 H, COCH3 from C-5), 2.74 (d, J 2,3 = 2.9 Hz, 2 H, H-2a and H-2b), 4.17 (m, Ј 5,6 = 4.1, Ј 6,7а = 5.0, Ј 6,7b = 3.2 Hz, 1 H, H-6), 4.20 (dd, J 6,7a = 5.0, J 7a,7b = 11.8 Hz, 1 H, H-7a), 4.35 (dd, J 6,7b = 3.2, J 7a,7b = 11.8 Hz, 1 H, H-7b), 4.86 (m, 1 H, H-3), 4.90 (d, J 3,4 = 4.2 Hz, 1 H, H-4), 5.21 (d, J 5,6 = 4.1 Hz, 1 H, H-5). 13C NMR (100 MHz, CDCl3): δ = 20.3 (COCH3 from C-7), 20.4 (COCH3 from C-5), 35.7 (C-2), 62.9 (C-7), 77.4 (C-5), 78.0 (C-3), 83.1 (C-6), 86.7 (C-4), 169.4 (COCH3 from C-5), 170.4 (COCH3 from C-7), 173.8 (C-1). HRMS (ESI): m/z [M + Na]+ calcd for C11H14NaO7: 281.0632; found: 281.0627.
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