Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2023; 34(14): 1699-1703
DOI: 10.1055/s-0042-1751400
DOI: 10.1055/s-0042-1751400
letter
Published as part of the Special Section 13th EuCheMS Organic Division Young Investigator Workshop
New Synthetic Approach to Protulactone A and Structural Analogues
This 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).
![](https://www.thieme-connect.de/media/synlett/202314/lookinside/thumbnails/st-2022-k0495-l_10-1055_s-0042-1751400-1.jpg)
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 relationshipSupporting 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
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References and Notes
- 1 Swathi J, Narendra K, Sowjanya KM, Krishna Satya A. Afr. J. Biochem. Res. 2013; 7: 184
- 2 Sohn JH, Oh H. Bull. Korean Chem. Soc. 2010; 31: 1695
- 3 Markovič M, Kooš P, Čarny T, Sokoliova S, Bohačikova N, Moncol J, Gracza T. J. Nat. Prod. 2017; 80: 1631
- 4 Lv Q, Chang C, Li Y, Du Y, Liu J. Tetrahedron 2020; 76: 131290
- 5 Benedeković G, Kovačević I, Popsavin M, Francuz J, Kojić V, Bogdanović G, Popsavin V. Tetrahedron 2015; 71: 4581
- 6 Srećo Zelenović B, Grabež S, Popsavin M, Kojić V, Francuz J, Popsavin V. J. Serb. Chem. Soc. 2020; 85: 1539
- 7 Djokić S, Francuz J, Popsavin M, Rodić MV, Kojić V, Stevanović M, Popsavin V. Bioorg. Chem. 2022; 127: 105980
- 8 Iga DP, Iga S, Predescu NF, Nicolescu A. Rev. Chim. (Bucharest) 2007; 58: 969
- 9 Morris PE. Jr, Kiely DE. J. Org. Chem. 1987; 52: 1149
- 10a Sheldrick GM. Acta Crystallogr., Sect. A: Found. Adv. 2015; 71: 3
- 10b Sheldrick GM. Acta Crystallogr., Sect. C: Struct. Chem. 2015; 71: 3
- 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.
- 15 Mata Z, Martinez MB, Perez JA. G. Carbohydr. Res. 1992; 225: 159
- 16 Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seniff D, Boyd MR. Cancer Res. 1988; 48: 4827
For X-ray crystallography, see: