Total Synthesis of Eleuthoside A; Application of Rh-Catalyzed Intramolecular Cyclization of Diazonaphthoquinone

Abstract

The first total synthesis of (±)-eleutherol and eleuthoside A, the natural cytotoxic substances extracted from medicinal Indonesian plant, is described. First, the synthesis of (±)-eleutherol has been ­accomplished in nine steps starting from bromo methoxy aldehyde with the aid of diazo-transfer chemistry approach. Second, a metal-­catalyzed intramolecular cyclization reaction of the corresponding ­diazonaphthoquinone led to the desired eleuotherol, which served as a precursor to eleuthoside A. Then, several glycosidation routes, using different glucosyl donors, were experimented to reach effective O-glycosidation of eleutherol. The only successful strategy involved Koenigs–Knorr glycosidation using peracetyl glycosyl bromide in the presence of Ag₂O and quinoline. This strategy furnished our desired acetylated glycoside of β-configuration, regioselectively. Finally, deacetylation and successive separation of diastereomers were conducted to give eleuthoside A.

Key words

diazonapthoquinone - rhodium - eleutherol - eleuthoside A - glycosidation - intramolecular cyclization - 1 Introduction - 2 Results and Discussion - 2.1 Synthetic Strategy - 2.2 Synthesis of Aglycone, Eleutherol - 2.3 Glycosidation and Synthesis of Eleuthoside A - 3 Conclusions

• References and Notes

• 1 There have been reported two kinds of eleuthoside A. One is isolated by Kashman Y. et al. and the other is (3R)-4-(β-d-glucopyranosyloxy)-5-methoxy-3-methyl-naphtho[2,3-c]furan-1(3H)-one, isolated by Shibuya H. et al.² In this paper, synthetic study of latter eleuthoside A and related compounds are described. For the isolation of eleuthoside A, see: Ketzinel S. Rudi A. Schleyer M. Benayahu Y. Kashman YJ. Nat. Prod. 1996; 59: 873
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• 22 Experimental Procedure and Physical Data of Eleuthoside A (1) The solid of peracetyl glycoside 20 (8.0 mg, 0.1 mmol) was dissolved in MeOH (2 mL), and then, K₂CO₃ (4.8 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature until TLC showed complete conversion of starting material (1 h). Then, the reaction mixture was concentrated under reduced pressure and purified by PTLC eluting with (CHCl₃/MeOH, 6:1) to afford (1.5 mg, 20%) eleuthoside A (1) as a single isomer along with 28% mixed isomer with the ratio 1/3-epi-1 (3:1) and 8% mixed isomer with the ratio 1:1. The spectral data of the white crystals of the natural isomer will be detailed below Mp 210 °C. R_f = 0.42 (CHCl₃/MeOH, 6:1), [α]_D –58.6 (c 0.0015, in MeOH at 25 °C). ¹H NMR (500 MHz, CD₃OD): δ = 8.22 (s, 1 H, H-9), 7.68 (d, 1 H, J = 8.0 Hz, H-8), 7.54 (dd, 1 H, J = 7.9, 8.0 Hz, H-7), 7.15 (d, 1 H J = 7.9 Hz, H-6), 6.07 (q, 1 H, J = 6.6 Hz, H-3), 5.01 (d, 1 H, J = 7.6 Hz, H-1′), 4.02 (s, 3 H, OCH₃), 3.72 (dd, 1 H, J = 2.1, 11.6 Hz, H-6B′), 3.61 (dd, 2 H, H-2′, H-6A′), 3.49 (dd, 1 H, J = 9.2, 9.5 Hz, H-3′), 3.42 (dd, 1 H, J = 9.4, 9.5 Hz, H-4′), 3.12 (ddd, 1 H, J = 2.1, 5.8, 9.4 Hz, H-5′), 1.74 (d, 3 H, J = 6.6 Hz, 3-CH₃). ¹ H NMR (500 MHz, CDCl₃): δ = 8.27 (s, 1 H, H-9), 7.68 (d, 1 H, J = 8.0 Hz, H-8), 7.53 (dd, 1 H, J = 7.9, 8.0 Hz, H-7), 7.10 (d, H J = 7.9 Hz, H-6), 5.91 (q, 1 H, J = 6.6 Hz, H-3), 4.95 (d, 1 H, J = 7.6 Hz, H-1′), 4.02 (s, 3 H, OCH₃), 3.82 (s, 2 H, br OH), 3.78–3.72 (m, 2 H, J = 7.4, 9.5 Hz, H-6B′, H-6A′), 3.68 (d, 2 H, H-2, H-4′, J = 8.8, 9.5 Hz), 3.49 (dd, 1 H, J = 9.2, 9.5 Hz, H-3′), 3.12 (ddd, 1 H, J = 4.5, 8.8, 9.0 Hz, H-5′), 2.84 (s, 1 H, br-OH), 2.73 (s, 1 H, br-OH), 1.73 (d, 3 H, J = 6.5 Hz, 3-CH₃). ¹³C NMR (125 MHz, CD3OD): δ = 170.9, 156.0, 146.4, 139.3, 138.0, 127.06, 124.5, 122.6, 122.6, 122.3, 108.3, 104.7, 79.5, 76.9, 76.4, 74.6, 70.1, 61.0, 54.7, 17.9. IR (ATR): 3404 (OH), 2971, 1750 (C=O), 1586, 1033 cm^–1. HRMS (ESI⁺): m/z = 429 [M + Na+]; calcd for C₂₀H₂₂NaO₉: 429.1162; found: 429.1154.
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