Total Synthesis of Aloin by Regioselective Diels–Alder Reactions Connecting Two 3-Silylbenzynes and a 2-Stannylfuran

Abstract

The first synthesis of aloin, a natural anthrone C-glycoside, was achieved through two sequential Diels–Alder (DA) reactions connecting two 3-silylbenzynes and a 2-stannylfuran. The silyl and stannyl substituents contributed to the regioselectivity of the two DA reactions and the 9,10-ether cleavage of the DA adduct. Subsequent conversion of the silyl groups into hydroxy groups and a C10-glycosylation completed the synthesis of aloin.

Key words

total synthesis - aloin - Diels–Alder reaction - benzynes - stannylfurans - glycosylation

Publication History

Received: 29 December 2024

Accepted after revision: 19 February 2025

Accepted Manuscript online:
19 February 2025

Article published online:
01 April 2025

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• 20 Aloin (4) A brown test tube was charged with 24 (13 mg, 20 μmol), capped with a septum, and evacuated and purged with Ar ten times. 1 M aq NaOH (2.0 mL, 2 mmol) was added, and the mixture was stirred for 15 min at RT. 1 M aq HCl (3.0 mL) was added from a syringe under an Ar atmosphere at 0 ℃, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, EtOAc–MeOH (20:1)] to afford a yellow solid; yield: 7.8 mg (19 μmol, 95%; 1:1 mixture of two diastereomers at the C10 position); mp 113–115 ℃. IR (NaCl): 3377, 2922, 2853, 1637, 1617, 1602, 1571 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.50 (t, J = 7.9 Hz, 1 H), 7.49 (t, J = 8.5 Hz, 1 H), 7.10–7.07 (m, 4 H), 6.89–6.86 (m, 4 H), 4.66–4.62 (m, 6 H), 3.58 (dd, J = 10.9, 1.8 Hz, 1 H), 3.56 (dd, J = 10.9, 1.8 Hz, 1 H), 3.42 (dd, J = 10.9, 1.8 Hz, 2 H), 3.40–3.36 (m, 2 H), 3.26 (td, J = 8.7, 1.8 Hz, 2 H), 3.03 (t, J = 9.4 Hz, 1 H), 3.01 (t, J = 9.2 Hz, 1 H), 2.95–2.89 (m, 4 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 193.41, 193.39, 161.1, 160.94, 160.91, 160.8, 152.2, 151.4, 145.9, 145.7, 142.1, 141.8, 136.1, 135.3, 120.3, 118.9, 117.8, 117.4, 117.1, 116.2, 115.82, 115.76, 115.7, 115.4, 112.7, 112.3, 85.2, 85.1, 80.9, 80.8, 78.22, 78.16, 70.3, 70.23, 70.21, 70.1, 62.41, 62.37, 61.4 (2C), 44.2, 43.9. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₁H₂₂NaO₉: 441.1156; found: 441.1151.