Organocatalytic Synthesis of Enantioenriched β-Arylsplitomicins

Abstract

By employing a chiral bifunctional thiourea–tertiary amine as catalyst, domino Michael-type Friedel–Crafts alkylation/cyclization of β-naphthols with akylidene Meldrum’s acids was realized. The reactions afforded various enantioenriched β-arylsplitomicins with good yields (up to 99%) in moderate enantio­selectivities (up to 79%).

Key words

domino reaction - alkylation - cyclization - phenols - organocatalysis - asymmetric catalysis

• References

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• 7 General Procedure for Organocatalytic Domino Michael-Type Friedel-–Crafts Alkylation/Cyclization of 2-Naphthol 5a with Alkylidene Meldrum’s Acids 6a–u Catalyst 4i (8.2 mg, 0.02 mmol, 10 mol%), 2-naphthol 5a or 5b (0.3 mmol), corresponding alkylidene Meldrum’s acid (0.2 mmol) and 30 mg of 4 Å MS were added to a 10 mL tube and warmed to 40 °C under argon. Then dry 1,2-dichloro-ethane (4.0 mL) were added. After the reaction was conducted at 40 °C for 20 hours, the mixture was subjected to flash chromatography on silica gel with petroleum ether–ethyl acetate as the eluent to give the pure product 7. The ee value was determined using established HPLC techniques with chiral stationary phases
• 8 1-(4-Nitrophenyl)-1H-benzo[f]chromen-3(2H)-one (7a) White solid, mp 55–56 °C. This product was obtained in 94% yield after flash chromatography and in 64% ee as determined by HPLC [Daicel Chirapak AD-H, n-hexane–i-PrOH = 70:30, 1.0 mL/min, λ = 254 nm]: t _R = 9.65 (major), 14.21 (minor) min. [α]_D ²⁵ +4.7 (c 0.6, CHCl₃); ¹H NMR (300 MHz, CDCl₃): δ = 8.14 (d, J = 8.7 Hz, 2 H), 7.94–7.88 (m, 2 H), 7.68 (d, J = 7.1 Hz, 1 H), 7.51–7.46 (m, 2 H), 7.38 (d, J = 8.9 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 2 H), 5.07 (d, J = 6.8 Hz, 1 H), 3.31 (dd, J₁  = 7.3 Hz, J₂  = 16.0 Hz, 1 H), 3.17 (dd, J₁  = 1.8 Hz, J₂  = 15.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.18, 149.81, 147.75, 147.22, 131.05, 130.62, 130.53, 128.92, 128, 127.79, 125.53, 124.4, 122.39, 117.47, 115.95, 37.25, 36.83. ESI-HRMS Calcd for C₁₉H₁₃NNaO₄ [M + Na]⁺: 342.0737. Found: 342.0741