Synthesis of 1C-Aryl/Alkyl 2C-Branched Sugar-Fused Isochroman Derivatives by Sequential Prins and Friedel–Crafts Cyclizations on a Perlin Aldehyde Derived Substrate

Abstract

The synthesis of C-aryl/alkyl 2C-branched sugar-fused isochromans by using a carbohydrate-derived starting material is described. Our approach makes use of sequential Prins and Friedel–Crafts cyclizations in which a Perlin aldehyde derived homoallylic alcohol is converted into the target molecule. This strategy works well with many aldehydes and gives good yields with excellent selectivity.

Key words

Perlin aldehyde - Prins cyclization - Friedel–Crafts cyclization - isochromans - tandem reactions

• References and Notes

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• 22 Prins Cyclization; General Procedure BF₃·OEt₂ (1.2 equiv) was added to a stirred solution of homoallylic alcohol 6 (100 mg, 0.239 mmol) and aldehyde 7 (0.359 mmol) in dry CH₂Cl₂ (3 mL) at 0 °C, and the mixture was stirred at r.t. under N₂ for the specified time (Table 2). When the reaction was complete (TLC), the reaction was quenched with sat. aq NaHCO₃ (3.0 mL), and the mixture was extracted with CH₂Cl₂ (2 × 3 mL). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄), and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, EtOAc–hexane) to afford the pure compound.
• 23 PTSA-Catalyzed Isomerization; General Procedure A 5-mL flask was charged with a mixture of the dihydropyran intermediate 8 and Prins/Friedel–Crafts cyclized product 9 (0.1 mmol) in toluene (3.0 mL), and PTSA·H₂O (10 mol% PTSA) was added. The mixture was stirred at the reflux and monitored periodically by TLC. Upon completion of the reaction, the toluene was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc–hexane) to afford the Prins/Friedel–Crafts cyclized product 9 as the sole product.(1S,2R,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-(4-tolyl)-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9a) Viscous liquid; yield: 83 mg (69%); R_f  = 0.5 (hexane–EtOAc, 9:1); [α]_D ²⁵ +10.5 (c 0.62, CH₂Cl₂). IR (neat): 2922, 1453, 1063, 814, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.02 (m, 18 H), 4.86 (dd, J = 33.0, 14.0 Hz, 2 H), 4.69 (d, J = 10.2 Hz, 1 H), 4.58 (q, J = 12.4 Hz, 2 H), 4.38–4.29 (m, 2 H), 3.85–3.70 (m, 4 H), 3.45–3.32 (m, 2 H), 3.21 (t, J = 10.7 Hz, 1 H), 2.36 (s, 3 H), 2.28–2.21 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.87, 138.25, 138.18, 137.85, 137.66, 136.20, 129.11, 128.40, 128.34, 127.82, 127.78, 127.75, 127.70, 127.44, 127.05, 126.29, 125.38, 124.73, 82.18, 80.16, 73.79, 73.57, 73.29, 70.18, 68.61, 67.39, 45.10, 40.38, 21.37. HRMS: m/z [M + NH₄]⁺ calcd for C₃₅H₄₀NO₄: 538.2957; found: 538.2958. (1S,2R,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-phenyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9b) Viscous liquid; yield: 74 mg (61%); R_f  = 0.5 (hexane–EtOAc, 9:1); [α]_D ²⁵ +52.8 (c 0.14, CH₂Cl₂). IR (neat): 2923, 1453, 1064, 738, 698 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.58–6.92 (m, 19 H), 4.86 (dd, J = 40.6, 14.0 Hz, 2 H), 4.73 (d, J = 10.2 Hz, 1 H), 4.59 (q, J = 12.4 Hz, 2 H), 4.33 (s, 2 H), 3.86–3.70 (m, 4 H), 3.46–3.36 (m, 1 H), 3.33 (dd, J = 9.9, 1.9 Hz, 1 H), 3.23 (t, J = 10.6 Hz, 1 H), 2.33–2.19 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 140.79, 138.82, 138.18, 138.10, 136.19, 128.43, 128.35, 128.04, 127.91, 127.82, 127.74, 127.46, 127.07, 126.32, 125.41, 124.69, 116.68, 82.29, 80.13, 73.74, 73.54, 73.30, 70.12, 68.43, 67.37, 45.12, 40.32. HRMS: m/z [M + NH₄]⁺calcd for C₃₄H₃₈NO₄: 524.2801; found: 524.2809. (1S,2R,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-(4-nitrophenyl)-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9c) Viscous liquid; yield: 85.6 mg (65%); R_f  = 0.4 (hexane–EtOAc, 8:2); [α]_D ²⁵ +59.1 (c 0.12, CH₂Cl₂). IR (neat): 2922, 1605, 1520, 1347, 1072, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.13 (d, J = 8.6 Hz, 2 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.37–7.11 (m, 14 H), 4.96–4.77 (m, 3 H), 4.63–4.54 (m, 2 H), 4.35 (dd, J = 40.1, 11.9 Hz, 2 H), 3.88–3.77 (m, 3 H), 3.69 (dd, J = 10.9, 5.7 Hz, 1 H), 3.36 (t, J = 9.8 Hz, 1 H), 3.31 (dd, J = 10.0, 1.8 Hz, 1 H), 3.20 (t, J = 10.6 Hz, 1 H), 2.21 (t, J = 10.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 148.10, 147.67, 138.58, 137.68, 137.57, 136.11, 128.67, 128.55, 128.40, 128.06, 127.80, 127.71, 127.60, 127.21, 126.57, 125.58, 124.32, 123.57, 81.17, 80.15, 73.59, 73.43, 70.05, 67.86, 67.30, 45.11, 40.25. HRMS: m/z [M + NH₄]⁺ calcd for C₃₄H₃₇N₂O₆: 569.2652; found: 569.2652. (1S,2R,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-(4-fluorophenyl)-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9d) Viscous liquid; yield: 78 mg (62%); R_f  = 0.5 (hexane–EtOAc, 9:1); [α]_D ²⁵ +16.7 (c 0.32, CH₂Cl₂). IR (neat): 2924, 2868, 1129, 1101, 853 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.44–6.74 (m, 18 H), 4.86 (dd, J = 34.3, 14.0 Hz, 2 H), 4.70 (d, J = 10.2 Hz, 1 H), 4.63–4.54 (m, 2 H), 4.33 (q, J = 12.0 Hz, 2 H), 3.88–3.67 (m, 4 H), 3.42–3.30 (m, 2 H), 3.20 (t, J = 10.6 Hz, 1 H), 2.21 (t, J = 10.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 163.78, 161.31, 138.75, 138.04, 137.94, 136.62, 136.16, 129.54, 129.46, 128.46, 128.35, 128.00, 127.88, 127.83, 127.71, 127.49, 127.10, 126.38, 125.44, 124.60, 115.32, 115.11, 81.56, 80.14, 73.65, 73.53, 73.34, 70.10, 68.31, 67.35, 45.19, 40.34. HRMS: m/z [M + NH₄]⁺ calcd for C₃₄H₃₇FNO₄: 542.2707; found: 542.2706. (1S,2R,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-(4-chlorophenyl)-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9e) Viscous liquid; yield: 75 mg (58%); R_f  = 0.5 (hexane–EtOAc, 9:1); [α]_D ²⁵ +9.4 (c 0.46, CH₂Cl₂). IR (neat): 2922, 1453, 1493, 1361, 1029, 735, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.47–7.01 (m, 18 H), 4.85 (dd, J = 34.4, 14.0 Hz, 2 H), 4.68 (d, J = 10.1 Hz, 1 H), 4.63–4.52 (m, 2 H), 4.38–4.28 (m, 2 H), 3.86–3.74 (m, 3 H), 3.70 (dd, J = 10.7, 5.4 Hz, 1 H), 3.41–3.30 (m, 2 H), 3.19 (t, J = 10.6 Hz, 1 H), 2.19 (t, J = 10.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 139.33, 138.74, 137.98, 137.90, 136.15, 133.69, 129.26, 128.57, 128.49, 128.37, 127.90, 127.72, 127.51, 127.12, 126.42, 125.46, 124.57, 81.59, 80.15, 73.62, 73.55, 73.35, 70.09, 68.29, 67.35, 45.12, 40.33. HRMS: m/z [M + H]⁺ calcd for C₃₄H₃₄ClO₄: 541.2146; found: 541.2147 (1S,2R,4R,4aS,10bR)-1,4-Bis[(Benzyloxy)methyl]-2-(4-bromophenyl)-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9f) Viscous liquid; yield: 85 mg (61%); R_f  = 0.5 (hexane–EtOAc, 9:1); [α]_D ²⁵ +50.6 (c 0.32, CH₂Cl₂). IR (neat): 2923, 1486, 1071, 745, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.55–6.98 (m, 18 H), 4.85 (dd, J = 34.7, 14.0 Hz, 2 H), 4.67 (d, J = 10.2 Hz, 1 H), 4.62–4.53 (m, 2 H), 4.39–4.27 (m, 2 H), 3.87–3.65 (m, 4 H), 3.42–3.28 (m, 2 H), 3.19 (t, J = 10.7 Hz, 1 H), 2.19 (t, J = 10.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 139.85, 138.74, 137.97, 137.89, 136.14, 131.52, 129.62, 128.50, 128.37, 127.90, 127.72, 127.51, 127.13, 126.42, 125.46, 124.56, 121.88, 81.65, 80.16, 73.61, 73.56, 73.36, 70.10, 68.30, 67.35, 45.08, 40.34. HRMS: m/z [M + H]⁺ calcd for C₃₄H₃₇BrNO₄: 602.1906; found: 602.1906. (1S,2R,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-(2-naphthyl)-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9g) Viscous liquid; yield: 69 mg (52%); R_f  = 0.5 (hexane–EtOAc, 9:1); [α]_D ²⁵ +49.3 (c 0.32, CH₂Cl₂). IR (neat): 3028, 2861, 1495, 1453, 1064, 744, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.86–7.77 (m, 4 H), 7.56–7.44 (m, 3 H), 7.34–7.10 (m, 14 H), 4.89 (dt, J = 38.7, 14.1 Hz, 3 H), 4.60 (q, J = 12.5 Hz, 2 H), 4.31 (s, 2 H), 3.90–3.79 (m, 3 H), 3.76 (dd, J = 11.2, 5.6 Hz, 1 H), 3.46 (t, J = 9.8 Hz, 1 H), 3.38–3.33 (m, 1 H), 3.27 (t, J = 10.6 Hz, 1 H), 2.38 (t, J = 10.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 138.80, 138.16, 138.05, 136.19, 133.42, 133.36, 128.40, 128.36, 128.26, 128.22, 127.78, 127.74, 127.46, 127.22, 127.10, 126.36, 126.10, 126.03, 125.68, 125.43, 124.72, 82.49, 80.22, 73.77, 73.55, 73.34, 70.12, 68.57, 67.41, 44.98, 40.41. HRMS: m/z [M + NH₄]⁺ calcd for C₃₈H₄₀NO₄: 574.2957; found: 574.2954. (1S,2S,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-methyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9h) Viscous liquid; yield: 80 mg (78%); R_f  = 0.6 (hexane–EtOAc, 9:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.42–6.97 (m, 14 H), 4.80 (dd, J = 52.1, 14.0 Hz, 2 H), 4.60 (s, 2 H), 4.51 (dd, J = 36.6, 12.0 Hz, 2 H), 3.82 (dd, J = 9.4, 5.1 Hz, 1 H), 3.76 (d, J = 9.9 Hz, 1 H), 3.71–3.63 (m, 1 H), 3.63–3.56 (m, 3 H), 3.15 (t, J = 10.9 Hz, 1 H), 2.74 (t, J = 10.7 Hz, 1 H), 2.03–1.94 (m, 1 H), 1.39 (d, J = 6.2 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 142.25, 138.74, 138.39, 138.14, 135.95, 128.54, 128.39, 127.91, 127.89, 127.85, 127.54, 127.13, 126.35, 125.25, 124.07, 79.59, 73.61, 73.54, 73.21, 70.66, 70.29, 67.01, 44.70, 41.14, 19.86. HRMS: m/z [M + H]⁺ calcd for C₂₉H₃₃O₄: 445.2379; found: 445.2377. (1S,2S,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-ethyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9i) Viscous liquid; yield: 77 mg (73%); R_f  = 0.6 (hexane–EtOAc, 9:1); [α]_D ²⁵ +9.4 (c 0.18, CH₂Cl₂). IR (neat): 2925, 1495, 1089, 746, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.39–7.02 (m, 14 H), 4.82 (dd, J = 50.1, 14.0 Hz, 2 H), 4.62 (s, 2 H), 4.51 (dd, J = 41.7, 12.0 Hz, 2 H), 3.85 (d, J = 10.8 Hz, 1 H), 3.75 (d, J = 9.8 Hz, 1 H), 3.66–3.51 (m, 3 H), 3.42 (dd, J = 12.9, 5.4 Hz, 1 H), 3.15 (t, J = 9.6 Hz, 1 H), 2.72 (t, J = 10.8 Hz, 1 H), 2.14–2.01 (m, 1 H), 1.91 (ddd, J = 14.3, 7.3, 2.3 Hz, 1 H), 1.59–1.51 (m, 1 H), 1.06 (t, J = 7.3 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 138.91, 138.50, 138.15, 135.91, 128.52, 128.37, 127.87, 127.69, 127.46, 127.10, 126.32, 125.22, 124.02, 81.88, 79.77, 73.49, 73.10, 70.77, 70.19, 66.96, 42.37, 41.40, 26.08, 10.47. HRMS: [M + H]⁺ m/z calcd for C₃₀H₃₅O₄: 459.2535; found: 459.2536. (1S,2S,4R,4aS,10bR)-1,4-Bis[(benzyloxy)methyl]-2-propyl-1,2,4,4a,6,10b-hexahydropyrano[3,4-c]isochromene (9j) Viscous liquid; yield: 78 mg (71%); R_f  = 0.6 (hexane–EtOAc, 9:1); [α]_D ²⁵ +26.6 (c 0.56, CH₂Cl₂). IR (neat): 2926, 1454, 1088, 745, 697cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.89–6.81 (m, 14 H), 4.81 (dd, J = 41.4, 14.0 Hz, 2 H), 4.61 (s, 2 H), 4.51 (dd, J = 26.5, 12.0 Hz, 2 H), 3.84 (dd, J = 10.8, 1.6 Hz, 1 H), 3.74 (dd, J = 9.8, 1.5 Hz, 1 H), 3.64–3.44 (m, 4 H), 3.15 (t, J = 9.6 Hz, 1 H), 2.77–2.62 (m, 1 H), 2.05 (ddd, J = 14.3, 8.9, 2.8 Hz, 1 H), 1.83–1.32 (m, 4 H), 0.94 (t, J = 7.2 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 138.92, 138.53, 138.13, 135.91, 128.52, 128.37, 127.97, 127.89, 127.69, 127.46, 127.12, 126.32, 125.22, 124.02, 80.46, 79.77, 73.49, 73.09, 70.66, 70.19, 66.96, 42.79, 41.49, 35.30, 29.85, 19.20, 14.32. HRMS: m/z [M + NH₄]⁺ calcd for C₃₁H₄₀NO₄: 490.2957; found: 490.2957. [(2R,3S,4S,5S,6S)-3-(Acetyloxy)-6-methyl-4-(2-tolyl)tetrahydro-2H-pyran-2,5-diyl]di(methylene) diacetate (11) Pd(OH)₂ (10% on C; 10 mg) was added to a stirred solution of Prins product 9h (100 mg, 0.225 mmol) in anhyd MeOH (3 mL). The mixture was degassed for a minute under vacuum and then stirred under H₂ gas (1 atm). After 24 h, when complete consumption of the starting material was observed, the mixture was filtered and concentrated in vacuo. The residue was then dissolved in dry CH₂Cl₂ (3 mL) and treated with Ac₂O (0.5 mL), Et₃N (0.5 mL), and a catalytic amount of DMAP. The mixture was stirred for 12 h and then the reaction was quenched with sat. aq NaHCO₃ (5 mL). The aqueous layer was extracted with EtOAc (2 × 5 mL), and the combined organic extracts were washed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane–EtOAc, 4:1) to give a colorless oil; yield: 73 mg (83%); [α]_D ²⁵ +12.0 (c 1.0, CH₂Cl₂). IR (neat): 2925, 1744, 1371, 1227, 1044 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.03 (m, 4 H), 5.10–5.05 (m, 1 H), 4.19 (dd, J = 12.2, 5.6 Hz, 1 H), 4.09 (ddd, J = 17.3, 12.0, 2.6 Hz, 2 H), 3.70– 3.64 (m, 2 H), 3.54 (dd, J = 11.8, 3.1 Hz, 1 H), 3.35 (t, J = 11.2 Hz, 1 H), 2.32 (s, 3 H), 2.09 (s, 3 H), 2.01 (s, 3 H), 1.99–1.93 (m, 1 H), 1.70 (s, 3 H), 1.36 (d, J = 6.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 171.15, 170.66, 169.16, 137.32, 136.85, 130.24, 127.14, 126.86, 126.60, 77.82, 75.20, 72.69, 63.66, 62.31, 47.41, 43.47, 21.06, 20.88, 20.37, 19.81, 19.37. HRMS: m/z [M + Na]⁺ calcd for C₂₁H₂₈NaO₇: 415.1733; found: 415.1731.