Synlett 2017; 28(11): 1346-1352
DOI: 10.1055/s-0036-1588156
letter
© Georg Thieme Verlag Stuttgart · New York

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

Parasuraman Rajasekaran
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India   Email: [email protected]
,
Yakkala Mallikharjunarao
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India   Email: [email protected]
,
Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208016, India   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 12 January 2017

Accepted after revision: 19 February 2017

Publication Date:
09 March 2017 (online)


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.

Supporting Information

 
  • 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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%); Rf  = 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.