Synthesis of protoberberine alkaloids

A One-Pot Cascade to Protoberberine Alkaloids via Stevens Rearrangement of Nitrile-Stabilized Ammonium Ylides

“…9,10 These activities have partly been attributed to their DNA intercalating capability 11 as well as to their general electrophilic reactivity. 12 In spite of their biological activity, surprisingly few methods 13 for the synthesis of the quaternary protoberberines have been developed. 14−21 These include Donohoe's palladium-catalyzed enolate arylation constructing the complete carbon backbone before introduction of the nitrogen 22 and Kametani's thermolysis of benzocyclobutenesubstituted 3,4-dihydroisoquinolines, which undergo ring enlargement via o-quinodimethane intermediates.…”

“…32,48 5.18 (d, J = 14.9 Hz, 1H, H-2), 4.95 (d, J = 14.9 Hz, 1H, H-2), 4.09 (t, J = 6.0 Hz, 2H, H-3′), 3.82 (s, 3H, C 6 ′−OCH 3 ), 3.77 (s, 3H, C 7 ′−OCH 3 ), 3.34 (t, J = 6.0 Hz, 2H, C-4′). 13 49 To a solution of tetrahydroisoquinoline (10.5 g, 10.0 mL, 78.8 mmol) in DCM (150 mL) was added NBS (15.7 g, 88.2 mmol, 1.1 equiv), and the mixture was stirred for 1 h at room temperature. To the mixture, an aqueous 30% NaOH solution (50 mL) was added dropwise over a period of 30 min, and the mixture was stirred for 2.5 h at ambient temperature.…”

“…1 H NMR, COSY (600 MHz, DMSO-d 6 ): δ = 10.04 (s, 1H, H-8), 9.12 (s, 1H, H-13), 8.42 (d, J = 8.4, 1H, H-9), 8.27 (d, J = 8.1, 1H, H-12), 8.20 (ddd, J = 8.1, 6.8, 1.1 Hz, 1H, H-11), 7.97 (ddd, J = 8.4, 6.8, 1.1 Hz, 1H, H-10), 7.77 (s, 1H, H-1), 7.13 (s, 1H, H-4), 4.88 (t, J = 6.4 Hz, 2H, H-6), 3.95 (s, 3H, OCH 3 ), 3.88 (s, 3H, OCH 3 ), 3.26 (t, J = 6.4 Hz, 2H, H-5). 13 C NMR, HMBC, HSQC (151 MHz, DMSO-d 6 ): δ = 151.9 (C q OMe), 150.4 (C8), 148.8 (C q OMe), 139.9 (C13a), 138. Method B.…”

“…1 H NMR, COSY (600 MHz, DMSO-d 6 ): δ = 9.55 (s, 1H, H-8), 8.88 (s, 1H, H-13), 7.71 (s, 1H, H-9), 7.66 (s, 1H, H-1), 7.62 (s, 1H, H-12), 7.10 (s, 1H, H-4), 4.79 (t, J = 6.4 Hz, 2H, H-6), 4.07 (s, 3H, OCH 3 ), 4.00 (s, 3H, OCH 3 ), 3.93 (s, 3H, OCH 3 ), 3.87 (s, 3H, OCH 3 ), 3.22 (t, J = 6.4 Hz, 2H, H-5). 13 C NMR, HMBC, HSQC (151 MHz, DMSO-d 6 ): δ = 157.4 (C q OMe), 152.2 (C q OMe), 151.5 (C q OMe), 148.7 (C q OMe), 145.6 (C8), 138.4 (C13a), 136.7 (C12a), 128.6 (C4a), 122.0 (C8a), 118.9 (C13b), 118.0 (C13), 111.3 (C4), 108.5 (C1), 106.5 (C9), 4.76 (t, J = 6.3 Hz, 2H, H-6), 3.93 (s, 3H, OCH 3 ), 3.87 (s, 3H, OCH 3 ), 3.21 (t, J = 6.3 Hz, 2H, H-5). 13 C NMR, HMBC, HSQC (75 MHz, DMSO-d 6 ): δ = 156.0 (C q OCH 2 O), 151.7 (C q OMe), 150.8 (C q OCH 2 O), 148.7(C q OMe), 145.9 (C8), 138.9 (C14a), 138.9 (C q ), 128.8 (C4a), 123.5 (C q ), 118.7 (C14), 118.7 (C14b), 111.4 (C4), 108.8 (C1), 103.9 (C9), 103.7 (C11), 102.5 (C13), 56.2 (OCH 3 ), 55.9 (OCH 3 ), 54.7 (C6), 26.0 (C5).…”

“…13 C NMR, HMBC, HSQC (151 MHz, DMSO-d 6 ): δ = 157.4 (C q OMe), 152.2 (C q OMe), 151.5 (C q OMe), 148.7 (C q OMe), 145.6 (C8), 138.4 (C13a), 136.7 (C12a), 128.6 (C4a), 122.0 (C8a), 118.9 (C13b), 118.0 (C13), 111.3 (C4), 108.5 (C1), 106.5 (C9), 4.76 (t, J = 6.3 Hz, 2H, H-6), 3.93 (s, 3H, OCH 3 ), 3.87 (s, 3H, OCH 3 ), 3.21 (t, J = 6.3 Hz, 2H, H-5). 13 C NMR, HMBC, HSQC (75 MHz, DMSO-d 6 ): δ = 156.0 (C q OCH 2 O), 151.7 (C q OMe), 150.8 (C q OCH 2 O), 148.7(C q OMe), 145.9 (C8), 138.9 (C14a), 138.9 (C q ), 128.8 (C4a), 123.5 (C q ), 118.7 (C14), 118.7 (C14b), 111.4 (C4), 108.8 (C1), 103.9 (C9), 103.7 (C11), 102.5 (C13), 56.2 (OCH 3 ), 55.9 (OCH 3 ), 54.7 (C6), 26.0 (C5). ESI-MS: m/z (%) = 336.2 (100) [M] + .…”