Molecular Iodine Assisted Electrocyclisation: Synthesis of Arcyriaflavin A and Formal Synthesis of Staurosporinone

Prachi Torney; Rajendra Shirsat; Santosh Tilve

doi:10.1055/s-0034-1378536

Synlett, Table of Contents

Synlett 2014; 25(15): 2121-2126
DOI: 10.1055/s-0034-1378536

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Molecular Iodine Assisted Electrocyclisation: Synthesis of Arcyriaflavin A and Formal Synthesis of Staurosporinone

Prachi Torney

Department of Chemistry, Goa University, Goa 403206, India Fax: +91(832)6519317 Email: stilve@unigoa.ac.in

,

Rajendra Shirsat

Department of Chemistry, Goa University, Goa 403206, India Fax: +91(832)6519317 Email: stilve@unigoa.ac.in

,

Santosh Tilve*

Department of Chemistry, Goa University, Goa 403206, India Fax: +91(832)6519317 Email: stilve@unigoa.ac.in

› Author Affiliations

Abstract

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Abstract

A new method for the synthesis of the indolocarbazole alkaloid arcyriaflavin A is described. The synthetic strategy employs a graphite-catalysed alkenation, one-pot oxidation–Wittig reaction, iodine-catalysed electrocyclisation and nitrene insertion as the key steps. The strategy also constitutes a formal synthesis of another indolocarbazole alkaloid staurosporinone.

Key words

indolocarbazole - electrocyclisation - iodine - aromatisation - graphite - domino

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References

References and Notes

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19 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA. Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PM. W, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 03, Revision C.02. Gaussian, Inc; Wallingford CT: 2004
20 Synthesis of 3-Vinyl Indole-2-methanols 8a,b: To a magnetically stirred suspension of indole-2-methanol (2.0 g, 13.6 mmol) and graphite (0.2 g, 16.7 mmol) in a 1:1 mixture of EtOH and H₂O (20 mL) was added dimethyl acetylenedicarboxylate (2.8 g, 20.4 mmol) dropwise and the mixture was stirred at r.t. for 48 h. The mixture was then filtered, washed with EtOH (5 mL), the filtrate concentrated and the residue extracted with CHCl₃ (3 × 10 mL). The combined organic extracts were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a mixture of crude alcohols 8a,b (3.5 g, 90%). These were separated using column chromatography (CHCl₃–MeOH, 95:5). The E/Z ratio after isolation was found to be 88:12. Z-Isomer 8a: yellow solid; mp 169–170 °C. IR (KBr): 3523–3381 (br), 1712 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 3.70 (s, 3 H, OMe), 3.84 (s, 3 H, OMe), 4.67 (d, J = 5.2 Hz, 2 H, CH₂), 5.74 (t, J = 5.2 Hz, 1 H, OH), 6.15 (s, 1 H, HC=C), 7.10 (t, J = 5.2 Hz, 1 H, ArH), 7.16 (t, J = 7.2 Hz, 1 H, ArH), 7.46 (d, J = 8.4 Hz, 2 H, ArH), 11.30 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 51.9 (Me), 52.7 (Me), 56.2 (CH₂), 105.7 (Cq), 112.6 (CH), 113.4 (CH), 118.9 (CH), 121.2 (CH), 122.5 (CH), 126.2 (CH), 135.7 (Cq), 142.9 (Cq), 143.9 (Cq), 166.0 (CO), 169.1 (CO). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₅NO₅Na: 312.0848; found: 312.0850. E-Isomer 8b: bright yellow oily liquid. IR (KBr): 3523–3381 (br), 1710 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 3.54 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 4.44 (d, J = 5.2 Hz, 2 H, OCH₂), 5.40 (t, J = 5.2 Hz, 1 H, OH), 6.83 (s, 1 H, HC=C), 6.97 (t, J = 7.6 Hz, 1 H, ArH), 7.08 (m, 2 H, ArH), 7.37 (d, J = 8.0 Hz, 1 H, ArH), 11.41 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 52.1 (Me), 53.1 (Me), 56.4 (Me), 105.0 (Cq), 111.9 (CH), 118.8 (CH), 119.8 (CH), 121.5 (CH), 126.1 (CH), 127.5 (Cq), 135.6 (Cq), 136.3 (Cq), 140.4 (Cq), 165.7 (CO), 167.8 (CO). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₅NO₅Na: 312.0848; found: 312.0850. Synthesis of 2,3-Divinylindole 7: A mixture of 8a,b (1.0 g, 3.44 mmol) and o-nitrobenzyltriphenylphosphonium bromide (4.94 g, 10.3 mmol) in CHCl₃ (20 mL) containing freshly prepared MnO₂ (1.5 g, 17.2 mmol) was stirred at r.t. for 12 h. After complete conversion of the alcohol to aldehyde (monitored by TLC) Et₃N (1.45 mL, 10.3 mmol) was added and the reaction was continued for a further 12 h. The mixture was then filtered and concentrated. The crude residue was purified using flash chromatography, eluting with EtOAc and hexanes (30:70) and isolated as an orange syrup (mixture of four isomers as seen from the ¹H NMR spectrum) in 75% yield (1.08 g). IR (KBr): 3350, 1720, 1710, 1519, 1340 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.51–4.12 (s, 6 H, 2 × OMe), 6.45–8.09 {m, [6.45 (d, J = 12.0 Hz), 6.74 (d, J = 7.6 Hz), 6.81 (d, J = 16.4 Hz), 8.10 (d, J = 1.2 Hz), 8.09 (d, J = 3.2 Hz)], 11 H, 2 × HC=C, ArH}, 8.92 (s, 1 H, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 50.9, 51.0 (OMe), 51.9, 52.0 (OMe), 109.9, 110.2 (CH), 110.5 (Cq), 114.2 (CH), 118.4. 118.5 (CH), 119.5 (2 × CH), 119.6 (CH), 120.7 (CH), 121.0 (CH), 122.4 (CH), 122.9 (CH), 123.8 (CH), 124.0 (CH), 125.4 (CH), 126.4 (CH), 126.6 (Cq), 126.9 (CH), 127.8 (CH), 128.5 (CH), 128.6 (CH), 129.2 (CH), 131.0 (CH), 131.1 (Cq), 131.6 (Cq), 131.7 (Cq), 132.0 (CH), 132.6 (CH), 132.8 (Cq), 134.7 (Cq), 135.6 (Cq), 135.9 (Cq), 136.1 (Cq), 146.6 (Cq), 164.4, 164.8 (CO), 166.0, 166.3 (CO). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₈N₂O₆Na: 429.1063; found: 429.1065. Synthesis of 2-Nitrophenyl Carbazole 6: To a solution of 2,3-divinyl indole 7 (0.2 g, 0.5 mmol) in nitromethane (30 mL) was added I₂ (30 mol%) and the mixture was heated at 95 °C for 24 h. The reaction was cooled to r.t. and to this was added sodium thiosulfate (0.5 g) and stirring was continued for 2 h. The mixture was filtered with suction and the filtrate was concentrated under reduced pressure to give the crude product which, on purification using flash chromatography (hexanes–EtOAc, 60:40), gave a yellow crystalline solid in 68% yield (0.135 g); mp 212–213 °C. IR (KBr): 3285, 1724, 1701, 1522, 1350 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 3.50 (s, 3 H, OMe), 4.01 (s, 3 H, OMe), 7.25 (t, J = 7.2 Hz, 1 H, ArH), 7.49 (m, 3 H, ArH), 7.63 (d, J = 8.0 Hz, 1 H, ArH), 7.69 (t, J = 7.8 Hz, 1 H, ArH), 7.80 (t, J = 7.6 Hz, 1 H, ArH), 7.94 (d, J = 8.0 Hz, 1 H, ArH), 8.15 (d, 1 H, ArH), 12.00 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 52.1 (OMe), 52.8 (OMe), 111.8 (CH), 113.4 (CH), 118.1 (Cq), 118.9 (Cq), 120.0 (CH, Cq), 121.6 (CH), 123.9 (CH), 127.3 (CH), 127.7 (Cq), 129.0 (CH), 132.0 (CH), 133.1 (CH), 135.5 (Cq), 135.7 (Cq), 140.7 (Cq), 141.0 (Cq), 148.1 (Cq), 166.6 (CO), 168.3 (CO). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₆N₂O₆Na: 427.0906; found: 427.0907. Synthesis of Indolocarbazole Diester 5: 2-Nitrophenyl carbazole 6 (0.15 g, 0.37 mmol) was refluxed in Ph₂O (5 mL) along with Ph₃P (0.24 g, 0.93 mmol) for 1.5 h. The mixture was then subjected to column chromatography during which Ph₂O was eluted using hexanes. Further elution using EtOAc and hexanes (55:45) furnished pale yellow crystals of indolocarbazole diester in 55% yield (0.076g); mp >300 °C. IR (KBr): 3491, 1686 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 4.01 (s, 6 H, OMe), 7.25 (t, J = 7.6 Hz, 2 H, ArH), 7.49 (t, J = 7.6 Hz, 2 H, ArH), 7.78 (d, J = 8.0 Hz, 2 H, ArH), 8.10 (d, J = 8.0 Hz, 2 H, ArH), 11.64 (s, 2 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 52.5 (2 × OMe), 112.0 (2 × CH), 115.9 (2 × Cq), 118.2 (2 × Cq), 119.7 (2 × CH), 121.7 (2 × Cq), 121.7 (2 × CH), 125.8 (2 × CH), 26.7 (2 × Cq), 139.8 (2 × Cq), 168.6 (2 × CO). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₆N₂O₄Na: 395.1008; found: 395.1003. Synthesis of Anhydride 4: Indolocarbazole diester 5 (0.1 g, 0.27 mmol) was refluxed with KOH (0.1 g, 1.7 mmol) in MeOH for 12 h. The MeOH was then distilled off and the residue was dissolved in EtOAc. The solution was then extracted in H₂O (4 × 10 mL) and the combined aqueous layers were acidified using concd HCl. The brown precipitate was dissolved in EtOAc, the solution washed with H₂O, dried, filtered and concentrated. After trituration of the residue with Et₂O, the product was obtained as a brown solid in 85% yield (0.075 g); mp >300 °C. IR (KBr): 3391, 1819, 1730 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 7.38 (t, J = 7.2 Hz, 2 H, ArH), 7.59 (t, J = 8.0 Hz, 2 H, ArH), 7.84 (d, J = 8.2 Hz, 2 H, ArH), 8.75 (d, J = 8.0 Hz, 2 H, ArH), 11.99 (s, 2 H, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 112.4 (2 × CH), 115.6 (2 × Cq), 117.6 (2 × Cq), 120.8 (2 × CH), 120.9 (2 × Cq), 123.3 (2 × CH), 127.3 (2 × CH), 129.80 (2 × Cq), 140.2 (2 × Cq), 164.8 (2 × CO). Synthesis of Arcyriaflavin A (1): Anhydride 4 (0.2 g, 0.61 mmol) was heated with ammonium acetate at 140 °C for 3 h. On cooling, H₂O was added and the mixture was extracted with EtOAc (6 × 20 mL). The combined organic layers were dried, filtered and concentrated under reduced pressure to obtain orange crystals of arcyriaflavin A in 72% yield; mp >300 °C. IR (KBr): 3586, 3231, 1726, 1692 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 7.36 (t, J = 7.6 Hz, 2 H, ArH), 7.56 (t, J = 7.6 Hz, 2 H, ArH), 7.82 (d, J = 8.4 Hz, 2 H, ArH), 8.99 (d, J = 8.0 Hz, 2 H, ArH), 11.01 (s, 1 H, NH-imide), 11.85 (s, 2 H, NH-indole). ¹³C NMR (100 MHz, DMSO): δ = 112.0 (2 × CH), 115.5 (2 × Cq), 119.8 (2 × Cq), 120.23 (2 × CH), 121.5 (2 × Cq), 124.3 (2 × CH), 126.8 (2 × CH), 129.0 (2 × Cq), 140.3 (2 × Cq), 171.3 (2 × CO).

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