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Synlett 2014; 25(15): 2121-2126
DOI: 10.1055/s-0034-1378536
letter
© Georg Thieme Verlag Stuttgart · New York

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
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Publikationsverlauf

Received: 08. April 2014

Accepted after revision: 20. Juni 2014

Publikationsdatum:
06. August 2014 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information
 

  • References and Notes


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  • 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).