Total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids, xiamycins C–F via Csp3–H functionalization

Concise total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids, xiamycin C (2a), D (2b), E (2c) and F (2d), have been achieved via a late-stage oxidative δ-Csp3–H functionalization of an advanced pentacyclic enone intermediate 8. This strategy takes advantage of ipso-nitration of naturally occurring abietane diterpenoids to synthesize o-bromo nitroarene derivative 11. A Suzuki–Miyaura coupling of 11 with phenylboronic acid followed by Cadogan's ring closure provided a modular approach to a carbazole ring required for a functionalized pentacyclic core of indolosesquiterpene alkaloids.


Preparation of Fuming Nitric Acid:
In an oven-dried round-bottom flask 40 g of powder potassium nitrate was charged with 60 mL of conc. sulfuric acid. Then the solution was set with a distillation condenser and distillation was performed at 130 ᵒ C to collect around 30 mL of fuming nitric acid.
Then solid compound (+)-12 (800 mg, 2.03 mmol, 1.0 equiv.) was directly charged into the previously cooled fuming nitric acid system and the whole solution was scratched well with a spatula maintaining the -40 ᵒC temperature. After scratching the solution for 5 minutes, the reaction was quenched with excess of water. The reaction mixture was then partitioned Supporting Information 6 S6 between water and dichloromethane. The organic layer was then washed with saturated bicarbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was then purified by column chromatography with 5% EtOAc in n-hexane to afford (+)-11 as yellow foam [635 mg, 79% yield (brsm)].

Suzuki-Miyaura Coupling of (+)-11 with Phenylboronic acid:
In an oven-dried round-bottom flask, compound (+)-11 (2.1 g, 5.3 mmol, 1 equiv.) was taken in 20 mL mixed solvent system of benzene: ethanol: water (2:1:1) equipped with a magnetic Supporting Information 8 S8 stir-bar. Then benzene boronic acid (775 mg, 6.36 mmol, 1.2 equiv.) and potassium carbonate (1.5 g, 10.6 mmol, 2 equiv.) were directly added to the reaction mixture. After the complete dissolution of the solid materials the reaction mixture was degassed for 10 mins using N2 gas balloon. Then tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.11 mmol, 0.02 equiv.) was rapidly added and the reaction mixture was allowed to reflux at 100  C on a preheated oil-bath for 8 h maintaining N2 inertness until the full consumption of starting material (monitored by TLC). The mixture was cooled and was poured into an aqueous ammonium chloride solution.
The mixture was extracted with 20% EtOAc in n-hexane (25 mL X 2). The combined organic layers were washed with brine (20 mL X 1), dried over Na2SO4 and concentrated in a rotary evaporator under reduced pressure. Now the crude product was purified by flash chromatography with 5% EtOAc in n-hexane to afford (+)-10 as yellow foam (1.92 g, 92% yield).

Synthesis of Enone (+)-8 by reaction with SeO2 in AcOH and water:
Supporting Information 15 S15 A mixture of (+)-7 (770 mg, 1.45 mmol, 1.0 equiv.) and selenium dioxide (804 mg, 7.27 mmol, 5.0 equiv.) were dissolved in 12 mL solvent mixture of acetic acid and water (3:1). The reaction mixture was refluxed for 6 h on a preheated oil-bath at 100 ºC. After complete consumption of starting material (monitored by TLC) the reaction mixture was cooled to room temperature and diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate solution.
The reaction mixture was extracted with EtOAc (10 mL X 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in a rotary evaporator under reduced pressure. The residue was purified by flash chromatography with 20% EtOAc in n-hexane to afford (+)-8 as yellow gel (643 mg, 84% yield).

Supporting Information 22
S22 taken in 2 mL of Ac2O and catalytic H2SO4 was added at 25 ºC. After that reaction mixture was run for 1 h at 25 ºC. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (5 mL). The organic layer was quenched with saturated NaHCO3 solution (5 mL X 1). Then reaction mixture was partitioned between water and EtOAc (5 mL X 2) and organic layer was dried over Na2SO4 and concentrated under reduced pressure.

Synthesis of compound (−)-19 from (−)-8c:
In an oven-dried round-bottom flask compound (−)-8c (32 mg, 0.06 mmol, 1.0 equiv.) was taken in 1 mL of Ac2O and catalytic H2SO4 was added at 25 ºC. After 5 minutes solid NBS (11 mg, 0.061 mmol, 1.1 equiv.) was added to reaction mixture and run for 1 h at 25 ºC. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous Na2S2O3 solution. The reaction mixture was then partitioned between water and EtOAc (3 mL X 2). The organic layer was washed with saturated NaHCO3 solution (2 mL X 1) and dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography with 16% EtOAc in n-hexane to afford (−)-19 as yellow gel (21 mg, 57% yield).

Partial Hydrogenation of (+)-20:
In an oven-dried round-bottom flask compound (+)-20 (50 mg, 0.092 mmol, 1.0 equiv.) was taken in 3 mL of methanol and degassed with N2 balloon for 10 min and then 2.5 mg of Pd/C (5% w/w) was added to the reaction mixture. H2 gas was purged constantly at 25 ºC using a H2 gas balloon for 2 h until the full consumption of starting material. Then the solvent was evaporated and the crude product was purified by column chromatography with 30% EtOAc in n-Hexane to afford compound (+)-21 with partial hydrogenation as white foam (45.8 mg, 92% yield). [α] 25 589 = +62.54 (c = 0.78, CHCl3).

S28
In an oven-dried round-bottom flask (+)-20 (260 mg, 0.48 mmol, 1.0 equiv.) was taken in 5 mL of methanol and degassed with N2 balloon for 10 min and then 13 mg of Pd/C (5% w/w) was added to the reaction mixture. H2 gas was purged constantly at 25 ºC using a H2 gas balloon for 12 h until the full consumption of starting material. Then the solvent was evaporated and the crude product was purified by column chromatography with 30% EtOAc in n-Hexane to afford diketone (+)-5 as colorless foam (226 mg, 88% yield). [α] 25 589 = +84.00 (c = 0.84, CHCl3).      (+)-2d (15 mg, 0.040 mmol, 1.0 equiv.) was taken in MeOH (2 mL) and cooled the reaction vessel at −10 °C. NaBH4 was slowly added (1.5 mg, 0.040 mmol, 1.0 equiv.) portion wise and it was allowed to stir for an additional 4 h. Upon completion of the reaction (judged by running TLC), the reaction was quenched with saturated aqueous NH4Cl solution (2 mL), and the aqueous mixture was extracted with EtOAc (5 mL X 3). All organic layers were dried over Na2SO4 and concentrated in a rotary evaporator under vacuum to give crude product, which

Comparison of 13 C-NMR Data:
Oh's Isolation report