Total synthesis of (±)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization

The synthesis of tetracyclic indole alkaloid (±)-decursivine was accomplished using BINOL-phosphoric acid catalyzed tandem oxidative cyclization as a key step with (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidizing agent. This represents one of the shortest and highest yielding routes for the synthesis of (±)-decursivine from readily available starting materials.


Results and discussion
In continuation of our work towards developing antimalarial heterocyclic compounds 12,13 and indole-containing natural products 14,15 , we report a 5-step total synthesis of (±)-decursivine, an antimalarial indole alkaloid, from inexpensive and commercially available starting materials. Our retrosynthetic plan is illustrated in Fig. 2. We envisaged that decursivine 1 could be obtained from 3 via tandem oxidative cyclization, which in turn could be prepared by a simple coupling reaction from readily available starting materials, serotonin hydrochloride 4 and 3,4-(methylenedioxy)cinnamic acid 5.
Our initial efforts towards the synthesis of (±)-decursivine 1 is described in Fig. 3. Coupling of serotonin hydrochloride 4 with 3,4-(methylenedioxy)cinnamic acid 5 using HBTU afforded key intermediate 3. Direct conversion of 3 into 1 via tandem oxidative cyclization (oxidation through single-electron transfer followed by cycloaddition) was unsuccessful via both photochemical and electrochemical approaches despite varying oxidizing agents and reaction conditions. In many attempts, 3 underwent decomposition (Table 1). www.nature.com/scientificreports/ These failures motivated us to protect the indole and amide -NH groups (Fig. 4). The hydroxy group of 3 was first protected using TBSCl, then the indole and amide -NH groups were protected by heating a mixture of 6, Boc 2 O, and DMAP in THF at reflux. Silyl group deprotection of compound 7 by treatment with TBAF yielded hydroxy derivative 8. With compound 8 on hand, we investigated tandem oxidative cyclization reaction under various conditions ( Table 2).
Oxidation of Boc-protected compound 8 through single-electron transfer, followed by cyclization using different oxidizing agents or photochemical approaches (entries 1-7) did not yield the desired product. Instead, compound 8 underwent decomposition. We then turned our attention towards a two-electron oxidation/cyclization approach using a hypervalent iodine reagent. In the literature, hypervalent iodine has been used for the oxidative [3 + 2] cycloaddition of various phenols and styrenes to yield 2,3-dihydrobenzofuran derivatives [16][17][18][19][20] . Based upon these findings, we treated compound 8 with a hypervalent iodine reagent, (bis(trifluoroacetoxy)iodo) benzene (PIFA), and product 1 was obtained in 47% yield (entry 8). The moderate yield of the product could be due to partial decomposition of the quinone intermediate (formed in situ) before undergoing the cycloaddition. Masson's group 21 recently reported the use of chiral phosphoric acid to catalyze the intermolecular oxidative [3 + 2] cycloaddition for the asymmetric synthesis of 3-aminodihydrobenzofurans. With the idea of stabilizing the    (entry 9) as a catalyst. Under these conditions, the reaction was sluggish, forming trace amounts of product that was only observed by LC-MS. Using (±)-BINOL phosphoric acid (entry 10), the reaction was faster and the product was obtained in higher yield. The proposed mechanism for the (±)-BINOL phosphoric acid-catalyzed [3 + 2] cycloaddition is shown in Fig. 5. PIFA oxidizes 8 to form quinone intermediate 9 which may be stabilized by (±)-BINOL phosphoric acid through hydrogen bonding 21 to give adduct 10. Intramolecular cyclization of adduct 10 forms eight-membered lactam intermediate 11 that loses a proton to generate phenolic species 12. During this process, (±)-BINOL phosphoric acid is released for the next catalytic cycle. Finally, annulation of 12 leads to the formation of 2,3-dihydrobenzofuran containing compound 13 (N-Boc-protected decursivine) 8 .

Conclusion
In conclusion, we have developed a concise total synthesis of (±)-decursivine, an antimalarial natural product via a cascade oxidative cyclization using PIFA as an oxidizing agent and (±)-BINOL phosphoric acid as a catalyst with a good overall yield of 43.8%.

Synthesis of compound (±)-decursivine 1.
(i) Without catalyst: To a solution of compound 8 (30 mg, 0.05 mmol) in HFIP (5 mL) was added PIFA (28 mg, 0.06 mmol) in one portion under an argon atmosphere and the mixture was stirred at room temperature for 6 h. TFA (20 µL, 0.26 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. The crude product was purified using flash chromatography on a Biotage Snap Cartridge (KP-Sil 10 g) using a gradient solvent system (30% to 90% ethyl acetate in hexanes) to give product 1 ( www.nature.com/scientificreports/ (ii) With catalyst: To a solution of compound 8 (30 mg, 0.05 mmol) in HFIP (5 mL) was added (±)-BINOL phosphoric acid (1 mg, 0.0025 mmol) and PIFA (28 mg, 0.06 mmol) in one portion under an argon atmosphere and the reaction mixture was stirred at room temperature for 3 h. TFA (20 µL, 0.26 mmol) was then added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NaHCO 3 and extracted with EtOAc (3 × 20 mL). The combined organic phases was dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure. Crude product was purified using flash chromatography on a Biotage Snap Cartridge (KP-Sil 10 g) using a gradient solvent system (30% to 90% ethyl acetate in hexanes) to give product 1 (14 mg, 74% yield). 1 H NMR and mass data are same as mentioned above and matches with the literature data 1,5,6,8 .