Synlett 2013; 24(15): 1998-2002
DOI: 10.1055/s-0033-1339484
letter
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis and Structural Revision of Incargutines A and B

Atsushi Kinbara
a  School of Pharmaceutical Sciences, Ohu University, Misumido 31-1, Tomita-machi, Koriyama, Fukushima 963-8611, Japan
,
Takehiro Yamagishi
a  School of Pharmaceutical Sciences, Ohu University, Misumido 31-1, Tomita-machi, Koriyama, Fukushima 963-8611, Japan
,
Hiroki Ouchi
a  School of Pharmaceutical Sciences, Ohu University, Misumido 31-1, Tomita-machi, Koriyama, Fukushima 963-8611, Japan
,
Hiroaki Miyaoka*
b  School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Fax: +81(42)6763073   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 12 June 2013

Accepted after revision: 01 July 2013

Publication Date:
12 August 2013 (online)


Abstract

We achieved the first total synthesis of (±)-incargutines A and B, which were isolated from the roots of Incarvillea arguta, utilizing In(OTf)3-catalyzed enolization of cyclohexenone derivatives subsequent to an intramolecular Alder–Rickert reaction. At first, we synthesized the proposed structures of incargutines A and B. The spectral data of the synthetic proposed compounds did not correspond to those of the natural products. Then, we synthesized the methyl regioisomers of the proposed structures. Spectral data of these synthetic compounds were identical to those of natural incargutines A and B. Therefore, the structures of incargutines A and B were clearly established to be the methyl regioisomers.

Supporting Information

 
  • References and Notes

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  • 14 Experimental Procedure and Analytical Data of (±)-Incargutine A (25)To a solution of alcohol 39 (85.5 mg, 0.305 mmol) in CH2Cl2 (5.0 mL) were added MCPBA (65%, 306 mg, 2.75 mmol) and Sc(OTf)3 (75.1 mg, 0.153 mmol) at 0 °C under Ar atmosphere, and the mixture was stirred at r.t. for 96 h. The reaction mixture was extracted with CH2Cl2, and the organic layer was washed with sat. aq NaHCO3 solution (3×) and 10% Na2S2O3 aq solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (hexane–EtOAc, 4:1) to give a mixture of the product and unidentified contaminants, which was used for the next reaction without further purification. To a suspension of the above mixture and NaHCO3 (156 mg, 1.86 mmol) in CH2Cl2 (5.0 mL) was added Dess–Martin periodinane (157 mg, 0.371 mmol) at 0 °C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched by addition of a mixture of sat. aq Na2S2O3 solution and sat. aq NaHCO3 solution (1:1), and the mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was used for the next reaction without further purification. To a solution of the above crude product in THF (3.0 mL) was added 10% HCl aq solution (3.0 mL) at 0 °C, and the mixture was stirred at r.t. for 12 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with sat. aq NaHCO3 solution, H2O and brine, and then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by a preparative TLC (hexane–EtOAc, 8:1) to give (±)-incar-gutine A (25, 30.8 mg, 40% yield, 3 steps) as a white solid; mp 166–167 °C. IR (neat): 3259, 1663, 1610, 1585, 1515, 1438 cm–1. 1H NMR (400 MHz, CDCl3): δ = 10.18 (1 H, s), 7.69 (1 H, d, J = 7.8 Hz), 7.31 (2 H, d, J = 8.5 Hz), 7.24 (1 H, m), 6.91 (2 H, d, J = 8.5 Hz), 4.91 (1 H, m), 3.59 (1 H, m), 3.26–3.40 (2 H, m), 2.36 (1 H, m), 1.79 (1 H, m), 0.82 (3 H, d, J = 6.9 Hz). 13C NMR (100 MHz, CDCl3): δ = 192.7, 155.3, 148.4, 146.5, 144.3, 133.0, 130.9, 129.9, 129.7, 129.7, 128.4, 115.4, 115.4, 37.7, 33.3, 29.9, 19.7. MS–FAB: m/z = 253 [M + H]+. HRMS–FAB: m/z [M + H]+ calcd for C17H17O2: 253.1229; found: 253.1218.
  • 15 Experimental Procedure and Analytical Data of (±)-Incargutine B (26)To a solution of (±)-incargutine A (25, 10.5 mg, 0.0416 mmol) and CH(OMe)3 (0.050 mL, 0.440 mmol) in MeCN (2.0 mL) was added Amberlyst-15 (7.3 mg) at 0 °C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched by addition of a sat. aq NaHCO3 solution. The mixture was filtered and then extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by a preparative TLC (hexane–EtOAc, 5:1) to give (±)-incargutine B (26, 11.5 mg, 93% yield) as a colorless oil. IR (neat): 3375, 1612, 1592, 1519, 1214, 1108 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.36 (1 H, d, J = 7.8 Hz), 7.27 (2 H, m), 7.08 (1 H, d, J = 7.8 Hz), 6.86 (2 H, d, J = 8.4 Hz), 5.41 (1 H, s), 4.81 (1 H, m), 3.55 (1 H, m), 3.37 (6 H, s), 2.92–3.04 (2 H, m), 2.30 (1 H, m), 1.71 (1 H, m), 0.80 (3 H, d, J = 6.9 Hz). 13C NMR (100 MHz, CDCl3): δ = 154.6, 146.9, 142.0, 138.7, 134.1, 132.2, 129.8, 129.8, 127.6, 124.6, 115.1, 115.1, 102.7, 53.2, 53.2, 38.2, 33.3, 29.3, 19.9. MS–FAB: m/z = 267, 298 [M]+. HRMS–FAB: m/z [M]+ calcd for C19H22O3: 298.1569; found: 298.1579.