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Synlett 2020; 31(16): 1581-1586
DOI: 10.1055/s-0040-1707201
DOI: 10.1055/s-0040-1707201
letter
Total Synthesis of Stemoamide, 9a-epi-Stemoamide, and 9a,10-epi-Stemoamide: Divergent Stereochemistry of the Final Methylation Steps
Financial support from the Academy of Finland (Projects 259532, 297874, 307624) and NKFIH Hungary (Grant No. K-112028) are gratefully acknowledged.Further Information
Publication History
Received: 16 April 2020
Accepted after revision: 15 June 2020
Publication Date:
27 July 2020 (online)
![](https://www.thieme-connect.de/media/synlett/202016/lookinside/thumbnails/st-2020-b0218-l_10-1055_s-0040-1707201-1.jpg)
Abstract
Total syntheses of stemoamide, 9a-epi-stemoamide, and 9a,10-epi-stemoamide by a convergent A + B ring-forming strategy is reported. The synthesis required a diastereoselective late-stage methylation of the ABC stemoamide core that successfully enabled access to three of the four possible diastereomeric structures. For the natural stemoamide series, the diastereoselectivity can be rationalized both by kinetic and thermodynamic arguments, whereas for the natural 9a-epi-stemoamide series, the kinetic selectivity is explained by the prepyramidalization of the relevant enolate.
Key words
total synthesis - Stemona alkaloids - cyclic stereocontrol - Mukaiyama–Michael reaction - DFT calculationSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1707201.
- Supporting Information
-
References and Notes
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- 17 See the Supporting Information for {1H}13C shift comparisons.
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- 19 The DFT calculations were carried out using the ωB97X-D functional along with the Def2SVP and Def2TZVPP basis sets. The reported relative stabilities were obtained from solution-phase Gibbs free energies. For details, see the Supporting Information.
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- 20b In our hands, rapid quench and extraction of the norstemoamide (1) methylation reaction gave a mixture of diastereomers that was characterized without further purification.
- 21 tert -Butyl ( RS )-2-oxo-5-{(2 R ,3 R )-5-oxo-2-[3-(tosyloxy)propyl]tetrahydrofuran-3-yl}-2,5-dihydro-1 H -pyrrole-1-carboxylate (14, -14) epi To a stirred solution of tosylate 12 (100 mg, 0.34 mmol, 1.0 equiv) at –25 °C in DCM (10 mL) was added TBSOTf (8 μL, 9 mg, 0.1 equiv) and HFIP (35 μL, 57 mg, 1.0 equiv). To this solution was then added silyloxypyrrole 13 (201 mg, 0.67 mmol, 2.0 equiv) in DCM (0.5 mL), and the resulting solution was stirred for 8 h. The reaction was quenched with pH 7.0 buffer (2 mL), and vigorously stirred for 1 h at rt to hydrolyze all silylated product. The resulting mixture was then extracted with EtOAc (5 × 3 mL), the combined organic layers dried with Na2SO4, and concentrated in vacuo. Purification of the residue by CombiFlash automated chromatography system (10% EtOAc/hexane to 80% EtOAc/hexane) afforded 14 and epi-14 as a white foam (121 mg, 75%, dr ca. 1:1 with slight variation between batches). Rf (60% EtOAc/hexane) = 0.19 (ninhydrin, brown). 1H NMR (500 MHz, CDCl3, diastereomers overlapping, integrals were normalized to 1 H for signal at δ = 6.21 ppm): δ = 7.75–7.82 (m, 2 H), 7.33–7.39 (m, 2 H), 7.07 (dt, J = 6.2, 2.1 Hz, 1 H), 6.29–6.25 (m, 1 H), 4.74 (dt, J = 4.0, 1.8 Hz, 0.5 H), 4.72 (dt, J = 4.0, 1.8 Hz, 0.5 H), 4.42–4.40 (m, 0.5 H), 4.17–4.11 (m, 1 H), 4.08–3.90 (m, 1.5 H), 3.91–3.88 (m, 0.5 H), 3.26–3.22 (m, 0.5 H), 3.22–3.16 (m, 0.5 H), 2.88–2.83 (m, 0.5 H), 2.45 (s, 3 H), 2.43–2.38 (m, 0.5 H), 2.04 (t, J = 2.5 Hz, 0.5 H), 1.95–1.62 (m, 4 H), 1.57 (s, 3.5 H), 1.56 (s, 3.5 H). 13C NMR (126 MHz, CDCl3, diastereomers overlapping): δ = 174.8, 168.2, 168.1, 149.9, 149.8, 145.52, 145.49, 145.2, 145.1, 132.9, 130.5, 130.13, 130.10, 129.8, 128.0, 84.5, 84.3, 80.5, 78.7, 69.52, 69.47, 63.1, 62.7, 40.1, 40.0, 31.8, 31.7, 30.8, 28.3, 28.2, 28.0, 25.1, 25.02, 21.83, 21.82 ppm. FTIR (film): ν = 2978 (weak), 2934 (weak), 1769, 1738, 1771, 1353, 1310, 1172, 1153, 816, 662, 553 cm–1. HRMS (ESI+): m/z [M + Na] calcd for [C23H29NO8SNa+]: 502.1506; found: 502.1511, Δ = –0.5 mDa.
- 22 Stemoamide (2) To a solution of norstemoamide 1 (5.0 mg, 0.024 mmol, 1.0 equiv) in THF (0.5 mL) LiHMDS (27 μL, 4.4 mg, 0.026 mmol, 1.1 equiv, 1.0 M in THF) was added at –78 °C. After 10 min the reaction mixture was warmed to 0 °C for 10 min and then recooled to –78 °C. To the stirred yellow suspension, methyl iodide (7 μL, 17 mg, 0.12 mmol, 5.0 equiv) was added dropwise. After 3 h the reaction mixture was quenched with sat. aq NH4Cl (0.5 mL) and extracted with EtOAc (5 × 2 mL). Combined organic layers were dried with Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc to 5% MeOH/EtOAc) gave (±)-stemoamide (2) as a white solid (3.3 mg, 62%). Note: X-ray quality crystals were obtained upon slow evaporation from EtOAc. Spectroscopic data matched those reported previously.3,4a,b,e Rf (10% MeOH/EtOAc) = 0.34 (KMnO4). 1H NMR (500 MHz, CDCl3): δ = 4.19 (app. td, J = 4.8, 10.7 Hz, 1 H), 4.16 (td partially obstructed, J = 3.0, 14.8 Hz, 1 H), 4.02 (td, J = 10.7, 6.4 Hz, 1 H), 2.26–2.68 (m, 1 H), 2.60 (dq, J = 12.3, 6.9 Hz, 1 H), 2.40–2.46 (m, 4 H), 2.04–2.10 (m, 1 H), 1.87–1.91 (m, 1 H), 1.74 (app. dq, J = 12.3, 10.7 Hz, 1 H), 1.51–1.60 (m, 2 H), 1.33 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 177.5, 174.2, 77.8, 56.0, 52.9, 40.4, 37.5, 35.0, 30.8, 25.8, 22.7, 14.3 ppm. FTIR (film): ν = 3501, 2935, 1764, 1676, 1420, 1190, 1008 cm–1.
- 23 9a,10-epi-Stemoamide (9a,10-epi-2) To a solution of 9a-epi-norstemoamide (9a-epi-1, 16.0 mg, 0.76 mmol, 1.0 equiv) in THF (1 mL) at –78 °C was added LiHMDS (84 μL, 14 mg, 0.84 mmol, 1.1 equiv, 1.0 M in THF). After 10 min the reaction mixture was warmed to 0 °C for 10 min and then recooled to –78 °C. To the stirred yellow suspension methyl iodide (38.8 μL, 54 mg, 0.38 mmol, 5.0 equiv) was added dropwise. After 3 h the reaction mixture was quenched with sat. aq NH4Cl (0.5 mL) and extracted with EtOAc (5 × 2 mL). Combined organic layers were dried with Na2SO4 and concentrated in vacuo. Flash chromatography (5% MeOH/EtOAc) gave 9a,10-epi-stemoamide (9a,10-epi-2) as a white solid (12.0 mg, 70%); mp 127.3–127.9 °C. Rf (10% MeOH/EtOAc) = 0.32 (KMnO4). 1H NMR (500 MHz, CDCl3): δ = 4.51 (td, J = 10.7, 4.8 Hz, 1 H), 3.90 (ddd, J = 14.6, 6.3, 3.6 Hz, 1 H), 3.65 (ddd, J = 10.4, 7.3, 6.2 Hz, 1 H), 3.04 (ddd, J = 14.3, 10.7, 3.1 Hz, 1 H), 2.81 (app. pent, J = 7.7 Hz, 1 H), 2.52–2.41 (3 H, m), 2.37–2.29 (1 H, m), 2.25 (app. td, J = 7.8, 10.4 Hz, 1 H), 1.98–1.66 (4 H, m), 1.30 (d, J = 7.7 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 178.2, 174.1, 80.6, 57.9, 52.5, 40.9, 38.6, 30.3, 30.2, 23.3, 21.8, 11.0 ppm. FTIR (film): ν = 2940, 1773, 1681, 1208, 1005 cm–1. HRMS (ESI+): m/z [M + H] calcd for [C12H17NO3H+]: 224.1208; found: 224.1201, Δ = –0.7 mDa.
- 24 9a-epi-Stemoamide (9a-epi-2) To a solution of 9a,10-epi-stemoamide (9a,10-epi-2, 6.0 mg, 2.7 μmol, 1.0 equiv) in methanol (0.5 ml) was added potassium carbonate (3.7 mg, 2.7 μmol, 1.0 equiv). The resulting suspension was stirred at rt for 48 h, concentrated in vacuo and acidified with 2 M HCl (0.5 mL). The resulting solution was extracted with DCM (5 × 1 mL) and the combined organic layers dried with Na2SO4. The solvent was evaporated in vacuo to give a 3:1 mixture of 9a-epi-stemoamide (9a-epi-2) and 9a,10-epi-stemoamide (9a,10-epi-2, 5.0 mg, 84% recovery). A sample of 9a-epi-2 for further NMR analysis was purified by flash column chromatography (5% MeOH/EtOAc to 8% MeOH/EtOAc). Rf (10% MeOH/EtOAc) = 0.32 (KMnO4 stain). 1H NMR (500 MHz, CDCl3): δ = 4.30 (ddd, J = 10.9, 10.0, 5.2 Hz, 1 H), 3.89 (ddd, J = 14.6, 6.4, 3.3 Hz, 1 H), 3.58 (td, J = 9.1, 6.6 Hz, 1 H), 3.14 (ddd, J = 14.6, 9.3, 3.4 Hz, 1 H), 2.37–2.52 (m, 3 H), 2.28–2.36 (m, 1 H), 2.24 (ddt, J = 15.2, 8.0, 3.1 Hz, 1 H), 1.94 (dt, J = 11.0 Hz, 10.2 Hz, 1 H), 1.79–1.88 (m, 2 H), 1.73 (ddt, J = 13.4, 11.1, 6.7 Hz, 1 H), 1.67–1.61 (m, 1 H), 1.39 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 177.6, 174.3, 81.2, 62.2, 55.4, 40.4, 40.0, 30.9, 30.5, 25.0, 22.5, 15.5 ppm. FTIR (film): 2924, 2851, 1774, 1683, 1278, 1177, 1010 cm–1. HRMS (ESI+): m/z [M + H] calcd for [C12H17NO3H+]: 224.1286; found: 224.1300, Δ = –1.4 mDa.
- 25 For an expanded computational study of the effect of enolate pyramidalization on the stereochemistry of methylation reactions of trans-fused butyrolactones, see: Csókás D, Siitonen JH, Pihko PM, Pápai I. Org. Lett. 2020; 22: 4597
For recent total syntheses, see:
For representative similar methylations of ring-fused butanolides, see: