Total Synthesis of Stemoamide, 9a-epi-Stemoamide, and 9a,10-epi-Stemoamide: Divergent Stereochemistry of the Final Methylation Steps

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 calculation

• References and Notes

• 1 New address: Department of Chemistry, Rice University, 6500 Main Street, Houston, TX 77030, USA.
• 2a Pilli RA, Ferreira de Oliveira MC. Nat. Prod. Rep. 2000; 17: 117
• 2b Pilli RA, Rosso GB, Ferreira de Oliveira MC. Nat. Prod. Rep. 2010; 27: 1908
• 3 Lin W.-H, Ye Y, Xu R.-S. J. Nat. Prod. 1992; 55: 571

For recent total syntheses, see:
• 4a Yoritate M, Takahashi Y, Tajima H, Ogihara C, Yokoyama T, Soda Y, Oishi T, Sato T, Chida N. J. Am. Chem. Soc. 2017; 139: 18386
• 4b Nakayama Y, Maeda Y, Hama N, Sato T, Chida N. Synlett 2016; 48: 1647
• 4c Mi X, Wang Y, Zhu L, Wang R, Hong R. Synthesis 2012; 44: 3432
• 4d Honda T, Matsukawaa T, Takahashia K. Org. Biomol. Chem. 2011; 9: 673
• 4e Torssel S, Wanngren E, Somfai P. J. Org. Chem. 2007; 72: 4246
• 4f Li Z, Zhang L, Qiu FG. Asian J. Org. Chem. 2014; 3: 52
• 4g Brito GA, Sarotti AM, Wipf P, Pilli RA. Tetrahedron Lett. 2015; 56: 6664
• 5 For the seminal work, see: Yasushi K, Koichi N. Bull. Chem. Soc. Jpn. 1996; 7: 2063
• 6 Gao P, Tong Z, Hu H, Xu P.-F, Liu W, Sun C, Zhai H. Synlett 2009; 2188

For representative similar methylations of ring-fused butanolides, see:
• 7a Matsumoto K, Koyachi K, Shindo M. Tetrahedron 2013; 69: 1043
• 7b Evans MA, Morken JP. Org. Lett. 2005; 7: 3371
• 7c Lee E, Yoon CH, Sung Y.-S, Kim YK, Yun M, Kim S. J. Am. Chem. Soc. 1997; 119: 8391
• 7d Jung ME, Im G.-YJ. Tetrahedron Lett. 2003; 49: 4962
• 8a Kemppainen EK, Sahoo G, Piisola A, Hamza A, Kótai B, Pápai I, Pihko PM. Chem. Eur. J. 2014; 20: 5983
• 8b Kemppainen EK, Sahoo G, Valkonen A, Pihko PM. Org. Lett. 2012; 14: 1086
• 9 The tosylation proceeded very slowly under standard TsCl/ DMAP/Et₃N conditions, see: Yoshida Y, Sakakura Y, Aso N, Okada S, Tanabe Y. Tetrahedron 1999; 55: 2183
• 10a Duret P, Figadère B, Hocquemiller R, Cavé A. Tetrahedron Lett. 1997; 51: 8849
• 10b Yu Q, Wu Y, Wu Y.-L, Xia L.-JTang M.-H. Chirality 2000; 12: 127
• 10c Ye J.-L, Zhang Y.-F, Liu Y, Zhang J.-Y, Ruan Y.-P, Huang P.-Q. Org. Chem. Front. 2015; 2: 697
• 11a Casiraghi G, Battistini L, Curti C, Rassu G, Zanardi F. Chem. Rev. 2011; 111: 3076
• 11b Casiraghi G, Rassu G. Synthesis 1995; 607
• 11c Jusseau X, Chabaud L, Guillou C. Tetrahedron 2014; 16: 2595
• 11d Suga H, Takemoto H, Kakehi A. Heterocycles 2007; 71: 361
• 12 Colomer I, Chamberlain AE. R, Haughey MB, Donohoe TJ. Nat. Rev. Chem. 2017; 1: 1
• 13 If the N-Boc group of 14 was removed before hydrogenation, a double-bond migration to form a tertiary enamide was observed.
• 14 Bogliotti N, Dalko P, Cossy J. J. Org. Chem. 2006; 71: 9528
• 15 For a similar equilibration of 9,10-epi-stemoamide, see: Khim S.-K, Schultz AG. J. Org. Chem. 2004; 69: 7734
• 16 For the C₁₀ epimers in the 9a-epi series, DFT calculations predicted that the anti diastereomer 9a-epi-2 is 0.7 kcal/mol more stable than the syn isomer 9a,10-epi-2, which is in good agreement with the isomeric ratio obtained via equilibration (dr 1:3), see the Supporting Information.
• 17 See the Supporting Information for {¹H}¹³C shift comparisons.
• 18 For the relevance of using the simple molecular model that does not involve the Li⁺ ion in the calculations, see the Supporting Information.
• 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.
• 20a For an experimental evidence for the epimerization at C10, see: Jacobi PA, Lee KJ. J. Am. Chem. Soc. 1997; 199: 3409
• 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). R_f (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 R_f (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. R_f (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). R_f (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