Network-analysis-guided synthesis of weisaconitine D and liljestrandinine

Abstract

General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three families of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites.

Figure 1. Molecules references in this work and design strategy

Figure 1A: Selected C-18, C-19, and C-20 aconitine type and denudatine type diterpenoid alkaloids. Figure 1B: Perspective drawings of weisaconitine D (in box), retrosynthetic analysis highlighting maximally bridging rings (in red) and the corresponding bridgehead atoms (in purple) as well as the labeling of rings and atom numbering for the aconitine-type skeleton (in box). Figure 1C: Highlighted bonds that are forged in three different Diels-Alder approaches to the A ring of diterpenoid alkaloids.

Figure 2

Figure 2A: Reaction sequence for the total synthesis of weisaconitine D. Reagents and conditions: 1. 9 (1.0 equiv.), 8 (2.0 equiv.), toluene, 110 °C, 64 h. 2. Pd/C (10 wt%), H₂ gas (1 atm), EtOAc, room temperature (r.t.), 3 h, 70% over two steps. 3. LiHMDS (1.3 equiv.), PhNTf₂ (1.4 equiv.), THF, −78 °C to r.t., 12 h. 4. NaCN (2.2 equiv.), Pd(PPh₃)₄ (0.06 equiv.), CuI (0.12 equiv.), MeCN, reflux, 2 h, 70% over two steps. 5. Lithium boronate 11 (3.0 equiv.), [RhCOD(OH)]₂ (0.05 equiv.), dioxane/water, 16 h, 60%. 6. Red-Al® (10 equiv.), CH₂Cl₂, −78 °C to r.t., 1 h, 82%. 7. Dess-Martin periodinane (2.0 equiv.), NaHCO₃ (5.0 equiv.), CH₂Cl₂, 0 °C, 1.5 h, 91%. 8. PPh₃MeBr (3.0 equiv.), LiHMDS (2.5 equiv.), THF, 0 °C to r.t., 1 h, 94%. 9. RhCl(PPh₃)₃ (0.3 equiv.), CH₃CHNOH/PhMe, reflux, 15 h, 81%. 10. KOH (3.4 equiv.), Phenyliodonium diacetate (1.3 equiv.), MeOH, 0 °C to r.t., 3 h. 11. TBAF (3.0 equiv.), THF, r.t., 5 h, 96% over 2 steps. 12. MsCl (1.5 equiv.), CH₂Cl₂/Et₃N, 0 °C, 3 h, 96%. 13. KOtBu (3.0 equiv.), THF, 0 °C to r.t., 2 h, 76%. 14. 2N HCl/iPrOH, 0 °C to r.t., 3.5 h, 99%. 15. Phenyliodonium diacetate (1.5 equiv.), NaHCO₃ (5.0 equiv.), MeOH, 0 °C, 1 h, 99%. 16. p-xylene, 150 °C, 17.5 h, 77%. 17. NaBH₄ (3.0 equiv.), MeOH, 0 °C to r.t., 3 h. 18. CHCl₃/TFA/water, 4 °C, 2 h, 99% over 2 steps. 19. MOMCl (4.9 equiv.), DIPEA (10 equiv.), 4 °C to r.t., 16 h, 92%. 20. NaBH₄ (3.3 equiv.), MeOH, 4 °C, 2 h, 95%. 21. Tf₂O (10 equiv.), pyridine, CH₂Cl₂, −78 °C to r.t., 16 h. 22. DBU (3.3 equiv.), DMSO, 120 °C, 1 h, 55% over 2 steps. 23. mCPBA (5.2 equiv.), CH₂Cl₂, 0 °C to r.t., 16 h, 83%. 24. NaH (15 equiv.), EtI (15 equiv.), THF, 40 °C, 16 h, 95%. 25. Cp₂TiCl₂ (2.2 equiv.), Mn (7.6 equiv.), H₂O (38 equiv.), THF, r.t., 16 h. 26. NaH (12 equiv.), Me₂SO₄ (7 equiv.), THF, 60 °C, 2 h, 66% over 2 steps. 27. 4M KOH, ethylene glycol, 100 °C, 120 h. 28. Ac₂O (9.4 equiv.), pyridine (28 equiv.), CH₂Cl₂, 0 °C to r.t., 16 h. 29. LAH (10 equiv.), Et₂O, 40 °C, 2 h; 2N HCl, THF, 16 h, 54% over 3 steps. Figure 2B: CYLview images of various intermediates (24, 25) and of derivatized weisaconitine D (26). Most hydrogens (except stereocenters) have been removed for clarity.

Figure 3

Figure 3A: Reaction sequence for the synthesis of liljestrandinine. Reagents and conditions: 1. Oxalyl chloride (2. 9 equiv.), DMSO (6.2 equiv.), Et₃N (12 equiv.), CH₂Cl₂, −78 °C to r.t., 1 h, 95%. 2. Formaldehyde (21 equiv.), 2N KOH, MeOH, r.t., 15 h, 96%. 3. MsCl (3.5 equiv.), pyridine, 0 °C to r.t., 2 h, 78%. 4. KOtBu (5 equiv.), THF, 50 °C, 4 h. 5. 0.5M NaOMe in MeOH, 120 °C, 24 h. 6. Methyl chloroformate (20 equiv.), K₂CO₃ (40 equiv.), acetone, reflux, 20 h; 2N HCl, isopropanol, r.t., 4.5 h, 26% yield over 3 steps. Figure 3B: Enantioselective Diels–Alder cycloaddition approach employing dienophile 29.

Figure 4

Figure 4A: Selected molecules of a test set analyzed using the newly developed graphing program to detect the maximally bridging ring. The program output is a pdb image in gray. The maximally bridging ring is indicated by a combination of gray and purple spheres. The purple spheres represent bridgehead atoms in the maximally bridging ring and the gray spheres represent other atoms in the maximally bridging ring. ChemDraw renditions of the graphing program output are provided for longifolene and liljestrandinine. For an extensive test set, see the SI. 3D views of the output of the test set are located at http://www.cadrerl.com/ring/. To use the program go to http://www.cadrerl.com/maxbridge. Figure 4B: ChemDraw renditions of the program output. Conducted for the denudatine core and other key retrosynthetic disconnections applied in this work and in Ref. . Figure 4C: ChemDraw renderings of the program output for the aconite core and key retrosynthetic disconnections applied in Ref. and in this work.