The total synthesis of (-)-cyanthiwigin F by means of double catalytic enantioselective alkylation

Abstract

Double catalytic enantioselective transformations are powerful synthetic methods that can facilitate the construction of stereochemically complex molecules in a single operation. In addition to generating two or more stereocentres in a single reaction, multiple asymmetric reactions also impart increased enantiomeric excess to the final product in comparison with the analogous single transformation. Furthermore, multiple asymmetric operations have the potential to independently construct several stereocentres at remote points within the same molecular scaffold, rather than relying on pre-existing chiral centres that are proximal to the reactive site. Despite the inherent benefits of multiple catalytic enantioselective reactions, their application to natural product total synthesis remains largely underutilized. Here we report the use of a double stereoablative enantioselective alkylation reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F (ref. 8). By employing a technique for independent, selective formation of two stereocentres in a single stereoconvergent operation, we demonstrate that a complicated mixture of racemic and meso diastereomers may be smoothly converted to a synthetically useful intermediate with exceptional enantiomeric excess. The stereochemical information generated by means of this catalytic transformation facilitates the easy and rapid completion of the total synthesis of this marine natural product.

Figure 1

Structure and retrosynthesis of cyanthiwigin F.

Figure 2. Synthesis of diketone 6

a, Implementation of the double asymmetric alkylation. 8→7: (1) NaH (2.5 equiv.), allyl alcohol (0.28 equiv.), diallyl succinate (8, 1.0 equiv.), PhMe (toluene), 95 °C, 2 h; (2) K₂CO₃ (4.1 equiv.), diallyl succinylsuccinate (1.0 equiv.), MeI (5.1 equiv.), acetone, 50 °C, 6 h, 51% yield over two steps. 7→6: Pd(dmdba)₂ (0.05 equiv.), S-t-BuPHOX (12, 0.055 equiv.), Et₂O, 25 °C, precomplexation for 30 min, then bis(β-ketoester) 7 (1.0 equiv.), 25 °C for an additional 10 h, 78% yield, 4.4:1 diastereomeric ratio (d.r.), 99% enantiomeric excess. b, Stereochemical analysis for the stereoconvergent double decarboxylative alkylation of 7. dmdba, bis(3,5-dimethoxybenzylidene)acetone; t-BuPHOX, t-butyl phosphinooxazoline. For tabulated spectral data of all depicted compounds, please see the Supplementary Information.

Figure 3. Synthesis of cyanthiwigin F

a, Completion of the cyanthiwigin F (1) synthesis. 6→4: (1) KHMDS (1.1 equiv.), diketone 6 (1.0 equiv.), THF, −78 °C, 30 min, then PhN(Tf)₂ (1.2 equiv.), THF, −78 °C, 6 h, 84% yield; (2) Zn powder (7.5 equiv.), 1,2-dibromoethane (1.2 equiv.), TMSCl (0.33 equiv.), THF, 65 °C for 15 min, then 4-iodo-2-methyl-1-butene (1.5 equiv.), 65 °C, 2 h, then enol triflate (1.0 equiv.), Pd(PPh₃)₄ (0.05 equiv.), 65 °C, 3 h, 78% yield. 4→15: Tetraene 4 (1.0 equiv.), ruthenium catalyst 13 (0.1 equiv.), benzene, 40 °C, 30 min, then vinyl boronate 14 (5.0 equiv.), 40 °C, 20 h, then NaBO₃·H₂O (6.0 equiv.), THF/H₂O, 23 °C, 1 h, 51% yield. 15→16: Bicyclic aldehyde 15 (1 equiv.), t-butyl thiol (t-BuSH, 3.0 equiv.), AIBN (1.5 equiv.), benzene, 80 °C, 22 h, 57% yield. 16→1: (1) KHMDS (1.1 equiv.), diketone 16 (1 equiv.), THF, −78 °C, 30 min, then PhN(Tf)₂ (1.15 equiv.), THF, −78 °C, 3 h, 60% yield; (2) CuCN (1.5 equiv.), i-PrMgCl (3.0 equiv.), THF, −78 °C to 0 °C, then 0 °C for 10 min, Pd(dppf)Cl₂ (0.15 equiv.), enol triflate (1.0 equiv.), THF, 0 °C, 3 h, 63% yield of a 1.8:1 mixture of 1:17. b, Oak Ridge Thermal Ellipsoid Plot drawing of 16 (shown with 50% probability ellipsoids). KHMDS, potassium bis(trimethylsilyl)amide; THF, tetrahydrofuran; PhN(Tf)₂, phenyl bis(trifluoromethane)sulfonimide; TMSCl, trimethylsilyl chloride; AIBN, 2,2’-azobis(isobutyronitrile); dppf, 1,1’-bis(diphenylphosphino)ferrocene. For tabulated spectral data of all depicted compounds, and crystallographic data of tricyclic diketone 16, please see the Supplementary Information.