Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

Abstract

In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol (1) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E (2) and taxabaccatin III (3), have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The strategy holistically mimics nature's approach (two-phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox-isomerization to set the key trans-diol present in 2 and 3. This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion, thus empowering a medicinal chemistry campaign that is not wedded to semi-synthesis.

Keywords: X-ray diffraction; natural products; oxidations; terpenes; total synthesis.

Figure 1

Taxol™ (1) and taxane family members ordered in sequential oxidation levels.

Figure 2

Conditions: 8. Na (5 × 7 equiv., each portion added every 30 min), iPrOH, 80 °C, 3 h, 63% (11% epi-9, see SI); 9. VO(acac)₂ (0.05 equiv.), TBHP (1.1 equiv.), DCE, 0→23 °C, 2 h; then aq. NaOH (3M, 8.3 equiv.), DMSO, 140 °C (sealed tube), 4 h, 67%; 10. Ac₂O (6 equiv.), Et₃N (8 equiv.), DMAP (0.2 equiv.), THF, 60 °C, 10 h, 89%; 11. Cr(V) (4 equiv.), 15-crown-5 (5 equiv.), MnO₂ (20 equiv.), tBuOMe, 90 °C (sealed tube), 36 h, 14 50%, 13 29%; 12. NBS (1.05 equiv.), BPO (0.2 equiv.), CCl₄, 80 °C, 15 min; then TMSOH (xs.), 2,6-tert-butylpyridine (5 equiv.), AgOTf (5 equiv.), toluene, 23 °C, 1.5 h, 79%; 13. Burgess reagent (2 equiv.), toluene, 80 °C, 1 h; then DIBALH (15 equiv.), toluene, −78→23 °C, 15 min, 81%; 14. KHMDS (12 equiv.), MOMCl (12 equiv.), THF, −78→23 °C, 30 min; then IBX (26 equiv.), DMSO, 80 °C, 20 h, 67%; 15. Et₂NLi (2 equiv.), MoOPh (4 equiv.), THF, 23→−20→23 °C, 20 min; then Cu(OAc)₂ (40 equiv.), MeOH, 23 °C, 5 h, 19 77%, 17 12%; 16. LiAlH(OtBu)sBu₂ (2.5 equiv.), THF, 23 °C, 1 min; then H₂O (66 equiv.), evaporated to dryness and CH₂Cl₂, 23 °C, 8 h; Na (Hg) (2.2 equiv.), MeOH, 23 °C, 30 min, 72%; 17. Ac₂O (10 equiv.), Et₃N (10 equiv.), DMAP (1 equiv.), THF, 60 °C, 9 h, 85%; 18. CBr₄ (50 equiv.), iPrOH, 82 °C, 8 min; then Ac₂O (360 equiv.), Et₃N (96 equiv.), DMAP (100 equiv.), 23 °C, 30 min.

Figure 3

Exploration of an alternative cyclase phase endpoint for taxane synthesis.