Scalable Synthesis of (-)-Thapsigargin

Abstract

Total syntheses of the complex, highly oxygenated sesquiterpenes thapsigargin (1) and nortrilobolide (2) are presented. Access to analogues of these promising bioactive natural products has been limited to tedious isolation and semisynthetic efforts. Elegant prior total syntheses demonstrated the feasibility of creating these entitites in 36-42 step processes. The currently reported route proceeds in a scalable and more concise fashion by utilizing two-phase terpene synthesis logic. Salient features of the work include application of the classic photosantonin rearrangement and precisely choreographed installation of the multiple oxygenations present on the guaianolide skeleton.

Figure 1

(A) A two-phase approach to thapsigargin (1) and nortrilobolide (2); (B) an inspiring precedent from Barton; (C) a graphical representation of the oxidase phase challenge.

Scheme 1. Concise Synthesis of (−)-Thapsigargin (1)

Reagents and conditions: (a) EVK (1.2 equiv) 15% KOH/MeOH; then O₂ (1 atm) (50%); (b) TMSOTf (2.5 equiv), Et₃N (5 equiv), CH₂Cl₂, 1.5 h, 0 °C; then NBS (1.3 equiv), 2 h; then DBU (10 equiv), THF, 50 °C, 16 h; then HCl (3M), 3 h, 23 °C (85%); (c) Burgess reagent (1.6 equiv), MeCN, 5 h, 80 °C; then K₂CO₃ (2 equiv), H₂O, 25 min, 23 °C; then tBuOH, AD-mix-α, 24 h, 0 °C (MeCN/tBuOH/H₂O 1:1:1) (60% dr. 5:1); (d) TBSCl (2 equiv), imidazole (2 equiv), dioxane, 5 h, 23 °C; then NaHCO₃ (10 equiv), SeO₂ (10 equiv), 24 h, 105 °C (52%); (e) PBu₃ (2 equiv), DEAD (2 equiv), butyric acid (2 equiv), 16 h, 0–23 °C (60%); (f) hv, AcOH (0.01 M), 14 h, 23 °C (50%); (g) KMnO₄ (2.1 equiv), octanoic acid (35 equiv), octanoic anhydride (9.5 equiv), PhH, 20 h, 85 °C (67%); (h) OsO₄ (10 mol %) NMO (2 equiv), citric acid (2 equiv), 36 h, 50 °C (acetone/tBuOH/H₂O 1:1:1) 13 h, 50 °C (33%); (i) Py.SO₃ (20 equiv), pyridine (30 equiv), DMSO, DIPEA (20 equiv), CH₂Cl₂, 46 min, 0 °C (43%); (j) Zn(BH₄)₂ (11.7 equiv), Et₂O, 1 h, – 20 °C (88%); (k) PhCOCl (3 equiv), angelic acid (3 equiv), Et₃N (3 equiv), PhMe, 72 h, 90 °C (59%). EVK = ethyl vinyl ketone, TMSOTf = trimethylsilyl trifluoromethanesulfonate, NBS = N-bromosuccinimide, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, TBSCl = tert-butyldimethylsilyl chloride, DEAD = diethyl azodicarboxylate, DIPEA = diisopropylethylamine, DMSO = dimethyl sulfoxide.

Scheme 2. Ten-Step Synthesis of (−)-Nortrilobolide (2)

Reagents and conditions: (a) OsO₄ (10 mol %) NMO (2 equiv), citric acid (2 equiv), 24 h, 50 °C (acetone/tBuOH/H₂O 1:1:1); then TBAF (1 M THF, 10 equiv), AcOH, 24 h, 0 °C (50%). (b) Py.SO₃ (20 equiv), pyridine (30 equiv), DMSO, DIPEA (30 equiv), CH₂Cl₂, 24 h, 0 °C (80%); (c) NaBH₄ (1 equiv), CeCl₃.7H₂O (1 equiv), MeOH, 50 min, – 20 °C; (d) angelic anhydride (21 equiv), NaHCO₃ (9.7 equiv), 16 h, 80 °C (48% over 2 steps). Py = pyridine, NMO = N-methylmorpholine N-oxide, TBAF = tetrabutylammonium fluoride, DMSO = dimethyl sulfoxide.