Total Synthesis of (-)-Mitrephorone A Enabled by Stereoselective Nitrile Oxide Cycloaddition and Tetrasubstituted Olefin Synthesis

Abstract

A highly enantioselective and diastereoselective total synthesis of the diterpenoid (-)-mitrephorone A is presented. Key to the synthesis are stereocontrolled 1,4-semihydrogenation of a 1,3-diene to a tetrasubstituted double bond, enzyme-catalyzed malonate desymmetrization, and highly diastereoselective nitrile oxide cycloaddition. The streamlined strategy is a considerable improvement to those reported earlier in terms of diastereo- and enantioselectivity. For the first time, the combination of modern Pd-cross-coupling with Cr-catalyzed reduction allows for rapid access to tetrasubstituted olefins with full stereocontrol.

Scheme 1. (−)-Mitrephorone A (1) and Retrosynthetic Analysis

Scheme 2. Stereochemical Considerations Associated with Olefin Functionalization

Scheme 3. Synthesis of Tetrasubstituted Olefin via Ireland–Claisen Rearrangement

Reagents and conditions: (a) TBSCl, imidazole, DMAP, CH₂Cl₂, r.t., 73%; (b) isopropenylmagnesium bromide (14), LaCl₃·2LiCl, THF, then 13, 0 °C to r.t., 86%, dr = 6:5; (c) PhNMe₂, AcCl, 50 °C, 64%; (d) LiHMDS, TBSCl, HMPA, THF, −78 °C to r.t., then 1 M HCl; (e) MeI, K₂CO₃, DMF, r.t., 87% over two steps, dr = 2.3:1; (f) DIBAL-H, PhMe, −78 °C to r.t., 59% trans-17, 27% cis-17.

Scheme 4. Conceptual Approach to Tetrasubstituted Olefin Synthesis via Cross-Coupling and 1,4-Semihydrogenation

Scheme 5. Synthesis of Isoxazoline 26 via Nitrile Oxide Cycloaddition

Reagents and conditions: (a) Pd(PPh₃)₄ (3 mol%), NaHCO₃, DME–H₂O (9:1), 80 °C, then HCl, MeOH, r.t., 66%; (b) TBSCl, imidazole, DMAP (20 mol%), CH₂Cl₂, r.t., 94%; (c) H₂ (70 bar), [Cr(CO)₃(η⁶-MeOBz)] (50 mol%), acetone, 120 °C, 97%; (d) TBAF, THF, r.t., 91%; (e) pig liver esterase (PLE), aq NaOH, 0.1 M pH 7 sodium phosphate buffer–DMSO (10:1), r.t., dr = 20:1; (f) TBSCl, imidazole, DMAP, CH₂Cl₂, r.t.; K₂CO₃, MeOH–THF–H₂O (20:10:3), r.t.; (g) ClCO₂Me, Et₃N, THF, 0 °C to r.t.; NaBH₄, MeOH, 0 °C, 68% over three steps; (h) DMP, t-BuOH, CH₂Cl₂, r.t., 71%; (i) H₂NOH·HCl, EtOH–pyr (8:1), r.t., 82%; (j) PhI(OAc)₂, MeOH, 0 °C; PhMe, Δ, 64%; (k) TBAF, THF, 60 °C, 99%; (l) DMP, t-BuOH, CH₂Cl₂, r.t., 86%; (m) MeLi, THF–Et₂O (3:1), −78 °C; (n) DMP, t-BuOH, CH₂Cl₂, r.t., 94% over two steps.

Figure 1

Putative transition states for nitrile oxide cycloaddition.

Scheme 6. Envisioned Optimization of the Route

Scheme 7. Synthesis of Vinyl Boronate 33

Reagents and conditions: (a) pig liver esterase (PLE), aq NaOH, 0.1 M pH 7 sodium phosphate buffer–DMSO (10:1), r.t.; (b) ClCO₂Me, Et₃N, THF, 0 °C to r.t.; NaBH₄, MeOH, 0 °C, 64% from 29e; (c) TBDPSCl, imidazole, DMAP (20 mol%), CH₂Cl₂, r.t., 95%; (d) PPTS (20 mol%), EtOH, r.t.; (e) DMP, t-BuOH, CH₂Cl₂, r.t., 87% over two steps; (f) MePPh₃Br, KOt-Bu, THF, r.t., 86%; (g) isopropenylboronic acid pinacol ester (18d), Grubbs second-generation catalyst (10 mol%), CH₂Cl₂, 50 °C, 49%.

Scheme 8. Synthesis of Tetrasubstituted Olefin 37

Reagents and conditions: (a) TMSCl, imidazole, THF, r.t., then KHMDS, −78 °C, then Comins reagent (34), −78 °C, then aq HCl, r.t., 79%; (b) DMP, t-BuOH, CH₂Cl₂, r.t., 85%; (c) MeLi, THF, −78 °C; (d) DMP, t-BuOH, CH₂Cl₂, r.t., 52% over two steps; (e) 33, Pd(PPh₃)₄ (2.5 mol%), NaHCO₃, DME–H₂O (9:1), 85 °C, 65%; (f) H₂ (70 bar), [Cr(CO)₃(η⁶-MeOBz)] (50 mol%), acetone, 120 °C, 93%.

Scheme 9. Synthesis of 42 via Nitrile Oxide Cycloaddition

Reagents and conditions: (a) TBAF, THF, r.t.; (b) DMP, t-BuOH, CH₂Cl₂, r.t., 73% over two steps; (c) H₂NOH·HCl, pyr–EtOH (8:1), r.t., 85%; (d) PhI(OAc)₂, MeOH, 0 °C; PhMe, Δ, 52%; (e) Me₃OBF₄, CH₂Cl₂, r.t., then TMSOTf, Et₃N, r.t., 69%; (f) Zn, AcOH, 50 °C, 65%; (g) H₂ (1 atm), Pd/C (30 mol%), EtOAc, r.t., 77%; (h) H₂ (1 atm), Pd/C, EtOAc–AcOH (5:1), 80 °C, 72%.

Scheme 10. Completion of the Synthesis

Reagents and conditions: (a) KOt-Bu, O₂, THF, −78 °C, then PPh₃, −78 °C to r.t., 72%; (b) DMP, t-BuOH, CH₂Cl₂; SiO₂, hexane–EtOAc (3:1), 74%; (c) PhI(OH)OTs, NaHCO₃, CH₂Cl₂, 72%.