Nineteen-step total synthesis of (+)-phorbol

Abstract

Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes, germacrenes, taxanes and ingenanes have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C-C bond constructions and C-H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.

Figure 1. A two-phase approach to ingenanes and tiglianes enables a concise approach to the legendary phorbol structure

Figure 2

19-step total synthesis of 1. Reagents and conditions: 7. Mn(acac)₂, PhSiH₃, O₂, EtOH, then TMSOTf, Et₃N, CH₂Cl₂, 0 °C, 70%. 8. TFDO, CH₂Cl₂, 0 °C, then ZnI₂, MgI₂, Et₂O. 9. Mn(acac)₂, PhSiH₃, O₂, PPh₃, EtOH, 2 steps (34% 10 + 62% 7). 10. RuCl₃, NaBrO₃, NaHCO₃, EtOAc, CH₃CN, H₂O, 96%. 11. TFAA, DMAP, CH₂Cl₂, 0 °C, then Zn, AcOH, CH₂Cl₂, then Ac₂O, DMAP, CH₂Cl₂, 0 °C, then Et₃N, DMF, 60 °C, 64%. 12. TsNHNH₂, MeOH, reflux, then NaBH₃CN, AcOH, reflux, 40%. 13. CrO₃, 3,5-DMP, CH₂Cl₂, 0 °C to rt, 46%. 14. TMSN₃, DCE, 70 °C, then I₂, DCE, pyridine, 70 °C. 15. Me₄Sn, PdCl₂(PhCN)₂, AsPh₃, CuI, NMP, 80 °C, 2 steps (64% 18 + 33% 17). 16. HF·Pyridine, THF, 0 °C. 17. Martin Sulfurane, DCE, 60 °C, then SeO₂, benzene, 80 °C, 2 steps 51%. 18. NaBH₄, MeOH, -40 °C, then Ac₂O, DMAP, CH₂Cl₂, 93%. 19. NaBH(OAc)₃, benzene, reflux, then TBAF, THF, 0 °C, then Ba(OH)₂, MeOH, 72%.

Figure 3

(a) Structural analysis of intermediate 7 calculated using MacroModel 10.8 (Schrödinger LLC) (b) C NMR can be used to predict the most nucleophilic methylene C–H bond after taking into account the role of other factors (see text)