Collective Total Synthesis of Casbane Diterpenes: One Strategy, Multiple Targets

Abstract

Of the more than 100 casbane diterpenes known to date, only the eponymous parent hydrocarbon casbene itself has ever been targeted by chemical synthesis. Outlined herein is a conceptually new approach that brings not a single but a variety of casbane derivatives into reach, especially the more highly oxygenated and arguably more relevant members of this family. The key design elements are a catalyst-controlled intramolecular cyclopropanation with or without subsequent equilibration, chain extension of the resulting stereoisomeric cyclopropane building blocks by chemoselective hydroboration/cross-coupling, and the efficient closure of the strained macrobicyclic framework by ring-closing alkyne metathesis. A hydroxy-directed catalytic trans-hydrostannation allows for late-stage diversity. These virtues are manifested in the concise total syntheses of depressin, yuexiandajisu A, and ent-pekinenin C. The last compound turned out to be identical to euphorhylonal A, the structure of which had clearly been misassigned.

Keywords: alkyne metathesis; cyclopropanes; hydrostannation; macrocycles; terpenes.

Figure 1

Selection of naturally occurring casbane diterpenes.

Scheme 1

Diversity‐oriented retrosynthetic analysis.

Scheme 2

a) NaOAc, THF, reflux, 70 %; b) (i) p‐acetamidobenzenesulfonyl azide, Et₃N, MeCN; (ii) LiOH, H₂O, 75 %; c) [Rh₂(5S‐MEPY)₄]⋅(MeCN)₂ (0.6 mol %), CH₂Cl₂, reflux, 87 %, 93 % ee; d) Dibal‐H, CH₂Cl₂, −78 °C; e) Ph₃P=CH₂, THF, 0 °C→RT, 55 % (over both steps); f) DMP, CH₂Cl₂, 0 °C→RT; g) CBr₄, PPh₃, CH₂Cl₂, 0 °C; h) nBuLi, Et₂O/DMPU, then MeI, −78 °C→RT, 51 % (19, over three steps), 63 % (20, over four steps, cis/trans=1:9); i) K₂CO₃, MeOH, 50 °C; Dibal‐H=diisobutylaluminum hydride, DMP=Dess–Martin periodinane, DMPU=N,N′‐dimethylpropyleneurea.

Scheme 3

a) (i) nBuLi, THF, −78 °C→−30 °C; (ii) (PhMe₂Si)₂Cu(CN)Li₂, −78 °C, 90 %; b) nBuLi, PhMe₂SiCl, THF, −30 °C→RT, quant.; c) [(PPh₃)₂NiCl₂] (8 mol %), MeMgBr, toluene, reflux, 91 %; d) I₂, PPh₃, imidazole, CH₂Cl₂, 0 °C→RT, 93 %; e) DMP, CH₂Cl₂, 0 °C→RT; f) MeC≡CMgBr, THF, 0 °C, 78 % (over both steps); g) TBDPSCl, imidazole, CH₂Cl₂/DMF, 84 %; h) NIS, 2,6‐lutidine, HFIP, CH₂Cl₂, −20 °C, 89 %; i) (i) 25, Zn, LiCl, TMSCl, 1,2‐diiodoethane, THF; ii) Pd(PPh₃)₄ (6 mol %), 82 %; j) TBAF, THF, 0 °C→RT, 84 %; k) NIS, HFIP, 0 °C, 73 % (dr=42:58); l) NIS, HFIP, HOAc, 0 °C, 70 %; DMF=N,N‐dimethylformamide, HFIP=hexafluoroisopropanol, NIS=N‐iodosuccinimide, TBAF=tetra‐n‐butylammonium fluoride, TBDPS=tert‐butyldiphenylsilyl.

Figure 2

Structure of 34 in the solid state (casbane numbering scheme).

Scheme 4

a) 9‐H‐9‐BBN, THF, 0 °C→RT; b) 31, [(dppf)PdCl₂] (10 mol %), Ba(OH)₂⋅8 H₂O, 69 %; c) 37 (20 mol %), 38 (22 mol %), MS 5 Å, toluene, reflux, 60 % (34+35); d) [Cp*RuCl]₄ (2.5 mol %), Bu₃SnH, CH₂Cl₂, 88 % (36); e) MeI, Pd(PPh₃)₄ (5 mol %), [Bu₄N][Ph₂PO₂], CuTC, DMF, 67 %; f) MnO₂, CH₂Cl₂, 73 %; g) MeLi, THF, then DMF, −78 °C→RT, 68 % (4), 53 % (5‐epi‐4); 9‐BBN=9‐borobicyclo[3.3.1]nonane, Cp*=pentamethylcyclopentadienyl, CuTC=copper thiophene‐2‐carboxylate.

Scheme 5

a) 20, 9‐H‐9‐BBN, THF, 0 °C→RT, then 31, [(dppf)PdCl₂] (5 mol %), Ba(OH)₂⋅8 H₂O, 82 %; b) 37 (20 mol %), 38 (22 mol %), MS 5 Å, toluene, reflux, 76 % (40+41); c) [Cp*RuCl]₄ (2.5 mol %), Bu₃SnH, CH₂Cl₂, 65 % (42) + 12 % (isomer, see the Supporting Information), ^[62] 74 % (43); d) MeLi, THF, then DMF, −78 °C→RT, 61 % (ent‐12), 69 % (44); e) MeLi, THF, then CO₂, −78 °C→RT, 51 %.