Exploiting the Pd- and Ru-catalyzed cycloisomerizations: enantioselective total synthesis of (+)-allocyathin B2

Abstract

Pd- and Ru-catalyzed cycloisomerizations of 1,6-enynes are compared and contrasted. Such considerations led to the enantioselective synthesis of a cyathin terpenoid, (+)-allocyathin B(2) (1). The synthesis features a Pd-catalyzed asymmetric allylic alkylation (AAA) to install the initial quaternary center, a Ru-catalyzed diastereoselective cycloisomerization to construct the six-membered ring, and a diastereoselective hydroxylative Knoevenagel reaction to introduce the final hydroxyl group. We demonstrate for the first time a mechanism-based stereochemical divergence in Pd- and Ru-catalyzed cycloisomerization reactions as well as in creation of alkene geometry with alkynes bearing a carboalkoxy group. Mechanistic rationalization is proposed for these observations.

Figure 1

Pd-Catalyzed Cycloisomerization Mechanism.

Figure 2

Ru-Catalyzed Cycloisomerizations Mechanism.

Figure 3

X-ray Crystallography of Compound 17.

Figure 4

Proposed Rationale for the Palladium-Catalyzed Cycloisomerization of Compound 24.

Figure 5

Mechanistic Rationale for the Ru-Catalyzed Cycloisomerization of Compounds 14 and 23.

Scheme 1

Retrosynthetic Analysis

Scheme 2

Synthesis of Substrate 14a ^a (a) LDA, [(η³-C₃H₅)PdCl]₂ (0.5 mol%), (S,S)-L* (1 mol%), allyl acetate, Me₃SnCl, t-BuOH, 83%, 95% ee; (b) Me₂CuLi, −20 °C to rt, 85%; (c) LDA, PhNTf₂, 98%; (d) Pd₂(dba) ₃CHCl₃ (2.5 mol%), PPh₃ (20 mol%), CuI (5 mol%), TMS-acetylene, n-BuNH₂, 50 °C, 85%; (e) 9-BBN; H₂O₂, NaOH, 87%; (f) (COCl)₂, DMSO, Et₃N, − 78 °C to rt, 84%; (g) CBr₄, PPh₃, 94%; (h) n-BuLi, ClCO₂Me, −78 °C to rt, 99%; (i)Me₂CuLi, −78 °C, 93%; (j) DIBAL-H, −78 °C to rt, 94%; (k) TBAF, 97%.

Scheme 3

Synthesis of Epoxide 19a ^a (a) PhS(O)CH₂CN, piperidine, 69%; (b) 10% Pd/C, H₂ (1 atm), 98%; (c) mCPBA, 76%; or NBS, water, 46%; or VO(acac)₂, TBHP, 80%.

Scheme 4

Pd-Catalyzed Cycloisomerizaton of Compound 23a ^a (a) OsO₄ (1 mol%), NMO; NaIO₄, 84%; (b) NaBH₄, 94%; (c) PPh₃, I₂, ImH, 93%; (d) t-BuLi, ZnCl₂, −78 °C to rt, then Pd(PPh₃)₄ (5 mol%), 22; (e) TBAF, 72% from 21; (f) Pd₂(dba)₃CHCl₃, o-CF₃BzOH, 70 °C, 54%.

Scheme 5

Pd-Catalyzed Cycloisomerizaton of Compound 28a ^a (a) (COCl)₂, DMSO, NEt₃, 88%; (b) Ph₃PCHCO₂Et, 98%; (c) DIBAL-H, −78 °C to rt, 96%; (d) TBAF, 92%; (e) Pd₂(dba)₃CHCl₃, o-CF₃BzOH, 70 °C, 54%.

Scheme 6

Ru-Catalyzed Cycloisomerizaton of Compound 31a ^a (a) TBSCl, ImH, 99%; (b) CpRu(CH₃CN)₃PF₆ (10 mol%), 53%; (c) TFA, H₂O, 0 °C to rt, 83%.

Scheme 7

Synthesis of Epoxide 40.a ^a (a) CpRu(CH₃CN)₃PF₆ (35 mol%), 29%; (b) PhS(O)CH₂CN, piperidine, 44%, dr > 20:1; (c)10% Pd/C, H₂ (1 atm), 87%; (d) VO(acac)₂, TBHP, 52%.

Scheme 8

Mechanistic Rationale for the Hydroxylative Knoevenagel Reaction to Form 38.

Scheme 9

Preparation of Substrates 47 and 48a–c and their Cycloisomerization Reactionsa ^a (a) t-BuLi, ZnCl₂, −78 °C to rt, then Pd(PPh₃)₄ (5 mol%), 22; (b) K₂CO₃, MeOH, 68% from 21; (c) n-BuLi, ClCO₂NEt₂ (47); ClCO₂CH₃ (48a); ClCO₂i-Pr (48b); ClCO₂t-Bu (48c), 99%; (d) TBAF, 52–55%; (e) CpRu(CH₃CN)₃PF₆ (20 mol%).

Scheme 10

Synthesis of (+)-allocyathin B₂a ^a (a) PhS(O)CH₂CN, piperidine, 75%; (b) 10% Pd/C, H₂, 83%; (c) DIBAL-H; (d) KOH, MeOH, 60 °C, 51% from 55.

Scheme 11

Mechanistic Rationale for the Hydroxylative Knoevenagel Reaction to Form 54.