Stereoselective Synthesis of Bisfuranoxide (Aurochrome, Auroxanthin) and Monofuranoxide (Equinenone 5',8'-Epoxide) Carotenoids by Double Horner-Wadsworth-Emmons Reaction

Abstract

The stereoselective synthesis of C₄₀-all-trans-carotenoids with the formal hexahydrobenzofuran skeletons aurochrome, auroxanthin, and equinenone-5',8'-epoxide is reported. The synthesis is based on a one-pot or stepwise double Horner-Wadsworth-Emmons (HWE) reaction of a terminal enantiopure C₁₅-5,6-epoxycyclohexadienylphosphonate and a central C₁₀-trienedial. The ring expansion of the epoxycyclohexadienylphosphonate, generated by a Stille cross-coupling reaction, to the hexahydrobenzofuran skeleton was promoted by the reaction conditions of the HWE reaction prior to double-bond formation.

Scheme 1. Putative Biogenetic Relationships between Carotenoid 5′,8′-Epoxides/Furanoxides (2a, 2b, 4, and 6) and Carotenoid 5′,6′-Epoxides (1, 3, and 5)

Scheme 2. Bis-HWE Condensation of C₁₀-Dialdehyde 7 and the Corresponding Phosphonates (8–11) for the Synthesis of Enantiopure Aurochrome (4), Auroxanthin (6), and Echinenone 5′,8′-Epoxide (2a and 2b)

Scheme 3. (A) Double HWE Reaction for the Total Synthesis of Enantiopure (5R,8R,5′R,8′R)-Aurochrome (4) and (3S,5R,8R,3′S,5′R,8′R)-Auroxanthin (6); (B) Proposed Reaction Pathway from the Dienylphosphonate

Conditions: (a) Pd(PPh₃)₄, CuTC, [Ph₂PO₂][NBu₄], DMF, 25 °C, 98% for 8; 52% for 9. (b) i. KOtBu (2.2 molar equiv for 8; 4.6 molar equiv for 9), THF, −30 °C, 30 min; ii. −30 to 0 °C, 1 h, 53% for 4; 65% for 6.

Scheme 4. Double HWE Reaction for the Synthesis of Echinenone 5′,8′-Epoxide (2a/2b)

Reagents and reaction conditions: (a) Pd(PPh₃)₄, CuTC, [Ph₂PO₂][NBu₄], DMF, 25 °C, 99%; (b) TBDMSCl, imidazole, DMF, 0 to 25 °C, 82%; (c) NaHMDS, THF, −78 to −30 °C, 1 h, 89%; (d) i. KOtBu THF, −30 °C, 30 min; ii. −30 to 0 °C, 1 h; (e) TBAF, THF, 25 °C, 47% (combined yield); (f) IBX, DMSO, 25 °C, 30 h, 74%.