A Synthetic Approach to the Furanocembrane Carbon Skeleton by a Regio­selective Bromine-Magnesium Exchange Reaction

Abstract

The dibromofuran 6 was prepared in four steps from dibromofurfural 3 in 73% yield. It was regioselectively metalated by a bromine-magnesium exchange reaction and was added to aldehyde 7. Alcohol 8 was obtained by this key step in 75% yield. ­Further functionalization reactions led to the precursors 17-19 for an intramolecular Nozaki-Hiyama coupling. The ring-closing Nozaki-Hiyama protocol was successfully implemented in the ­synthesis of the macrocyclic propargylic alcohol 20.

cross-coupling - furans - metalations - natural products - terpenoids

References

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<A NAME="RG43504ST-16">16</A>

Bromine-Magnesium Exchange and Carbonyl Addition.
A solution of dibromofuran 6 (426 mg, 0.89 mmol) in THF (15 mL) was cooled to -35 °C. An iso-propylmagnesium bromide solution (1.0 M in Et₂O, 1.06 mL, 1.06 mmol) was added and the solution was stirred for 90 min. Aldehyde 7 (246 mg, 1.17 mmol) was added and the reaction mixture was stirred overnight. NH₄Cl solution (20 mL) was added and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (25 mL) and dried over Na₂SO₄. After removal of the solvents the crude product was purified by flash chromatography (silica, pentane-EtOAc 95:5) to give 8 as a colorless oil. ¹H NMR (360 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.01 (s, 3 H), 0.13 (s, 9 H), 0.83 (s, 9 H), 1.23 (t, ³ J = 7.5 Hz, 3 H), 1.56 (s, 3 H), 1.60-1.73 (m, 2 H), 2.08-2.20 (m, 2 H), 2.75 (td, ³ J = 10.2 Hz, ³ J = 3.0 Hz, 1 H), 2.88 (m, 2 H), 3.73 (m, 2 H), 4.22 (q, ³ J = 7.5 Hz, 2 H), 4.67-4.73 (m, 3 H), 6.68 (s, 1 H), 7.34 (s, 1 H). ¹³C NMR (90.6 MHz, CDCl₃):
δ = -5.3, -5.3, 0.2, 1.1, 14.4, 17.8, 18.3, 19.8, 26.0, 28.3, 31.9, 51.6, 61.0, 62.3, 68.3, 84.9, 99.5, 107.1, 114.7, 117.7, 126.3, 128.3, 142.5, 150.6, 153.4, 167.7. HRMS: m/z calcd for C₂₅H₃₈BrO₅Si₂ [M⁺ - t-Bu]: 553.1441; found: 553.1438; m/z calcd for C₂₈H₄₄BrO₅Si₂ [M⁺ - Me]: 595.1910; found: 595.1939.

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<A NAME="RG43504ST-20">20</A> For a related macrocyclization by Nozaki-Hiyama coupling, see: Aissa C. Dhimane A.-L. Malacria M. Synlett  2000,  1585 

<A NAME="RG43504ST-21">21</A>

Reaction conditions: CrCl₃ (7.2 equiv), LiAlH₄ (3.6 equiv) in THF, 0 °C to r.t., then syringe pump addition of 18 in THF at r.t. (3 h).