Stereoselective Total Synthesis of the Tricyclic Sesquiterpene (±)-Kelsoene by an Intramolecular Cu(I)-Catalyzed [2+2]-Photocycloaddition Reaction

Abstract

The sesquiterpene kelsoene (1) has been stereoselectively prepared starting from the known 1,2,3-trisubstituted cyclopentane 7 in 14 synthetic operations. The intramolecular Cu(I)-catalyzed photocycloaddition of the precursor 10 which proceeded in 89% yield established the relative configuration of the two stereogenic centers (C-1, C-8) within the cyclobutane ring. The stereo­chemistry at C-6 was adjusted by the stereoselective hydrogenation of the unsaturated enone 15.

cycloadditions - photochemistry - ring closure - terpenoids - total synthesis

References

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14

Procedure for the photocycloaddition 10 → 11: A 15 mL quartz tube was charged with diene 10 (66.0 mg, 0.28 mmol) in 5 mL of anhydrous Et₂O. After addition of copper(I) trifluoromethane sulfonate (CuOTf) (25 mg, 0.05 mmol) the tube was sealed with a rubber septum under an argon atmosphere and the mixture was shaken until the CuOTf was mostly dissolved. The resulting solution was irradiated (light source: Rayonet RPR-2537 Å) for 11 h. The reaction mixture was diluted with Et₂O (10 mL) and washed with a mixture of ice (7 g) and concentrated aqueous NH₃ (7 g). The organic layer was separated, dried over Na₂SO₄ and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography (pentane). Compound 11 (58.5 mg, 89%) was obtained as a yellow oil. NMR data are provided for the major diastereoisomer. ¹H NMR (300 MHz, CDCl₃): δ = 0.98 (d, J = 6.4 Hz, 3 H), 1.20-1.25 (m, 1 H), 1.42-1.55 (m, 2 H), 1.70 (s, 3 H), 1.60-1.68 (m, 3 H), 2.00 (s, 3 H), 2.40-2.55 (m, 2 H), 4.00-4.15 (m, 2 H), 4.65-4.75 (m, 2 H), 4.90-5.15 (m, 2 H), 5.62-5.80 (m, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 19.2 (q), 19.7 (q), 20.9 (q), 30.8 (t), 33.6 (t), 37.5 (d), 44.9 (d), 49.4 (d), 50.7 (d), 65.9 (t), 110.6 (t), 117.3 (t), 136.7 (d), 148.7 (s), 170.9 (s). Anal. calcd. for C₁₅H₂₄O₂ (236.35): C, 76.23; H, 10.24; found: C, 76.12; H, 10.12.

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19

In our hands, the Wittig reaction (MePPh₃ ⁺I^-, t-BuOK in THF, r.t., 1 h, then addition of ketone 16, reflux, 8 h), produced a lipophilic reaction product which was not separable from the desired product by conventional chromatographic means (column chromatography, HPLC, or preparative GC). In this respect, the use of Ti-based methylenation procedures (cf. ref. [8] [9] ) appears to be more suitable and is recommended.

20

Although commercially available (-)-β-citronellene served as starting material for the synthesis of compound 7 the product we obtained was fully racemic. The racemization occurs in the course of the Knoevenagel reaction (see ref. [13] ).