Concise Enantiospecific Synthesis of (+)-Calvine

Abstract

We report herein an efficient enantiospecific synthesis of (+)-calvine in nine steps from (R)-epichlorohydrine. The convergent synthesis is based on an olefin cross-metathesis (CM) reaction of a chiral homoallylamine and an enone. Subsequent reductive ­cyclization and lactonization of the cis-2,6-disubstituted piperidine intermediate furnished the product in good yield.

Key words

olefin cross-metathesis - hydrogenation - lactones - ruthenium catalyst - alkaloids

References and Notes

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10

The optical rotation of the product [α]_D ²⁰ +8.7 (c 1.4, CHCl₃) was in agreement with the reported value {lit.¹¹ [α]_D ²⁵ +8.3 (c 1.4, CHCl₃)}.

13

Preparation and Selected Data of Enone 2. [Ru] (11 mg, 18 µmol) was added to a solution of homoallylamine 4 (76 mg, 0.2 mmol) and enone ester 3 (60 mg, 0.4 mmol) in anhyd CH₂Cl₂ (4.7 mL) under a nitrogen atmosphere. The mixture was heated at reflux for 20 h. The solvent was evaporated and the residue was purified by column chromatography (SiO₂, cyclohexane-EtOAc 3:2) to give 2 (70 mg, 70%, as keto-enol mixture) as a brown oil. [α]_D ²⁰ -8.0 (c 1, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.81 (br s, 3 H, H-12), 1.20 (br s, 8 H, H-9-11), 1.45-1.59 (m, 2 H, H-8), 2.20-2.68 (m, 2 H, H-6), 3.29 (br s, 2 H, H-13), 3.45 (s, H-2 keto), 3.50 (br s, 2 H, H-14), 3.68, 3.70 (s, 3 H, OCH ₃), 4.05 (br s, 1 H, H-7), 4.96 (s, H-2 enol), 5.12 (s, 2 H, H-16), 5.69-5.85 and 6.05-6.20 (m, 1 H, H-4), 6.45-6.62 and 6.69-6.86 (m, 1 H, H-5), 7.21-7.41 (br s, 5 H, Ar), 11.75 (s, OH enol) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.0 (C-12), 22.6 (C-11), 26.1 (C-10), 31.6 (C-9), 33.1, 33.4 (C-8), 36.5, 37.0 (C-6), 46.4, 46.7 (C-13), 51.3 (C-7), 52.4 (OMe), 61.6, 62.6 (C-14), 67.2, 67.8 (C-15), 90.5 (C-2), 126.6 (C-4), 1276.9, 128.1, 128.3, 128.7, 131.3, 136.8 (Ar), 145.9, 147.0 (C-5), 155.6 (C-16), 173.3 (C-1), 191.7 (C-3) ppm.

18

Preparation and Selected Data of Piperidine 1. Cross-metathesis product 2 (270 mg, 0.64 mmol) in isopropyl ether (20 mL) was hydrogenated over 10% Pd/C (68 mg, 60 µmol) at 3 bar and 40 °C for 3 d. After filtration over Celite^® and evaporation, the residue was purified by column chromatography (SiO₂, CH₂Cl₂-MeOH-NH₃ 97:3:0.1) to afford piperidine 1 (105 mg, 61%) and calvine (20 mg, 13%) as a light-yellow oil. [α]_D ²⁰ +8.5 (c 1.3, CH₂Cl₂). ¹H NMR (200 MHz, CDCl₃): δ = 0.88 (t, J = 7 Hz, 3 H, H-13), 1.10-1.80 (m, 14 H, H-3-5,9-12), 2.39 (dd, J = 15, 9 Hz, 1 H, H-7), 2.51-2.77 (m, 4 H, H-6,7,14), 3.09-3.25 (m, 1 H, H-2), 3.46 (t, J = 6 Hz, 2 H, H-15), 3.68 (s, 3 H, OCH ₃) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.1 (C-13), 21.7 (C-4), 22.7 (C-12), 26.2 (C-3), 27.0 (C-10), 27.3 (C-5), 32.1 (C-11), 34.1 (C-9), 39.3 (C-7), 48.4 (C-14), 51.7 (OMe), 58.3 (C-2), 60.5 (C-15), 61.9 (C-6), 173.0 (C-8) ppm.

20

Preparation and Selected Data of (+)-Calvine.
To a solution of 1 (12 mg, 44 µmol) in benzene (3 mL), p-TSA monohydrate (9.2 mg, 48 µmol) was added and the mixture was heated at reflux under a nitrogen atmosphere for 18 h. Then, CH₂Cl₂ (10 mL) and sat. aq NaHCO₃ solution (10 mL) were added and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL), and the collected organic layers were evaporated to give neat calvine (7 mg, 66%) as a light-yellow oil. [α]_D ²⁰ +18.3 (c 0.35, CH₂Cl₂) {lit.² [α]_D ²⁰ +18 (c 0.66, CH₂Cl₂)}. ¹H NMR (200 MHz, CDCl₃): δ = 0.88 (t, J = 7 Hz, 3 H, H-13), 1.15-1.81 (m, 14 H, H-3-5,9-12), 2.19-2.89 (m, 5 H, H-6,7,14), 3.23-3.37 (m, 1 H, H-2), 4.21-4.36 (m, 2 H, H-15) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.1 (C-13), 21.5 (C-4), 22.7 (C-12), 24.6 (C-3), 25.2 (C-5), 32.3 (C-10, 11), 34.2 (C-9), 43.2 (C-7), 53.5 (C-14), 59.0 (C-2), 62.8 (C-6), 69.0 (C-15), 174.7 (C-8) ppm.