Study of the Cross-Metathesis Reaction of α-Hydroxy β,γ-Unsaturated Amides towards a Rapid and Flexible Total ­Synthesis of Symbioramide and its Isomer

Abstract

The reactivity of novel α-hydroxy β,γ-unsaturated amides in cross-metathesis reactions was extensively studied and used to perform a short total synthesis of symbioramide and its isomer from ­l-serine methyl ester.

Key words

γ-silyl butenamides - cross-metathesis - hydroxyamide - synthesis - symbioramide

• References and Notes

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For examples of Lewis acids assisted cross-metathesis, see:
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• 18 Representative Experimental Procedure and Characterization Data Compound 23: Allyltrimethylsilane (6.7 mL, 42 mmol, 3.0 equiv) was dissolved in dry CH₂Cl₂ (20 mL), then acryloyl chloride (1.12 mL, 14 mmol, 1.0 equiv), and HG(II) (219 mg, 2.5 mol%) were added. The reaction mixture was stirred at r.t. for 4 h. The obtained solution was slowly added to a solution of O-protected l -serine methyl ester 22 (5 g, 14 mmol, 1.0 equiv) in CH₂Cl₂ (15 mL) at –20 °C. i-Pr₂EtN (4.86 mL, 28 mmol, 2.0 equiv) was then added to the solution and stirred for 1 h. After completion, the reaction was quenched with sat. aq NH₄Cl solution and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane/EtOAc, 8:2) to give the corresponding product as a brown waxy solid 23 (5.84 g, 84%). R_f = 0.48 (cyclohexane/EtOAc, 8:2). [α]_D ²⁵ +24.0 (c 1.0, CHCl₃). IR (neat): ν = 2953, 2858, 1747, 1661, 1627, 1504, 1428, 1248, 1111, 847, 701 cm^–1.¹H NMR (300 MHz, CDCl₃): δ = 7.63–7.58 (m, 4 H), 7.43–7.35 (m, 6 H), 6.95 (dt, J = 15.1, 8.8 Hz, 1 H), 6.29 (d, J = 8.2 Hz, 1 H), 5.67 (d, J = 15.1 Hz, 1 H), 4.81 (dt, J = 8.1, 2.9 Hz, 1 H), 4.04 (ddd, J = 57.0, 10.2, 3.0 Hz, 2 H), 3.74 (s, 3 H), 1.72 (d, J = 8.8 Hz, 2 H), 1.04 (s, 9 H), 0.06 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.6, 165.1, 143.0, 135.0, 134.9, 132.5, 132.3, 129.4, 129.4, 127.3, 120.8, 64.1, 53.7, 51.6, 26.2, 23.7, 18.8, –2.3. HRMS (ESI+): m/z calcd for C₂₇H₄₀NO₄Si₂ [M + H]⁺: 498.2496; found: 498.2500. Compound 25: Allylic alcohol 24 (2.64 g, 6 mmol, 1.0 equiv) was dissolved in dry CH₂Cl₂ (2 mL) with alkene (5.18 mL, 3.0 mmol, 3.0 equiv). Then HG(II) (94 mg, 2.5 mol%) was added, and the reaction mixture was stirred at r.t. for 24 h. The solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography purified by column chromatography (CH₂Cl₂/EtOAc, 9:1). The product was obtained as a mixture of diastereoisomers; only the major isomer is described; colorless oil (1.79 g, 47%). R_f = 0.73 (CH₂Cl₂/EtOAc, 9:1). IR (neat): ν = 2924, 2954, 1751, 1659, 1520, 1112, 823, 701 cm^–1.¹H NMR (300 MHz, CDCl₃): δ = 7.60–7.58 (m, 4 H), 7.43–7.36 (m, 6 H), 7.09 (d, J = 8.2 Hz, 1 H), 5.95 (dt, J = 15.3, 6.6 Hz, 1 H), 5.57 (dd, J = 15.4, 7.6 Hz, 1 H), 4.68 (dt, J = 8.3, 2.4 Hz, 1 H), 4.54 (d, J = 7.6 Hz, 1 H), 4.01 (ddd, J = 13.2, 10.1, 2.6 Hz, 2 H), 3.75 (s, 3 H), 3.25 (br s, 1 H), 2.05 (dt, J = 8.7, 6.8 Hz, 2 H), 1.41–1.26 (m, 24 H), 1.03 (s, 9 H), 0.88 (t, J = 6.6 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 170.5, 137.0, 135.5, 135.5, 132.7, 132.6, 130.0, 127.9, 127.8, 127.1, 73.0, 64.2, 54.2, 52.5, 32.3, 32.0, 29.7, 29.7, 29.6, 29.5, 29.4, 29.3, 28.9, 26.7, 22.7, 19.3, 14.2. HRMS (ESI+): m/z calcd for C₃₈H₆₀NO₅Si [M+H]⁺: 638.4241; found: 638.4236.