A Concise and Versatile Total Synthesis of All Stereoisomers of Tarchonanthuslactone

Abstract

We describe the versatile and concise total synthesis of all stereoisomers of tarchonanthuslactone from (R)- or (S)-3-hydroxybutyrate via eight steps. The key steps of the synthesis include a highly diastereoselective chelation-controlled Mukaiyama aldol reaction of a p-methoxybenzyl-protected aldehyde and a Yamaguchi lactonization of a δ-hydroxy-trans-α,β-unsaturated carboxylic acid.

Key words

total synthesis - tarchonanthuslactone - chelation-controlled Mukaiyama aldol reaction - δ-hydroxy-trans-α,β-unsaturated carboxylic acid - Yamaguchi lactonization

• References and Notes

• 1 These two authors contributed equally to this work.
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• 12 The stereochemistry of the new stereogenic center of 3 and its syn isomer were determined by NOESY spectra after protection of the diol with PMB group (Scheme 6).
• 13 Experimental Procedure To a solution of 3 (530 mg, 1.72 mmol) in THF–MeOH–H₂O (2:1:1, 40 mL) was added LiOH (824 mg, 34.4 mmol) at r.t. and then kept the reaction stirring for 1 h. After that, the mixture was acidified with a solution of 1 M aq HCl to pH 5–6. Then it was extracted with CH₂Cl₂ (3 × 100 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the crude acid which was used for the next reaction without further purification. Subsequently, to the above crude acid in the solution of CH₂Cl₂ (0.5 mL) and pyridine (4.4 mL) was added 2,4,6,-trichlorobenzoyl chloride (0.3 mL, 1.9 mmol) at 0 °C. The resulting mixture was stirred for 1 h before being quenched with a solution of sat. NaHCO₃ (15 mL). The resulting mixture was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification by flash chromatography (hexane–EtOAc, 1:1) offered the desired compound 7 (414 mg, 87% yield) as a yellow oil. [α]_D ²⁵ –79.3 (c 0.44, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.11 (d, J = 8.4 Hz, 2 H), 6.73–6.70 (m, 3 H), 5.87 (d, J = 10.0 Hz, 1 H), 4.54–4.47 (m, 1 H), 4.42 (d, J = 10.8 Hz, 1 H), 4.21 (d, J = 10.8 Hz, 1 H), 3.83–3.74 (m, 1 H), 3.65 (s, 3 H), 2.21–2.10 (m, 2 H), 1.75–1.69 (m, 1 H), 1.61–1.55 (m, 1 H), 1.08 (d, J = 6.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.3, 159.1, 145.2, 130.6, 129.3, 121.2, 113.7, 74.8, 70.7, 70.4, 55.2, 42.9, 29.8, 19.8. ESI-HRMS: m/z calcd for C₁₆H₂₀O₄Na [M + Na]⁺: 299.1254; found: 299.1252.
• 14 (+)-7-epi-Tarchonanthuslactone [α]_D ²⁵ 26.5(c 0.78, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 6.87–6.84(m, 1 H), 6.73–6.68 (m, 2 H), 6.53 (d, J = 8.0 Hz, 1 H), 5.99 (d, J = 10.0 Hz, 1 H), 5.14–5.11 (m, 1 H), 4.14–4.08 (m, 1 H), 2.79 (t, J = 6.8 Hz, 2 H), 2.57 (t, J = 6.8 Hz, 2 H), 2.22–2.20 (m, 2 H), 1.85–1.76 (m, 2 H), 1.20 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 165.3, 145.9, 143.8, 142.5, 132.4, 120.7, 120.1, 115.2, 74.5, 67.1, 41.1, 36.1, 30.2, 29.4, 20.4. ESI-HRMS: m/z calcd for C₁₇H₂₀O₆Na [M + Na]⁺: 343.1152; found: 343.1149.
• 15 (+)-Tarchonanthuslactone [α]_D ²⁵ 56.8 (c 0.41, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 6.84–6.72 (m, 3 H), 6.57 (d, J = 8.0 Hz, 2 H), 6.00 (d, J = 10.0 Hz, 1 H), 5.07–5.05 (m, 1 H), 4.19–4.10 (m, 1 H), 2.82 (t, J = 6.8 Hz, 2 H), 2.60 (t, J = 7.2 Hz, 2 H), 2.26–2.05 (m, 3 H), 1.77–1.72 (m, 1 H), 1.24 (d, J = 6.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.9, 165.2, 145.7, 144.0, 142.4, 132.6, 120.8, 120.3, 115.4, 75.2, 67.2, 40.8, 35.9, 30.1, 29.0, 20.4. ESI-HRMS: m/z calcd for C₁₇H₂₀O₆Na [M + Na]⁺: 343.1152; found: 343.1152.