Total Synthesis of the Proposed Structure for Itralamide B

Abstract

A stereocontrolled total synthesis of the cyclodepsipeptide, itralamide B, has been achieved. Both R- and S-stereoisomers of the side chain were attached to the macrocyclic ring, however, the synthesized structure appears to be different from that of the marine natural product.

Key words

natural products - total synthesis - macrolactonization - configuration determination - stereoselectivity

• References and Notes

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• 25 Synthesis of Itralamide B (1): Compound 18 (23.0 mg, 0.03 mmol, 1.0 equiv) was dissolved in CH₂Cl₂ (1.0 mL) at 0 °C, and BF₃·OEt₂ (34 μL, 0.3 mmol, 10.0 equiv) was added dropwise to the solution at 0 °C. The reaction solution was allowed to warm to r.t. and stirred for 0.5–1.0 h (reaction monitored by TLC). The reaction was quenched by the addition of saturated NH₄Cl (2 mL) and diluted with CH₂Cl₂ (60 mL). The organic phase was washed with saturated NH₄Cl (3 × 20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo to afford the crude hydroxy acid. A solution of this hydroxy acid in THF–PhMe (10 mL, 1:1) was slowly added to a solution of DMAP (33 mg, 0.3 mmol, 10.0 equiv) and MNBA (47 mg, 0.14 mmol, 5.0 equiv) in PhMe (10 mL) at 0 °C. The reaction mixture was warmed to r.t., then stirred and heated to 60 °C for 2 d. The reaction mixture was diluted with EtOAc (100 mL) and washed successively with saturated NH₄Cl (3 × 20 mL) and brine (2 × 20 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc) to afford (S)-itralamide B (1; 5.0 mg, 21%). (S)-Itralamide B (1): [α]_D ²⁵ –44.63 (c 0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.12 (m, 5 H), 6.90 (d, J = 9.6 Hz, 1 H), 6.47 (d, J = 8.0 Hz, 1 H), 5.99 (d, J = 2.9 Hz, 1 H), 5.75–5.65 (m, 2 H), 5.53–5.43 (m, 1 H), 5.08 (q, J = 6.8 Hz, 1 H), 4.98 (dd, J = 7.9, 4.2 Hz, 1 H), 4.71 (dd, J = 9.4, 4.1 Hz, 1 H), 4.62 (q, J = 7.6 Hz, 1 H), 3.66 (dd, J = 15.5, 4.9 Hz, 1 H), 3.33 (d, J = 23.6 Hz, 3 H), 3.19 (d, J = 7.1 Hz, 3 H), 3.17–3.07 (m, 3 H), 3.07–2.94 (m, 3 H), 2.87 (dd, J = 15.6, 12.1 Hz, 1 H), 2.80 (d, J = 4.0 Hz, 1 H), 2.76–2.65 (m, 1 H), 2.46 (dd, J = 16.5, 7.5 Hz, 1 H), 2.28–2.21 (m, 1 H), 2.06–1.99 (m, 1 H), 1.29 (d, J = 2.0 Hz, 3 H), 1.26 (d, J = 2.8 Hz, 3 H), 1.20 (dd, J = 6.6, 3.5 Hz, 3 H), 1.08–1.01 (m, 6 H), 0.92 (dd, J = 9.4, 7.2 Hz, 6 H), 0.80 (d, J = 6.8 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 174.89, 172.84, 172.53, 170.65, 170.17, 169.90, 169.47, 137.35, 128.54, 128.34, 126.48, 78.18, 69.62, 56.92, 56.75, 54.69, 54.68, 53.98, 51.43, 40.65, 35.75, 33.92, 33.77, 32.15, 31.83, 31.12, 31.00, 30.54, 19.90, 19.63, 17.82, 17.10, 15.61, 15.35, 14.10, 13.82. HRMS (ESI): m/z [M+Na]⁺ calcd for C₃₈H₅₈Cl₂N₆NaO₈ ⁺: 819.3585; found: 819.3587. (R)-Itralamide B (1): [α]_D ²⁵ –42.33 (c 0.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.16 (m, 5 H), 6.89 (d, J = 9.1 Hz, 1 H), 6.48 (d, J = 7.8 Hz, 1 H), 6.04 (d, J = 2.9 Hz, 1 H), 5.78–5.63 (m, 1 H), 5.49 (dd, J = 6.6, 3.2 Hz, 1 H), 5.45–5.35 (m, 1 H), 5.12–5.02 (m, 1 H), 4.98 (dd, J = 7.8, 4.2 Hz, 1 H), 4.71 (dd, J = 9.3, 4.0 Hz, 1 H), 4.67–4.55 (m, 1 H), 3.66 (dd, J = 15.3, 5.1 Hz, 1 H), 3.28 (d, J = 63.9 Hz, 3 H), 3.18 (s, 3 H), 3.13 (d, J = 23.1 Hz, 3 H), 3.01 (d, J = 11.3 Hz, 3 H), 2.93 (d, J = 15.7 Hz, 1 H), 2.90–2.78 (m, 1 H), 2.78–2.67 (m, 1 H), 2.43 (dd, J = 16.7, 6.0 Hz, 1 H), 2.25 (dd, J = 11.9, 5.9 Hz, 1 H), 2.04 (d, J = 9.5 Hz, 1 H), 1.38 (dd, J = 18.4, 7.2 Hz, 3 H), 1.30 (d, J = 6.7 Hz, 3 H), 1.20 (d, J = 6.6 Hz, 3 H), 1.06 (d, J = 6.8 Hz, 6 H), 0.92 (dd, J = 11.7, 7.0 Hz, 6 H), 0.80 (d, J = 6.8 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 174.88, 172.83, 172.56, 170.68, 170.17, 169.85, 169.51, 137.37, 128.55, 128.34, 126.48, 78.02, 69.64, 56.88, 56.75, 54.75, 54.22, 53.99, 51.47, 40.45, 35.98, 33.97, 33.78, 32.18, 31.85, 31.12, 31.02, 30.55, 19.89, 19.63, 17.82, 17.09, 17.07, 15.60, 15.05, 13.83 ppm. HRMS (ESI): m/z [M+Na]⁺ for C₃₈H₅₈Cl₂N₆NaO₈ ⁺: 819.3585; found: 819.3589.
• 26 See the Supporting Information for detailed analyses.