A Straightforward Synthesis of Emericellamide A Using Matteson’s Homologation Approach

Abstract

The Matteson homologation is the perfect approach for the synthesis of polyketide–peptide natural products such as the emericellamides. In only four steps, the polyketide fragment with three stereogenic centers can be obtained as a single stereoisomer. The peptide fragment is easily available via solid-phase peptide synthesis.

Key words

boronic esters - Matteson homologation - natural products - peptides - stereoselective synthesis

Publication History

Received: 22 March 2023

Accepted after revision: 19 April 2023

Accepted Manuscript online:
19 April 2023

Article published online:
30 May 2023

• References and Notes

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• 16 General Procedure (GP): Matteson Homologation In a flame-dried Schlenk tube, a solution of anhydrous dichloromethane (2.5 equiv) in anhydrous THF (2.0 mL/mmol) was cooled to –100 °C and nBuLi (2.5 M in hexane, 1.1 equiv) was added dropwise. After stirring for 30 min at this temperature, boronic ester (1.0 equiv) in anhydrous THF (1.5 mL/mmol) was added slowly and the resulting solution was stirred at –100 °C for a further 30 min. Thereafter, ZnCl₂ (1.1–1.3 equiv; flame-dried in vacuo) was dissolved in anhydrous THF (0.8 mL/mmol ZnCl₂) and added to the reaction mixture. The solution was stirred for 1 d while warming to room temperature to give the corresponding α-chloroboronic ester. After cooling to 0 °C, nucleophile solution (1.5–2.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature until full conversion. The mixture was then added to a separatory funnel containing saturated NH₄Cl-solution and pentane and the phases were separated. The aqueous phase was extracted three times with pentane and the combined organic phases were dried over MgSO₄. After removing the solvent in vacuo, the crude product was purified by column chromatography For compounds 8 and 9, the procedure was slightly modified by isolating the α-chloroboronic ester. After the homologation step, the reaction mixture was worked up as described above. For the further conversion, the isolated α-chloroboronic ester and ZnCl₂ (1.1 equiv; flame-dried in vacuo) was dissolved in anhydrous THF (4.0 mL/mmol) and cooled to 0 °C. Afterwards, the nucleophile solution (2.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature until full conversion
• 17a Hiscox WC, Matteson DS. J. Org. Chem. 1996; 61: 8315
• 17b Matteson DS, Man H.-W. J. Org. Chem. 1994; 59: 5734
• 18 Preparation of Boronic Ester 6: According to the GP,¹⁶ methylboronic ester 5 (2.98 g, 11.9 mmol) was stirred with dichloromethane (1.92 mL, 29.8 mmol), nBuLi (5.24 mL, 13.1 mmol), ZnCl₂ (1.79 g, 13.1 mmol) and HexMgCl (11.9 mL, 23.8 mmol, 2.0 M in THF) for 3 d. After purification by column chromatography (silica, pentane/Et₂O 99:1), the boronic ester 6 (3.20 g, 9.17 mmol, 77%) was obtained as a colorless oil. R_f (6) = 0.60 (silica, pentane/Et₂O 97:3). [α]_D ²⁰ –37.8 (c = 1.0, CHCl₃). ¹H NMR (CDCl₃, 500 MHz): δ = 0.87 (t, J = 6.9 Hz, 3 H), 0.91–1.00 (m, 2 H), 0.97 (d, J = 7.3 Hz, 3 H), 1.02–1.08 (m, 2 H), 1.10–1.23 (m, 6 H), 1.23–1.34 (m, 12 H), 1.40–1.47 (m, 1 H), 1.57–1.60 (m, 2 H), 1.66–1.68 (m, 2 H), 1.75–1.77 (m, 6 H), 3.81–3.84 (m, 2 H). ¹³C NMR (CDCl₃, 125 MHz): δ = 14.1, 15.8, 22.6, 25.9, 26.0, 26.5, 27.4, 28.2, 28.9, 29.5, 31.9, 33.4, 43.1, 83.1. HRMS (CI): m/z [M + H]⁺ calcd for C₂₂H₄₂ ¹¹BO₂ ⁺: 349.3272; found: 349.3281.
• 19 Preparation of Boronic Ester 7: According to the GP,¹⁶ boronic ester 6 (1.71 g, 4.91 mmol) was stirred with dichloromethane (790 μL, 12.3 mmol), nBuLi (2.16 mL, 5.40 mmol) and ZnCl₂ (736 mg, 5.40 mmol). The nucleophile solution was prepared by adding (4-methoxyphenyl)methanol (975 μL, 7.85 mmol) to a suspension of NaH (294 mg, 7.36 mmol, 60% in mineral oil) in anhydrous DMSO (10.7 mL) and anhydrous THF (2.7 mL). After addition of the nucleophile solution, the reaction mixture was stirred for 1 d. The crude product was purified by column chromatography (silica, pentane/Et₂O 95:5) to give the boronic ester 7 (2.11 g, 4.22 mmol, 86%) as a colorless oil. R_f (7) = 0.63 (silica, pentane/Et₂O 9:1). [α]_D ²⁰ –16.2 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.87 (t, J = 7.3 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.95–1.02 (m, 2 H), 1.04–1.10 (m, 3 H), 1.13–1.34 (m, 16 H), 1.43–1.50 (m, 1 H), 1.58–1.61 (m, 2 H), 1.67–1.69 (m, 2 H), 1.75–1.81 (m, 5 H), 3.11 (d, J = 6.0 Hz, 1 H), 3.80 (s, 3 H), 3.88–3.90 (m, 2 H), 4.36–4.54 (m, 2 H), 6.84–6.86 (m, 2 H), 7.26–7.27 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.1, 16.9, 22.7, 25.9, 26.0, 26.4, 27.5, 27.6, 28.4, 29.6, 31.9, 33.8, 35.4, 43.0, 55.2, 72.2, 83.6, 113.5, 129.3, 131.5, 158.9. HRMS (CI): m/z [M–H]⁺ calcd for C₃₁H₅₀ ¹¹BO₄ ⁺: 497.3802; found: 497.3785.
• 20 Matteson DS, Peterson ML. J. Org. Chem. 1987; 52: 5116
• 21 Preparation of Boronic Ester 8: According to the modified GP,¹⁶ boronic ester 7 (1.36 g, 2.73 mmol) was stirred with dichloromethane (439 μL, 6.82 mmol), nBuLi (1.20 mL, 3.00 mmol), ZnCl₂ (1.15 g, 8.46 mmol) and MeMgCl (2.27 mL, 6.82 mmol, 3 M in Et₂O) for 4 d. After purification by column chromatography (silica, pentane/Et₂O 97:3), boronic ester 8 (1.15 g, 2.18 mmol, 80%) was obtained as a colorless oil. R_f (8) = 0.31 (silica, pentane/Et₂O 95:5). [α]_D ²⁰ –28.4 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.99 (d, J = 7.6 Hz, 3 H), 0.94–1.03 (m, 4 H), 1.08–1.34 (m, 18 H), 1.55–1.57 (m, 3 H), 1.63–1.67 (m, 2 H), 1.71–1.73 (m, 5 H), 1.79–1.81 (m, 2 H), 3.31 (t, J = 5.7 Hz, 1 H), 3.77–3.79 (m, 2 H), 3.79 (s, 3 H), 4.42–4.57 (m, 2 H), 6.84–6.86 (m, 2 H), 7.25–7.27 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 11.8, 14.1, 15.2, 22.7, 25.9, 26.0, 26.4, 27.6, 27.8, 28.5, 29.6, 32.0, 33.8, 35.9, 43.0, 55.3, 72.0, 83.4, 86.2, 113.5, 128.7, 131.8, 158.7. HRMS (CI): m/z [M–H]⁺ calcd for C₃₃H₅₄ ¹¹BO₄ ⁺: 525.4120; found: 525.4125.
• 22 Matteson DS, Beedle EC. Tetrahedron Lett. 1987; 28: 4499
• 23 Preparation of Amide 10: According to the modified GP,¹⁶ boronic ester 8 (2.12 g, 4.03 mmol) was stirred with dichloromethane (648 μL, 10.1 mmol), nBuLi (1.77 mL, 4.43 mmol), and ZnCl₂ (1.70 g, 12.5 mmol) to give the corresponding α-chloroboronic ester (2.30 g, 4.00 mmol). The crude product was dissolved in tBuOH (35 mL) and 2-methyl-2-butene (9.00 mL, 84.9 mmol) was added. A solution of NaClO₂ (4.56 g, 40.3 mmol, 80%) and KH₂PO₄ (5.48 g, 40.3 mmol) in H₂O (35 mL) was added and the reaction mixture was stirred at room temperature for 1 d. Thereafter, the reaction solution was acidified with citric acid (10 vol%) and the aqueous phase was extracted three times with Et₂O. The combined organic phases were washed with saturated Na₂S₂O₃-solution, dried over MgSO₄ and concentrated under reduced pressure to give a mixture of the carboxylic acid 9 and the chiral auxiliary (2.02 g) as a yellow oil without further purification. The mixture was then dissolved in anhydrous dichloromethane (20 mL) and H-Gly-OBn∙HCl (1.06 g, 5.24 mmol) was added. After cooling to 0 °C, DIPEA (1.55 mL, 8.87 mmol), HOBt (679 mg, 4.43 mmol) and EDC∙HCl (850 mg, 4.43 mmol) were added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue redissolved in ethyl acetate. The solution was washed with KHSO₄ solution (1 M), saturated NaHCO₃ solution, and saturated NaCl solution, the organic phase was dried over MgSO₄ and concentrated under reduced pressure. The residue was dissolved in Et₂O (15 mL) and methylboronic acid (265 mg, 4.43 mmol) was added. After stirring for 1 h, the solvent was removed in vacuo and the product was purified by column chromatography (silica, pentane/ethyl acetate 75:25) to give the amide 10 (1.33 g, 2.74 mmol, 68% over two steps) as a colorless oil. R_f (10) = 0.42 (silica, pentane/ethyl acetate 7:3). [α]_D ²⁰ –7.5 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.22–1.31 (m, 9 H), 1.41–1.48 (m, 1 H), 1.68–1.73 (m, 1 H), 2.53 (quint, J = 7.1 Hz, 1 H), 3.47 (dd, J = 7.2, 4.0 Hz, 1 H), 3.78 (s, 3 H), 3.88 (dd, J = 18.3, 4.7 Hz, 1 H), 4.15 (dd, J = 18.3, 5.8 Hz, 1 H), 4.45–4.53 (m, 2 H), 5.15 (s, 2 H), 6.55 (t, J = 5.0 Hz, 1 H), 6.82–6.85 (m, 2 H), 7.21–7.24 (m, 2 H), 7.31–7.38 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0, 14.1, 15.7, 22.7, 27.3, 29.5, 31.9, 34.1, 35.5, 41.3, 44.5, 55.2, 67.0, 74.9, 85.0, 113.7, 128.3, 128.5, 128.6, 129.2, 130.9, 135.3, 159.1, 169.7, 175.8. HRMS (CI): m/z [M + H]⁺ calcd for C₂₉H₄₂NO₅ ⁺: 484.3057; found: 484.3064.
• 24 Preparation of Alcohol 11: To a solution of amide 10 (1.19 g, 2.47 mmol) in anhydrous dichloromethane (15 mL) was added dropwise a solution of TFA (951 μL, 12.3 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. After stirring at 0 °C for 30 min, the solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed twice with saturated NaHCO₃ solution and saturated NaCl solution, the organic phase was dried over MgSO₄ and concentrated in vacuo. After purification by column chromatography (silica, pentane/ethyl acetate 75:25), the alcohol 11 (710 mg, 1.95 mmol, 79%) was obtained as a light-yellow oil. R_f (11) = 0.25 (silica, pentane/ethyl acetate 7:3). [α]_D ²⁰ –2.3 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.86–0.90 (m, 6 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.23–1.32 (m, 9 H), 1.38–1.44 (m, 1 H), 1.57–1.63 (m, 1 H), 2.45 (quint, J = 7.1 Hz, 1 H), 2.59 (bs, 1 H), 3.56 (dd, J = 7.5, 3.8 Hz, 1 H), 4.01 (dd, J = 18.3, 5.3 Hz, 1 H), 4.15 (dd, J = 18.3, 5.8 Hz, 1 H), 5.15–5.22 (m, 2 H), 6.32–6.34 (m, 1 H), 7.32–7.39 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.9, 14.1, 14.6, 22.6, 27.1, 29.5, 31.9, 34.0, 35.1, 41.4, 44.1, 67.4, 76.3, 128.4, 128.6, 128.7, 135.0, 170.2, 176.7. HRMS (CI): m/z [M + H]⁺ calcd for C₂₁H₃₄NO₄ ⁺: 364.2482; found: 364.2488.
• 25 Neises B, Steglich W. Angew. Chem., Int. Ed. Engl. 1978; 17: 522 ; Angew. Chem. 1978, 90, 556
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• 27 Devos A, Remion J, Frisque-Hesbain A, Colens A, Ghosez L. J. Chem. Soc., Chem. Commun. 1979; 1180
• 28 Preparation of Ester 12: To a solution of compound 11 (416 mg, 1.14 mmol) and Boc-Ala-OH (433 mg, 2.29 mmol) in anhydrous dichloromethane (7.5 mL) were added DCC (378 mg, 1.83 mmol) and 4-pyrrolidinylpyridine (203 mg, 1.37 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, pentane/ethyl acetate 75:25) to give the ester 12 (568 mg, 1.06 mmol, 93%, dr = 81:19 according to ¹H NMR) as a colorless oil. R_f (12) = 0.45 (silica, pentane/ethyl acetate 6:4). Major-12: ¹H NMR (400 MHz, CDCl₃): δ = 0.87 (t, J = 6.2 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H), 1.08–1.13 (m, 1 H), 1.15 (d, J = 7.1 Hz, 3 H), 1.21–1.31 (m, 9 H), 1.37 (d, J = 7.3 Hz, 3 H), 1.41 (s, 9-H), 1.75–1.81 (m, 1 H), 2.69 (quint, J = 7.2 Hz, 1 H), 4.07 (d, J = 4.5 Hz, 2 H), 4.29 (quint, J = 7.4 Hz, 1 H), 5.06 (dd, J = 7.5, 4.4 Hz, 1 H), 5.14–5.22 (m, 3 H), 6.36 (bs, 1 H), 7.31–7.39 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.6, 14.1, 14.7, 18.3, 22.6, 26.8, 28.3, 29.4, 31.8, 33.5, 34.3, 41.4, 43.6, 49.4, 67.2, 78.6, 79.7, 128.3, 128.5, 128.6, 135.2, 155.2, 170.1, 172.2, 172.7, 173.7. HRMS (CI): m/z [M + H]⁺ calcd for C₂₉H₄₇N₂O₇ ⁺: 535.3378; found: 535.3382.
• 29 Samaranayake G, Glasser WG. Carbohydr. Polym. 1993; 22: 1
• 30 Preparation of Compound 13: The ester 12 (205 mg, 383 μmol) was dissolved in anhydrous dichloromethane (600 µL) and HCl solution (960 μL, 3.83 mmol, 4 M in dioxane) was added dropwise at 0 °C. The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to obtain the deprotected ester (179 mg, 380 μmol) as a white foam without further purification. Thereafter, the crude product and the tripeptide 4 (185 mg, 460 μmol) were dissolved in anhydrous dichloromethane (4 mL) and two drops of DMF were added for better solubility. After cooling to 0 °C, DIPEA (134 μL, 766 μmol) and HATU (218 mg, 575 μmol) were added and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with KHSO₄ (1 M), saturated NaHCO₃ and saturated NaCl solution, the organic phase was dried over MgSO₄ and concentrated in vacuo. After purification by reversed-phase flash chromatography (H₂O/MeCN 9:1 → MeCN), the compounds major-13 (195 mg, 238 μmol, dr > 99:1 according to ¹H NMR data) and minor-13 (72 mg, 88.0 μmol, dr = 67:34 according to ¹H NMR data) were both obtained as white solids. Major-13: R_f (13) = 0.09 (silica, pentane/ethyl acetate 1:1). [α]_D ²⁰ –18.6 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.85–0.94 (m, 12 H), 0.95–0.97 (m, 6 H), 1.13 (d, J = 7.0 Hz, 3 H), 1.21–1.30 (m, 10 H), 1.38 (d, J = 7.3 Hz, 3 H), 1.42 (d, J = 7.2 Hz, 3 H), 1.46 (s, 9 H), 1.62–1.68 (m, 1 H), 1.70–1.77 (m, 3 H), 2.08–2.16 (m, 1 H), 2.75 (quint, J = 7.3 Hz, 1 H), 3.79 (t, J = 5.0 Hz, 1 H), 4.02 (dd, J = 18.0, 4.9 Hz, 1 H), 4.20 (dd, J = 17.6, 5.9 Hz, 1 H), 4.30–4.35 (m, 1 H), 4.49 (quint, J = 7.5 Hz, 1 H), 4.60 (quint, J = 7.6 Hz, 1 H), 4.96 (d, J = 4.9 Hz, 1 H), 5.08 (dd, J = 8.8, 3.1 Hz, 1 H), 5.11–5.18 (m, 2 H), 6.43 (d, J = 6.4 Hz, 1 H), 6.86 (bs, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.30–7.37 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.0, 14.1, 14.2, 17.3, 17.6, 17.9, 19.2, 21.4, 22.6, 23.1, 25.0, 27.1, 28.2, 29.4, 29.9, 31.8, 33.6, 34.1, 40.4, 41.2, 43.1, 48.1, 49.1, 52.7, 61.3, 66.9, 78.6, 81.2, 128.2, 128.4, 128.6, 135.3, 156.6, 170.4, 171.2, 171.7, 171.8, 172.3, 174.4. HRMS (CI): m/z [M–Boc+H]⁺ calcd for C₃₈H₆₄N₅O₈ ⁺: 718.4749; found: 718.4747.
• 31 Chen S, Xu J. Tetrahedron Lett. 1991; 32: 6711
• 32 Preparation of Emericellamide A: The depsipeptide 13 (115 mg, 141 μmol) was dissolved in MeOH (1.4 mL) and Pd/C (15.0 mg, 14.0 μmol, 10%) was added. After stirring at room temperature under H₂ atmosphere (1 bar) for 2 h, the reaction mixture was filtered and concentrated under reduced pressure to give the crude product (95.6 mg, 131 μmol) as a white solid. Thereafter, the crude product dissolved in anhydrous dichloromethane (600 μL) was cooled to 0 °C and HCl (4 M in dioxane, 350 μL, 1.41 mmol) was added dropwise. After stirring at room temperature for 90 min, the solution was again concentrated under reduced pressure to obtain the globally deprotected depsipeptide (81.0 mg, 121 μmol) as a white solid without further purification. Next, the deprotected crude product was suspended in anhydrous MeCN (141 mL) and FDPP (103 mg, 268 μmol) was added at 0 °C. The suspension was stirred at 0 °C for 20 min and DIPEA (94.0 μL, 536 μmol) was added dropwise over 30 min. Afterwards, the reaction mixture was stirred at room temperature for 15 h and the solvent was removed in vacuo. Purification by reversed-phase flash chromatography (H₂O/MeCN 9:1 → MeCN) and preparative HPLC (H₂O/ MeCN 6:4 → 1:9) gave emericellamide A (41.1 mg, 67.0 μmol, 48% over three steps) as a white solid. R_f (Emericellamide A) = 0.02 (silica, pentane/ethyl acetate 1:1). [α]_D ²⁰ –42.9 (c = 2.0, MeOH) {lit.4 [α]_D ³⁰ –42.99 (c = 2.0, MeOH)}. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.82 (d, J = 6.0 Hz, 3 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.83 (t, J = 7.0 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 7.0 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 6 H), 0.99–1.13 (m, 2 H), 1.18–1.28 (m, 8 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 7.3 Hz, 3 H), 1.53–1.65 (m, 3 H), 1.65–1.70 (m, 1 H), 1.84–1.93 (m, 1 H), 2.87 (dq, J = 9.9, 6.9 Hz, 1 H), 3.62 (dd, J = 17.6, 2.3 Hz, 1 H), 3.98 (dd, J = 8.3, 8.2 Hz, 1 H), 4.00–4.12 (m, 3 H), 4.33 (dd, J = 17.3, 5.5 Hz, 1 H), 4.92 (dd, J = 10.0, 1.8 Hz, 1 H), 7.39 (d, J = 6.8 Hz, 1 H), 7.50 (dd, J = 5.3, 2.3 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 8.01 (d, J = 3.8 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 12.9, 13.9, 14.3, 16.3, 18.2, 18.7, 19.0, 20.6, 22.0, 23.2, 24.5, 26.5, 28.8, 30.1, 31.2, 33.2, 33.5, 40.3, 41.0, 42.4, 47.3, 48.2, 51.7, 60.0, 76.6, 168.8, 170.8, 171.1, 171.3, 171.4, 172.9. HRMS (CI): m/z [M + H]⁺ calcd for C₃₁H₅₆N₅O₇ ⁺: 610.4174; found: 610.4172.