Direct Domino Synthesis of Azido-Dienoic Acids: Potential Linker Units

Caroline Souris; Frédéric Frébault; Davide Audisio; Christophe Farès; Nuno Maulide

doi:10.1055/s-0033-1338452

Synlett, Inhaltsverzeichnis

Synlett 2013; 24(10): 1286-1290
DOI: 10.1055/s-0033-1338452

letter

Direct Domino Synthesis of Azido-Dienoic Acids: Potential Linker Units

Caroline Souris

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany eMail: maulide@kofo.mpg.de

,

Frédéric Frébault

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany eMail: maulide@kofo.mpg.de

,

Davide Audisio

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany eMail: maulide@kofo.mpg.de

,

Christophe Farès

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany eMail: maulide@kofo.mpg.de

,

Nuno Maulide*

Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany eMail: maulide@kofo.mpg.de

› Institutsangaben

Abstract

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Abstract

We report an atom-economical domino synthesis of functionalized and stereodefined dienes. This method hinges on an allylic alkylation–electrocyclic ring-opening sequence and allows direct access to doubly vinylogous azido-dienoic acids bearing challenging substitution patterns. This class of compounds represents useful linkers in chemical biology by virtue of the orthogonality between the azido and carboxylic acid moieties.

Key words

azide - dienes - electrocyclic - allylic alkylation - bioconjugation

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Referenzen

References and Notes

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12 In the absence of Pd⁰, a notoriously slow background reaction leading to the same product takes place. The use of NaN₃ as nucleophile afforded azidodiene 4a and its olefin isomer in a 1:1 ratio and lower yield (65%). For details, see the Supporting Information.
13 Even if azido nucleophiles generally lead to products of global retention in palladium-mediated allylic alkylation, exceptions are well documented in the literature (especially when a monodentate ligand is used). See, for example: Murahashi SI, Taniguchi Y, Imada Y, Tanigawa Y. J. Org. Chem. 1989; 54: 3292
14 The reaction can be performed in up to 3.0 mmol scale affording 350 mg of the desired dienoic acid 4a.
15 General Procedure for the Synthesis of Azidodiene 4 In a Schlenk flask, Pd(PPh₃)₄ (9.0 mg, 8 μmol, 5 mol%) was evacuated/backfilled with argon three times and dissolved in THF (3.1 mL). TMSN₃ (36 μL, 0.312 mmol, 2.0 equiv) was added to the stirred solution of Pd(PPh₃)₄, and the mixture was cooled to 0 °C. After 5 min, an Et₂O solution of lactone 1 (0.20 M in Et₂O, 0.78 mL, 0.156 mmol, 1.0 equiv) was added dropwise to the mixture, and the mixture was then stirred at 0 °C for 2 days. The solution was quenched with H₂O, and Et₂O was added to the mixture. The organic phase was extracted three times with sat. NaHCO₃. The aqueous phases were acidified using 1 M HCl, extracted three times with EtOAc, and the combined extracts were evaporated to give the azido diene. (2E,4E)-5-Azidopenta-2,4-dienoic Acid (4a) Compound 4a was obtained as a yellow powder in 81% yield according to the general procedure. ¹H NMR (300 MHz, CD₃COCD₃): δ = 7.30 (dd, J = 15.4, 11.4 Hz, 1 H), 7.01 (d, J = 13.2 Hz, 1 H), 6.18 (dd, J = 13.2, 11.4 Hz, 1 H), 5.90 (d, J = 15.4 Hz, 1 H). ¹³C NMR (75 MHz, CD₃COCD₃): δ = 167.8, 142.6, 138.8, 120.7, 118.2. FTIR (neat): ν_max = 2926, 2567, 2283, 2103, 1673, 1619, 989 cm^–1. ESI-HRMS: m/z calcd for C₅H₅N₃O₂ [M]⁺: 139.0380; found: 139.0382.

16a Dilling WL. Org. Photochem. Synth. 1976; 2: 5
16b For the synthesis of 2-tosyl-2-azabicyclo[2.2.0]hex-5-en-3-one (1d), see also ref. 9c

17 See Supporting Information for details.
18 Dorie JP, Martin ML, Odiot S, Tonnard F. Org. Magn. Reson. 1973; 5: 265
19 Isomura K, Okada M, Taniguchi H. Chem. Lett. 1972; 629
20 It should be noted, however, that these rules, while applicable to the series at hand, should not be used indiscriminately without consideration for possible steric and electronic effects of additional substitutions. See Supporting Information for tabular data on coupling constants and chemical shifts
21 For further details, see Supporting Information.

For overviews of ‘click’ chemistry, see:

22a Huisgen R In 1,3-Dipolar Cycloadditional Chemistry . Padwa A. Wiley; New York: 1984: 1-176
22b Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004
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22e Bock VD, Hiemstra H, van Maarseveen JH. Eur. J. Org. Chem. 2006; 51

23 General Procedure for the Click Reaction According to Conditions B To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) in THF (0.5 mL) was added the corresponding acetylene (0.21 mmol, 2.0 equiv) followed by H₂O (0.25 mL). The reaction mixture was stirred at r.t. for 12 h. EtOAc was added to the mixture, and the resulting solution was washed with three times with 1 M HCl. The organic phase was dried over MgSO₄, filtered, and the solvent was removed under vacuum to afford the desired triazole 5d. (2E,4E)-5-(4,5,6,7,8,9-Hexahydro-1H-cycloocta[d][1,2,3]triazol-1-yl)penta-2,4-dienoic Acid (5d) Compound 5d was obtained in quantitative yield. ¹H NMR (500 MHz, CD₃COCD₃): δ = 7.71 (d, J = 13.6 Hz, 1 H), 7.50 (dd, J = 15.4, 11.9 Hz, 1 H), 7.26 (dd, J = 13.6, 11.9 Hz, 1 H), 6.20 (d, J = 15.4 Hz, 1 H), 2.96 (t, J = 6.7 Hz, 2 H), 2.88 (t, J = 6.7 Hz, 2 H), 1.89–0.86 (m, 8 H). ¹³C NMR (125 MHz, CD₃COCD₃): δ = 167.7, 145.7, 142.4, 134.5, 130.4, 124.2, 119.4, 29.5, 26.9, 26.8, 25.4, 25.1, 21.7. FTIR (neat): ν_max = 2922, 2859, 1683, 1619, 1049, 995 cm^–1. ESI-HRMS: m/z calcd for C₁₃H₁₆N₃O₂ [M – H]^–: 246.1259; found: 246.1248.
24 General Procedure for the Click Reaction According to Conditions A To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) and the corresponding acetylene (0.21 mmol, 2.0 equiv) in THF (0.5 mL) was added a solution of CuSO₄·5H₂O (5.4 mg, 0.02 mmol, 0.2 equiv) in H₂O (0.25 mL) followed by a solution of sodium ascorbate (13 mg, 0.06 mmol, 0.6 equiv) in H₂O (0.25 mL). The reaction mixture was stirred at r.t. for 12 h. EtOAc was added to the mixture, and the resulting solution was washed three times with 1 M HCl. The organic phase was dried over MgSO_4,filtered, and the solvent was removed under vacuum to afford the desired triazole 5.
25 Procedure for the Click Reaction in Buffer Solution To a mixture of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) and the corresponding acetylene (0.21 mmol, 2.0 equiv) in t-BuOH (0.5 mL) was added a solution of CuSO₄·5H₂O (5.4 mg, 0.02 mmol, 0.2 equiv) in H₂O (0.25 mL), followed by a solution of sodium ascorbate (13 mg, 0.06 mmol, 0.6 equiv) in H₂O (0.25 mL). Finally, a 0.5 mL solution of 0.1 M Tris·HCl in H₂O was added. The reaction mixture was stirred at r.t. for 12 h. EtOAc was added to the mixture, and the resulting solution was washed three times with 1 M HCl. The organic phase was dried over MgSO₄, filtered, and the solvent was removed under vacuum to afford the desired triazole 5a. (2E,4E)-5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)penta-2,4-dienoic Acid (5a) Compound 5a was obtained as a yellow paste in 85% yield according to conditions C. ¹H NMR (500 MHz, CD₃COCD₃): δ = 8.35 (s, 1 H), 7.94 (d, J = 14.2 Hz, 1 H), 7.50 (dd, J = 15.1, 11.4 Hz, 1 H), 7.21 (dd, J = 14.2, 11.4 Hz, 1 H), 6.17 (d, J = 15.1 Hz, 1 H), 4.55 (s, 2 H), 3.35 (s, 3 H). ¹³C NMR (125 MHz, CD₃COCD₃): δ = 167.3, 146.5, 141.8, 132.4, 128.8, 122.1, 119.2, 66.0, 58.1. FTIR (neat): ν_max = 3094, 2931, 2887, 1677, 1644, 1619, 1044, 993 cm^–1. ESI-HRMS: m/z calcd for C₉H₁₀N₃O₃ [M – H]^–: 208.0726; found: 208.0728.

26a Landsteiner K. The Specificity of Serological Reactions . Harvard University Press; Cambridge (USA): 1945: 156
26b Shreder K. Methods 2000; 20: 372

For hapten applications, see:

27a Fujii Y, Ikeda Y, Fujii M, Yamazaki M. Biol. Pharm. Bull. 1994; 17: 467
27b Johnson RD, Runzheimer HV, Sommer RG, Kin FY. US 4,822,747, 1989
27c Papasarantos I, Klimentzou P, Koutrafouri V, Anagnostouli M, Zikos C, Paravatou-Petsotas M, Livaniou E. Appl. Biochem. Biotechnol. 2010; 162: 221

28 General Procedure for the Coupling of N-Nucleophiles (Conditions A) To a solution of azido diene 4a (15 mg, 0.11 mmol, 1.0 equiv) and amine 10.12 mmol, 1.1 equiv) in CH₂Cl₂ (2 mL) were added HOBt (16 mg, 0.12 mmol, 1.1 equiv) and EDCI (23 mg, 0.12 mmol, 1.1 equiv) at 0 °C. The resulting mixture was allowed to warm to r.t. and stirred for 12 h. H₂O (5 mL) and CH₂Cl₂ (5 mL) were added, and the organic layer was washed with sat. NaHCO₃, brine, and dried over MgSO₄. After filtering, the solvent was removed under vacuum, and the product was purified by column chromatography on silica gel (pentane–EtOAc, 95:5) to afford the desired amides 6. (S)-tert-Butyl 2-[(2E,4E)-5-Azidopenta-2,4-dienamido]-3-(4-hydroxyphenyl)propanoate (6a) Compound 6a was obtained as a pale yellow oil in 55% yield. ¹H NMR (500 MHz, CD₃COCD₃): δ = 8.23 (s, 1 H), 7.28 (br d, J = 8.5 Hz, 1 H), 7.15 (app t, J = 12.7 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 2 H), 6.87 (d, J = 12.7 Hz, 1 H), 6.74 (d, J = 7.5 Hz, 2 H), 6.11 (d, J = 14.8 Hz, 1 H), 6.05 (app t, J = 12.7 Hz, 1 H), 4.62 (m, 1 H), 2.98 (dd, J = 13.9, 6.1 Hz, 1 H), 2.91 (d, J = 13.9, 8.1 Hz, 1 H), 1.39 (s, 9 H). ¹³C NMR (125 MHz, CD₃COCD₃): δ = 171.7, 165.8, 157.1, 137.8, 136.9, 131.3 (2 C), 128.7, 124.1, 118.6, 115.9 (2 C), 81.6, 55.4, 37.8, 28.1 (3 C). FTIR (neat): ν_max = 3303, 2978, 2939, 2106, 1719, 1513, 1147 cm^–1. ESI-HRMS: m/z calcd for C₁₈H₂₂N₄O₄Na [M + Na⁺]: 381.1534; found: 381.1533. General Procedure for the Coupling of O-Nucleophiles To a stirred solution of azido diene 4a (0.07 mmol, 1.0 equiv) in CH₂Cl₂ (1 mL) were added DMF (1 drop) followed by oxalyl chloride (0.01 mmol, 1.5 equiv) at 0 °C. After 30 min, the solution was added to a mixture of alcohol (0.09 mmol, 1.1 equiv) and NaH (60% in mineral oil, 0.09 mmol, 1.1 equiv) in CH₂Cl₂ (1 mL). The resulting mixture was stirred for 12 h at r.t. H₂O (5 mL) and CH₂Cl₂ (5 mL) were added to the reaction mixture, and the layers were separated. The organic phase was washed three times with H₂O, brine, and dried over MgSO₄. The solvent was removed under vacuum, and the product was purified by column chromatography on silica gel (pentane–EtOAc, 6:4) to afford the desired ester 6. (2E,4E)-(3S,10S,13R,14S,17R)-14-Hydroxy-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl 5-Azidopenta-2,4-dienoate (6c) Compound 6c was obtained as a colorless solid in 22% yield. ¹H NMR (500 MHz, CD₃COCD₃): δ = 7.29 (m, 1 H), 7.01 (t, J = 11.3 Hz, 1 H), 6.17 (t, J = 11.8 Hz, 1 H), 5.93–5.87 (m, 2 H), 5.01 (d, J = 18.5 Hz, 1 H), 4.85 (d, J = 18.5 Hz, 1 H), 3.28 (s, 1 H), 2.27–2.11 (m, 2 H), 2.09–2.08 (m, 3 H), 1.96–1.20 (m, 18 H), 0.98 (s, 3 H), 0.91 (s, 3 H). ¹³C NMR (125 MHz, CD₃COCD₃): δ = 176.3, 174.6, 160.8, 124.4, 123.9, 117.8, 115.6, 110.5, 85.5, 74.1, 70.7, 51.8, 50.6, 42.5, 40.4, 40.3, 36.2, 36.0, 33.6, 31.4, 31.4, 27.6, 27.4, 25.8, 24.1, 22.1, 22.0, 16.2. FTIR (neat): ν_max = 2929, 2101, 1746, 1701, 1602, 1165, 989 cm^–1. ESI-HRMS: m/z calcd for C₂₈H₃₈N₃O₅ [M + H]⁺: 496.2806; found: 496.2809.

Zusatzmaterial

Supporting Information