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, Cette première étape d'iodation a été décrite auparavant par Ayed et ses collaborateurs, en utilisant du diiode en présence de morpholine dans du benzène sur l'alcyne (R)-56a. 49 (Schéma 18) Schéma 18 : Synthèse de (R)-73 décrite par Ayed et ses collaborateurs (i) I2, morpholine

, Etant donné que l'utilisation du benzène est très contrôlée actuellement, celui-ci a été remplacé par du toluène qui possède des propriétés physico-chimiques similaires. Or, dans ce solvant, vol.19

, Afin de réaliser cette iodation, les conditions décrites par Crossley et Hein ont été appliquées sur (R)-56a. 50,51 Dans un premier temps, la formation de l'iodure d

, Ensuite, l'ajout de l'alcyne (R)-56a avec de CuI conduit au produit iodé (R)-73 avec un rendement de 45%

, Bestmann-Ohira reagent (0.029 mol; 5.55 g). The crude product was purified by flash chromatography (eluent: 0-80% PE/EtOAc) and 1.65 g (38% yield) of pure product were obtained as yellow oil

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.40, 1.42, 1.50 (3s, 15H, C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, 3 (C(CH3)2, C-5), vol.93

. Pe/etoac, 8/2; Ninhydrin)

, S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1,2,3-triazol-1-yl)propanoate

X. Method, Starting from azide (S)-44a (3.0 mmol, vol.730

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.33 (s, 9H, C(CH3)3); 1.38 (s, 9H, C(CH3)3); 3.64 (s, 3H, CO2CH3)

1. , N. H. , and J. =. , Hz, vol.7, p.39

C. Nmr-(dmso--d6,-75 and M. , CH3)3); 28.3 (3-CH3, (CH3)3); 35.6 (CH2, C-5), vol.49, pp.28-29

/. Etoac and . Pe,

, UPLC: tR: 3.52 min; purity, p.96

M. , calcd for C17H30N5O6, 400.2196, found 400.2195. (R) methyl-2-((tert-butoxycarbonyl)amino)-3-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-1, HRMS, vol.2

X. Method, Starting from azide (R)-44b (2.4 mmol; 600 mg), N-Boc-propargylamine 47 (2.4 mmol; 380 mg), sodium L-ascorbate (0.48 mmol; 95 mg) and CuSO4?5H2O (0.24 mmol

, The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 758 mg

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.33 (s, 9H, C(CH3)3); 1.38 (s, 9H, C(CH3)3); 3.64 (s, 3H, CO2CH3)

1. , N. H. , and J. =. , Hz, vol.7, p.39

C. Nmr-(dmso--d6,-75 and M. , CH3)3); 28.3 (3-CH3, (CH3)3); 35.6 (CH2, C-5), vol.49, pp.28-29

, >99.5%. UPLC: tR: 3.43 min; purity: 98%. HRMS

, S) methyl -2-((tert-butoxycarbonyl)amino)-3-(4-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-1-yl)propanoate

X. Method, Starting from azide (S)-44a (1.84 mmol; 450 mg), N-Boc butynylamine 49 (1.84 mmol; 310 mg), sodium L-ascorbate (0.36 mmol; 70 mg) and CuSO4?5H2O (0.18 mmol

, The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 634 mg

H. Nmr and . Dmso--d6,

H. Hz,

C. Nmr and . Dmso--d6,

, IR (cm -1, p.1684

, EtOAc/PE: 8/2; Ninhydrin)

, UPLC: tR: 3.46 min; purity, p.97

M. , (R) methyl -2-((tert-butoxycarbonyl)amino)-3-(4-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-1-yl)propanoate, HRMS

X. Method, Starting from azide (R)-44b (2.0 mmol, vol.500

, 340 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 634 mg

H. Nmr and . Dmso--d6,

H. Hz,

C. Nmr and . Dmso--d6,

, EtOAc/PE: 8/2; Ninhydrin)

, UPLC: tR: 3.48 min; purity, >99.5%, p.100

, S) methyl-2-((tert-butoxycarbonyl)amino)-3-(4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoate

X. Method, 0 mmol; 500 mg), but-3-yn-1-ol 57b (2.0 mmol; 155 µl), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography, Starting from azide (S)-44a, p.76

H. Nmr and . Dmso--d6, CH3)3); 2.74 (t, 2H, CH2, J = 6, 300 MHz) ?: 1.33 (s, 9H, vol.9

N. H. Hz, 79 (s, 1H, CH, vol.7

C. Nmr and . Dmso--d6, CH3)3); 29.1 (CH2, C-5), vol.49

M. , , pp.80-82

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.54 min; purity, p.100

M. , HRMS

X. Method, 0 mmol; 500 mg), but-3-yn-1-ol 57b (2.0 mmol; 155 µl), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography, Starting from azide (R)-44b, pp.475-74

H. Nmr and . Dmso--d6, CH3)3); 2.74 (t, 2H, CH2, J = 6, 300 MHz) ?: 1.33 (s, 9H, vol.9

N. H. Hz, 79 (s, 1H, CH, vol.7

C. Nmr and . Dmso--d6, CH3)3); 29.1 (CH2, C-5), vol.49

M. , , pp.80-82

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.52 min; purity, p.98

M. , calcd for C13H23N4O5, 315.1668, found 315.1669. (S) methyl-1-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate, HRMS, issue.S

X. Method, Starting from azide (S)-44a (1.84 mmol; 450 mg), methyl propiolate 59a (1, vol.84

, 165 µl), sodium L-ascorbate (0.36 mmol; 70 mg) and CuSO4?5H2O (0.18 mmol; 45 mg). The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 510 mg

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.30 (s, 9H, (CH3)3); 3.66 (s, 3H, CO2CH3)

C. Nmr and . Dmso--d6, 75 MHz) ?: 27, vol.9, pp.3-3

/. Etoac and . Pe,

, UPLC: tR: 3.01 min; purity, p.96

, HRMS

, R) methyl-1-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazole-4-carboxylate

X. Method, Starting from azide (R)-44b (2.0 mmol; 500 mg), methyl propiolate 59a (2.0 mmol

, 182 µl), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-70% PE/EtOAc) and 566 mg

H. Nmr, DMSO -d6, 300 MHz) ?: 1.30 (s, 9H

C. Nmr and . Dmso--d6, 75 MHz) ?: 27, vol.9, pp.3-3

/. Etoac and . Pe,

, UPLC: tR: 3.02 min; purity, p.98

M. , -((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)acetic acid, HRMS, issue.2

X. Method, Starting from azide (S)-44a (4.0 mmol; 1.00 g), but-3-ynoic acid 59b (4.0 mmol; 340 mg), sodium L-ascorbate (0.8 mmol; 160 mg) and CuSO4?5H2O (0.4 mmol; 100 mg). The crude product was purified by C18 flash chromatography, p.64

H. Nmr and . Dmso--d6,

C. Nmr and . Dmso--d6, CH3)3); 35.6 (CH2, C-5), 75 MHz) ?: 28, vol.9, pp.3-3

, 2 (CO2H, C-6), vol.170

, IR (cm -1, p.1704

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.45 min; purity, p.86

, HRMS

, -((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)acetic acid

X. Method, 0 mmol; 1.00 g), but-3-ynoic acid 59b (4.0 mmol; 340 mg), sodium L-ascorbate (0.8 mmol; 160 mg) and CuSO4?5H2O (0.4 mmol; 100 mg). The crude product was purified by C18 flash chromatography, Starting from azide (R)-44b

H. Nmr and . Dmso--d6,

C. Nmr and . Dmso--d6, C-5); 49.0 (CH2, C-2), vol.34

, IR (cm -1, p.1704

/. Etoac and . Meoh, 95/5; Ninhydrin)

, UPLC: tR: 2.62 min; purity, p.97

M. , (R)-tert-butyl 4-(1-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl, HRMS, issue.2

X. Method, 0 mmol; 500 mg), alkyne (R)-56a (2.0 mmol; 460 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-50% PE/EtOAc) and 655 mg, Starting from azide (S)-44a

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.55 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.93 min; purity, p.97

, HRMS

, tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl

X. Method, 0 mmol; 500 mg), alkyne (R)-56a (2.0 mmol; 460 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-50% PE/EtOAc) and 754 mg, Starting from azide (R)-44b

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.56 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.93 min; purity, p.98

M. , 2615, found 470.2613. (S)tert-butyl-4-(1-((S)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl, HRMS, vol.470, issue.2

X. Method, 0 mmol; 500 mg), alkyne (S)-56b (2.0 mmol; 460 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-50% PE/EtOAc) and 790 mg, Starting from azide (S)-44a

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.56 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6, , vol.27

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.90 min; purity, p.98

, HRMS

, tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)-2,2-dimethyloxazolidine-3-carboxylate

X. Method, 0 mmol; 500 mg), alkyne (S)-56b (2.0 mmol; 460 mg), sodium L-ascorbate (0.4 mmol; 80 mg) and CuSO4?5H2O (0.2 mmol; 50 mg). The crude product was purified by flash chromatography (eluent: 0-50% PE/EtOAc) and 727 mg, Starting from azide (R)-44b

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.27, 1.33, 1.42, 1.48 and 1.55 (5s, 24H, 2-C(CH3), vol.3

C. Nmr and . Dmso--d6,

, PE/EtOAc: 5/5; Ninhydrin)

, UPLC: tR: 3.91 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (S)-58a (0.75 mmol; 300 mg). The crude product was purified

H. Hz,

C. Nmr-(d2o, 75 MHz) ?: 34.1 (CH2, C-5), vol.53

, IR (cm -1 ): 1587 (?C=O), vol.3012

, D 25 = -12 (H2O; c = 1.30)

, UPLC: tR: 0.52 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (R)-58b (0.75 mmol; 300 mg). The crude product was purified

H. Hz,

C. Nmr-(d2o, 75 MHz) ?: 34.1 (CH2, C-5), vol.53

, C-4), vol.176

, UPLC: tR: 0.52 min; purity, p.96

M. , HRMS

Y. Method, Starting from triazole (S)-58c (0.72 mmol; 300 mg). The crude product was purified

, H-5); 3.30 (t, 2H, J =, vol.6, issue.6

C. Nmr-(d2o, 75 MHz) ?: 22.9 (CH2, C-5), vol.38

, IR (cm -1, p.1601

, UPLC: tR: 0.53 min; purity, p.91

M. , Chapitre 2 : Partie expérimentale (R)-2-amino-3-(4-(2-aminoethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS, 1126.

Y. Method, Starting from triazole (R)-58d (0.72 mmol; 300 mg). The crude product was purified

H. Nmr, H-5); 3.30 (t, 2H, D2O, 300 MHz) ?: 3.08 (t, 2H, J = 6.9 Hz, vol.6

C. Nmr-(d2o, 75 MHz) ?: 22.9 (CH2, C-5), vol.38

, C-3), vol.143

, IR (cm -1, p.1599

, UPLC: tR: 0.53 min; purity, p.90

M. , HRMS, 1147.

Y. Method, Starting from triazole (S)-58e (0.99 mmol; 300 mg). The crude product was purified

H. Hz, 97 (s, 1H, vol.7

C. Nmr-(d2o, 75 MHz) ?: 49.7 (CH2, C-5), vol.54

, UPLC: tR: 0.58 min; purity, p.88

M. , HRMS

Y. Method, Starting from triazole (R)-58f (1.6 mmol; 485 mg). The crude product was purified

H. Hz,

C. Nmr-(d2o, 75 MHz) ?: 49.7 (CH2, C-5), vol.54

, C-4), vol.170

, UPLC: tR: 0.58 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (S)-58g (0.63 mmol; 200 mg). The crude product was purified

C. Nmr-(d2o, 75 MHz) ?: 27.6 (CH2, C-5)

, UPLC: tR: 0.66 min; purity, p.96

M. , HRMS

Y. Method, Starting from triazole (R)-58h (0.63 mmol; 200 mg). The crude product was purified

J. 1h,

C. Nmr-(d2o, 75 MHz) ?: 27.6 (CH2, C-5)

, UPLC: tR: 0.68 min; purity, p.86

M. , HRMS

Y. Method, Starting from triazole (S)-60a (0.60 mmol; 200 mg). The crude product was purified

H. Nmr,

, 66 (s, 1H, H-3), vol.8

C. Nmr and . Dmso--d6, C-2); 52.0 (CH, C-1), 75 MHz) ?: 48.9 (CH2, vol.130

, UPLC: tR: 0.57 min; purity, p.90

M. , HRMS

Y. Method, Starting from triazole (R)-60b (0.60 mmol; 200 mg). The crude product was purified

H. Nmr,

, 65 (s, 1H, H-3), vol.8

C. Nmr and . Dmso--d6, C-2), 75 MHz) ?: 48.9 (CH2, vol.51

, UPLC: tR: 0.57 min; purity, p.90

M. , HRMS

Y. Method, Starting from triazole (S)-60c (0.60 mmol; 200 mg). The crude product was purified

C. Nmr-(d2o, 75 MHz) ?: 31.5 (CH2, C-5), vol.49

(. and C. ,

, IR (cm -1, p.1580

, UPLC: tR: 0.63 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (R)-60d (0.60 mmol; 200 mg). The crude product was purified

H. Nmr-(d2o, 300 MHz) ?: 3.79 (s, 2H, H-5)

C. Nmr-(d2o, 75 MHz) ?: 33.1 (CH2, C-5), vol.49

(. and C. ,

, IR (cm -1, p.1575

, UPLC: tR: 0.63 min; purity: 100%

M. , (R)-1-amino-2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS

Y. Method, Starting from triazole (2S, 4R)-61a (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 20 mg

H. Nmr, D2O, 300 MHz) ?: 3.94 (m, 2H, CH2

C. Nmr-(d2o, 75 MHz) ?: 48.6 (CH2, C-5), vol.51

, C-3), vol.143

, UPLC: tR: 0.52 min; purity: 100%

M. , (R)-1-amino-2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS

Y. Method, Starting from triazole (2R, 4R)-61b (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 40 mg

C. Nmr-(d2o, 75 MHz) ?: 48.5 (CH2, C-5), vol.49, p.6

, C-3), vol.141

, UPLC: tR: 0.52 min; purity: 100%

M. , (S)-1-amino-2-hydroxyethyl)-1H-1,2,3-triazol-1-yl)propanoic acid, HRMS

Y. Method, Starting from triazole (2S, 4S)-61c (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 33 mg

H. Nmr, D2O, 300 MHz) ?: 3.95 (m, 2H, CH2

C. Nmr-(d2o, 75 MHz) ?: 48.5 (CH2, C-5); 51.5 (CH2, C-2), vol.54

, C-3); 143.0 (C, C-4), vol.173

, UPLC: tR: 0.52 min; purity: 100%

M. , HRMS

Y. Method, Starting from triazole (2R, 4S)-61d (0.42 mmol; 200 mg). The crude product was purified using a cation exchange resin column (0.05 M NH4OH elution) and 20 mg

H. Nmr, D2O, 300 MHz) ?: 3.91 (m, 2H, CH2

C. Nmr-(d2o, 75 MHz) ?: 48.6 (CH2, C-5), vol.52

, C-3); 144.5 (C, C-4), vol.174

, UPLC: tR: 0.52 min; purity: 100%

M. , + calcd for C7H14N5O3, 216.1097, found 216.1105. (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-chloropropanoate, HRMS, p.66

Z. Method, Starting from N-Boc-serine methyl ester (S)-42a (2 g, 9.12 mmol), p.10

, 37 g, 10 mmol). The crude product was purified by flash chromatography (eluent: 0-10% PE/EtOAc) and 1.08 g (50% yield) of pure product were obtained as white powder

C. Nmr and . Dmso--d6,

, PE/EtOAc: 9/1; Ninhydrin)

, S)-tert-butyl 4-(chloromethyl)-2,2-dimethyloxazolidine-3-carboxylate, p.67

A. A. Method, Starting from alcohol oxazolidine alcohol (S)-51a (2 g, 8.64 mmol), PPh3 (2.95 g, 11 mmol) and CCl4 (1.1 mL, 11 mmol). The crude product was purified by flash chromatography (eluent: 0-10% PE/EtOAc) and 990 mg

H. Nmr and . Dmso--d6, 300 MHz) ?: 1.42, 1.48 (2s, 15H, C(CH3)3, H-5 and H-6)

C. Nmr and . Dmso--d6,

, PE/EtOAc: 9/1; Ninhydrin)

, S)-tert-butyl 4-(iodoethynyl)-2,2-dimethyloxazolidine-3-carboxylate, p.73

A. B. Method, CuI (42 mg, 0.22 mmol), Niodomorpholine (1.66 g, 4.88 mmol). The crude product was purified by flash chromatography (eluent: 0-10% PE/EtOAc) and 1 g, Starting from alkyne (R)-56a (1 g, 4.43 mmol)

H. Nmr and . Dmso--d6, , vol.3

C. Nmr and . Dmso--d6, C(CH3)3, C-6 and C-7); 29.8 (C?CI, C-1), 75 MHz) ?: 24.5, 25.9, vol.66

, PE/EtOAc: 9/1; Ninhydrin)

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S. Rausch, A. Hänchen, A. Denisiuk, M. Löhken, T. Schneider et al., Feglymycin Is an Inhibitor of the Enzymes MurA and MurC of the Peptidoglycan Biosynthesis Pathway, ChemBioChem, vol.12, issue.8, pp.1171-1173, 2011.

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, Résumé de la thèse

, Cela est d'autant plus accentué par la mauvaise utilisation des antibiotiques combinée au manque d'intérêt de l'industrie pharmaceutique. Il est donc urgent de trouver de nouvelles cibles antibactériennes et de nouveaux agents antibactériens pour lutter contre les bactéries multirésistantes, L'émergence récente et continuelle de souches bactériennes résistantes aux antibiotiques

, La première stratégie vise à concevoir et à synthétiser de nouveaux inhibiteurs d'histidine kinase (HK, protéine impliquée dans le mécanisme de résistance) à caractère d'adjuvant d'antibiotiques

, Parmi les 47 composés synthétisés, deux dérivés thiophènes, deux dérivés sulfonates et trois dérivés sulfonamides présentent des valeurs inhibitrices de HK inférieures à 50 µM. Ces valeurs ont été améliorées par rapport aux précédents inhibiteurs synthétisés au laboratoire. Par ailleurs, trois dérivés furanes ont inhibé la croissance bactérienne de bactéries à Gram-positif comme à

, Gram-négatif. Finalement, un chlorhydrate d'amine présente une activité adjuvante d'antibiotique

, La deuxième stratégie menée, vise à inhiber la voie de biosynthèse de la lysine qui est un des principaux résidus impliqués dans la biosynthèse du peptidoglycane. Ceci est possible par la synthèse d'acides aminés non usuels à base de triazole ou d'alcyne, analogues de l'acide diaminopimélique (précurseur de la lysine, Au total 16 acides aminés de type triazole ont été synthétisés et leurs activités biologiques sont en cours de réalisation