Simple Synthesis of 3-Acetamido-β-resorcylic
Acids as Potential FabF and FabH Inhibitors without Using Protecting
Groups

Nenad Maraš; Petra Štefanič Anderluh; Uroš Urleb; Marijan Kočevar

doi:10.1055/s-0028-1087544

LETTER

Simple Synthesis of 3-Acetamido-β-resorcylic Acids as Potential FabF and FabH Inhibitors without Using Protecting Groups

Nenad Maraš^a, Petra Štefanič Anderluh^b, Uroš Urleb^b, Marijan Kočevar*^a
^a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax: +386(1)2419220; e-Mail: marijan.kocevar@fkkt.uni-lj.si;
^b Lek Pharmaceuticals d.d., Verovškova 57, 1526 Ljubljana, Slovenia

Abstract

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Abstract

A simple two-step strategy for the synthesis of 3-acetamido-β-resorcylic acids as potential platensimycin analogues was developed. It avoids the use of protecting group chemistry and starts from 2-aminoresorcinol, which is first N-acylated and then subjected to a modified Kolbe-Schmitt carboxylation to yield the desired 3-acetamido-β-resorcylic acids.

Key words

phenols - acylations - carboxylic acids - drugs - antibiotics

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References and Notes

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15

General Procedure for the Preparation of N -Acyl-2,6-dihydroxyanilines 5a-e Using Acid Chlorides: To a solution of 2-aminoresorcinol (4; 7 mmol) in EtOAc (30 mL) stirred in an ice bath was added pyridine (0.76 mL, 10 mmol) followed a dropwise introduction of a solution of an acid chloride (6 mmol) in EtOAc (30 mL). After 1 h the reaction mixture was washed with H₂O (30 mL), aq NaHCO₃ (5%, 30 mL), aq HCl (1 M, 30 mL), H₂O (30 mL), then dried over Na₂SO₄ and evaporated in vacuo yielding 5.
General Procedure for the Preparation of N -Acyl-2,6-dihydroxyanilines 5f-j Using Acids and CDI: To a solution of a carboxylic acid (1.16 g, 6 mmol) in THF (10 mL) was added carbonyldiimidazole (1.00 g, 6 mmol). After stirring for 1 h at r.t., it was added to a solution of 2-aminoresorcinol (4) (7 mmol) in EtOAc (30 mL). The mixture was left stirring for 24 h at r.t., washed with diluted hydrochloric acid (3%; 30 mL), aq NaHCO₃ (3%; 30 mL), H₂O (30 mL), dried over Na₂SO₄ and evaporated in vacuo to give 5. General Procedure for the Kolbe-Schmitt Carboxy-lation: To the solution of 5 (4 mmol) in DMSO (35 mL) in an autoclave (300 mL size) was added anhyd K₂CO₃ (1.70 g, 12 mmol) followed by the addition of dry ice (CO₂; ca. 20 g). The autoclave was immediately closed and heated at 120 ˚C for 12 h. After carefully opening the autoclave, in order to release the CO₂ pressure, the reaction mixture was diluted with H₂O (100 mL) and extracted with EtOAc (4 × 30 mL). The extract was washed with NaHCO₃ (3%, 30 mL), H₂O (30 mL), dried over Na₂SO₄ and evaporated in vacuo to give the unreacted starting material 5. The diluted reaction mixture was then acidified with hydrochloric acid (to pH ca. 3), saturated with NaCl and extracted with EtOAc (4 × 30 mL). The extract was washed with brine (30 mL), dried over Na₂SO₄ and evaporated in vacuo to give a crude product 6, which was further purified.
All the products gave satisfactory analytical and spectroscopic data.
Selected Characterization Data for the Representative Products: N -(2,6-Dihydroxyphenyl)-3,3-dimethylbutanamide (5a): off-white product (84% yield); mp 164-167 ˚C. ^¹H NMR (DMSO-d ₆): δ = 1.04 (s, 9 H, t-Bu), 2.36 (s, 2 H, CH₂CO), 6.38 (d, J = 8.1 Hz, 2 H, ArH), 6.88 (t, J = 8.1 Hz, 1 H, ArH), 9.28 (s, 1 H, NH), 9.41 (s, 2 H, 2 × OH). ^¹³C NMR (DMSO-d ₆): δ = 29.6, 30.7, 48.3, 107.8, 114.5, 126.4, 151.5, 172.1. IR (KBr): 1637, 1591, 1536, 1481, 1371 cm^-¹. MS (EI): m/z = 223 (14) [M⁺], 125 (100). HRMS (EI): m/z [M]⁺ calcd for C₁₂H₁₇NO₃: 223.1208; found: 223.1216. Anal. Calcd for C₁₂H₁₇NO₃: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.79; H, 7.83; N, 6.09.
N -(2,6-Dihydroxyphenyl)-5-oxohexanamide (5g): off-white crystalline product (77% yield); mp 128-131 ˚C. ^¹H NMR (DMSO-d ₆): δ = 1.77 (m, 2 H, CH₂), 2.09 (s, 3 H, Me), 2.39 (t, J = 7.3 Hz, 2 H, CH₂), 2.51 (t, J = 7.3 Hz, 2 H, CH₂), 6.34 (d, J = 8.1 Hz, 1 H, ArH), 6.87 (t, J = 8.1 Hz, 2 H, ArH), 9.22 (s, 1 H, NH), 9.29 (s, 2 H, OH). ^¹³C NMR (DMSO-d ₆): δ = 19.5, 29.7, 34.3, 41.8, 107.5, 113.9, 126.5, 152.0, 172.7, 208.0. IR (KBr): 1692, 1645, 1605, 1536, 1379 cm^-¹. MS (EI): m/z (%) = 237 (7) [M⁺], 125 (100), 113 (10), 85 (20). HRMS (EI): m/z calcd for C₁₂H₁₅NO₄: 237.1001; found: 237.1006. Anal. Calcd for C₁₂H₁₅NO₄: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.85; H, 6.44; N, 5.87.

3-[(3,3-Dimethylbutanoyl)amino]-2,4-dihydroxybenzoic Acid (6a): crystalline solid (25% yield); mp 198-200 ˚C (dec.). ^¹H NMR (DMSO-d ₆): δ = 1.04 (s, 9 H, t-Bu), 2.21 (s, 2 H, CH₂), 6.43 (d, J = 8.8 Hz, 1 H, ArH), 7.56 (d, J = 8.8 Hz, 1 H, ArH), 8.91 (s, 1 H, NH), 10.21 (s, 1 H, OH), 11.81 (br s, 1 H, OH), 12.60-14.40 (br s, 1 H, CO₂H). ^¹³C NMR (DMSO-d ₆): δ = 29.6, 30.6, 48.7, 104.4, 107.9, 113.0, 128.8, 158.8, 159.0, 170.7, 172.2. IR (KBr): 1642, 1533, 1437, 1379, 1253 cm^-¹. MS (EI): m/z = 267 (24) [M⁺], 169 (54), 151 (100), 125 (28). Anal. Calcd for C₁₃H₁₇NO₅: C, 58.42; H, 6.41; N, 5.24. Found: C, 58.69; H, 6.69; N, 5.15.
3-[(Adamantan-1-ylacetyl)amino]-2,4-dihydroxybenzoic Acid (6h): mp >180 ˚C (dec.). ^¹H NMR (DMSO-d ₆): δ = 1.55-1.72 (m, 12 H, 6 × adamantyl CH₂), 1.89-1.97 (m, 3 H, 3 × adamantyl CH), 2.10 (s, 2 H, CH₂), 6.43 (d, J = 8.8 Hz, 1 H, ArH), 7.56 (d, J = 8.8 Hz, 1 H, ArH), 8.91 (s, 1 H, NH), 10.23 (s, 1 H, OH), 11.84 (br s, 1 H, OH), 13.46 (br s, 1 H, CO₂H). ^¹³C NMR (DMSO-d ₆): δ = 28.0, 32.4, 36.4, 41.9, 49.7, 104.3, 108.0, 113.1, 128.7, 158.6, 158.8, 170.0, 172.2. IR (KBr): 1709, 1641, 1536, 1449, 1395, 1269 cm^-¹. MS (ESI): m/z = 346 [MH⁺]. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₄NO₅: 346.1654; found: 346.1662. Anal. Calcd for C₁₉H₂₃NO₅: C, 66.07; H, 6.71; N, 4.06. Found: C, 66.34; H, 7.02; N, 3.92.
2,4-Dihydroxy-3-[({[1 R -(2- endo ,3- exo )]-3-hydroxy-4,7,7-trimethylbicyclo[2.2.1]hept-2-yl}acetyl)amino]benzoic Acid (6k): white powder (15% yield); mp 167-169 ˚C. ^¹H NMR (DMSO-d ₆): δ = 0.78 (s, 3 H, Me), 0.81 (s, 3 H, Me), 1.03 (s, 3 H, Me), 0.91 (m, 2 H), 1.35-1.51 (m, 3 H), 1.64 (br, 1 H), 2.30-2.43 (m, 2 H), 3.07 (br, 1 H, CH₂, bicycloheptyl), 4.62 (br s, 1 H, OH), 6.43 (d, J = 8.8 Hz, 1 H, ArH), 7.57 (d, J = 8.8 Hz, 1 H, ArH), 9.10 (s, 1 H, NH), 10.10 (s, 1 H, OH), 11.84 (br s, 1 H, OH), 13.5 (br s, 1 H, CO₂H). ^¹³C NMR (DMSO-d ₆): δ = 11.7, 19.6, 20.0, 20.7, 34.1, 36.9, 46.0, 47.0, 47.8, 49.0, 83.7, 104.4, 107.9, 112.8, 128.8, 158.6, 158.8, 172.1, 172.2. IR (KBr): 1645, 1541, 1383, 1296, 1248 cm^-¹. MS (ESI): m/z = 364 [MH⁺]. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₆NO₆: 364.1760; found: 364.1772.