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Synlett 2009(3): 437-440  
DOI: 10.1055/s-0028-1087544
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Nenad Maraša, Petra Štefanič Anderluhb, Uroš Urlebb, 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
Further Information

Publication History

Received 24 October 2008
Publication Date:
21 January 2009 (online)

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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

    References and Notes

  • 1a Wang J. Soisson SM. Young K. Shoop W. Kodali S. Galgoci A. Painter R. Parthasarathy G. Tang YS. Cummings R. Ha S. Dorso K. Motyl M. Jayasuriya H. Ondeyka J. Herath K. Zhang C. Hernandez L. Allocco J. Basilio . Tormo JR. Genilloud O. Vicente F. Pelaez F. Colwell L. Lee SH. Michael B. Felcetto T. Gill C. Silver LL. Hermes JD. Bartizal K. Barrett J. Schmatz D. Becker JW. Cully D. Singh SB. Nature (London)  2006,  441:  358 
    Google Scholar
  • 1b Singh SB. Jayasuriya H. Ondeyka JG. Herath KB. Zhang C. Zink DL. Tsou NN. Ball RG. Basilio A. Genilloud O. Diez MT. Vicente F. Pelaez F. Young K. Wang J. J. Am. Chem. Soc.  2006,  128:  11916 
    Google Scholar
  • 1c Basilio A, Genilloud O, Hernandez P, Singh SB, Tormo JR, and Wang J. inventors; Int. Patent,  WO2005009391.  ; Chem. Abstr. 2005, 142, 196607
  • 2a Nicolaou KC. Li A. Edmonds DJ. Angew. Chem. Int. Ed.  2006,  45:  7086 
    Google Scholar
  • 2b Zou Y. Chen C.-H. Taylor CD. Foxman BM. Snider BB. Org. Lett.  2007,  9:  1825 
    Google Scholar
  • 2c Nicolaou KC. Tang Y. Wang J. Chem. Commun.  2007,  1922 
    Google Scholar
  • 2d Nicolaou KC. Edmonds DJ. Li A. Scott Tria G. Angew. Chem. Int. Ed.  2007,  46:  3942 
    Google Scholar
  • 2e Matsuo J. Takeuchi K. Ishibashi H. Org. Lett.  2008,  10:  4049 
    Google Scholar
  • 2f Lalic G. Corey EJ. Org. Lett.  2007,  9:  4921 
    Google Scholar
  • 2g Tiefenbacher K. Mulzer J. Angew. Chem. Int. Ed.  2007,  46:  8074 
    Google Scholar
  • 2h Ghosh AK. Xi K. Org. Lett.  2007,  9:  4013 
    Google Scholar
  • 2i Li P. Payette JN. Yamamoto H. J. Am. Chem. Soc.  2007,  129:  9534 
    Google Scholar
  • 3 Tiefenbacher K. Mulzer J. Angew. Chem. Int. Ed.  2008,  47:  2548 
    Google Scholar
  • 4a Jayasuriya H. Herath KB. Zhang C. Zink DL. Basilio A. Genilloud O. Diez MT. Vicente F. Gonzalez I. Salazar O. Pelaez F. Cummings R. Ha S. Wang J. Singh SB. Angew. Chem. Int. Ed.  2007,  46:  4684 
    Google Scholar
  • 4b Basilio A, Genilloud O, Jayasuriya H, Gonzalez I, Singh SB, Salazar O, and Wang J. inventors; Int. Patent,  WO2005115400.  ; Chem. Abstr. 2005, 144, 5523
  • 5a Nicolaou KC. Lister T. Denton RM. Montero A. Edmonds DJ. Angew. Chem. Int. Ed.  2007,  46:  4712 
    Google Scholar
  • 5b Nicolaou KC. Tang Y. Wang J. Stepan AF. Li A. Montero A. J. Am. Chem. Soc.  2007,  129:  14850 
    Google Scholar
  • 5c Singh SB. Herath KB. Wang J. Tsou N. Ball RG. Tetrahedron Lett.  2007,  48:  5429 
    Google Scholar
  • 5d Yeung Y.-Y. Corey EJ. Org. Lett.  2008,  10:  3877 
    Google Scholar
  • 6 Häbich D. von Nussbaum F. ChemMedChem  2006,  1:  951 
    CrossrefGoogle Scholar
  • 7 Heretsch P. Giannis A. Synthesis  2007,  2614 
    Article in Thieme ConnectGoogle Scholar
  • 8 Nicolaou KC. Tria GS. Edmonds DJ. Angew. Chem. Int. Ed.  2008,  47:  1780 
    CrossrefGoogle Scholar
  • 9 Hayashida J. Rawal VH. Angew. Chem. Int. Ed.  2008,  47, 4373 
    Google Scholar
  • 10 Lindsey AS. Jeskey H. Chem. Rev.  1957,  57:  583 
    CrossrefGoogle Scholar
  • 11 Reimer K. Tiemann F. Ber. Dtsch. Chem. Ges.  1876,  9:  1285 
    CrossrefGoogle Scholar
  • 12 Sasson Y. Razintsky M. J. Chem. Soc., Chem. Commun.  1985,  1134 
    CrossrefGoogle Scholar
  • 13 Nierenstein M. Clibbens DA. Org. Synth., Coll. Vol. II   Wiley; New York: 1943.  p.557 
    Google Scholar
  • 14 Meek WH. Fuchsman CH. J. Chem. Eng. Data  1969,  14:  388 
    CrossrefGoogle Scholar
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.