Advertisement

Fully Synthetic Tetracyclines: Increasing Chemical Diversity to Combat Multidrug-Resistant Bacterial Infections

  • Cuixiang Sun
  • Xiao-Yi Xiao
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 26)

Abstract

A convergent total synthesis platform has enabled diverse modifications of the tetracycline chemical space that were previously inaccessible or difficult to access by traditional semisynthesis. Using this powerful chemical synthesis technology, new tetracycline scaffolds were designed leading to the discovery of novel, fully synthetic tetracyclines with potent, broad-spectrum antibacterial activity against multidrug-resistant (MDR) Gram-positive and Gram-negative pathogens. This discovery effort produced a number of tetracycline antibiotic development candidates currently in various stages of clinical study, including eravacycline (TP-434), which has advanced into several late-stage clinical trials in patients with complicated intro-abdominal infections (cIAI) and in patients with complicated urinary tract infections (cUTI). This chapter describes the design, synthesis, and evaluation of several fully synthetic tetracycline series, including the disubstituted tetracyclines (fluorocyclines), the heterocyclines, and the polycyclines.

Keywords

Broad spectrum Eravacycline Michael–Dieckmann reaction Multidrug resistant (MDR) Structure-activity relationship, Total synthesis TP-271 

Notes

Acknowledgments

Many thanks to Sean Connell for providing Fig. 2.

References

  1. 1.
    Duggar BM (1948) Aureomycin: a product of continuing search for new antibiotics. Ann N Y Acad Sci 51:177–181. doi: 10.1111/j.1749-6632.2011.06254.xCrossRefPubMedGoogle Scholar
  2. 2.
    Finlay AC, Hobby GL, P’an SY, Regna PP, Routien JB, Seeley DB, Shull GM, Sobin BA, Solomons IA, Vinson JW, Kane JH (1950) Terramycin, a new antibiotic. Science 111:85. doi: 10.1126/science.111.2874.85CrossRefPubMedGoogle Scholar
  3. 3.
    Booth JH, Morton J, Petisi JP, Wilkinson RG, Williams JH (1953) Tetracycline. J Am Chem Soc 75:4621. doi: 10.1021/ja01114a535CrossRefGoogle Scholar
  4. 4.
    Conover LH, Moreland WT, English AR, Stephens CR, Pilgrim FJ (1953) Terramycin XI. Tetracycline. J Am Chem Soc 75:4622–4623. doi: 10.1021/ja01114a537CrossRefGoogle Scholar
  5. 5.
    Minieri PP, Soko, H, Firman MC (1956) Tetracycline and chlorotetracycline. US2734018Google Scholar
  6. 6.
    Hawkey PM (2008) The growing burden of antimicrobial resistance. J Antimicrob Chemother 62(Suppl. 1):i1–i9. doi: 10.1093/jac/dkn241CrossRefPubMedGoogle Scholar
  7. 7.
    Chopra I, Roberts M (2001) Tetracycline antibiotics: model of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 65:232–260. doi: 10.1128/MMBR.65.2.232-260.2001CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Levy SB (1989) Evolution and spread of tetracycline resistance determinants. J Antimicrob Chemother 24:1–3. doi: 10.1093/jac/24.1.1CrossRefPubMedGoogle Scholar
  9. 9.
    Lomovskaya O, Watkins WJ (2001) Efflux pumps: their role in antibacterial drug discovery. Curr Med Chem 8:1699–1711. doi: 10.2174/0929867013371743CrossRefPubMedGoogle Scholar
  10. 10.
    Speer BS, Shoemaker NB, Salyers AA (1992) Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance. Clin Microbiol Rev 5:387–399CrossRefGoogle Scholar
  11. 11.
    Yonath A (2005) Antibiotics targeting ribosomes: resistance, selectivity, synergism, and cellular regulation. Annu Rev Biochem 74:649–679. doi: 10.1146/annurev.biochem.74.082803.133130CrossRefPubMedGoogle Scholar
  12. 12.
    Grossman TH (2016) Tetracycline antibiotics and resistance. Cold Spring Harb Perspect Med 17:a025387. doi: 10.1101/cshperspect.a025387CrossRefGoogle Scholar
  13. 13.
    Stephens CR, Murai K, Rennhard HH, Conover LH, Brunings KJ (1958) Hydrogenolysis studies in the tetracycline series–6-deoxytetracyclines. J Am Chem Soc 80:5324–5325. doi: 10.1021/ja01552a082CrossRefGoogle Scholar
  14. 14.
    Stephens CR, Beereboom JJ, Rennhard HH, Gordon PN, Murai K, Blackwood RK, Wittenau MS (1963) 6-Deoxytetracyclines. IV. Preparation, C-6 stereochemistry, and reactions. J Am Chem Soc 85:2643–2652. doi: 10.1021/ja00900a027CrossRefGoogle Scholar
  15. 15.
    Spencer JL, Hlavka JJ, Petisi J, Krazinski HM, Boothe JH (1963) 6-Deoxytetracyclines. V. 7,9-disubstituted products. J Med Chem 6:405–407. doi: 10.1021/jm00340a014CrossRefPubMedGoogle Scholar
  16. 16.
    Martell MJ, Boothe JH (1967) The 6-deoxytetracyclines. VII. Alkylated aminotetracyclines possessing unique antibacterial activity. J Med Chem 10:44–46. doi: 10.1021/jm00313a009CrossRefPubMedGoogle Scholar
  17. 17.
    Church RFR, Schaub RE, Weiss MJ (1971) Synthesis of 7-dimethylamino-6-demethyl-6-deoxytetracycline (minocycline) via 9-nitro-6-demethyl-6-deoxytetracycline. J Org Chem 36:723–725. doi: 10.1021/jo00804a025CrossRefPubMedGoogle Scholar
  18. 18.
    Sum P-E, Lee VJ, Testa RT, Hlavka JJ, Ellestad GA, Bloom JD, Gluzman Y, Tally FP (1994) Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 37:184–188. doi: 10.1021/jm00027a023CrossRefPubMedGoogle Scholar
  19. 19.
    Jones CH, Petersen P (2005) Tigecycline: a review of preclinical and clinical studies of the first-in-class glycylcycline antibiotic. Drugs Today 41:637–659. doi: 10.1358/dot.2005.41.10.937460CrossRefPubMedGoogle Scholar
  20. 20.
    Olson MW, Ruzin A, Feyfant E, Rush III TS, O’Connell J, Bradford PA (2006) Functional, biophysical, and structural basis for antibacterial activity of tigecycline. Antimicrob Agents Chemother 50:2156–2166. doi: 10.1128/AAC.01499-05CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wright PM, Seiple IB, Myers AG (2014) The evolving role of chemical synthesis in antibacterial drug discovery. Angew Chem Int Ed 53:8840–8869. doi: 10.1002/anie.201310843CrossRefGoogle Scholar
  22. 22.
    Kaewpoowat Q, Ostrosky-Zeichner L (2015) Tigecycline: a critical safety review. Expert Opin Drug Saf 14:335–342. doi: 10.1517/14740338.2015.997206CrossRefPubMedGoogle Scholar
  23. 23.
    Mitscher LA (1978) The chemistry of the tetracycline antibiotics. Marcel Dekker, New YorkGoogle Scholar
  24. 24.
    Nelson ML, Ismail MY, McIntyre L, Bhatia B, Viski P, Hawkins P, Rennie G, Andorsky D, Messersmith D, Stapleton K, Dumornay J, Sheahan P, Verma AK, Warchol T, Levy SB (2003) Versatile and facile synthesis of diverse semisynthetic tetracycline derivatives via Pd-catalyzed reactions. J Org Chem 68:5838–5851. doi: 10.1021/jo030047dCrossRefPubMedGoogle Scholar
  25. 25.
    Bodersen DE, Clemons WM, Carter AP, Morgan-Warren RJ, Wimberly BT, Ramakrishan V (2000) The structure basis for the action of the antibiotics tetracycline, pactamycin, and hygromycin B on the 30S ribosomal subunit. Cell 103:1143–1154. doi: 10.1016/S0092-8674(00)00216-6CrossRefGoogle Scholar
  26. 26.
    Schedlbauer A, Kaminishi T, Ochoa-Lizarralde B, Dhimole N, Zhou S, López-Alnoso JP, Connell SR, Fucini P (2015) Structural characterization of an alternative mode of tigecycline binding to the bacterial ribosome. Antimicrob Agents Chemother 59:2849–2854. doi: 10.1128/AAC.04895-14CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cammarata A, Yau SJ (1970) Predictability of correlations between in vitro tetracycline potencies and substituent indices. J Med Chem 13:93–97. doi: 10.1021/jm00295a024CrossRefPubMedGoogle Scholar
  28. 28.
    Hlavka JJ, Schneller A, Krazinski H, Boothe JH (1962) The 6-deoxytetracyclines: III. Electrophilic and nucleophilic substitution. J Am Chem Soc 84:1426–1430. doi: 10.1021/jm201465wCrossRefGoogle Scholar
  29. 29.
    Stephens CR, Conover LH, Hochstein FA, Regna PP, Pilgrim FJ, Brunings KJ, Woodward RB (1952) Terramycin. VIII. Structure of aureomycin and terramycin. J Am Chem Soc 74:4976–4977. doi: 10.1021/ja01139a533CrossRefGoogle Scholar
  30. 30.
    Hochstein FA, Stephens CR, Conover LH, Regna PP, Pasternack R, Gordon PN, Pilgrim FJ, Brunings KJ, Woodward RB (1953) The structure of terramycin. J Am Chem Soc 75:5455–5475. doi: 10.1021/ja01118a001CrossRefGoogle Scholar
  31. 31.
    Conover LH, Butler K, Johnston JD, Korst JJ, Woodward RB (1962) The total synthesis of 6-demethyl-6-deoxytetracycline. J Am Chem Soc 84:3222–3224. doi: 10.1021/ja00875a063CrossRefGoogle Scholar
  32. 32.
    Korst JJ, Johnston JD, Butler K, Bianco EJ, Conover LH, Woodward RB (1968) The total synthesis of dl-6-demehtyl-6-deoxytetracycline. J Am Chem Soc 90:439–457. doi: 10.1021/ja01004a041CrossRefGoogle Scholar
  33. 33.
    Gurevich AI, Karapetyan MG, Kolosov MN, Korobko VG, Onoprienko VV, Popravko SA, Shemyakin MM (1967) Synthesis of 12a-dehydroxy-5a,6-anhydrotetracycline. The first total synthesis of the naturally occurring tetracycline. Tetrahedron Lett 8:131–134. doi: 10.1016/S0040-4039(00)90501-XCrossRefGoogle Scholar
  34. 34.
    Muxfeldt H, Rogalski W (1965) Tetracyclines. V. A total synthesis of (±)-6-deoxy-6-demethyltetracycline. J Am Chem Soc 87:933–934. doi: 10.1021/ja01082a056CrossRefPubMedGoogle Scholar
  35. 35.
    Muxfeldt H, Hardtmann G, Kathawala F, Vedejs E, Mooberry JB (1968) Tetracyclines. VII. Total synthesis of dl-terramycin. J Am Chem Soc 90:6534–6536. doi: 10.1021/ja01025a063CrossRefPubMedGoogle Scholar
  36. 36.
    Muxfeldt H, Hass G, Hardtmann G, Kathawala F, Mooberry JB, Vedejs E (1979) Tetracyclines. 9. Total synthesis of dl-terramycin. J Am Chem Soc 101:689–701. doi: 10.1021/ja00497a035CrossRefGoogle Scholar
  37. 37.
    Stork G, La Clair JJ, Spargo P, Nargund RP, Totah N (1996) Stereocontrolled synthesis of (±)-12a-deoxytetracycline. J Am Chem Soc 118:5304–5305. doi: 10.1021/ja960434nCrossRefGoogle Scholar
  38. 38.
    Tatsuta K, Yoshimoto T, Gunji H, Okado Y, Takahashi M (2000) The first total synthesis of natural (−)-tetracycline. Chem Lett 29:646–647. doi: 10.1246/cl.2000.646CrossRefGoogle Scholar
  39. 39.
    Charest MG, Lerner CD, Brubaker JD, Siegel DR, Myers AG (2005) A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 308:395–398. doi: 10.1126/science.1109755CrossRefPubMedGoogle Scholar
  40. 40.
    Charest MG, Siegel DR, Myers AG (2005) Synthesis of (−)-tetracycline. J Am Chem Soc 127:8292–8293. doi: 10.1021/ja052151dCrossRefPubMedGoogle Scholar
  41. 41.
    Liu F, Myers AG (2016) Development of a platform for the discovery and practical synthesis of new tetracycline antibiotics. Curr Opin Chem Biol 32:48–57. doi: 10.1016/j.cbpa.2016.03.011CrossRefPubMedGoogle Scholar
  42. 42.
    Brubaker JD, Myers AG (2007) A practical, enantioselective synthetic route to a key precursor to the tetracycline antibiotics. Org Lett 9:3523–3525. doi: 10.1021/ol071377dCrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Xiao X-Y, Hunt DK, Zhou J, Clark RB, Dunwoody N, Fyfe C, Grossman TH, O’Brien WJ, Plamondon L, Ronn M, Sun C, Zhang W-Y, Sutcliffe JA (2012) Fluorocyclines. 1. 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J Med Chem 55:597–605. doi: 10.1021/jm201465wCrossRefPubMedGoogle Scholar
  44. 44.
    Clark RB, Hunt DK, Me H, Achorn C, Chen C-L, Deng Y, Fyfe C, Grossman TH, Hogan PC, O’Brien WJ, Plamondon L, Ronn M, Sutcliffe JA, Zhu Z, Xiao X-Y (2012) Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy. J Med Chem 55:606–622. doi: 10.1021/jm201467rCrossRefPubMedGoogle Scholar
  45. 45.
    Clark RB, He M, Deng D, Sun C, Chen C-L, Hunt DK, O’Brien WJ, Fyfe C, Grossman TH, Sutcliffe JA, Achorn C, Hogan PC, Katz CE, Niu J, ZhangW-Y, Zhu Z, Ronn M, Xiao X-Y (2013) Synthesis and biological evaluation of 8-aminomethyltetracycline derivatives as novel antibacterial agents. J Med Chem 56:8112–8138. doi: 10.1021/jm1015389CrossRefPubMedGoogle Scholar
  46. 46.
    Zhang W-Y, Sun C, Hunt DK, He M, Deng Y, Zhu Z, Chen C-L, Katz CE, Niu X, Hogan PC, Xiao X-Y, Dunwoody N, Ronn M (2016) Process development and scale-up of fully synthetic tetracycline TP-2758: a potent antibacterial agent with excellent oral bioavailability. Org Process Res Dev 20:284–296. doi: 10.1021/acs.oprd.5b00404CrossRefGoogle Scholar
  47. 47.
    Clark RB, He M, Fyfe C, Lofland D, O’Brien WJ, Plamondon L, Sutcliffe JA, Xiao X-Y (2011) 8-azatetracyclines: synthesis and evaluation of a novel class of tetracycline antibacterial agents. J Med Chem 54:1511–1528. doi: 10.1021/jm1015389CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sun C, Wang Q, Brubaker JD, Wright PW, Lerner CD, Noson K, Charest MG, Siegel DR, Wang Y-M, Myers AG (2008) A robust platform for the synthesis of new tetracycline antibiotics. J Am Chem Soc 130:17913–17927. doi: 10.1021/ja806629eCrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Sun C, Hunt DK, Clark RB, Lofland D, O’Brien WJ, Plamondon L, Xiao X-Y (2011) Synthesis and antibacterial activity of pentacyclines: a novel class of tetracycline analogs. J Med Chem 54:3704–3731. doi: 10.1021/jm1015389CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sun C, Hunt DK, Chen C-L, Deng Y, He M, Clark RB, Fyfe C, Grossman TH, Sutcliffe JA, Xiao X-Y (2015) Design, synthesis, and biological evaluation of hexacyclic tetracyclines as potent, broad-spectrum antibacterial agents. J Med Chem 58:4703–4712. doi: 10.1021/acs.jmedchem.5b00262CrossRefPubMedGoogle Scholar
  51. 51.
    Sussman RJ (2015) I. Synthesis of C4-modified tetracyclines II. Aldolizations of pseudoephenamine glycinamide and applications toward the synthesis of monocyclic β-lactam antibiotics. Doctoral dissertation, Harvard University, Graduate School of Arts & SciencesGoogle Scholar
  52. 52.
    O’Shea R, Moser HE (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51:2871–2878. doi: 10.1021/jm700967eCrossRefPubMedGoogle Scholar
  53. 53.
    Nikaido H, Thanassi DG (1993) Penetration of lipophilic agents with multiple protonation sites into bacterial cells: tetracyclines and fluoroquinolones as examples. Antimicrob Agents Chemother 37:1393–1399CrossRefGoogle Scholar
  54. 54.
    Ambrose PG, Bhavnani SM, Rubino GM, Louie A, Gumbo T, Forrest A (2007) Pharmacokinetics-pharmacodynamics of antibacterial therapy: it’s not just for mice anymore. Clin Infect Dis 44:79–86. doi: 10.1086/510079CrossRefPubMedGoogle Scholar
  55. 55.
    Meagher AK, Ambrose PG, Grasela TH, Ellis-Grosse EJ (2005) The pharmacokinetic and pharmacodynamic profile of tigecycline. Clin Infect Dis 41:S333–S340. doi: 10.1086/431674CrossRefPubMedGoogle Scholar
  56. 56.
    Deng Y, Plamondon L, Sun C, Xiao X-Y, Zhou J, Sutcliffe JA, Ronn MP (2011) Tetracycline compounds. PCT Int. Appl. WO 2011025982 A2 20110303Google Scholar
  57. 57.
    Hlavka JJ, Krazinski H, Boothe JH (1962) The 6-deoxytetracyclines. IV. A photochemical displacement of a diazonium group. J Org Chem 27:3674–3675. doi: 10.1021/jo01057a501CrossRefGoogle Scholar
  58. 58.
    Doerschuk AP, Bitler BA, McCormick JRD (1955) Reversible isomerization in the tetracycline family. J Am Chem Soc 77:4687. doi: 10.1021/ja01622a085CrossRefGoogle Scholar
  59. 59.
    McCormick JRD, Fox SM, Smith LL, Bitler BA, Reichenthal J, Origoni VE, Muller WH, Winterbottom R, Doerschuk AP (1957) The reversible epimerization occurring in the tetracycline family. The preparation, properties and proof of structure of some 4-epitetracyclines. J Am Chem Soc 79:2849–2858. doi: 10.1021/ja01568a050CrossRefGoogle Scholar
  60. 60.
    Wang Y, Castaner R, Bolos J, Estivill C (2009) Amadacycline: tetracycline antibiotic. Drugs Future 34:11–15. doi: 10.1358/dof.2009.034.01.1324393CrossRefGoogle Scholar
  61. 61.
    Sutcliffe JA, O’Brien W, Fyfe C, Grossman TH (2013) Antibacterial activity of eravacycline (TP-434), a novel fluorocycline, against hospital and community pathogens. Antimicrob Agents Chemother 57:5548–5558. doi: 10.1128/AAC.01288-13CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Bush K, Jacoby GA (2010) Updated functional classification of β-lactamases. Antimicrob Agents Chemother 54:969–976. doi: 10.1128/AAC.01009-09CrossRefPubMedGoogle Scholar
  63. 63.
    Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, Sutcliffe JA, Horn P (2016) Assessing the efficacy and safety of eravacycline vs. ertapenem in complicated intra-abdominal infections in the investigating Gram-Negative infections treated with eravacycline (IGNITE 1) trial. JAMA Surg. doi: 10.1001/jamasurg.2016.4237CrossRefPubMedGoogle Scholar
  64. 64.
    Zhanel GG, Cheung D, Adam H, Zelenitsky S, Golden A, Schweizer F, Gorityala B, Lagacé-Wiens PRS, Walkty A, Gin AS, Hoban DJ, Karlowsky JA (2016) Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs 76:567–588. doi: 10.1007/s40265-016-0545-8CrossRefPubMedGoogle Scholar
  65. 65.
    Huang Z, Zhang H, Zhou G (2010) Preparation of guanidylalkylacyl-substituted tetracycline derivatives. Faming Zhuanli Shenqing, CN 101684083Google Scholar
  66. 66.
    Koza DJ (2000) The synthesis of 8-substituted tetracycline derivatives, the first 8-position C-C bond formation. Tetrahedron Lett 41:5017–5020. doi: 10.1016/S0040-4039(00)00768-1CrossRefGoogle Scholar
  67. 67.
    Nelson ML, Koza D (2002) Preparation of 7,8 and 9-substituted tetracycline derivatives. PCT Int Appl. WO 2002004404Google Scholar
  68. 68.
    Nelson M (2002) Preparation of 8-substituted tetracycline derivatives for pharmaceutical use as antibacterial agents. PCT Int Appl. WO 2002012170Google Scholar
  69. 69.
    Sum PE, Lee VJ, Tally FP (1994) Synthesis of novel tetracycline derivatives with substitution at the C-8 position. Tetrahedron Lett 35:1835–1836. doi: 10.1016/S0040-4039(00)73173-XCrossRefGoogle Scholar
  70. 70.
    Sum PE, Lee VJ, Hlavka JJ, Testa RT (1994) Preparation of 7-(substituted)-8-(substituted)-9-(substituted glycyl)amido-6-demethyl-6-deoxytetracyclines. European Patent Application No. EP 582789Google Scholar
  71. 71.
    Sum PE, Lee VJ, Hlavka JJ, Testa RT (1994) Preparation of 7-(substituted)-8-(substituted)-9-(substituted amino)-6-demethyl-6-deoxytetracyclines as antibiotic agents. European Patent Application No. EP 582810Google Scholar
  72. 72.
    Deng Y, Sun C, Hunt DH, Corey F, Chen C-L, Grossman TH, Sutcliffe JA, Xiao X-Y (2017) Heterocyclyl tetracyclines. 1. 7-trifluoromethyl-8-pyrrolidinyltetracyclines: potent, broad spectrum antibacterial agents with enhanced potency against Pseudomonas aeruginosa. J Med Chem 60:2498–2512. doi: 10.1021/acs.jmedchem.6b01903CrossRefPubMedGoogle Scholar
  73. 73.
    He Y, Mahmud H, Moningka R, Lovely CJ, Dias HVR (2006) Cyclization reactions of N-acryloyl-2-aminobenzaldehyde derivatives: formal total synthesis of martinellic acid. Tetrahedron 62:8755–8769. doi: 10.1016/j.tet.2006.06.104CrossRefGoogle Scholar
  74. 74.
    Fyfe C, Sutcliffe JA, Grossman TH (2012) Development and characterization of a Pseudomonas aeruginosa in vitro coupled transcription-translation assay system for evaluation of translation inhibitors. J Microbiol Methods 90:256–261. doi: 10.1016/j.mimet.2012.05.018CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ronn M, Zhu Z, Hogan PC, Zhang W-Y, Niu J, Katz CE, Dunwoody N, Gilicky O, Deng Y, Hunt DK, He M, Chen C-L, Sun C, Clark RB, Xiao X-Y (2013) Process R&D of eravacycline: the first fully synthetic fluorocycline in clinical development. Org Process Res Dev 17:838–845. doi: 10.1021/op4000219CrossRefGoogle Scholar
  76. 76.
    Zhang W-Y, Che Q, Crawford S, Ronn M, Dunwoody N (2017) A divergent route to eravacycline. J Org Chem 82:936–943. doi: 10.1021/acs.joc.6b02442CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Tetraphase Pharmaceuticals, Inc.WatertownUSA

Personalised recommendations