Synlett 2019; 30(20): 2268-2272
DOI: 10.1055/s-0039-1690232
letter
© Georg Thieme Verlag Stuttgart · New York

Gram-Scale Solution-Phase Synthesis of Heptapeptide Side Chain of Teixobactin[1]

Sangeetha Donikela
a  Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Telangana, India   Email: srivaric@iict.res.in
b  Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
,
a  Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Telangana, India   Email: srivaric@iict.res.in
,
Vishnuvardhan Nomula
a  Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Telangana, India   Email: srivaric@iict.res.in
,
a  Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Telangana, India   Email: srivaric@iict.res.in
b  Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
,
a  Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, Telangana, India   Email: srivaric@iict.res.in
b  Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
› Author Affiliations
S. D. thanks University Grants Commission (UGC), New Delhi for research fellowship. K. N. thanks Women Scientists Scheme (WOS-A, Grant No. SR/WOS-A/CS-58/2017), Department of Science & Technology (DST), Government of India for fellowship and research grant. P. S. M. thanks Indian Council of Medical Research (ICMR), Government of India for research grant (Grant No. AMR/IN/111/2017-ECD-II). S. C. thanks the Department of Science and Technology (DST), Government of India for a J C Bose fellowship (Grant No. SB/S2/JCB-002/2015).
Further Information

Publication History

Received: 03 September 2019

Accepted after revision: 14 October 2019

Publication Date:
25 October 2019 (online)


These authors contributed equally to this work

Abstract

We report herein a scalable synthesis of linear heptapeptide side chain of the depsipeptide natural product teixobactin through solution phase. The synthesis of heptapeptide was achieved through an efficient coupling of suitably protected tripeptide and tetrapeptide comprising of three d-amino acids and four usual l-amino acid subunits.

Supporting Information

 
  • References and Notes

  • 1 CSIR-IICT communication number: IICT/Pubs./2019/316.
    • 2a Willyard C. Nature 2017; 543: 7643
    • 2b Von Nussbaum F, Süssmuth RD. Angew. Chem. Int. Ed. 2015; 54: 6684 ; Angew. Chem. 2015, 127, 6784
    • 2c Arias A, Murray CB. E. N. Engl. J. Med. 2015; 372: 1168
    • 2d Tobin KC. Nature Rev. Microbiol. 2015; 13: 126
    • 2e Hunter P. EMBO Rep. 2015; 16: 563
    • 2f Kostic M. Chem. Biol. 2015; 22: 159
    • 2g Piddock LJ. V. J. Antimicrob. Chemother. 2015; 70: 2679
  • 3 Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP, Mueller A, Schaeberle TF, Hughes DE, Epstein S, Jones M, Lazarides L, Steadman VA, Cohen DR, Felix CR, Fetterman KA, Millett WP, Nitti AG, Zullo AM, Chen C, Lewis K. Nature 2015; 517: 455
    • 4a Ng V, Chan WC. Chem. Eur. J. 2016; 22: 12606
    • 4b Öster C, Walkowiak GP, Hughes DE, Spoering AL, Peoples AJ, Catherwood AC, Tod JA, Lloyd AJ, Herrmann T, Lewis K, Dowson CG, Lewandowski JR. Chem. Sci. 2018; 9: 8850
  • 5 Atkinson DJ, Naysmith BJ, Furkert DP, Brimble MA. Beilstein J. Org. Chem. 2016; 12: 2325
    • 6a Jin K, Sam LH, Laam PoK. H, Lin D, Ghazvini Zadeh EH, Chen S, Yuan Y, Li X. Nat. Commun. 2016; 7: 12394
    • 6b Giltrap AM, Dowman LJ, Nagalingam G, Ochoa JL, Linington RG, Britton WJ, Payne RJ. Org. Lett. 2016; 18: 2788
    • 6c Zong Y, Fang F, Meyer KJ, Wang L, Ni Z, Gao H, Lewis K, Zhang J, Rao Y. Nat. Commun. 2019; 10: 3268
  • 7 Jad YE, Acosta GA, Naicker T, Ramtahal M, El-Faham A, Govender T, de la Torre HG, Albericio F. Org. Lett. 2015; 17: 6182
    • 8a Parmar A, Iyer A, Vincent CS, Van Lysebetten D, Prior SH, Madder A, Taylor EJ, Singh I. Chem. Commun. 2016; 52: 6060
    • 8b Parmar A, Iyer A, Lloyd DG, Vincent CS, Prior SH, Madder A, Taylor EJ, Singh I. Chem. Commun. 2017; 53: 7788
    • 8c Parmar A, Lakshminarayanan R, Iyer A, Mayandi V, Goh ET. L, Lloyd DG, Chalasani ML. S, Verma NK, Prior SH, Beuerman RW, Madder A, Taylor EJ, Singh I. J. Med. Chem. 2018; 61: 2009
  • 9 Yang H, Chen KH, Nowick JS. ACS Chem. Biol. 2016; 11: 1823
  • 10 Abdel Monaim SA. H, Jad YE, Acosta GA, Naicker T, Ramchuran EJ, El-Faham A, Govender T, Kruger HG, de la Torre BG, Albericio F. RSC Adv. 2016; 6: 73827
  • 11 Abdel Monaim SA. H, Jad YE, Ramchuran EJ, El-Faham A, Govender T, Kruger HG, de la Torre BG, Albericio F. ACS Omega 2016; 1: 1262
  • 12 Wu C, Pan Z, Yao G, Wang W, Fang L, Su W. RSC Adv. 2017; 7: 1923
  • 13 Parmar A, Prior SH, Iyer A, Vincent C, Van Lysebetten D, Breukink E, Madder A, Taylor EJ, Singh I. Chem. Commun. 2017; 53: 2016
  • 14 Yang H, Du Bois DR, Ziller JW, Nowick JS. Chem. Commun. 2017; 53: 2772

    • For selected papers, see:
    • 15a Chandrasekhar S, Babu BN, Prabhakar A, Sudhakar A, Reddy MS, Kiran MU, Jagadeesh B. Chem. Commun. 2006; 1548
    • 15b Chandrasekhar S, Kiranmai N, Kiran MU, Devi AS, Reddy GP. K, Idris M, Jagadeesh B. Chem. Commun. 2010; 46: 6962 ; and the references cited therein
  • 16 Chandrasekhar S, Pendke M, Muththe C, Akondi SM, Mainkar PS. Tetrahedron Lett. 2012; 53: 1292
    • 17a Andersson L, Blomberg L, Flegel M, Lepsa L, Nilsson B, Verlander M. Biopolymers 2000; 55: 227
    • 17b Chandrudu S, Simerska P, Toth I. Molecules 2013; 18: 4373
  • 18 Craig W, Chen J, Richardson D, Thorpe R, Yuan Y. Org. Lett. 2015; 17: 4620
  • 19 Parmar A, Iyer A, Prior SH, Lloyd DG, Goh ET. L, Vincent CS, Palmai-Pallag T, Bachrati CZ, Breukink E, Madder A, Lakshminarayanan R, Tayler EJ, Singh I. Chem. Sci. 2017; 8: 8183
  • 20 Yang H, Wierzbicki M, Du Bois DR, Nowick JS. J. Am. Chem. Soc. 2018; 140: 14028
  • 21 Gao B, Chen S, Hou YN, Zhao YJ, Ye T, Xu Z. Org. Biomol. Chem. 2019; 17: 1141
    • 22a Gunjal VB, Reddy DS. Tetrahedron Lett. 2019; 60: 1909
    • 22b Dhara S, Gunjal VB, Handore KL, Reddy DS. Eur. J. Org. Chem. 2016; 4289
    • 23a Reddy GV, Kumar RS. C, Shankaraiah G, Babu KS, Rao JM. Helv. Chim. Acta 2013; 96: 1590
    • 23b Malkov A, Varnkova K, Cerny M, Kocovsky P. J. Org. Chem. 2009; 74: 8425
    • 23c Ferrie L, Reymond S, Capdevielle P, Cossy J. Org. Lett. 2006; 8: 3441
  • 24 Hartwig S, Nguyen MM, Hecht S. Polym. Chem. 2010; 1: 69
  • 25 Long B, Zhang J, Tang X, Wu Z. Org. Biomol. Chem. 2016; 14: 9712
  • 26 Synthetic Procedure for Key Dipeptide Intermediate, Methyl O-Benzyl-N-[(tert-butoxycarbonyl)-l-isoleucyl]-l-serinate (7) To a mixture of commercially available Boc-l-Ser(OBn)-OH (11, 5 g, 16.9 mmol, 1.0 equiv) in MeOH (50 mL) under nitrogen atmosphere, was added MeCOCl (1.8 mL, 25.3 mmol, 1.5 equiv) slowly at 0 °C. The reaction mixture was stirred at reflux for 3 h, and the solvent was distilled off in vacuo to get l-Ser(OBn)-OMe as a hydrochloride (4.1 g, 16.9 mmol). In another round-bottomed flask, Boc-l-isoleucine (12, 3.9 g, 16.9 mmol, 1.0 equiv) was dissolved in CH2Cl2 (50 mL) under nitrogen atmosphere, and HOBt (2.5 g, 18.5 mmol, 1.1 equiv) and EDC·HCl (4.85 g, 25.3 mmol, 1.5 equiv) were added sequentially at 0 °C and stirred for 15 min. To this reaction mixture was added dropwise a solution of the above-obtained l-Ser(OBn)-OMe hydrochloride salt (4.1 g, 16.9 mmol, 1.0 equiv) and DIPEA (11.5 mL, 67.6 mmol, 4.0 equiv) in dry CH2Cl2 (20 mL) at 0 °C and stirred for 1 h. Then reaction mixture was maintained at room temperature for 12 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NH4Cl solution (2 × 75 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 solution (2 × 75 mL) followed by brine solution (75 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (15% EtOAc in hexanes) to give key dipeptide 7 (6.39 g, 90%) as white solid. Rf = 0.5 (20% EtOAc in hexanes); mp 160–162 °C; [α]D 20 +26.30 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.31 (m, 2 H), 7.31–7.23 (m, 3 H), 6.67 (d, J = 6.9 Hz, 1 H), 5.10 (d, J = 7.4 Hz, 1 H), 4.73 (dt, J = 7.9, 3.1 Hz, 1 H), 4.50 (q, J = 12.2 Hz, 2 H), 4.08–3.98 (m, 1 H), 3.89 (dd, J = 9.5, 3.2 Hz, 1 H), 3.72 (s, 3 H), 3.66 (dd, J = 9.5, 3.2 Hz, 1 H), 1.95–1.79 (m, 1 H), 1.51–1.45 (m, 1 H), 1.44 (s, 9 H), 1.20–1.09 (m, 1 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.4, 170.5, 155.7, 137.5, 128.6, 128.0, 127.8, 79.9, 73.4, 69.6, 59.2, 52.6, 37.8, 28.4, 24.8, 15.6, 11.7 ppm. IR (thin film): νmax = 3285, 2964, 2928, 1707, 1642, 1512, 1367, 1165, 863, 749, 666 cm–1. HRMS (ESI): m/z calcd for [M + Na]+ C22H34N2O6Na: 445.2315; found: 445.2313.
  • 27 Synthetic Procedure for Tripeptide, Methyl O-Benzyl-N-(tert-butoxycarbonyl)-d-alloisoleucyl-l-isoleucyl-l-serinate (14) To a solution of Boc-Ile-Ser(OBn)-OMe (7, 5.0 g, 11.83 mmol, 1.0 equiv) in dry CH2Cl2 (5.0 mL) under nitrogen atmosphere was added TFA (5.0 mL, 65.2 mmol, 5.53 equiv) at 0 °C and stirred for 30 min at this temperature. Then reaction was maintained at room temperature for 2 h. After completion, the volatiles were removed in vacuo. The residue was dried under high vacuum for 1 h to get the corresponding amine salt (5.2 g, crude) as a pale brown thick liquid which was used for the next step directly. Boc-d-allo-isoleucine (10, 2.73 g, 11.80 mmol, 1.0 equiv) was dissolved in CH2Cl2 (30 mL) under nitrogen atmosphere. HOBt (1.75 g, 12.98 mmol, 1.1 equiv) and EDC·HCl (3.4 g, 17.7 mmol, 1.5 equiv) were added sequentially at 0 °C. A mixture of amine salt (5.2 g, crude, ca. 11.9 mmol, 1.0 equiv) and DIPEA (8.08 mL, 47.32 mmol, 4.0 equiv) in dry CH2Cl2 (50 mL) was added dropwise to the above reaction mixture at 0 °C and stirred for 30 min. Then reaction mixture was maintained at room temperature for 18 h. After completion of reaction, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed with saturated aqueous NH4Cl solution (2 × 75 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 solution (2 × 75 mL) followed by brine solution (75 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc in hexanes) to give tripeptide 14 (5.16 g, 82%, over 2 steps) as white solid. Rf  = 0.5 (30% EtOAc in hexanes); mp 134–136 °C; [α]D 20 +13.80 (c 1, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.37–7.24 (m, 5 H), 6.75–6.64 (m, 2 H), 5.02 (d, J = 6.6 Hz, 1 H), 4.73 (dt, J = 8.0, 3.2 Hz, 1 H), 4.57–4.43 (m, 2 H), 4.41 (dd, J = 8.6, 6.3 Hz, 1 H), 4.24–4.10 (m, 1 H), 3.89 (dd, J = 9.5, 3.3 Hz, 1 H), 3.73 (s, 3 H), 3.64 (dd, J = 9.5, 3.0 Hz, 1 H), 2.07–1.95 (m, 1 H), 1.95–1.85 (m, 1 H), 1.58–1.48 (m, 1 H), 1.44 (s, 9 H), 1.42–1.34 (m, 1 H), 1.24–1.12 (m, 2 H), 0.98–0.87 (m, 9 H), 0.82 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.8, 170.8, 170.4, 155.8, 137.5, 128.6, 128.1, 127.8, 80.1, 73.4, 69.5, 58.3, 57.5, 52.7, 37.7, 37.3, 28.4, 26.6, 24.9, 15.4, 14.2, 11.8, 11.5 ppm. IR (thin film): νmax = 3323, 2966, 2930, 1747, 1658, 1501, 1365, 1211, 1163, 1020, 867, 749, 665 cm–1. HRMS (ESI): m/z calcd for [M + Na]+ C28H45N3O7Na: 558.3155; found: 558.3156.