Synthesis of Lincosamide Analogues via Oxime Resin Aminolysis

Abstract

In this work, the synthetic development of an oxime resin aminolysis to lincosamide analogues is described. This synthetic endeavor hinges on a protecting-group-free strategy of the amino sugar nucleophiles. The cleavage from the solid support is achieved under mild conditions in a buffer solution and allows the preparation of a wide diversity of amino acid moieties onto glycosylamine scaffolds. The strategy is further exploited using methylthiolincosamine to generate rapidly complex lincomycin analogues. The results pave the way to access efficiently novel potentially relevant antibacterial compounds.

Key words

lincosamide analogues - oxime resin aminolysis - protecting-group-free synthesis - lincomycin analogues - antibacterial compounds - solid-phase synthesis

Publication History

Received: 10 August 2022

Accepted after revision: 21 September 2022

Accepted Manuscript online:
21 September 2022

Article published online:
03 November 2022

• References and Notes

• 1 Spizek J, Novotna J, Rezanka T. Adv. Appl. Microbiol. 2004; 56: 121
• 2a Schlunzen F, Zarivach R, Harms J, Bashan A, Tocilj A, Albrecht R, Yonath A, Franceschi F. Nature 2001; 413: 814
• 2b Tenson T, Lovmar M, Ehrenberg M. J. Mol. Biol. 2003; 330: 1005
• 3 Kirillov S, Porse BT, Vester B, Woolley P, Garett R. FEBS Lett. 1997; 406: 223
• 4 Mason DJ, Dietz A, De Boer C.. Antimicrob. Agents Chemother. 1962; 554
• 5 Sztarricskai F, Batta G, Dinya G, Hornyak M, Roth E. J. Antibiot. 1999; 52: 1050
• 6a Schroeder W, Bannister B, Hoeksema H. J. Am. Chem. Soc. 1967; 89: 2448
• 6b Sztarricskai F, Dinya Z, Batta G, Masuma R, Omura S. Magy Kem. Foly., Kem. Kozl. 1997; 103: 524
• 6c Collin M.-P, Hobbie SN, Bottger EC, Vasella A. Helv. Chim. Acta 2008; 91: 1838
• 6d Argoudelis AD, Coats JH, Mason DJ, Sebek OK. J. Antibiot. 1969; 22: 309
• 6e Magerlein BJ, Kagan F. J. Med. Chem. 1969; 12: 780
• 6f Magerlein BJ. J. Med. Chem. 1972; 15: 1255
• 6g Birkenmeyer RD, Kroll SJ, Lewis C, Stern KF, Zurenko GE. J. Med. Chem. 1984; 27: 216
• 6h Pospisil S, Sedmera P, Halada P, Havlicek L, Spizek J. Tetrahedron Lett. 2004; 45: 2943
• 7a Sztarricskai F, Dinya G, Batta A, Mocsrai M, Hollosi Z, Majer R, Masuma R, Omura S. J. Antibiot. 1997; 50: 866
• 7b Collin M.-P, Hobbie SN, Bottger EC, Vasella A. Helv. Chim. Acta 2009; 92: 230
• 8 Hanessian S, Kothakonda KK. Bioorg. Med. Chem. 2005; 13: 5283
• 9a Umemura E, Wakiyama Y, Kumura K, Ueda K, Masaki S, Watanabe T, Yamamoto M, Hirai Y, Fushimi H, Yoshida T, Ajito K. J. Antibiot. 2013; 66: 195
• 9b Umemura E, Kumura K, Masaki S, Ueda K, Wakiyama Y, Sato Y, Yamamoto M, Ajito K, Watanabe T, Kaji C. US 20100184746A1, 2010
• 9c Lewis J, Patel DV, Kumar AS, Gordeev MF. WO 2004016632 A2
• 9d Sztaricskai F, Dinya Z, Puskaa MM, Batta G, Masuma R, Omura S. J. Antibiot. 1996; 49: 941
• 10a Osono T, Umezawa H. J. Antimicrob. Chemother. 1985; 16: 151
• 10b Magerlein BJ, Birkenmeyer RD, Kagan F. Antimicrob. Agents Chemother. 1966; 727
• 10c Birkenmeyer RD, Kagan F. J. Med. Chem. 1970; 13 : 616
• 11 Hirai Y, Maebashi K, Yamada K, Wakiyama Y, Kumura K, Umemura E, Ajito K. J. Antibiot. 2021; 74: 124
• 12 Mitcheltree MJ, Pisipati A, Syroegin EA, Silvestre KJ, Klepacki D, Mason JD, Terwilliger DW, Testolin G, Pote AR, Wu KJ. Y, Ladley RP, Chatman K, Mankin AS, Polikanov YS, Myers AG. Nature 2021; 599: 507
• 13 Mitcheltree MJ, Stevenson JW, Pisipati A, Myers AG. J. Am. Chem. Soc. 2021; 143: 6829
• 14 Mason JD, Terwilliger DW, Pote AR, Myers AG. J. Am. Chem. Soc. 2021; 143: 11019
• 15a Bauman AC, Broderick JC, Dacus RM. IV, Grover DA, Trzupek LS. Tetrahedron Lett. 1993; 34: 7019
• 15b DeGrado WF, Kaiser ET. J. Org. Chem. 1980; 45: 1295
• 15c DeGrado WF, Kaiser ET. J. Org. Chem. 1982; 47: 3258
• 16a Bérubé C, Gagnon D, Borgia A, Richard D, Voyer N. Chem. Commun. 2019; 55: 7434
• 16b Bérubé C, Borgia A, Voyer N. Org. Biomol. Chem. 2018; 16: 9117
• 16c Voyer N, Lavoie A, Pinette M, Bernier J. Tetrahedron Lett. 1994; 35: 355
• 17 Tremblay T, Robert-Scott G, Bérubé C, Carpentier A, Voyer N, Giguère D. Chem. Commun. 2019; 55: 13741
• 18a Ramesh R, Sonawane S, Reddy DS, Bandichhor R. Protecting-Group-Free Synthesis of Drugs and Pharmaceuticals . In Protecting-Group-Free Organic Synthesis . Fernandes RA. Wiley; Hoboken: 2018: 155-181
• 18b Young IS, Baran PS. Nat. Chem. 2009; 1: 193
• 18c Trost BM. Science 1991; 254: 1471
• 18d Wender PA, Verma VA, Paxton TJ, Pillow TH. Acc. Chem. Res. 2008; 41: 40
• 19a Bérubé C, Borgia A, Gagnon D, Mukherjee A, Richard D, Voyer N. J. Nat. Prod. 2020; 83: 1778
• 19b Smith RA, Bobko MA, Lee W. Bioorg. Med. Chem. Lett. 1998; 8: 2369
• 20a Cordero-Vargas A, Sartillo-Piscil F. Protecting-Group-Free Synthesis in Carbohydrate Chemistry. In Protecting-Group-Free Organic Synthesis . Fernandes RA. Wiley; Hoboken: 2018: 183-200
• 20b Tanaka T. Protecting-Group-Free Synthesis of Glycosyl Derivatives, Glycopolymers, and Glycocojugates. In Protecting-Group-Free Organic Synthesis. Fernandes RA. Wiley; Hoboken: 2018: 201-228
• 20c Vasicek T, Spiwok V, Cerveny J, Petraskova L, Bumba L, Vrbata D, Pelantova H, Kren V, Bojarova P. Chem. Eur. J. 2020; 26: 9620
• 20d Dussouy C, Téletchéa S, Lambert A, Charlier C, Botez I, De Ceuninck F, Grandjean C. J. Org. Chem. 2020; 85: 16099
• 20e Tejler J, Leffler H, Nilsson UJ. Bioorg. Med. Chem. Lett. 2005; 15: 2343
• 20f Bergh A, Leffler H, Sundin A, Nilsson UJ, Kann N. Tetrahedron 2006; 62: 8309
• 21 St-Gelais J, Giguère D. Synthesis 2021; 53: 3735
• 22 Cheng JM. H, Chee SH, Knight DA, Acha-Orbea H, Hermans IF, Timmer MS. M, Stocker BL. Carbohydr. Res. 2011; 346: 914
• 23 Typical Experimental Procedure for the Cleavage of Oxime Resin To a peptide synthesis vessel was added the oxime resin (1.1 mmol g^–1, 1.25 equiv) and was swelled with CH₂Cl₂ (3 × 5 mL). To a solution of the oxime resin in CH₂Cl₂/DMF (8:2, 0.02 M) were added amino sugar (1 equiv) and DIPEA (2.5 equiv). The vessel was mechanically stirred for a few seconds, and acetic acid (5 equiv) was added to the mixture. The peptide synthesis vessel was mechanically stirred at room temperature until starting material was consumed (overnight). The content of the vessel was then collected in a flask and the resin was washed with CH₂Cl₂ (3 × 5 mL) and MeOH (3 × 5 mL). The organic phase was concentrated under reduced pressure, and the resulting crude was purified by flash column chromatography. Characterization Data for S-Methyl 6-Deoxy-6-{[N-(N-acetyl)-glycinyl]}-l-leucylamido-α-thiolincosaminide (10) R_f = 0.49 (silica, MeOH/DCM, 1:4); [α]_D ²⁵ 96.2 (c 0.3, MeOH). IR (ATR, diamond): ν = 3307, 1659, 1642, 1285, 1075, 1049 cm^–1. ¹H NMR (500 MHz, D₂O): δ = 5.35 (d, ³ J _H1–H2 = 5.8 Hz, 1 H, H1), 4.34 (dd, ³ J _{CHαLeu–CH2αβLeu} = 9.8 Hz, ³ J _{CHαLeu-CH2αβLeu} = 5.0 Hz, 1 H, CHαLeu), 4.29 (dd, ³ J _H6–H5 = 9.7 Hz, ³ J _H6–H7 = 4.5 Hz, 1 H, H6), 4.23 (dd, ³ J _H5–H6 = 9.7 Hz, ³ J _H5–H4 = 1.2 Hz, 1 H, H5), 4.111 (qd, ³ J _H7–H8a = ³ J _H7–H8b = ³ J _H7–H8c = 6.5 Hz, ³ J _H7–H6 = 4.5 Hz, 1 H, H7), 4.095 (dd, ³ J _H2–H3 = 10.2 Hz, ³ J _H2–H1 = 5.7 Hz, 1 H, H2), 3.93 (dd, ³ J _H4–H3 = 3.2 Hz, ³ J _H4–H5 = 1.2 Hz, 1 H, H4), 3.89 (d, ² J _{CH2aGly–CH2bGly} = 17.0 Hz, 1 H, CH₂bGly), 3.64 (dd, ³ J _H3–H2 = 10.4 Hz, ³ J _H3–H4 = 3.2 Hz, 1 H, H3), 2.13 (s, 3 H, SCH₃), 2.05 (s, 3 H, COCH₃), 1.71–1.57 (m, 3 H, CH₂βLeu, CHγLeu), 1.13 (d, ³ J _CH3(8)–H7 = 6.5 Hz, 3 H, CH₃(8)), 0.94 (d, ³ J _{CH3δ1Leu–CHγLeu} = 6.1 Hz, 1 H, CH₃δ1Leu), 0.88 (d, ³ J _{CH3δ2Leu–CHγLeu} = 6.1 Hz, 1 H, CH₃δ2Leu) ppm. ¹³C NMR (126 MHz, D₂O): δ = 174.9, 174.8, 171.7 (3 C, 3 × CO), 88.0 (1 C, C1), 70.2 (1 C, C3), 69.4 (1 C, C5), 68.3 (1 C, C4), 67.6 (1 C, C2), 66.7 (1 C, C7), 53.1 (1 C, C6), 52.7 (1 C, CHαLeu), 42.4 (1 C, CH₂Gly), 39.6 (1 C, CH₂βLeu), 24.2 (1 C, CH₂γLeu), 22.0 (1 C, CH₃δ1Leu), 21.6 (1 C, COCH₃), 20.5 (1 C, CH₃δbLeu), 15.9 (1 C, C8), 12.8 (1 C, SCH₃) ppm. HRMS (ESI) m/z [M + H]⁺ calcd for C₁₉H₃₆N₃O₈S⁺: 466.2218; found: 466.2209. Characterization Data for S-Methyl 6-Deoxy-6-{[N-(N-tert-butoxycarbonyl)-l-phenylalanyl]-l-alanylamido}-α-thiolincosaminide (11) R_f = 0.32 (silica, MeOH/DCM, 1:9); [α]_D ²⁵ 120.4 (c 0.4, MeOH). IR (ATR, diamond): ν = 3333, 2926, 1691, 1631, 1530, 1168, 1050 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.31–7.19 (m, 5 H, Ar–Phe), 5.26 (d, ³ J _H1–H2 = 5.6 Hz, 1 H, H1), 4.33 (q, ³ J _{CHαPhe–CH3aAla} = ³ J _{CHαPhe–CH3bAla} = ³ J _{CHαPhe–CH3cAla} = 7.3 Hz, 1 H, CHαAla), 4.32 (dd, ³ J _{CHαPhe–CH2bPhe} = 9.9 Hz, ³ J _{CHαPhe–CH2aPhe} = 4.7 Hz, 1 H, CHαPhe), 4.25–4.18 (m, 2 H, H5, H6), 4.09 (dd, ³ J _H2–H3 = 10.1 Hz, ³ J _H2–H1 = 5.6 Hz, 1 H, H2), 4.00 (p, ³ J _H7–H8a = ³ J _H7–H8b = ³ J _H7–H8b = ³ J _H7–H6 = 6.2 Hz, 1 H, H7), 3.95 (d, ³ J _H4–H3 = 3.4 Hz, 1 H, H4), 3.56 (dd, ³ J _H3–H2 = 10.2 Hz, ³ J _H3–H4 = 3.4 Hz, 1 H, H3), 3.16 (dd, ² J _{CH2aPhe–CH2bPhe} = 13.9 Hz, ³ J _{CH2aPhe–CHαPhe} = 4.7 Hz, 1 H, CH₂aPhe), 2.80 (dd, ² J _{CH2bPhe–CH2aPhe} = 14.1 Hz, ³ J _{CH2bPhe–CHαPhe} = 9.9 Hz, 1 H, CH₂bPhe), 2.10 (s, 3 H, SCH₃), 1.39 (d, ³ J _{CH3Ala–CHαAla} = 7.3 Hz, 3 H, CH₃Ala), 1.35 (s, 9 H, C(CH₃)₃), 1.19 (d, ³ J _{C H3 (8)–H7} = 6.4 Hz, 3 H, CH₃(8)) ppm. ¹³C NMR (126 MHz, CD₃OD): δ = 175.7, 174.5, 157.8 (3 C, 3 × CO), 138.7, 130.4, 129.4, 127.7 (6 C, Ar–Phe), 89.9 (1 C, C1), 80.7 (1 C, C(CH₃)₃), 71.9 (1 C, C3), 70.8 (1 C, C5), 70.4 (1 C, C4), 69.5 (1 C, C2), 68.1 (1 C, C7), 57.2 (1 C, CHαPhe), 55.8 (1 C, C6), 50.9 (1 C, CHαAla), 39.1 (1 C, CH₂Phe), 28.7 (3 C, C(CH₃)₃), 18.5 (1 C, C8), 17.9 (1 C, CH₃Ala), 13.6 (1 C, SCH₃) ppm. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₄₂N₃O₉S⁺: 572.2636; found: 572.2640.