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

• References and Notes

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• 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.