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The Journal of Organic Chemistry
Hz, 1H, H5), 5.95 (s, 1H, H13), 5.37 (d, J = 10.4 Hz, 1H, H9), 5.13 (d, J =
matography (acetone/pentane = 2/3) gave the allylated fidaxomicin
7a (384 mg, 89%) as a colourless, amorphous solid; Rf = 0.2 (ace-
tone/pentane = 2/3); [α]D26 = –43.3° (c 0.58, CHCl3); IR (cm-1) ν 3472,
2976, 2934, 2878, 1701, 1642, 1382, 1247, 1067, 1024; 1H NMR (400
MHz, acetone-d6) δ 7.22 (d, J = 11.4 Hz, 1H), 6.62 (dd, J = 15.2, 11.5
Hz, 1H), 6.13 (dddt, J = 32.0, 17.2, 10.4, 5.8 Hz, 2H), 5.96 (ddd, J =
14.7, 9.6, 4.7 Hz, 1H), 5.83 (s, 1H), 5.62 (t, J = 8.2 Hz, 1H), 5.43 (ddq, J
= 20.4, 17.2, 1.6 Hz, 2H), 5.33–5.23 (m, 2H), 5.21 (dt, J = 10.5, 1.6 Hz,
1H), 5.02 (t, J = 9.7 Hz, 1H), 4.99 (d, J = 10.1 Hz, 1H), 4.77 (d, J = 1.3
Hz, 1H), 4.76–4.69 (m, 1H), 4.64 (d, J = 0.8 Hz, 1H), 4.63–4.58 (m, 4H),
4.53 (ddt, J = 11.8, 5.8, 1.4 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.26 (br
s, 1H), 4.02 (p, J = 6.4 Hz, 1H), 3.95 (dd, J = 3.4, 1.2 Hz, 1H), 3.75–3.66
(m, 3H), 3.59 (ddd, J = 3.1, 2.3, 1.3 Hz, 1H), 3.55 (dd, J = 3.6, 0.8 Hz,
1H), 3.52 (s, 3H), 2.94–2.59 (m, 6H), 2.56 (p, J = 7.0 Hz, 1H), 2.52–
2.38 (m, 1H), 1.99–1.87 (m, 1H), 1.81 (d, J = 1.4 Hz, 3H), 1.73 (d, J =
1.4 Hz, 3H), 1.66 (dd, J = 1.4, 0.7 Hz, 3H), 1.33 (d, J = 6.1 Hz, 3H),
1.30–1.21 (m, 1H), 1.19–1.12 (m, 15H), 1.09 (d, J = 0.6 Hz, 3H), 0.82
(t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ 176.7, 167.8,
166.4, 153.8, 151.9, 145.2, 143.3, 139.9, 136.8, 136.8, 136.0, 134.1,
134.0, 133.7, 128.6, 128.1, 126.3, 125.9, 125.4, 123.9, 122.2, 118.7,
118.7, 101.8, 96.7, 93.2, 81.8, 78.2, 77.4, 77.4, 76.3, 75.6, 74.9, 73.7,
72.8, 72.7, 72.6, 72.3, 72.2, 70.7, 70.1, 70.0, 69.9, 69.6, 67.7, 67.5,
63.4, 61.7, 55.5, 55.4, 42.0, 37.2, 34.7, 32.0, 30.6, 28.7, 28.3, 26.5,
25.6, 20.7, 19.4, 19.1, 18.6, 18.3, 17.4, 15.2, 14.4, 13.8, 11.1; HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C58H82Cl2O18Na 1159.4770; Found
1159.4766. m.p. = 109–110 °C.
9.2 Hz, 1H, H11), 5.10 (t, J = 9.8 Hz, 1H, H4’), 4.98 (d, J = 5.6 Hz, 1H,
H17), 4.65 (s, 1H, H1’), 4.60 (d, J = 9.6 Hz, 1H, H15), 4.57 (d, J = 11.4
Hz, 1H, H20a), 4.42 (d, J = 11.4 Hz, 1H, H20b), 4.29 (s, 1H, H7), 4.23
(q, J = 6.6 Hz, 1H, H18), 3.81 (dd, J = 9.9, 3.4 Hz, 1H, H3’), 3.63 – 3.55
(m, 2H, H2’, H5’), 3.52 (s, 3H, H7’), 3.23 (p, J = 7.6 Hz, 1H, H10), 3.01
(qd, J = 7.3, 2.1 Hz, 2H, H8’’’), 2.62 (ddd, J = 15.5, 7.0, 3.3 Hz, 1H,
H6a), 2.46 (ddt, J = 14.5, 9.0, 4.9 Hz, 2H, H6b, H16a), 2.13 (d, J = 14.1
Hz, 1H, H16b), 1.78 (s, 3H, H25), 1.68 (s, 3H, H24), 1.64 (s, 3H, H21),
1.42 (dt, J = 18.5, 7.0 Hz, 2H, H22), 1.30 (d, J = 6.2 Hz, 3H, H6’), 1.21
(dt, J = 7.4, 4.1 Hz, 6H, H19, H9’’’), 0.89 (t, J = 7.3 Hz, 3H, H23); 13C
NMR (126 MHz, acetone-d6) δ 169.7 (C1’’’), 167.2 (C1), 156.2 (C3’’’ or
5’’’), 154.5 (C3’’’ or 5’’’), 145.8 (C3), 144.0 (C5), 142.7 (C7’’’), 136.1
(C12 or 14), 133.6 (C11), 133.5 (C8), 131.2 (C12 or 14), 128.2 (C9),
127.6 (C4), 126.0 (C13), 125.1 (C2), 114.9 (C6’’’), 110.2 (C2’’’), 108.4
(C4’’’), 101.6 (C1’), 82.2 (C15), 82.0 (C18), 81.8 (C2’), 80.4 (C17), 79.3
(C17), 77.7 (C4’), 73.0 (C7), 72.4 (C3’), 70.7 (C5’), 63.0 (C20), 61.8
(C7’), 40.2 (C10), 38.2 (C6), 35.6 (C16), 29.6 (C22), 26.4 (C8’’’), 20.1
(C19), 18.8 (C24), 18.3 (C6’), 16.2 (C25), 15.3 (C21), 14.5 (C9’’’), 12.4
(C23); IR (cm-1) ν 2967, 2930, 2872, 1693, 1641, 1591, 1445, 1405,
1375, 1313, 1241, 1198, 1144, 1112, 1067, 1021, 985, 917, 871, 855,
798, 760, 735, 691. HRMS was measured as a mixture of (15R)-6 and
(15S)-6: HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C41H54Cl2O12Na
831.2885; Found 831.2893: Minor isomer (15S)-6: Rf = 0.66 (ace-
tone/pentane = 3/2); [α]D25 = –38° (c 0.26, CHCl3); 1H NMR (600 MHz,
acetone-d6) δ 7.39 (d, J = 11.3 Hz, 1H, H3), 6.68 (dd, J = 15.1, 11.4 Hz,
1H, H4), 6.19 (ddd, J = 14.8, 9.3, 5.1 Hz, 1H, H5), 6.12 (s, 1H, H13),
5.34 (d, J = 9.9 Hz, 1H, H9), 5.28 (d, J = 7.8 Hz, 1H, H11), 5.11 (t, J =
9.7 Hz, 1H, H4´), 5.10 (d, J = 4.0 Hz, 1H, H15), 5.00 (dd, J = 11.6, 3.9
Hz, 1H, H17), 4.70 (d, J = 0.9 Hz, 1H, H1´), 4.60 (d, J = 11.7 Hz, 1H,
H20), 4.45 (d, J = 11.7 Hz, 1H, H20), 4.33 (s, 1H, H7), 4.07 (q, J = 6.6
Hz, 1H, H18), 3.82 (dd, J = 9.9, 3.4 Hz, 1H, H3´), 3.66 – 3.56 (m, 2H,
H2´ H5´), 3.53 (s, 3H, H(OMe)), 3.21 (dq, J = 10.0, 7.3 Hz, 1H, H10),
3.01 (qd, J = 7.4, 4.6 Hz, 2H, H8´´´), 2.73 (d, J = 15.3 Hz, 1H, H6), 2.50
(ddd, J = 15.1, 9.3, 3.7 Hz, 1H, H6), 2.13 (ddd, J = 13.2, 11.7, 4.1 Hz,
1H, H16), 1.91 (s, 3H, H21), 1.75 (d, J = 1.5 Hz, 3H, H24), 1.72 – 1.68
(m, 1H, H16), 1.69 (s, 3H, H25), 1.42 (dt, J = 13.3, 7.2 Hz, 1H, H22),
1.38 – 1.31 (m, 1H, H22), 1.30 (d, J = 6.1 Hz, 3H, H6´), 1.22 (d, J = 6.6
Hz, 3H, H19), 1.21 (t, J = 7.5 Hz, 3H, H9´´´), 0.86 (t, J = 7.4 Hz, 3H,
H23); 13C NMR (151 MHz, acetone-d6) δ 169.78 (C1´´´), 166.91 (C1),
156.38 (C3´´´), 154.85 (C5´´´), 146.97 (C3), 145.45 (C5), 142.74 (C7´´´),
136.27 (C11), 136.10 (C13), 134.81 (C8), 133.74 (C12), 133.28 (C14),
127.92 (C4), 127.28 (C9), 125.13 (C2), 115.04 (C6´´´), 109.74 (C2´´´),
108.36 (C4´´´), 101.75 (C1´), 81.85 (C5´), 80.91 (C15), 80.36 (C18),
77.63 (C4´), 77.35 (C17), 73.06 (C7), 72.42 (C3´), 70.79 (C2´), 63.11
(C20), 61.82 (C-OMe), 39.76 (C10), 36.79 (C6), 35.93 (C16), 30.64
(C22), 26.42 (C8´´´), 20.80 (C19), 18.64 (C24), 18.33 (C6´), 18.23 (C25),
14.82 (C21), 14.54 (C9´´´), 12.06 (C23); IR (cm-1) ν 2969, 2932, 2873,
1698, 1638, 1590, 1449, 1367, 1311, 1240, 1198, 1167, 1142, 1110,
1088, 1063, 1023, 1003, 943, 902, 858, 884, 858, 799.
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(2R,3R,6S)-6-(((3E,5E,8S,9E,11S,12R,13E,15E,18S)-11-ethyl-8-
hydroxy-18-((R)-1-hydroxyethyl)-12-(((3aS,4R,7S,7aS)-7-
(isobutyryloxy)-6,6-dimethyl-2-oxotetrahydro-4H-[1,3]dioxolo[4,5-
c]pyran-4-yl)oxy)-9,13,15-trimethyl-2-oxooxacyclooctadeca-
3,5,9,13,15-pentaen-3-yl)methoxy)-4-hydroxy-5-methoxy-2-
methyltetrahydro-2H-pyran-3-yl
2,4-bis(allyloxy)-3,5-dichloro-6-
ethylbenzoate (carbonate and allyl protected fidaxomicin, 7b). To a
solution of allyl protected, semisynthetic fidaxomicin 7a (130 mg,
0.11 mmol) in CH2Cl2 (5.0 mL) at room temperature, Et3N (0.32 mL,
2.3 mmol, 21 equiv) and 1,1’-carbonyldiimidazole (28 mg, 0.17 mmol,
1.5 equiv) were added and the mixture was stirred for 24 h. Then it
was quenched with sat. NH4Cl (10 mL) and extracted with CH2Cl2 (1 x
10 mL). The combined organic layers were dried over MgSO4, filtered
and concentrated. Purification by column chromatography (Et2O
only) gave the desired carbonate and allyl protected fidaxomicin 7b
(120 mg, 90%). Rf = 0.85 (acetone/pentane = 2/3); [α]D25 = –55.3° (c
0.02, MeOH); IR (cm-1) ν 3485, 2976, 2935, 1813, 1738, 1701, 1247,
1
1066, 1023, 734; H NMR (400 MHz, acetone-d6) δ 7.19 (d, J = 11.4
Hz, 1H), 6.63 (dd, 14.4, 12.0 1H), 6.17 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H),
6.09 (ddt, J = 17.1, 10.4, 5.8 Hz, 1H), 6.00–5.90 (m, 1H) 5.93 (s, 1H),
5.74 (d, J = 6.9 Hz, 1H), 5.61 (dd, J = 8.1, 8.1 Hz, 1H), 5.43 (ap ddq, J =
20.4, 17.2, 1.6 Hz, 1H), 5.31–5.23 (m, 2H), 5.21–5.16 (m, 2H), 5.18 (d,
J = 3.2 Hz, 1H), 5.12–4.99 (m, 3H), 4.72–4.67 (m, 1H), 4.64 (s, 1H),
4.64–4.57 (m, 4H), 4.53 (dddd, J = 11.7, 5.8, 1.4, 1.4 Hz, 1H), 4.39 (d, J
= 11.5 Hz, 1H), 4.29–4.24 (m, 1H), 4.07–4.00 (m, 2H), 3.86 (d, J = 10.1
Hz, 1H), 3.80 (d, J = 9.8 Hz, 1H), 3.75 (d, J = 4.2 Hz, 1H), 3.73–3.66 (m,
1H), 3.55 (d, J = 3.3 Hz, 1H), 3.55–3.50 (m, 1H), 3.52 (s, 3H), 2.92–
2.62 (m, 6H), 2.50 (ddd, J = 14.7, 9.6, 4.4 Hz, 1H), 2.40 (ddd, J = 13.7,
8.3, 4.4 Hz, 1H), 1.96–1.90 (m, 1H), 1.89 (ap s, 3H), 1.79 (ap s, 3H),
1.68 (ap s, 3H), 1.33 (d, J = 6.2 Hz, 3H), 1.25–1.12 (m, 19H), 0.82 (t, J =
7.4 Hz, 3H); 13C NMR (101 MHz, acetone-d6) δ 176.0, 168.1, 166.5,
154.7, 153.9, 152.0, 145.1, 143.1, 140.0, 137.3, 136.0, 135.5, 134.7,
134.1, 134.1, 128.7, 128.4, 127.5, 126.0, 125.6, 123.8, 122.3, 118.8,
118.7, 101.9, 95.3, 93.0, 81.9, 78.5, 77.5, 76.4, 76.4, 75.4, 75.0, 73.3,
73.1, 72.9, 72.4, 70.7, 66.1, 63.5, 61.8, 42.8, 37.4, 34.6, 28.5, 28.4,
26.0, 25.6, 23.9, 20.4, 19.2, 19.0, 18.3, 17.4, 15.3, 14.4, 13.8, 11.2;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C59H80Cl2O19Na 1185.4563;
found: 1185.4558.
Protection of Fidaxomicin (1).
(2R,3R,6S)-6-(((3E,5E,8S,9E,11S,12R,13E,15E,18S)-12-
(((2R,3S,4R,5S)-3,4-dihydroxy-5-(isobutyryloxy)-6,6-
dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-ethyl-8-hydroxy-18-((R)-
1-hydroxyethyl)-9,13,15-trimethyl-2-oxooxacyclooctadeca-
3,5,9,13,15-pentaen-3-yl)-methoxy)-4-hydroxy-5-methoxy-2-
methyltetrahydro-2H-pyran-3-yl
2,4-bis(allyloxy)-3,5-dichloro-6-
ethylbenzoate (Allyl protected fidaxomicin, 7a). To a solution of
natural fidaxomicin (1) (400 mg, 0.38 mmol) in DMF (10 mL), K2CO3
(209 mg, 1.51 mmol, 4.0 equiv) was added. To the suspension, allyl
bromide (82 µL, 0.95 mmol, 2.5 equiv) was added and the colourless
reaction mixture was stirred at 45 °C for 3 h. The orange-red reaction
mixture was quenched with sat. NH4Cl and the mixture was extracted
with AcOEt 3 times. The organic layers were washed with brine, dried
over MgSO4, filtered and concentrated. Purification by column chro-
(2R,4S,5R)-6-(((3E,5E,8S,9E,11S,12R,13E,15E,18S)-8-((tert-
butyldimethylsilyl)oxy)-18-((R)-1-((tert-
butyldimethylsilyl)oxy)ethyl)-11-ethyl-12-(((4R,7S,7aR)-7-
11
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