T. Mayer, M. E. Maier
FULL PAPER
6), 133.8 (C-4), 136.0 (C-1Ј), 145.4 (C-4ЈЈ), 158.1 (C-2), 160.1 (C-
3Ј), 164.9 (COO) ppm. HRMS (ESI): calcd. for C25H26F3N5O5 [M
+ H]+ 534.19585; found 534.19543; ∆(rel.) = 0.79 ppm.
41.0 Hz, CCF3), 37.9 (C-6), 38.3 (C-16), 39.0 (C-22), 40.6 (C-20),
41.6 (C-8), 42.2 (C-9), 42.9 (C-18), 55.6 (14-OMe), 58.8
(CH2CϵC), 60.1 (2-OMe), 68.7 (ArOCH2CH2), 69.6 (ArOCH2),
71.5 (C-17), 75.6 (C-21), 76.1 (CϵCH), 76.6 (C-23), 77.3 (C-15),
80.3 (C-7), 80.6 (CϵCH), 83.3 (C-14), 99.8 (C-19), 112.3 (Ar-3),
NMR Spectroscopic Data for Bafilomycin A1 (27): 1H NMR
(400 MHz, [D6]acetone): δ = 0.76 (d, J = 6.8 Hz, 3 H, Me-33), 0.86
(d, J = 6.8 Hz, 3 H, Me-30), 0.91 (m, 9 H, Me-25, Me-28, Me-32),
0.98 (d, J = 7.1 Hz, 3 H, Me-31), 1.03 (d, J = 7.1 Hz, 3 H, Me-27),
1.08–1.13 (m, 2 H, 20-H), 1.22–1.30 (m, 1 H, 22-H), 1.77 (q, J =
7.0 Hz, 1 H, 18-H), 1.83–1.90 (m, 2 H, 8-H, 24-H), 1.92 (s, 3 H,
Me-29), 1.97 (d, J = 0.8 Hz, 3 H, Me-26), 1.99–2.03 (m, 9-H), 2.11–
2.20 (m, 2 H, 16-H, 20-H), 2.49–2.58 (m, 1 H, 6-H), 3.22 (s, 3 H,
14-OMe), 3.27–3.31 (m, 1 H, 7-H), 3.44 (dd, J = 10.4, 2.0 Hz, 1 H,
23-H), 3.53 (ddd, J = 15.4, 10.3, 5.4 Hz, 1 H, 21-H), 3.62 (s, 3 H,
2-OMe), 4.05 (t, J = 8.8 Hz, 1 H, 14-H), 4.11 (d, J = 5.6 Hz, 1 H,
7-OH), 4.17 (ddd, J = 10.7, 4.2, 1.5 Hz, 1 H, 17-H), 4.71 (d, J =
4.3 Hz, 1 H, 17-OH), 5.0 (dd, J = 8.3, 1.0 Hz, 1 H, 15-H), 5.13 (dd,
J = 14.9, 9.1 Hz, 1 H, 13-H), 5.24 (d, J = 2.0 Hz, 1 H, 19-OH),
5.78 (d, J = 10.6 Hz, 1 H, 11-H), 5.95 (d, J = 8.8 Hz, 1 H, 5-H),
1
119.4 (Ar-5), 122.9 (q, JCF = 273.7 Hz, CF3), 124.7 (Ar-1), 125.1
(C-11), 126.9 (C-13), 132.4 (Ar-6), 132.7 (C-4), 133.7 (Ar-4), 134.2
(C-3), 134.4 (C-12), 141.9 (C-2), 144.8 (C-10), 145.7 (C-5), 158.7
(Ar-2), 166.0 (ArCO2), 167.7 (C-1) ppm. HRMS (ESI): calcd. for
C49H67F3N2O12 [M + Na]+ 955.45383; found 955.45387; ∆(rel.) =
0.04 ppm.
2-Azidoethylamine (29): 2-Bromoethylamine hydrobromide
(500 mg, 2.44 mmol) was added to a solution of sodium azide
(475.9 mg, 7.32 mmol, 3 equiv.) in H2O (2 mL). The stirred solution
was heated to 75 °C for 21 h before it was cooled to 0 °C. Et2O
(2 mL) was added followed by solid KOH (800 mg). The organic
phase was separated and the aqueous layer extracted with Et2O
(3ϫ10 mL). The combined organic layers were dried with MgSO4,
filtered, and the solvent removed carefully by rotary evaporation
(35 °C, 750 mbar) to afford the azide 29 (171 mg, 1.99 mmol, 82%)
as a colorless liquid. Rf = 0.39 (EtOAc/MeOH, 3:1). 1H NMR
(400 MHz, CDCl3): δ = 1.27 (s, 2 H, NH2), 2.80–2.84 (m, 2 H,
CH2N3), 3.30 (t, J = 5.7 Hz, 2 H, CH2NH2) ppm. 13C NMR
(100 MHz, CDCl3): δ = 41.2 (CH2NH2), 54.6 (CH2N3) ppm.
6.66 (dd, J = 10.9, 4.0 Hz, 1 H, 12-H), 6.70 (s, 1 H, 3-H) ppm. 13
C
NMR (100 MHz, [D6]acetone): δ = 7.3 (Me-31), 10.3 (Me-30), 12.6
(Me-32), 14.1 (Me-26), 14.7 (Me-33), 17.7 (Me-27), 20.3 (Me-29),
21.7 (Me-25), 22.2 (Me-28), 28.7 (C-24), 37.9 (C-6), 38.2 (C-16),
41.6 (C-8), 41.9 (C-22), 42.2 (C-9), 43.0 (C-18), 44.5 (C-20), 55.6
(14-OMe), 60.1 (2-OMe), 70.4 (C-21), 71.5 (C-17), 76.9 (C-23), 77.4
(C-15), 80.3 (C-7), 83.3 (C-14), 99.7 (C-19), 125.2 (C-11), 126.9 (C-
13), 132.7 (C-4), 134.1 (C-3), 134.4 (C-12), 141.9 (C-2), 144.8 (C-
10), 145.7 (C-5), 167.7 (C-1) ppm.
1-{[5-(2-Oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-
pentanoyl]oxy}pyrrolidine-2,5-dione (31): N-Hydroxysuccinimide
(56.5 mg, 0.49 mmol, 1.2 equiv.) followed by EDC (86.9 µL,
0.49 mmol, 1.2 equiv.) was added to a solution of -biotin
(100.0 mg, 0.41 mmol) in DMF (10 mL). The solution was stirred
for 21 h at room temperature. The solvent was evaporated in vacuo
and the resulting residue dissolved in CH2Cl2 (200 mL). The or-
ganic phase was washed with NaHCO3 solution (2ϫ10 mL) and a
saturated NaCl solution (1ϫ10 mL), dried with MgSO4, and fil-
tered. The solvent was removed under vacuo to give biotin-NHS
31 (71.0 mg, 0.21 mmol, 51 %) as a colorless solid. 1H NMR
(400 MHz, [D6]DMSO): δ = 1.35–1.54 (m, 3 H, 4Ј-H, 5Ј-H), 1.58–
1.68 (m, 3 H, 3Ј-H, 5Ј-H), 2.57 (d, J = 11.4 Hz, 1 H, SCH2), 2.66
(t, J = 7.3 Hz, 2 H, 2Ј-H), 2.78–2.85 [m, 5 H, CH2CH2 (succinyl),
SCH2], 3.06–3.12 (m, 1 H, SCH), 4.11–4.16 (m, 1 H, 3a-H), 4.27–
4.32 (m, 1 H, 6a-H), 6.36 (s, 1 H, 1-NH), 6.42 (s, 1 H, 3-NH) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 24.3 (C-3Ј), 25.4 [CH2CH2
(succinyl)], 27.6 (C-5Ј), 27.8 (C-4Ј), 30.0 (C-2Ј), 39.9 (SCH2), 55.2
(SCH), 59.2 (C-6a), 61.0 (C-3a), 162.7 [(HN)2CO], 168.9 (CO2),
170.3 [N(CO)2] ppm.
21-O-{2-[2-(Prop-2-ynyloxy)ethoxy]-4-[3-(trifluoromethyl)-3H-di-
aziren-3-yl]benzoyl}bafilomycin A1 (28): Benzoic acid 22 (10.5 mg,
32.1 µmol, 2 equiv.) followed by DMAP (4.1 mg, 33.7 µmol,
2.1 equiv.), and EDC (6.0 µL, 33.7 µmol, 2.1 equiv.) were added to
a stirred solution of bafilomycin A1 (10.0 mg, 16.1 µmol) in CH2Cl2
(2 mL) . After stirring for 24 h at room temperature, additional
acid 22 (5.3 mg, 16.1 µmol, 1 equiv.), DMAP (2.3 mg, 19.3 µmol,
1 equiv.), and EDC (3.4 µL, 19.3 µmol, 1.2 equiv.) were added and
stirring was continued for a further 24 h. The solvent was evapo-
rated in vacuo and the resulting crude product purified by flash
chromatography (hexane/EtOAc, 3:2) to afford ester 28 (11.9 mg,
12.7 µmol, 79%) as a colorless solid as well as unreacted bafilomy-
cin A1 (2.0 mg, 3.2 µmol). Rf = 0.56 (hexane/EtOAc, 3:2). 1H NMR
(600 MHz, [D6]acetone): δ = 0.81 (d, J = 6.9 Hz, 3 H, Me-33), 0.87
(d, J = 6.9 Hz, 3 H, Me-30), 0.91 (d, J = 6.5 Hz, 6 H, Me-25, Me-
32), 0.96 (d, J = 6.9 Hz, 3 H, Me-28), 1.01 (d, J = 7.1 Hz, 3 H,
Me-31), 1.04 (d, J = 6.9 Hz, 3 H, Me-27), 1.35–1.40 (m, 1 H, 20-
H), 1.68 (ddq, J = 16.9, 10.5, 6.5 Hz, 1 H, 22-H), 1.84–1.89 (m, 2
H, 8-H, 18-H), 1.92 (s, 3 H, Me-29), 1.93–1.96 (m, 1 H, 24-H), 1.97 N-(2-Azidoethyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-
(d, J = 1.2 Hz, 3 H, Me-26), 2.01 (d, J = 10.8 Hz, 1 H, 9-H), 2.16
(ddq, J = 17.6, 6.9, 0.6 Hz, 1 H, 16-H), 2.40 (dd, J = 11.8, 4.9 Hz,
1 H, 20-H), 2.51–2.57 (m, 1 H, 6-H), 2.94 (t, J = 2.4 Hz, 1 H,
pentanamide (32): Et3N (0.03 mL, 0.20 mmol, 1 equiv.) was added
to a solution of 2-azidoethylamine (29) (24.1 mg, 0.28 mmol,
1.4 equiv.) in DMF (3 mL), followed by the addition of biotin-NHS
CϵCH), 3.23 (s, 3 H, 14-OMe), 3.28–3.31 (m, 1 H, 7-H), 3.63 (s, 31 (70.0 mg, 0.20 mmol) in DMF (2 mL). The resulting solution
3 H, 2-OMe), 3.63–3.65 (m, 1 H, 23-H), 3.88–3.90 (m, 2 H, Ar-
was stirred at room temperature for 24 h. The solvent was evapo-
OCH2CH2), 4.05 (app. t, J = 8.9 Hz, 1 H, 14-H), 4.11 (d, J =
rated in vacuo and the crude product purified by flash chromatog-
5.5 Hz, 1 H, 7-OH), 4.19 (ddd, J = 10.7, 4.3, 1.6 Hz, 1 H, 17-H), raphy (acetone/MeOH, 10:1) to give the desired azido-biotin 32
4.25 (d, J = 2.4 Hz, 2 H, CH2CϵCH), 4.27–4.30 (m, 2 H, Ar-
OCH2), 4.78 (d, J = 3.7 Hz, 1 H, 17-OH), 4.97 (dd, J = 8.6, 1.2 Hz,
1 H, 15-H), 5.11–5.20 (m, 2 H, 13-H, 21-H), 5.45 (d, J = 1.8 Hz, 1
H, 19-OH), 5.79 (d, J = 10.8 Hz, 1 H, 11-H), 5.95 (d, J = 8.8 Hz,
(47.7 mg, 0.15 mmol, 75%) as a colorless solid. Rf = 0.22 (acetone/
MeOH, 10:1). 1H NMR (400 MHz, [D6]DMSO): δ = 1.20–1.38 (m,
2 H, 4Ј-H), 1.39–1.55 (m, 3 H, 3Ј-H, 5Ј-H), 1.55–1.65 (m, 1 H, 5Ј-
H), 2.06 (t, J = 7.3 Hz, 2 H, 2Ј-H), 2.56 (d, J = 12.9 Hz, 1 H,
1 H, 5-H), 6.66 (dd, J = 14.9, 10.8 Hz, 1 H, 12-H), 6.70 (d, J = SCH2), 2.80 (dd, J = 12.4, 5.1 Hz, 1 H, SCH2), 3.05–3.11 (m, 1 H,
0.6 Hz, 1 H, 3-H), 6.90 (d, J = 0.6 Hz, 1 H, 3-ArH), 7.01 (dd, J =
8.1, 0.8 Hz, 1 H, 5-ArH), 7.78 (d, J = 8.1 Hz, 1 H, 6-ArH) ppm.
13C NMR (100 MHz, [D6]acetone): δ = 7.4 (Me-31), 10.3 (Me-30),
SCH), 3.19–3.24 (m, 2 H, CH2CH2N3), 3.31 (d, J = 7.6 Hz, 2 H,
CH2N3), 4.08–4.14 (m, 1 H, 3a-H), 4.26–4.32 (m, 1 H, 6a-H), 6.35
(s, 1 H, 1-NH), 6.42 (s, 1 H, 3-NH), 8.03 (t, J = 5.3 Hz, 1 H,
12.8 (Me-32), 14.1 (Me-26), 14.6 (Me-33), 17.7 (Me-27), 20.3 (Me- CONH) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 25.2 (C-3Ј),
2
29), 21.6 (Me-25), 22.2 (Me-28), 28.7 (C-24), 29.1 (q, JCF
=
28.0 (C-5Ј), 28.2 (C-4Ј), 35.1 (C-2Ј), 38.1 (CH2CH2N3), 39.9
4718
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Eur. J. Org. Chem. 2007, 4711–4720