Synthesis and preliminary biological evaluation
stirred overnight and then evaporated to dryness under
reduced pressure. The crude product was dissolved in
dichloromethane and filtered through a short pad of silica
reaction mixture was allowed to reach room temperature
where it was stirred for an additional hour. The reaction
mixture was then evaporated to dryness under reduced
pressure and the crude product was purified by flash col-
umn chromatography on silica gel (hexane/ethyl ace-
tate = 7/3) to afford 6 (186.4 mg, 65 %) as a clear
1
gel to afford 4 (3.72 g, 95 %) as a clear oil. H NMR
(CDCl3, 400 MHz) d 1.41 (s, 9H, C(CH3)3), 1.42 (s, 9H,
C(CH3)3), 2.38 (s, 3H,CH3N), 2.65 (t, J = 5.2 Hz, 2H,
HOCH2CH2N), 2.86 (t, J = 5.6 Hz, 2H, ArOCH2CH2N),
2.95-3.05 (m, 2H, ArCH2CH), 3.60 (t, J = 5.2 Hz, 2H,
HOCH2CH2N), 4.03 (t, J = 5.6 Hz, 2H, ArOCH2CH2N),
4.40 (q, J1 = 7.9 Hz and J2 = 6.3 Hz, 1H, ArCH2CH),
4.96 (d, J = 7.9 Hz, 1H, NHBoc), 6.82 (d, J = 8.6 Hz,
2H, ArH), 7.07 (d, J = 8.6 Hz, 2H, ArH).13C NMR
(CDCl3, 100 MHz) d 28.1, 28.4, 37.7, 42.5, 55.0, 56.3,
58.7, 59.2, 66.1, 79.7,82.1, 114.5, 128.7, 130.7, 155.2,
157.8, 171.1.Varian HiResMALDI MS m/z calculated for
C23H39N2O6 [M?H]? 439.2803, measured 439.2807.
1
colorless oil. H NMR (CDCl3, 400 MHz) 1.41 (s, 9H,
C(CH3)3), 1.42 (s, 9H, C(CH3)3), 2.42 (s, 3H, CH3N), 2.88
(t, J = 5.7 Hz, 2H, ArOCH2CH2N), 2.93 (t, J = 7.6 Hz,
2H, BrCH2CH2N), 2.96–3.02 (br, 2H, ArCH2CH), 3.43 (t,
J = 7.6 Hz, 2H, BrCH2CH2N), 4.05 (t, J = 5.7 Hz, 2H,
ArOCH2CH2N), 4.40 (q, J1 = 7.9 Hz and J2 = 6.1 Hz,
1H, ArCH2CH), 4.96 (d, J = 7.9 Hz, 1H, NHBoc), 6.82 (d,
J = 8.6 Hz, 2H, ArH), 7.07 (d, J = 8.7 Hz, 2H, ArH). 13
C
NMR (CDCl3, 100 MHz) 28.1, 28.5, 29.8, 37.7, 42.9, 55.1,
56.2, 59.5, 66.2, 79.7,82.1, 114.6, 128.7, 130.7, 155.2,
157.8, 171.2. ESI-QTOF MS m/z calculated for C23H38Br
N2O5 [M?H]? 501.1959, measured 501.1953.
Tert-butyl-2-((tert-butoxycarbonyl)amino)-3-(4-(2-((2-
chloroethyl)(methyl)amino)ethoxy)phenyl)-propanoate (5)
Tert-butyl-2-((tert-butoxycarbonyl)amino)-3-(4-(2-((2-
A
solution of methanesulfonyl chloride (130 mg,
iodoethyl)(methyl)amino)ethoxy)phenyl)-propanoate (7)
1.14 mmol) in dichloromethane (1 ml) was added dropwise
within 10 min to a solution of compound 4 (416 mg,
0.95 mmol) and triethylamine (259 mg, 2.56 mmol) in
dichloromethane (5 ml) at -40 °C. The reaction mixture
was left to stir overnight while the temperature reached
10 °C. The mixture was diluted with dichloromethane,
washed once with 5 % NaHCO3 solution, water and brine,
dried over sodium sulfate, filtered and evaporated to dry-
ness. The crude was purified by flash column chromatog-
raphy (hexane/ethyl acetate/triethylamine 7:3:0.1) to afford
5 (270 mg, 62 %) as a clear oil.1H NMR (CDCl3,
400 MHz) d 1.41 (s, 9H, C(CH3)3), 1.42 (s, 9H, C(CH3)3),
2.42 (s, 3H, CH3N), 2.83–2.91 (m, 4H, ClCH2CH2N and
ArOCH2CH2N), 2.94–3.03 (br, 2H, ArCH2CH), 3.58 (t,
J = 7.0 Hz, 2H, ClCH2CH2N), 4.04 (t, J = 5.8 Hz, 2H,
ArOCH2CH2N), 4.40 (q, J1 = 7.7 Hz and J2 = 6.1 Hz,
1H, ArCH2CH), 4.96 (d, J = 7.7 Hz, 1H,NHBoc), 6.82 (d,
J = 8.4 Hz, 2H, ArH), 7.07 (d, J = 8.5 Hz, 2H, ArH).13C
NMR (CDCl3, 100 MHz) d 28.0, 28.4, 37.6, 41.6, 43.0,
55.0, 56.3, 59.4, 66.2, 79.6,82.0, 114.5, 128.4, 130.6,
155.1, 157.7, 171.1. ESI-QTOF MS m/z calculated for
C23H38ClN2O5 [M?H]? 457.2464, measured 457.2463.
Iodine (276.1 mg, 1.09 mmol) was added to a solution of
triphenylphosphine (286.4 mg, 1.09 mmol) and N-ethyldi-
isopropylamine (DIPEA) (163.2 mg, 1.26 mmol) in dichlo-
romethane (4.6 ml) at 0 °C. Under strict exclusion of light, a
solution of compound 4 (396 mg, 0.9 mmol) in dichloro-
methane (2.6 ml) was added dropwise. After 10 min of
stirring at 0 °C, the reaction mixture was allowed to reach
room temperature and stirred for 4 h. The solvent was then
removed with a stream of argon and the crude was purified
by flash column chromatography on silica gel (hexane/ethyl
acetate = 7.5/2.5) to afford 7 (304.2 mg, 61 %) as a yel-
1
lowish oil. H NMR (CDCl3, 400 MHz) d 1.41 (s, 9H,
C(CH3)3), 1.42 (s, 9H, C(CH3)3), 2.40 (s, 3H,CH3N),
2.84–2.92 (m, 4H, ICH2CH2N and ArOCH2CH2N),
2.95–3.03 (br, 2H, ArCH2CH), 3.22 (t, J = 7.8 Hz, 2H,
ICH2CH2N), 4.05 (t, J = 5.7 Hz, 2H, ArOCH2CH2N), 4.40
(q, J1 = 7.6 Hz and J2 = 6.0 Hz, 1H, ArCH2CH), 4.96 (d,
J = 7.6 Hz, 1H, NHBoc), 6.82 (d, J = 8.6 Hz, 2H, ArH),
7.07 (d, J = 8.6 Hz, 2H, ArH). 13C NMR (CDCl3,
100 MHz) d 28.1, 28.5, 37.7, 42.5, 55.1, 55.8, 60.5, 66.3,
79.7,82.1, 114.6, 128.5, 130.7, 155.3, 157.8, 171.2. ESI-
QTOF MS m/z calculated for C23H38IN2O5 [M?H]?
549.1820, measured 549.1831. Note Since the compound is
rather unstable, spectroscopic properties were measured
without any delays and by taking related precautions.
Tert-butyl-3-(4-(2-((2-bromoethyl)(methyl)
amino)ethoxy)phenyl)-2-(tert-butoxycarbonyl)amino)-
propanoate (6)
Triphenylphosphine (183.4 mg, 0.70 mmol) was added to
an ice-cooled solution of 4 (250.7 mg, 0.57 mmol) in DCM
(2.8 ml) and the solution was stirred for 15 min. Under
protection from light, CBr4 (288.3 mg, 0.869 mmol) was
then added portion wise. After stirring for 1 h at 0 °C, the
Tert-butyl-2-((tert-butoxycarbonyl)amino)-3-(4-(2-((2-
fluoroethyl)(methyl)amino)ethoxy)phenyl)-propanoate (8)
Method A Via fluorination of the iodo compound 7. To a
solution of compound 7 (304.2 mg, 0.56 mmol) in
123