(76%) of 10. HRMS: m/z calculated for C14H17N3O2, 259.1321;
observed [M + H]+ 259.1329. 1H-NMR spectrum (400 MHz,
MeOH-d4, δ): 8.85 (1H, s, imidazole), 7.07–7.55 (6H, m,
8.6 Hz), 3.69 (5H, m, OCH3 and C(O)CH2I), 3.14 (1H, dd,
PhCH2CH, JH–H = 5.5 Hz, JH–H = 14.1 Hz), 2.97 (1H, dd,
PhCH2CH, 3JH–H = 8.6 Hz, 2JH–H = 14.1 Hz).
3
2
2
NCH2Ph and imidazole), 4.52 (1H, d, NCH2Ph, JH–H = 12.7
Hz), 4.40 (2H, m, NCH2Ph and NCHCO2H), 3.61 (1H, dd,
Nα-Histidinyl-acetyl-phenylalanine (12)
3
2
NCHCH2, JH–H = 3.7 Hz, JH–H = 14.9 Hz), 3.51 (1H, dd,
3
2
NCHCH2, JH–H = 9.8 Hz, JH–H = 14.9 Hz), 2.92 (3H, s,
PhCH2N(CH3)).
From the previous step, 11 (236 mg, 0.68 mmol) was used
without further purification. To this, 1.1 equivalents of neutral-
ized H-His(Trt)-O(tBu) (340.5 mg, 0.75 mmol) was added in
CH2Cl2 and refluxed for 48 h. The solution was then concen-
trated on a rotary evaporator and dried on high vacuum, which
yielded 529 mg of the crude protected 12. The crude material
was then purified by flash column chromatography using an
eluent system of 92% CH2Cl2, 7% MeOH and 1% NEt3. This
yielded 250 mg (0.37 mmol, 55%) of pure trityl protected 12.
The trityl containing 12 (220 mg, 0.33 mmol) was then depro-
tected using a 50 : 50 mixture of CH2Cl2 and TFA and 1 equival-
ent (52.2 μL, 0.33 mmol) of triethylsilane. This was stirred at
room temperature for approximately 4 h, at which point it could
be concentrated on a rotary evaporator by azeotroping with
excess CH2Cl2. It was dried on high vacuum to yield 18.5 mg
(0.05 mmol, 15%) of 12. HRMS: m/z calculated for
Rhenium(I) tricarbonyl-Nα-benzyl(methyl)-L-histidine (3)
The histidine chelator 10 (272 mg, 1.05 mmol) was coordinated
with 1.2 equivalents of [Re(CO)3(H2O)3]OTf (12.6 mL of a 0.1
M solution, 1.26 mmol) and 5 equivalents of NaOH (1.05 mL of
a 5 M solution, 5.25 mmol) in a solution of methanol (3 mL)
and water (6 mL). This was stirred at 80 °C for 2 h. The coordi-
nated product precipitated and was collected by centrifugation
and washed with water. This resulted in 342 mg (62%) of 3.
HRMS: m/z calculated for NaC17H16O5N3185/187Re, 550.0518/
552.0546; observed [M + Na]+ 550.0524/552.0539. 1H-NMR
spectrum of isomers of 3 (minor isomer denoted by ′)
(400 MHz, MeOH-d4, δ): 8.14 (0.2H, s, imidazole′), 8.11 (1H, s,
C18H23N4O5, 375.1668; observed [M + H]+ 375.1671. H-NMR
1
imidazole), 7.39–7.50 (5H, m, ar), 7.18 (0.2H, s, imidazole′),
2
spectrum (400 MHz, MeOH-d4, δ): 8.84 (1H, s, imidazole), 7.42
(1H, s, imidazole), 7.18–7.29 (5H, m, ar), 4.76 (1H, dd,
7.05 (1H, s, imidazole), 4.78 (1H, d, PhCH2N(Me), JH–H
=
2
13.5 Hz), 4.43 (1H, d, PhCH2N(Me), JH–H = 13.5 Hz), 4.38
3
3
2
NCHCO2H, JH–H = 5.1 Hz, JH–H = 8.6 Hz), 4.05 (1H, dd,
(0.2H, d, PhCH2N(Me)′, JH–H = 7.0 Hz), 3.94 (0.2H, dd,
3
2
N(Me)CHCH2′, 3JH–H = 4.9 Hz, 2JH–H = 15.6 Hz), 3.79 (1H, dd,
N(Me)CHCH2, 3JH–H = 3.3 Hz, 3JH–H = 4.9 Hz), 3.38 (0.2H, dd,
N(Me)CHCH2′, 3JH–H = 4.7 Hz, 2JH–H = 18.6 Hz), 3.18 (1H, dd,
N(Me)CHCH2, 3JH–H = 3.1 Hz, 2JH–H = 18.8 Hz), 3.07 (1H, dd,
PhCH2CH, JH–H = 5.9 Hz), 3.92 (1H, d, PhCH2CH, JH–H
16.0 Hz), 3.80 (1H, d, PhCH2CH, JH–H = 16.0 Hz), 3.70 (3H,
=
2
2
s, MeOC(O)), 3.35 (2H, d, C(O)CH2NH, JH–H = 6.3 Hz), 3.18
3
2
(1H, dd, CO2HCHCH2, JH–H = 5.1 Hz, JH–H = 13.7 Hz), 2.98
(1H, dd, CO2HCHCH2, 3JH–H = 8.6 Hz, 2JH–H = 13.7 Hz).
3
2
N(Me)CHCH2, JH–H = 4.8 Hz, JH–H = 18.6 Hz), 2.85 (3H, s,
N(Me)CHCH2). 13C-NMR Spectrum (100 MHz, MeOH-d4, δ):
183.71 (CHC(O)O), 141.46 (ar), 133.85 (imidazole), 133.54
(ar), 132.02 (ar), 130.43 (ar), 129.74 (ar), 116.59 (imidazole),
73.06 (NCHCO2), 63.30 (PhCH2N), 45.65 (PhCH2N(CH3)),
26.11 (NHCHCH2).
Rhenium(I) tricarbonyl-Nα-histidinyl-acetyl-phenylalanine (4)
The purified 12 (18.5 mg, 0.05 mmol) was coordinated with 1.2
equivalents of [Re(CO)3(H2O)3]OTf (600 μL of a 0.1 M sol-
ution, 0.06 mmol) and 5 equivalents of NaHCO3 (21.2 mg,
0.25 mmol) in a mixture of methanol (3 mL) and water (6 mL).
This was stirred at 80 °C for 2 h. The precipitate was collected
by centrifugation and washed with water. This resulted in
N-Iodocarbonyl-O-methyl phenylalanine (11)
H-Phe-OMe·HCl (520 mg, 2.41 mmol) was neutralized by stir-
ring in CH2Cl2 with 1 equivalent of triethylamine (336 μL,
2.41 mmol) at room temperature for approximately 30 min. 1.1
equivalents of bromoacetic acid (37.1 mg, 2.65 mmol) was then
pre-activated with 1.1 equivalents of EDC (411 mg, 2.65 mmol)
in CH2Cl2 for approximately 5 min. This solution was added to
the reaction mixture and allowed to stir at room temperature
overnight. The crude solution was concentrated on a rotary evap-
orator. This was then purified using flash column chromato-
graphy using an eluent system of 99% CH2Cl2 and 1% MeOH.
The column yielded 330 mg of crude 11. This was dissolved in
acetone and 1.1 equivalents of NaI (213 mg, 1.41 mmol) was
added. The solution was refluxed overnight. The solid NaCl
could then be filtered off, and the resulting filtrate concentrated
on a rotary evaporator and dried under high vacuum, to yield
236 mg (0.68 mmol, 53%) of 11. HRMS: m/z calculated for
C12H14INO3, 347.0018; observed [M + H]+, 347.0022. 1H-NMR
spectrum (400 MHz, MeOH-d4, δ): 7.20–7.29 (5H, m,
185/
26.4 mg (82%) of 4. HRMS: m/z calculated for C21H22N4O8
187Re, 643.0968/645.0995; observed [M + H]+ 643.1015/
645.0984. 1H-NMR spectrum (600 MHz, DMF-d7, δ): 8.82 (1H,
3
d, MeOC(O)CHNH, JH–H = 8.2 Hz), 8.27 (1H, t, imidazole,
4JH–H = 1.2 Hz), 7.24–7.35 (5H, m, ar), 7.21 (1H, d, imidazole,
4JH–H = 1.2 Hz), 6.23 (1H, dd, C(O)CH2NHRe, JH–H = 2.9 Hz,
3
3JH–H = 10.5 Hz), 4.74 (1H, m, MeOC(O)CHNH), 4.01 (1H, dd,
3
2
C(O)CH2NHRe, JH–H = 3.5 Hz, JH–H = 15.8 Hz), 3.86 (1H,
3
2
dd, C(O)CH2NHRe, JH–H = 10.5 Hz, JH–H = 15.8 Hz), 3.69
(3H, s, MeOC(O)), 3.49 (1H, t, NHCH(O)CH2, 3JH–H = 4.1 Hz),
3
3.23 (2H, d, NHCH(O)CH2, JH–H = 2.3 Hz), 3.16 (1H, dd,
3
2
PhCH2CH, JH–H = 5.9 Hz, JH–H = 14.1 Hz), 3.01 (1H, dd,
PhCH2CH, 3JH–H = 9.4 Hz, 2JH–H = 14.1 Hz).
Acknowledgements
Financial assistance was gratefully received from the Natural
Sciences and Engineering Research Council (NSERC) of
3
3
CHCH2Ph), 4.63 (1H, dd, PhCH2CH, JH–H = 5.5 Hz, JH–H
=
This journal is © The Royal Society of Chemistry 2012
Dalton Trans., 2012, 41, 2950–2958 | 2957