M. Jamous et al. / Tetrahedron Letters 53 (2012) 6810–6814
6811
Fmoc or Alloc groups.21 It has therefore been employed in Fmoc-
strategy of peptide synthesis for example as the synthon
Fmoc-Asp(1-methyl-1-phenylethyl ester)-OH.
NH
CCl3
NaH, CCl3CN
OH
Br
Et2O, 0 °C to rt
1 h, 85%
O
The preparation of bromoacetic acid 1-methyl-1-phenylethyl
ester (2) was performed successfully from the intermediate
1-methyl-1-phenylethyltrichloroacetimidate (1) (Scheme 1). The
esterification of bromoacetic acid with 1 in DCM yielded 2 in 77%
yield. The efficiency of this reaction can be explained by the fact
that alkyltrichloroacetimidates are more reactive than the com-
pounds previously used for the formation of bulky aliphatic
esters-including alkenes in the presence of strong acid or acid
anhydrides or acids and DCC and the corresponding aliphatic
alcohol.22 We envisaged that 1-methyl-1-phenylethyltrichloro-
acetimidate would be a more convenient source of the 1-methyl-
1-phenylethyl cation in the preparation of 1-methyl-1-phenylethyl
esters. The 1-methyl-1-phenylethyltrichloroacetimidate required
was prepared as described by Fabrice et al.23 and Wessel at al.24
1
O
O
HO
Br
DCM, n-hexane
rt, 1 h, 77%
O
2
Scheme 1. Synthesis of bromoacetic acid 1-methyl-1-phenylethyl ester.
The use of esters derived from 1-methyl-1-phenylethanol as
protecting groups was explored by Blotny and Taschner.19 OPp
esters are significantly more sensitive toward acid than tBu esters.
Deprotection occurs with 2% trifluoroacetic acid in DCM. These
conditions do not affect tBu or Boc groups.20 In addition, OPp esters
show excellent stability under the removal conditions applied for
O
O
O
O
O
O
OH
N
N
N
N
N
N
N
N
Br
O
O
O
O
O
Pd(PPh3)4, morpholine
CH2Cl2, rt, 2 h, 77%
K2CO3, MeCN
rt, 16 h, 93%
O
O
O
O
O
O
O
6
O
4
O
NH
N
O
O
O
NH HN
3
O
O
OH
N
N
N
N
N
N
N
N
Br
O
O
O
O
O
Pd(PPh3)4, morpholine
CH2Cl2, rt, 3 h, 35%
O
O
K2CO3, MeCN
rt, 8 h, 81%
O
O
O
O
5
7
Scheme 2. Synthesis of DOTA-tris(tBu ester) and DOTA-tris(OPp ester).
Table 1
Analytical data (1H, 13C NMRa and ESI-MSb)
Compound 1H NMR (500 MHz, DMSO-d6)
1C NMR (125 MHz, DMSO-d6)
ESI-MS (m/z) for
2
4
d = 7.41–7.39 (m, 2H), 7.37–7.34 (m, 2H), 7.30–7.26 (m, 1H), 3.80 d = 165.5, 144.8, 128.3, 127.3, 124.2, 83.9, 28.3, 27.2
(s, 2H), 1.82 (s, 6H)
d = 5.94–5.86 (m, 1H), 5.32–5.19 (m, 2H), 4.59–4.57 (m, 2H),
d = 173.5, 173.2, 173.1, 132.6, 118.9, 81.8, 81.7, 65.6, 55.7,
C31H56N4O8 [M],
3.73–3.73 (m, 2H), 3.44–2.84 (m, 22H), 1.41–1.40 (m, 27H)
55.5, 54.8, 51.2, 50.6, 50.2, 28.2, 27.9
[M+H]+ (calculated):
613.4160 (613.4176)
5
6
7
8
9
d = 7.32–7.17 (m, 15H), 5.84–5.71 (m, 1H), 5.24–5.16 (m, 2H),
4.42–4.29 (m, 2H), 3.39–3.32 (m, 2H), 3.31–2.69 (m, 22H), 1.58
(s, 12H), 1.54 (s, 6H)
d = 4.10–3.48 (m, 8H), 3.45–2.89 (m, 16H), 1.45 (s, 9H), 1.38 (s,
18H)
d = 172.5, 172.4, 172.3, 145.9, 145.8, 132.7, 128.5, 128.4,
127.2, 124.4, 124.3, 118.6, 83.1, 65.4, 65.3, 55.6, 54.5, 28.9,
28.7
C46H62N4O8 [M],
[M+H]+ (calculated):
799.4642 (799.4646)
d = 158.7, 158.3, 81.9, 54.7, 54.3, 53.9, 53.9, 51, 48.9, 28.2
C28H52N4O8 [M],
[M+H]+ (calculated):
573.3854 (573.3863)
d = 7.35–7.26 (m, 12H), 7.24–7.15 (m, 3H), 3.59–3.41 (m, 2H),
3.38–3.24 (m, 6H), 3.06–2.57 (m, 14H), 1.69–1.61 (m, 18H)
d = 177.7, 176.1, 174.9, 150.9, 150.8, 133.8, 133.3, 132, 131.9,
129.3, 129.1, 87.6, 87.4, 61, 60.8, 60.4, 58, 56.9, 54.7, 52.2,
33.9, 33.8
C43H58N4O8 [M],
[M+H]+ (calculated):
759.4344 (759.4333)
d = 7.38–7.33 (m, 6H), 7.33–7.29 (m, 6H), 7.26–7.19 (m, 7H),
7.16–7.12 (m, 1H), 4.65–4.58 (m, 1H), 3.8–3.46 (m, 8H), 3.13–
3.09 (m, 2H), 3.05–2.72 (m, 16H), 1.74 (s, 18H)
d = 7.26–7.22 (m, 4H), 7.19–7.15 (m, 1H), 4.61–4.57 (m, 1H),
3.91–3.38 (m, 8H), 3.13–2.76 (m, 18H), 1.45 (s, 9H), 1.43 (s, 18H) 54.9, 54.2, 51.7, 49.1, 38.5, 28.2, 28.1
d = 172.5, 158.6, 158.3, 146, 145.9, 138.2, 129.6, 128.8, 128.6,
C52H68N6O8 [M],
128.4, 127.4, 127.3, 126.7, 124.7, 124.6, 83.1, 55.2, 54.3, 54.3, [M+H]+ (calculated):
52.2, 52.1, 51.3, 49.1, 38.4, 29, 28.9
d = 172.5, 158.6, 158.3, 138.1, 129.7, 128.5, 126.7, 81.7, 55.2,
905.5182 (905.5176)
C37H62N6O8 [M],
[M+H]+ (calculated):
719.5245 (719.4707)
a
Proton and carbon NMR spectra were recorded on a Varian Mercury Plus 500 MHz spectrometer at 25 °C.
A mass spectrometer supporting orbitrap technology (Exactive, Thermo Fisher Scientific) was used to analyze the compounds and the peptides synthesized.
b