The Journal of Organic Chemistry
Note
NMR (101 MHz, CDCl3) δ 160.3, 158.5, 142.1, 141.0, 130.8, 130.6,
128.6, 128.3, 128.2, 117.7, 104.1, 98.1, 92.1, 78.1, 55.5, 55.3, 46.2; ESI
HRMS calcd for C40H39O6N3IS [M + H]+ = 816.15988; Mass found
[M + H]+ = 816.16011.
peptide 11. Before cleavage of the peptides from the resin, the resin
was washed thoroughly with diethyl ether (5 times), methanol (5
times), and DCM (5 times). The peptides were cleaved with 5% TIPS
and 5% water in TFA (3 times 1 h). The cleavage mixture was
evaporated to dryness in vacuo. The resulting solid was triturated with
diethyl ether, dissolved in water/acetonitrile and subsequently
lyophilized overnight. Pure peptides were obtained after purification
by preparative HPLC. For peptide 9; ESI HRMS calcd for
(S)-Methyl-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-
(4-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-1-trityl-1H-imida-
zol-2-yl)propanoate (8). A 65 mg (1 mmol) portion of Zn(0)
(dust) was weighted into a pear-shaped flask and flame-dried. Twenty
milligrams of I2 dissolved in 3 mL of dry DMF was added (the yellow
color disappeared after approximately 1 min). A 160 mg (0.36 mmol)
portion of (R)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-
3-iodopropanoate 7 together with 20 mg of iodine was added, and the
RM was stirred until TLC indicated full consumption of 7.26 The
stirring was stopped, and the unreacted Zn was allowed to precipitate.
Two milliliters of the supernatant was taken out in a syringe and
directly added to a prestirred solution of 6 mg (0.006 mmol) of
Pd2(dba)3, 6 mg (0.012 mmol) of Xphos, and 100 mg (0.12 mmol) of
6 suspended in 1 mL of dry DMF. The RM was aged for 2 h at 40 °C,
poured into satd NaHCO3(aq), and extracted twice with EtOAc. The
combined EtOAc layers were washed with satd NaCl(aq), dried over
MgSO4(s), concentrated, and dried under vacuum. The product was
purified by SiO2 column chromatography and eluted with toluene/
EtOAc (9:1) to obtain 66 mg of 8 as a pale yellow foam (53% yield
C25H36O7N9S [M + H]+ = 606.24529; Mass found [M + H]+
=
606.24433. For peptide 10; ESI HRMS calcd for C26H51O7N16S [M +
H]+ = 731.38419; Mass found [M + H]+ = 731.38311. For peptide 11;
ESI HRMS calcd for C118H217O34N44S [M + 5H]5+ = 565.32594; Mass
found [M + 5H]5+ = 565.32579.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR, LC−MS, and HR-MS spectra for all new
compounds and HPLC, LC−MS, and HR-MS spectra for the
peptides. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
from 6): Rf = 0.63 (toluene/EtOAc 1:1); [α]20 +22.2 (c = 0.4,
■
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.58
(t, J = 8.0 Hz, 2H), 7.35 (m, 11H), 7.22 (m, 5H), 7.06 (m, 6H), 6.45
(d, J = 8.8 Hz, 1H), 6.39 (dd, J = 8.4 Hz, J = 2.4 Hz, 2H), 6.28 (d, J =
2.4 Hz, 1H), 4.60 (d, 16.0 Hz, 1H), 4.45 (d, 16.0 Hz, 1H), 4.39 (m,
2H), 4.20 (m, 2H), 3.74 (s, 6H), 3.71 (s, 3H), 3.58 (s, 6H), 2.57 (dd, J
= 17.2 Hz, J = 4.0 Hz, 1H)), 2.07 (dd, J = 17.2 Hz, J = 4.0 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 171.7, 160.2, 158.4, 156.5, 149.2,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Dr. Herbert Waldmann, Department of
Chemical Biology, Max-Planck Institute of Molecular Physiol-
ogy, for his generous and unconditional support. C.H. thanks
AstraZeneca AB, Sweden, for financial support. We thank Mr.
Sascha Gentz for operating the automated peptide synthesizer.
144.2, 144.0, 141.4, 141.4, 141.1, 137.7, 130.5, 130.1, 128.7, 128.6,
127.9, 127.8, 127.4, 127.4, 125.6, 125.5, 125.0, 120.1, 117.9, 104.3,
98.1, 76.3, 67.6, 55.5, 55.2, 52.7, 51.7, 47.3, 46.5, 32.8; ESI HRMS
calcd for C59H57O10N4S [M + H]+ = 1013.37899. Mass found [M +
H]+ = 1013.37950.
(S)-2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-3-(4-(N,N-
bis(2,4-dimethoxybenzyl)sulfamoyl)-1-trityl-1H-imidazol-2-yl)-
propanoic Acid (1). A 500 mg (0.49 mmol) portion of 8 was
dissolved in 10 mL of DCE. An 894 mg (5.0 mmol) portion of
Sn(Me)3OH was added. The RM was heated at 65 °C for 18 h, when
TLC indicated complete disappearance of SM. The RM was poured
into citric acid and extracted with DCM (2 × 20 mL). The DCM was
dried over MgSO4(s), concentrated, and dried under vacuum. The
product was purified by SiO2 column chromatography and eluted with
toluene/EtOAc (1:1) to obtain 425 mg of 1 as a pale yellow foam
(86% yield from 7): Rf = 0.20 (toluene/EtOAc 1:1); [α]20D +19.8 (c =
0.3, CHCl3) ; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H),
7.56 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.35 (m, 11H), 7.22
(m, 5H), 7.06 (m, 6H), 6.45 (d, J = 8.8 Hz, 1H), 6.39 (dd, J = 8.4 Hz,
J = 2.4 Hz, 2H), 6.28 (d, J = 2.4 Hz, 1H), 4.60 (d, 16.0 Hz, 1H), 4.45
(d, 16.0 Hz, 1H), 4.39 (m, 2H), 4.20 (m, 2H), 3.74 (s, 6H), 3.71 (s,
3H), 3.58 (s, 6H), 2.57 (dd, J = 17.2 Hz, J = 4.0 Hz, 1H)), 2.07 (dd, J
= 17.2 Hz, J = 4.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 172.2,
160.4, 158.5, 155.6, 148.9, 144.1, 144.0, 141.5, 141.4, 140.6, 137.0,
130.8, 130.0, 128.8, 128.1, 128.0, 127.5, 127.3, 125.4, 125.3, 124.9,
120.2, 117.5, 104.3, 98.3, 67.4, 55.5, 55.4, 53,7, 51.7, 47.2, 46.6, 34.2,
29.9; ESI HRMS calcd for C58H55O10N4S [M + H]+ = 999.36334;
Mass found [M + H]+ = 999.36386.
Peptides 9−11. Peptide 11 was synthesized using Tentagel Rink-
amide resin as solid phase employing 10 equiv of amino acid and 10
equiv of HBTU for all amino acids except 1 (2 equiv) which was
coupled using 2 equiv of HOAt, 2 equiv of HATU, and 5 equiv of
DIPEA in DMF. The coupling reaction was allowed to proceed
overnight at room temperature. The resin was pre-swollen by
treatment with DCM (15 min). Removal of the Fmoc protecting
group was performed by treatment with 20% piperidine in DMF (3
times 10 min). The resin was washed with DMF three times. Peptides
9 and 10 were synthesized manually on a Tentagel Rink-amide resin
preloaded with glycine using the same procedures as described for
REFERENCES
■
(1) Klumpp, S.; Krieglstein, J. Sci. Signaling 2009, 2, No. pe13.
(2) Besant, P. G.; Attwood, P. V. Biochim. Biophys. Acta, Proteins
Proteomics 2005, 1754, 281.
(3) Klumpp, S.; Bechmann, G.; Maeurer, A.; Krieglstein, J. Top. Curr.
Genet. 2004, 5, 131.
(4) Ek, P.; Pettersson, G.; Ek, B.; Gong, F.; Li, J.-P.; Zetterqvist, O.
Eur. J. Biochem. 2002, 269, 5016.
(5) Klumpp, S.; Hermesmeier, J.; Selke, D.; Baumeister, R.; Kellner,
R.; Krieglstein, J. J. Cereb. Blood Flow Metab. 2002, 22, 1420.
(6) Krieglstein, J.; Lehmann, M.; Maeurer, A.; Gudermann, T.;
Pinkenburg, O.; Wieland, T.; Litterscheid, S.; Klumpp, S. Neurochem.
Int. 2008, 53, 132.
(7) Xu, A.; Hao, J.; Zhang, Z.; Tian, T.; Jiang, S.; Hao, J.; Liu, C.;
Huang, L.; Xiao, X.; He, D. Lung cancer 2010, 67, 48.
(8) Gong, W.; Li, Y.; Cui, G.; Hu, J.; Fang, H.; Jin, C.; Xia, B.
Biochem. J. 2009, 418, 337.
(9) Ma, R.; Kanders, E.; Sundh, U. B.; Geng, M.; Ek, P.; Zetterqvist,
O.; Li, J.-P. Biochem. Biophys. Res. Commun. 2005, 337, 887.
(10) Solution structure and catalytic mechanism of human protein
histidine phosphatase 1, see: Gong, W.; Li, Y.; Cui, G.; Hu, J.; Fang,
H.; Jin, C.; Xia, B. Biochem. J. 2009, 418, 337−344.
(11) Schenkels, C.; Erni, B.; Reymond, J.-L. Bioorg. Med. Chem. Lett.
1999, 9, 1443.
(12) Kee, J.-M.; Villani, B.; Carpenter, L. R.; Muir, T. W. J. Am.
Chem. Soc. 2010, 132, 14327.
(13) McAllister, T. E.; Nix, M. G.; Webb, M. E. Chem. Commun.
(Cambridge, U. K.) 2011, 47, 1297.
(14) Chen Yen, T.; Xie, J.; Seto Christopher, T. J. Org. Chem. 2003,
68, 4123.
(15) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S.; Elliott, J.;
Mowbray, C. E. J. Org. Chem. 1998, 63, 7875.
2051
dx.doi.org/10.1021/jo2025702 | J. Org. Chem. 2012, 77, 2047−2052