m, 2-H), 4.82–4.70 (0.4 H, m, 2-H), 4.40–3.98 (2 H, m, 5-H, 6-H),
3.80–3.60 (6 H, m, CO2CH3, NCO2CH3), 2.85–2.60 (1 H, m, 6-H),
2.35–2.18 (1 H, m, 3-H), 2.10–1.92 (1 H, m, 4-H), 1.91–1.69
(1 H, m, 3-H), 1.65–1.35 (18 H, m, 2 × CMe3), 1.30–1.05 (1 H, m,
4-H); dC (63 MHz, CDCl3) 171.80 (CO2CH3), 163.8, 156.8, 156.5,
(ESI): m/z = 591 [M + Na]+ 100%; HRMS (ESI) m/z calcd for
C29H36N4O8Na [M + Na]+ 591.2431, found 591.2435.
5-guanidinopiperidine-2-carboxylic acids 17
Method A. Guanidino compound 16 (0.5 mmol scale) was
heated at reflux in 6 M aqueous HCl (6 mL) for 4 days then
concentrated in vacuo. The resulting powder was submitted to
purification by C-18 reverse phase column chromatography (H2O)
to afford the final arginine mimetic 17 (69–79%).
=
=
155.9, 153.4 (N-C O, C N), 83.6; 79.8, 79.6 (CMe3), 53.7, 53.6,
53.3, 53.2, 52.6 (CH-2, CO2CH3, NCO2CH3), 46.1 (CH-5), 45.8
(CH2-6) 28.4, 28.2 (CMe3), 27.7, 27.6 (CH2-3), 25.7, 25.4 (CH2-4);
MS (ESI): m/z = 481 [M + Na]+ 100%; HRMS (ESI) m/z calcd
for C20H34N4O8Na [M + Na]+ 481.2274, found 481.2256.
Method B (for derivatives 16a). Guanidino compound 16a
(0.1–0.3 mmol scale) was refluxed in chloroform (1–3 mL) in
the presence of trimethylsilyl iodide (16 equiv.) for 24 h. The
reaction mixture was quenched by addition of 3 mL of saturated
methanol with HCl(g) then concentrated under vacuum prior to
purification by C-18 reverse phase column chromatography (H2O)
as in Method A.
(2S*,5R*)-1-tert-Butyl 2-methyl-5-(N,Nꢀ-bis(benzyloxycarbonyl)-
guanidino)piperidine-1,2-dicarboxylate trans-16b
To a solution of the amino ester trans-15b (80.5 mg, 0.33 mmol)
in DCM (4 mL), were added N,Nꢀ-bis(benzyloxycarbonyl)-S-
methylisothiourea (328 mg, 0.92 mmol), triethylamine (55 lL,
0.39 mmol) and mercury dichloride (255 mg, 0.94 mmol). The
mixture was stirred at r.t. for 16 h then concentrated in vacuo.
Purification by flash column chromatography (DCM→DCM–
MeOH 97 : 3) afforded the 5-guanidino compound trans-16b as
a colourless oil (150 mg, 80%). Rf = 0.46 (DCM–MeOH 99 : 1);
mmax(neat)/cm−1 3322, 3291, 2950, 1798, 1728, 1695, 1633, 1617,
1566, 1452, 1423, 1377, 1364, 1336, 1300, 1240, 1199, 1124, 1046;
dH (250 MHz, CDCl3; Me4Si) 11.67 (1 H, s, NHZ), 8.79 (1 H,
d, J 7.0, NH), 7.44–7.08 (10 H, m, HAr.), 5.20–4.65 (5 H, m,
2 × OCH2Ph, 2-H), 4.40–3.95 (2 H, m, 5-H, 6-H), 3.68 (3 H, s,
CO2CH3), 3.22–2.93 (1 H, m, 6-H), 2.20–2.00 (1 H, m, 3-H), 1.98–
1.72 (2 H, m, 3-H, 4-H), 1.63–1.16 (10 H, m, CMe3, 4-H); dC
(63 MHz, CDCl3) 171.7 (CO2CH3), 163.8, 155.7, 155.4, 153.9 (N–
(2S*,5R*)-17 (trans isomer). dH (250 MHz, D2O) 3.95–3.77
(2 H, m, 2-H, 5-H), 3.76–3.62 (1 H, m, 6-H), 3.15–2.95 (1 H, m,
6-H), 2.58–2.41 (1 H, m, 3-H), 2.39–2.25 (1 H, m, 4-H), 2.05–
1.65 (2 H, m, 3-H, 4-H); dC (63 MHz, D2O) 174.2 (CO2H), 159.1
=
(C N), 59.4 (CH-2), 48.4 (CH2-6), 48.1 (C-5) 31.1 (CH2-4), 27.2
(CH2-3); MS (FAB): m/z = 187 [M + H]+ 100%; Anal. Calcd. for
C7H16Cl2N4O2·0.75H2O: C, 30.84; H, 6.47; N, 20.55. Found: C,
30.94; H, 6.39; N, 20.13.
(2S*,5S*)-17 (cis isomer). dH (250 MHz, D2O) 4.17–3.97 (2 H,
m, 2-H, 5-H), 3.58–3.39 (2 H, m, 6-H), 2.34–2.06 (3 H, m, 3-H,
4-H), 2.02–1.82 (1 H, m, 4-H); dC (63 MHz, D2O) 173.8 (CO2H),
=
159.2 (C N), 58.3 (CH-2), 47.7 (CH2-6), 46.9 (CH-5), 28.4 (CH2-
4), 24.3 (CH2-3); MS (FAB): m/z = 187 [M + H]+ 100%; Anal.
Calcd. for C7H16Cl2N4O2·1.75H2O: C, 28.93; H, 6.76; N, 19.28.
Found: C, 28.39; H, 6.40; N, 19.81.
=
=
C O, C N), 136.8, 134.7 (CAr.), 128.9, 128.7, 128.6, 128.5, 128.2,
128.0 (CHAr.), 80.9 (CMe3), 68.3, 67.3 (2 × OCH2Ph), 54.6, 53.1
(CH-2), 52.4 (CO2CH3), 45.5 (CH2-6), 44.8, 44.5 (CH-5), 28.3
(CMe3), 24.9 (CH2-4), 21.4 (CH2-3); MS (ESI): m/z = 591 [M +
Na]+ 100%; HRMS (ESI) m/z calcd for C29H36N4O8Na [M + Na]+
591.2431, found 591.2402.
Acknowledgements
This manuscript is dedicated to the memory of Professor Yoshihiro
Matsumura of Nagasaki University, who contributed so greatly to
the field of electro-organic chemistry during the 40 years prior to
his untimely death (April 14, 2007).
(2S*,5S*)-1-tert-Butyl 2-methyl -5-(N,Nꢀ-bis-
(benzyloxycarbonyl)guanidino)piperidine-1,2- dicarboxylate
cis-16b
References
Guanylation of the cis-amino ester compound cis-15b (93 mg,
0.38 mmol) was carried out as for its trans isomer. Flash column
chromatography (DCM→DCM–MeOH 97 : 3) afforded the 5-
guanidino compound cis-16b as a colourless oil (181 mg, 83%).
Rf = 0.44 (DCM–MeOH 99 : 1); mmax(neat)/cm−1 3271, 2976, 1785,
1741, 1728, 1690, 1646, 1620, 1584, 1452, 1431, 1382, 1367, 1333,
1297, 1281, 1263, 1212, 1147, 1052; dH (250 MHz, CDCl3; Me4Si)
11.73 (1 H, s, NHZ), 8.16 (1 H, br s, NH), 7.46–7.17 (10 H, m,
HAr.), 5.25–5.00 (4 H, m, 2 × OCH2Ph), 4.95–4.62 (1 H, m, 2-H),
4.35–3.93 (2 H, m, 5-H, 6-H), 3.72 (3 H, s, CO2CH3), 2.70–2.53
(1 H, m, 6-H), 2.35–2.13 (1 H, m, 3-H), 2.06–1.90 (1 H, m, 4-
H), 1.88–1.65 (1 H, m, 3-H), 1.41 (9 H, s, CMe3), 1.28–1.05 (1
H, m, 4-H); dC (63 MHz, CDCl3) 171.8 (CO2CH3), 163.8, 155.6,
1 (a) Y. F. Chang, Neurochem. Res., 1982, 7, 577–588; (b) L. IJlst, I.
de Kromme, W. Oostheim and R. J. Wanders, Biochem. Biophys. Res.
Commun., 2000, 270, 1101–1105; (c) T. M. Zabriskie, W. L. Kelly and
X. Liang, J. Am. Chem. Soc., 1997, 119, 6446–6447.
2 (a) F. Couty, Amino Acids, 1999, 16, 297–320; (b) C. Kadouri-Puchot
and S. Comesse, Amino Acids, 2005, 29, 101–130; (c) W. Gu, M. Cueto,
P. R. Jensen, W. Fenical and R. B. Silverman, Tetrahedron, 2007, 63,
6535–6541.
3 (a) Z. Zhao, X. Liu, Z. Shi, L. Danley, B. Huang, R.-T. Jiang and M.-
D. Tsai, J. Am. Chem. Soc., 1996, 118, 3535–3536; (b) T. D. Copeland,
E. M. Wondrak, J. Tozser, M. M. Roberts and S. Oroszlan, Biochem.
Biophys. Res. Commun., 1990, 169, 310–314; (c) G. J. Hanson, J. L.
Vuletich, L. J. Bedell, C. P. Bono, S. C. Howard, J. K. Welply, S. L.
Woulfe and M. L. Zacheis, Bioorg. Med. Chem. Lett., 1996, 6, 1931–
1936; (d) G. T. Wang, B. Lane, S. W. Fesik, A. Petros, J. Luly and G. A.
Krafft, Bioorg. Med. Chem. Lett., 1994, 4, 1161–1166; (e) Y. Tsuda,
M. Cygler, B. F. Gibbs, A. Pedyczak, J. Fe´thie`re, S. Y. Yue and Y.
Konishi, Biochemistry, 1994, 33, 14443–14451; (f) R. T. Shuman, R. B.
Rothenberger, C. S. Campbell, G. F. Smith, D. S. Gifford-Moore, J. W.
Paschal and P. D. Gesellchen, J. Med. Chem., 1995, 38, 4446–4453.
=
=
155.3, 154.9, 153.9 (N–C O, C N), 136.7, 134.6 (CAr.), 128.9,
128.8, 128.5, 128.4, 128.2, 128.0 (CHAr.), 80.7 (CMe3), 68.3, 67.3
(2 × OCH2Ph), 53.9, 52.6 (CH-2), 52.3 (CO2CH3), 46.7 (CH-5),
45.7, 44.9 (CH2-6), 28.3 (CMe3), 27.6 (CH2-4), 25.2 (CH2-3); MS
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