Ion Pairing in Flexible Zwitterions
(CH2), 79.8 (Cq), 171.9 (Cq); FT-IR ν˜ (thin film, NaCl) [cm-1] )
[m], 1300 [s], 1243 [s], 1152 [s], 1050 [w], 843.7 [m], 789 [w],
757 [w], 602 [w]; HR-MS (ESI pos) m/z ) 460.217 (calculated
for M + Na+: 460.2172).
3375 [m], 2928 [w], 1723 [s], 1454 [s], 1369 [s], 848 [m].
1
5e: yield: 99%; H NMR (400 MHz, CDCl3) δ ) 1.23-1.28
(m, 2H, CH2), 1.35 (s, 9H, CH3), 1.37-1.41 (m, 2H, CH2), 1.47-
1.55 (m, 2H, CH2), 2.12 (t, 2H, J ) 7.44, CH2), 2.60 (t, 2H, J )
6.69, CH2); 13C NMR (100 MHz, CDCl3) δ ) 24.7 (CH2), 26.2
(CH2), 27.9 (CH3), 33.2 (CH2), 35.4 (CH2), 41.8 (CH2), 79.8 (Cq),
171.9 (Cq); FT-IR ν˜ (thin film, NaCl) [cm-1] ) 3378 [m], 2931
[w], 1729 [s], 1457 [s], 1367 [s], 848 [m].
6d (fully protected): yield: 83%; Rf ) 0.62 (SiO2, ethyl acetate/
cyclohexane ) 8/2); mp: 99 °C; 1H NMR (400 MHz, DMSO-d6)
δ ) 1.38 (s, 9H, CH3), 1.46 (s, 9H, CH3), 1.50-1.54 (m, 4H, CH2),
2.22 (t, 2H, J ) 6.9, CH2,), 3.22 (dt, 2H, J ) 5.68, J ) 5.84, CH2),
6.76 (m, 2H, CH), 8.30 (t, 1H, J ) 5.16, NH), 8.54 (br s, 1H,
NH), 9.31 (br s, 1H, NH), 10.83 (br s, 1H, NH), 11.08 (br s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6) δ ) 22.1 (CH2), 27.8 (CH3),
28.5 (CH2), 34.4 (CH2), 79.4 (Cq), 111.6 (CH), 129.5 (Cq), 159.5
(Cq), 172.2 (Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3386 [m], 3270
[m.], 2976 [m], 2932 [m], 1730 [s], 1632 [s], 1552 [s], 1467 [s],
1365 [s], 1298 [m], 1236 [s], 1151 [s], 835 [m], 786 [w], 755 [w],
601 [w]; HR-MS (ESI pos) m/z ) 474.233 (calculated for M +
Na+: 474.2328).
6d (fully protected, methyl ester): yield: 66%; Rf ) 0.51 (SiO2,
ethyl acetate/ cyclohexane ) 8/2); mp: 73 °C; 1H NMR (400 MHz,
DMSO-d6) δ ) 1.46 (s, 9H, CH3), 1.50-1.61 (m, 4H, CH2), 2.34
(t, 2H, J ) 7.32, CH2,), 3.23 (dt, 2H, J ) 5.96, J ) 6.16, CH2),
3.58 (s, 3H, CH3), 6.77 (s, 1H, CH), 6.80 (s, 1H, CH), 8.31 (t, 1H,
J ) 5.56, NH), 8.56 (br s, 1H, NH), 9.31 (br s, 1H, NH), 10.83 (br
s, 1H, NH), 11.29 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6) δ ) 22. (CH2), 27.8 (CH3), 28.6 (CH2), 33.0 (CH2), 38.2 (CH2),
51.2 (CH3), 80.9 (Cq), 111.7 (CH), 113.8 (CH), 129.6 (Cq), 158.5
(Cq), 159.6 (Cq), 173.3 (Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3450
[s], 3402 [s], 3297 [s], 2977 [m], 2949 [m], 2877 [m], 1736 [s],
1630 [s], 1559 [s], 1510 [s], 1469 [s], 1371 [m], 1346 [s], 1292
[s], 1232 [s], 1045 [m], 838 [m], 785 [m], 753 [m], 597 [m]; HR-
MS (ESI pos) m/z ) 410.204 (calculated for M + H+: 410.2039).
6e (fully protected): yield: 90%; Rf ) 0.57 (SiO2, hexane/ethyl
acetate ) 3/2); mp: 100 °C; 1H NMR (400 MHz, DMSO-d6) δ )
1.27-1.33 (m, 2H, CH2).1.37 (s, 9H, CH3), 1.46 (s, 9H, CH3),
1.47-1.55 (m, 4H, CH2), 2.18 (t, 2H, J ) 7.32, CH2,), 3.21 (dt,
2H, J ) 6.04, J ) 6.72, CH2), 6.75 (s, 1H, CH), 6.81 (s, 1H, CH),
8.28 (t, 1H, J ) 5.44, NH), 8.56 (br s, 1H, NH), 9.31 (br s, 1H,
NH), 10.84 (br s, 1H, NH), 11.26 (br s, 1H, NH); 13C NMR (100
MHz, DMSO-d6) δ ) 24.3 (CH2), 25.8 (CH2), 27.7 (CH3), 28.8
(CH2), 34.7 (CH2), 38.4 (CH2), 79.3 (Cq), 111.5 (CH), 113.5 (CH),
124.1 (Cq), 129.7 (Cq), 158.4 (Cq), 159.4 (Cq), 172.2 (Cq); FT-
IR ν˜ (KBr-pellet) [cm-1] ) 3400 [m], 3320 [m], 2980 [m], 1730
[s], 1550 [s], 1469 [s], 1393 [s], 1300 [m], 1243 [s], 1152 [s], 1050
[w], 843.7 [m], 789 [w], 760 [w], 602 [w]; HR-MS (ESI pos) m/z
) 460.217 (calculated for M + Na+: 460.2172).
Methyl 5-Aminopentanoate Hydrochloride (11d). A suspen-
sion of 5-aminovaleric acid (4.00 g, 34.1 mmol, 1 equiv) in 2,2-
dimethoxypropane (106.3 g, 1.02 mol, 30 equiv) was stirred
vigorous while adding concentrated hydrochloric acid (17 mL). The
solution was stirred for further 24 h at room temperature. After
that, the dark red solution was concentrated in vacuo and the
resulting brown solid was treated with diethyl ether. The precipitat-
ing solid was filtered off, washed several times with diethyl ether
and recrystallized from ethanol/ethyl acetate (60 mL, v/v 95/5),
providing the product as a white crystalline solid (3.71 g, 65%).
mp: 142 °C; 1H NMR (400 MHz, CDCl3) δ ) 1.73-1.86 (m, 4H,
CH2), 2.35-2.40 (m, 2H, CH2), 2.99-3.11 (m, 2H, CH2), 3.67 (s,
3H, CH3), 8.23 (s, 3H, NH3+); 13C NMR (100 MHz, CDCl3) δ )
21.9 (CH2), 27.1 (CH2), 33.3 (CH2), 39.8 (CH2), 51.9 (CH3), 173.8
(Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3047 [m], 2948 [m], 2876
[m], 1735 [s], 1588 [m], 1566 [m], 1509 [m], 1441 [m], 1345 [m],
1271 [m], 1198 [s], 745 [w]; HR-MS (ESI pos) m/z ) 132.10175
(calculated for M+: 132.1024).
General Procedure for the Synthesis of the Fully Protected
Zwitterions of 6. A mixture of the Boc-protected guanidiniocar-
bonylpyrrole compound 4 (1 equiv), PyBOP (1 equiv), and
N-methylmorpholine (2 mL) was stirred in DMF (25 mL) at r.t for
15 min. The amino ester (1.2 equiv) was added to the solution and
then stirred for 12 h at room temperature. The resulting brown
solution was hydrolyzed with water (50 mL), and the precipitate
was filtered and dried in the desiccator over phosphorus pentoxide.
The resulting solid was purified by column chromatography,
yielding a colorless crystalline powder.
6a (fully protected): yield: 95%; Rf ) 0.25 (SiO2, cyclohexane/
acetone ) 3/2); mp: 157 °C; 1H NMR (400 MHz, DMSO-d6) δ )
1.40 (s, 9H, CH3), 1.46 (s, 9H, CH3), 3.88 (d, 2H, J ) 5.8, CH2),
6.81 (br s, 2H, CH), 8.56 (br s, 1H, NH), 8.71 (t, 1H, J ) 5.8,
NH), 9.32 (br s, 1H, NH), 10.83 (br s, 1H, NH), 11.20 (br s, 1H,
NH); 13C NMR (100 MHz, DMSO-d6) δ ) 26.3 (CH3), 27.7 (CH3),
41.3 (CH2), 80.7 (Cq), 112.0 (CH), 158.3 (Cq), 160.0 (Cq), 169.0
(Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3401 [m], 3295 [m], 2978
[w], 2927 [w], 1722 [s], 1637 [s], 1544 [m], 1471 [m], 1369 [m],
1288 [s], 1236 [s], 1151 [s], 843 [w]; HR-MS (ESI pos) m/z )
432.185 (calculated for M + Na+: 432.1859).
The fully protected zwitterions were deprotected and converted
into their picrate salts according to the general procedures detailed
in the Supporting Information.
1
6a (picrate salt): mp: 243-244 °C (decomp); H NMR (400
6b (fully protected): yield: 85%; Rf ) 0.43 (SiO2, cyclohexane/
acetone ) 3/2); mp: 98 °C; 1H NMR (400 MHz, DMSO-d6) δ )
1.39 (s, 9H, CH3), 1.46 (s, 9H, CH3), 2.46 (t, 2H, J ) 6.84 Hz,
CH2), 3.42 (dt, 2H, J ) 5.8, J ) 6.8, CH2), 6.74-6.81 (m, 2H,
CH), 8.40 (t, 1H, J ) 5.4, NH), 8.56 (br s, 1H, NH), 9.31 (br s,
1H, NH), 10.83 (br s, 1H, NH), 11.24 (s, 1H, NH); 13C NMR (100
MHz, DMSO-d6) δ ) 27.7 (CH3), 35.0 (CH2), 40.2 (CH2), 79.9
(Cq), 111.7 (CH), 159.6 (Cq), 170.6 (Cq); FT-IR ν˜ (KBr-pellet)
[cm-1] ) 3387 [w], 2921 [w], 1727 [m], 1634 [s], 1554 [s], 1301
[s], 1243 [s], 844 [m]; HR-MS (ESI pos) m/z ) 446.201 (calculated
for M + Na+: 446.2015).
MHz, DMSO-d6) δ ) 3.94 (d, 2H, J ) 5.8, CH2), 6.91-6.93 (m,
1H, CH), 7.03-7.05 (m, 1H, CH), 8.16 (br s, 4H, NH), 8.59 (s,
2H, CH), 8.82 (t, 1H, J ) 5.8, NH), 10.95 (br s, 1H, NH), 12.47
(br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ ) 40.7 (CH2),
112.6 (CH), 115.5 (CH), 124.3 (Cq), 125.2 (CH), 125.7 (Cq), 132.2
(Cq), 142.0 (Cq), 155.0 (Cq), 159.4 (Cq), 159.5 (Cq), 161.0 (Cq),
171.1 (Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3404 [m], 3325 [m],
3168 [m], 1703 [s], 1611 [s], 1557 [m], 1427 [w], 1365 [m], 1337
[s], 1268 [s], 1082 [w], 911[w], 816 [w], 763 [w]; HR-MS (ESI
pos) m/z ) 254.089 (calculated for M+: 254.0889).
1
6c (fully protected): yield: 83%; Rf ) 0.57 (SiO2, hexane/ethyl
6b (picrate salt): mp: 250-251 °C (decomp); H NMR (400
1
acetate ) 3/2); mp: 100-103 °C; H NMR (400 MHz, DMSO-
MHz, DMSO-d6) δ ) 3.43 (dt, J ) 6.3 Hz, 2H, CH2), 6.86-6.88
(m, 1H, CH), 7.01-7.03 (m, 1H, CH), 8.17 (br s, 4H, NH), 8.55
(t, J ) 11.6, 1H, NH), 8.59 (s, 2H, CH), 10.95 (br s, 1H, NH),
12.43 (br s, 1H, NH); one CH2 peak is superposed by the solvent
signal; 13C NMR (100 MHz, DMSO-d6) δ ) 33.7 (CH2), 35.1
(CH2), 112.5 (CH), 115.4 (CH), 125.2 (CH), 125.4 (Cq), 132.6 (Cq),
141.9 (Cq), 154.8 (Cq), 159.1 (Cq), 159.4 (Cq), 160.8 (Cq), 172.8
(Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3400 [m], 3325 [m], 3168
[m], 1705 [s], 1611 [s], 1557 [m], 1427 [w], 1370 [m], 1335 [s],
d6) δ ) 1.33 (s, 9H, CH3), 1.34 (s, 9H, CH3), 1.62-1.69 (m, 2H,
CH2), 2.19 (t, 2H, J ) 7.5, CH2,), 3.15-3.20 (m, 2H, CH2), 6.71
(s, 1H, CH), 6.75 (s, 1H, CH), 8.25 (t, 1H, J ) 5.5, NH), 8.50 (br
s, 1H, NH), 9.25 (br s, 1H, NH), 10.78 (br s, 1H, NH), 11.22 (br
s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ ) 25.1 (CH2), 28.1
(CH3), 32.7 (CH2), 38.4 (CH2), 79.9 (Cq), 112.0 (CH), 158.8 (Cq),
160.0 (Cq), 172.3 (Cq); FT-IR ν˜ (KBr-pellet) [cm-1] ) 3385 [m],
3320 [br. m.], 2979 [m], 1728 [s], 1556 [s],1469 [s], 1393[s], 1369
J. Org. Chem, Vol. 72, No. 16, 2007 6169