G. Pattenden, T. Thompson / Tetrahedron Letters 43 (2002) 2459–2461
2461
hydrogen cyclopeptide diastereoisomers.10,11 No coales-
cence of signals was observed in the H NMR spectrum
CH2), 3.57 (m, 3H, 3×CH2CHaHbNH), 3.01 (m, 3H,
3×CH2CHaHbNH), 2.47 (m, 3H, HC(CHaHbCONH)3),
2.38 (m, 1H, HC(CHaHb)3), 2.29 (m, 3H, HC(CHaHb)3),
2.11 (m, 3H, 3×NHCHCHaHb), 1.97 (m, 3H, 3×
NHCHCHaHb), 1.69 (m, 6H, 3×CH2); lC (90 MHz,
CDCl3) 172.4 (s), 169.8 (s), 159. 6 (s), 149.2 (s), 123.7 (d),
49.9 (d), 40.7 (t), 38.8 (t), 35.9 (d), 35.3 (t), 24.8 (t);
HRMS (ES) m/z 728.2101; calcd for C31S3N9O6H38 ([M+
H]+): 728.2107.
1
upon heating the mixture to 100°C and the two sets of
amide protons (l 8.42 and l 8.36) were clearly visible at
elevated temperatures. The presence of diastereoisomers
was further reinforced in the 13C NMR spectrum which
showed differing sets of absorptions for the two
cyclopeptides. The spectroscopic data for the cage
cyclopeptides synthesised in this study, by themselves,
did not allow an unambiguous distinction between the
two sets of ‘inside’ and ‘outside’ diastereoisomers, i.e.
10 and 11 and also 17 and 18.12 Further studies are
underway to resolve the stereochemical assignments
and also to investigate the ion-binding and transport
properties of these novel cyclopeptides.
9. Philips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams,
D. R. Org. Lett. 2000, 2, 1165.
10. Data for 17/18: mp 290–291°C (decomp.) (from CHCl3);
[h]2D93 184.4 [c=1.0, CHCl3]; IR (cm−1): 3388, 1742, 1688,
1600; lH (360 MHz, CDCl3) 8.59 (6H, m, 3×NHCH,
3×NHCH), 8.33 (s, 3H, 3×NCꢀCHO), 8.32 (s, 3H, 3×
NCꢀCHO), 5.49–5.42 (m, 9H, 3×NHCH, 3×CHCHaHb,
3×NHCH), 5.24 (dd, 3H, J=11.5, 1.5 Hz, 3×CHCHaHb),
4.01 (dd, 3H, J=11.5, 1.9 Hz, 3×CHCHaHb), 3.93 (dd,
3H, J=11.8, 2.4 Hz, 3×CHCHaHb), 2.43–1.86 (m, 14H,
HC(CH2)3, HC(CH2)3, HC(CH2)3, HC(CH2)3); lC (90
MHz, CDCl3) 171.0 (s), 170.6 (s), 160.1 (s), 159.8 (s),
158.9 (s), 158.8 (s), 142.4 (d), 142.1 (d), 135.1 (s), 135.1
(s), 64.0 (t), 62.2 (t), 48.8 (d), 48.6 (d), 38.2 (t), 37.2 (t),
34.1 (d), 28.4 (d); HRMS (ES) m/z 621.1239; calcd for
C25N6O12H22Na ([M+Na]+): 621.1193.
Acknowledgements
We thank Dr. Luis Castro for his support during this
study and Merck, Sharp and Dohme for financial
assistance.
11. Variable temperature 1H NMR data for 17/18: lH (360
MHz, DMSO-d6, 298 K) 9.00 (s, 3H, 3×NCꢀCHO), 8.97
(s, 3H, 3×NCꢀCHO), 8.38 (d, 6H, J=7.5 Hz, 3×NHCH,
3×NHCH), 5.66 (d, 3H, J=7.4 H, 3×NHCH), 5.60 (d,
3H, J=7.2 Hz, 3×NHCH), 5.17 (d, 3H, J=11.5 Hz,
3×CHCHaHb), 5.00 (d, 3H, J=10.5 Hz, 3×CHCHaHb),
4.09 (d, 3H, J=10.0 Hz, 3×CHCHaHb), 4.01 (d, 3H,
J=11.5 Hz, 3×CHCHaHb), 3.30 (d, 6H, J=8.6 Hz,
References
1. Hamamoto, Y.; Endo, M.; Nakagawa, M.; Nakanishi,
T.; Mizukawa, K. J. Chem. Soc., Chem. Commun. 1983,
323.
2. Admi, V.; Afek, U.; Carmeli, S. J. Nat. Prod. 1996, 59,
396.
3. Michael, J. P.; Pattenden, G. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1.
HC(CH2CO2)3),
2.70
(d,
3H,
J=13.3
Hz,
HC(CHaHbCO2)3), 2.46–2.10 (m, 2H, HC(CH2CO2)3,
HC(CHaHbCO2)3), 2.00 (m, 3H, HC(CHaHbCO2)3); lH
(360 MHz, DMSO-d6, 373 K) 8.71 (s, 3H, 3×NCꢀCHO),
8.67 (s, 3H, 3×NCꢀCHO), 8.42 (m, 3H, 3×NHCH), 8.36
(m, 3H, 3×NHCH), 5.56 (m, 6H, 3×NHCH, 3×NHCH),
5.05 (d, 3H, J=11.4 Hz, 3×CHCHaHb), 4.97 (d, 3H,
J=11.8 Hz, 3×CHCHaHb), 4.17 (d, 3H, J=11.2 Hz,
3×CHCHaHb), 4.12 (d, 3H, J=11.4 Hz, 3×CHCHaHb),
2.68 (m, 9H, HC(CH2CO2)3, HC(CHaHb)3), 2.45 (m, 2H,
HC(CH2CO2)3, HC(CHaHbCO2)3), 2.06 (dd, 3H, J=
14.6, 11.0 Hz, HC(CHaHbCO2)3).
4. Mink, D.; Mecozzi, S.; Rebek, J., Jr. Tetrahedron Lett.
1998, 39, 5709.
5. Pattenden, G.; Thompson, T. J. Chem. Soc., Chem. Com-
mun. 2001, 717.
6. Nasielski, J.; Chao, S. H.; Nasielski-Hinkens, R. Bull.
Soc. Chim. Belg. 1989, 98, 375.
7. Data for 10: mp 273–274°C (decomp.) (from CHCl3–
Et2O); [h]3D01 4.80 (c=0.5, CHCl3); IR (cm−1): 3435, 3400,
2960, 1672, 1549; lH (360 MHz, CDCl3) 8.39 (d, 3H,
J=9.6 Hz, 3×NHCH), 8.07 (s, 3H, 3×NCꢀCHS), 6.69, (t,
3H, J=5.9 Hz, 3×CH2NH), 5.59 (m, 3H, 3×
NHCHCH2), 3.42 (m, 3H, 3×CH2CHaHbNH), 3.19 (m,
3H, 3×CH2CHaHbNH), 2.61 (m, 1H, HC(CH2CONH)3),
2.39 (m, 6H, HC(CH2CONH)3), 2.08 (m, 3H, 3×
NHCHCHaHb), 1.92–1.71 (9H, m, 3×NHCHCHaHb, 3×
CH2); lC (90 MHz, CDCl3) 171.8 (s), 169.9 (s), 159.5 (s),
149.2 (s), 123.4 (d), 49.2 (d), 39.3 (t), 38.4 (t), 36.4 (t),
31.5 (d), 26.1(t); HRMS (ES) m/z 728.2108; calcd for
C31S3N9O6H38 ([M+H]+): 728.2107.
12. In an attempt to resolve these issues, we carried out
energy minimisation and Monte Carlo conformational
searches on the diastereoisomers 10/11 and 17/18 using
the MacroModel 5.5 implementation of the AMBER*
force field. These data could be interpreted, based on the
assumption that the observed ratios of diastereomeric
products reflected the relative ease of the final cyclisation
steps, to indicate that structures 11 and 17 would be the
major products resulting from the cyclooligomerisations
of 9 and 16, respectively, i.e. the minimum energy con-
formers were calculated to have the following values: 10:
E=−67.0 kJ mol−1, 11: E=−77.4 kJ mol−1, 17: E=57.82
8. Data for 11: mp 252–253°C (decomp.) (from CHCl3–
Et2O); [h]3D00 −44.0 [c=0.5, CHCl3]; IR (cm−1): 3402,
2927, 2855, 1729, 1666, 1549; lH (360 MHz, CDCl3) 8.49
(d, 3H, J=9.1 Hz, 3×NHCH), 8.11 (s, 3H, 3×NCꢀCHS),
6.84 (br m, 3H, 3×CH2NH), 5.70 (m, 3H, 3×NHCH-
kJ mol−1, 18: E=−122.62 kJ mol−1
.