4
Tetrahedron
stability of foldamer octomer 34 in methanol was evaluated at
but not at higher oligomer levels in the control of folding
conformation.
different temperature. Within the tested temperature range of 5
to 80 °C, the CD spectra (Figure 6) indicated that temperature
change caused little variation in the CD signature in terms of the
CD peaks’ wavelengths and ellipticity intensities. This suggests
that the foldamer’s folding order of octomer 34 is stable up to 80
Acknowledgments
Financial support was provided partly by NSF (CHE
0515635) and (DGE-0841377). ZH thanks Der-Min Fan
scholarship.
°
C.
The iso-butyric amide capped monomer of bicyclic -amino
acid 35 was synthesized as a tool molecule to investigate amide
conformation preference. Two conformers, determined by NMR
experiments (Figure 7), were observed in ~6/4 ratio favoring the
cis conformer. This is opposite to the observation from the parent
methanopyrrolidine--amino acid 6, which has mainly the trans
form (6:4 trans:cis) for the monomer.11 This subtle difference
resulting from the C6 substitution is attributed to the steric
interaction between the N2 and C6, which slightly favors the cis
conformation by placing the two substituents opposite each other.
The iso-butyric amide capped dipeptide 36 was synthesized.
NMR investigation of the two major conformations of the
internal amide bond of dipeptide 36 were identified in ~4:3 ratio
favoring the trans-36 (Figure 7).
References and notes
1
2
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Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H.
Nature 2000, 404, 565.
(a) Hintermann, T.; Seebach, D. Chimia 1997, 251, 244. (b)
Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H.
J. Am. Chem. Soc. 2002, 124, 7324. (c) Schmitt, M. A.; Weisblum,
B.; Gellman, S. H. J. Am. Chem. Soc. 2007, 129, 417.
Abele, S.; Vogtli, K.; Seebach, D. Helv. Chim. Acta 1999, 82,
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Huck, B. R.; Langenhan, J. M.; Gellman, S. H. Org. Lett. 1999, 1,
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Huck, B. R.; Fisk, J. D.; Guzei, I. A.; Carlson, H. A.; Gellman, S.
H. J. Am. Chem. Soc. 2003, 125, 9035.
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Wittelsberger, A.; Keller, M.; Scarpellino, L.; Patiny, L.; Acha-
Orbea, H.; Mutter, M. Angew. Chem., Int. Ed. 2000, 39, 1111.
Shoulders, M. D.; Raines, R. T. Annu. Rev. Biochem. 2009, 78,
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Caumes, C.; Delsuc, N.; Azza, R. B.; Correia, I.; Chemla, F.;
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1
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0. M. Hosoya, Y. Otani, M. Kawahata, K. Yamaguchi, T. Ohwada,
J. Am. Chem. Soc. 2010, 132, 14780.
1. Krow, G. R.; Liu, N.; Sender, M.; Lin, G.; Centafont, R.; Sonnet,
P. E.; DeBrosse, C.; Ross, C. W.; Carroll, P. J.; Shoulders, M. D.;
Raines, R. T. Org. Lett. 2010, 12, 5438.
1
1
2. Krow, G. R.; Cannon, K. C. Heterocycles 2004, 62, 877.
3. (a) Kwak, Y.; Winkler, J. D. J. Am. Chem. Soc. 2001, 123, 7429.
(b) Winkler, J. D.; Ragains, J. R. Org. Lett. 2006, 8, 4437. (c)
Fitzgelad, M. E.; Winkler, J. D. Synlett. 2009, 4, 562 (d) Krow, G.
R.; Huang, Q.; Lin, G.; Centafont, R. A.; Thomas, A. M.; Gandla,
D.; DeBrosse, C.; Carroll, P. J. J. Org. Chem. 2006, 71, 2090.
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Figure 7. Cis/trans conformation of 35 and 36.
1
2
005, 1751, 119.
In summary, an efficient synthesis of C6-benzyloxylmethy-
Supplementary Material
2
,4-methanopyrrolidine--amino acid methyl ester (16) was
developed. The C6-substituted derivatives and peptide oligomers
up to octamer based on MetPyr--amino acid were prepared. The
uniformity of foldamers with an increase in order for longer
oligomers are largely self-driven with minimum solvent and
temperature effects. C6-Substitution on MetPyr--amino acid
subtly modifies amide cis/trans geometry in monomer and dimer,
Experimental procedures and compound characterizations are
available in the supplementary PDF file.
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