Chemistry Letters Vol.33, No.4 (2004)
469
uct 9 in modest yield (33%).
termined structure and their incorporation into biologically
relevant oligopeptide sequences.19
The acid labile protective groups in 9 were removed with a
mixture of TFA/water (99/1) and the resulting free acid was
condensed with HCl.H–Gly–Val–OMe to give compound 10
in 64% over the two steps. Finally, cleavage of the oNs groups
in 10 afforded 11 in excellent yield.
This work was financially supported by Unilever.
References and Notes
1
2
3
4
A. Giannis and T. Kolter, Angew. Chem., Int. Ed., 32, 1244 (1993).
J. Gante, Angew. Chem., Int. Ed., 33, 1699 (1994).
F. Schweizer, Angew. Chem., Int. Ed., 41, 230 (2002).
S. A. W. Gruner, E. Locardi, E. Lohof, and H. Kessler, Chem. Rev.,
102, 491 (2002).
R. M. J. Liskamp, Recl. Trav. Chim. Pays-Bas, 113, 1 (1994).
J. S. Nowick, E. M. Smith, and M. Pairish, Chem. Soc. Rev., 1996,
401.
K. D.Stigers, M. J. Soth, and J. S. Nowick, Curr. Opin. Chem.
Biol., 3, 714 (1999).
K. Burgess, Acc. Chem. Res., 34, 826 (2001).
T. K. Chakraborty, S. Ghosh, S. Jayaprakash, J. A. R. P. Sharma,
V. Ravikanth, P. V. Diwan, R. Nagaraj, and A. C. Kunwar, J. Org.
Chem., 65, 6441 (2000).
In the NOESY spectrum of 11 (CDCl3) several inter-residue
interactions can be observed, the most significant crosspeaks of
medium intensity corresponding to NH Leu/H2, NH Leu/H3,
NH Gly/H4, and NH Gly/H5 (Figure 1). We conclude that the
second amino acid residues (i.e. Leu and Gly) are in close prox-
imity to the scaffold, indicating a folded structure.
5
6
H-2
H-4
H-5
7
H-6
Phe
β
α
α
Val
Ile
αThr
Thr
H-6'
H-1'
α Gly
H-3
α Ala
α Phe
8
9
β
Leu
H-1
α
ppm
NH Val
7.0
7.2
7.4
7.6
7.8
8.0
8.2
H arom. Phe
10 T. K. Chakraborty, S. Ghosh, M. H. V. Ramana Rao, A. C.
Kunwar, H. Cho, and A. K. Ghosh, Tetrahedron Lett., 41, 10121
(2000).
11 D. E. Koshland, Angew. Chem., Int. Ed., 33, 2375 (1994).
12 J. J. Turner, N. Wilschut, H. S. Overkleeft, W. Klaffke, G. A. van
der Marel, and J. H. van Boom, Tetrahedron Lett., 40, 7039
(1999).
13 J. J. Turner, D. V. Filippov, M. Overhand, G. A. van der Marel,
and J. H. van Boom, Tetrahedron Lett., 42, 5763 (2001).
14 N. Chatani, T. Ikeda, T. Sano, N. Sonoda, H. Kurosawa, Y.
Kawasaki, and S. Murai, J. Org. Chem, 53, 3387 (1988).
15 All new compounds were fully characterised by 1H and 13C NMR
spectroscopy as well as mass spectrometry. Data for compound 11:
1H NMR (600 MHz, CDCl3): ꢁ 8.03 (m, 1H, NH Gly), 7.75 (d, 1H,
NH Leu, JNH;ꢀ ¼ 8:9 Hz), 7.45 (d, 1H, NH Thr, JNH;ꢀ ¼ 7:6 Hz),
7.37 (d, 1H, NH Ile, JNH;ꢀ ¼ 8:3 Hz), 7.32–7.19 (m, 5H, Harom
NH Ile
NH Thr
NH Leu
NH Gly
4.5
4.0
3.5
3.0
2.5 ppm
Figure 1. Expansion of NOESY spectrum of 11 in CDCl3.
Next we investigated the presence of hydrogen bonding in-
teractions that may be responsible for the observed folded con-
formation. The temperature dependence of chemical shifts of
the amide protons in 11 using DMSO-d6 (Figure 2) indicate that
two amides are partially shielded from the solvent and involved
in ‘intermediate’ hydrogen bonding interactions. The amides
concerned, NH Gly (ꢂ2:7 ppb/K) and NH Leu (ꢂ3:3 ppb/K),
both belong to the second amino acid residues (counting from
the scaffold) in their respective strands.
These findings may be explained by the presence of a weak
hydrogen bonding interaction between the NHs of the second
amino acid residues and its nearest scaffold OHs. Such an H-
bonding interaction is supported by the observations made by
Chakraborty and co-workers for molecules with similar struc-
ture.9,10,18 Current research activities are aimed at the futher de-
velopment of carbohydrate derived scaffolds that induce a prede-
Ph), 6.92 (d, 1H, NH Val, JNH;ꢀ ¼ 8:6 Hz), 4.61 (m, 1H, H
ꢀ
Leu), 4.51 (dd, 1H, H Val, J ¼ 4:9 Hz), 4.49 (dd, 1H, H
ꢀ
ꢀ
ꢀ;ꢂ
Ile, J ¼ 5:0 Hz), 4.44 (dd, 1H, H Thr, J ¼ 4:1 Hz), 4.19
ꢀ
ꢀ;ꢂ
ꢀ;ꢂ
0
ꢀ
(m, 1H, H Thr), 4.00 (m, 2H, H and H Gly), 3.95 (m, 1H,
ꢀ
ꢂ
H3), 3.75–3.71 (m, 9H: 2 ꢃ OMe, H2, H4, and H5), 3.34 (dd,
0
1H, H Phe, J ¼ 3:7 Hz, J
¼ 9:9 Hz), 3.26 (q, 1H, H Ala,
ꢀ
ꢀ
ꢀ;ꢂ
ꢀ;ꢂ
J
¼ 6:9 Hz), 3.20 (1/2ABX, 1H, H Phe), 2.75 (1/2ABX,
0 0
ꢀ;ꢂ
ꢂ
1H, H6), 2.66 (ABX, 2H, H1 and H1 , J1;2 ¼ 3:5 Hz, J1 ;2
¼
0
5:2 Hz), 2.66–2.62 (m, 2H, H6 and H Phe), 2.16 (m, 1H, H
0
ꢂ
ꢃ
ꢂ
Val), 1.91 (m, 1H, H Ile), 1.61–1.55 (m, 3H: 2 ꢃ H and H
ꢂ
ꢂ
Leu), 1.44–1.15 (m, 2H, 2 ꢃ H Ile), 1.34 (d, 3H, H Ala), 1.16
ꢃ
ꢂ
(d, 3H, H Thr, J ¼ 6:4 Hz), 0.97–0.90 (m, 18H: 6 ꢃ H Val,
ꢃ
ꢃ
ꢃ;ꢂ
6 ꢃ H Leu, 3 ꢃ H Ile, 3ꢃ H Ile). 13C NMR (150 MHz, CDCl3):
0
ꢃ
ꢁ
ꢁ
ꢁ 176.1, 174.3, 173.4, 172.3, 172.0, 170.2, 169.5 (7 ꢃ C=O),
137.0 (Cq Ph), 129.0, 128.8, 127.1 (CHarom Ph), 83.1, 82.6 (C5/
C2), 73.1 (C4), 72.0 (C3), 66.9 (C Thr), 64.6 (C Phe), 58.3
ꢀ
(C Ala), 57.6 (C Thr), 57.2 (C Val), 56.8 (C Ile), 52.3, 52.2
ꢂ
ꢀ
ꢀ
ꢀ
ꢀ
Val -6.0
ppb/K
(2 ꢃ OMe), 51.1 (C Leu), 50.6 (C6), 50.1 (C1), 42.9 (C Gly),
8.2
8.1
ꢀ
41.7 (C Leu), 39.6 (C Phe), 37.2 (C Ile), 31.1 (C Val), 25.0
ꢀ
ꢂ
(C Ile), 24.8 (C Leu), 23.0 (CH3), 21.8 (CH3), 19.2 (C Ala),
ꢂ
ꢂ
ꢂ
ꢃ
ꢃ
ꢂ
Gly -2.7
ppb/K
8
7.9
7.8
7.7
7.6
7.5
18.9 (CH3), 18.1 (C Thr), 17.7 (CH3), 15.5 (CH3), 11.6 (CH3).
ꢃ
MS (ESI): m=z 894.5 [M + H]þ, 916.5 [M + Na]þ.
16 T. W. Greene and P. G. Wuts, ‘‘Protecting groups in Organic
Synthesis,’’ 3rd ed., Wiley Interscience, New York (1999).
17 The oligopeptide sequences were synthesised according to stand-
ard peptide coupling protocols in solution, using commercially
available amino acid building blocks and EDC, HOBt and
DIPEA.
Leu -3.3
ppb/K
Thr -5.4
ppb/K
290
310
330
350
18 T. K. Chakraborty, S. Jayaprakash, P. V. Diwan, R. Nagaraj, S. R.
B. Jampani, and A. C. Kunwar, J. Am. Chem. Soc., 120, 12962
(1998).
Ile -4.3
ppb/K
Temp/K
Figure 2. Temperature dependence of the chemical shifts of
NHs in 11.
19 M. S. Cubberley and B. L. Iverson, Curr. Opin. Chem. Biol., 6, 650
(2001).
Published on the web (Advance View) March 23, 2004; DOI 10.1246/cl.2004.468