β2,2-aminoxy acids: A new building block for turns and helices

Article abstract of DOI:10.1021/ja026966n

The conformational properties of peptides 1-4 built from 3-aminoxy-2,2-dimethyl-propionic acid, a β^2,2-aminoxy acid, were investigated by NMR spectroscopy and X-ray crystallography. A novel β N-O turn involving a nine-membered-ring intramolecular hydrogen bond between NH_i+2 and CO_i was formed in diamides 1 and 2, which was further stabilized by another six-membered-ring intramolecular hydrogen bond between NH_i+2 and NO_i+1. Triamides 3 and 4 displayed a well-defined helical structure featuring two consecutive β N-O turns. The X-ray structure of 4 revealed that the amide carbonyl group at position i+2 was twisted +65.9° from that at i position, suggesting a novel 1.7₉ helix. Therefore, β^2,2-aminoxy acid can be used as a new building block for turns and helices. Copyright

Full text of DOI:10.1021/ja026966n

Published on Web 08/06/2002
â2,2-Aminoxy Acids: A New Building Block for Turns and Helices
Dan Yang,* Yu-Hui Zhang, and Nian-Yong Zhu
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong
Received May 20, 2002
After the intensive research on â-peptides,1,2 γ-peptides have been
Table 1. Chemical Shifts of the Amide NHs of 1-4 (1.56 mM in
CDCl3 at Room Temperature)
found to form stable and well-defined secondary structures such
as turns, helices, or sheets. Hanessian et al. and Seebach et al.
discovered that γ4-peptides, γ2,4-peptides, or γ2,3,4-peptides formed
stable 2.614 helices with as few as four residues in solution3-8 and
solid state,6 and that other γ2,4-peptides preferred a reverse turn
structure.5,9 Schreiber et al. found both parallel and antiparallel sheet
structures in γ-peptides consisting of R,â-unsaturated γ-amino
acids.10 More recently, Smith and Gellman reported another parallel
sheet structure in γ-peptides of trans-3-aminocyclopentanecarboxy-
lic acid.11 We have been interested in the secondary structures of
peptides composed of â-aminoxy acids, a novel class of γ-amino
acid analogues in which the γ-carbon is replaced with an oxygen.
Here we report â2,2-aminoxy acids, a subclass of â-aminoxy acids
with two side chains on the R-carbon, as a new building block for
turns and helices.
NH (ppm)
NH (ppm)
NH (ppm)
a
b
c
1
7.10 (t)
7.85 (t)
7.82 (d)
7.92 (d)
2
3
4
8.52 (s)
8.55 (s)
10.29 (s)
11.74 (s)
following standard methods of peptide coupling.14 Table 1 sum-
marizes the chemical shifts of the amide protons of 1-4 (1.56 mM
in CDCl3) at room temperature. The N-oxy amide NHb of 3 and
regular amides NHc of 1-3 appeared unusually downfield and
showed little change (∆δ ) 0.02-0.60 ppm) when the solutions
were diluted from 200 to 1.56 mM in CDCl3, or when DMSO-d6
was added gradually to a 5 mM solution of 1-3 in CDCl3.14 In
contrast, the signal of N-oxy amide NHa of 2 was found rather
upfield and changed dramatically (∆δ ) 1.18-1.96 ppm) upon
dilution in CDCl3 or DMSO-d6 addition.14 The H NMR dilution
1
studies could not be performed for triamide 4 because of its poor
solubility in CDCl3. Nevertheless, the chemical shifts of its amide
protons NHb and NHc at 1.56 mM in CDCl3 were even more
downfield than those of 3, while proton Ha showed similar chemical
shift as that of 2. Taken together, these results suggest that amide
NHc in 1-4 and NHb in 3 and 4 form intramolecular hydrogen
bonds, whereas amide NHa in both 2 and 4 is solvent accessible.
The above results also suggested that the size of the amide groups
at both ends has little effect on the formation of intramolecular
hydrogen bonds.
Diamide 2 and triamide 4 turned out to be highly crystalline
compounds. The X-ray structures of both compounds are shown
in Figure 1. Compound 2 adopted a novel â N-O turn structure
characterized by a nine-membered-ring hydrogen bond between Cd
Oi and NHi+2, which was further stabilized by another six-
membered-ring hydrogen bond between NHi+2 and NOi+1. The
N-O bond was anti to the CR-Câ bond with a 172° dihedral angle
NOCâCR.
We previously reported that R-aminoxy acids induced Ν-Ã turn
structures involving a strong eight-membered-ring intramolecular
hydrogen bond,12 and that the homochiral oligomers of D-R-aminoxy
acids adopted a right-handed 1.88 helix consisting of consecutive
N-O turns.13 Compared with R-aminoxy acids, â-aminoxy acids
have an extra carbon atom in the backbones, and thus it is interesting
to investigate whether the intramolecular hydrogen bond between
adjacent residues can be retained.
Figure 1b shows a well-defined helical structure of 4. The helix
was composed of two consecutive nine-membered-ring intramo-
lecular hydrogen bonds, i.e., two â N-O turns. The hydrogen-
bonding distance between NHi+2 and OdCi was 1.93 Å for the
first â N-O turn and 2.29 Å for the second turn. The shorter NH‚
‚‚OdC distance in the first hydrogen bond reflected the higher
acidity of an aminoxy amide NH compared to a normal amide NH.
In both â N-O turns, the N-O bond was anti to the CR-Câ bond
with similar dihedral angle NOCâCR (170° and 174°). The amide
carbonyl group at position i + 2 was twisted +65.9° from that at
i position, suggesting a novel 1.79 helix. Similar to the 1.88 helix
found in peptides of D-R-aminoxy acids,13a the side chains pointed
in the lateral directions of the helix. However, the distance between
R-carbons at i and i + 2 positions of 1.79 helix was longer (7.1 Å)
than that in the 1.88 helix (6.5 Å).
Diamides 1, 2 and triamides 3 and 4, all consisting of 3-aminoxy-
2,2-dimethyl-propionic acid (a â2,2-aminoxy acid), were synthesized
* Corresponding author. E-mail: yangdan@hku.hk.
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J. AM. CHEM. SOC. 2002, 124, 9966-9967
10.1021/ja026966n CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
that form novel â Ν-Ã turns and helices. Given that â-aminoxy
acids have more backbone substitution patterns, it will be interesting
to explore the potential of other â-aminoxy acids as foldamers.
Acknowledgment. This work was supported by The University
of Hong Kong and Hong Kong Research Grants Council. D.Y.
acknowledges the Bristol-Myers Squibb Foundation for an Unre-
stricted Grant in Synthetic Organic Chemistry and the Croucher
Foundation for a Croucher Senior Research Fellowship Award. We
thank Professor Yun-dong Wu and Dr. Shi-Wei Luo for helpful
discussion.
Supporting Information Available: Preparation and characteriza-
tion data for 1-4; 1H NMR dilution data and DMSO-d6 addition data
for 1-3; 2D NOESY spectra for 2 and 4; X-ray structural analysis of
2 and 4, containing tables of atomic coordinates, thermal parameters,
bond lengths, and angles (PDF); X-ray crystallographic file (CIF). This
material is available free of charge via the Internet at http://pubs.acs.
org.
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