Parallel sheet structure in cyclopropane γ-peptides stabilized by C-H...O hydrogen bonds

Article abstract of DOI:10.1039/b611882h

A three-residue trans-cyclopropane γ-peptide adopts an infinite parallel sheet structure in the solid state stabilized by intermolecular C-H...O hydrogen bonds, as demonstrated by single crystal X-ray diffraction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b611882h

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Parallel sheet structure in cyclopropane c-peptides stabilized by
…
C–H O hydrogen bonds{
M. Khurram N. Qureshi and Martin D. Smith*
Received (in Cambridge, UK) 21st August 2006, Accepted 24th October 2006
First published as an Advance Article on the web 6th November 2006
DOI: 10.1039/b611882h
A three-residue trans-cyclopropane c-peptide adopts an infinite
parallel sheet structure in the solid state stabilized by
…
intermolecular C–H O hydrogen bonds, as demonstrated by
single crystal X-ray diffraction.
Hydrogen bonding is ubiquitous in biological systems; its role
encompasses the reactivity and specificity of enzymatic reactions,
the stability of proteins, and the formation and stabilization of
secondary structural elements.1 Although the factors influencing
the folding of proteins are manifold, hydrogen bonding between
NH and CLO functional groups plays a pivotal role. The design of
non-natural oligomeric species that emulate protein-like folding
into secondary structural elements relies on an understanding and
2
…
manipulation of these NH CO hydrogen bonding patterns. This
has been elegantly demonstrated in b- and c-amino acid
derivatives3 that adopt specific helix4 and sheet conformations.5
…
The role of other hydrogen bonding interactions, such as C–H
O
hydrogen bonds6 has been recognised in proteins,7 and in
particular, sheets,8 but there are few examples of the exploitation
of this interaction in the development of novel folding backbones.9
As part of a programme investigating the factors that affect the
preference for inter- rather than intra-molecular hydrogen bonding
in short c-peptides, we have designed a simple c-amino acid
derivative 1 with a cyclopropane ring constraint in the backbone
and examined the conformation of simple oligomeric species 2
(Fig. 1).
Recrystallization of a trimeric derivative of 1 from methanol
and chloroform provided crystals of sufficient quality for X-ray
diffraction; the structure of this compound 3 is pictured in Fig. 2A.
Examination of the single crystal X-ray data{ demonstrates that
the trimeric c-peptide 3 adopts an extended conformation, and
self-assembles into an infinite sheet structure through an
intermolecular hydrogen bond network in which the amide N–H
protons and the C–H bond on the cyclopropane adjacent to the
amide group function as hydrogen bond donors (Fig. 2B).10 This
Fig. 1 c-Amino acid building block and oligomeric derivatives.
Fig. 2 A, Parallel sheet structure (H-bonds in red); B, X-ray structure of
trimer 3 showing arrangement of strands in an infinite hydrogen bonded
parallel sheet (the cyclopropane ring of residue C is disordered over two
sites but for clarity only one of the disordered groups has been depicted);
C, view of sheet unit from C to N terminus; D, view of sheet unit from N
to C terminus; E, crystal packing. (H-bonds are in yellow throughout.)
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: mds44@cam.ac.uk;
Fax: +44 1223 336362; Tel: +44 1223 336511
{ Electronic supplementary information (ESI) available: Full experimental
details and data. See DOI: 10.1039/b611882h
5006 | Chem. Commun., 2006, 5006–5008
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bifurcated hydrogen bonding pattern—when one oxygen lone pair
interacts with an amidic NH proton, and another with a CaH
proton11—has been observed in adjacent peptide strands in
b-sheets. The planarity of the hydrogen bonding interaction
stabilizing the sheet structure can be seen in Fig. 2C and Fig. 2D;
there is little elevation from the amide plane to the donor group.
…
Although the strength of the CH O interaction in proteins is not
conclusively known, a series of theroretical studies has suggested
that it may play a significant role in determining both protein
conformation12 and stability.13 The close CH O contacts in 3
…
Scheme 1 Reagents and conditions: (i) (iPrO)2POCH2CO2 Pr, NaH,
i
involve hydrogen atoms attached to the a-position of the peptide
backbone that are also a component of the cyclopropane. The
enhanced hydrogen bonding capabilities of this functional group
may be ascribed to the electron-withdrawing carbonyl group
acting in concert with the increased acidity of the cyclopropane
system (relative to an acylic hydrocarbon).14 Crystal packing in the
trimer 3 (Fig. 2E) clearly shows the two molecules in the unit cell
and illustrates the infinite sheet structure. This also serves to
demonstrate how substitution adjacent to the amino group could
affect the overall structure. In general, angle and distance criteria
are used to classify close heteroatom contacts as hydrogen bonds,15
i
toluene, PrOH (cat.), 60 to 90 uC; (ii) H2, Pd/C, EtOH; (iii) MsCl,
Et3N, CH2Cl2; (iv) NaN3, DMF, 90 uC.
dependent on the reaction temperature,20 and it was found that
heating at 60 uC for 2 h led to consumption of the epoxide starting
material (presumably to give an intermediate phosphonate) and
subsequent heating to 90 uC afforded the trans-cyclopropane 5.
Debenzylation was achieved by hydrogenolysis with palladium on
carbon in ethanol to give a primary alcohol (98% yield) that could
be converted to mesylate 6 in 90% yield by treatment with
methanesulfonyl chloride in the presence of triethylamine.
Subsequent dispacement of this sulfonate ester by sodium azide
in DMF at 90 uC afforded the c-amino acid derivative 1 in 64%
overall yield from cyclopropane 5. In this fashion, multigramme
quantities of enantioenriched 1 can be prepared in 60% overall
yield in four steps from (S)-benzyl glycidol.
…
though there are examples of CH O hydrogen bonds that do not
satisfy these demands.16 High resolution protein structures have
…
been demonstrated to contain b-sheet regions with short CH
…
O
distances, and in these examples, the average CH O distances
…
8
and CH O angles are 3.29 s and 143u respectively. The values
for the peptide 3 are presented in Table 1.
These show a remarkably close correspondence to the average
values in proteins and are consistent with the similarity of these
interactions to those observed in nature. b-Peptides containing
cyclopropanes have been demonstrated to fold into a ribbon-type
arrangement,17 though the geminal nature of the substitution in
these materials precludes the cyclopropane from acting as a
hydrogen bond donor.
An iterative approach was adopted for the generation of
oligomeric derivatives, and this necessitated the formation of
amino and carboxylate components. With this in mind, isopropyl
ester 1 was converted to its respective acid 7 by treatment with
aqueous sodium hydroxide followed by protonation with 3N HCl.
Hydrogenation of azide 1 with hydrogen in the presence of
palladium black gave amine 8, which was characterized as an
N-acyl derivative.21 A range of peptide coupling protocols was
investigated for the formation of the dimeric derivative 9
(Scheme 2) but it was found that coupling of fragments 7 and 8
with TBTU and Et3N in a CH2Cl2–DMF mixture was most
effective, and afforded compound 9 in 73% yield. The formation of
a trimeric derivative was inefficient using diimide reagents, and it
was more useful to generate pentafluorophenyl ester 10 (72% yield
from the ester 9) prior to coupling with the amine 8; this afforded
the trimeric derivative 3 in 80% yield. The oligomer 3 is sparingly
soluble in non-polar solvents such as chloroform (at concentra-
tions below 15 mM), forming gel-like structures at higher
The synthesis of oligomeric materials such as 2 requires efficient
access to enantiopure c-peptide building blocks on a multigramme
scale. The key step in the generation of the ring-constrained
backbone of the c-peptide is a Wadsworth–Emmons cyclopropa-
nation18 (Scheme 1). Treatment of commercially available
(S)-benzyl glycidol 4 with triisopropylphosphonoacetate and
sodium hydride in the presence of catalytic isopropyl alcohol gave
exclusively trans-cyclopropane 5 (as confirmed by nOe studies) in
92% yield on 10 g scale. It has been demonstrated that this
transformation proceeds with inversion of configuration at the
epoxide stereocentre.19,20 The efficiency of this transformation is
Table 1 Interstrand distances (s) and hydrogen bond angles (u)a
…
D (CH O)
…
D (NH O)
…
h (CH O)
…
h (NH O)
…
d (CH O)
…
d (NH O)
Residue
A
B
C
a
3.3
3.2
3.2
—
2.9
2.9
143
142
142
—
160
165
2.3
2.3
2.3
—
2.0
2.0
Residues are labelled alphabetically from the N to the C terminus. Measurements are defined according to the donor group on the
appropriate residue. Angles and distances are defined below:
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Chem. Commun., 2006, 5006–5008 | 5007

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data. CCDC 617972. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b611882h
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(ii) H2 (g), Pd black, EtOH; (iii) TBTU, Et3N, CH2Cl2–DMF (2 : 1 v/v),
1 equiv. of 7; (iv) pentafluorophenol, EDCI, CH2Cl2, sonication; (v)
HOBt, CH2Cl2, Na2CO3, 1 equiv. of 8.
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concentrations, presumably due to the formation of extended sheet
arrangements and aggregation; however, it readily dissolves in
more polar solvent mixtures, such as chloroform–methanol (9 : 1)
or DMSO. At concentrations of less than 15 mM in CDCl3 there
is no evidence of inter- or intra-molecular hydrogen bonding, on
the basis of the chemical shifts of the amide protons of 3.{
Elegant syntheses of c-substituted variants of 1 have been
recently reported,22 and materials such as these may prove useful
in further design iterations based on this backbone. The sheet
structure of trimer 3 offers a glimpse of the potential of such
supramolecular building blocks,23 and suggests that this bifurcated
hydrogen bonding motif may be useful in the generation of
catalytic molecules24 and higher order structures.
15 T. Steiner, Angew. Chem., Int. Ed., 2002, 41, 48.
The authors would like to thank Dr John Davies (University of
Cambridge) for X-ray crystallography, the EPSRC for financial
assistance towards the purchase of a Nonius CCD diffractometer,
the Pakistani HEC (to M. K. N. Q.), the Royal Society for a URF
(to M. D. S.), the EPSRC National Mass Spectrometry Service
(Swansea) and Dr D. J. Fox for helpful discussions.
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21 The free amine is prone to uncontrolled intermolecular polymerization if
stored neat.
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Notes and references
{ Crystal data for 9: C18H27N5O4, M = 377.45, monoclinic, P21, a =
4.8023(1), b = 8.6693(2), c = 24.1050(5) s, b = 93.793(2)u, V =
1001.36(4) s3, Z = 2, m = 0.090 mm21, F(000) = 404, T = 220(2) K. Of
8057 reflections collected, 2142 were unique (Rint = 0.033), F2 refinement:
R1 = 0.045, wR2 = 0.107 [I . 2s(I)], and R1 = 0.048, wR2 = 0.111 on all
5008 | Chem. Commun., 2006, 5006–5008
This journal is ß The Royal Society of Chemistry 2006