Controlling the sign and magnitude of screw-sense preference from the C-terminus of an achiral helical foldamer

Article abstract of DOI:10.1039/c4cc03261f

The global screw-sense preference of an achiral helical oligomer may be controlled by a single chiral monomer located at one terminus. Remarkably, maximal control is induced in oligomers of the achiral quaternary amino acid Aib by a single C-terminal alaninamide residue, probably because the Ala side chain, though small, is compatible with a 3₁₀ helical conformation. The presence or absence of a C-terminal hydrogen bond donor determines the screw sense of the entire oligomer. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03261f

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Controlling the sign and magnitude
of screw-sense preference from the
C-terminus of an achiral helical foldamer†
Cite this: Chem. Commun., 2014,
50, 7949
Received 1st May 2014,
Accepted 5th June 2014
Bryden A. F. Le Bailly and Jonathan Clayden*
DOI: 10.1039/c4cc03261f
www.rsc.org/chemcomm
The global screw-sense preference of an achiral helical oligomer may be
We now report a quantitative analysis of the role played by a
controlled by a single chiral monomer located at one terminus. Remark- chiral C-terminal residue in determining the global screw-sense
ably, maximal control is induced in oligomers of the achiral quaternary preference of a series of otherwise achiral Aib-based oligomers 3.
amino acid Aib by a single C-terminal alaninamide residue, probably The compounds in question were synthesised by ligating a range of
because the Ala side chain, though small, is compatible with a 310 helical amino acid derivatives H–Xaa–Y (esters Y = OR or amides Y = NHR or
conformation. The presence or absence of a C-terminal hydrogen bond NR2) to the C terminus of an Aib pentamer 2, as shown in Scheme 1.
donor determines the screw sense of the entire oligomer.
Derivatives of tertiary amino acids (H–Xaatert–Y) coupled cleanly
using the coupling agent EDC in the presence of HOBt. Derivatives
of quaternary amino acids (H–Xaaquat–Y) failed to couple under
these conditions, but nonetheless cleanly opened the azlactone
derivative of 2 (generated using EDC) on reflux in acetonitrile.
In order to quantify the screw-sense preference induced by the
C-terminal residues, the N-terminal Aib residue of the pentamer 2
was isotopically labelled in an enantioselective manner with 13C.
The required protected amino acid R-1 was synthesised from L-Ala
by a method10 that enriches the 13C abundance in the pro-R methyl
group to ca. 80% and the pro-S methyl group to ca. 20%.
The adoption of well-defined conformations is a characteristic
feature of many classes of biomolecules, and understanding the
encoding of conformational features within the primary structure
of proteins is an important challenge.1 Foldamers are synthetic
oligomers and polymers that likewise adopt well-defined conforma-
tions,2 and their utility depends on using simple structural features
(dipole orientation, hydrogen bonding ability, stereochemical
configuration) to induce global conformational, and hence ultimately
functional, consequences.3 We4 and others5,6 have shown that
helical oligomers containing the achiral quaternary amino acid
Aib (a-aminoisobutyric acid)7 adopt preferentially a left- or a
right-handed4a global screw sense as a result of the local stereo-
chemical influence of a chiral N-terminal amino acid residue,4a–j,5a
a chiral diol bound to an N-terminal boronate binding site,4k or a
chiral carboxylic acid ion-paired with an N-terminal amino group.5b
These N-terminal controllers of global conformation function by
providing appropriately orientated hydrogen-bond acceptors that
organise the N-terminal NH groups of the overall 310 helical
structure7 of the oligomer into a left- or a right-handed b-turn.8
Little is known about the propensity of achiral peptide helices
to have their screw sense induced from the C terminus. Chiral
C-terminal residues induce some degree of screw-sense preference
in short achiral helices,5c,6 but a comparison9 between an N- and a
C-terminal controller suggested that C-terminal control was sub-
ordinate to N-terminal control.
The 13C NMR spectrum of each oligomer 3 was acquired at
+23 1C in CD3OD, a solvent in which the NMR spectra of Aib
oligomers show no concentration-dependent effects.11 The chemical
shift separation Ddfast between the minor and major 13C NMR
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL,
UK. E-mail: clayden@man.ac.uk
† Electronic supplementary information (ESI) available: Full experimental details
and spectroscopic information. CCDC 994389. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c4cc03261f
Scheme 1 Synthesis of the 13C labelled oligomers 3.
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Table 1 Conformational preferences in Aib oligomers 3 carrying C-terminal controllers Xaa-Y
Entry
Compound
Residue Xaa
R1
R2
Y
Ddfasta/ppb
|Ddslow|b/ppb
h.e.c/%
h.r.d
1
2
3-Ala-NHt-Bu
3-AlaNHMe
Ala
Ala
Me
Me
H
H
NHt-Bu
NHMe
+1807
+1883
2415
—
+75
+78
88 : 12
89 : 11
3
3-Ala-N(CH2)4
Ala
Me
H
À800
—
À33
33 : 67
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3-Abu-NHt-Bu
3-Ser(Ot-Bu) f-NHt-Bu
3-Pro-NHt-Bu
3-Phe-NHt-Bu
3-Phe-NHTs
3-Val-NHt-Bu
3-Tle-NHt-Bu
3-aMv-NHt-Bu
3-aMv2-NHt-Bu
3-Ala-Ot-Bu
3-Phe-Ot-Bu
3-Val-Ot-Bu
3-Tle-Ot-Bu
3-aMv-Ot-Bu
Abue
Et
H
H
H
H
H
H
H
Me
Me
H
H
H
H
Me
NHt-Bu
NHt-Bu
NHt-Bu
NHt-Bu
NHTs
NHt-Bu
NHt-Bu
NHt-Bu
NHt-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
+1857
+668
—
—
—
2410
—
2420
—
—
—
—
+77
+28
+16
+70
+36
+71
+65
+70
+80
À55
À34
À46
À35
À43
88 : 12
64 : 36
58 : 42
85 : 15
68 : 32
86 : 14
83 : 17
85 : 15
90 : 10
22 : 78
33 : 67
27 : 73
32 : 68
28 : 72
Ser(O-t-Bu) f
Pro
CH2Ot-Bu
–(CH2)3CH–
Bn
Bn
i-Pr
t-Bu
i-Pr
i-Pr
Me
Bn
+376
Phe
Phe
Val
tert-Leu
a-MeVal
a-MeVal2
Ala
Phe
Val
+1676
+1057
+1726
+1575
+1710
+1943
À1336
À816
À1112
À838
À1037
2427
2441
—
i-Pr
t-Bu
i-Pr
tert-Leu
a-MeVal
—
a
minor
fast
major
fast
b
Chemical shift separation between minor and major labelled peaks [d
À d
] in the 13C NMR spectrum in CD3OD at +23 1C. Modulus of
the chemical shift separation between labelled peaks in the 13C NMR spectrum in CD3OD at À40 1C. Where no value for Ddslow was measured, an
c
average value of Ddslow = 2420 was employed. Helical excess = Ddfast/|Ddslow| interpreted as {[P] À [M]}/{[P] + [M]}. Positive values indicate right-
d
e
f
handed screw sense predominates. Helical ratio = [P] : [M]. Abu = (S)-(+)-2-aminobutyric acid = L-(+)-butyrine. Serine side-chain protected as its
t-butyl ether.
signals of each oligomer is reported in Table 1. For a number of the slowly inverting helix. Thus, at fast exchange, the value of Ddfast
oligomers, the 13C NMR spectrum was also acquired at À70 1C in is dependent only on the equilibrium ratio of the M and P
CD3OD. Variable temperature NMR over the range À70 to +40 1C helices,4c,e and the value Ddfast/|Ddslow| may be interpreted as helical
(Fig. 1b) showed that spectra at the upper and lower limits of this excess (h.e.), as reported in Table 1.
range provided suitable values for chemical shift separation at
The sign of the helical excess was deduced from the location of
and the values the major signal arising from the 13C-labelled Aib residue. The pro-R
methyl group of an Aib residue resonates upfield of the pro-S methyl
4c
slow and fast exchange Ddslow and Ddfast
,
obtained at À70 1C for Ddslow are also reported in Table 1.
The measured values of Ddslow are constant within 1% across group in a right handed (P) 310 helix and downfield in a left handed
the compounds studied, consistent with the assumption4c that the (M) 310 helix.4d,12 Positive values of Ddfast thus correspond to
spatial separation between the 13C NMR reporter and the chiral P helicity, a deduction confirmed by circular dichroism (Fig. 1a):
C-terminal residue ensures that the anisochronicity of the 13C labels the negative diagnostic band at 205 nm4e,13 for 3-Ala-NHt-Bu
at low temperature results entirely from their local interaction with confirms P helicity, and the positive band at 205 nm for 3-Ala-Ot-
Bu confirms M helicity.
The first conclusion that can be drawn from the results in Table 1
is that C-terminal secondary amides of L-amino acids, whether
tertiary (entries 1 and 2, 4–10) or quaternary (entries 11 and 12),
induce P helicity, while C-terminal esters (entries 13–17) and a
tertiary amide (entry 3) induce M helicity. We deduce that the
divergent behaviour of these two groups of compounds is due to
the ability of the secondary amides to use their NH group to form an
additional C-terminal hydrogen bond, promoting continuation of a
310 helical structure, as illustrated in Fig. 2a. It is well established
that L residues located within a 310 helix promote right-handed
screw-sense preference,4a,14 and Fig. 2c illustrates the mechanism by
which a bulky R1 substituent exerts this effect by lying perpendicular
to the plane of the adjacent amide group. The weak preference
induced by ProNHt-Bu (entry 6) is likely to be due to the bend
induced by a Pro residue,15 preventing or weakening this C-terminal
hydrogen bond. By contrast, the inability of C-terminal esters to
Fig. 1 (a) Circular dichroism spectra of 3-Ala-NHt-Bu and 3-Ala-Ot-Bu at
+20 1C in MeOH, measured at 7 Â 10À4 mol dmÀ3. The signs of the bands
at 205 nm4e,13 indicate a P (right-handed) screw-sense preference in
continue a hydrogen-bonded network gives rise to the well-known
3-Ala-NHt-Bu and an M (left-handed) screw-sense preference in 3-Ala-
Ot-Bu; (b) Variable temperature 13C NMR spectra of 3-Ala-NHt-Bu at 10 1C
‘Schellman motif’,16 in which dipole repulsion leads to a local helical
inversion. Such a motif is evident in the X-ray crystal structure of
3-Ala-Ot-Bu (Fig. 3). A single L residue adopting this motif has been
intervals from À70 1C (bottom) to +40 1C (top). Coalescence occurs
between À50 and À20 1C.
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and Abu are readily accommodated by the steric demands of the
3
10 helical environment.19 Although the steric differentiation at the
stereogenic centre of Val, Phe and tert-Leu (entries 7–10) is greater,
these residues have a lower propensity for helix formation,20 and
presumably favour alternative conformations with lower screw-
sense preferences. The lower screw-sense control induced by
Ser(Ot-Bu)NHt-Bu (entry 5) suggests that more remote steric bulk
is likewise not well tolerated by a 310 helical structure. a-MeVal,
being quaternary, is compatible with a 310 helix,4d,21 the greater
selectivity observed with Ala vs. a-MeVal being simply due to the
steric differentiation between Me vs. H and i-Pr vs. Me.
In conclusion, C-terminal L amino acid residues induce a
preferred right-handed screw sense as their amide derivatives
and left-handed screw sense as their ester derivatives in a series
of helical Aib oligomers. Screw-sense control is maximised by
residues that can participate in a 310 helical structure, namely
L-Ala and the dimer of L-a-MeVal.
This work was supported by the European Research Council
(AdG ROCOCO) and by the EPSRC (grant number EP/K039547).
Jonathan Clayden holds a Royal Society Wolfson Research
Merit Award.
Fig. 2 Conformations of Aib oligomers 3 bearing (a) a C-terminal sec-
ondary amide function and (b) C-terminal ester (or tertiary amide) func-
tion, with (c) and (d) showing Newman projections of their C-termini
viewed from N-terminal direction to illustrate the origin of the conforma-
tional preference.
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`
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(entries 1, 2 and 13), rather than the more bulky chiral amino acids.
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which induces comparably high screw-sense control when located at
the N terminus4d,e) exerts more powerful control (80% h.e.) than
AlaNHt-Bu.
`
`
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`
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`
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termination of helices by Pro (ref. 15).
in a P helix appears upfield when incorporated within the 310 helix 18 The X-ray crystal structure of 3-Ala-Ot-Bu has been deposited with
itself (this work and ref. 4d) but downfield when incorporated into a the CCDC, deposition number 994389.
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7952 | Chem. Commun., 2014, 50, 7949--7952
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