Chemical communication: Conductors and insulators of screw-sense preference between helical oligo(aminoisobutyric acid) domains

Article abstract of DOI:10.1039/c2cc00060a

¹H NMR studies quantify the abilities of achiral amino acids to communicate a left-handed screw-sense preference from one helical Aib ₄ domain to another: certain quaternary amino acids (e.g. Ac ₆c) act as effective conductors of conformational preference while others (e.g. diphenylglycine) acts as insulators.

Full text of DOI:10.1039/c2cc00060a

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Chirality
web themed issue
Guest editors: David Amabilino and Eiji Yashima
All articles in this issue will be gathered together
online at
www.rsc.org/chiral

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 3397–3399
www.rsc.org/chemcomm
COMMUNICATION
Chemical communication: conductors and insulators of screw-sense
preference between helical oligo(aminoisobutyric acid) domainswz
Thomas Boddaert, Jordi Sola, Madeleine Helliwell and Jonathan Clayden*
Received 4th January 2012, Accepted 30th January 2012
DOI: 10.1039/c2cc00060a
1H NMR studies quantify the abilities of achiral amino acids to
communicate a left-handed screw-sense preference from one
helical Aib4 domain to another: certain quaternary amino
acids (e.g. Ac6c) act as effective conductors of conformational
preference while others (e.g. diphenylglycine) acts as insulators.
Comparing the degree of helical preference induced at the
terminus of oligomers of varying lengths showed that each
additional Aib residue increased the likelihood of a helix
reversal by only 3.5%, while each Gly residue was associate
with a 17.5% chance of helix reversal.
Similar studies on all-Aib oligomers, using 13C labels in
successive residues, gave a probability of helix reversal of only
2.5% at each monomer.7c Aib oligomers are 310 helices,4 and
in a crystallographic study we showed that the incorporation
of a single Gly residue in the middle of a run of 16 Aib units
was sufficient to perturb the favoured conformation in its
vicinity away from 310 towards an a-helical conformation.11
We ascribe the lower fidelity associated with the Gly residue to
its conformational versatility: Gly is a common component of
b-turns and b-sheets.12
We now describe the synthesis and analysis, by NMR, of the
helical fidelity exhibited by a range of linking residues 2a–k
inserted into the middle of a oligo-Aib chain. The resulting
oligomers 1a–k are represented schematically in Fig. 1. They
consist of a screw-sense ‘inducer’, in this case a chiral N-terminal
amino acid L-Phe, which imparts a preference7c for left handed13
helicity to an adjacent achiral but helical Aib4 domain. Linking
this helical domain to a second achiral helical Aib4 domain is the
linking monomer 2 whose helix-conducting capability is under
investigation. The second helical Aib4 domain is terminated by
an NMR ‘reporter’, an achiral residue (in this case glycinamide)
containing a pair of diastereotopic groups (here protons) whose
There are numerous examples of naturally occurring and
synthetic oligomers with helical conformations in which each
individual monomer is chiral: the DNA double helix and the
protein a helix are archetypal structures in nature,1 and the
field of foldamers2 explores the challenge of synthesising
artificial structures with related conformational predictability.
Oligomers of achiral monomers may likewise be helical,3,4 but
in the absence of an external enantiomerically pure influence, such
oligomers are necessarily conformationally racemic, in other words
their M and P conformers must equally populated. However, even
very small influences may displace this equilibrium in favour of
either the left or right handed conformer.5 Of particular interest
and utility are conformational controllers—especially switchable
ones—located at the terminus of an otherwise achiral oligomeric
structure, as the control they exert can be used to transmit
stereochemical information through the helix.6–9
For conformational communication to persist over long
distances (in other words, on the multi-nanometre scale10) requires
an extended structure with a high degree of conformational
uniformity, in which each structural component of the helix
induces its neighbour to propagate the helix with a high degree
of fidelity. We have used NMR to quantify helical preference,
using the fact that for a helical oligomer in the fast exchange
regime (i.e. one in which the helices interconvert too fast to give
separate signals by NMR) the chemical shift separation between
diastereotopic signals is proportional to the excess of one helical
screw-sense over the other (the ‘helical excess’, h.e.).7c Using this
method, we showed that a single N-terminal chiral amino acid is
sufficient to induce a helix built from achiral Aib4Gly pentamers to
maintain a preferred helicity over distances of at least 4 nm.7a
School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL, UK. E-mail: clayden@man.ac.uk
w This article is part of the ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: Full
characterisation data, NMR and CD spectra for new compounds.
CCDC 859548 & 859547. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc00060a
Fig. 1 Probing conformational communication through achiral linkers.
aN of next residue shown as part of linker.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3397–3399 3397

chemical shift separation is proportional to the degree to
which the helical preference imparted to the N-terminus has
been transmitted to the C-terminus.7c,14 We show that some
linkers 2 exhibit a fidelity comparable to that of Aib, and
effectively ‘conduct’ the screw sense preference at one end of the
oligomer through to the other. By contrast, other oligomers
show a low degree of helix fidelity, and act as ‘insulators’,
preventing information about screw sense being transmitted
between helical domains.
Table 1 Conformational preference at the C-terminus of oligomers 1
as a measure of helical conductivity of residues 2
Conductivity relative
to Aib (%)
Linker residue 2
Dd (GlyNH2 CHAHB)
2a (Aib)
138
133
140
145
o5
120
82
100
97
101
105
o4
87
2b (Ac5c)
2c (Ac6c)
2d (Thp)
2e (Dpg)
2f (DPhe)
2g (Gly)
2h (b-Ala)
2i (GlyGly)
2j (Trz)
The oligomers 1 were made by the routes illustrated in Scheme 1
(full details are provided in supporting informationz). The Aib
tetramer 3, made by the reported7a iterative homologation of
aminoisobutyric acid tert-butyl ester with azidoisobutyryl chloride,
was deprotected at its C-terminus with CF3CO2H and coupled
with glycinamide to give the azide 4. Reduction to the amine 5
provided the C-terminal segment of the target peptides. Meanwhile,
the tetramer 3 was reduced at the N-terminus and coupled with
Cbz-L-PheOH to give 6 which was deprotected to give the free acid
7, providing the N-terminus of the target peptides.
59
52
72
o5
o4
19
36
14
26
2k (TrzGly)
chemical shift difference observed using the all-Aib oligomer
1a and those of other members of the series. In addition to the
observed value of Dd, the Table shows the helix conductivity
of each residue relative to Aib, derived simply from the ratio of
DdLink/DdAib.
The central linker groups were in most cases introduced by
coupling a Cbz protected amino acid derivative Cbz-2 to 5 to yield
the protected peptides 8b–e and 8g–i. N-terminal deprotection to
yield amines 9 and opening of the azlactone derivative of 7 gave
peptides 1b–e and 1g–i. 1f, 1j and 1k were derived from 7 by a
different strategy: 10 and 11 were made by coupling racemic
phenylserine or propargylamine respectively to the C-terminus
of 7. Formation of the azlactone of 10 with concurrent
elimination, followed by ring opening with 5 gave 1f.9 Dipolar
cycloaddition with 4 in the presence of copper(I) acetate gave 1j.16
1k was made by dipolar cycloaddition with azidoacetic acid,
followed by coupling with 5. Finally, 1a was made directly by
coupling CbzAibGlyNH2 with the nonamer CbzPheAib8OH 12.7c
1H NMR spectra of the oligomers were acquired at 500 MHz
in methanol17 at 23 1C, at a constant concentration of 0.05 M,
and the chemical shift separation Dd between the two signals
comprising the AB system of the glycinamide for each oligomer is
shown in Table 1.18 We have recently shown that an N-terminal
Cbz-L-Phe residue induces a preference for left-handed helicity13
in an oligo-Aib chain, and that the ratio between the M and
P helical conformers can be quantified as 65 : 35 using a
13C reporter at residue 6 of Cbz-L-PheAib9Ot-Bu.7c In general,
Dd in the NMR reporter is proportional to the ‘helical excess’ of
the Aib oligomer. With the GlyNH2 reporter in use here,
absolute levels of helical control cannot be determined,19 but
informative comparisons can nonetheless be made between the
In general, quaternary amino acids strongly favour the
formation of 310 helical structures,4,20 and the high, and
almost identical, values for Dd shown with 2a–d as linkers
suggest that all four oligomers 1a–d adopt a similar helical
structure whose dominant conformation is a stable 310 helix of
defined screw sense persisting the full length of the chain.
Dehydroamino acids also participate in 310 helical structures,9
though the value of Dd from dehydrophenylalanine 2f (DPhe)
suggests that the resulting helical conformation is less stable.
In earlier work we showed that Gly residues are less effective
than Aib in the communication of helical preference, with the
substitution of Aib for Gly in peptides comparable to 1a and
1g leading to a 36% drop in screw-sense control.7a In the
molecules now under investigation the presence of a Gly
residue has a comparable effect on the transmission of screw
sense control, with Gly a showing 41% decrease in helix
fidelity in 1g relative to Aib in 1a.22 b-Amino acids are
promoters of helical structures,23 but the geometry of achiral
b-Ala means it is only half as effective as Aib in communication
of the screw-sense in 1h. The flexibility of the GlyGly dimer
insulates the N-terminal helical domain of 1i from the C-terminal
one. Since the oligo-Aib tetramer is made as an azide, we hoped
to use a copper-promoted cycloaddition as an efficient way of
ligating the portions of the peptide.16 However, the two variants
of the triazole linker 2j and 2k also gave levels of conductivity too
low to be of use.
Scheme 1 Synthesis of the oligomers. a CF3CO2H, CH2Cl2; b Ac2O, 120 1C, 2 h; c GlyNH2ꢀHCl, Et3N, MeCN, 3 days; d H2, Pd/C, MeOH;
e HOBt, EDC, CH2Cl2; f HOBt, HBTU, i-Pr2NEt, CH2Cl2; g Cbz-2, cyanuric fluoride, py, CH2Cl2 then with 5 i-Pr2NEt, 4 days; h MeCN, 90 1C,
3 days; i LiOH, THF, H2O; j CuOAc, DMF, 80 1C, 30 min.
c
3398 Chem. Commun., 2012, 48, 3397–3399
This journal is The Royal Society of Chemistry 2012

Diphenylglycine (Dpg) 2e is also a quaternary amino acid,
but its presence in contrast blocks transmission of chirality
from the N-terminal to the C-terminal helical domains of 1e.
We presume this is due to the well-established tendency of
quaternary amino acids more hindered than diethylglycine
(Deg) to adopt a non-helical, planar 2.05 conformation,20,21
which prevents the two helical domains of the peptide from
communicating with one another.
5 M. M. Green, C. Andreola, B. Munoz, M. P. Reidy and K. Zero,
J. Am. Chem. Soc., 1988, 110, 4063. See also S. Cantekin, D. W. R.
Balkende, M. J. Smulders, A. R. A. Palmans and E. W. Meijer,
Nat. Chem., 2011, 3, 42.
6 D. Pijper and B. L. Feringa, Angew. Chem., Int. Ed., 2007,
46, 3693.
7 (a) J. Clayden, A. Castellanos, J. Sola and G. A. Morris, Angew.
Chem., Int. Ed., 2009, 48, 5962; (b) J. Sola, S.-P. Fletcher,
A. Castellanos and J. Clayden, Angew. Chem., Int. Ed., 2010,
49, 6836; (c) J. Sola, G. A. Morris and J. Clayden, J. Am. Chem.
Soc., 2011, 133, 3712; (d) J. Clayden, A. Lund, L. Vallverdu
M. Helliwell, Nature, 2004, 431, 966.
8 N. Ousaka, Y. Takeyama, H. Iida and E. Yashima, Nat. Chem.,
2011, 3, 856.
9 N. Ousaka and Y. Inai, J. Org. Chem., 2009, 74, 1429.
10 J. Clayden, Chem. Soc. Rev., 2009, 38, 817.
11 J. Sola, M. Helliwell and J. Clayden, Biopolymers, 2011, 95, 62.
12 C. M. Wilmot and J. M. Thornton, J. Mol. Biol., 1988, 203, 221;
C. Ramakrishnan and N. Srinivasan, Curr. Sci., 1990, 59, 851;
C. N. Pace and J. M. Scholtz, Biophys. J., 1998, 75, 422.
13 R. A. Brown, T. Marcelli, M. De Poli, J. Sola and J. Clayden,
Angew. Chem., Int. Ed., 2012, 51, 1395.
´ and
The CD spectra of 1a–d showed positive bands at ca. 208
and 220 nm characteristic of left handed 310 helices.13,24 1b and
1c both crystallised in 310 helical conformations, though in
both cases the unit cell contained both a left and a right
handed helix.25
In conclusion, achiral residues inserted into a helical oligomer
of Aib monomers display varying propensities for communication
of screw sense preference through the helix, as detected by an
NMR reporter at the C-terminus of the helical chain. The
quaternary amino acids Ac5c and Ac6c perform as well as Aib,
DPhe slightly less so. Gly and b-Ala conduct about 50–60% of the
helical preference from one domain to the other, while triazolyl
based linkers and very hindered quaternary amino acid diphenyl-
glycine are essentially conformational insulators, preventing the
two halves of the helix from communicating. Future work will aim
to build functional foldamers from oligomers containing Aib
units, and the information gained here on the relative tendencies
of a range of monomers to participate in helical folding will be
valuable and informative.
14 We have previously employed AibCH2OH (ref. 7a), 13C-labelled
Aib (ref. 7b, 13) and a mid-chain Gly (ref. 15) as reporters of screw-
sense control: we find the C-terminal GlyNH2 to be a versatile,
easily introduced alternative. For a related approach to the study
of helix propensity with aromatic amide monomers, see: C. Dolain,
J.-M. Leger, N. Delsuc, H. Gornitzka and I. Huc, Proc. Natl.
Acad. Sci. U. S. A., 2005, 102, 16146.
15 J. Sola, M. Helliwell and J. Clayden, J. Am. Chem. Soc., 2010,
132, 4548.
16 Y. Chen and Z. Guan, J. Am. Chem. Soc., 2010, 132, 4577.
17 Previous work has shown that the correlation of chemical shift
difference Dd with the excess of one of the two helical conformations
is most reliable in methanol, in which we observe no dependence of
This work was funded by the EPSRC.
Dd on concentration. See ref. 7a–c.
2 1/2
]
18 Dd for an AB system is given by n0Dd = [(f1 ꢁ f3)2 ꢁ JAB
=
[(f2 ꢁ f4)2 ꢁ JAB
]
2 1/2 = [(f1–f4)(f2–f3)]1/2 where f1,2,3,4 are the observed
Notes and references
resonance frequencies in order of the four lines comprising the AB
multiplet, JAB is the coupling constant, and n0 is the spectrometer
frequency (in this case, 500 MHz). Dd is reported in parts per billion
(ppb).
1 L. Pauling, R. B. Corey and H. R. Branson, Proc. Natl. Acad. Sci.
U. S. A., 1951, 37, 205; R. E. Dickerson, H. R. Drew, B. N. Conner,
R. M. Wing, A. V. Fratini and M. L. Kopka, Science, 1982,
216, 475; J. D. Dunitz, Angew. Chem., Int. Ed., 2001, 40, 4167.
2 S. Hecht and I. Huc, Foldamers, Wiley-VCH, Weinheim, 2007;
G. Guichard and I. Huc, Chem. Commun., 2011, 47, 5933; D. J. Hill,
M. J. Mio, R. B. Prince, T. S. Hughes and J. S. Moore, Chem. Rev.,
2001, 101, 3893; S. H. Gellman, Acc. Chem. Res., 1998, 31, 173.
3 E. Yashima, K. Maeda, H. Iida, Y. Furusho and K. Nagai, Chem.
Rev., 2009, 109, 6102; T. Nakano and Y. Okamoto, Chem. Rev., 2001,
101, 4013; M. M. Green, K.-S. Cheon, S.-Y. Yang, J.-W. Park,
S. Swansberg and W. Liu, Acc. Chem. Res., 2001, 34, 672; R. J. M.
Nolte, Chem. Soc. Rev., 1994, 23, 11; J. Clayden, L. Lemiegre and
M. Helliwell, J. Org. Chem., 2007, 72, 2302; J. Clayden, L. Lemiegre,
G. A. Morris, M. Pickworth, T. J. Snape and L. H. Jones, J. Am.
Chem. Soc., 2008, 130, 15193; I. Huc, Eur. J. Org. Chem., 2004, 17;
I. Saraogi and A. D. Hamilton, Chem. Soc. Rev., 2009, 38, 1726.
4 J. Venkatraman, S. C. Shankaramma and P. Balaram, Chem. Rev.,
2001, 101, 3131; V. Moretto, M. Crisma, G. M. Bonora,
C. Toniolo, H. Balaram and P. Balaram, Macromolecules, 1989,
22, 2939; I. L. Karle and P. Balaram, Biochemistry, 1990, 29, 6747;
C. Toniolo, M. Crisma, G. M. Bonora, E. Benedetti, B. di Blasio,
V. Pavone, C. Pedone and A. Santini, Biopolymers, 1991, 31, 129;
C. Toniolo and E. Benedetti, Trends Biochem. Sci., 1991, 350;
J. D. Augspurger, V. A. Bindra, H. A. Scheraga and A. Kuki,
Biochemistry, 1995, 34, 2566; C. Toniolo, M. Crisma, F. Formaggio
and C. Peggion, Biopolymers, 2001, 60, 396; J. R. Kumita,
C. J. Weston, L.-P. Choo-Smith, G. A. Woolley and O. S. Smart,
Biochemistry, 2003, 42, 4492; I. L. Karle, Biopolymers, 2001, 60, 351.
19 We have so far been unable to find conditions that allow us to
measure the value of DdH at slow exchange with a GlyNH2
reporter, a value necessary for the accurate determination of
screw-sense preference (ref. 7c).
20 C. Toniolo, M. Crisma, F. Formaggio and C. Peggion, Biopolymers,
2001, 60, 396.
21 F. Formaggio, M. Crisma, C. Peggion, A. Moretto, M. Venanzi and
C. Toniolo, Eur. J. Org. Chem., 2012, 167 and references therein.
22 The Gly linker itself contains diastereotopic protons which also act
as a reporter of helix fidelity, and show values of Dd consistent with
those reported in similar compounds containing mid-chain Gly
residues (ref. 7a,15).
23 D. Seebach and J. L. Matthews, Chem. Commun., 1997, 2015;
T. Beke, C. Somlai and A. Perczel, J. Comput. Chem., 2006, 27, 20.
24 It is worth noting that the NMR method described here gives no
information about the sense of helical induction (M vs. P) and it is
possible, though unlikely, that some of the monomers tested might
in fact invert the helical preference from M to P in the C-terminal
helical domain (for an instance of such a motif in an aromatic
oligoamide, see V. Maurizot, C. Dolain, Y. Leydet, J.-M. Leger,
P. Guionneau and I. Huc, J. Am. Chem. Soc., 2004, 126, 10049).
A negative band in the CD spectrum of 1f at 280 nm also indicates
left handed helicity: see ref. 9 and references therein.
25 See also ref. 11. X-ray data for 1b and 1c have been deposited with
the Cambridge Crystallographic Data Centre, deposition references
859548 & 859547.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3397–3399 3399