Foldamer-mediated remote stereocontrol: >1,60 asymmetric induction

Article abstract of DOI:10.1002/anie.201308264

An N-terminal L-α-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac₆c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm. Reaction at a distance: By inducing a quantitative, persistent preference for right-handed helicity, chirality at one end of an otherwise achiral helical molecule is able to control the stereoselectivity of reactions at sites located up to 60 bonds away, shattering previous records for remote stereochemical control. Copyright

Full text of DOI:10.1002/anie.201308264

Angewandte
Chemie
DOI: 10.1002/anie.201308264
Remote Stereocontrol Very Important Paper
Foldamer-Mediated Remote Stereocontrol: > 1,60 Asymmetric
Induction**
Liam Byrne, Jordi Solꢀ, Thomas Boddaert, Tommaso Marcelli, Ralph W. Adams,
Gareth A. Morris, and Jonathan Clayden*
Abstract: An N-terminal l-a-methylvaline dimer induces
complete conformational control over the screw sense of an
otherwise achiral helical peptide foldamer formed from the
achiral quaternary amino acids Aib and Ac6c. The persistent
right-handed screw-sense preference of the helix enables
remote reactive sites to fall under the influence of the terminal
chiral residues, and permits diastereoselective reactions such as
alkene hydrogenation or iminium ion addition to take place
with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction.
Stereochemical information may be communicated in this way
over distances of up to 4 nm.
appropriate controller and a reactive site through a molecular
fragment strongly disposed to adopt a helical structure, we
show that it becomes possible for the controlling center to
govern the stereochemical environment at a remote reactive
site located several nanometers away.
The helical foldameric parts of our molecules were made
from oligomers of aminoisobutyric acid (Aib, 1) and 1-
aminocyclohexanecarboxylic acid (Ac6c, 2) (Figure 1a). Pep-
tide-like oligomers of these achiral quaternary amino acids
typically adopt well-defined 310 helical structures in solu-
tion,[11] but because the individual amino acids each possess
a plane of symmetry, their oligomers exist as a rapidly
interconverting[12,13] equal mixture of left- and right-handed
helices. A bias towards a single screw sense[14] was induced by
ligating to the N-terminus of these oligomers one or more
residues of the chiral quaternary amino acid l-a-methylvaline
(aMv, 3). The structure of l-a-methylvaline is compatible
with the 310 helical structure of Aib oligomers,[15] and we
reasoned that incorporating a sufficient number of chiral
quaternary l-amino acid residues would maximize the
chances of inducing a high degree of preference for the
right-handed[16] screw sense in the helical chain. Two oligo-
mers were synthesized, 4 and 5, containing one and two aMv
residues respectively (Figure 1b). Circular dichroism (CD)
spectra of 4 and 5 in MeOH, and titration of 5 in THF with
DMSO, were consistent with the adoption of a characteristic
310 helical structure in these solvents (see the Supporting
Information).
I
n a typical stereoselective reaction, existing stereochemistry
governs the formation of a new stereogenic center by
controlling the direction of attack of a reagent or a catalyst
at a reactive site. Close spatial contact between the control-
ling center and the reaction site is typically required, and 1,2-
or 1,3-asymmetric induction (where the two sites are sepa-
rated by one or two bonds) can routinely be expected to give
high levels of stereoselectivity.[1] Asymmetric induction over
longer distances (“remote asymmetric induction” usually
refers to 1,4-asymmetric induction and beyond) is possible,[2]
but only if the flexibility of the molecule is limited, usually by
the (sometimes temporary) formation of a cyclic structure.[3]
Asymmetric induction can be achieved over more than 20
bonds[4] in non-cyclic molecules by using semi-rigid structures
in which relayed interactions between a series of polarized
groups allow a controlling stereogenic center to influence the
local environment of a remote reactive site.[5]
Before carrying out the remote stereoselective reactions,
we quantified the screw-sense preference induced in the
Here we present a way to achieve asymmetric induction
over much greater distances by using molecules that have
inherent helicity, or foldamers.[6,7] The conformational prop-
erties of foldamers as structural analogues of biomolecules
have been investigated widely,[7–9] but their ability to control
reactivity remains largely unexplored.[10] By linking an
helical chains of the oligomers 4 and 5 by incorporating a 13
C
label asymmetrically into the two methyl groups of the fifth
Aib residue of the chain.[17] The anisochronicity of the two 13
C
labeled Me groups in the 13C NMR spectra in MeOH and in
THFof both 4 and 5 confirmed that the population of left- and
right-handed helical conformers is unequal,[13] and the
location of the majority of the label in the same (upfield)
member of the pair of anisochronous signals, in conjunction
with the CD spectra in MeOH, indicates that both 4 and 5
prefer a right-handed preferred screw sense.[16] Analysis of the
spectra acquired at a range of temperatures (Figure 1c,d and
the Supporting Information) showed that while the oligomer
5 displays good conformational selectivity for the right-
handed screw sense in MeOH, in THF (and especially at low
temperature) the preference for a single, right-handed, screw
sense becomes almost quantitative. At À508C, for example,
we calculate that the 13C-labelled residue of 5 finds itself in
a right-handed helical environment more than 98% of the
time. Data for both 4 and 5, in MeOH and in THF at + 408C
[*] Dr. L. Byrne, Dr. J. Solꢀ, Dr. T. Boddaert, Dr. R. W. Adams,
Prof. G. A. Morris, Prof. J. Clayden
School of Chemistry, University of Manchester
Oxford Rd., Manchester M13 9PL (UK)
E-mail: clayden@man.ac.uk
Dr. T. Marcelli
Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio
Natta”, Politecnico di Milano (Italy)
[**] This work was funded by the European Research Council through
Advanced Grant ROCOCO and by the EPSRC through grant EP/
I007989. We thank Dr. James Raftery for determining the X-ray
crystal structure of 6b.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308264.
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Table 1: Conformational preferences in 4 and 5 derived by analysis of
their 13C NMR spectra.
Compound
Solvent
T [8C]
K[a]
h.e.[b] [%]
50
P:M[c]
4
4
5
5
5
5
MeOH
MeOH
MeOH
MeOH
THF
+40
À50
+40
À50
+40
À50
75:25
83:17
83:17
91:9
96:4
98.5:1.5
4.9
9.5
60
64
92[d]
THF
[a] Equilibrium constant K for interconversion of P and M conformers at
À508C, calculated by line shape analysis of the variation of the 13C NMR
spectrum with temperature. [b] The value Ddfast/Ddslow (see Figure 1c,d)
interpreted as “helical excess” (that is, [P]À[M]/[P]+[M]).[13] [c] Calcu-
lated ratio of P and M conformers derived from either K or h.e. [d] Value
is identical upon two-fold dilution.
Support for the conclusion that an N-terminal l-aMv
dimer provides close to quantitative screw-sense control was
provided by conformational analysis of two related com-
pounds, 6a Cbz(aMv)2Aib4GlyNH2 and 6b Ac-
(aMv)2Aib4GlyNH2 (Figure 1e). The X-ray crystal structure
of 6a shows a well-formed right-handed 310 helix, and density
functional theory calculations on 6b indicate that the lowest
energy left-handed helical conformation is more than
10 kJmolÀ1 higher in energy than the lowest energy right-
handed helical conformation.
Our next challenge was to utilize the helical screw-sense
preference to induce, at a distance, the formation of a new
stereogenic center.[18] To demonstrate the possibility of an
asymmetric reaction induced solely by the screw sense of
a helix, we made oligomers 7 and 8 in which the 13C labeled
Aib probe of 4 and 5 was replaced by a reactive, but still
achiral, Z-didehydrophenylalanine (DPhe) residue (Scheme
Figure 1. Control of screw sense in foldamers built from achiral
monomers: (a) Achiral and chiral monomers 1–3; b) Induction of
helicity in 13C-labeled oligomers 4 and 5; c) Stacked plots of the
13C NMR spectrum of 5 in methanol, indicating a strong preference for
right-handed helical screw sense, which rises to almost quantitative
control (d) in THF. Blue points are experimental data; red lines are
best-fit line shapes (see the Supporting Information). The ratio of
Ddfast/Ddslow gives an estimate of the “helical excess” at the 13C label at
temperatures above coalescence; full line shape analysis (see Ref. [13]
and the Supporting Information) allows calculation of the helical
excess at all temperatures (Table 1); e) X-ray crystal structure of 6a
(orange; Ph removed for clarity) and calculated lowest energy con-
formation of 6b (yellow).
and at À508C, are shown in Table 1. Two chiral residues are
evidently necessary to induce this almost complete screw-
sense preference: studies of related compounds containing
three chiral residues (see the Supporting Information)
showed that the third offered no improvement in the degree
of conformational control.
Scheme 1. Asymmetric induction of an l-Phe residue by hydrogenation
of a didehydrophenylalanine residue embedded in an induced right-
handed helix.
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1).[14c,19] This unsaturated residue was converted into phenyl-
alanine by chemoselective hydrogenation in the presence of
Crabtreeꢀs catalyst,[20] [Ir(cod)(PCy3)(py)]+PF6À, in ethanol or
in dichloromethane. Two diastereoisomeric products were
formed in each case, and the synthesis of authentic samples of
10a and 10b from l- and d-Phe showed that the major
compound was the l-Phe containing oligomer. The ratios of
9a:9b and of 10a:10b are shown in Scheme 1. Selectivities
were higher in the reactions of 8 than of 7, and were higher in
dichloromethane than in ethanol. Hydrogenation of 8 in
dichloromethane gave more than 95:5 selectivity for the
formation of 10a, which arises from attack of hydrogen on the
Re-face of the double bond of 7 (the back face as shown in
Scheme 1). Given the remoteness of the nearest stereogenic
center, we propose that this selectivity arises purely from the
preferred screw sense of the helical foldamer structure in
which the reactive site is embedded. Lower selectivities with
hydroxylic solvents and with a single controlling chiral residue
presumably result from the lower levels of screw-sense
control attained in these cases (see Table 1).
enamide 12 (Scheme 2).[21] Protonation of 12 (which is an
inconsequential mixture of geometrical isomers) by trifluoro-
methanesulfonic acid in THF at À508C in the presence of
1,3,5-trimethoxybenzene gave acyliminium ion 13, which was
trapped in situ by the arene to yield a pair of diastereoiso-
meric amides 14a and 14b in a ratio of 93:7. Authentic
samples of 14a and 14b were made by coupling amines R-15
and S-15 of known absolute configuration[22] with the hexamer
16. This allowed us to deduce that the arene attacks the rear
face of the iminium ion 13, the face that is more exposed in
the proposed hydrogen-bonded structure shown in Scheme 2.
To confirm that the observed diastereoselectivity is indeed the
result of an intramolecular relay mediated by the screw sense
of the helical foldamer, a control experiment was carried out
in which the chiral inducer is in a separate molecule from the
reactive enamide residue. Thus chiral oligomer 17 and achiral
N-allyl amide 18 gave, after isomerization and trapping,
oligomer 19 in racemic form, ruling out mechanisms of
asymmetric induction involving intermolecular interaction
between the reactive iminium ion and the chiral portion of the
oligomer.
Next, we sought reactions of terminal prochiral groups
that would allow asymmetric induction to be relayed from one
end of a foldamer chain to the other. A survey of the reactions
With this evidence that the remote asymmetric reactions
at the terminus of a helical foldamer may be mediated solely
by the screw sense of the foldamer, we proceeded to lengthen
the chain by successive homologation of 16 with achiral
helical fragments 20 comprising Ac6cAib4 pentamers, as
shown in Scheme 3a. A series of carboxylic acids 21–23
were coupled with allylamine to make the amides 24–26, and
then isomerized to their enamide isomers 27–29. The
enamides 27 and 28 were treated with trifluoromethanesul-
fonic acid in the presence of 1,3,5-trimethoxybenzene to give
amide products 30 and 31 as mixtures of diastereoisomers
(Scheme 3b,c). Authentic samples of both diastereoisomeric
products were synthesized from 21 or 22 and the enantiomers
=
=
=
of C-terminal reactive C C, C O, and C N groups revealed
that trapping of a C-terminal N-acyliminium ion by a nucle-
ophilic arene takes place with excellent diastereoselectivity.
N-Allyl amide 11 was isomerized with a Ru catalyst to the
1
of 15, and comparison by H NMR (800 MHz, [D8]THF) of
these compounds with the product mixtures 30 and 31 by
1H NMR showed that selectivities remained close to 10:1 in
these reactions, even as the remote relationship between the
controlling center and the newly formed asymmetric center
was extended from 1,16 in 14 to 1,31 in 30 to 1,46 in 31.
Finally, under the same conditions, enamide 29 yielded
two diastereoisomers of the product 32 in a ratio of 88:12
(Scheme 3d). This reaction displays 1,61 asymmetric induc-
tion, a value almost three times the greatest through-bond
distance previously reported,[4] representing the communica-
tion of stereochemical information over a distance of about
4 nm,[23] through more than six induced right-handed turns of
the helical structure.
To summarize, we have shown that the screw sense of
a molecular helix, induced under thermodynamic control, can
act as the mechanism by which information may be trans-
mitted over long distances (over 60 bonds) on the molecular
scale. By inducing complete preference for right-handed
helicity in a chain having no inherent screw-sense preference
of its own, an appropriate controller enables distant reactive
sites to fall under its influence, resulting in a reaction
displaying 1,61 asymmetric induction. Such remote control
of chemical reactivity is characteristic of allosteric enzymes
and receptors, and conceptually similar designs could be used
Scheme 2. a) Diastereoselective acyliminium addition by end-to-end
asymmetric induction though a helical oligomer; b) Identification of
the diastereoisomers by synthesis from authentic samples of 15;
c) Control experiment: racemic product results when the controller
and the reactive site are in different molecules.
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Scheme 3. Remote asymmetric induction through achiral helices. a) Synthesis of the three oligomers 21–23 and their conversion to the enamides
27–29. b) 1,31 Asymmetric induction through nine achiral residues to yield 30. c) 1,46 Asymmetric induction through fourteen achiral residues to
yield 31. d) 1,61 Asymmetric induction through nineteen achiral residues to yield 32.
[6] a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173; b) D. J. Hill,
to make artificial analogues of such biological signal trans-
duction mechanisms.
M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore, Chem. Rev.
2001, 101, 3893.
[7] a) Foldamers: Structure, Properties and Applications (Eds.: I.
Received: September 20, 2013
Huc, S. Hecht), Wiley-VCH, Weinheim, 2007; b) E. Yashima, K.
Published online: November 8, 2013
Maeda, H. Iida, Y. Furusho, K. Nagai, Chem. Rev. 2009, 109,
6102; c) T. Nakano, Y. Okamoto, Chem. Rev. 2001, 101, 4013.
Keywords: acyliminium ions · asymmetric induction ·
helical molecules · peptides · remote stereocontrol
[8] a) N. Ousaka, Y. Takeyama, H. Iida, E. Yashima, Nat. Chem.
2011, 3, 856; b) N. Ousaka, Y. Takeyama, E. Yashima, Chem.
Eur. J. 2013, 19, 4680.
[9] R. A. Brown, V. Diemer, S. J. Webb, J. Clayden, Nat. Chem.
2013, 5, 853.
[10] Helical polymers have nonetheless been used as chiral supports
for asymmetric catalysis: a) M. Reggelin, M. Schultz, M.
Holbach, Angew. Chem. 2002, 114, 1684; Angew. Chem. Int.
Ed. 2002, 41, 1614; b) T. Yamamoto, M. Suginome, Angew.
Chem. 2009, 121, 547; Angew. Chem. Int. Ed. 2009, 48, 539, and
references therein.
[11] a) C. Toniolo, M. Crisma, F. Formaggio, C. Peggion, Biopolymers
2001, 60, 396; b) J. Venkatraman, S. C. Shankaramma, P.
Balaram, Chem. Rev. 2001, 101, 3131.
[12] R.-P. Hummel, C. Toniolo, G. Jung, Angew. Chem. 1987, 99,
1180; Angew. Chem. Int. Ed. Engl. 1987, 26, 1150.
[13] J. Solà, G. A. Morris, J. Clayden, J. Am. Chem. Soc. 2011, 133,
3712.
[14] Screw-sense bias in related achiral Aib-rich oligomers has been
induced through the following strategies, but in no case has the
level of screw-sense control exceeded about 3:1 (50% h.e.). For
covalent attachment of a chiral controller, see, for example: a) B.
Pengo, F. Formaggio, M. Crisma, C. Toniolo, G. M. Bonora, Q. B.
Broxterman, J. Kamphius, M. Saviano, R. Iacovino, F. Rossi, E.
Benedetti, J. Chem. Soc. Perkin Trans. 2 1998, 1651; b) J.
Clayden, A. Castellanos, J. Solà, G. A. Morris, Angew. Chem.
2009, 121, 6076; Angew. Chem. Int. Ed. 2009, 48, 5962; c) J. Solà,
.
[1] a) A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93,
1307; b) I. Fleming, J. Chem. Soc. Perkin Trans. 1 1992, 3363;
c) P. B. Brady, B. J. Albert, M. Akakura, H. Yamamoto, Chem.
Sci. 2013, 4, 3223.
[2] a) K. Mikami, M. Shimizu, H.-C. Zhang, B. E. Maryanoff,
Tetrahedron 2001, 57, 2917; b) H. Sailes, A. Whiting, J. Chem.
Soc. Perkin Trans. 1 2000, 1785; c) J. Clayden, Chem. Soc. Rev.
2009, 38, 817.
[3] a) P. Linnane, N. Magnus, P. Magnus, Nature 1997, 385, 799; b) N.
Magnus, P. Magnus, Tetrahedron Lett. 1997, 38, 3491; c) Y.
Tamai, T. Hattori, M. Date, H. Takayama, Y. Kamikubo, Y.
Minato, S. Miyano, J. Chem. Soc. Perkin Trans. 1 1999, 1141;
d) M. Date, Y. Tamai, T. Hattori, H. Takayama, Y. Kamikubo, S.
Miyano, J. Chem. Soc. Perkin Trans. 1 2001, 645; e) J. S. Carey, S.
MacCormick, S. J. Stanway, A. Teerawutgulrag, E. J. Thomas,
Org. Biomol. Chem. 2011, 9, 3896.
[4] J. Clayden, A. Lund, L. Vallverdffl, M. Helliwell, Nature 2004,
431, 966.
[5] a) J. Clayden, N. Vassiliou, Org. Biomol. Chem. 2006, 4, 2667;
b) J. Clayden, L. Vallverdffl, M. Helliwell, Chem. Commun. 2007,
2357; c) J. Clayden, A. Lund, L. H. Youssef, Org. Lett. 2001, 3,
4133; d) J. Clayden, J. H. Pink, S. Yasin, Tetrahedron Lett. 1998,
39, 105.
154
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 151 –155

Angewandte
Chemie
S. P. Fletcher, A. Castellanos, J. Clayden, Angew. Chem. 2010,
122, 6988; Angew. Chem. Int. Ed. 2010, 49, 6836; Ref. [8];
Ref. [13]; for reversible covalent binding to a chiral ligand, see
Ref. [9]; for reversible non-covalent binding to a chiral ligand,
see: d) Y. Inai, K. Tagawa, A. Takasu, T. Hirabayashi, T.
Oshikawa, M. Yamashita, J. Am. Chem. Soc. 2000, 122, 11731;
e) N. Ousaka, Y. Inai, J. Org. Chem. 2009, 74, 1429, and
references therein.
[17] S. P. Fletcher, J. Solà, D. Holt, R. A. Brown, J. Clayden, Beilstein
J. Org. Chem. 2011, 7, 1304.
[18] For a pioneering study of the use of helicity to mediate remote
asymmetric induction, see C. R. Noe, M. Knollmüller, P.
Ettmayer, Angew. Chem. 1988, 100, 1431; Angew. Chem. Int.
Ed. Engl. 1988, 27, 1379.
[19] T. Boddaert, J. Clayden, Chem. Commun. 2012, 48, 3397.
[20] R. Crabtree, Acc. Chem. Res. 1979, 12, 331.
[21] K. Sorimachi, M. Terada, J. Am. Chem. Soc. 2008, 130, 14452.
[22] The enantiomers of 15 were made by the method of Ellman: G.
Liu, D. A. Cogan, J. A. Ellman, J. Am. Chem. Soc. 1997, 119,
9913.
[23] J. Solà, M. Helliwell, J. Clayden, Biopolymers 2011, 95, 62; for
a 310 helix with a “rise per residue” of 1.94 Š, see: R. Gessmann,
H. Brückner, K. Petratos, J. Pept. Sci. 2003, 9, 753.
[15] a) C. Toniolo, A. Polese, F. Formaggio, M. Crisma, J. Kamphuis,
J. Am. Chem. Soc. 1996, 118, 2744; b) M. De Poli, M. De Zotti, J.
Raftery, J. A. Aguilar, G. A. Morris, J. Clayden, J. Org. Chem.
2013, 78, 2248.
[16] R. A. Brown, T. Marcelli, M. De Poli, J. Solà, J. Clayden, Angew.
Chem. 2012, 124, 1424; Angew. Chem. Int. Ed. 2012, 51, 1395.
Angew. Chem. Int. Ed. 2014, 53, 151 –155
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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