Switching and Conformational Fixation of Amides Through Proximate Positive Charges

Article abstract of DOI:10.1002/anie.201502474

Tertiary amides, which usually occur as cis/trans mixtures, can be effectively shifted to the cis conformation by placing a positive charge in close proximity to the amide carbonyl. This effect was used to prepare cis-configured prolyl amides and to facilitate a strongly rotamer-dependent radical cyclization. Taking charge of conformation: Tertiary amides, which usually occur as cis/trans mixtures, can be effectively shifted to the cis conformation by placing a positive charge in close proximity to the amide carbonyl. This effect was used to prepare cis-configured prolyl amides and to facilitate a strongly rotamer-dependent radical cyclization.

Full text of DOI:10.1002/anie.201502474

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Angewandte
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International Edition: DOI: 10.1002/anie.201502474
German Edition: DOI: 10.1002/ange.201502474
Amide Conformation
Switching and Conformational Fixation of Amides Through Proximate
Positive Charges**
Amelie L. Bartuschat, Karina Wicht, and Markus R. Heinrich*
Dedicated to Professor Klaus Müller (Hoffmann-La Roche AG, Basel)
Abstract: Tertiary amides, which usually occur as cis/trans
mixtures, can be effectively shifted to the cis conformation by
placing a positive charge in close proximity to the amide
carbonyl. This effect was used to prepare cis-configured prolyl
amides and to facilitate a strongly rotamer-dependent radical
cyclization.
A
mide bonds represent the central and most important
structural motif in peptides and many other natural and
synthetic products.[1] The partial double-bond character is
essential to achieving a high degree of conformational
stability in small molecules, as well as in large macromolec-
ular architectures including enzymes, transmembrane recep-
tors, or ion channels.[2] Although the precision of such
complex structures is a key element in selective molecular
recognition, there has always been a considerable interest in
how the conformational distribution of amide bonds could be
influenced.[3] From a biological point of view, such insights
into the cis–trans isomerization of amides can enable tuning
of the activation barrier of receptors or ion channels, as has
been recently reported for the 5-hydroxytryptamine type 3 (5-
HT3) receptor.[4]
Scheme 1. Conformationally switchable and non-switchable amide
derivatives.
system.[8a] As initially observed by Raines,[9] a second carbon-
yl unit (see amide 4[6b]) can also provide the required p*
orbital. Alternatively, hydrogen bonds may be used to
influence the ratio of rotamers.[8]
An interesting extension of the principle to exploit n!
p*Aryl interactions was developed by Yamasaki and Kage-
chika[10] (Scheme 1). Since the aromatic system of 5 can be
switched from an electron-rich to a comparably electron-poor
state through double protonation, the preferred conformation
of the amide bond becomes pH dependent.
Against this background, we asked whether a conforma-
tionally pH-dependent tertiary amide unit might not be
conceivable through a more biomimetic and structurally more
simple modification, whereby the latter aspect could in turn
allow broad applicability. Herein, we present first insights into
the pH-dependent effects of simple aminoalkyl groups and
related basic moieties on the conformation of tertiary amides,
along with applications of the new type 6 conformational
switches.
In general, and in the absence of special effects, secondary
amides largely occur in the trans conformation, whereas cis/
trans mixtures are usually observed for tertiary amides, with
isomeric ratios depending on the nature and size of the
substituents on the nitrogen atom.[2] By placing a bulky unit,
such as a tert-butyl group, on the nitrogen atom of a secondary
amide, the activation barrier for the isomerization of 1 is
lowered and the equilibrium regarding the two original
substituents is shifted towards the cis rotamer (Scheme 1).[5]
A stronger influence on the conformational distribution
was observed for the pyridinium- and triazolium-substituted
amides 2 and 3.[6,7] These effects are explained by n!p*Aryl
interactions between the carbonyl oxygen and an antibinding
orbital of the adjacent electron-deficient aromatic ring
[*] M.Sc. A. L. Bartuschat, K. Wicht, Prof. Dr. M. R. Heinrich
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry
Friedrich-Alexander-Universität Erlangen-Nürnberg
Schuhstraße 19, 91052 Erlangen (Germany)
Inspired by an ongoing study on US28 receptor ligands,[11]
which revealed a surprising pH dependence for the amide
conformation, we prepared the structurally simplified
amide 7 to study the underlying effects in detail (Table 1).
As expected, amide 7 initially occurred as a cis/trans mixture
with no clear preference for either rotamer in all of the
solvents selected for the experiments.[12a] The slightly
increased Kcis/trans value found in methanol (entry 2) might
be due to micelle formation, which was observed for this
E-mail: Markus.Heinrich@fau.de
Homepage: http://www.medchem.uni-erlangen.de/heinrichlab/
[**] We are grateful to Lisa Beyer and Nina Hegmann for experimental
assistance and to Dr. Reiner Waibel (NMR) and Julia Staudenecker
(micelle measurements) for helpful support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502474.
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Table 1: Conformational fixation through protonation or quaternisation:
Solvent effects.
Figure 1. Influence of imidazolylmethyl, pyridinylmethyl, and N-Boc-
aminoethyl side chains on the conformation of amides in CDCl3.
PMB=para-Methoxybenzyl. Boc=tert-Butyloxycarbonyl.
Entry
Amine 7[a]
cis/trans
Solvent
Ammonium salt[b]
7a or 7b
(Kcis/trans
)
cis/trans (Kcis/trans)
1
2
3
4
5
6
7
60:40 (1.5)
67:33 (2.0)
59:41 (1.4)
59:41 (1.4)
57:43 (1.3)
CDCl3
>95:5 (>19) (7a)
90:10 (9) (7a)
90:10 (9) (7a)
>95:5 (>19) (7a)
>95:5 (>19) (7a)
90:10 (9) (7a)
CD3OD
(D3C)2SO
C6D6
CD3CN
D2O-CD3OD
CDCl3
methanol, where protonation led to a change from Kcis/trans
=
1.6 to Kcis/trans = 6.7 for imidazole 8, and from Kcis/trans = 1.3 to
cis/trans = 6.7 for pyridine derivative 9, each time after the
K
[c]
–
addition of two equivalents of TFA (see the Supporting
Information for detailed titration experiments).
60:40 (1.4)
>95:5 (>19) (7b)
[a] For the preparation of 7 see Ref. [11] and the Supporting Information.
[b] Ammonium salts obtained through the addition of TFA (trifluoro-
acetic acid; 5–10 equiv) or CH3I (1.0 equiv). [c] Not determined owing to
low solubility. [d] Ratio of >95:5 assumed if minor isomer could not be
N-Boc-protection of the aminoethyl side chain, as in
urethane 10, demonstrated that a hydrogen bond alone has
only a weak effect (Kcis/trans = 2.1) without support from
a positive charge.[12d] After methylation of 10, compound 11
was found to occur in the usual ratio for unprotonated species.
Since proline plays an unique role in the folding and
stability of proteins and peptides,[15] this amino acid was
chosen for a first application. Proline, when incorporated in
peptides, represents the only proteinogenic amino acid that
occurs as a tertiary amide so that the cis as well as the trans
rotamer should be observed.[16] However, only 10% of the
peptidyl-CO-N-prolyl bonds in native proteins are present as
cis rotamers (Scheme 2),[16c] and the conformation of the
pyrrolidine ring was also found to have a strong effect on the
stability and folding properties of peptides and proteins
(Scheme 2). In this context, a number of 3- and 4-substituted
prolines were prepared,[17,18] whereby the latter represents by
far the more common approach and has frequently been used
to tune the properties of collagen[9,19] and other biomole-
cules[20] (Scheme 2).
1
detected by H NMR.
solvent and mixtures containing up to 40% water, but not for
dimethyl sulfoxide or acetonitrile (entries 3 and 5). Proto-
nation to give 7a (entries 1–6), or quaternization to give 7b
(entry 7), however, led to a clear predominance of the cis
rotamers.[12b] In chloroform, benzene, and acetonitrile, the
minor trans rotamers of 7a and 7b could no longer be
1
detected by H NMR spectroscopy (entries 1, 4, 5, and 7).
Since slightly lower ratios were observed for dimethyl
sulfoxide and methanol, as well as methanol in water, the
overall trend is comparable to the solvent effects on the
magnitude of n!p*Aryl interactions in triazolium-substituted
amides 3 (Scheme 1).[7]
From a very general point of view, the two ammonium
groups in amides 7a and 7b appear to strongly stabilize the cis
rotamers through a form of ionic interaction. This interaction
can be rationalized by assuming a greater participation of the
multiply charged mesomeric forms 7a’ or 7b’. Interestingly,
the conformational fixation does not require the presence of
a hydrogen bond, since the quaternary ammonium ion is able
to exert a similar effect (compare entries 1 and 7).[13]
Not many approaches have yet appeared for developing
switchable proline derivatives, however. A recent report with
(4S)-amino-proline 12 demonstrated that an ionic interaction
between a protonated amine and a carbonyl unit (see amide 7,
Table 1) can effectively be used to modulate the conformation
To investigate whether the remarkable conformational
fixation induced by the ammonium alkyl side chain can also
be achieved with other protonated moieties so that conforma-
tional switches could be designed for different ranges of pH
values, we prepared the tertiary amides 8 and 9 (Figure 1).[14]
The imidazole derivative 8 showed a relatively strong prefer-
ence for the cis rotamer even before protonation, which is
probably due to hydrogen bonding,[9b] and full conversion to
the cis rotamer took place upon the addition of TFA.[12b–d] By
contrast, the effect of the pyridylmethyl side chain was found
to be similar to that of aliphatic amines in the unprotonated
state (Table 1), but turned out to be slightly weaker in the
protonated state, since a Kcis/trans value of only 13 was
reached.[12a–d] Slightly weaker effects were observed in
Scheme 2. Conformational studies on proline derivatives.
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Table 3: Radical cyclization reactions.
of the pyrrolidine ring, but this approach leaves the cis/trans
ratio of the amide more or less unchanged.[21,22] Aiming at
proline derivatives with a clear preference for the cis rotamer,
only the introduction of sterically demanding substituents in
5-position, as in amides 13a[23] and 13b[24] (Scheme 2), or
conformational fixation through the introduction of a covalent
linkage have so far been successful.[25]
To study whether the directing effect of an aminoalkyl
group might also be applicable to modulating the cis/trans
ratio of prolyl amides, the derivatives 14 and 15 were
prepared (Table 2 and the Supporting Information). The 3-
phenylpropionyl unit was chosen to facilitate detection by UV
Entry
Amide
16, 17: R=
cis/trans[a]
18/19[b]
18
%
19
%
[c]
[c]
1
2
3
4
5
6
7
16a: H
16b: Bn
16c: Bu
16d: (CH2)2NHBoc
17c: Bu
<5:95
42:58
60:40
75:25
54:46
74:26
>95:5
<5:95
68:32
76:24
96:4
50:50
50:50
57:43
–
68
21
18
5
44
57
61
Table 2: Reference compound 14 and 5-(aminoalkyl)-substituted proline
derivative 15.
39[d]
30[d]
43[e]
39[d]
29[d]
32[e]
17d: (CH2)2NHBoc
17e:[f] (CH2)2NH3
+
[a] Ratio determined for starting materials by 1H NMR in CDCl3. [b] Ratio
1
determined by H NMR (CDCl3) for crude product mixtures. [c] Yields
after purification by column chromatography. [d] Yields determined by
addition of an internal standard (dimethyl terephthalate) to the crude
product mixture. [e] Yields determined by addition of an internal
standard (maleic acid) to the crude product mixture. [f] Amide 17e
prepared from 17d through treatment with TFA. AIBN=azobisisobu-
tyronitrile. TTMSS=tris(trimethylsilyl)silane.
Entry
Solvent
cis/trans
14[a,c]
15[a–c]
15·TFA
1
2
3
4
5
CDCl3
C6H6
CD3CN
CD3OD
D2O
18:82
15:85
19:81
19:81
18:82[d]
32:68
25:75
27:73
36:64
33:67[d]
>95:5[e]
>95:5[e]
>95:5[e]
95:5
reactants 16b and 16c and resulted in a predominance of the
cyclic amides 18b and 18c over the reduced compounds 19b
and 19c.[27] A further increase in selectivity could be achieved
with an N-Boc-protected aminoethyl group (entry 4), which
influences the cis/trans ratio of 16d through hydrogen
bonding.[9b, 28] Since the reaction of 16d had already given
a high proportion of cyclized product 18d, less favorable
conditions were chosen to probe the effect of the protonated
aminoethyl side chain. Specifically, the reaction temperature
was lowered to room temperature[26] and the reductant
tris(trimethylsilyl)silane[29] was no longer added by syringe
pump but in one batch at the beginning. Under these
conditions, the performance of the n-butyl and the NHBoc-
ethyl derivatives 17c and 17d decreased, and 1:1 mixtures of
18c/19c and 18d/19d were obtained (entries 5 and 6). The
strong conformational fixation induced by the protonated
aminoethyl side chain in 17e (cis/trans > 95:5 ; entry 7), was
then able to bring about the production of cyclized amide 18e
in a larger amount than the reduced product 19e.
In summary, we have shown that the conformation of
tertiary amides can be effectively modulated through a pos-
itive charge located in close proximity to the carbonyl oxygen
atom. The underlying interaction of the carbonyl unit and the
covalently attached ammonium ions turned out to be
independent of the presence of a hydrogen bond. First
applications of this effect include the preparation of prolyl
amides with a strong preference for the cis conformation and
the enhancement of radical cyclization reactions for convert-
ing amides into lactams. Future research is directed towards
the introduction of the new and switchable amide derivatives
into peptides and other biomolecules, as well as towards
studies on the biological effects of this modification.[30]
87:13
[a] For the preparation of 14 and 15, see Supporting Information.
[b] Ratio determined in the presence of K2CO3. [c] Assignment of cis and
trans rotamers is in agreement with reported 13C NMR data and NOESY
experiments for compound 14. See Refs. [12e] and [16a]. [d] Addition of
10% CD3OD to increase solubility. [e] Ratio of >95:5 assumed if minor
isomer could not be detected by 1H NMR.
spectroscopy. Whereas the prolyl amide 14, which served as
a reference compound, and the unprotonated amino alkyl
derivative 15 showed the expected predominance of the trans
rotamers with very little dependence on the solvent, proto-
nation of the aminoalkyl group in 15 led to more or less full
conversion to the cis rotamer.[12e] The responsible ionic
interaction was again slightly weakened by the protic solvents
methanol and water (entries 4 and 5), but in chloroform,
benzene, or acetonitrile, the trans rotamer could not be
detected by 1H NMR after protonation (entries 1–3; see
Supporting Information for NMR titration experiments).
To investigate the synthetic applicability of the conforma-
tional fixation, we selected a group of radical cyclization
reactions that are known to be highly dependent on amide
conformation (Table 3). Since radicals usually have a short
lifetime, with no reversible resting state, it is favorable with
regard to cyclization if amide 16 is largely present as the cis
rotamer or the barrier to rotation is lowered by elevated
temperatures.[26] The unfavorable trans conformation, by
contrast, can be expected to lead to reduction. It was thus
not surprising that the secondary amide 16a, which occurs
solely as the trans isomer, was reduced to 19a with no bicyclic
amide 18a being detected (entry 1).
The attachment of an n-butyl or a benzyl group to the
amide (entries 2 and 3) led to improved cis/trans ratios for the
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d) M. D. Shoulders, R. T. Raines, Annu. Rev. Biochem. 2009, 78,
929 – 958.
Keywords: amide bond · ammonium ions · conformation ·
proline · rotamers
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Received: March 17, 2015
Published online: July 1, 2015
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