Organocatalytic Access to a cis-Cyclopentyl-γ-amino Acid: An Intriguing Model of Selectivity and Formation of a Stable 10/12-Helix from the Corresponding γ/α-Peptide

Article abstract of DOI:10.1021/jacs.9b10861

In this study, we have developed a highly enantioselective organocatalytic route to the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which has a cis-configuration between the C- and N-termini around the cyclopentane core. Kinet

Full text of DOI:10.1021/jacs.9b10861

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Article
Organocatalytic Access to a cis-Cyclopentyl-#-amino
Acid: An Intriguing Model of Selectivity and Formation of
a Stable 10/12-Helix from the Corresponding #/#-Peptide
Rossana Fanelli, Dénes Berta, Tamas Foldes, Edina Rosta, Robert Andrew
Atkinson, Hans-Jörg Hofmann, Kenneth Shankland, and Alexander J. A. Cobb
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10861 • Publication Date (Web): 10 Dec 2019
Downloaded from pubs.acs.org on December 11, 2019
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Organocatalytic Access to a
cis-Cyclopentyl-γ-amino Acid: An Intriguing
Model of Selectivity and Formation of a Stable
10/12-Helix from the Corresponding
γ/α-Peptide.
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Rossana Fanelli,† D´enes Berta,† Tam´as F¨oldes,† Edina Rosta,† Robert Andrew
Atkinson,‡ Hans-J¨org Hofmann,¶ Kenneth Shankland,§ and Alexander J. A.
Cobb∗,†
†Department of Chemistry, King’s College London, 7 Trinity Street, London SE1 1DB, UK
‡Randall Division of Cell and Molecular Biophysics, and Centre for Biomolecular
Spectroscopy, King’s College London, London, UK
¶Institut fu¨r Biochemie, Universit¨at Leipzig, Bru¨derstrasse 34, 04103 Leipzig, Germany
§School of Chemistry, Food and Pharmacy, University of Reading, Whiteknights, Reading
RG6 6AD, UK
E-mail: andre.cobb@kcl.ac.uk
Abstract
In this study, we have developed a highly enantioselective organocatalytic route to
the (1S,2R)-2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor, which
has a cis-configuration between the C- and N-termini around the cyclopentane core.
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Kinetic measurements show that the product distribution changes over time due to
epimerization of the C1 center. Computations suggest the cis-selectivity is a result
of selective C-C bond formation, whilst subsequent steps appear to influence the se-
lectivity at higher temperature. The resulting γ-amino acid residue was incorporated
into a novel γ/α-peptide which forms a well-ordered 10/12-helix with alternate H-bond
directionality in spite of the smallest value of the ζ-angle yet observed for a helix of this
type. This highly defined structure is a result of the narrow range of potential ζ-angles
in our monomer. In contrast, the larger range of potential ζ-values observed for the
corresponding trans-system can be fulfilled by several competing helical structures.
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Introduction
Foldamers – non-natural oligomers capable of forming secondary structures1–6 - represent an
intriguing class of macromolecules whose utilities range from molecular recognition7,8 and
peptidomimetics3,4,9–11 to catalysis12–15 and drug delivery.16–18
Chief amongst these systems are the peptidic foldamers which are composed of non-
natural amino acid monomers. There are two main reasons for the interest they have gar-
nered. First is their potential to generate new and fascinating architectures, capable of
displaying side chains in different ways compared to native structures. Second and impor-
tant from a biological perspective, is that these systems are resistant to protease degradation
– an important facet in peptidomimetics.19
One of the most successful approaches to ensuring that these non-natural units are ca-
pable of facilitating secondary structure formation is to design them such that they are con-
formationally restricted. This ensures that the relative arrangement of the C- and N-termini
are fixed within the optimal parameters required for secondary structure formation.20–22
For these reasons, the asymmetric synthesis of conformationally restricted β- and γ-amino
acids has received a great deal of attention, as has their application to foldamer design. The
reason for desiring such diversity is simple – the more monomers one can access, the more
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secondary structures become available and thus a greater range of exploitable chemical space
is accessible, which is of great importance in fields such as peptidomimetics and catalysis.
Several monomers of this type have been utilized to these ends,23–26 but one that has been
particularly elusive, owing to a lack of synthetic access to it has been the cis-cyclopentyl
γ-amino acid system. In this report, we describe the organocatalytic development of this
simple but challenging monomer, which uncovers an intriguing model of selectivity and
we also demonstrate that it forms a highly organised and stable 10/12-helix beyond that
observed for the corresponding trans-system.25
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Results and discussion
cis-γ-Cyclopentane Amino Acid Synthesis.
We have ourselves contributed extensively to the asymmetric synthesis of conformationally
restricted unnatural amino acids, including six-membered γ-amino acids or their precur-
sors (e.g. 2, Scheme 1a)27 as well as other five-membered systems28,29 and linear δ3-amino
acids.30 At the same time, Gellman reported a synthesis of the related cis-cyclohexyl sys-
tem 5 (Scheme 1b)23 using secondary amine catalysis, and recently used the same approach
to access the analogous trans-five-membered system 7 (Scheme 1c).25 However, we desired
access to a five-membered γ-amino acid with a cis-arrangement around the ring as we were
curious about what the effect of this more conformationally restrained geometry would be
when incorporated into a foldamer. Having successfully demonstrated that an organocat-
alytic 5-exo-trig can lead to cis-selectivity in a different process,29 we felt that a similar
intramolecular approach would be our best chance of attaining our desired cis-target with
good selectivity. The only previous access to this system was achieved by Ley and co-workers
who obtained the cis-γ-amino acid residue in 10% enantiomeric excess over 7 steps, using
an enzyme-mediated resolution.31
We therefore decided to return to secondary amine catalysis in order to accomplish this,
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Scheme 1: (a) Our previous work on unnatural γ-amino acid synthesis.27 (b) Gellman and co-
workers’ access to trans-cyclohexane γ-amino acid precursor.26 (c) Gellman and co-workers’
access to trans-cyclopentane γ-amino acid precursor.25 (d) We theorized that we would be
able to access the cis-system through a stereoselective intramolecular nitro-Michael addition.
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with the view of using enamine chemistry to access the desired cis-cyclopentane system via
an intramolecular conjugate addition onto a nitro-olefin (Scheme 1d). We began our efforts
with the most basic 7-nitro-hept-6-en-1-al system 10, made in 4 steps from cyclohexene (for
full technical details, see SI), and were delighted to observe that the substrate was rapidly
converted to the desired cyclic structure 11, following an in situ reduction with sodium
borohydride to prevent possible epimerization (Table 1).
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In these initial screens, the preference for the cis-isomer did not appear to be strong
at first. However, we were pleased to see that enantioselectivities were reasonable – partic-
ularly with respect to the Ley-Yamamoto-Armuddsen tetrazolic organocatalyst VI (Table
1, Entry 6).32–38 It was noted with some interest at this stage that the enantioselectivities
of the two isolated cis- and trans-products were markedly different and our rationale for
this is discussed later in the manuscript. Nevertheless, in order to continue optimizing both
diastereo- and enantioselectivity, we began by lowering the temperature to find to our de-
light that for the tetrazolic catalyst VI although the enantioselectivity was not affected, the
diastereoselectivity was much improved (albeit at the expense of reaction time, Entry 8).
Intriguingly, neither co-catalyst nor organocatalyst loading improved selectivities (see SI for
full study) but a major influence was both the solvent (dichloroethane) and the concentration
of the reaction, where although a more dilute system made the reaction much slower, both
diastereoselectivity and enantioselectivity improved remarkably (Entry 14). Of particular
note, with these optimized conditions, the reaction is scalable up to 7 mmol maintaining
yields and selectivities.
Pleasingly we were able to deduce the absolute stereochemistry of our product from the
single-crystal X-ray diffraction of the corresponding (-)-camphonyl ester 12 which confirmed
a (1S,2R)-configuration. (Figure 1).
Although we had now managed to access our desired target for foldamer design in ex-
cellent stereoselectivity, we also wished to see if our methodology could be applied to other
substrates. In that respect, we were able to access cyclopentylketone 13 from the corre-
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Table 1: Optimisation Study (Abridged)a
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11
12
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O
∗
∗
OH
1. Catalyst (20 mol%)
O2N
H
NO2
2. NaBH4, MeOH
10
11
Me
O
N
Ph
Ph
Ph
OH
N
Me
Me
N
N
H
N
H
Ph
OTMS
N
H
N
H2
HN N
Ph
Cl
III
IV
V
VI
Entry
Catalyst Solvent Conc,
T, °C
Time,
hb
Yield,
dr,d
cis:trans
1:4
1:8
1:1
1:1
1:6
2:1
1:1
3:1
1:1
1:1
3:2
7:1
6:1
17:2
10:1
ee,e %
c
m
%
1f
2f
3
4
5
6
7
8
9
10
11
12
13
14
15
III
VI
III
IV
V
VI
III
VI
VI
VI
VI
VI
VI
VI
VIi
CH2Cl2 0.2
CH2Cl2 0.2
CH2Cl2 0.2
CH2Cl2 0.2
CH2Cl2 0.2
CH2Cl2 0.2
CH2Cl2 0.2
CH2Cl2 0.2
rt
rt
0
0.3
1.5
1
62
91
57
5h
42
62
20
62
54
52
11
53
66
74
43
nd,-59
nd, 72
-87,g-27
nd,nd
-68,-74
83,g 71
36, 53
82, 22
65, 56
50, 38
-10
0
96
0
72
0
14
-20
-20
-20
-20
-20
-20
-20
-20
-20
>24
22
25
24
26
50
48
168
168
b
MeCN
THF
0.2
0.2
0.2
0.2
0.1
0.05
0.05
MeOH
DCE
DCE
DCE
DCE
85, 54
89
93
92,-11
a
See Supporting Information for full optimization study.
aldehyde as observed by tlc. Isolated yield over two steps.
crude mixture. Determined by HPLC analysis using a chiral OD column for the cis diastereomer
and a chiral AS column for the trans diastereomer.
aldehyde product without any further reduction with NaBH4.
Time for complete consumption of
c
d
1
Determined by H NMR on the
e
f
Yield, dr and ee were calculated of the
g
Determined by HPLC analysis
h
i
using a chiral AD-H column. Reaction did not go to completion. 2 mol% of catalyst loading.
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O
(S)
O
O
(S)
(R)
O
(R)
8
NO2
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12
Figure 1: X-ray crystal structure of the alcohol derivative (CCDC: 1947228) 12.
sponding nitroolefin substrate, as well as the fascinating indane system 14 albeit with a
1:1 diastereomeric ratio. Nevertheless, the excellent enantioselectivities of the isolated cis-
systems was very pleasing (Figure 2).
OH
O
H
NO2
H
NO2
H
H
13
56%
dr 1:1
cis 84% ee
14
73%
dr 1:1
cis 90% ee
Figure 2: Our methodology could be applied to simple ketones as well as the intriguing
indane system 14.
As briefly mentioned above, during our studies it became apparent that the diastere-
oselectivity and enantioselectivity of this reaction was not straightforward. To begin with,
the enantioselectivity of the cis-conformer was far superior to that of the trans-conformer.
Additionally, it was observed that prolonged reaction times would not only decrease the
diastereomeric ratio of the cis- and trans-adducts, but also that the enantiomeric excesses
of these were changeable, with the cis-system being degraded and the trans-one being en-
hanced. We theorized two possibilities for this time dependent selectivity. First, that the
simple reverse reaction could be occurring, ultimately resulting in the thermodynamically
favourable trans-system becoming more predominant via a less enantioselective transition
state. Second that there are two independent and competing pathways to the cis-and trans-
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adducts that over time are subjected to a catalyst-assisted epimerization through a product
enamine. Examining the ratio of the four enantiomers during and after the reaction, one
can notice a redistribution driven by thermodynamics converting both cis-products to their
respective C1-epimeric trans-products (Figure 3).
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(a)
100
(1S,2S)- trans
(1R,2S)-cis
(1R,2R)-trans
(1S,2R)-cis
50
0
t1
t2
cis = 80% ee cis = 44% ee
trans = 60% ee trans = 66% ee
(b)
Figure 3: Proportion of enantiomers of the five-membered ring 11 at t1 and at t2 performing
the reaction in CH2Cl2 at rt for investigative purposes.
Figure 3b shows the ratio of each enantiomer at t1 (2 hours from beginning of reaction)
and at t2 (23 hours from beginning of reaction). Interestingly, the decrease of concentration of
the (1S,2R)-cis-enantiomer matches with the increase in concentration of the (1R,2R)-trans-
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enantiomer, and similarly, the ratio difference of the (1R,2S)-cis enantiomer matches with
the ratio difference of the (1S,2S)-trans enantiomer. This suggests that the major (1S,2R)-
cis-enantiomer is converted to the (1R,2R)-trans-enantiomer and the minor (1R,2S)-cis-
enantiomer is converted to the (1S,2S)-trans-enantiomer, implying that C1-epimerization is
certainly one aspect of the story.
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Theoretically, a retro-Michael reaction could also lead to the conversion of cis-enantiomers
to the thermodynamically more favoured trans-enantiomers. Interestingly, however, this
study shows that the enantiomeric ratio of the trans-product is not maintained as one would
expect if this were the case, but instead undergoes an enantioenrichment.
Computational Investigation of Stereoselectivity.
In order to gain a complete understanding of this, we turned to computational studies to
ascertain the most energetically likely pathways in the formation of each diastereomer. Cal-
culations were performed for substrate 10 in the presence of catalyst VI. Our goal was to
establish a model which accounts for the initial cis-selectivity and its observed change in
enantiomeric excess over time. Conformational sampling was carried out using mixed low-
mode Monte-Carlo search39–41 as implemented in Schrodinger 2017-142 based on the OPLS
2005 all atom force field,43–45 followed by conformational clustering. Kohn-Sham DFT calcu-
lations were done for the mechanistic studies using Gaussian09 Rev.E.46 The presented result
were obtained employing the ωB97XD range separated hybrid functional,47 with the basis 6-
311G(d,p) for optimization, frequency and solvent calculations and the 6-311++G(3df,3pd)
basis for electronic energies.48–50 Thermochemical corrections were calculated according to
Grimme’s qRRHO51 approximation as implemented in goodvibes.52 Solvent corrections are
determined for DCE using PCM solvent model with Truhlar’s SMD parametrization.53,54
The proposed catalytic cycle is depicted in Scheme 2.
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O
O
5
6
7
8
O2N
O2N
N
N
N
cis-15
trans-15
N
N
N
HN N
OH
9
HN N
OH
10
11
12
13
14
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N
N
NO2
10g
N
N
NO2
10g
N
N
N
N
N
N
N
H
HN N
H
N
VI
N
O
OH
NO2
H
10f
O2N
H
OH
NO2
10
10f
protonation step
H2O
protonation step
10e
H2O
N
cis path
trans path
10e
!"
CC bond
formation step
N
N
N
N
N
N
N
H2O
HN N
HN N
N
N
N
NO
O
O
N
2H
N
N
N
N
N
O2N
N
O
O
10e
N
HN
N
N
NO2
N
10e
H
10a
CC bond
formation step
10b
N
10b
N
N
N
10b
NO
2HN
10d (resting state)
Scheme 2: Mechanistic proposal of the 5-exo-trig cyclisation.
N
N
N
N
N
N
N
N
N
N
NO
HN N
2HN
HN N
O
N
O
N
O
O
10d (resting state)
10c
10e
Figure 4: Possible intermediates after the CC bond formation.
We focused on the carbon-carbon bond forming and the subsequent protonation step
as well as the intermediates connecting them as they have been shown to be of paramount
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(1S,2R)-cis
(1S,2S)-trans
(1R,2S)-cis
(1R,2R)-trans
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0
-5
-10
-15
10
10b
10b‡
10d
10e
10e‡
15
Figure 5: Calculated Gibbs free profile for the catalytic cycle of shown in Scheme 2.
importance. The transition states of the addition step shed light on the coordinating nature
of the tetrazole moiety of the catalyst. The most stable conformers feature a strong H-
bonding interaction between the tetrazole ring which is maximized in the path of the product
(1S,2R)-15 (Figure 6), with a small cost of strain in the pyrrolidine ring.
In a similar manner to the intermediates observed by Seebach and Hayashi,55 Black-
mond,56–59 Wennemers,60 Pihko and Papa´i61,62 in studies performed with the Hayashi-
Jørgensen catalyst, there are three intermediates the addition step can result in (Figure
4). In a moderately polar solvent as DCE, the zwitterionic structure 10c is thermodynam-
ically unfavoured. The formation of a four-membered ring (10d) in a trans-configuration
is rendered impossible due to extreme ring strain, while it is found to be rather stable in
the cis-path, (even if the applied level of theory might overestimate its stability). Thus the
oxazine oxide (OO) 10e intermediate is left the sole option in the trans-path, as shown in
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49
50
51
52
53
54
55
56
57
58
59
60
Figure 6: C-C bond forming transition states on the (1S,2S) (left) and (1S,2R) (right) paths.
Scheme 2. In the absence of co-catalyst, the addition of the previously condensed water to
form the product hemiaminal can happen in two ways. Either the oxygen undergoes a nu-
cleophilic attack on the iminium carbon, which is unlikely, since in abundant intermediates
the centre does not bear a positive charge, or the water protonates the nitronate moiety,
ultimately breaking the auxiliary ring formed in the intermediates. The superiority of the
latter scenario is further underlined by the assistance of the tetrazole ring once again, act-
ing as a Brønsted acid to stabilize the transiently forming hydroxide anion. This structure
quickly results in formation of the product hemiaminal (10g in Scheme 2). Interestingly,
the protonation step favours the trans products, because the ring configuration enables a
more concerted set of bonds forming and breaking as depicted in Figure 7. The overall free
energy profile is shown in Figure 5. The relative free energies of the transition states of the
aforementioned steps are close to each other. Due to the involvement of the water in the
second step, the thermodynamic corrections, introduced as Grimme’s qRRHO,51 increase
the uncertainty of the comparison of these steps, possible overestimating the barrier of the
protonation step. Nevertheless, the temperature dependence of the qRRHO term of the
protonation transition state is considerably higher than that of the first step, which may
also account for the temperature dependent selectivity (see SI for full details).
Assuming that the addition step determines the selectivity, cis diastereomers form faster
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53
54
55
56
57
58
59
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Figure 7: Protonation step transition states on the (1S,2S) (left) and (1S,2R) (right) paths.
and with higher enantioselectivity. This model is in line with the experimental evidence
shown in Figure 3 for the C1 epimerization where (1S,2R)-15 and (1R,2S)-15 convert to
(1R,2R)-15 and (1S,2S)-15, respectively.
In summary, the existence of two independent pathways to the cis- and trans-adducts
has some unexpected consequences. First, for reasons explained in the selectivity model,
the ee of the cis- is superior to that of the trans-adduct. Second, that this cis-product can
epimerise to the trans-adduct under the reaction conditions.
If the trans-product was solely formed by epimerization of the cis-adduct, the enan-
tiomeric excess would be the same. However, although this C2-epimerization is clearly
happening (with the products of this being of the same high enantiopurity), it is also being
incorporated into the original trans-selective pathway which is, as mentioned, of a much lower
enantioselectivity. As a consequence the overall impression given is that the trans-adduct
becomes increasingly enantioenriched as more of the corresponding and purer cis-adduct
epimerises to it. On the other hand, the enantioselectivity of the cis-enantiomer decreases
with time and this can be simply explained by the fact that the high difference of concen-
tration of the two enantiomers leads to the epimerization in greater quantities of the major
cis enantiomer, likely via 1st order kinetics, and ultimately adversely effecting the er of that
system.
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Structural Characterisation of γ/α-Foldamers Containing the cis-
5
6
7
Cyclopentyl Monomer.
8
9
Following both ours,27 and the Gellman group’s23–26 syntheses of γ-amino acids, their use
within foldamer constructs has attracted great interest. In the main these systems have
employed a cyclic backbone; a common feature which results in a conformational restriction
that is beneficial for foldamer formation. For example, Gellman has accessed foldamers based
on cis- and trans-cyclohexyl based γ-systems (A, B and C in Figure 8).23,24,26 Of particular
note is also the Balaram and co-workers’ α/γ-peptide containing the constrained achiral γ-
residue gabapentin (D, Figure 8).63,64 System D allowed the arrangement of the secondary
structure which contained, until now, one of the smallest ζ-angles known and leading to
a 12/10-helix. The trans-cyclopentyl system has also been exploited (E, Figure 8) but a
noticeable absence from these studies have been the cis-cyclopentane γ-amino acids that
are the subject of this study (Figure 8) owing to the aforementioned lack of methodology
towards them in any enantiopure sense.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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44
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46
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48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
H
H
H
H
H
NH
NH
NH
H
A
C
B
O
O
H
H
N
H
HN
HN
O
H
H
D
E
This work
Figure 8: Constrained carbocyclic γ-amino acids that promote helical foldamers.
Having successfully achieved the synthesis of the cis-γ-amino acid precursor 11, our
next task was to synthesize the corresponding 1:1 γ/α-hexapeptide for secondary structure
analysis and this is summarized in Scheme 3.
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Zn powder
NH4Cl
THF/MeOH
1) PCC (2 mol%)
H5IO6 (2.2 eq)
MeCN, 0 °C
Me
OBn
O
Me
OBn
O
O
O
O2N
OH
O2N
NH
H2N
NH
H
H
2) iPr2NEt, HOBt
EDCI
L-Ala-OBz-TsOH
CH2Cl2
H
H
H
H
>99%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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48
49
50
51
52
53
54
55
56
57
58
59
60
11
16
17
68% from 11
Boc2O
CH2Cl2
iPr2NEt
Me
OBn
Me
OH
O
O
O
Pd/C, H2 (1 atm)
BocHN
NH
O
BocHN
NH
17
MeOH
>99%
H
H
H
H
58%
18
19
Me
O
Me
O
iPr2NEt, HOBt,
EDCI, DMF
O
O
NH OBn
BocHN
NH HN
17
19
+
H
H
25%
H
H
20
1) HCl (4N in dioxane)
2) 19, iPr2NEt, HOBt
EDCI, DMF
Me
O
Me
O
Me
O
O
O
O
NH OBn
NH HN
BocHN
NH HN
20
H
H
H
H
20%
H
H
21
Scheme 3: γ/α-Peptides 18, 20 and 21 synthesis.
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To begin with, dipeptide precursor 16 was accessed through the PCC oxidation of γ-
nitroalcohol 11 followed by peptide coupling with benzoyl protected l-alanine. The result-
ing species was then reduced using zinc powder to unmask the primary amine which was
protected using Boc anyhydride, giving C-terminus protected NH2-dipeptide-OBn 17. Boc
protection of dipeptide 17 then allowed us to access to the N-terminus protected BocNH-
dipeptide-OH derivative 19 using standard reduction conditions. The crystalline nature of
intermediate 18 enabled collection of single-crystal X-ray diffraction data, which not only
confirmed the configuration of our cyclopentane system, but also allowed us to analyse the
internal torsional angles of our γ-residue (Figure 9).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OBn
(S)
O
BocHN
NH
O
(S)
(R)
18
Figure 9: Asymmetric unit of the single-crystal X-ray structure of Boc-protected dipeptide
18 (CCDC: 1947227).
With dipeptides 17 and 19 in hand, we were able to couple them to generate tetramer
20. The N-terminus of this was then exposed on treatment with HCl in dioxane, allowing for
the coupling of a second dipeptide 19 and finally access to the desired hexapeptide system
21 (Scheme 3). Owing to the short length of tetramer 20, we focused on the structural
characterisation of the hexamer 21.
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The very good dispersion of proton signals allowed for the near total assignment based
5
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1
on H-1H COSY, ROESY and TOCSY NMR. Four out of six amide peaks were found at
7
8
9
δ > 7 ppm, which is a typical feature of H-bonded protons (Figure 10). A self-aggregation
experiment was performed which suggested that there was no change in aggregation over the
concentration range explored. As the concentration is low (down to 40 µM in CDCl3), it is
likely that the molecules are monomeric throughout.
10
11
12
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16
17
18
19
20
21
22
23
24
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57
58
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1
Figure 10: H NMR spectra in CDCl3 at a concentration of 0.2 mm for the characterisation
of γ/α peptide 21.
DMSO titration experiments were then conducted to identify protons that were not
engaged in intramolecular H-bonding, thus discriminating free and H-bonded signals giving
further structural information. Figure 11b shows the change in chemical shift (∆δ) of each
residue after consecutive additions of DMSO (5, 10, 15, 25, 50, 100 µL). Only the l-Ala (2)
amide peak, which is highlighted in red, is strongly shifted downfield after the addition of
DMSO and thus is the only residue not involved in H-bonding (Figure 11), giving further
support to the proposed helical structure.
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O
O
O
H
N
H
N
HN
O
O
N
H
N
O
N
H
H
O
O
O
7
8
9
(a)
0.2
10
11
12
13
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15
16
17
18
19
20
21
22
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26
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AMCP (1)
L-Ala (2)
AMCP (3)
L-Ala (4)
AMCP (5)
L-Ala (6)
0.0
-0.2
-0.4
-0.6
-0.8
0 1050 0 1050 0 1050 0 1050 0 1050 0 1050
DMSO added [µL]
(b)
(c)
Figure 11: DMSO titration of 2mm γ/α-peptide 21 in CDCl3: (a) H-bonding and solvent
exposed amide protons in the proposed γ/α-peptide 10/12-helical structure. The amide
proton circled in red are expected to exhibit the largest chemical shift change upon DMSO
addition. (b) Change of chemical shift of NH peaks with progressive DMSO addition. (c)
1
Amide peak region of H NMR spectra collected with addition of 0, 10, 25, 50 and 100 µL
of DMSO added to a 2mm solution of hexamer 21 in CDCl3.
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This was further supported by detailed analysis of the obtained 2-D NMR data, which
showed three medium range cross peaks (Types i, ii and iv in Table 2), characteristic of
12/10-helices for α/γ-peptides25,26,65 (relative positions of interacting amino acids γ1 →
α2/γ1 ← α4) and therefore of a 10/12-helical structure for γ/α-peptides(α1 → γ2/α1 ← γ4,
2).21 Like Gellman we do not see interaction iii,25 however we do see interaction iv, which
might be one reason that we see a more ordered structure.26,65 In addition, we also observed
strong interactions between HCα of α residues with HCβ of i +1 α-residues and HCγ of
γ-residues with HCα of the i+2 γ-residues (Table 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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54
55
56
57
58
59
60
Table 2: Significant observed NOE cross peaks for hexamer 21 and characteristic NOE cross
peaks of 12/10-helical structures.
strong
medium
weak
AMCP (1)
AMCP (3)
AMCP (5)
H
O
H
O
H
O
H
H
H
H
H
N
H
N
H
H
HN
O
H
H
O
N
H
N
H
O
N
H
H
H
O
O
O
H
L-Ala (2)
L-Ala (4)
L-Ala (6)
(i) HC[α] of [α]-residue (i) to NH of [α]-residue (i + 2) strong and medium
(ii) NH of [γ]-residue (i) to NH of [α]-residue (i+ 1) medium and weak
(iii) HC[γ] of [γ]-residue (i) to NH of [α]-residue (i +1) not observed
(iv) HC[α] of [α] residue (i) to HC[α] of [γ]-residue (i +1) weak
(v) NH of [γ]-residue (i) to HC[α] of [α]-residue (i +1)
˚
NOE cross peak
NMR distance A
Designation
weak
medium
strong
medium
strong
strong
medium
weak
weak
HCα (2) - HCα (3) - iv
HCα (2) - NH (4) - i
HCα (2) - HCβ (4)
NH (3) - NH (4) - ii
HCγ''(3) - HCα (5)
HCα (4) - HCβ (5)
HCα (4) - NH (6) - i
HCα (4) - HCα (5) - iv
NH (5) - NH (6) - ii
4.28
3.47
2.99
3.46
2.62
2.96
3.47
3.96
3.79
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The determined NOE cross peaks were used as molecular restrictions to identify the
most populated lowest energy conformations of the γ/α-peptide 21. Based on the NMR
data, 55 conformers of the hexapeptide were identified employing Monte-Carlo methods
(details in SI) and further optimized with DFT empoying the long range corrected ωB97XD
functional together with the 6-311G** basis set.47 The overlay of the conformers above
1% population (assuming Boltzmann distribution) is depicted in Figure 12. Five out of six
residues correspond clearly to a well defined 10/12-helix with backbone dihedral values listed
in Table 3.
10
11
12
13
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15
16
17
18
19
20
21
22
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57
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60
(b)
(a)
O
O
O
H
N
H
N
HN
O
O
N
H
N
H
O
N
H
O
O
O
(c)
Figure 12: Overlap of the 9 lowest energy structures of 21 obtained with a computational
study where residue AMCP (1) and side chains have been omitted, as well as simplification
of the terminal protecting groups for the purposes of clarity. (a) Backbone of oligomer 21.
(b) Top view of helical backbone structure of 21. (c) H-bond directionality for the oligomer
21.
Most interesting is examination of the backbone torsion angle ζ, representing rotation
around the bond of the cyclopentane ring that is part of the peptide sequence. The values
for this angle are strongly restricted in case of the cis-configuration on this bond. In the
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Table 3: Backbone torsion angles of hexamer 21 from NMR analysisa and X-ray data for
dipeptide 18.
6
7
8
9
ψ
OBn
φ
φ
O
ψ
θ
BocHN
N
H
(S)
O
(S)
(R)
ζ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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52
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18
Residue
φ
θ
ζ
ψ
Hexamer 21
AMCP (1)
l-Ala (2)
AMCP (3)
l-Ala (4)
AMCP (5)
l-Ala (6)
26.0±75 9.7±50 35.3±23 -103.0±8
-72.8±8 128.7±34
61.0±3 43.5±3 41.9±1 -119.0±4
-72.8±4 141.7±2
-
-
-
-
59.0±1 46.2±2 28.4±1 -119.7±3
-63.9±1
-96.3
-
176.7
-
-
29.4
-
139.9±10
-100.1
1.1
X-ray Dipeptide crystal 18 cis-AMCP (1)
l-Ala(2)
-125.7
a
ωB97XD/6-311G** level of density functional theory.
case of (1S,2R)- or, alternatively, (1R,2S)-configuration, theoretical studies show that only
a relatively small range of values of about 0°, ±30° or ±45° are possible, dependent on which
bond of the envelope conformation of the ring is selected to be part of the peptide sequence
(pseudorotation). In good agreement, the values for ζ from the NMR analysis are in between
30-45°. Based on quantum chemical calculations, a catalog of all helical folding patterns in
conformationally unrestricted α/γ-peptides is available.21 Comparing our structure with
the catalogue data shows that it corresponds to the most stable mixed 12/10-helix in the
catalogue. The backbone torsion angles of the idealized helix are φ = 66°, θ = 32°, ζ =
48°, ψ = -129° for the γ-amino acid constituent and φ = -67° and ψ = 148° for the α-amino
acid constituent.21,22 The same helix type was also found by Balaram and co-workers in
α/γ-peptides with the γ-amino acid gabapentine.63
The situation is distinctly different in case of a trans-arrangement on the cyclopentane
ring with 1S,2S- or 1R,2R-configuration. Here, much more values for the torsion angle ζ are
possible, which occur in a greater number of potential helical structures. Thus, competition
between these trans-structures may prevent stable secondary structure formation. Indeed,
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studies on peptides with such constituents by Gellman and coworkers25 indicate a much
weaker tendency to form ordered helical structures, although a tendency in direction of a
10/12-helix found by Sharma and coworkers65 became visible.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Conclusions
In conlusion, we have developed a highly stereoselective organocatalytic route to the (1S,2R)-
2-(aminomethyl)cyclopentane-1-carboxylic acid monomer precursor. This selectivity has
been explained computationally and found to be a result of two independent pathways with
a favourable kinetic profile towards the cis-system. Prolonged reaction times erode both
the enantiopurity of the cis-adduct and the diastereomeric ratio via C2-epimerization that
unusually also leads to the apparent enantioenrichment of the trans-adduct. γ/α-Oligomers
were then synthesized and it was found that the hexamer populated a 10/12-helix. The
cis-γ-residue contains the smallest ζ-angles reported for this type of helix and in contrast
to the one reported by Balaram and co-workers63 the helix seems tighter due to the even
smaller ζ-angles. This highly organized secondary structure does not seem to occur in the
corresponding trans-system, possibly owing to the greater number of potential conformations
in that system resulting in a greater range of helices.25
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Acknowledgement
5
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9
We would like to thank our funders King’s College London (to. R. F.) and the ERC
(Project No. 757850 BioNet to D. B. and T. F.). We are grateful to the UK Materials
and Molecular Modelling Hub for computational resources, which is partially funded by
EPSRC (EP/P020194/1). D.B. and E.R. are grateful for the Nuffield Foundation and the
summer students Angelo Davis and Fangling Zheng for their commitment.
10
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Supporting Information Available
Experimental procedures and characterization data for all new compounds.
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