NMR-based assignment of isoleucine: Vs. allo -isoleucine stereochemistry

Article abstract of DOI:10.1039/c7ob01995e

A simple ¹H and ¹³C NMR spectrometric analysis is demonstrated that permits differentiation of isoleucine and allo-isoleucine residues by inspection of the chemical shift and coupling constants of the signals associated with the proton and carbon at the α-stereocentre. This is applied to the estimation of epimerisation during metal-free N-arylation and peptide coupling reactions.

Full text of DOI:10.1039/c7ob01995e

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NMR-based assignment of isoleucine vs. allo-
isoleucine stereochemistry†
Cite this: DOI: 10.1039/c7ob01995e
Zoe J. Anderson, Christian Hobson, Rebecca Needley, Lijiang Song,
Michael S. Perryman, Paul Kerby and David J. Fox
*
1
13
Received 10th August 2017,
A simple H and C NMR spectrometric analysis is demonstrated that permits differentiation of isoleucine
and allo-isoleucine residues by inspection of the chemical shift and coupling constants of the signals
associated with the proton and carbon at the α-stereocentre. This is applied to the estimation of epimeri-
sation during metal-free N-arylation and peptide coupling reactions.
Accepted 19th September 2017
DOI: 10.1039/c7ob01995e
rsc.li/obc
these effects and so is much more difficult to epimerise to give
Introduction
7
a,8
the less common L-allo-isoleucine stereoisomer.
This lack
The assignment of the relative stereochemistry of amino-acid of reactivity allows the β-configuration at the carbon to act as a
residues within complex natural products is normally achieved marker for epimerisation at the α-carbon. Isoleucine as a
by degradation of the product to its constituent fragments, fol- marker for the study of racemisation during peptide synthesis
9
lowed by reaction with a chiral derivatising agent, commonly has been known for a number of years, but the final assess-
1
Marfey’s reagent. During peptide coupling, epimerisation is ment of chiral purity is usually performed by hydrolysis fol-
1
0
usually measured by HPLC separation of the diastereoisomeric lowed by analytical chromatography.
products. H, C and N NMR spectrometry can also be
2
1
13
15
To our knowledge, only two reports exist describing the
used to calculate the level of epimerisation, either via chiral specific differentiation of L-isoleucine and D-allo-isoleucine by
3
1
derivatisation or with a chiral shift reagent. Recently, during
H NMR spectrometry. In 1983, Khatskevich et al. reported
4
5
the structural assignment and synthesis of the azolemycins, that both the chemical shift and the coupling constants for
we noted that the H NMR spectrum of the isoleucine portion the hydrogen at the α-carbon differed for N-benzoyl-L-isoleu-
1
of the natural product was significantly different from its allo- cine methyl ester and N-benzoyl-D-allo-isoleucine methyl ester
3
isoleucine diastereoisomer.
L-Isoleucine is one of the common amino-acids found in
eukaryotic and prokaryotic proteins, but is unusual in that it
((2S,3S) diastereoisomer, δH ppm 4.70, dd, JCH–CH 5.15 Hz),
3
J
CH–NH 8.62 Hz; ((2R,3S) diastereoisomer, δ
H
ppm 4.90, dd,
6
3
3
11
JCH–CH 4.30 Hz, J
CH–NH
9.0 Hz). Similarly, in 2003 Biron and
possesses two stereogenic centres. It can therefore exist as four Kessler noted that, when hydrolysing N -methyl-N -o-NBS-L-
distinct stereoisomers (Fig. 1). Epimerisation at the α-centre isoleucine methyl ester, epimerisation at the α-stereocentre
α
α
7
can occur due to resonance stabilisation and electron-with- could be observed by the appearance of a new peak (corres-
drawing effects from the amino- and carboxy-groups to give ponding to the D-allo-isoleucine stereoisomer α-CH) downfield
D-allo-isoleucine. In contrast, the β-centre is distanced from from the usual peak observed for the L-isoleucine-derived
1
2
stereoisomers. During the course of our studies into peptide
bond synthesis, we decided to use this difference between
1
L-isoleucine and its epimer, D-allo-isoleucine by H NMR
spectrometry to easily assess the comparative levels of epimeri-
sation during a range of reactions of molecules with a
C-terminal L-isoleucine residue.
A range of C- and N-substituted isoleucine-containing mole-
cules were synthesised using pure L-isoleucine and then
repeated for comparison with a mixture of L-isoleucine and
D-allo-isoleucine by standard methods (Fig. 2, see ESI† for
details). N-Undec-10-enoyl 5a and N-benzoyl-L-isoleucine 6a
were epimerised to a mixture of L-isoleucine and D-allo-isoleu-
Fig. 1 Isoleucine and allo-isoleucine stereochemistry.
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry,
CV4 7AL, UK. E-mail: d.j.fox@warwick.ac.uk
1
3
cine derivatives using the method of du Vigneaud et al.
†
Electronic supplementary information (ESI) available: Synthesis details, NMR
spectra and chiral HPLC chromatograms. See DOI: 10.1039/c7ob01995e
Compounds lacking an N-terminal acyl group were synthesised
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Scheme 2 Reagents and conditions: (i) 11, PyBOP, iPr
2 2 2
NEt CH Cl ,
−
20 °C, 4 h.
Fig. 2 Isoleucine derivatives prepared wth L-isoleucine and a mixture of In each case, the products were obtained as a mixture of dia-
L-isoleucine and D-allo-isoleucine stereochemistry.
stereoisomers in roughly the same proportions as the starting
materials. Again, it was possible to distinguish between the
L-isoleucine and D-allo-isoleucine derivatives by H NMR spec-
1
from an epimeric mixture of D-allo-isoleucine and L-isoleucine, trometry (Scheme 3). For comparison, both 15 and 16 were
prepared from L-isoleucine according to the method of also prepared using a direct PyBOP mediated peptide coupling
1
4
Yamada et al. In addition, a model dipeptide octanoyl-glycyl- reaction between propylamine and the equivalent acids 5a and
isoleucine was prepared as both the methyl ester 9 and the 10a (not shown, see ESI†).
1
acid 10, again diastereoisomerically pure and as a mixture
The H NMR spectra of the isoleucine derivatives were
recorded in CDCl , CD OD and (CD ) SO, both as a mixture of
(Scheme 1).
3
3
3 2
For the isoleucine derivatives 2 to 7, differences of diastereoisomers and, where possible, as the single diastereo-
1
L-isoleucine and D-allo-isoleucine stereochemistry due to epi- isomer (Tables 1–3). 700 MHz H NMR spectra were obtained
merisation were readily observed by the appearance of a new and, after calibration against the internal solvent peak, the
peak, assignable as the proton at the α-stereocentre of D-allo- chemical shifts and coupling constants for the α-CH hydrogen
1
3
isoleucine by comparison with the equivalent compound pre- were measured. C NMR spectra were also obtained for most
13
pared from a diastereoisomeric mixture of amino-acids. of these compounds at 100 MHz in CDCl only. The C chemi-
3
Compounds 5 and 10 were coupled to fluorenylmethane thiol cal shifts corresponding to the α-CH were measured (Table 1).
1
5
1
1 according to the method of Crich et al., to give the corres-
The general trends noted earlier were further supported by
ponding thioesters 12 and 13 respectively (Scheme 2). In each these results. In all cases we found that the α-CH chemical
case, considerable epimerisation at the L-isoleucine stereocen- shift for the D-allo-isoleucine diastereoisomer occurs at a
tre of the products 12a and 13a was readily identified by the higher chemical shift than that for the L-isoleucine diastereo-
1
3
appearance of a new peak in the H NMR spectrum, assignable isomer. In addition, the JCH–CH coupling constants for the
as the proton at the α-stereocentre of D-allo-isoleucine, by com- L-isoleucine diastereoisomer α-CH are always larger, and the
parison with the equivalent products 12b and 13b prepared
from the diastereoisomeric mixtures 5b and 10b. N-Propyl
amides 15 and 16 were prepared by deprotection of the thio-
esters and reaction with the sulphonamide of propylamine 14.
Scheme 1 Reagents and conditions: (i) EDCI, HOBt, NMM, EtOH, 0 °C
Scheme 3 Reagents and conditions: (i) Piperidine, DMF, rt, 1.5 h; (ii)
Cs CO , DMF, 14, rt, 1 h.
to rt, 17 h; (ii) LiOH, THF, H
2
O, 0 °C, 4 h.
2
3
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3
Table 1 Chemical shifts and coupling constants of L-isoleucine and
D-allo-isoleucine diastereoisomers 3 to 16
J
CH–NH coupling constants are usually smaller, than those for
the D-allo-isoleucine diastereoisomer.
Generally, the difference in chemical shifts corresponding
3
a
3
a
J
CH–CH
J
CH–NH
to the α-CH of L-isoleucine and D-allo-isoleucine was greatest
α-CH
̲
(ppm)
(Hz)
(Hz)
α-C ̲H (ppm)
1
in DMSO-d6 and smallest in CDCl , but the α-CH H NMR
3
Entry
L
D-allo
L
D-allo
L
D-allo
L
D-allo
peaks were always sufficiently distinct not to overlap at both
7
00 MHz and 400 MHz. This suggests they would be suitable
3
4
5
6
7
9
1
1
1
1
1
3.80
3.87
4.62
4.86
4.84
4.54
4.53
4.63
4.53
4.21
4.34
3.90
3.99
4.75
4.98
4.95
4.65
4.69
4.76
4.66
4.32
4.45
5.5
4.9
5.1
4.9
5.2
5.3
5.3
5.1
4.8
7.9
7.5
4.0
3.3
4.0
3.9
4.0
4.1
4.5
4.0
4.0
6.6
5.7
10.0
9.5
8.0
8.1
8.4
8.4
7.5
8.2
8.8
7.9
7.5
10.0
9.9
8.6
8.5
8.8
8.8
8.5
9.1
8.8
8.4
8.8
60.2
59.9
56.5
57.0
56.8
56.7
56.9
63.2
63.8
57.5
56.7
59.0
58.6
55.2
55.7
55.8
55.6
n/a
61.8
62.3
57.0
55.6
for the approximate assignment of relative stereochemistry of
isoleucine residues in compounds with unknown relative
stereochemistry. The C NMR data also suggest a useful trend
with the chemical shift corresponding to the α-CH of the D-
allo-isoleucine derivative always occurring at a lower chemical
shift than that for the L-isoleucine derivative, in most cases by
more than 1 ppm. Taken in conjunction with the H NMR
data, the C NMR data are also likely to prove extremely useful
for the approximate assignment of relative stereochemistry of
isoleucine residues in novel natural products.
1
3
̲
0
2
3
5
6
1
13
a
To the nearest 0.1 Hz.
N-Arylation and peptide coupling
Table 2 Chemical shifts and coupling constants of L-isoleucine and reactions
D-allo-isoleucine diastereoisomers 2 to 16 in CD
3
OD
N-Heteroaryl-amine derivatives, including N-aryl-α-amino-acid
3
a
α-CH (ppm)
̲
J
CH–CH (Hz)
derivatives, provide important building blocks for a number of
1
6
biologically active products. We considered whether the
NMR-based trends described above for distinguishing L-iso-
and D-allo-isoleucine derivatives would apply to N-aryl com-
pounds. A range of methods for N-arylation have been
described, including the use of copper, palladium and nickel
Entry
L
D-allo
L
D-allo
2
3
4
5
6
7
9
1
1
1
1
1
4.00
3.70
3.67
4.37
4.57
4.56
4.42
4.40
4.31
4.33
4.15
4.20
4.03
3.82
3.82
4.54
4.74
4.74
4.56
4.55
4.48
4.48
4.31
4.35
4.0
7.0
5.5
5.8
6.4
6.9
6.0
5.3
6.1
5.7
8.3
7.5
3.9
5.0
4.5
4.7
5.0
5.6
4.4
4.0
5.1
4.8
6.7
5.7
1
6e,17
catalysis.
reported,
N-Arylations of chiral amino-acids have been
and while some methods involve harsh con-
17c,18
0
2
3
5
6
ditions that risk racemisation, other methods are much milder
and can occur without loss of stereochemical integrity as part
19
of amino-acid analysis.
To test these methods L-isoleucine methyl ester hydro-
chloride 2a was heteroarylated with four imidoylchloride-like
aryl chlorides in metal free conditions (Table 4). As expected
a
To the nearest 0.1 Hz.
1
in the mildly basic reaction conditions, H NMR analysis indi-
cated that arylations proceeded without significant epimerisa-
Table 3 Chemical shifts and coupling constants of L-isoleucine dia- tion (17a–20a) when compared to reactions of a diastereoiso-
stereoisomers and D-allo-isoleucine diastereoisomers 1–16 in (CD SO
meric mixture of L-iso- and D-alloisoleucine methyl esters 17b–
3 2
)
1
2
0b (not drawn, see ESI†). The product ratios measured by H
3
a
3
a
α-CH
̲
(ppm)
D-allo
J
CH–CH (Hz)
J
CH–NH (Hz)
NMR were confirmed by HPLC. Peptide couplings of
N-arylated amino-acids have been used in the synthesis of a
variety of peptidomimetic molecules, including DNA topo-
Entry
L
L
D-allo
2.9
L
D-allo
b
b
b
b
1
2
3
4
5
6
7
9
3.05
3.91
3.54
3.52
4.17
4.33
4.36
4.23
4.19
4.15
4.15
4.10
4.12
3.08
3.92
3.69
3.67
4.35
4.53
4.55
4.39
4.36
4.33
4.33
4.25
4.25
3.2
4.2
7.5
6.0
6.5
7.6
7.7
6.6
5.9
7.4
6.2
8.5
7.5
20
21
22
isomerases, cathepsin S. inhibitors, and benzoxaborales.
3.8
6.0
4.5
5.0
5.8
6.4
5.1
4.4
5.1
5.1
6.3
5.7
9.0
9.0
8.1
7.6
7.7
8.4
8.6
7.4
8.4
8.5
8.8
10.0
9.5
8.5
8.5
8.0
8.6
8.8
8.7
8.6
9.0
9.2
We decided to extend the current study to include the syn-
thesis of two N-aryl isoleucylglycine methyl esters, as well as
the related N-benzoyl and N-tosyldipeptides for comparison.
N-Aryl methyl esters 18a and 20a were hydrolysed and coupled
to glycine methyl ester without isolation of the acids. Acids 4a
and 6a were coupled directly (Table 5). Dipeptides 21a–23a
were produced as essentially single diastereoisomers, by com-
parison by both NMR spectrometry and HPLC with authentic
stereoisomeric mixture 21b–24b (not drawn, see ESI†). The
N-benzoyl product 24a was produced as a near equal mixture
1
1
1
1
1
0
2
3
5
6
a
b
To the nearest 0.1 Hz. Not measurable.
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Table 4 N-Arylation reactions of isoleucine methyl ester
Product
Heterocycle
Yield %
(2S,3S) : (2R,3S) by NMR
(2S,3S) : (2R,3S) by HPLC
a
17a
55
>95 : 5
>99 : 1
b
1
1
2
8a
9a
0a
30
>95 : 5
>95 : 5
>95 : 5
99 : 1
>99 : 1
>99 : 1
b
33
b
36
a
b
Microwave, 80 °C, sealed tube, 2 h. 20 °C, 1 atm, 12 h.
9
c
Table 5 Peptide coupling reactions of N-arylated isoleucine derivatives
α-carbon and 5(4H)-oxazolone formation. In practise, these
are normally minimised by careful control of reaction tempera-
ture, pH and N-substituent on the C-terminal amino-acid.
Generally, N-amido amino-acids are more prone to racemisa-
tion than N-carbamate amino-acids (e.g. N-Cbz, N-Boc or
N-Fmoc amino acids) having a greater tendency to oxazolone
9c,25
formation.
Despite this, the benzoxazole and triazine active
esters do not epimerise during peptide coupling via the related
imidazolinone even though the heterocyclic nitrogens are in an
analogous position to that of the amide oxygen in the benz-
amide (Scheme 4). Such a difference may be due to reduced
nitrogen nucleophilicity because of increased steric crowding
compared to the amide. Relative basicity does not correlate with
nucleophilicity in this case as, even though 2-amino-4,6-
(
2S,3S) : (2R,3S)
(2S,3S) : (2R,3S)
by HPLC
Entry
R
Yield
50%
by NMR
21a
>95 : 5
>99 : 1
22a
76%
97 : 3
>97 : 3
26
dimethoxy-s-triazine is a very weak base in water, 2-amino-
2
7
2
2
3a
4a
84%
54%
>95 : 5
44 : 56
>99 : 1
benzoxazole has a pKaH(H
2
O) of 3.73, and is therefore signifi-
2
8
cantly more basic than benzamide (pKaH(H
2
O) = −1.53).
1
13
Analysis of the H NMR and C NMR data for the N-aryl
esters and the dipeptides show that the trends in relative
chemical shift and coupling constants for the (2S,3S)- and
Not measured
2
Reagents (i) LiOH H O, THF then EDCI, HOBt, NMM, EtOH, 0 °C to rt,
17 h.
of diastereoisomers. While it is well known that N-benzoyl
amino acids tend to racemise during standard peptide coup-
2
3
24
ling reactions, and that N-sulfonyl amino acids do not, to
the best of our knowledge, there is little quantitative infor-
mation regarding the levels of epimerisation of the C-terminal
N-arylated amino-acids during these peptide coupling reac-
tions. There are two main mechanisms of epimerisation
Scheme 4 Potential racemization mechanism of N-imidoyl amino-
during peptide coupling reactions, deprotonation of the acids during peptide coupling.
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Table 6 Chemical shifts and coupling constants L-isoleucine and D-allo-isoleucine diastereoisomers of N-aryl and dipeptide compounds in CDCl
3
3
a
3
a
α-CH
̲
(ppm)
J
CH–CH (Hz)
J
CH–NH (Hz)
α-C ̲H (ppm)
Entry
L
D-allo
L
D-allo
c
L
D-allo
L
D-allo
b
b
b
b
c
c
c
17
18
19
20
21
22
23
24
4.76
4.58
4.63
4.59
4.30
4.47
3.55
4.57
4.93
58.5
60.4
62.1
57.9
61.7
59.3
61.5
57.9
57.4
59.4
60.5
56.8
60.8
58.1
60.2
57.1
4.70b
4.79
4.73b
4.48
4.64
3.67
4.69
c5.5
c5.0
c4.5
8.5
8.5
c8.5
9.0
9.0
c9.5
c4.5
7.5
4.0
7.0
5.0
5.5
5.5
7.5
8.5
8.5
8.5
8.5
8.5
a
b
c
To the nearest 0.5 Hz. Value is the centre of an undefined multiplet. Not measurable.
(2R,3S)-diastereoisomers described above apply to these formations, or if the stereochemical differences cause a signifi-
compounds as well (Table 6).
cant change in backbone conformation which is itself the
3
4
While L-isoleucine is the most common diastereoisomer in reason for the observed differences in the NMR spectra.
natural products, D-allo-isoleucine is also fairly common in Differentiation between these two possibilities may be effected
microbial peptides, including the sporidemolides, stendomy- by studying pairs of stereoisomers with defined conformations
cin, angolide, actinomycin C, calpinactam and peptidolipin N. e.g. involving cyclic peptides of various sizes. Conformational
2
9
A. In addition, D-allo-isoleucine has been identified in pep- analysis would be supported with molecular modelling. While
3
3
tides isolated from the skin of the yellow bellied toad, Bombina the analysis of the spectra from teixobactin, which contains
3
0
variegate. Unsurprisingly, considering the comparative stabi- both linear and cyclic isoleucine-containing regions, indicates
lity of the β-CH of isoleucine peptides containing L-allo-isoleu- that the trends presented in this paper may be applicable to
cine and D-isoleucine are far less common, though a few more complex peptides, the issues of conformation and
̲
3
1
examples do exist. Alteration of relative stereochemistry of additional stereochemistry are the subjects of future work in
isoleucine within a peptide can have significant effects of its our laboratory and results will be reported in due course.
structure and folding, and potentially its biological activi-
3
1d,32
ty.
The ability to distinguish between, and potentially
predict, the stereochemistry isoleucine diastereoisomers by a
non-destructive method such as NMR, instead of peptide
Conflicts of interest
hydrolysis, is valuable, particularly for complex natural There are no conflicts to declare.
proteins, which are often only obtained in minute quantities.
While in this study we cannot distinguish between L-allo-
isoleucine and D-allo-isoleucine, and between the L- and
D-isoleucine, the comparative rarity of the D- and L-allo forms
Acknowledgements
means that this method will prove extremely useful. This We wish to thank the EPSRC (DTA studentship for ZJA) and
method can be applied to the structure of the antibiotic the University of Warwick (PhD studentships for MSP and PK,
3
3
peptide teixobactin. By hydrolysis, and derivatisation using URSS funding for CH) for funding, and Prof. G Challis for
Marfey’s method, teixobactin was found to contain three useful discussions. Data are available at http://wrap.warwick.
L-isoleucines and one D-allo-isoleucine. It is worth noting that ac.uk/74515.
the full assignments of the NMR spectra of the peptide in
1
deuteriated DMSO show that in the H NMR spectrum the
peak corresponding to the α-CH hydrogen of the D-allo-
isoleucine residue has a higher chemical shift (4.36 ppm) than
Notes and references
the peaks due to the α-CH hydrogens of the three L-isoleucine
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2 R. Bhushan and H. Brückner, Amino Acids, 2004, 27, 231–
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13
residues (4.29, 4.12 and 4.03 ppm), and that in the C NMR
spectrum the peak corresponding to the α-CH carbon of the
D-allo-isoleucine has a lower chemical shift (56.8 ppm) than
those corresponding to α-CH carbons of the three L-isoleucine
residues (57.3, 57.8 and 57.9 ppm), in agreement with the
trends observed in Tables 1–3 and 6.
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observed are due to purely stereochemical differences in
amino-acid derivatives with otherwise similar backbone con-
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