α-Methyl phenylglycines by asymmetric α-arylation of alanine and their effect on the conformational preference of helical Aib foldamers

Article abstract of DOI:10.1039/c8ob00551f

α-Arylated alanine derivatives were made enantioselectively by migratory rearrangement of a urea derivative using (R,R)-pseudoephedrine as a chiral auxiliary. Incorporation of a single residue of the product α-methyl phenylglycine into an otherwise achiral oligomer of aminoisobutyric acid oligomer induced a preferred screw sense, detectable by a NMR reporter located at the remote terminus of the oligomer. The magnitude of the screw sense induction was greater when the chiral residue was located at the N-terminus of the foldamer, and in some cases the sense of induction was opposite to that of related α-methylated amino acids with α-substituents other than aryl.

Full text of DOI:10.1039/c8ob00551f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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α-Methyl phenylglycines by asymmetric α-arylation of alanine
and their effect on the conformational preference of helical Aib
foldamers
Received 00th January 20xx,
Accepted 00th January 20xx
Romain Costil,a Fernando Fernández Nieto,b Rachel C. Atkinson,b and Jonathan Claydena*
DOI: 10.1039/x0xx00000x
www.rsc.org/
α-Arylated alanine derivatives were made enantioselectively by
migratory rearrangement of urea derivative using (R,R)-
O
a
pseudoephedrine as a chiral auxiliary. Incorporation of a single
residue of the product α-methyl phenylglycine into an otherwise
achiral oligomer of aminoisobutyric acid oligomer induced a
preferred screw sense, detectable by a NMR reporter located at
the remote terminus of the oligomer. The magnitude of the screw
sense induction was greater when the chiral residue was located
at the N-terminus of the foldamer, and in some cases the sense of
induction was opposite to that of related α-methylated amino
acids with α-substituents other than aryl.
O
N
O
O
F
O
N+
N
O
HN
Famoxadone
(fungicide)
AZD9164
(antimuscarinic)
Figure 1: Examples of bioactive α-methyl phenylglycine derivatives.
Incorporation of an additional substituent at the α position of a
In general, quaternary amino acids have been synthesised by
alkylation of their naturally occurring tertiary parent, with the
configuration of the product being controlled either by some
form of chiral memory or by an asymmetric alkylation step.7
The corresponding introduction of an aryl substituent is a
much more challenging prospect. We have shown that N’-aryl
urea derivatives of amino acids undergo rearrangements that
yield hydantoin derivatives of quaternary amino acids bearing
an α aryl substituent,8 and Kawabata et al. concurrently
reported a related reaction that allows incorporation of aryl
substituents with chiral memory.9 More recently, we reported
a general approach to the stereoselective arylation of α-amino
acids using pseudoephedrine as a chiral auxiliary.10 This
rearrangement was facilitated by temporary in situ protection
of the urea as its N- or O-silyl derivative by treatment with
trimethylsilyl chloride.
We now report that it is possible to synthesise enantio-
enriched α-methyl phenylglycine derivatives by a practical
modification of this rearrangement method, in which a 2,4-
dimethoxybenzyl (DMB) group is used for protection of the
urea N atom. We show that the resulting quaternary amino
acid may be incorporated into a helical Aib-containing
oligomer at either the C- or the N-terminus, and that the
stereogenic centre of this single quaternary residue may
typical proteinogenic amino acid has important consequences
for the properties of the resulting quaternary amino acid.
Several families of fungal non-ribosomal peptides incorporate
quaternary amino acids into their type sequence. The most
common of these is the achiral residue α-aminoisobutyric acid
(Aib),1 but also prevalent are the dialkylated chiral residues as
isovaline, α-methylvaline, and α-methyl phenylalanine. These
quaternary amino acid residues typically induce a strong
preference for helical conformations, and extensive
conformational studies have been carried out on peptides
containing such residues.2
α-Methyl phenylglycine ((αMe)Phg) and its derivatives
have been studied over the last two decades in programs
involving peptide conformation and catalysis,3 as resolving
agents in resolutions through selective crystallization4 or as
alternative sweeteners.5 Its derivatives are also found as a
structural feature in many targets of medicinal chemistry
(Figure 1),6 making effective methods for its synthesis
particularly valuable.
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Table 1: Stereoelective rearrangement of the pseudoephedrine derived compounds
induces a screw sense preference in the whole of the resulting
helical oligomer.
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DOI: 10.1039/C8OB00551F
Ar
O
OH
Ar
Results and Discussion
DMB
O
LDA, LiCl
N
N
N
N
THF
–78 °C to rt, 3 h
N
Enantioselective α-arylation of alanine
R'
DMB
O
O
R'
Starting materials 3a-d for stereoselective rearrangement
were made straightforwardly from alanine derivatives in four
steps (Scheme 1). N-protection of alanine esters 1 with the
2,4-dimethoxybenzyl (DMB) group was achieved by reductive
amination with 2,4-dimethoxybenzaldehyde. Coupling of the
amine with a series of carbamoyl chlorides, followed by
hydrolysis of the ester moiety with lithium hydroxide in a
biphasic system, afforded carboxyureas 2a-d in excellent
yields. These carboxylic acids were coupled to (R,R)-
pseudoephedrine without epimerisation using standard
coupling reagents EDC.HCl and HOBt.H2O to give 3a-d in
excellent overall yield.
The reaction conditions for stereoselective arylation were
optimised by exploring base-promoted phenyl migration
within compound 3a. Optimal conditions were found to
require an excess of lithium diisopropylamide (LDA) in THF in
the presence of ten equivalents of lithium chloride. Full
conversion was attained after deprotonation at –78 °C
followed by a period of three hours at room temperature. As
observed previously by IR,8 enolate formation is followed by
migration of the ring to the α position of the alanine residue,
followed by cyclisation to the hydantoin with concurrent
expulsion of the pseudoephedrine auxiliary. N-to-C migration
of a selection of aryl rings was performed in moderate to good
yield (Table 1), with enantiomeric excesses ranging from near-
racemic (compound 4c) to complete enantiopurity (compound
4a). The reason for the strong variation in stereoselectivity
with migrating ring is unclear, and shows that an alternative
more general method is required for rings other than phenyl.11
3a-d
4a-d
Entry
Product
Ar
Ph
R’
Yield
69%
56%
58%
37%
e.r
1
2
3
4
4a
4b
4c
4d
CH3
CH3
CH2CH3
CH3
>99:1
69:31
55:45
78:22
2-MeOC6H4
Naphthyl
2-pyridyl
a
b, c
O
DMB
O
HN
O
N
87%
69%
H2N
N
N
(2 steps)
O
O
O
4a
5a
(R)-(αMe)PhgOMe
[α]D20= –61.1 (lit. –51.85)
Scheme 2: Hydrolysis of the hydantoin. Reagents and conditions: (a) TfOH, TFA,
0°C; (b) NaOH, H2O, dioxane, 100°C; (c) SOCl2, MeOH, rt. DMB
dimethoxybenzyl.
= 2,4-
Enantiopure hydantoin 4a was converted into the
corresponding amino acid methyl ester (Scheme 2). Acidic
removal of the dimethoxybenzyl group afforded free
hydantoin 5a, which was hydrolysed under basic conditions to
α-methyl phenylglycine, isolated as its methyl ester.
Comparison of the optical rotation with reported values
allowed us to assign the stereochemistry at the quaternary
carbon to be R.5 Interestingly, the stereocenter formed in this
rearrangement is the opposite of the major enantiomer
formed in our previous, protecting group-free, rearrangement
using the same enantiomer of pseudoephedrine.10
Deprotection of hydantoin 4b followed by hydrolysis gave only
the corresponding amino N-methyl amide 6b despite forcing
conditions (See the Supporting Information for details),
suggesting that additional substitution not only decreases
stereoselectivity but also hinders significantly the hydrolysis of
the products.
O
Ar
a, b, c
OR
H2N
N
N
COOH
O
R'
DMB
1a: R = CH3
2a: Ar = Ph, R' = CH3
2b: Ar = 2-MeOC6H4, R' = CH3
2c: Ar = 1-Naphthyl, R' = CH2CH3
2d: Ar = 2-pyridyl, R' = CH3
1b: R = CH2CH3
Synthesis and conformation of foldamers containing an α-aryl
quaternary amino acid residue
d
Homo-oligomers of the achiral quaternary amino acid Aib form
310 helices as an interconverting mixture of M and P
enantiomeric conformers, but even a single chiral amino acid
can powerfully bias the M:P ratio, with the absolute screw
sense induction depending on the nature and location of the
chiral residue.12 No information is available on the influence of
α-arylated residues on screw sense preference, so the chiral
quaternary amino acid derivatives previously made were
coupled to achiral Aib oligomers at either the N- or the C-
O
OH
Ar
N
N
N
R'
DMB
O
3a-d
Scheme 1: Reagents and conditions: (a) 2,6-dimethoxybenzaldehyde, NaOAc,
NaHB(OAc)3, EtOH, rt; (b) ArN(R’)COCl, triethylamine, MeCN, reflux; (c) LiOH,
THF/H2O, 45°C; (d) EDC.HCl, HOBt.H2O, (R,R)-pseudoephedrine, CH2Cl2, rt. DMB =
2,4-dimethoxybenzyl.
2 | J. Name., 2012, 00, 1-3
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terminus and their conformational influence was explored by
NMR and by Circular Dichroism (CD).
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DOI: 10.1039/C8OB00551F
(αMe)PhgOMe was converted to its N-methyl amide
derivative 6a (See SI for details) and, together with its ortho-
methoxylated analogue 6b, coupled to the C-terminus of an
Aib tetramer by nucleophilic attack on the foldamer’s
azlactone derivative 7 (Scheme 3). In order to monitor the
global screw sense preference of the resulting foldamer, the
tetramer was coupled to a N-terminal azepine probe.12b,13
Hydrogenation of the N-terminal azide allowed introduction of
the probe in good yield by acylation with its succinimidyl ester
derivative.
Addition of DMSO-d6 to a solution of 9a in CD2Cl2/CD3OH
9:1 led to a significant deshielding of the two highest field N-H
protons (Figure 2). This downfield shift suggests that the two
NH protons furthest from the controller in 9a are not part of a
hydrogen-bonding network, consistent with the adoption of a
310-helical conformation. Further support for this
interpretation was gained from the CH–NH regions of the
Figure 2: DMSO-d6 titration of 9a (approx. 0.01 M in CD2Cl2/CD3OH 9:1)
ROESY spectrum in CD2Cl2/CD3OH. A diagnostic CHβ –NHi+3
i
cross peak is visible (Figure 3, circled in red), confirming the
presence of a 310-helix along the structure of 9a. The absence
of CHi–NHi+4 cross peak suggests that there is no α-helical
contribution to the structure.
N
H
O
N
O
N3
O
O
O
2
H
7
CH3CN, reflux
Figure 3: Aromatic region of the ROESY spectrum of 9a (approx. 0.01
CD2Cl2/CD3OH 9:1).
M in
H2N
H
N
N
H
N
H
N
H
then
H2, Pd/C, MeOH
O
4
Ar
Ar
6a: Ar = Ph
8a: Ar = Ph
8b: Ar = 2-MeOPh
30000
20000
10000
6b: Ar = 2-MeOPh
O
O
H
N
a, b
N
N
N
H
H
O
4
Ar
9a: Ar = Ph
9b: Ar = 2-MeOPh
Scheme 3: Reagents and conditions: (a) DSC, DCM, rt; (b) 6,7-Dihydro-5H-
dibenz[c,e]azepine hydrochloride, DIPEA, MeCN, rt. DSC
carbonate.
0
= N,Nʹ-Disuccinimidyl
200
250
300
350
Wavelength (nm)
Figure 4: CD spectrum of 9a (0.68 mM in MeOH).
1H NMR in CD3OD revealed diastereotopic signals for the
methylene groups of the azepine probe, indicating an excess of
one screw-sense conformer over the other.14 By comparison
with the values obtained for other conformational controllers
with known equilibrium ratios,13a we deduced that (R)-
(αMe)Phg exhibits rather modest levels of control, with a
helical excess (h.e.) of just 10% in a mixture of CD3OH and
CDCl3 (9:1). The ortho-methoxy substituent of compound 9b
increases the control slightly to a h.e. of 21% in deuterated
methanol.
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Figure 5: Variable Temperature 1H NMR of 10 (approx. 0.01 M in CD3OH).
The CD spectrum of peptide 9a in methanol showed a local
maximum centered around 250 nm for the biaryl probe (Figure
4). The molar ellipticity at this wavelength indicates a helical
excess of about 7% induced at the probe (in line with the low
value deduced by 1H NMR spectroscopy), and its positive value
indicates a right-handed (or P) screw-sense preference in
solution. C-terminal amides of D-amino acids typically induce
View Article Online
DOI: 10.1039/C8OB00551F
9000
7000
5000
3000
1000
-1000
-3000
-5000
-7000
M
helices whether the chiral residue is tertiary or
quaternary,12c so this weak preference is opposite to that
induced by related amino acids, presumably because of the
unusual α-arylated structure of the controlling residue.
The effect of introducing 6a at the N-terminus of the
oligomer was explored using an Aib tetramer bearing a C-
terminal thionoglycine probe (Scheme 4).15 The methyl ester of
6a was first capped with a carboxybenzyl (Cbz) protecting
group and hydrolysed to the corresponding carboxylic acid.
Tetramethylfluoroformamidinium hexafluorophosphate was
used to form its acyl fluoride derivative, which was coupled to
a hexamer already containing the embedded thioamide probe
to afford foldamer 10.
200
250
300
350
Wavelength /nm
Figure 6: CD spectrum of 10 (0.62 mM in MeOH).
The CD spectrum of the foldamer shows the typical absorption
band for the π-π* transition of the thionoglycine probe
centered at 268 nm (Figure 6). The negative value of the
ellipticity in this region indicates a left-handed screw-sense
preference (or M helix) for compound 10, indicating that, at
this N terminus of the foldamer, (R)-(αMe)Phg induces the
same screw-sense preference as the related quaternary amino
acid (R)-(αMe)Val, presumably by the mechanism of induction
previously proposed.12,16,17
1
Variable Temperature H NMR of peptide 10 in CD3OH,
between 5 and 35°C showed a significant downfield drift of the
chemical shift of two of the amide protons. This suggests that
only these two amide protons lie outside of the hydrogen-
bonded network, consistent with the folding of 10 into a 310
helix (Figure 5). In CD3OD at room temperature, the foldamer
shows a characteristic pair of signals for the diastereotopic
methylene protons of the thionoglycine residue, centred
around 4.20 ppm. Comparison of their anisochronicity with
reported values15 indicates that this N-terminal controller
induces a helical excess of 42%, similar to that of L-CbzPhe.
Conclusions
Aryl substituents may be introduced enantioselectively to the
α-carbon of alanine derivatives using the base-promoted
rearrangement of a urea derivative carrying using pseudo-
ephedrine as a chiral auxiliary. While migration of a phenyl ring
occurs with excellent enantiomeric excess, other migrating
rings showed low selectivity or low yield. Protection of the
urea by 2,4-dimethoxybenzyl permits simple operational
conditions, leading to quaternary arylated amino acids after
deprotection and hydrolysis of the resulting hydantoin.
Isolation of the opposite enantiomer to that obtained by a
previously reported procedure10 allows access to both
enantiomers of the quaternary amino acid derivative by using
the same chiral auxiliary.
O
O
a - d
H
H
N
N
OCH3
N
H
O
CbzHN
H2N
S
O
O
4
(R)-(αMe)PhgOMe
10
Scheme 4: Reagents and conditions: (a) CbzCl, DIPEA, CH2Cl2, rt; (b) NaOH, MeOH, H2O,
rt; (c) TFFH, Pyridine, CH2Cl2, rt; (d) H-Aib4Gly-ψ[CSNH]AibOMe, DIPEA, CH2Cl2, rt.
(αMe)Phg 6a (and its ortho-methoxylated derivative 6b)
participates in a 310 helix when incorporated at either the N- or
the C- terminus of an Aib oligomer. While these two unnatural
amino acid derivatives induce moderate control over the
overall screw-sense from the C-terminus, (αMe)Phg displays
more promising levels of conformational control from the N-
terminus.
Acknowledgements
This work was supported by the European Research Council
(Advanced Grant ROCOCO).
Conflicts of interest
4 | J. Name., 2012, 00, 1-3
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16 M. De Poli, M. De Zotti, J. Raftery, J. A. Aguilar,VieGw. AArt.icMle Oonrlrinies
and J. Clayden, J. Org. Chem., 2013, 78D, 2O2I:4180..11039/C8OB00551F
17 The molar ellipticity at this wavelength is consistent with a
foldamer with a helical excess of only 16%. This discrepancy
is presumably due to the Cotton effect arising from the
aromatic ring in the chiral residue. Related ‘local’ effects
have been shown to make CD an unreliable reporter of
screw sense preference in some cases, see: R. A. Brown, T.
Marcelli, M. De Poli, J. Solà and J. Clayden Angew. Chem. Int.
Ed., 2012, 51, 1395.
There are no conflicts to declare.
Notes and references
1
2
3
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8
9
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10 R. C. Atkinson, F. Fernández-Nieto, J. Mas Roselló and J.
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11 D. Leonard, J. W. Ward and J. Clayden, Manuscript in
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14 Chemical shift separation quantifies conformational
preference in a system such as this, which is in fast
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Graphical abstract:
Asymmetric arylation of an alanine derivative provides (R)-α-methyl phenylglycine, which induces a right handed screw
sense in an Aib oligomer.