Asymmetric α-arylation of amino acids

Article abstract of DOI:10.1038/s41586-018-0553-9

Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds^1,2. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods^3–8, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging⁹. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules^10,11. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N′-arylurea adduct¹² of an imidazolidinone derivative⁶ of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.

Full text of DOI:10.1038/s41586-018-0553-9

Letter
https://doi.org/10.1038/s41586-018-0553-9
Asymmetric α-arylation of amino acids
Daniel J. Leonard1, John W. Ward1 & Jonathan Clayden1*
Quaternary amino acids, in which the α-carbon that bears the amino cis-3-Ala-a in high yield (Fig. 2a, Extended Data Table 1, entry 1).
and carboxyl groups also carries two carbon substituents, have an The major trans diastereoisomer of 1-Ala (which characteristically and
important role as modifiers of peptide conformation and bioactivity diagnostically exhibited slow N–CO rotation by NMR; Supplementary
and as precursors of medicinally important compounds1,2. In Information) was much less reactive. The urea trans-3-Ala-a was
contrast to enantioselective alkylation at this α-carbon, for which formed only when trans-1-Ala was activated with potassium iodide20,
there are several methods3–8, general enantioselective introduction and a reaction time of 45 h in refluxing CH2Cl2 was required for accept
of an aryl substituent at the α-carbon is synthetically challenging9. able yields (Fig. 2a, Extended Data Table 1, entries 2–4).
-
Nonetheless, the resultant α-aryl amino acids and their derivatives
We were now in a position to address the question of the key C–C
are valuable precursors to bioactive molecules10,11. Here we describe bond forming step: whether ureas 3-Ala can undergo the rearrange-
the synthesis of quaternary α-aryl amino acids from enantiopure ment we had discovered with other amino acid enolates to provide
amino acid precursors by α-arylation without loss of stereochemical a means of arylating the amino acid α-centre in a diastereoselective
integrity. Our approach relies on the temporary formation of manner. cis- and trans-3-Ala-a were each cooled and treated with base
a second stereogenic centre in an N′-arylurea adduct12 of an to form an enolate, which was allowed to warm to room temperature.
imidazolidinone derivative6 of the precursor amino acid, and uses Initial experiments with lithium diisopropylamide (LDA) showed that
readily available enantiopure amino acids both as a precursor and enolate formation was complete at −78°C (Extended Data Table 2,
as a source of asymmetry. It avoids the use of valuable transition entry 1), and that warming to room temperature was sufficient to
metals, and enables arylation with electron-rich, electron-poor and induce 1,4 migration of the phenyl ring to the enolate carbon to yield
heterocyclic substituents. Either enantiomer of the product can be the C-arylated product imidazolidinone 4-Ala-a from trans-3 and its
formed from a single amino acid precursor. The method is practical enantiomer ent-4-Ala-a from cis-3 (Extended Data Table 2, entries
and scalable, and provides the opportunity to produce α-arylated 2, 3). The best yields were obtained on forming the enolate at 0°C,
quaternary amino acids in multi-gram quantities.
and even with the milder base potassium bis(trimethylsilyl)amide
Among the most practical and widely used methods13,14 for the syn- (KHMDS), 4-Ala-a was formed in 95% yield from trans-3-Ala as a
thesis of α-alkylated amino acids are those that use a readily available single diastereoisomer on a>1-g scale (Extended Data Table 2, entry 4).
chiral amino acid both as a starting material and as a source of chirality, These conditions (shown as method A in Fig. 2a) were identified as
using the principle of ‘self-regeneration of stereocentres’6. This strategy optimal, and a similar yield of the enantiomeric product ent-4-Ala
relies on the diastereoselective formation of an imidazolidinone or oxa- was obtained under these conditions from cis-3-Ala (Extended Data
zolidinone, which creates a new stereogenic centre. The configuation Table 2, entry 5). In neither case was any trace of the other diastereo-
of this stereocentre is retained during the formation of a planar amino isomer of 4-Ala detectable in the product by 1H NMR, and high-
acid enolate, and it then directs alkylation of the enolate to form a performance liquid chromatography on a chiral stationary phase
quaternary stereocentre with control over absolute configuration.
indicated that the product was essentially enantiomerically pure, with
The mechanistically unusual15 N-to-C aryl migration that occurs in an enantiomeric ratio (e.r.) of>99:1.
anionic derivatives of ureas was first reported in the construction of
stereodefined quaternary centres from configurationally stable organo-
lithiums12, and it has been used to prepare racemic 5,5-disubstituted
Enantiopure quaternary
α-arylated amino acids
Readily available
amino acids
hydantoins16. Stereoselective versions of this hydantoin synthesis using
conformational chiral memory17 or a stoichiometric auxiliary18 sug
-
H
R
R
Ar
CO2H
gested that a practical stereoselective modification of this intramolec-
ular arylation based on imidazolidinone alkylation chemistry might
offer a strategy for the synthesis of unavailable enantiopure α-arylated
amino acids (Fig. 1).
H2N
CO2H
H2N
A
E
Stereoselective
heterocycle
formation
Hydrolysis
We therefore explored N′-aryl ureas as a potential intramolecular
source of the coupling partner for a corresponding arylation reaction. A
versatile synthesis of the N-carbamoylimidazolidinones 3 was required,
and our initial synthetic approach is shown in Fig. 2a. Treatment of
l-AlaNHMe with pivaldehyde and trifluoroacetic acid formed the trans
diastereoisomer of the imidazolidinone trifluoroacetate salt with good
selectivity19. In situ chloroformylation with triphosgene in base gave high
yields of the N-chloroformylimidazolidinones 1-Ala, as a 4:1 mixture
of the trans and cis diastereoisomers trans-1-Ala and cis-1-Ala. These
were readily separated by column chromatography and their relative
configurations were established by X-ray crystallography (Fig. 2b) and
nuclear Overhauser effect experiments (Supplementary Information).
The minor diastereoisomer cis-1-Ala acylated N-methylaniline
Ar
Ar
N
MeHN
Stereoselective
rearrangement
R
Ar
O
R
N
N
H
R
N
Enolate
formation
O
O
O
N
O
N
O
N
N
t-Bu
t-Bu
t-Bu
B
C
D
Fig. 1 | Stereoselective arylation of amino acids. Our strategy for
stereoselective arylation of amino acids by way of imidazolidinyl ureas is
shown. An amino acid (A) is converted diastereoselectively into an
imidazolidinone (B) carrying a pendent urea function. Treatment with
base forms an enolate (C) in which the aromatic substituent (Ar) of the
urea migrates to the rear face of the imidazolidone, directed by the bulky
tert-butyl group, as indicated by the red dotted arrows. Hydrolysis of the
(PhNHMe) cleanly in refluxing dichloromethane to give the urea product (D) provides the quaternary α-aryl amino acid (E).
1School of Chemistry, University of Bristol, Bristol, UK. *e-mail: j.clayden@bristol.ac.uk
4
O C t O B e r 2 0 1 8 | V O L 5 6 2 | N A t U r e | 1 0 5
© 2018 Springer Nature Limited. All rights reserved.

reSeArCH Letter
(Method B)
a
ArNHMe (1.2 equiv.),
KHMDS (3 equiv.),
THF, –78 °C–RT
1. NaH, MeI, DMF,
0 °C–RT, 18 h
2. HCl (6 M, aq.)/EtOH
(10:1), 160 °C, MW, 3 h
Ar
R
R
O
KHMDS
(1.5 equiv.),
THF, 0 °C–RT
ArNHMe
(1.1 equiv.)
Ar
R
O
R
N
NHMe
O
S-selective route
O
Ar
R
H2N
Cl
N
O
O
N
N
N
(Method D)
(Method A)
O
1. t-BuCHO (1.1 equiv.),
CF3CO2H (2.0 equiv.),
CH2Cl2, reꢀux, 18 h
N
Et3N (1.5 equiv.)
KI (1.1 equiv.),
CH2Cl2
MeHN
H2N
CO2H
N
Me
t-Bu
Me
L-AlaNHMe (R = Me)
L-PheNHMe (R = Bn)
L-LeuNHMe (R = i-Bu)
t-Bu
Me
t-Bu
trans-3
Me
(S)-5
trans-1
4
reꢀux, 45 h
2. Cl3COCO2CCl3
(0.45 equiv.),
2,6-lutidine (1.2 equiv.),
CH2Cl2, –78 °C–RT, 18 h
1-Ala 90%, 80:20 d.r.
1-Phe 68%, 70:30 d.r.
1-Leu 82%, 70:30 d.r.
t-BuCHO
R-selective
route
MgSO4,
CH2Cl2,
18 h, RT
Ar
R
1. NaH, MeI, DMF,
0 °C–RT, 18 h
2. HCl (6 M, aq.)/EtOH
O
KHMDS
(1.5 equiv.),
THF, 0 °C–RT
R
O
Ar
O
R
ArNHMe
(1.1 equiv.)
Ar
O
N
N
O
R
O
Cl
N
(10:1), 160 °C, MW, 3 h
MeHN
N
R
N
Me
t-Bu
cis-3
(Method A)
N
Et3N (1.5 equiv.)
Me KI (0–1.1 equiv.),
CH2Cl2,
H2N
CO2H
N
(Method D)
NHMe
Me
t-Bu
t-Bu
N
t-Bu
ent-4
Me
(R)-5
O
cis-1
O
2
Ar
reꢀux, 18–45 h
N
Cl
Toluene,
reꢀux
(Method C)
Me
F
e
Cl
F
d
b
BocHN
Boc-7-Ala-d
CO2H
CO2H
HO2C
Cl
FmocHN
CbzHN
CO2H
46%
Fmoc-7-Ala-c
Cbz-7-Ala-d
Cl
66%
96%
H2N
CO2H H2N
CO2H
H2N
CO2H
ii
ii
ii
5-Ala-a
77%
5-Ala-b′
77%
5-Ala-c
83%
iii
Cl
F
iv
5
H2N
CO2Me
F
Br
9
92%
iv
8-Ala-c-OMe
Ph
CO2H
5-Phe-c
Ph
88%
H
H2N
H2N
CO2H
H2N
CO2H
N
CO2Et
Br
CbzHN
c
F
5-Phe-e
83%
5-Ala-d
Ph
CO2Me
O
77%
82%
Ph
v
HO2C
Cl
H2N
8-Phe-e-OMe
i
Br
O
O
ent-4
81%
HN
O
HN
O
Ph
O
N
N
6-Phe-e (R = t-Bu) 66%
6-Phe-e′ (R = H) 94%
H2N
CO2H
H2N
CO2H
HN
O
vi
N
6-Leu-d
6-Leu-i
5-Leu-c
5-Leu-b′
R
50%
60%
74%
76%
Fig. 2 | Arylation of amino acids by way of imidazolidinone ureas.
representative α-arylated amino acids 5 formed by the methylation and
hydrolysis of 4. e, Derivatization of representative quaternary α-arylated
amino acids 5 by N-protection, peptide coupling, esterification or
hydantoin formation. Conditions: ii, 1. N-Methyl-N-(trimethylsilyl)
trifluoroacetamide, CH2Cl2, reflux, 4 h; 2. CbzOSu or Boc2O or FmocOSu
(OSu, N-hydroxysuccinimide), CH2Cl2, RT, 16 h; 3. MeOH, RT, 15 min;
iii, 1. K-Oxyma, EDC·HCl (EDC, 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide), i-Pr2NEt, DMF, 0 °C–RT, 15 min; 2. l-Phe-OEt·HCl,
N,N-diisopropylethylamine, 72 h; iv, Me3SiCHN2, benzene/MeOH (4:1),
RT, 18 h; v, 1. t-BuNCO, CH2Cl2, reflux, 18 h; 2. t-BuOK, THF, RT,
18 h; vi, HBr, acetic acid (1:1), 120 °C, 18 h.
a, Synthetic pathways from l-amino acids to quaternary α-arylated amino
acids 5 by way of N-chloroformylimidazolidinones 1 or imines 2, N′-aryl
imidazolinyl ureas 3, and C-aryl imidazolidinones 4. The sequence shown
by the orange arrows starting from 1 constitutes an S-selective route to 5
from an l-amino acid, whereas the sequence shown by the purple arrows
from 2 constitutes an R-selective route from an l-amino acid. DMF,
dimethylformamide; MW, microwave; RT, room temperature. b, The
stereochemistry of trans-1-Ala is confirmed by X-ray crystallography.
c, Representative α-arylated hydantoins formed by hydrolysis of ent-4.
Conditions: i, HCl (6 M, aq.), 130 °C (sealed tube), 18 h. d, Yields of
Either enantiomer of the product 4-Ala could be formed from the were unproductive even when using KI as an activator (Extended Data
same l-Ala starting material, simply by the choice of route. However, Table 1, entry 6).
some work on the synthesis of 3 was still needed for this to become a
A more robust synthesis of trans-4 was obtained by returning to the
general method for the arylation of amino acids other than alanine. Two easily formed N-chloroformylimidazolidinones trans-1 as alternative
problems remained: first, although cis-3-Phe was successfully formed precursors. Although acylation of a neutral N-methylaniline with trans-1
from cis-1 in the presence of KI (Extended Data Table 1, entry 5), had proved insufficiently general as a way of making 3 (Extended
cis-1 was generally available only in impractically small quantities as it Data Table 1, entry 6), reaction of trans-1-Ala, trans-1-Phe or trans-1-
is formed as the minor diastereoisomer in the preceding chloroformyla- Leu with the anions of a range of N-methyl anilines, formed using an
tion step. Second, the unreactivity of the major diastereoisomer trans-1 excess of KHMDS, not only promoted the acylation of the amine to give
meant that trans-3 could not be formed reliably by this route from trans-3 but also led to deprotonation and rearrangement of 3 to give 4.
amino acids other than alanine: attempted acylations using trans-1-Phe Optimized conditions for this one-pot procedure (labelled method B
1 0 6
| N A t U r e | V O L 5 6 2 | 4 O C t O B e r 2 0 1 8
© 2018 Springer Nature Limited. All rights reserved.

Letter reSeArCH
S-selective route
R-selective route
KHMDS (1.5 equiv.),
THF, 0 °C–RT, 4 h
a
b
R
Ar
N
R
R
O
R
Ar
O
O
O
1. KHMDS (1.2 equiv.),
THF, –78 °C–0 °C, 2 h
S
S
S
R
Ar
O
O
O
O
MeHN
Cl
N
N
N
MeHN
N
+ ArNHMe
2. KHMDS (1.2 equiv.),
THF, 0 °C–RT, 18 h
N
N
N
N
Me
t-Bu
Me
t-Bu
Me
t-Bu
cis-3
Me Ar
Me
t-Bu
Me
trans-1
4
4
Me
CO
Ph
Ar
CO
Ar
Ar
Ph
CO
N
CO
N
N
N
Ar: Ph
4-CN
(R) 4-Ala-a, 95%, >99:1 e.r.
(R) 4-Ala-b, 96%, 96:4 e.r.
(R) 4-Ala-c, 94%, >99:1 e.r.
(R) 4-Ala-d, 95%, 93:7 e.r.
(R) 4-Ala-i, 94%a
Ar: Ph
4-CN
(R) 4-Phe-a, 98%, >99:1 e.r.
(R) 4-Phe-b, 85%, >99:1 e.r.
(R) 4-Phe-c, 88%, >99:1 e.r.
(R) 4-Phe-d, 84%, >99:1 e.r.
Ar: Ph
4-CN
(S) 4-Ala-a, 80%, >99:1 e.r.
(S) 4-Ala-b, 79%, 97:3 e.r.
(S) 4-Ala-c,94%, 90:10 e.r.
(S) 4-Ala-d, 84%, 92:8 e.r.
(S) 4-Ala-m, 54%a
Ar: Ph
4-CN
(S) 4-Phe-a, 80%, >99:1 e.r.
(S) 4-Phe-b,77%, >99:1 e.r.
(S) 4-Phe-c,89%, 97:3 e.r.
4-Cl
4-Cl
4-F
4-Cl
4-F
4-Cl
a
4-F
3-Br
(S) 4-Phe-e, 74%
4-Me (R) 4-Phe-i, 80%, >99:1 e.r.
3-OMe
3,5-Cl (S) 4-Phe-f,84%a
4-Me
3-OMe (S) 4-Phe-k,94%, >99:1 e.r.
4-Me
4-Py
3-Py
2-Py
(R) 4-Ala-j, 90%a
(S) 4-Ala-n, 91%a
4-OMe
3-OMe (R) 4-Ala-k, 91%a
(R) 4-Phe-k, 88%, >99:1 e.r.
2-OMe (R) 4-Phe-l, 84%, 98:2 e.r.
(S) 4-Phe-i,83%, >99:1 e.r.
(S) 4-Ala-o, 94%, 96:4 e.r.
2-OMe
2-Py
(S) 4-Phe-l,56%, 97:3 e.r.
(R) 4-Ala-o, 97%, 98:2 e.r.
XO
Ph
CO
Ar
Ar
N
OBn
Ar
N
N
CO
CO
N
CO
H
(R) 4-Tyr-a,85%, >99:1e.r.
X =
4-CN
4-Cl
4-F
Ar: Ph
Ar:
(R) 4-Leu-b, 87%, >99:1 e.r.
(R) 4-Leu-c, 87%, >99:1 e.r.
(R) 4-Leu-d, 83%, >99:1 e.r.
(R) 4-Leu-i, 81%, 98:2 e.r.
(S) 4-TyrOBn-a, 95%, >99:1 e.r. Ar: 4-CN (S) 4-Leu-b,84%, >99:1 e.r.
(S) 4-TyrOBn-g, 92%a
(S) 4-Leu-c,87%, >99:1 e.r.
(S) 4-Leu-d,76%, >99:1 e.r.
Bn (R) 4-TyrOBn-a, 88%, >99:1 e.r.
3-F,4-Br
2-naphthyl
2-OMe
4-Cl
a
BnN
4-F
(S) 4-TyrOBn-h, 62%
N
(S) 4-TyrOBn-l, 60%a
4-Me
4-Me (S) 4-Leu-i, 64%, 98:2 e.r.
MeS
N
CO
Ph
Ar
Ar
N
Ar
CO
Ph
(R) 4-Trp-o,90%, >99:1 e.r.
N
CO
CO
N
Ph
d
(S) 4-Phg-b, 78%, 81:19 e.r.c
(S) 4-Phg-c, 99%, 87:13 e.r.c
(S) 4-Phg-d, 82%a,c
Ar: 4-CN
(R) 4-Phg-b,56%, 95:5 e.r.
(R) 4-Phg-c,76%, 94:6 e.r.d
Ar: 4-CN
Ar: 4-CN
4-Cl
(R) 4-Met-b, 86%, >99:1 e.r.
(R) 4-Met-c, 86%, >99:1 e.r.
(R) 4-Met-i, 73%, >99:1 e.r.
(R) 4-Met-o, 90%, >99:1 e.r.
N
CO
2-Cl
4-Cl
4-F
4-OMe (R) 4-Phg-j,67%, 95:5 e.r.d
4-Me
(R) 4-Val-a, 98%, 91:9 d.r.a,b
(S) 4-Phg-j, 92%, 85:15 e.r.c
(R) 4-Phg-p,80%a,d
C6D5
4-OMe
2-py
c
CN
Cl
F
Br
Me
OMe
D
D
Br
Cl
Cl
F
OMe
N
D
D
N
N
D
MeO
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
Fig. 3 | Scope of the imidazolidinone arylation: amino acids and
methods. ae.r. not determined; bLiNEt2 used instead of KHMDS
migrating groups. a, Product structures, yields and e.r. from use of the
optimized R-selective route via l-amino-acid-derived imidazolidinones
cis-3. Ar indicates either the aryl substituent itself or the substituent(s)
on a phenyl ring. b, Product structures, yields and e.r. from use of the
optimized S-selective route via l-amino-acid-derived imidazolidinones
trans-1. c, Structures of the aryl substituents introduced by these
(which gave no product). The product 4-Val-a contained some of the
epimeric imidazolidinone as a result of incompletely diastereoselective
rearrangement. cd-Phenylglycine was used as starting material, so product
has S absolute configuration. dd-Phenylglycine was used as starting
material, so product has R absolute configuration.
in Fig. 2a) involved two separate additions of KHMDS. Method B pro- Et3N no product was obtained (entry 9). We assume that under these
vided an efficient synthesis of an array of products, including 4-Ala, conditions of nucleophilic catalysis, cyclization to the imidazolidinone
4-Phe and 4-Leu, which bore a representative selection of substituted is reversible, with the rather unreactive carbamoyl chloride selectively
aryl rings in high yield and high diastereoselectivity (Supplementary acylating the less hindered cis diastereoisomer. The method was suc-
Information).
cessfully used to form cis-N-carbamoylimidazolidinones cis-3-Ala,
To explore a similarly efficient route to ent-4 from the same l-amino cis-3-Phe and cis-3-Leu bearing substituted aryl rings by way of their
acids, we turned to an alternative synthesis of cis-3 with complementary imines 2 (Supplementary Information). These imidazolidinone sub-
diastereoselectivity. It has been shown that, whereas trans imidazo- strates were subjected to the conditions (method A) previously opti-
lidinones are formed at lower temperatures under acidic conditions, mized for cis- and trans-3-Ala to yield the products ent-4, enantiomeric
diastereoselectivity towards cis N-acylimidazolidinones can be achieved with those formed from trans-3.
by acylation of the pivaldimine derivatives of amino acids, probably
The S-selective and R-selective routes highlighted by the orange and
because of the cis-selectivity exhibited by cyclization of the hindered, purple arrows in Fig. 2a thus provide enantiocomplementary syntheses
planar N-acyliminium intermediate21. We found that urea cis-3-Ala of the imidazolidinones 4 and ent-4 from the representative l-amino
was indeed formed when the imine 2-Ala was acylated with N-methyl- acids l-Ala, l-Phe and l-Leu. These structures are simple derivatives of
N-phenylcarbamoyl chloride (Fig. 2a, Extended Data Table 1, entries quaternary amino acids, and were converted into the target α-arylated
7, 8). Optimal yields of the pure cis diastereoisomer were obtained amino acids 5 by hydrolysis under acidic conditions. Excellent yields
in refluxing toluene or dichloroethane in the presence of 5 mol% of the enantiopure amino acids 5 were obtained by N-methylation of
4-dimethylaminopyridine (entries 10, 11), but with stoichiometric the urea function of 4 followed by microwave heating with 6 M HCl
4
O C t O B e r 2 0 1 8 | V O L 5 6 2 | N A t U r e | 1 0 7
© 2018 Springer Nature Limited. All rights reserved.

reSeArCH Letter
Fig. 4 | Mechanism of the rearrangement.
a, Proposed reaction pathway, with approximate
C=O stretching frequencies. b, In situ infrared
trace (first-derivative plot) of the reaction of
cis-3-Ala-a, showing diagnostic changes in
carbonyl-stretching frequencies. c, Plot of
absorbance against time for peaks at 1,711
cm−1 (red, starting material), 1,629 cm−1
(blue, enolate (C)) and 1,611 cm−1 (green,
product anion (D−)). d, Hammett plot of logkobs
against σ−, consistent with rate-determining
rearrangement for electron-rich rings and
rate-determining deprotonation for electron-
deficient rings. The gradient of the electron-
rich domain on the left of the plot, ρ=+4.5, is
consistent with substantial charge build-up on
the aryl substituent during the rearrangement.
a
X
X
X
Me
Me
Me
N
N
N –
Base
~1,710 cm–1
MeOH
~1,700 cm–1
Me
O–
O
4-Ala
O
O
N
O
N
O
N
~1,610 cm–1
~1,660 cm–1
~1,630 cm–1
N
N
N
t-Bu
Me
t-Bu
Me
t-Bu
cis-3-Ala
Enolate C
Product anion D–
b
c
1,711 cm–1
100
50
0
4-Ala-a
Add MeOH
20
D–
1,611 cm–1
C
D–
C
1,629 cm–1
Add base
0
cis-
Add base
Add MeOH
3-Ala-a
0
5
10
15
20
1,750
1,700
Wavenumber (cm–1
1,650
1,600
Time (min)
)
d
3
2
1
0
H
m-OMe
p-Cl
p-F
p-CN
p-Me
p-OMe
V–
–0.4
0
+0.4
+0.8
V–
(Fig. 2a, method D, Fig. 2d). The p-cyano function of 4-Ala-b and migrating group, with conjugated (h), electron-deficient (b) and elec-
4-Leu-b was hydrolysed under these conditions to give the carboxy- tron rich (i–l) rings all taking part in the reaction. All three orientations
lated phenylglycine derivatives 5-Ala-b′ and 5-Leu-b′. 5-Ala-b′ is the of a pyridyl ring (m–o) gave rearranged products regiospecifically.
mGluR antagonist (S)-M4CPG10.
Beyond alanine, phenylalanine and leucine, the functionalized side
Hydrolysis without preliminary N-methylation led to competitive chains of methionine, tyrosine and tryptophan were tolerated, with
formation of the corresponding N-methylhydantoins 6 in moderate arylation of tyrosine being successful even without the protection of
yield (Fig. 2c) owing to cyclization of the urea onto the newly revealed its hydroxyl group. Phenylglycine (Phg) was also arylated, enabling
carboxylic acid. These hydantoins 6 could be hydrolysed cleanly to 5 the enantioselective synthesis of chiral diaryl glycine derivatives 4-Phg
in a second step, but are nonetheless themselves valuable target struc- (including the enantioselectively deuterated 4-Phg-p). With phenyl-
tures2. A more versatile synthesis of 6 was obtained by treatment of the glycine, it was necessary to use method B (starting from trans-1-Phg)
methyl ester 8-Phe-e-OMe with tert-butyl isocyanate to give 6-Phe-e, to ensure high enantiomeric ratios, as its acidifying side chain evidently
the tert-butyl group being removable to give 6-Phe-e′ under acidic leads to some racemization in the synthesis of cis-3-Phg via imine
conditions (Fig. 2e).
2-Phg. Arylation of the sterically hindered 3-Val failed with KHMDS,
Derivatives of the arylated amino acids that are of value in syn- but rearrangement of 3-Val-a to 4-Val-a proceeded in excellent yield
thetic procedures such as peptide formation were also formed from with lithium diethylamide, a more powerful and less bulky base. A
5 (Fig. 2e). Protection of the amino or carboxyl group gave the car- slight loss in diastereoselectivity was seen in this reaction, possibly
boxybenzyl (Cbz)-, tert-butyloxycarbonyl (Boc)- or fluorenylmethyl- due to the more demanding steric requirements of a transition state in
oxycarbonyl (Fmoc)-protected carbamates 7 and the esters 8. Despite which the tert-butyl and isopropyl groups are both on the same side of
the steric hindrance of the quaternary amino acid, dipeptide 9 was the imidazolidinone ring.
formed cleanly on coupling Cbz-7-Ala-d to l-Phe-OEt under standard
The mechanism by which the enolate of 3 forms 4 is intriguing. The
conditions.
reaction bears some similarity to the Smiles and Truce–Smiles rear-
After showing that the base-promoted rearrangement of 3 provides a rangements22,23, but is distinguished from almost all known examples
viable method for the arylation of an initial selection of amino acids, we of these rearrangements by the lack of requirement for an electron-defi-
returned to the synthesis of 4 and ent-4 with the aim of extending the cient migrating ring. Sensitivity to electronic features may be measured
scope to the synthesis of other amino acids, and exploring the scope of by the Hammett reaction constant ρ, and we explored the kinetics of the
migrating aryl groups that can be tolerated by the method. The optimal reaction by in situ infrared spectroscopy in order to estimate a value of
conditions of the S-selective route and the R-selective route were applied ρ for the rearrangement.
to a range of starting materials that were derived from amino acids, and
the successful outcomes of these reactions are summarized in Fig. 3.
Preliminary studies by infrared spectroscopy using cis-3-Ala-a
under the optimized conditions for the reaction (1.5 equiv. KHMDS
Halogenated (c–g) rings, even those bearing bromo substituents, in tetrahydrofuran (THF) at room temperature) revealed no reac-
rearranged without evidence of dehalogenation or benzyne formation. tion intermediates, which indicates that rearrangement is faster than
Sterically hindered ortho-substituted (l) and 1-naphthyl rings (h) also enolate formation at room temperature. Changing the base to LDA
rearranged in good yield. Despite the fact that the rearrangement is and carrying out the rearrangement at −20°C decreased the rate of
formally an intramolecular nucleophilic aromatic substitution (SNAr) both deprotonation and rearrangement, and revealed an intermediate
reaction, it shows remarkable tolerance to variations in the aryl on the reaction pathway (Fig. 4a, b). This intermediate was identified
1 0 8
| N A t U r e | V O L 5 6 2 | 4 O C t O B e r 2 0 1 8
© 2018 Springer Nature Limited. All rights reserved.

Letter reSeArCH
9. Shirakawa, S., Yamamoto, K. & Maruoka, K. Phase-transfer-catalyzed
as the enolate C (Fig. 4a), on the basis that it has no C=O stretching
absorption corresponding to an amide carbonyl group (1,710 cm−1 in
cis-3-Ala-a), but retains the urea (1,630 cm−1) and aromatic (1,500–
1,600 cm−1) bands. The rate of decay of this intermediate was identi-
cal for both cis-3-Ala-a and trans-3-Ala-a, which confirms that it is
a common intermediate from both diastereoisomers, and treatment
of the isolated product with LDA gave an infrared spectrum identical
to that of the species present at the end of the reaction, identifying
it as the product anion D− (Fig. 4a). Confirmation that the reaction
is intramolecular was provided by a crossover experiment in which
cis-3-Ala-b was mixed with cis-3-Met-c (both of which rearrange at
comparable rates) and treated with KHMDS. A mass spectrum of the
crude reaction mixture showed molecular ions corresponding only to
4-Ala-b and 4-Met-c (Supplementary Information).
asymmetric SNAr reaction of α-amino acid derivatives with arene chromium
complexes. Angew. Chem. Int. Ed. 54, 838–840 (2015).
10. Ma, D. W. Conformationally constrained analogues of l-glutamate as
subtype-selective modulators of metabotropic glutamate receptors. Bioorg.
Chem. 27, 20–34 (1999).
11. Sonowal, H. et al. Aldose reductase inhibitor increases doxorubicin-
sensitivity of colon cancer cells and decreases cardiotoxicity. Sci. Rep. 7,
3182 (2017).
12. Clayden, J., Dufour, J., Grainger, D. M. & Helliwell, M. Substituted
diarylmethylamines by stereospecifc intramolecular electrophilic arylation of
lithiated ureas. J. Am. Chem. Soc. 129, 7488–7489 (2007).
13. Wang, X.-J. et al. Asymmetric synthesis of LFA-1 inhibitor BIRT2584 on metric
ton scale. Org. Process Res. Dev. 15, 1185–1191 (2011).
14. Yee, N. K. et al. Practical synthesis of a cell adhesion inhibitor by self-
regeneration of stereocenters. Tetrahedron Asymmetry 14, 3495–3501 (2003).
15. Grainger, D. M. et al. The mechanism of the stereospecifc intramolecular
arylation of lithiated ureas: the role of Li+ probed by electronic structure
calculations, and by NMR and IR spectroscopy. Eur. J. Org. Chem. 4, 731–743
(2012).
A Hammett plot was constructed by treating a series of imidazolid-
inones 3-Ala that bore a selection of aryl substituents with an excess 16. Atkinson, R. C. et al. Intramolecular arylation of amino acid enolates. Chem.
Commun. 49, 9734–9736 (2013).
(5 equiv.) of LDA at −20°C, and the formation of the product anion
17. Tomohara, K., Yoshimura, T., Hyakutake, R., Yang, P. & Kawabata, T. Asymmetric
D− was monitored using its characteristic infrared bands at around
α-arylation of amino acid derivatives by Clayden rearrangement of ester
enolates via memory of chirality. J. Am. Chem. Soc. 135, 13294–13297 (2013).
18. Atkinson, R. C., Fernández-Nieto, F., Mas Roselló, J. & Clayden, J.
1,690 and 1,630 cm−1. Under these conditions, the formation of the
product from the enolate followed first-order kinetics, and the linear
Pseudoephedrine-directed asymmetric α-arylation of α-amino acid derivatives.
Angew. Chem. Int. Ed. 54, 8961–8965 (2015).
section of a plot of ln([D−]∞ − [D−]) against time gave a rate constant
k
obs for each substrate (Fig. 4c). A Hammett plot of log kobs against the
19. Nagib, D. A., Scott, M. E. & MacMillan, D. W. C. Enantioselective
α-trifuoromethylation of aldehydes via photoredox organocatalysis. J. Am.
Chem. Soc. 131, 10875–10877 (2009).
20. Wakeham, R. J., Taylor, J. E., Bull, S. D., Morris, J. A. & Williams, J. M. J. Iodide as
an activating agent for acid chlorides in acylation reactions. Org. Lett. 15,
702–705 (2013).
21. Naef, R. & Seebach, D. Preparation of the enantiomercially pure cis-
confgurated and trans-confgurated 2-(tert-butyl)-3-methylimidazolidin-4-
ones from the amino-acids (S)-alanine, (S)-phenylalanine, (R)-
phenylglycine, (S)-methionine, and (S)-valine. Helv. Chim. Acta 68, 135–143
(1985).
22. Holden, C. M. & Greaney, M. F. Modern aspects of the Smiles rearrangement.
Chem Eur. J. 23, 8992–9008 (2017).
23. Snape, T. J. A truce on the Smiles rearrangement: revisiting an old
reaction—the Truce–Smiles rearrangement. Chem. Soc. Rev. 37, 2452–2458
(2008).
24. Sung, R.-Y. et al. Kinetic studies on the nucleophilic substitution reaction of
4-X-substituted-2,6-dinitrochlorobenzene with pyridines in MeOH–MeCN
mixtures. Bull. Korean Chem. Soc. 30, 1579–1582 (2009).
25. Bunnett, J. F. & Zahler, R. E. Aromatic nucleophilic substitution reactions. Chem.
Rev. 49, 273–412 (1951).
26. Schimler, S. D. et al. Nucleophilic deoxyfuorination of phenols via aryl
fuorosulfonate intermediates. J. Am. Chem. Soc. 139, 1452–1455 (2017).
27. Neumann, C. N. & Ritter, T. Facile C–F bond formation through a concerted
nucleophilic aromatic substitution mediated by the PhenoFluor reagent. Acc.
Chem. Res. 50, 2822–2833 (2017).
28. Kwan, E. E., Zeng, Y., Besser, H. A. & Jacobsen, E. N. Concerted nucleophilic
aromatic substitutions. Nat. Chem. 10, 917–923 (2018).
substituent constant σ− is shown in Fig. 4d: the plot shows a down-
wards bend characteristic of a change in rate-determining step, with
enolate formation being rate-limiting for electron-deficient rings (no
enolate was detectable by infrared spectroscopy during the rearrange-
ment of 3-Ala-b or 3-Ala-c). For the electron-rich domain of the plot,
the value of ρ is +4.5, consistent with substantial build-up of negative
charge on the migrating ring during the reaction. This ρ value is none-
theless smaller in magnitude than those of ‘classical’ intermolecular
SNAr reactions24,25, which possibly indicates that the reaction proceeds
without the intermediacy of an anionic Meisenheimer complex26–28
.
Electron-rich substitution patterns are unreactive in such intermolec-
ular substitutions, and we assume that in our system the conforma-
tional restriction imposed by the urea linkage29 must enforce attack
of the enolate on the ring, irrespective of the inability of the ring to
stabilize a negative charge30. As a consequence, the aryl ring behaves
as an electrophile, much as alkylating agents do in ‘classical’ reactions
of enolates. This use of conformational restriction to induce electro-
philic reactivity in electron-rich substituents not only makes generally
available this otherwise elusive class of modified amino acids, but also
has the potential for wider application in synthesis.
29. Clayden, J., Hennecke, U., Vincent, M. A., Hillier, I. H. & Helliwell, M. The origin of
the conformational preference of N,N′-diaryl-N,N′-dimethyl ureas. Phys. Chem.
Chem. Phys. 12, 15056–15064 (2010).
30. Costil, R. et al. Heavily substituted atropisomeric diarylamines by unactivated
Smiles rearrangement of N-aryl anthranilamides. Angew. Chem. Int. Ed. 56,
12533–12537 (2017).
Data availability
Full experimental details and spectroscopic data are provided as Supplementary
Information.
Received: 6 March 2018;Accepted: 17August 2018;
Published online 3 October 2018.
Acknowledgements We acknowledge funding from the EPSRC (GR/L018527)
and ERC (Advanced Grant ROCOCO and Proof of Concept grant QUATERMAIN),
and we are grateful to M. M. Amer for assistance with the synthesis of starting
materials.
1. Toniolo, C., Crisma, M., Formaggio, F. & Peggion, C. Control of peptide
conformation by the Thorpe–Ingold efect (Cα-tetrasubstitution). Biopolymers
60, 396–419 (2001).
2. Meusel, M. & Gütschow, M. Recent developments in hydantoin chemistry.
A review. Org. Prep. Proced. Int. 36, 391–443 (2004).
Reviewer information Nature thanks T. Kawabata and the other anonymous
reviewer(s) for their contribution to the peer review of this work.
3. Cativiela, C. & Díaz-de-Villegas, M. D. Recent progress on the stereoselective
synthesis of acyclic quaternary α-amino acids. Tetrahedron Asymmetry 18,
569–623 (2007).
4. Hashimoto, T. & Maruoka, K. Recent development and application of chiral
phase-transfer catalysts. Chem. Rev. 107, 5656–5682 (2007).
5. Schöllkopf, U. Enantioselective synthesis of non-proteinogenic amino acids via
metallated bis-lactim ethers of 2,5-diketopiperazines. Tetrahedron 39,
2085–2091 (1983).
6. Seebach, D., Sting, A. R. & Hofmann, M. Self-regeneration of stereocenters
(SRS)—applications, limitations, and abandonment of a synthetic principle.
Angew. Chem. Int. Edn Engl. 35, 2708–2748 (1996).
7. Kawabata, T. & Fuji, K. Memory of chirality: asymmetric induction based on the
dynamic chirality of enolates. Top. Stereochem. 23, 175–205 (2003).
8. Branca, M. et al. Memory of chirality of tertiary aromatic amides: a simple and
efcient method for the enantioselective synthesis of quaternary α-amino acids.
J. Am. Chem. Soc. 131, 10711–10718 (2009).
Author contributions D.J.L., J.W.W. and J.C. devised the experiments; D.J.L. and
J.W.W. carried out the experiments; D.J.L., J.W.W. and J.C. analysed the results
and wrote the paper.
Competing interests The authors have filed a patent on this work (GB1621512.1).
Additional information
Extended data is available for this paper at https://doi.org/10.1038/s41586-
018-0553-9.
Supplementary information is available for this paper at https://doi.org/
10.1038/s41586-018-0553-9.
Reprints and permissions information is available at http://www.nature.com/
reprints.
Correspondence and requests for materials should be addressed to J.C.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
4
O C t O B e r 2 0 1 8 | V O L 5 6 2 | N A t U r e | 1 0 9
© 2018 Springer Nature Limited. All rights reserved.

reSeArCH Letter
Extended Data Table 1 | Optimizing the synthesis of 3
aReaction carried out at refux for 18 h unless otherwise indicated.
b1.5 equiv.
c1.1 equiv.
d45 h.
eMethod C.
f0.05 equiv.
© 2018 Springer Nature Limited. All rights reserved.

Letter reSeArCH
Extended Data Table 2 | Optimizing the rearrangement of 3 to 4
a1.5 equiv.
bYield of ent-cis-3-Ala-a formed by epimerization.
cNot determined.
dMethod A.
eReaction on 1.5-g scale.
© 2018 Springer Nature Limited. All rights reserved.