Synthesis of l -Kynurenine and Homo- l -Kynurenine via an Aza-Fries Rearrangement

Article abstract of DOI:10.1055/s-0040-1707223

l -Kynurenine, a non-proteinogenic amino acid, is the primary metabolite of tryptophan via the kynurenine pathway. Kynurenine is involved in a variety of biological processes occurring in the human body, notably in the central nervous system. Thus, the st

Full text of DOI:10.1055/s-0040-1707223

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–G
paper
A
en
E. Bonilla-Reyes et al.
Paper
Synthesis
Synthesis of L-Kynurenine and Homo-L-Kynurenine via an
Aza-Fries Rearrangement
Edgar Bonilla-Reyesa
Adrian Sánchez-Carrillob
Alfredo Vázquez*a
NH2
O
n
OMe
O
O
NHP
NH
H
O
n
N
hν
o-rearranged products
n = 1, protected kynurenine
n = 2, protected homokynurenine
OMe
n
a Departamento de Química Orgánica, Facultad de Química,
Universidad Nacional Autónoma de México, Ciudad Univer-
sitaria, 04510, Cd. Mx., México
OMe
O
NHP
MeCN
O
NHP
anilides
P = Boc, Cbz
H2N
n = 1, aspartic acid
n = 2, glutamic acid
joseavm@unam.mx
O
b Laboratorio de Investigación en Inmunoquímica, Hospital
Infantil de México Federico Gómez, Dr. Márquez 162, Col
Doctores, Cuauhtémoc, 06720, Cd. Mx., México
n
OMe
O
NHP
p-rearranged products
Received: 22.04.2020
Accepted after revision: 29.06.2020
Published online: 06.08.2020
O
NH2
O
O
NH2
O
O
OH
formamidase
OH
IDO
OH
DOI: 10.1055/s-0040-1707223; Art ID: ss-2020-m0220-op
NH
TDO
NH2
NH2
HN
CHO
Abstract L-Kynurenine, a non-proteinogenic amino acid, is the prima-
ry metabolite of tryptophan via the kynurenine pathway. Kynurenine is
involved in a variety of biological processes occurring in the human
body, notably in the central nervous system. Thus, the study of this
molecule offers multiple opportunities for drug discovery; however, an
essential prelude for biological studies is to secure the supply of ky-
nurenine and analogues thereof. A simple synthetic procedure for the
efficient preparation of enantiomerically pure L-kynurenine from L-as-
partic acid and its implementation to prepare homo-L-kynurenine from
L-glutamic acid is presented. The approach relies on a photochemical
aza-Fries rearrangement of the corresponding acyl-aniline as the funda-
mental transformation.
L-tryptophan (2)
N-formyl-L-kynurenine (3)
L-kynurenine (1)
Scheme 1 Metabolism of L-tryptophan via the kynurenine pathway (KP)
Age-associated decline in NAD is connected with age-
associated diseases, including metabolic and neurodegener-
ative conditions.7 Some preclinical studies suggest the in-
volvement of KP in the pathophysiology of stroke and its
potential as a pharmacological target for stroke and related
complications.8
It has been demonstrated that kynurenine is an endoge-
nous ligand for the aryl hydrocarbon (AH) receptor.9 More
recently, it was established that some compounds formed
during the KP might have either neuroprotective or neuro-
toxic properties,1c and they have the potential to be used as
specific biomarkers for patients diagnosed with amyo-
trophic lateral sclerosis.10 One metabolite of the KP (3-hy-
droxykynurenine-3-O--glucoside, 3-HKG) functions in the
primate lens as a filter of 295–400 nm light, thus protecting
the retina from damaging UV radiation.11 Consequently, the
kynurenine pathway has promising potential for drug dis-
covery.1c,12 For instance, inhibitors of enzymes in the ky-
nurenine pathway may be relevant for the treatment of
some of the diseases described above.13
Additionally, L-kynurenine has shown a sweetening
power 50 times greater than sucrose; however, the D-enan-
tiomer is tasteless and lacks biological activity.14
The kynurenine pathway (KP) starts with the conver-
sion of L-tryptophan (2) into N-formyl-L-kynurenine (3,
Scheme 1) mediated by the enzymes indoleamine 2,3-dioxy-
genase (IDO) and tryptophan 2,3-dioxygenase (TDO).1b,4
Key words L-kynurenine, homo-L-kynurenine, non-proteinogenic
amino acids, aza-Fries, photochemical rearrangement
Kynurenine (1), a non-proteinogenic amino acid, is the
principal intermediate within the metabolic pathway of
tryptophan (2). This catabolic pathway, also known as the
kynurenine pathway (KP),1a–c is responsible for the forma-
tion of the essential cofactor nicotinamide adenine dinucleo-
tide (NAD+)2 and several neuroactive intermediates. More
than 95% of tryptophan is metabolized through KP (Scheme
1)3 and, collectively, the metabolites of this pathway are
designated as kynurenines. Although most of them display
neuroactive properties, quinolinic acid, 3-hydroxy-
kynurenine, and kynurenic acid have vital roles in several
diseases of the central nervous system (CNS).4 The
kynurenine pathway is involved in the regulation of the im-
mune response and neurodegenerative diseases;5,6 likewise,
kynurenine can act as a vasodilator in inflammation pro-
cesses. Furthermore, this amino acid has been shown to
have endothelial relaxing properties.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
E. Bonilla-Reyes et al.
Paper
Synthesis
procedures. Using a related approach, Moriyama reported
in 1957 the preparation of kynurenine by reacting trypto-
phan with ascorbic acid, and Cu2SO4, in the presence of air,
even though the experimental evidence of kynurenine for-
mation is not well supported.19
A. Dalgliesh 195220
O
NH2
O
O
O
CO2Et
OH
Br
NHAc
CO2Et
NH2
NO2
rac-kynurenine
NO2
B. Salituro 198821
1. tBuLi, Me3SnCl
Cbz
Other strategies have been devised to this end. For in-
stance, the condensation of the sodium salt of diethylacet-
amidomalonate with o-nitrophenacylbromide, followed by
reduction of the nitro group and hydrolysis—with the con-
comitant decarboxylation—afforded kynurenine as a race-
mate (Scheme 2A).20 Salituro21 utilized the ortho-metala-
tion of N-Boc-aniline, followed by quenching with Me3SnCl
to obtain the stannylated derivative. Subsequent coupling
with the chloride derived from protected spartic acid in the
presence of Pd2(dba)3·HCl provided protected kynurenine
(Scheme 2B). After removal of the protective groups with
30% HBr/AcOH, kynurenine bis(hydrobromide salt) was ob-
tained in 35% overall yield. Negishi coupling between 2-iodo-
aniline and a serine-derived organozinc reagent, under a
carbon monoxide atmosphere, has also been used to afford
protected kynurenine in 52% yield (Scheme 2C).22
The use of protected 2-amino-4-bromopent-4-enoic
acid in a Suzuki coupling with an aryl boronic acid, fol-
lowed by ozonolysis of the resulting styrene, allowed the
preparation of alanine derivatives such as kynurenine
(Scheme 2E).23 The photocatalytic decomposition of trypto-
phan has also been reported to produce kynurenine.24 In
2006, Ferrini et al.25 reported the preparation of 2-aryl
amines in high yields by photochemical rearrangement of
aromatic amides when they were irradiated with UV light.
Cbz-tryptophan has been used to prepare L-kynurenine
upon reaction with the oxidizing mixture of DMSO/HCl in
AcOH, followed by additional oxidation with air (Scheme
2F).26
O
N
O
2.
O
NH2
O
·HBr
OH
Cl
O
NHBoc
Pd2(dba)3·HCl, toluene
3. 30% HBr/AcOH
NH2
HBr
C. Jackson 1995, 199722
O
NHBoc
OMe
I
NHBoc
CO (1 atm, balloon)
Pd(PPh3)4 (5 mol%)
THF, rt, 30 h
HIZn
+
CO2Me
O
NH2
NH2
D. Maitrani 201217
O
O
NHAc
OH
O
NH2
O
OH
OH
H3O+
O3
O
NHAc
NH
NH2
N
H
L-kynurenine
CHO
E. Lygo 200323
O
NHBoc
OH
CO2tBu
B(OH)2
NHBoc
BocHN
1. Pd(PPh3)4
2. O3
+
O
NHBoc
Br
F. Kleijn 201226
O
O
O
NHCbz
OH
OH
OH
DMSO
air
NHCbz
NHCbz
O
concd HCl
AcOH
O
NH2
O
N
N
H2
H
G. This work
NHBoc
NH2
O
OMe
B
O
H2N
O
hν
B
O
H2N
+
N
O
HO
NH2
H
O
O
Herein, we present a simple procedure for the prepara-
tion of the non-proteinogenic amino acid L-kynurenine
starting from L-aspartic acid through a photochemical ap-
proach, featuring an aza-Fries rearrangement. Furthermore,
the developed methodology was implemented to obtain
homo-L-kynurenine from L-glutamic acid.
Scheme 2 A–F: previous synthesis of kynurenine; G: this work.
Presumably, this transformation has inspired some report-
ed synthetic procedures to obtain kynurenine either as a ra-
cemate or in enantiopure form.
Deuterium labeled kynurenine has been obtained in en-
antiopure form by acylase catalyzed resolution.15 Neverthe-
less, from the synthetic standpoint, the most direct ap-
proach to obtain enantiopure kynurenine involves the oxi-
dative rupture of N-protected L-tryptophan derivatives.16
This approach has been employed to produce enantiopure
kynurenine (Scheme 2D)17 and some peptides containing
kynurenine,18 although using cumbersome purification
According to our original synthetic strategy, kynurenine
(1) could be prepared from acyl aniline 4 using a photo-
chemical aza-Fries rearrangement as the critical reaction.27
Compound 4 would be readily obtained from aniline (5)
and oxazaborolidinone 628 by using standard peptide chem-
istry procedures (Scheme 3).
In addition to the carboxy and C- amino functional-
ities, -amino acids can include side chains with additional
O
O
NH2
O
B
O
H2N
HO
OH
O
+
N
H2N
NH2
B
O
O
H
NH2
O
1
4
5
6
Scheme 3 Original synthetic strategy for kynurenine
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

C
E. Bonilla-Reyes et al.
Paper
Synthesis
reactive groups—such as the amino acids aspartic and ly-
sine—imposing chemoselectivity issues.26 Accordingly, per-
forming chemical reactions on the side chain of those ami-
no acids might be a daunting task, resulting in the forma-
tion of side products. Alternatives to address this selectivity
issue have been reported. For instance, the temporary in-
stallation into the molecule of a group to deter the reactivi-
ty of the carboxy and the amino functionalities, such as 9-
borabicyclo[3.3.1]nonane (9-BBN-H), has been used to pro-
tect both groups in the form of an oxazaborolidinone.28 Ox-
azaborolidinone 6 was prepared in good yield by refluxing
the corresponding amino acid 7 with 9-BBN-H in MeOH
(Scheme 4).
HCl/MeOH solution of 4,31 followed by transforming the re-
sulting hydrochloride into a carbamate either with (Boc)2O
or Cbz-Cl in the presence of Et3N, to provide the aspartic
acid derivatives 9a and 9b orthogonally protected in 83 and
74% yield, respectively.32
Individual degassed solutions of derivatives 9a and 9b in
MeCN were irradiated for 12–36 hours at 254 nm. Rear-
ranged products 10a and 10b were obtained in 50 and 47%
yield, along with the corresponding p-isomers 10a′ and
10b′ (20 and 24% yield, respectively), as shown in Scheme 5,
plus some unidentified compounds. The mechanism of the
photo-Fries rearrangement is known to proceed through
the excited state. Thus, the C–N bond in 9a* undergoes ho-
molytic cleavage giving N-radical I and acyl radical II, which
are held in the solvent cage. Recombination of I and II
would provide starting material. However, combination of
acyl radical II with the mesomeric radical o-I gives ortho-
rearranged product III, which, upon tautomerization, pro-
vides 10a. Similarly, combination of II with the mesomeric
radical p-I gives para-rearranged product IV, which tau-
tomerizes into the minor isomer 10a′.32
O
O
O
H
9-BBN-H
MeOH
HO
HO
N
1. PhNH2
O
OH
O
H2N
H2N
O
O
NH2
80%
2. T3P/Py/THF
90%
O
B
B
7
6
Scheme 4 Preparation acyl aniline 4 from L-aspartic acid
With the carboxy and amino groups masked, the next
step was the anilide formation. The use of aniline, pyridine,
and T3P proved to be a convenient way to perform this
transformation (Scheme 4).29 This method showed some
advantages in handling the product and reaction yield,
compared to other methods of activation for the carboxy
moiety such as the use of DCC or EDC.30 Early attempts to
carry out the Fries rearrangement were conducted with
compound 4; however, after 12 hours of UV irradiation (254
nm) of a degassed solution of 4 in MeCN, and monitoring
the course of the reaction by TLC, only degradation of oxaz-
oborolidinone was observed. To circumvent this obstacle,
replacing the 9-BBN protective groups was essential. Re-
moval of the 9-BBN protective group required to prepare
compound 9a and 9b was accomplished by refluxing an
Kynurenine derivatives 10a and 10b are reported pro-
tected with orthogonal groups to facilitate their manipula-
tion. Accessing free kynurenine would require standard
deprotection procedures.33
To obtain protected homo-L-kynurenin (15), commer-
cially available L-N-Boc-(Bn)-Glu-OH (11) was used. From
this amino acid, methyl ester 12 was obtained by the reac-
tion of 11 with MeI (K2CO3, acetone). Compound 12 was se-
lectively deprotected (H2, Pd/C, MeOH) to unblock the car-
boxyl group present in the side chain. The formation of am-
ide 14 was achieved with the use of T3P as the coupling
reagent. Amide 14 was then irradiated for 24 hours with UV
light (254 nm) under anhydrous conditions (degassed
MeCN) to provide orthogonally protected homo-L-kynurenine
A
O
NHPG
OMe
1. SOCl2, MeOH
70%
O
NHPG
OMe
B
O
O
H2N
hν
N
O
N
MeCN
24–36 h
2. (Boc)2O or CbzCl
H
NH2
H
O
O
4
9a: PG = Boc, 83%
9b: PG = Cbz, 74%
10a: PG = Boc, 50% + 10a' (p-isomer) 30%
10b: PG = Cbz, 47% + 10b' (p-isomer) 24%
O
NH2 HCl
OMe
N
H
8
O
B
*
O
R
NH
O
O
O
hv
R
R
R
II
N
N
NH
H
H
o-I
9a
I
II
9a*
O
O
O
O
O
R
R
R
R
R
HN
H2N
NH2
HN
NH
10a'
p-I
10a
IV
II
III
Scheme 5 A: Preparation of N-protected L-kynurenine via a photochemical aza-Fries reaction. B: Proposed mechanism for the aza-Fries rearrangement.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

D
E. Bonilla-Reyes et al.
Paper
Synthesis
O
O
O
O
O
O
MeI
H2, Pd/C
BnO
OH
NHBoc
BnO
OMe
NHBoc
HO
OMe
K2CO3
acetone
90%
MeOH, 24 h
92%
NHBoc
12
13
11
1. T3P/Py
2. PhNH2
8 h, 70%
O
O
O
O
hν
OMe
NHBoc
MeOH
24 h
N
OMe
NHBoc
H
NH2
15 55% + 15' (p-isomer) 28%
14
Scheme 6 Preparation of homo-L-kynurenine from L-glutamic acid
1H and 13C NMR spectra were recorded with Varian INOVA 300, 400
and 600 MHz spectrometers using CDCl3 as the solvent. 1H NMR data
are reported as chemical shift in ppm () with integration, coupling
constant in Hz and multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, bs = broad singlet, m = multiplet). IR spectra were recorded
with a Perkin–Elmer Spectrum 400 FT-IR/FIR spectrophotometer
with ATR. Mass spectra were recorded with a JEOL SMX-102a spec-
trometer. The progress of the reactions was monitored by TLC using
glass plates precoated with silica gel 60 F254 (0.5 mm, Machery-Na-
gel) and 60 F254 (0.5 mm, Merck). The spots were visualized by
short/long wavelength lamps and by charring the TLC plate after im-
mersion in a H2SO4/H2O solution of Ce(SO4)2/phosphomolybdic acid.
Column chromatography was performed using 230–400 mesh silica
gel.
15 in 55% along with the p-isomer 15′ in 28% yield (Scheme
6). All the intermediates and final products were satisfacto-
rily characterized.
It is worth mentioning that during the preparation of
protected kynurenine (10a and 10b) and protected homo-
kynurenine (15), the corresponding para-rearranged prod-
ucts 10a′, 10b′ and 15′ were consistently obtained and fully
characterized, albeit in lower yield than the main products.
Although these reactions have a detrimental impact on the
yield of our methodology, the simplicity, reproducibility,
mild reaction conditions, and the ease with which the reac-
tion products can be separated, compensate for the forma-
tion of regioisomers. Given the importance of the ky-
nurenine pathway, it might be worth investigating the pos-
sible bioactivity of the para-isomers reported herein.
Since the existing stereogenic centers in each interme-
diate subjected to the photochemical rearrangement are
not involved in the process, the stereochemical integrity
should not experience any change. HPLC analysis for the
crude reactions showed no evidence of epimerization
during the rearrangement.
-Amino acids, 9-BBN-H, solvents and all other reagents were pur-
chased from Sigma–Aldrich-Chemical Co. and, unless otherwise not-
ed, were used as received. All reactions were performed under nitro-
gen atmosphere. The photochemical reactions were degassed prior to
irradiation. THF was distilled from sodium benzophenone ketyl under
nitrogen prior to use. Et3N was distilled from CaH2.
(S)-4-(Carboxymethyl)-2,2-borabicycle[3.3.1]nonane-1,3,2-oxaza-
borolidin-5-one (6)
A mixture of amino acid 7 (0.5 g, 3.76 mmol) in MeOH (20 mL) was
heated to reflux until the mixture became homogeneous. Afterwards,
a 0.5 M solution of 9-BBN-H in THF (7.5 mL, 3.76 mmol) was added
dropwise and the heating was continued until the solution became
clear. The reaction mixture was cooled to ambient temperature and
concentrated in vacuo. The residue was suspended in hot THF (15 mL)
and the remnant solid was filtered. The filtrate was concentrated, and
the residue was triturated with hot hexanes to provide the oxaza-
borolidinone.
In conclusion, the fascinating and growing number of
investigations on the paramount role of kynurenine in
some essential biological processes occurring in the human
body and the opportunities that this molecule offers for
drug discovery would benefit from the development of sim-
ple and efficient protocols to obtain this remarkable amino
acid. Even though several synthetic procedures to prepare
kynurenine have been reported, some of them require the
use of the hazardous oxidant ozone and cumbersome puri-
fication procedures. In other reports, additional steps are
required to prepare the starting materials. We have devel-
oped a mild synthetic protocol that allows enantiopure ky-
nurenine to be obtained in good yield from readily available
starting materials. Our approach relies on the use of a pho-
tochemical aza-Fries rearrangement of an arylamide de-
rived from L-aspartic acid. We were delighted to prove that
the same protocol can be used to prepare homo-L-ky-
nurenine. We believe that our methodology can be of value
for the preparation of kynurenine derivatives required for
biological studies.
Yield: 0.76 g (80%); white solid; mp 220 °C (dec).
IR-FT ATR: 3221, 2921, 2842, 1704, 1681, 1216, 960 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 0.47 (bs, 1 H), 0.59 (bs, 1 H), 1.39–
1.78 (m, 12 H), 2.70–2.73 (d, J = 6 Hz, 2 H), 3.77–3.81 (m, 1 H), 5.96–
5.99 (dd, J = 9 Hz, 1 H), 6.43–6.46 (dd, J = 9 Hz, 1 H).
13C NMR (75 MHz, DMSO-d6):  = 23.9, 24.3, 25.2, 30.7, 30.9, 31.1,
31.2, 34.2, 51.1, 67.0, 171.6, 172.8.
MS (FAB): m/z = 254 [M + 1]+, 162, 102, 88, 55.
Amide Preparation; General Procedure
T3P (3.0 equiv) was added dropwise to a solution of the correspond-
ing acid (1 equiv) in THF at 0 °C. The resultant mixture was stirred un-
til it became homogeneous, followed by the slow addition of pyridine
(2 equiv) and aniline (2 equiv). The mixture was stirred at r.t. for 8 h,
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

E
E. Bonilla-Reyes et al.
Paper
Synthesis
the solvent (THF) was removed in vacuo, and the residue was redis-
solved in EtOAc (30 mL), washed with 10% citric acid (2 × 15 mL) and
dried (Na2SO4). The solvent was evaporated, and the residue was puri-
fied by column chromatography (silica gel, EtOAc–hexanes 30:70).
Methyl (S)-4-N2-[(Benzyloxycarbonyl)-N4-phenylamino]-4-oxo-
butanoate (9b)
Et3N (0.22 mL, 1.59 mmol) was added dropwise to a mixture of 8
(0.75 g, 1.45 mmol) and benzylchloroformate (0.2 mL, 1.45 mmol) in
CH2Cl2 (10 mL). The resultant mixture was stirred at r.t. for 24 h. The
solvent was removed and the residue was purified by column chro-
matography (silica gel, EtOAc–hexanes 30:70) to afford the desired
product.
(S)-4-(N-Carboxyphenylamide)-2,2-borabicycle[3.3.1]nonane-
1,3,2-oxazaborolidin-5-one (4)
Prepared from 6 (1.0 g, 3.95 mmol).
Yield: 0.38 g (74%); white solid; mp 148–151 °C.
IR-FT ATR: 3304, 1744, 1712, 1652, 1533, 1286, 1214 cm–1
Yield: 1.08 g (90%); yellow solid; mp 184–186 °C.
IR-FT ATR: 3275, 2919, 2842, 1702, 1659, 1598, 1532, 1298, 1198 cm–1
.
.
1H NMR (400 MHz, CDCl3):  = 2.90 (dd, J = 15.9, 3.9 Hz, 1 H), 3.10 (dd,
J = 16.0, 4.3 Hz, 1 H), 3.75 (s, 3 H), 4.63 (dd, J = 8.5, 4.4 Hz, 1 H), 5.11 (s,
2 H), 6.10 (d, J = 8.1 Hz, 1 H), 7.09 (t, J = 7.4 Hz, 1 H), 7.25–7.31 (m,
6 H), 7.44 (d, J = 7.9 Hz, 2 H), 7.70 (dd, J = 5.7, 3.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 38.9, 51.0, 53.0, 67.2, 120.1, 124.7,
127.9, 128.3, 129.0, 129.4, 136.2, 137.6, 156.5, 168.3, 171.9.
1H NMR (300 MHz, DMSO-d6):  = 0.58 (bs, 1 H), 0.66 (bs, 1 H), 1.41–
1.79 (m, 12 H), 2.88 (m, 2 H), 4.00–4.02 (m, 1 H), 6.08 (d, J = 12 Hz,
1 H), 6.52 (d, J = 9 Hz, 1 H), 7.08 (t, J = 7.0 Hz, 1 H), 7.34 (t, J = 7.6 Hz,
2 H), 7.62 (d, J = 7.8 Hz, 2 H), 10.15 (s, 1 H).
13C NMR (75 MHz, CD3OD):  = 20.2, 22.7, 23.3, 25.6, 30.3, 34.77, 51.0,
68.8, 118.9, 123.1, 128.5, 138.7, 168.0, 172.9.
MS (FAB): m/z = 357 [M + 1]+, 313.
MS (FAB): m/z = 329 [M + 1]+, 209, 191, 166, 127, 94, 85.
Methyl (S)-N2-[(tert-Butoxycarbonylamino)-N5-phenylamino]-5-
oxopentanoate (14)
Methyl (S)-5-Benzyl-(tert-butoxycarbonylamino)-5-oxopenta-
noate (12)
A mixture of 11 (1.0 g, 2.96 mmol), K2CO3 (0.41 g, 2.96 mmol) and MeI
(0.55 mL, 8.9 mmol) in anhydrous acetone (15 mL) was heated at re-
flux for 2 h under N2 atmosphere. The solvent was removed and the
residue was taken up in EtOAc (30 mL), washed with 10% citric acid
(2 × 15 mL) and dried on Na2SO4. The solvent was evaporated in vacuo
and the residue was purified by column chromatography (silica gel,
EtOAc–hexanes, 30:70) to afford the desired product.
Prepared from 13 (0.8 g, 3.06 mmol).
Yield: 0.72 g (70%); yellow oil.
IR-FT ATR: 3381, 2919, 1737, 1449, 1409, 1296 cm–1
1H NMR (400 MHz, CDCl3):  = 1.43 (s, 9 H), 1.91–1.97 (m, 1 H), 2.28–
2.25 (m, 1 H), 2.44 (t, J = 6.5 Hz, 2 H), 3.71 (s, 3 H), 4.35 (s, 1 H), 5.43
(d, J = 8.0 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.9 Hz, 2 H), 7.57
(d, J = 7.9 Hz, 2 H), 8.63 (bs, 1 H).
13C NMR (100 MHz, CDCl3):  = 28.3, 29.9, 33.9, 52.6, 80.5, 119.8,
124.0, 128.9, 138.2, 156.3, 170.4, 172.6.
MS (FAB): m/z = 337 [M + 1]+, 281, 237.
.
Yield: 0.94 g (90%); brown oil.
IR-FT ATR: 3374, 2977, 1734, 1711, 1499, 1366, 1156 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.39 (s, 9 H), 1.90–1.95 (m, 1 H), 2.15–
2.16 (m, 1 H), 2.39–2.44 (m, 2 H), 3.67 (s, 3 H), 4.27–4.31 (m, 1 H),
5.08 (s, 2 H), 5.20–5.23 (m, 1 H), 7.30 (m, 5 H).
Cleavage of Amino Acid-9-BBN Complex
13C NMR (100 MHz, CDCl3):  = 27.9, 28.5, 30.6, 52.6, 53.0, 66.7, 80.2,
SOCl2 (1.0 mL, 12.2 mmol) was slowly added to a flask containing
MeOH (10 mL) at 0 °C. The amino acid (1.0 g 2.9 mmol) was then add-
ed and the mixture was heated to reflux for 1 h. The solvent was re-
moved in vacuo and the residue was taken up in EtOAc (30 mL) and
stirred for 12 h at r.t. to provide a white solid. The mixture was fil-
tered, and the solid residue (8) was dried and used without further
purification to selectively protect the amino group.
128.4, 128.5, 128.8, 135.9, 155.5, 172.7, 172.9.
MS (EI): m/z = 351 [M]+, 107, 91, 79, 50.
(S)-4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxopentanoic
Acid (13)
A mixture of 12 (1.0 g, 2.84 mmol) and Pd/C (0.01 g, 10%w/w) in
MeOH (20 mL) was purged and stirred under H2 atmosphere (balloon)
for 5 h. The solution was filtered through a pad of Celite and the sol-
vent evaporated. The residue was purified by column chromatogra-
phy (silica gel, EtOAc–hexanes, 30:70) to afford the desired product.
Methyl (S)-N2-[(tert-Butoxycarbonylamino)-N4-phenylamino]-4-
oxobutanoate (9a)
Et3N (0.22 mL, 1.59 mmol) was added dropwise to a mixture of 8
(0.375 g, 1.45 mmol) and (Boc)2O (0.315 g, 1.45 mmol) in isopropyl
alcohol (10 mL). The resultant mixture was stirred for 24 h at ambient
temperature and then the solvent was removed under reduced pres-
sure. The residue was purified by column chromatography (silica gel,
EtOAc–hexanes 30:70) to provide the desired product.
Yield: 0.684 g (92%); colorless oil.
IR-FT ATR: 3347, 2978, 1735, 1708, 1513, 1157 cm–1
1H NMR (300 MHz, CDCl3):  = 1.27 (s, 9 H), 1.76–1.86 (m, 1 H), 1.97–
2.02 (m, 1 H), 2.27–2.29 (m, 2 H), 3.58 (s, 3 H), 4.25–4.04 (m, 1 H),
5.59 (d, J = 8.2 Hz, 1 H), 7.82 (bs, 1 H).
.
Yield: 0.39 g (83%); yellow solid; mp 128–131 °C.
IR-FT ATR: 3298, 1742, 1751, 1698, 1673, 1540, 1293, 1160 cm–1
13CNMR (75 MHz, CDCl3):  = 27.7, 28.3, 30.1, 51.8, 52.9, 80.0, 155.4,
172.7, 173.2.
.
1H NMR (400 MHz, CDCl3):  = 1.43 (s, 9 H), 2.88 (dd, J = 16.0, 4.2 Hz,
1 H), 3.07 (dd, J = 16.0, 4.1 Hz, 1 H), 3.74 (s, 3 H), 4.56 (dt, J = 9.0,
4.7 Hz, 1 H), 5.81 (d, J = 8.0 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 7.27 (t, J =
8 Hz, 2 H), 7.47 (d, J = 7.7 Hz, 2 H), 7.98 (bs, 1 H).
13C NMR (100 MHz, CDCl3):  = 28.3, 50.3, 52.8, 80.2, 119.9, 124.4,
128.9, 137.6, 155.8, 168.3, 172.0.
MS (EI): m/z = 260 [M]+, 202, 160, 146, 102, 57.
Photochemical aza-Fries Reaction; General Procedure
Photo-Fries rearrangement was performed using freshly distilled
MeCN (P2O5) as the solvent, to which a stream of nitrogen was bub-
bled under sonication for 10 min. The photochemical quartz reactor
(Ace Glass Incorporated, Cat. 7825-30) containing the corresponding
MS (FAB): m/z = 323 [M + 1]+, 267, 223.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

F
E. Bonilla-Reyes et al.
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Synthesis
arylamide (1 equiv) and a magnetic stirring bar was evacuated and re-
filled with nitrogen, followed by the addition of degassed MeCN (10
mL). The solution was then irradiated with UV light (254 nm) for 24–
36 h. Water was circulated through the condenser, to avoid evapora-
tion of the MeCN. After the irradiation time indicated for each reac-
tion, the solvent was evaporated under reduced pressure and the resi-
due was fractionated by column chromatography (silica gel, gradient),
commencing with 20% EtOAc in hexanes to obtain a compound iden-
tified as the ortho-rearranged product 10a (Rf = 0.3, 20% EtOAc in hex-
anes). After recovering unreacted starting material, an increase in the
polarity of the eluent (30% EtOAc in hexanes plus 5% of MeOH) al-
lowed the most polar compound to be obtained (Rf = 0.3, 30% EtOAc in
hexanes plus 5% of MeOH), identified as the para-rearranged product
10a′. The same procedure was used to purify compounds 10b, 10b′,
15 and 15′ with an irradiation time of 24 h.
MS (EI): m/z = 357 [M]+, 305, 238, 194.
Methyl (S)-4-(4-Aminophenyl)-2-(benzyloxycarbonylamino)-4-
oxobutanoate (10b′)
Prepared by following the general procedure from 9b (0.1 g, 0.27
mmol).
Yield: 0.024 g (24%); brown oil.
IR-FT ATR: 3456, 3347, 2952, 1705, 1548, 1499, 1337, 1208 cm–1
1H NMR (300 MHz, CDCl3):  = 3.35 (d, J = 15 Hz, 1 H), 3.58 (d, J =
15 Hz, 1 H), 3.68 (s, 3 H), 4.60–4.62 (m, 1 H), 5.11 (s, 2 H), 5.67–5.69
(d, J = 6 Hz, 1 H), 6.57–6.59 (d, J = 6 Hz, 2 H), 7.25–7.34 (m, 5 H), 7.68–
7.71 (d, J = 9 Hz, 1 H).
.
13C NMR (75 MHz, CDCl3):  = 41.3, 50.1, 52.7, 67.0, 116.0, 117.2,
117.4, 128.1, 128.5, 131.0, 135.0, 136.2, 150.5, 156.1, 172.1, 199.1.
MS (EI): m/z = 358 [M]+, 357.
Methyl (S)-4-(2-Aminophenyl)-2-(tert-butoxycarbonylamino)-4-
oxobutanoato (10a)
Methyl (S)-5-(2-Aminophenyl)-2-(tert-butoxycarbonylamino)-5-
oxopentanoate (15)
Prepared by following the general procedure from 9a (0.1 g,
0.31 mmol).
Prepared by following the general procedure from 14 (0.1 g, 0.29
mmol).
Yield: 0.051 g (50%); brown oil.
IR-FT ATR: 3457, 2977, 1699, 1617, 1485, 1365, 1157 cm–1
1H NMR (300 MHz, CDCl3):  = 1.44 (s, 9 H), 3.50 (dd, J = 17.9, 4.1 Hz,
1 H), 3.70–3.76 (m, 1 H), 3.70 (s, 3 H), 4.64–4.68 (m, 1 H), 5.61 (d, J =
15 Hz, 1 H), 6.24 (bs, 2 H), 6.63–6.66 (m, 2 H), 7.26–7.31 (m, 2 H), 7.68
(d, J = 7.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3):  = 28.3, 41.4, 49.5, 52.5, 79.9, 115.9, 117.1,
117.3, 131.0, 134.9, 150.6, 155.6, 172.5, 199.3.
MS (FAB): m/z = 323 [M + 1]+, 223.
.
Yield: 0.055 g (55%); brown oil.
IR-FT ATR: 3353, 2981, 1747, 1684, 1648, 1514, 1155 cm–1
.
1H NMR (600 MHz, CDCl3):  = 1.41 (s, 9 H), 2.03–2.05 (m, 1 H), 2.23–
2.29 (m, 1 H), 2.96–3.01 (m, 1 H), 3.05–3.11 (m, 1 H), 3.73 (s, 3 H),
4.35–4.37 (m, 1 H), 5.17 (d, J = 7.9 Hz, 1 H), 6.25 (bs, 1 H), 6.60–6.63
(m, 2 H), 7.22–7.26 (m, 1 H), 7.69 (d, J = 11.9 Hz, 1 H).
13C NMR (150 MHz, CDCl3):  = 27.3, 28.4, 35.0, 52.4, 53.2, 80.0, 115.9,
117.4, 131.0, 134.5, 150.4, 155.5, 173.1, 201.0.
MS (EI): m/z = 337 [M]+, 281, 237.
Methyl (S)-4-(4-Amyinophenyl)-2-(tert-butoxycarbonylamino)-4-
oxobutanoate (10a′)
Methyl (S)-5-(4-Aminophenyl)-2-(tert-butoxycarbonylamino)-5-
oxopentanoate (15′)
Prepared by following the general procedure from 9a (0.1 g,
0.31 mmol).
Prepared by following the general procedure from 14 (0.1 g, 0.29
mmol).
Yield: 0.030 g (30%); brown oil.
IR-FT ATR: 3365, 2977, 1696, 1593, 1485, 1366, 1160 cm–1
1H NMR (400 MHz, CDCl3):  = 1.39 (s, 9 H), 3.36 (dd, J = 17.8, 3.9 Hz,
1 H), 3.59 (dd, J = 17.8, 4.1 Hz, 1 H), 3.68 (s, 3 H), 4.60–4.62 (m, 1 H),
5.68 (d, J = 8.9 Hz, 1 H), 6.58 (d, J = 8.6 Hz, 2 H), 7.70 (d, J = 8.7 Hz,
2 H).
13C NMR (100 MHz, CDCl3):  = 28.3, 40.1, 49.7, 52.5, 63.6, 79.9, 113.6,
126.1, 130.7, 152.0, 155.7, 172.4, 195.6.
MS (FAB): m/z = 323 [M + 1]+, 223.
.
Yield: 0.028 g (28%); brown oil.
IR-FT ATR: 3361, 2962, 1699, 1684, 1593, 1162 cm1.
1H NMR (400 MHz, CDCl3):  = 1.40 (s, 9 H), 2.03–2.05 (m, 1 H), 2.20–
2.27 (m, 1 H), 2.89–3.04 (m, 2 H), 3.72 (s, 3 H), 4.33–4.34 (m, 1 H),
5.17 (d, J = 7.8 Hz, 1 H), 6.65 (d, J = 8.5 Hz, 2 H), 7.78 (d, J = 8.6 Hz,
2 H).
13C NMR (100 MHz, CDCl3):  = 28.2, 29.9, 33.9, 52.6, 52.7, 80.5, 119.7,
124.0, 128.9, 138.2, 150.9, 156.3, 170.4, 197.0.
MS (EI): m/z = 337 [M]+, 218, 158, 130, 120, 118.
Methyl (S)-4-(2-Aminophenyl)-2-(benzyloxycarbonylamino)-4-
oxobutanoate (10b)
Prepared by following the general procedure from 9b (0.1 g, 0.27
mmol).
Funding Information
Yield: 0.047 g (47%); brown oil.
IR-FT ATR: 3456, 3347, 2952, 1705, 1548, 1499, 1337, 1208 cm–1
The authors acknowledge Facultad de Química, Universidad Nacional
Autónoma de México (PAIP 50009062) for funding.
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1H NMR (300 MHz, CDCl3):  = 3.52 (d, J = 20.1 Hz, 1 H), 3.74 (s, 3 H),
4.70–4.72 (m, 1 H), 5.11 (s, 2 H), 5.89 (d, J = 8.9 Hz, 1 H), 6.23 (bs, 2 H),
6.62–6.69 (m, 2 H), 7.26–7.32 (m, 6 H), 7.66 (d, J = 7.3 Hz, 1 H).
Acknowledgment
13C NMR (75 MHz, CDCl3):  = 41.3, 50.1, 52.7, 67.0, 116.0, 117.2,
117.4, 128.1, 128.5, 131.0, 135.0, 136.2, 150.5, 156.1, 172.1, 199.1.
We are grateful to Rosa Isela del Villar, Nayeli López, Georgina Duarte
and Marisela Gutierrez for recording NMR, MS and IR spectra.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G

G
E. Bonilla-Reyes et al.
Paper
Synthesis
Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707223.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–G