A facile and regioselective multicomponent synthesis of chiral aryl-1,2-mercaptoamines in water followed by monoamine oxidase (MAO-N) enzymatic resolution

Article abstract of DOI:10.1039/c9ob01962f

A facile microwave assisted three-component protocol allows the synthesis of chiral aryl-1,2-mercaptoamines in water in a few minutes with high yields, bypassing the use of toxic aziridine intermediates. The chiral 1,2-mercaptoamines were then deracemized through enzymatic resolution of the racemates using monoamine oxidase (MAO-N) biocatalysts.

Full text of DOI:10.1039/c9ob01962f

Organic &
Biomolecular Chemistry
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A facile and regioselective multicomponent
synthesis of chiral aryl-1,2-mercaptoamines in
water followed by monoamine oxidase (MAO-N)
enzymatic resolution†
Cite this: Org. Biomol. Chem., 2019,
17, 8982
Received 7th September 2019,
Accepted 25th September 2019
Kate Lauder, a Domiziana Masci,a Anita Toscani,a Aya Al Mekdad,a
Gary W. Black, b Nicola L. Brown,b Nicholas J. Turner, c Renzo Luisi d and
DOI: 10.1039/c9ob01962f
a
rsc.li/obc
Daniele Castagnolo
*
A facile microwave assisted three-component protocol allows the described so far, such as the introduction of sulphur nucleo-
synthesis of chiral aryl-1,2-mercaptoamines in water in a few philes into α-amino acids or β-aminoalcohols,4 the ring-
minutes with high yields, bypassing the use of toxic aziridine inter- opening of N,S-heterocycles5 or the sulfenoamination of
mediates. The chiral 1,2-mercaptoamines were then deracemized alkenes.6 However, the most straightforward approach to 1,2-
through enzymatic resolution of the racemates using monoamine mercaptoamines remains the nucleophilic addition of
oxidase (MAO-N) biocatalysts.
a
sulphur nucleophile to an aziridine ring A (Fig. 1).7 The ring
opening reaction of aziridine substrates with thiols is generally
carried out in the presence of stoichiometric amounts of
Lewis acids (BF3·Et2O),7d,8 strong acids such TfOH7e or under
basic conditions to generate the thiolate nucleophiles.7a–c
Furthermore, thiols are often used in large excess (up to 20
eq.)7e and the reactions require high temperatures and long
reaction times to be completed.9
1,2-Mercaptoamines, also referred to as β-aminothiols, are a
class of organic compounds of wide interest that have found
broad application in synthetic, pharmaceutical and material
chemistry as well as in catalysis.1 The uniqueness and versati-
lity of these molecules resides in the presence of the two
nucleophilic N and S heteroatoms and in their ability to
chelate metals, making them ideal protein and metal ligands.
The 1,2-mercaptoamine scaffold is present in naturally-occur-
ring compounds such as the amino acid cysteine 1, cysteamine
2, taurine 3 and the penicillin antibiotics such 4, and can be
also found in commercially approved drugs like the antiretro-
viral agent nelfinavir 5, the ACE inhibitor zofenopril and the
anticancer amifostine (Fig. 1). Moreover, 1,2-mercaptoamine
derivatives are commonly used in chemistry as precursors in
the synthesis of a various N,S-heterocycles (e.g. thiazolines,
thiazolidines, thiomorpholines, thiazepines)1,2 or as ligands in
organometallic catalysis.3
In view of their broad application, a number of synthetic
methodologies to access 1,2-mercaptoamines has been
aSchool of Cancer and Pharmaceutical Sciences, King’s College London,
150 Stamford Street, SE1 9NH London, UK. E-mail: daniele.castagnolo@kcl.ac.uk
bDepartment of Applied Sciences, Northumbria University, Ellison Place, NE1 8ST
Newcastle upon Tyne, UK
cSchool of Chemistry, Manchester Institute of Biotechnology,
University of Manchester, 131 Princess Street, M1 7DN Manchester, UK
dDepartment of Pharmacy - Drug Sciences, University of Bari“A. Moro”,
Via E. Orabona 4, Bari 70125, Italy
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, full characterization of compounds, copies of spectra. See DOI:
10.1039/c9ob01962f
Fig. 1 Examples of 1,2-mercaptoamines and this work’s synthetic
strategy.
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Table 1 Optimisation of the reaction conditions for the one-pot micro-
Catalytic ZnCl2 was also found to promote the ring opening
of aziridines bearing specific protecting groups on the nitro-
gen.10 The aziridine ring-opening generally occurs on the less
hindered carbon, but other factors such as the nature of the
nucleophile or the substituents and the reaction conditions
may affect the regioselectivity, leading to complex mixtures of
regioisomers. A major limitation of these methods is rep-
resented by the use of the aziridine itself. In fact, the synthesis
of aziridine intermediates can be a challenge, often requiring
multiple steps, an appropriate protecting group strategy, the
use of chiral auxiliaries in case of asymmetric syntheses,11 or
harsh reaction conditions.11f In addition, substituted aziri-
dines can be carcinogenic12 and mutagenic13 due to their
ability to bind DNA, and in general are highly irritant to eyes,
skin and respiratory tract. All these factors, combined with
their high volatility, make aziridines a major non-desirable
hazard in chemistry laboratories.
As part of our studies aimed at the development of greener
and more sustainable methods for the synthesis of sulphur
derivatives and pharmaceutical scaffolds,14 herein we describe
a facile and regioselective microwave-assisted multicomponent
protocol to generate chiral aryl-1,2-mercaptoamines like B or C
(Fig. 1). The desired β-aminothiols are synthesised directly
from styrene sulfonium bromide (SBB), amines and thiols in
100% water, avoiding the use of acid/base catalysts and pro-
tecting groups as well as bypassing the formation and isolation
of aziridine intermediates. To the best of our knowledge, this
is the first regioselective multicomponent methodology for the
synthesis of 1,2-mercaptoamines which does not involve the
handling of aziridine intermediates. The methodology is selec-
tive to afford 1,2-mercaptoamines bearing a C–S stereocentre
(compound C) with a few exceptions where a selectivity
towards chiral amines B was observed.
wave-mediated synthesis of aminothiolsa
Time
(min)
Temp.
(°C)
Yield
(%)d
Entry Product
Solvent
Heating
1b
8a R = H H2O +
DCM
18 h +
24 h
15
15
20
15
15
10
10
10
10
20
30
30
30
20
30
30
Standardc 15e
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
DCM
60
60
60
60
80
50
80
100
150
80
80
80
100
120
120
150
150
150
160
160
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
MW
0
1–2
2
MeOH
MeOH
EtOH
Neat
H2O
H2O
H2O
H2O
H2O
0
5f
12
25
18f
20f
39
79
10
25
40
40
50
77
68
50
77
H2O
8b R =
Cl
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
10
20
30
20
30
a The ratio of the reactants has been kept constant during the optimi-
sation study with SBB (5a–b)/MeNH2/PhSH = 1 : 10 : 1.1. Attempts to
reduce the amount of amine led to poorer yields. b The reaction was
carried out in two steps. Aziridine 6 was synthesised and the crude
reacted with thiophenol. c The reaction was carried out in a water bath
at 30 °C. d Isolated yields were reported. e Overall yield over two steps.
f The formation of multiple side products was observed from the reac-
tion mixture.
Finally, with the aim of making the protocol more sustain-
able, the deracemization of the chiral 1,2-mercaptoamines via
enzymatic kinetic resolution or kinetic dynamic resolution which was probably lost during the work up of the first reac-
with monoamine oxidase (MAO-N) biocatalysts was investi- tion step. Surprisingly, only the isomer 8a bearing a C–S
gated. MAO-N enzymes have been widely studied as biocata- stereocentre was formed, indicating that the thiophenol
lysts for the production of enantiomerically pure amines attacks the aziridine 7 on the most hindered benzylic carbon.
through the deracemization of a range of chiral substrates15 The structure of 8a was determined by NMR and on the basis
and, more recently, have been exploited in the synthesis of the literature data reported for similar compounds.18 The
of nitrogen heterocycles.14b–c Turner and co-workers have 13C NMR of 8a presents a peak at 56.3 ppm compatible with a
mapped the substrate scope of MAO-N biocatalysts showing -CH2-NHMe carbon and a peak at 51.3 ppm compatible with a
that these enzymes sometimes show poor enzymatic activity -CH-SPh carbon. On the other hand, the -CH2-SPh peak of
on non-cyclic amine substrates. However, no biocatalytic β-aminothiols in 13C NMR is expected to fall at around
studies on 1,2-mercaptoamine derivatives bearing a C–S or a 40 ppm. In order to improve the yield of the reaction, the SBB,
C–N stereocentre have been carried out to date.16
the methylamine and the thiophenol were then mixed in a
The reaction of crystalline SBB 6a17 with methylamine and one-pot multicomponent fashion. We reasoned that the SBB
thiophenol via a two-steps route was initially investigated. The and the methylamine could react quickly leading to an aziri-
SBB was reacted with an excess of methylamine at room temp- dine intermediate which could be opened in situ by the thio-
erature leading to the corresponding aziridine 7 in 18 h. The phenol. Moreover, we decided to perform the reaction under
crude three-membered ring 7 was then opened by treatment microwave irradiation to reduce the reaction times as well as
with thiophenol in DCM for 24 h affording the 1,2-mercapto- the formation of potential side products. The SBB 6a, methyl-
amine 8a as sole isomer in low yields (15%) (Table 1, entry 1). amine and thiophenol were initially mixed in various solvents
The disappointing yield, observed in triplicate experiments, and irradiated under microwave at 60 °C. No significant for-
was attributed to the volatility of the aziridine intermediate mation of the aminothiol 8a was observed in DCM, MeOH or
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Table 2 Substrate scope of the multicomponent synthesis of 1,2-
mercaptoamines
EtOH, irrespective to the reaction time (Table 1, entries 2–5). A
negligible yield was also obtained when the reaction was per-
formed in neat (Table 1, entry 6). Surprisingly, when 100%
water was used as solvent, an improvement in the reaction
yield was observed after 15 minutes at 50 °C, with the for-
mation of 8a in 12% yield (Table 1, entry 7). The poor reactivity
observed with organic solvents could be ascribable in part to
the limited solubility of the sulfonium starting material. In
addition, it has been reported that microwave irradiation can
accelerate the reactions carried out in aqueous media and
improve the reaction yields.19 The increase of the temperature
proved to be partially beneficial (Table 1, entries 9 and 10),
while prolonged reaction times at 80 °C (30 minutes) led to 8a
in good 79% yield as single regioisomer (Table 1, entry 12).
Attempts to increase the reaction yield carrying out the multi-
component reaction at temperatures above 80 °C failed, prob-
ably due to the formation of by-products. Surprisingly, when
the chloro-SBB substrate 6b was used under the same reaction
conditions, the corresponding 1,2-aminomercaptane 8b was
obtained only with 10% conversion (Table 1, entry 13).
However, in this case, the increase in temperature proved to be
beneficial (Table 1, entries 14–17) with 8b was obtained in
77% yield when the reaction was carried out at 150 °C for
20 minutes (Table 1, entry 18). In this case, longer reaction
times or higher temperatures did not affect the reaction yield.
Also compound 8b was obtained as a single regioisomer
bearing a C–S stereocentre.
Methoda
R
R1
R2
Yieldb (%)
8a
8b
8c
8d
9e
8f
8g
9h
8i
8j
8k
8l
8m
9n
9o
8p
A
B
A
B
B
B
B
B
B
B
B
B
B
B
B
B
H
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
iPr
Et
79
77
55
72
44
80
83
71
62
57
57
46
59
42
48
67
Cl
Me
H
Cl
Me
H
Cl
Me
H
H
H
H
H
4-Me-Ph
4-Me-Ph
4-Me-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Br-Ph
4-MeO
Ph
Ph
Allyl
nPr
Bn
Me
Me
Me
H
H
a Method A: H2O, MW, 80 °C, 30 min. Method B: H2O, MW, 150 °C,
20 min. b Isolated yields were reported.
The scope of the multicomponent reaction was then
explored. Since the reaction proved to be substrate specific,
both Methods A (30 min at 80 °C) and B (20 min at 150 °C)
were applied to different substrates. The results and the best
reaction conditions are reported in Table 2. With the exception
of product 8a and 8c, obtained via Method A with 79% and
55% yields respectively, Method B proved to be the best in all
the remaining cases. Excellent yields (71–83%) were obtained
for aminothiols 8b, 8d, 8f–g while derivatives 8i–k and 8p were
recovered in good amounts (59–67%). Surprisingly, regio-
isomers 9e and 9h bearing a C–N stereocentre were obtained
as single products using the same methodology. The regio-
selectivity of aziridine ring opening is often determined by a
combination of multiple electronic and steric factors.11e,20 It is
Scheme 1 Proposed mechanism for the multicomponent reaction.
plausible that in the case of 9e and 9h the inductive effects of amine intermediate with elimination of HBr. Then, the cyclic
the substituents on the thiophenols (Cl and Me) combined aziridine 7 forms spontaneously by ring closure and elimin-
with the effect of the Cl-Ph substituent on the aziridine inter- ation of dimethyl sulphide. It is plausible that the aziridine
mediate may have favoured the attack of the nucleophile on ring is protonated in the reaction media (water). Two possible
the less hindered carbon. When EtNH2 and iPrNH2 were used pathways are possible: in pathway a, the attack of the nucleo-
as reagents, β-aminothiols 8l–m were obtained in good yields phile occurs on the more hindered and electrophilic benzylic
(59–46%). On the other hand, the reaction of 6a with methyl- carbon, leading in most of the cases to regioisomers 8.
amine and aliphatic thiols (allylthiol and n-propylthiol) led to However, the nature of the nucleophiles and the reagents may
regioisomers 9n–o bearing a C–N stereocentre.
affect the selectivity thus favouring the attack of the nucleo-
Also in this case, a nucleophilic attack at the less substi- philes on the less hindered carbon and leading in a few cases
tuted carbon of aziridine 7 occurred, probably due to elec- to isomers 9 thorugh pathway b.21
tronic factors.
The enantioselective synthesis of chiral 1,2-mercaptoamine
A plausible mechanism for the multicomponent reaction is derivatives has proved to be a challenge to date, especially for
illustrated in Scheme 1. The primary amine undergoes a derivatives bearing a C–S stereocentre, with only few methods
nucleophilic substitution on SBB 6 leading to a sulfonium described in the literature.22,1a In many cases, optically pure
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Table 3 Biocatalysed deracemization of 1,2-mercaptoamines 8
Entry
Cmpd.
Methoda
EKR
Biocatalyst
Product
Yieldb (%)
erc (ee%)
1
2
3
4
5
6
7
8
8a
MAO-D5
MAO-D9
MAO-D11
MAO-D9
MAO-D9
MAO-D9
MAO-D9
MAO-D9
MAO-D9
MAO-D9
MAO-D9
MAO-D9
(S)-8a
(S)-8a
(S)-8a
(S)-8b
(S)-8c
(S)-8d
(S)-8g
(S)-8k
(S)-8l
(S)-9n
(S)-9o
(S)-8p
—
55
—
40
18
—
52
—
—
52
68
—
52.5 : 47.5 (5)
95 : 5 (90)
63 : 37 (26)
60.5 : 39.5 (21)
67 : 33 (34)
58 : 5 : 41.5 (17)
77.5 : 22.5 (55)
65 : 35 (30)
64.5 : 35.5 (29)
51 : 49 (1)
53.5 : 46.5 (7)
71.5 : 28.5 (43)
8b
8c
8d
8g
8k
8l
9n
9o
8p
EKR
EKR
EKR
EKR
EKR
EKR
DD
9
10
11
12
DD
EKR
a EKR = enzymatic kinetic resolution; DD = dynamic deracemization. b Isolated yields were reported. c er = enantiomeric ratio. Determined by
chiral LC-MS using a Chiralpak IG column.
1,2-mercaptoamines are generated from enantiopure amino C–N stereocentre was also attempted using MAO-N biocatalysts in
acid precursors through multistep functionalization.1 Herein, the presence of BH3·NH3 (entries 10 and 11). However, in this
due to our previous experience in the biocatalytic synthesis of case, racemic mixtures of the amines were recovered.
enantiomerically pure substrates,14a,15 the enzymatic kinetic
resolution of chiral compounds 8 using MAO-N as biocatalysts
was investigated. Results are reported in Table 3.
Conclusions
The racemic amine 8a was first treated with freeze-dried
whole cells containing MAO-N variants D5, D9 and D11, selected In conclusion, a green and sustainable approach to chiral aryl-
on the basis of their known activity and selectivity towards 1,2-mercaptoamines has been developed through a novel micro-
primary and secondary amines.16 All the enzymatic biotransform- wave-assisted multicomponent reaction carried out in water.
ations were carried out at 37 °C in a buffer solution (pH = 7.8) The multicomponent reaction allows the regioselective syn-
using DMF as co-solvent according to standard protocols.15 thesis of a variety of β-aminothiols 8a–p bearing a C–S chiral
MAO-N are able to selectively oxidase one enantiomer into the stereocentre in short times and high yields, bypassing the use
corresponding imine 10 whilst leaving the other enantiomer of toxic aziridine substrates and avoiding organic and chlori-
unreacted. In the presence of MAO-N D9, amine 8a was derace- nated solvents as well as the purification of reaction intermedi-
mized affording the enantiomer (S)-8a with 95 : 5 er (90% ee) ates. In a few cases, the 2-aryl-1,2-mercaptoamine regioisomers
(Table 3, entry 2). The absolute configuration was assumed on the 9 were selectively obtained as single products. Finally, the de-
basis of the known selectivity of MAO-N biocatalyst for racemization of the chiral aryl-1,2-mercaptoamine derivatives
R-enantiomers.15 Attempts to isolate the imine 10 by LC-MS with MAO-N biocatalysts was explored leading, in some cases, to
failed, probably due to its poor stability and hydrolysis. Poor er enantioenriched compounds with high/good er. Additional
were obtained when MAO-N D5 and D11 variants (Table 3, entries studies on the biocatalytic synthesis of enantioenriched 1,2-
1 and 3) were used. Good selectivity was observed for amines 8g mercaptoamines 8 are currently in progress in our laboratories.
and 8p (Table 3, entries 7 and 12), while almost racemic mixtures
were recovered for other substrates. It is plausible that the C–S
stereocentre could racemise during the course of biocatalytic
Conflicts of interest
transformation thus accounting for poor enantioselectivity.23
Finally, a dynamic deracemization of derivatives 9n–o bearing a There are no conflicts to declare.
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