Enantioselective Synthesis of β-Methyl Amines via Iridium-Catalyzed Asymmetric Hydrogenation of N-Sulfonyl Allyl Amines

Article abstract of DOI:10.1002/adsc.201900748

The iridium-catalyzed asymmetric hydrogenation of several N-sulfonyl allyl amines is reported. All substrates can be easily obtained by the Ir-catalyzed isomerization of N-tosylaziridines reported previously. The commercially available threonine-derived phosphinite (UbaPHOX) iridium complex has been found to be the best catalyst for this catalytic application, affording β-methyl amines with good to excellent ee values (up to 94%). The synthetic potential of this novel methodology was demonstrated by the formal synthesis of Lorcaserin and LY-404187. (Figure presented.).

Full text of DOI:10.1002/adsc.201900748

Title: Enantioselective Synthesis of β-Methyl Amines via Iridium-
Catalyzed Asymmetric Hydrogenation of N-Sulfonyl Allyl Amines
Authors: Albert Cabré, Xavier Verdaguer, and Antoni Riera
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900748
Link to VoR: http://dx.doi.org/10.1002/adsc.201900748

10.1002/adsc.201900748
Advanced Synthesis & Catalysis
COMMUNICATION
Very Important Publication
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Synthesis of β-Methyl Amines via Iridium-Catalyzed
Asymmetric Hydrogenation of N-Sulfonyl Allyl Amines
Albert Cabré,a,b Xavier Verdaguer,a,b and Antoni Rieraa,b*
a
Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain.
antoni.riera@irbbarcelona.org. Tel (+34)934037093
Departament de Química Inorgànica i Orgànica, Secció Orgànica. Universitat de Barcelona, Martí i Franquès 1,
b
Barcelona E-08028, Spain.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
The
iridium-catalyzed
asymmetric
asymmetric induction. Conversely, Ir complexes
bearing chiral P,N-ligands[8] can be used in the
hydrogenation of poorly coordinative alkenes.
Although several minimally functionalized olefins
have been enantioselectively hydrogenated with Ir
complexes,[9] the range of substrates available is still
limited. In this context, reports of the asymmetric
synthesis of β-methyl amines from 2-aryl allylamines
are scarce. Zhang and co-workers developed a highly
enantioselective method for the synthesis of β-methyl
phthalimides based on the asymmetric hydrogenation
of 2-alkyl allylphthalimides using a Ru-C3-tunephos
catalyst.[10] However, hydrogenation of the only
example of 2-aryl allylphthalimide described in the
paper took place with low enantiomeric excess (55%
ee). The hydrogenation of N-acetamido 2-phenyl
allylamine using a cationic Ru complex bearing the
axially chiral ligand (-)-TMBTP gave an ee of 80%.[11]
However, in this case, the hydrogenation occurred
after partial isomerization to the enamide. Therefore,
to the best of our knowledge, there are no precedents
of Ir-catalyzed asymmetric hydrogenation of N-
sulfonyl 2-aryl allylamines.
hydrogenation of several N-sulfonyl allyl amines is
reported. All substrates can be easily obtained by the Ir-
catalyzed isomerization of N-tosylaziridines reported
previously. The commercially available threonine-derived
phosphinite (UbaPHOX) iridium complex has been found
to be the best catalyst for this catalytic application,
affording β-methyl amines with good to excellent ee values
(up to 94%). The synthetic potential of this novel
methodology was demonstrated by the formal synthesis of
Lorcaserin and LY-404187.
Keywords: iridium complexes; asymmetric catalysis;
hydrogenation; β-alkyl amines; Drug synthesis; Chiral
P,N-ligands
Chiral amines are key structural features in natural
products and fine chemicals.[1,2] Amines bearing a β-
methyl stereogenic center are present in numerous
bioactive compounds and pharmaceuticals.[3-5] Several
examples of this type of drugs are shown in Figure 1.
For example, Lorcaserin is a marketed anorectic for
which a synthesis based on asymmetric hydrogenation
have
not
been
described
to
date.[3]
Biarylpropylsulfonamides such as LY-404187 are
potent positive allosteric modulators of 2-amino-3-(5-
methyl-3-hydroxyisoxazol-4-yl)-propanoic
acid
potent
(AMPA) receptors.[4] NPS-1392 is
a
stereoselective antagonist of the NMDA receptor.[5]
The asymmetric hydrogenation is one of the most
important catalytic reactions in the preparation of
pharmaceuticals due to its atom economy, low
environmental impact and operational simplicity.[6] Ru
or Rh catalysts, which usually bear chiral phosphines,
can induce high enantioselectivity on substrates
functionalized with a coordinating group.[7] However,
when facing minimally functionalized olefins, these
catalysts commonly show low reactivity and
Figure 1. Examples of pharmaceutically active chiral β-
methyl amines.
1
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10.1002/adsc.201900748
Advanced Synthesis & Catalysis
of the reaction (Table 1, entry 8) or an increase of
hydrogen pressure (Table 1, entry 9) had a small effect
in the asymmetric induction. Finally, the reaction was
achieved with 1 mol % of catalyst loading and 1 bar of
hydrogen (Table 1, entry 10). Under these conditions
the reaction reached completion in only 3 h.
In theory, all compounds shown in Figure 1 can be
prepared by asymmetric hydrogenation of a suitable
allyl amine. However, the absence of appropriate
methodologies might be explained by the lack of easy
preparation procedures for 2-aryl allylamines. Our
group recently uncovered a new isomerization reaction
that provides N-sulfonyl 2-aryl allylamines 2 from N-
sulfonyl aziridines 1 (Scheme 1).[12] The isomerization
is catalyzed by the readily available Crabtree catalyst
and takes place with low catalyst loading, high
selectivity and mild reaction conditions.
We also tested the one pot procedure treating aziridine
1a with hydrogen (1-50 bar) in the presence of catalyst
4 (see SI). Although the N-tosyl 2-phenylpropanamine
3a was obtained cleanly, the maximum enantiomeric
excess that we could obtain was 83% ee. We believe
that this was due to the uncomplete selectivity of the
isomerization reaction. The presence of 3-7% of
racemic imine drops the enantioselectivity of the
overall reaction.
Herein, we report the Ir-catalyzed asymmetric
hydrogenation of N-sulfonyl allylic amines 2 to chiral
β-methyl amines 3 (Scheme 1; 16 examples). The
commercial iridium-UbaPhox catalyst[13] developed
by Pfaltz gave complete conversions and good to
excellent enantioselectivities. The high functional
group tolerance and the mild conditions employed in
this novel catalytic process are remarkable. To
showcase the applicability of this new enantioselective
methodology, the asymmetric synthesis of several
biologically active compounds is also described.
Table 1. Solvent screening and optimization of the
asymmetric hydrogenation of N-tosyl 2-phenyl allylamine
2a.a
Catalyst
(mol %)
Conv.
(%)b
ee
Entry
Solvent
P, T
(%)c
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
MeOH
THF
1 bar, rt
1 bar, rt
1 bar, rt
1 bar, rt
1 bar, rt
1 bar, rt
1 bar, rt
1 bar, 0ºC
30
75 (R)
82 (R)
76 (R)
74 (R)
83 (R)
88 (R)
93 (R)
93 (R)
>99
>99
>99
>99
>99
>99
>99
dioxane
Et2O
EtOAc
CH2Cl2
DCE
Scheme. 1. Synthetic approach to chiral β-
methylamines
DCE
Our studies first began with the asymmetric
hydrogenation of 2a, which was chosen as model
substrate (Table 1). This compound was easily
obtained by isomerization of the corresponding N-
tosyl aziridine which, in turn was prepared from 1-
methylstyrene. With 2a in hand, several Rh- and Ir-
catalysts were tested for their asymmetric
hydrogenation. However, the best results were
obtained using [((4S,5S)-Cy2-Ubaphox)Ir(COD)]
BArF (4), the threonine-based Ir-P,N catalysts
developed by Pfaltz.[13] The optimization of the
reaction conditions is shown in Table 1. Methanol
gave low conversion (Table 1, entry 1). Ethers such as
THF, dioxane and diethyl ether gave complete
conversions but moderate ee values (Table 1, entries
2-4). Ethyl acetate and dichloromethane gave better
results, but dichloroethane (DCE) (Table 1, entry 7,)
emerged as the best solvent for the reaction, with full
conversion and 93% ee. A decrease in the temperature
9
5
1
DCE
DCE
50 bar, rt
1 bar, rt
>99
>99
91 (R)
93 (R)
10d
a See Supporting Information for experimental details. Reactions were run in
a pressure reactor at 1 bar of H2 pressure. b Conversion was measured by 1H
NMR. c Enantiomeric excess was determined by chiral HPLC. d The reaction
was completed after 3 h.
To determine the scope of the reaction, we next
applied these optimal conditions to a range of N-
sulfonyl allylic amines. Up to 15 N-sulfonyl allylic
amines were tested showing excellent reactivity and
affording the chiral amines in high conversions and
with good to excellent ee values (Table 2). We
assumed that all products had R configuration by
analogy with 3a. The absolute configuration of 3a had
been stablished by derivatization of ethyl (R)-2-
phenylpropanoate.[14] In all cases, except 2d-e, the sign
of the rotation matched with 3a. We believe that in all
cases the sense of the induction is the same. Substrates
2
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10.1002/adsc.201900748
Advanced Synthesis & Catalysis
presenting substituents in ortho position (Table 2,
entries 3 and 6) and naphthalene (Table 2, entry 5)
required an increase in catalyst loading (2 mol %) to
assure full conversion. This novel catalytic
transformation demonstrated high functional group
tolerance when modifying the electronic character
inhibitors after simple tosyl deprotection and acylation
[15,16]
(see SI). The mesyl amine 2m is also a key
intermediate for the preparation of allosteric
modulators of AMPA receptor.[16,17] However, to
further showcase the applicability of our methodology,
and encouraged by the relevance of these chiral β-
methyl amines as fragments of biologically active
compounds we envisioned easy access to LY-404187
(electron-donor
and
electron-withdrawing
substituents) in the aryl group. The sulfonyl group was
also modified and we were pleased to see that when
replacing the tosyl group by a methyl or isopropyl
group, full conversion and excellent ee’s were also
achieved (Table 2, entries 10, 11, 12 and 13). Finally,
N-methyl, N-sulfonyl allylic amines 2o and 2p were
also hydrogenated affording the corresponding chiral
amines with 94% of enantiomeric excess in both cases
(Table 2, entries 14 and 15).
and
(R)-Lorcaserin.
To
obtain
the
biarylpropylsulfonamide LY-404187,[4] we designed a
3-step synthetic procedure starting from N-sulfonyl
aziridine 1l. The isomerization[12] of 1l to 2l and the
subsequent asymmetric hydrogenation to 3l took place
in excellent yields. Finally, the chiral amine 3l was
converted to the final product by a Suzuki-Miyaura
coupling. LY-404187, the potent potentiator of the
AMPA receptor, was obtained as the only product with
good yield and almost no loss of optical purity
(Scheme 2).
To check if the hydrogenation takes place after
isomerization to the corresponding enamide, labeling
studies were conducted. Allyl amine 2a was
hydrogenated with 1 bar of D2 and 1 mol % of 4 in
DCE. NMR analysis showed that the deuterium atoms
were exclusively found at the methyl and benzylic
positions. Therefore, the possible isomerization
previous to hydrogenation was ruled out (see SI).
Table 2. Scope of Asymmetric Hydrogenation of N-
Sulfonyl Allyl Amines
Scheme 2. Synthesis of LY-404187
Conv.
(%)b
ee
The anorectic drug Lorcaserin has a tetrahydro-3-
benzazepine skeleton, a common structural feature in
many natural and pharmaceutical products. Lorcaserin
has serotonergic properties and is currently used as a
weight-loss drug. Several racemic syntheses of this
compound have been reported. Only a few strategies
for the enantioenriched form of this drug can be found
in the literature, and most of them use kinetic
resolution or stoichiometric reagents.[18] We
envisioned to apply our novel catalytic asymmetric
methodology (Scheme 3). N-sulfonyl aziridine 1c was
isomerized[12] and the corresponding allyl amine was
hydrogenated to afford 3c in good yield and 89% ee.
Subsequent N-alkylation gave 5 in 68% yield.
Regioselective Lewis acid-promoted intramolecular
Friedel-Craft alkylation[3b] afforded the unsaturated 7-
membered ring. Finally, enamine hydrogenation gave
desired compound 6, which is a direct precursor of
Lorcaserin.[18c]
Entry
R1
R2
R2
(%)c
1
2
2b
2c
2d
2e
2f
p-Cl
m-Cl
o-Cl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
iPr
H
H
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
85
89
82
92
88
92
91
92
82
87
88
92
91
94
94
3d
4
H
p-Me
2-naphthyl
o-OMe
p-F
H
5d
6d
7
H
2g
2h
2i
H
H
8
m-F
H
9
2j
p-CF3
p-Br
p-I
H
10
11
12
13
14
15
2k
2l
H
iPr
H
2m
2n
2o
2p
H
Me
H
p-iBu
H
Me
H
Me
Me
Me
H
p-tolyl
a
b
All reactions were run in a pressure reactor at 1 bar of H2 pressure.
Conversion was measured by 1H NMR. c Enantiomeric ratio was determined
by chiral HPLC. d 2 mol% of catalyst was used.
Many biologically active compounds have amines
with a chiral methyl group in -position. Compound
2a is already a direct precursor of potassium channel
3
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10.1002/adsc.201900748
Advanced Synthesis & Catalysis
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In summary, we have shown that commercially
available complex Ir(UbaPHOX) (4) is an excellent
catalyst for the challenging asymmetric hydrogenation
of 2-aryl N-sulfonyl allylamines. The hydrogenation
takes place at low hydrogen pressure (1 bar) and with
only 1 mol % of catalyst in DCE at room temperature.
Since the starting amines can be easily obtained by Ir-
catalyzed isomerization of N-tosylaziridines, which in
turn can be prepared from the corresponding styrenes,
the overall sequence provides a straightforward and
practical route to chiral amines bearing a methyl group
in β position. These compounds are useful synthetic
intermediates since they are, or can be transformed
into, precursors of several biologically active
compounds. As a synthetic application of this
methodology, we have described the formal synthesis
of enantioenriched (R)-Lorcaserin and LY-404187.
5 S. T. Moe, S. M. Shimizu, D. L. Smith, B. C. Van
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Acknowledgements
We thank institutional funding from the Spanish Ministry of
Economy, Industry and Competitiveness (MINECO, CTQ2017-
87840-P) through the Centres of Excellence Severo Ochoa award,
and IRB Barcelona from the CERCA Programme of the Catalan
Government. A.C. thank MINECO for Ph.D. fellowship (FPU).
f) P. Etayo, A. Vidal-Ferran, Chem. Soc. Rev. 2013
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Advanced Synthesis & Catalysis
COMMUNICATION
Mild Iridium-Catalysed Isomerization of
Epoxides. Computational Insights and
Application to the Synthesis of β-Alkyl
Amines
Adv. Synth. Catal. 2019, Volume, Page –
Page
Albert Cabré,a,b Xavier Verdaguer*a,b and
Antoni Riera*a,b
6
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