Highly Enantioselective Iridium-Catalyzed Hydrogenation of 2-Aryl Allyl Phthalimides

Article abstract of DOI:10.1021/acs.orglett.9b03865

The iridium-catalyzed asymmetric hydrogenation of 2-aryl allyl phthalimides to afford enantioenriched β-aryl-β-methyl amines is presented. Recently developed Ir-MaxPHOX catalysts are used for this enantioselective transformation. The mild reaction conditions and the feasible removal of the phthalimido group makes this catalytic method easily scalable and of great interest to afford chiral amines. The importance of this new methodology is exemplified by the formal synthesis of (R)-Lorcaserin, OTS514, and enantiomerically enriched 3-methyl indolines.

Full text of DOI:10.1021/acs.orglett.9b03865

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Enantioselective Iridium-Catalyzed Hydrogenation of 2‑Aryl
Allyl Phthalimides
¥,§
Elia Romagnoli,¥ Pol Martínez-Balart,¥ Xavier Verdaguer,*,¥,§ and Antoni Riera*,¥,§
́
Albert Cabre,
¥Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac
10, 08028 Barcelona, Spain
§
̀
̀
́
̀
̀
Departament de Química Inorganica i Organica, Seccio Organica, Facultat de Química, Universitat de Barcelona, Martí i Franques
1, Barcelona E-08028, Spain
S
* Supporting Information
ABSTRACT: The iridium-catalyzed asymmetric hydrogenation of 2-aryl allyl phthalimides to afford enantioenriched β-aryl-β-
methyl amines is presented. Recently developed Ir-MaxPHOX catalysts are used for this enantioselective transformation. The
mild reaction conditions and the feasible removal of the phthalimido group makes this catalytic method easily scalable and of
great interest to afford chiral amines. The importance of this new methodology is exemplified by the formal synthesis of (R)-
Lorcaserin, OTS514, and enantiomerically enriched 3-methyl indolines.
he biological activity of many pharmaceutical compounds
and agrochemicals is intrinsically related to their absolute
one of the most practical and powerful approaches due to its
operational simplicity, high reactivity, and atom economy.6
However, most of the syntheses found in the literature are
performed by means of chiral resolution or by using
stoichiometric agents.7 To the best of our knowledge, there
are only few examples in which enantioenriched β-aryl
propanamines can be obtained by metal-catalyzed enantiose-
lective hydrogenation.8 In 2005, Zhang and co-workers
reported the asymmetric hydrogenation of 2-alkyl allyl
phthalimides using a Ru−C3−tunephos catalyst.8a However,
the scope of this reaction was focused on alkyl groups, and the
single example of 2-aryl allyl phthalimide gave only 55% ee of
the corresponding β-methylpropanamine. More recently, our
group reported the hydrogenation of N-sulfonyl allyl amines
using the iridium complex of Pfaltz’s catalyst Ubaphox.8d
Iridium complexes bearing chiral P,N ligands9 have been
successfully applied in the asymmetric hydrogenation of a wide
range of unfunctionalized or minimally functionalized olefins.10
Our group has developed several P-stereogenic chiral ligands.11
Recently, we designed a family of P,N-ligands (MaxPHOX)
that were coordinated to iridium.12 These catalysts can be
obtained from protected tert-butyl methyl phosphinous acid
and commercially available amino acids and amino alcohols.
T
molecular configuration.1 The asymmetric synthesis of chiral
compounds is, therefore, an essential field in organic chemistry.
In particular, chiral β-aryl propanamines are extremely
interesting candidates as precursors of pharmaceuticals and
active molecules:2 for example, Lorcaserin, an anorectic drug
that has been typically synthesized by chiral resolution;3
OTS514, a marketed inhibitor of a serine-threonine kinase that
is often overexpressed and transactivated in several types of
cancer;4 and LY-392098, a potent positive allosteric modulator
of 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-propanoic
acid (AMPA) receptor.5 Moreover, we can envision the
synthesis of several drug intermediates such as 3-methylindo-
lines in few steps from β-aryl propanamines (Figure 1).
Among the strategies to obtain enantioenriched β-aryl
propanamines, catalytic asymmetric hydrogenation provides
Figure 1. Examples of biologically active compounds containing a
chiral β-methyl amine.
Received: October 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
These iridium complexes have three chiral centers, so up to
four diastereoisomers (catalysts 1−4, Figure 2) can be
Table 1. Catalyst Screening and Optimization of the
Asymmetric Hydrogenation of 2-(2-Phenylallyl)isoindoline-
a
1,3-dione 5a
b
c
entry catalyst
loading
solvent
conv. (%)
ee (%)
6 (S)
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
2b
2c
2c
2c
2c
2c
2c
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
1 mol %
1 mol %
1 mol %
1 mol %
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
THF
>99
>99
>99
>99
>99
>99
>99
>99
60
64 (R)
20 (S)
32 (R)
69 (R)
90 (R)
89 (R)
90 (R)
89 (R)
n.d.
d
10
11
5
>99
e
f
CH2Cl2
98 (R) (96)
a
See Supporting Information for experimental details. Reactions were
Figure 2. Ir-MaxPHOX family of catalysts.
b
run in a pressure reactor at 1 barG of H2 pressure. Determined by 1H
NMR. Measured by chiral HPLC. Reaction was performed at 50 bar
of H2. Reaction was performed at ̵ 20 °C. Isolated yield.
c
d
e
f
obtained. Moreover, the substituent of the oxazoline ring can
be easily modified. This variety of structures facilitates the fine-
tuning of the catalyst. This strategy has allowed us to find an
excellent catalyst for the enantioselective hydrogenation of
cyclic enamides12a and N-aryl12b and N-alkyl12c imines.
Moreover, these catalysts also proved to be extremely efficient
in the isomerization of cyclic allyl carbamates, yielding high
levels of enantioselectivity.12d
Here, we present the asymmetric hydrogenation of N-
phthalimido 2-aryl allyl amines using an Ir-MaxPHOX catalyst
to obtain chiral β-methyl amines. It is worth noting that, in this
occasion, the best catalyst of the family (2c) had not been
described. To showcase the applicability of this reaction, the
formal enantioselective synthesis of several biologically active
compounds was performed.
solvent screening was performed at 1 bar of H2. With
dichloromethane the conversion after 12 h was still complete
(Table 1, entry 8); in contrast, with ethyl acetate or THF, the
reactivity decreased to 60% and 5%, respectively (Table 1,
entries 9 and 10). Using dichloromethane the reaction
temperature could be decreased to −20 °C, affording 6a
with an excellent 98% ee and full conversion (Table 1, entry
11).
A mechanistic study of this reaction using D2 revealed that
the hydrogenation occurred exclusively to the allylic bond and
that there was no prior isomerization to the corresponding
enamide (see Supporting Information).
With the optimal conditions in hand, we studied the scope
of the reaction. As seen in Scheme 1, halide-substituted aryl
groups were well-tolerated, with excellent enantioselectivities
in all cases (6b to 6e, Scheme 1). The catalyst loading for the
substrates with bromine (5d) and iodine (5e) had to be
increased to 2 mol % to ensure full conversion. Electron-
donating substituents such as methyl (6f) or isobutyl (6m)
gave 97% and 98% ee, respectively (Scheme 1). We then
expanded the substrates to meta-substituted aryl groups. Again,
and using only 1 mol % of catalyst 2c, chiral amines 6g and 6h
were afforded with excellent enantioselectivities. The asym-
metric hydrogenation ortho-substituted compounds (5i−k)
also gave excellent enantiomeric excesses except in the case of
the methoxy substituent (6i) that decreased to 83% ee. Finally,
an allyl amine with another aryl substituent such as a naphthyl
(5l) also afforded the corresponding amine 6l in 97% ee.
To showcase the applicability of our methodology, here we
disclose a novel, short, and efficient synthesis of (R)-
Lorcaserin, 8 (Scheme 2). We performed a gram-scale
enantioselective synthesis of 6g applying our optimal
conditions and decreasing the catalyst loading to 0.5 mol %.
Compound 6g was achieved with an excellent 98% ee without
recrystallization. Next, we deprotected the phthalimido group
with hydrazine in toluene to afford 7 in excellent yield (93%).
To the best of our knowledge, this is the most efficient catalytic
On the basis of our studies, N-phthalimido 2-phenyl allyl
amine (5a), which is easily synthesized in three steps from
acetophenone (see Supporting Information), was used as the
model substrate. The family of Ir-MaxPHOX catalysts was then
used for the asymmetric hydrogenation of 5a to afford chiral
amine 6a (Table 1). The standard conditions of the reaction
were as follows: dichloromethane as solvent, 1 bar of H2
pressure, and stirring overnight. The Ir-MaxPHOX catalysts
with an isopropyl in the oxazoline ring 1−4a were first tested
(Table 1, entries 1−4). All of them showed full conversion to
6a. In particular, catalyst 2a gave the best ee (64% ee, Table 1,
entry 2). Of note is the huge difference between the catalysts in
terms of chiral induction achieved by simply modifying the
relative configuration of their chiral centers. We then modified
the oxazoline substituent of 2 into an aromatic group, such as
phenyl (2b) or bulkier group such as tert-butyl (2c). In the first
case, the reactivity was not affected, but the enantioselectivity
was substantially improved (Table 1, entry 5). With 2c, the
enantiomeric excess was enhanced up to 90% without affecting
the conversion (Table 1, entry 6). The synthesis of this ligand
is described in the Supporting Information. Then we studied
the effect of the hydrogen pressure: when increased to 50 barG,
the enantioselectivity was not affected (Table 1, entry 7).
Finally, catalyst loading was decreased to 1 mol % and a
B
DOI: 10.1021/acs.orglett.9b03865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
(10) (Scheme 3). The enantioenriched phathalimide 6d was
deprotected by ethanolamine at reflux and protected as tert-
butyl carbamate. The resulting N-Boc amine 9 is a known
precursor of 10.4a
Scheme 1. Scope of the Catalytic Hydrogenation
Scheme 3. Formal Synthesis of OTS514, 10
Finally, the chiral amines prepared here can be used in the
synthesis of 3-methyl indolines.14 These compounds are
relevant precursors of a number of biologically active
compounds and natural products such as Duocarmycins,14a,15
the potent cytotoxic drug (+)-CC1065,14a,16 and the Akt/PBK
phosphorylation inhibitor 12,17 currently in clinical phases.
Thus, 3-methyl indoline 11 was readily prepared from amine
6k (Scheme 4) by phthalimido deprotection followed by
copper-catalyzed intramolecular Ullmann-type amination.18
Scheme 4. Enantioselective Synthesis of 3-Methyl Indoline
11
a
See Supporting Information for experimental details. Reactions were
run in a pressure reactor at 1 bar of H2 pressure. The reaction showed
full conversion for all the examples. Enantiomeric excess was
b
measured by chiral HPLC. Two mol % of catalyst 2c was used.
c
Three mol % of catalyst 2c was used.
Scheme 2. Formal Synthesis of (R)-Lorcaserin, 8
In summary, we have described a very efficient enantiose-
lective synthesis of β-aryl propanamines by means of iridium-
catalyzed asymmetric hydrogenation of N-phthalimido 2-aryl
propanamines using the Ir-MaxPHOX complex 2c. Excellent
enantiomeric excess values were obtained for wide range of
compounds (up to 13 examples) using low catalyst loading and
low hydrogen pressure. Several direct synthetic applications of
this novel and effective catalytic method have been disclosed
such as a formal synthesis of (R)-Lorcaserin and OTS514, as
well as a novel approach to enantiomerically enriched 3-methyl
indolines.
enantioselective synthesis of intermediate 7, a direct precursor
of (R)-Lorcaserin (8).13
The importance of the methodology developed here can also
be appreciated by using 6d in the formal synthesis of OTS514
C
DOI: 10.1021/acs.orglett.9b03865
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
P.; Ferlita, A.; Bartolo, V. D.; Montalto, G.; Banach, M.; Rizzo, M.
Novel anti-obesity drugs and plasma lipids. Clinc. Lipidol. 2014, 9,
179.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03865.
■
S
(4) (a) Nakamura, Y.; Matsuo, Y.; Hisada, S.; Walker, J. R.;
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Preparation of thieno[2,3-c]quinoline derivatives as PKB inhibitors
for treating cancer. PCT/US2011/030278. October 6, 2011. WO
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Development of Small Molecular Compounds Targeting Cancer Stem
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Kato, T.; Zewde, M.; Miyamoto, T.; Matsuo, Y.; Salgia, R.; Nakamura,
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Experimental procedure for the preparation of catalyst
2c; experimental procedures and 1H NMR and 13C
NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: antoni.riera@irbbarcelona.org.
*E-mail: xavier.verdaguer@irbbarcelona.org.
ORCID
́
Albert Cabre: 0000-0001-5256-8798
Xavier Verdaguer: 0000-0002-9229-969X
Antoni Riera: 0000-0001-7142-7675
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge 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. thanks
MINECO for a predoctoral FPU fellowship.
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Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004. (d) Noyori, R.
Asymmetric Catalysis: Science and Opportunities. Angew. Chem., Int.
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DOI: 10.1021/acs.orglett.9b03865
Org. Lett. XXXX, XXX, XXX−XXX