Design of oxa-spirocyclic PHOX ligands for the asymmetric synthesis of lorcaserin: Via iridium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1039/d0cc06311h

Phosphine-oxazoline (PHOX) ligands are a very important class of privileged ligands in asymmetric catalysis. A series of highly rigid oxa-spiro phosphine-oxazoline (O-SIPHOX) ligands based on O-SPINOL was synthesized efficiently, and their iridium complexes were synthesized by coordination of the O-SIPHOX ligands to [Ir(cod)Cl]2 in the presence of sodium tetrakis-3,5-bis(trifluoromethyl)phenylborate (NaBArF). The cationic iridium complexes showed high reactivity and excellent enantioselectivity in the asymmetric hydrogenation of 1-methylene-tetrahydro-benzo[d]azepin-2-ones (up to 99% yield and up to 99% ee). A key intermediate of the anti-obesity drug lorcaserin could be efficiently synthesized using this protocol.

Full text of DOI:10.1039/d0cc06311h

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DOI: 10.1039/D0CC06311H
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Design of Oxa-Spirocyclic PHOX Ligands for the Asymmetric
Synthesis of Lorcaserin via Iridium-Catalyzed Asymmetric
Hydrogenation
ceived 00th January 20xx,
Accepted 00th January 20xx
†a
†a
a
a
a, b*
and Xumu Zhanga*
Xiang-Yu Ye, Zhi-Qin Liang, Cong Jin, Qi-Wei Lang, Gen-Qiang Chen,
DOI: 10.1039/x0xx00000x
Phosphine-oxazoline (PHOX) ligands are a very important class of introduction of oxygen atom to the spirobiindane skeleton
privileged ligands in asymmetric catalysis. A series of highly rigid makes a great difference on the reactivity and enantioselectivity
oxa-spiro phosphine-oxazoline ligands (O-SIPHOX) based on O- of the resulting ligands. We envisioned that the O-SIPHOX
SPINOL were synthesized efficiently, and their iridium complexes ligands based on O-SPINOL will show different properties
were synthesized by coordination of the ligands O-SIPHOX to compared with SIPHOX.
[
Ir(cod)Cl]
2
in the presence of sodium tetrakis-3,5-
O
bis(trifluoromethyl)phenylborate (NaBArF). The cationic iridium
complexes showed high reactivity and excellent enantioselectivity
in the asymmetric hydrogenation of 1-methylene-tetrahydro-
benzo[d]azepin-2-ones (up to 99% yield, up to 99% ee). The key
intermediate of an anti-obesity drug Lorcaserin could be efficiently
synthesized with this protocol.
OH
OH
OH
OH
O
SPINOL
L = 3.394 Å
L: the distance between the two phenolic oxygen atoms
The data are collected from the corresponding crystal structures.
O-SPINOL
L = 4.822 Å
*
Figure 1. Comparison of the structures of SPINOL and O-SPINOL.
1
2
Ever since their first introduction by Helmchen, Pfaltz, and
3
Williams’s group in 1993, phosphine-oxazoline ligands (PHOX)
have found extensive applications in asymmetric catalysis, and
O
O
Pd(OAc) , dppp, CO
Et N, MeOH, DMSO
3
O
O
1) amino alcohol
DCC, HOBt, THF
2
4
OTf
CO2H
PPh2 2) Et N, MsCl, THF
3
varieties of chiral phosphine-oxazoline ligands such as
SimplePHOX, SIPHOX, SpinPHOX, BPPHOX and HMSI-PHOX
PPh2 then KOH, MeOH, THF
5
6
7
8
9
(
R)-1a
(R)-2a, 64% yield
have been designed and synthesized. As the chiral analogues of
the Crabtree’s catalyst, one of the most recognized uses of the
PHOX ligands is iridium-catalyzed asymmetric hydrogenation of
O
P
+
O
O
O
O
R
[
Ir(cod)Cl]2, NaBArF
DCM, reflux
N
N
PPh2
BArF
R
1
0
11
Ir
unfunctionalized olefins and imines. In 2006, Zhou and
coworkers reported the synthesis of highly rigid spiro
phosphine-oxazoline ligands based on spirobiindane skeleton,
termed as SIPHOX, and their application in the asymmetric
O
Ph2
L1, R = Ph, 66%
L2, R = iPr, 62%
L3, R = Bn, 61%
Cat 1, R = Ph, 84%
Cat 2, R = iPr, 75%
Cat 3, R = Bn, 82%
6
hydrogenation of imines. The SIPHOX ligands showed excellent
reactivities and enantioselectivities for a wide range of α,β-
unsaturated carboxylic acids and imines.
O
O
O
O
1) amino alcohol
DCC, HOBt, THF
Pd(OAc)2, dppp, CO
Et3N, MeOH, DMSO
OTf
CO2H
1
2
6, 13
P(DTB)2 then KOH, MeOH, THF
P(DTB)2 2) Et3N, MsCl, THF
In 2018, we reported the efficient synthesis of a structurally
unique oxa-spirocyclic diphenol, termed as O-SPINOL, and the
application of the O-SpiroPAP ligand in the dynamic kinetic
(
S)-1b
(S)-2b, 60% yield
O
P
+
1
4
resolution of Bringmann lactones.
diphosphine ligand O-SDP
Subsequently, the
O
O
O
O
[
Ir(cod)Cl]2, NaBArF
DCM, reflux
R
1
5
N
based on O-SPINOL was also
N
R
BArF
Ir
P(DTB)2
synthesized and applied in ruthenium-catalyzed asymmetric
hydrogenation of α,β-unsaturated carboxylic acids. The
O
(DTB)2
L4, R = Bn, 60%
L5, R = Ph, 59%
Cat 4, R = Bn, 81%
Cat 5, R = Ph, 81%
dppp: 1,3-Bis(diphenylphosphino)propane; DCC: dicyclohexyl carbodiimide; HOBt: 1-
Hydroxybenzotriazole.
†
Xiang-Yu Ye and Zhi-Qin Liang contributed equally to this work.
Shenzhen Grubbs Institute and Department of Chemistry, Southern University of
a
Scheme 1. Synthesis of the O-SIPHOX ligands.
Science and Technology, Shenzhen 518000, People’s Republic of China
b
Academy for Advanced Interdisciplinary Studies, Southern University of Science
and Technology, Shenzhen 518000, People’s Republic of China.
E-mail address: chengq@sustech.edu.cn, zhangxm@sustech.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
A series of O-SIPHOX ligands were synthesized from known synthetic route was reported, organocatalytic reduction of
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1
5
14
DOI: 10.1039/D0CC06311H
compound (R)-1a (L1-L3) and (S)-1b (L4 and L5) according to nitroolefin with Hantzsch ester was utilized to the synthesis of
6
previously reported procedures (Scheme 1).
After the key intermediate. Enantiopure Lorcaserin was obtained in 8
carbonylation, condensation and subsequent cyclization, the O- steps, which greatly limited its practical application (Scheme
2
0e
SIPHOX ligands (L1-L5) were obtained in moderate yields. The 2a). In 2019, Muthukrishnan and coworkers reported a more
iridium catalysts (Cat 1 to Cat 5) were feasibly synthesized by practical synthesis of Lorcaserin with hydrolytic kinetic
in the presence of resolution of epoxide as the key step (Scheme 2b).2 Despite
0a
coordination of O-SIPHOX to [Ir(cod)Cl]
2
sodium tetrakis-3,5-bis(trifluoromethyl)phenylborate (NaBArF) these advances in the asymmetric synthesis of Lorcaserin, the
in high yields.
development of more efficient synthetic route to Lorcaserin and
its derivatives is highly desirable. Herein, we report a highly
efficient and enantioselective synthesis of Lorcaserin and its
derivatives via iridium-catalyzed asymmetric hydrogenation of
1-methylene-tetrahydro-benzo[d]azepin-2-ones (Scheme 2c).
Cl
Cl
Cl
NH
NH
NH
Cl
Br
Lorcaserin
F
Cl
Br
O
NH
NH
NH
Table 1. Optimization of the reaction conditions.
O
O
Figure 2. Structures of some 5-HT2C receptor agonists for the
treatment of obesity.
O
catalyst (1 mol%), H2 (40 atm)
solvent, 24 h, 24 °C
O
NH
NH
O
O
3a
4a
On the other hand, tetrahydrobenzazepines are widely found
in many biologically active compounds and drug molecules.
Among them, Lorcaserin is an anti-obesity drug developed by
Arena pharmaceutical companies. Lorcaserin hydrochloride is a
selective 5-HT2c receptor agonist that has been approved by the
US Food and Drug Administration (FDA) in 2012 as an anti-
obesity drug.16 Many anti-obesity drugs such as sibutramine,
dexfenfluramine etc. were withdrawn from the market because
entrya
catalyst
solvent
yield (%)b
ee (%)c
1
2
3
4
5
6
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
MeOH
EtOH
99
46
33
50
96
26
33
90
99
38
5
48
83
74
99
84
74
99
99
99
99
-84
-88
-75
92
87
76
3
71
55
25
5
Cat 6
1
7
d
of the risk of the heart; however, Lorcaserin was found to be
the best safety of currently available medications with low
7
8
9
Rh(I)/L8
Rh(I)/L9
Rh(I)/L10
Rh(I)/L11
Rh(I)/L12
Rh(I)/L13
Rh(I)/L14
Rh(I)/L15
Cat 5
Cat 5
Cat 5
Cat 5
Cat 5
d
1
8
d
cardiovascular risk.
d
d
d
d
d
1
) Synthesis of Lorcaserin by organocatalytic reduction of niroolefin.
10
1
1
1
1
1
2
3
4
Cl
NO2 organocatalyst Cl
Hantzsch Ester
NO2
Cl
0
NH
44
40
97
97
97
97
98
98
90
2) Synthesis of Lorcaserin via hydrolytic kinetic resolution.
O
1
5
Cl
O
1
6
hydrolytic
Cl
Cl
kinetic resolution
NH
17
18
DCM
THF
dioxane
toluene
toluene
OH
Cl
OH
1
9
3) This work: synthesis of Lorcaserin via Ir(I)-catalyzed asymmetric hydrogenation.
20
21
Cat 5
Cat 7
O
O
asymmetric
Cl
hydrogenation Cl
Cl
NH
NH
NH
a
The reactions were conducted on 0.1 mmol scale. b Isolated yield. c
Determined by chiral HPLC. d Rh(nbd)
precursor. THF = tetrahydrofuran, DCM = dichloromethane.
Scheme 2. The development in the asymmetric synthesis of
Lorcaserin.
2 4
BF was used as the Rh(I)
Obesity has reached an alarming level in the world, with 13%
We synthesized compound 3a according to reported
1
9
21
of adults being obese and 39% being overweight. The procedures. The optimization of the reaction conditions was
development of highly efficient and selective methods for the conducted with compound 3a as a model substrate, and the
synthesis of Lorcaserin allows of no delay. During the last results were summarized in Table 1. Using iPrOH as solvent, we
decade, many efforts have been devoted to the synthesis of evaluated the efficacy Ir-O-SIPHOX catalyst in the presence of
Lorcaserin.20 Industrially, Lorcaserin was synthesized by the 40 atm H . 99% yield and 84% ee were achieved with Cat 1 as
2
chemical resolution of its racemates. Quantitative amount of catalyst. The yield dropped sharply for Cat 2 and Cat 3 (Table 1,
resolving reagent was needed to obtain the optically active entries 1-3). With Cat 4 as catalyst, compound 4a was produced
Lorcaserin, and the highest yield is limited to 50%. To increase in 92% ee, albeit with only 50% yield, the yield was increased to
the efficiency of the synthesis, some asymmetric synthetic 96% for Cat 5, whereas, the ee was dropped to 87% (Table 1,
routes were developed recently. In 2016, an asymmetric entries 4-5). Only 26% yield and 76% ee were achieved for Cat
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
6
(Table 1, entry 6). The Rh(I)/diphosphine catalytic system was the X-ray structure of compound 4e (CCDC numbVeierw1A9rt7icl4e7O0n1lin)e.
also evaluated, and the yields and enantioselectivities were not Compared with the current catalytic systeDmO,I:t1h0e.10C3o9//BDP0CECs0y6s3te11mH
satisfactory for a wide range of electron-donating diphosphine recently developed in our group is very effective for the
ligands such as DuanPhos, BPE, BDPP, WudaPhos and JosiPhos asymmetric hydrogenation of α,β-unsaturated carboxylic
2
3a
(Table 1, entries 7-11). Axially chiral diphosphine ligands BINAP, acids, however, the it has no activity for the α,β-unsaturated
SEGPHOS, BIPHEP could not give better results either (Table 1, ester or amide. The Ni/BPE system recently developed in our
2
3b
entries 12-14). Next, we put our attention to the screening of group also works well for the asymmetric hydrogenation of
solvents. Various protic and non-protic solvents were screened. α,β-unsaturated carbonyl compounds.23c The use of very
9
9% yield and 97% ee were achieved with MeOH as solvent and electron-rich ligands was necessary to achieve high activity.
Cat 5 as catalyst (Table 1, entry 15). The yield was dropped to The synthetic elaboration of the current reaction was
4% with retention of the enantioselectivity in the presence of demonstrated by its application in the asymmetric synthesis of
8
EtOH (Table 1, entry 16). Non-protic solvents such as DCM, THF, anti-obesity drug Lorcaserin. The asymmetric hydrogenation of
dioxane and toluene were also evaluated (Table 1, entries 17- 3c could be operated on 1 mmol scale with retention of the yield
2
(
0), and excellent yields and enantioselectivities were achieved and enantioselectivity, providing compound 4c with 99% yield
99% yield and 97% ee for THF, 99% yield and 98% ee for and 99% ee. Lorcaserin could be obtained after a single step
dioxane and toluene). Toluene and dioxane were identified as reduction of intermediate 4c according to reported procedure
2
4
the best solvents. It is noteworthy that Cat 7, the analogous (Scheme 4).
catalyst of Cat 5, could only produce compound 4a in 90% ee
O
O
Cat 5 (1 mol%), H2 (40 atm)
toluene, 24 oC, 24 h
(Table 1, entry 21).
R
NH
R
NH
O
P
+
+
O
Bn
Ph
HH
N
N
BArF
Ir
O
O
O
BArF
MeO
MeO
MeO
Cl
Ir
P
P
P
NH
NH
NH
Ph2
(DTB)
2
tBu
tBu
Cat 6
Cat 7
L8: (Rc,Sp)-DuanPhos
4a, 99% yield, 98% ee
4b, 99% yield, 98% ee
4c, 99% yield, 99% ee
Ph
Ph
O
O
O
PCy2
Br
PCy2
PPh2
P
P
NH
NH
Me
NH
P
Fe
Ph2P
PPh2
Cl
Br
Ph
Fe
Ph
NMe2
4d, 99% yield, 98% ee
4e, 99% yield, 97% ee
4f, 99% yield, 98% ee
L9: (R,R)-Ph-BPE
L10: (S,S)-BDPP
L11: (R,S)-JosiPhos L12: WudaPhos
O
O
O
Ph
O
NH
NH
O
O
HN
Bn
PPh2
PPh2
MeO
MeO
PPh2
PPh2
PPh2
PPh2
4
g, 99% yield, 99% ee
4h, 99% yield, 97% ee
4i, 99% yield, 77% ee
O
Ph
O
NBoc
L13: (R)-BINAP
L14: (R)-MeO-BIPHEP
L15: (S)-SEGPHOS
Ph
O
Figure 2. Structures of the catalysts or ligands that were screened.
O
N
H
O
O
O
j, 99% yield, 95% ee
4
4k, 98% yield, 8% ee a
4l, 99% yield, 42% ee a
The reaction was conducted at 60 atm and 60 oC with Cat 4 as catalyst
With the optimal reaction conditions in hand, we next
evaluated the substrate scope of the current reaction, and the
results were summarized in Scheme 3. For the methoxy or
dimethoxy substituted substrate 3a and 3b, 99% yield and 98%
ee were achieved respectively. Product 4c, a key intermediate
of Lorcaserin, was produced in 99% yield and 99% ee, and 99%
yield and 98% ee were observed for the 8-bromo substrate 3d.
The 7-Cl (3e, 99% yield, 97% ee) and 7-Br (3f, 99% yield, 98% ee)
substrates were suitable substrates for the current reaction
either. The reaction also worked well for 7-phenyl substrate 3g
a
Scheme 3. Substrate scope.
O
O
Cl
Cl
Cat 5 (1 mol%), H2 (40 atm)
toluene, 24 oC, 24 h
mmol scale
NH
NH
1
3c
4c, 99% yield, 99% ee
BH .THF
Cl
3
NH
THF, 0 oC to rt
(99% yield, 99% ee) and the unsubstituted substrate 3h (99%
5c, Lorcaserin
92% yield, 99% ee
yield, 97% ee). Only 77% ee was achieved for the non-cyclic
substrate 3i. The reaction also worked well for the N-
substituted substrate 3j (99% yield, 95% ee). Only 8% and 42%
ee were achieved for the unsaturated lactam 3k and lactone 3l
Scheme 4. Synthetic application.
In conclusion, we have designed and synthesized a series of
PHOX ligands, termed as O-SIPHOX based on O-SPINOL
skeleton. The O-SIPHOX ligands showed excellent reactivity and
o
respectively at 60 C with Cat 4 as the catalyst, indicating that
enantioselectivity
in
iridium-catalyzed
asymmetric
2
2
the lactam 3k and lactone 3l were not suitable substrates for
the current catalytic system possibly due to the nature of the
ligand (rigidity and longer P-N distance). The absolute
configuration of the product was unambiguously confirmed by
hydrogenation of 1-methylene-tetrahydro-benzo[d]azepin-2-
one derivatives, the products of which are key intermediates for
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a wide range of 5-HT2c receptor agonists. The anti-obesity drug Y.-B. Yu and Q.-L. Zhou, Angew. Chem., Int. Ed., 2013, 52, 1556-1559;
View Article Online
DOI: 10.1039/D0CC06311H
(c) S. Song, S.-F. Zhu, L.-Y. Pu and Q.-L. Zhou, Angew. Chem., Int. Ed.,
Lorcaserin could be efficiently synthesized by this protocol.
2
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ACKNOWLEDGMENT
G.-Q. Chen gratefully acknowledges the Free Exploration Fund
from the Shenzhen Science and Technology Innovation
Committee (JCYJ20170817105056467) and the Youth Fund
from National Natural Science Foundation of China (No.
(
g) S. Li, S.-F. Zhu, C.-M. Zhang, S. Song and Q.-L. Zhou, J. Am. Chem.
Soc., 2008, 130, 8584-8585.
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1901107). X. Zhang is indebted to Southern University of
Science and Technology (start-up fund), Shenzhen Science and
Technology Innovation Committee (Nos.
1
KQTD20150717103157174 and JSGG20170821140353405),
Guangdong Provincial Key Laboratory of Catalysis (No.
1
2
020B121201002), National Natural Science Foundation of
1
China (No. 21991113) and SZDRC Discipline Construction
Program for financial support.
1
1
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Conflicts of interest
9
The authors declare no competing financial interests.
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Codesido, J. Cruces, J. Brea, M. I. Loza, F. Alen, J. Botta, P. J.
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Page 5 of 5
ChemComm
Design of Oxa-Spirocyclic PHOX Ligands for the Asymmetric
Synthesis of Lorcaserin via Iridium-Catalyzed Asymmetric
Hydrogenation
A series of highly rigid oxa-spiro phosphine-oxazoline ligands (O-SIPHOX)
based on O-SPINOL were synthesized efficiently, andVie
t
w
he
A
i
r
r
ticl
i
e
ri
O
d
n
iulin
m
e
DOI: 10.1039/D0CC06311H
complexes were synthesized by coordination of the ligand O-SIPHOX to
Ir(cod)Cl] in the presence of sodium tetrakis-3,5-
[
2
O
+
bis(trifluoromethyl)phenylborate (NaBArF). The cationic iridium
complexes showed high reactivity and excellent enantioselectivity in the
asymmetric hydrogenation of 1-methylene-tetrahydro-benzo[d]azepin-2-
ones (up to 99% yield, up to 99% ee). The key intermediate of an anti-
obesity drug Lorcaserin could be efficiently synthesized with this protocol.
O
O
R
N
BArF
Ir
P
O
Ar2
O
Cl
Ir(I)-catalyst
toluene, H2(40 atm), 24 oC, 24 h
R
NH
R
NH
NH
up to 99% yield
up to 99% ee
Lorcacerin
(anti-obesity)
Xiang-Yu Ye, Zhi-Qin Liang, Cong Jin, Qi-Wei Lang, Gen-Qiang Chen,
Zhang*
*
and Xumu