Josiphos-Type Binaphane Ligands for Iridium-Catalyzed Enantioselective Hydrogenation of 1-Aryl-Substituted Dihydroisoquinolines

Article abstract of DOI:10.1021/acs.orglett.9b03251

Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.

Full text of DOI:10.1021/acs.orglett.9b03251

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Josiphos-Type Binaphane Ligands for Iridium-Catalyzed
Enantioselective Hydrogenation of 1‑Aryl-Substituted
Dihydroisoquinolines
Huifang Nie, Yupu Zhu, Xiaomu Hu, Zhao Wei, Lin Yao, Gang Zhou, Pingan Wang,* Ru Jiang,*
and Shengyong Zhang*
School of Pharmacy, Fourth Military Medical University, Xi’an, 710032, China
S
* Supporting Information
ABSTRACT: Convenient synthesis and useful application of a
series of Josiphos-type binaphane ligands were described. The
iridium complexes of these chiral diphosphines displayed
excellent enantioselectivity and good reactivity in the
asymmetric hydrogenation of challenging 1-aryl-substituted
dihydroisoquinoline substrates (full conversions, up to >99% ee,
4000 TON). The use of 40% HBr (aqueous solution) as an
additive dramatically improved the asymmetric induction of
these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted
tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.
1,2,3,4-Tetrahydroisoquinolines (THIQs) and their analogues
are a class of highly important biological active compounds.1
Their pharmacological activities usually involve multidrug
resistance reversal, antidiabetic properties, or central nervous
system (CNS) activities and so on.2 Thus, constant efforts
have been extensively devoted to the development of efficient
synthetic methods of THIQs. In particular, chiral 1-substituted
THIQs scaffolds are present ubiquitously in natural products,
pharmaceuticals, and bioactive compounds (Figure 1), such as
(S)-salsolidine,3a (S)-carnegine,3b (S)-norlaudanosine,3c solife-
nacin,3d AMPA receptor antagonist I,3e (S)-cryptostyline II,3f
(S)-cryptostyline III,3f TRPM8 channel receptor antagonist IV
and V,3g,h etc. Among various synthetic approaches to afford
chiral 1-substituted THIQs,2a,4 catalytic asymmetric hydro-
genation (AH) of 1-substituted 3,4-dihydroisoquinolines
(DHIQs) has been recognized as one of the most
straightforward, efficient, environmental-friendly, and cost-
effective approaches.
During the past two decades, considerable progress has been
made in the AH of 1-alkyl-3,4-DHIQs.5 However, the
Figure 1. Bioactive chiral 1-substituted THIQs. (S)-Salsolidine, (S)-
enantioselective hydrogenation of 1-aryl-3,4-DHIQs still
remains a great challenge, which has been attributed to greater
steric hindrance arising from the adjacent aromatic ring.5d,6 To
the best of our knowledge, there have been only very few
successful examples reported in literature. The first break-
through in the AH of 1-aryl-3,4-DHIQs was reported by
Zhang’s group in 2011. Excellent enantioselectivities (up to
99% ee) and high turnover numbers (up to 10 000) were
obtained using the iodine-bridged dimeric [{Ir(H)[(S,S)-(f)-
binaphane]}2(μ-I)3]+I− complex as the catalyst (Scheme 1).7
However, the enantioselectivities varied dramatically with the
substrates bearing a 1-ortho-substituted phenyl ring. Sub-
sequently, the [IrCODCl]2/(R)-3,5-diMe-Synphos catalyst
carnegine, (S)-norlaudanosine, AMPA receptor antagonist I,
solifenacin, (S)-cryptostyline II, (S)-cryptostyline III, TRPM8 channel
receptor antagonist IV and V.
was used for the process by Ratovelomanana-Vidal et al. via
activating the nitrogen atom of the dihydroisoquinoline ring.
Similarly, this catalytic system provided only moderate
enantioselectivities for sterically hindered 1-(2′-substituted-
aryl)-3,4-DHIQs.6b Then, Zanotti-Gerosa’s group successfully
Received: September 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03251
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Organic Letters
Letter
Scheme 1. Asymmetric Hydrogenation of 1-Aryl-3,4-DHIQs
Figure 2. Design of the Josiphos-type binaphane ligands 1.
Scheme 2. Synthesis of Josiphos-Type binaphane ligands 1
prepared the key intermediate of (S)-salsolidine by AH of 1-
phenyl-3,4-DHIQ hydrochloride on a 200 g scale (95% yield,
98% ee).6c Togni et al. also applied P-trifluoromethyl ligands to
the AH of 1-substituted-3,4-DHIQ hydrochlorides at 55−60
°C and 100 atm of H2, and a 96% ee value was obtained.6d
Recently, a dual stereocontrolled catalytic system in AH of 1-
substituted-3,4-DHIQs was established by Zhou’s group, and
both enantiomers of hydrogenation products were obtained
respectively by tuning the amount of NBS using the BINAP
ligand of the single configuration.8 Unfortunately, this catalytic
system seemed only to be effective in less sterically hindered 1-
(3′- or 4′-substituted-aryl)-3,4-DHIQs. Therefore, developing
additional enantioselective catalysts for the efficient con-
struction of chiral 1-aryl-substituted THIQ frameworks
through enantioselective hydrogenation is highly welcomed.
As part of our ongoing research toward the development of
metal-catalyzed asymmetric synthesis of biologically relevant
targets,9 we hope to develop an efficient catalytic system to
prepare the chiral 1-aryl-THIQs. Currently, the state-of-the-art
ligand for this transformation is (S,S)-f-binaphane explored by
Zhang et al. in 2001, which possesses strongly electron-
donating ability and backbone rigidity.10 As we all know, the
Josiphos ligands are a kind of privileged ligands and have
already been used in a wide variety of transformations, often
with high enantioselectivities and generally good to very high
s/c ratios.11 The two phosphine groups of Josiphos ligands
could be introduced separately, allowing the easy preparation
of numerous chiral ligands with diverse steric and electronic
properties. We then designed a new type of chiral ligand
combining the privileged skeleton of Josiphos and the axial
chiral phosphine moiety of f-binaphane, hoping to produce
new ligands with higher modularity and more convenient
modification (Figure 2). Herein, we report our efforts toward
the synthesis of this Josiphos-type binaphane ligands 1 and
their application in Ir-catalyzed AH of 1-aryl-3,4-DHIQs
(Scheme 1).
sulfonate ester in quantitative yield, and subsequent nickel-
catalyzed Kumada coupling with methyl magnesium bromide
led to 2,2′-dimethylbinaphthalene 4 in 94% yield.12a The
dilithium salt 5 was easily obtained by reaction of 4 with n-
butyl lithium in the presence of TMEDA.12b Then, according
to our published procedures,12c highly diastereoselective ortho-
lithiation of (R)-2 followed by treatment with PCl3 gave 6,
which was further transformed into monophosphine
(RC,SFc,Sax)-7 by reaction with dilithium salt 5 in 66% isolated
yield. Finally, the second phosphino group was introduced by a
stereospecific SN1-type reaction, of which the dimethylamino
moiety was substituted with retention of configuration in
moderate to good yields (65−80%).13 In addition, we
synthesized ligand (RC,SFc,Rax)-1e, which is the diasteroisomer
of ligand (RC,SFc,Sax)-1d, to investigate the chirality matching
between different chiral sources in the ligand.
Initial investigations began with the hydrogenation of the
standard substrate 1-phenyl-3,4-DHIQ (9a) using standard
conditions. The reaction proceeded smoothly when employing
(RC,SFc,Sax)-1a−1d and (RC,SFc,Rax)-1e as ligands to afford (S)-
1-phenyl-THIQ 10a in high yields (Table 1, entries 1−5). It is
noteworthy that the axial chirality at the binaphthalene
backbone of 1 had a pronounced influence on the stereo-
induction, and the chiralities with Sax, RFc, and RC were more
matched (entries 4 vs 5). With regard to the effect of the P-
substituents, the t-Bu group was highly beneficial in terms of
As illustrated in Scheme 2, the synthesis of Josiphos-type
binaphane ligands 1 is quite simple and straightforward starting
from commercially available (R)-Ugi’s amine (2) and optically
pure binol (3). (S)-3 was first converted to corresponding
B
DOI: 10.1021/acs.orglett.9b03251
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Asymmetric Hydrogenation of 1-Phenyl-3,4-DHIQ by Ir-1
b
c
Entry
Ligand
Solvent
Additive
T (°C)
Conv (%)
ee (%)
1
2
3
4
5
6
7
8
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1b
(RC,SFc,Sax)-1c
(RC,SFc,Sax)-1d
(RC,SFc,Rax)-1e
(RC,SFc)-1f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
THF
THF
THF
THF
I2, TFA
I2, TFA
I2, TFA
I2, TFA
I2, TFA
I2, TFA
I2, TFA
I2, TFA
none
I2
TFA
40% HBr
40% HBr
40% HBr
30
30
30
30
30
30
30
30
30
30
30
30
50
50
>99
>99
>99
>99
>99
65
81
60
22
65
15
35
21
84
74
75
85
>99
99
98
(RC,SFc)-1g
60
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1a
(RC,SFc,Sax)-1a
>99
>99
>99
>99
>99
98
9
10
11
12
13
14
d
THF
THF
e
85
a
b
Reaction conditions: Ir/ligand/additive/substrate = 1:2.2:20:200, (substrate) = 0.25 M, 50 atm H2, 30 °C, 12 h. Conversions were determined
c
1
by H NMR. Eantiomeric excesses were determined by chiral HPLC after the products were converted into the corresponding acetamides. The
absolute configuration is assigned by comparison of the rotation sign with literature7 data. Catalyst loading is 0.1 mol %. Catalyst loading is 0.02
d
e
mol %.
enantioselectivity and catalytic activity (entry 1). For
comparison, two classic Josiphos ligands (RC,SFc)-1f and
(RC,SFc)-1g were tested in the hydrogenation of 9a, but
lower enantioselectivities and yields were obtained (entries 6
vs 7). After screening for solvent, iridium precursor, additive,
temperature, and hydrogen pressure (see the Supporting
Information, Table S1), the transformation catalyzed by Ir-
(RC,SFc,Sax)-1a in THF at 30 °C and 50 atm H2 in the presence
of 40% HBr (aqueous solution) turned out to be optimal,
providing (S)-10a in quantitative yield and up to >99% ee
(entry 12). To the best of our knowledge, this is the best result
in AH of 1-phenyl-3,4-DHIQ compared with previous reports.
Combined with these results and the related mechanistic
research,8,14 we proposed that HBr was used not only to
activate the imine substrate through hydrogen bromide but
also to improve the performance of the catalyst via a six-
membered cyclic transition state due to the formation of salts
between the substrate and the hydrogen bromide (Figure 3).
To explore the substrate scope of this catalytic system, a
wide range of 1-aryl-3,4-DHIQs (9a−9v) were synthesized and
hydrogenated under the optimized reaction conditions. High
yields were obtained for all substrates, with good to excellent
enantioselectivities ranging from 85% to >99% ee (Scheme 3).
The stereochemical outcome of the substrates 9b−9i appears
to be insensitive to the nature and position of the substituents
present on the 1-phenyl ring, affording adducts with similar
enantioselectivities. A remarkable increase in enantioselectiv-
ities was observed when 6,7-dimethoxy was introduced in the
benzene ring of the dihydroisoquinoline core (9k−9m, 9o,
9q−9t), especially for the substrates bearing either electron-
donating or electron-withdrawing groups at the ortho (9k−
9m) or para position (9q−9t) of the pendant 1-phenyl ring. It
was worth mentioning that this catalytic system performed
very well in the asymmetric synthesis of several important
intermediates (10a, 10u, 10v, and 10q) of pharmaceuticals or
biological active compounds, for example, solifenacin, (S)-
cryptostyline II, (S)-cryptostyline III, and TRPM8 channel
receptor antagonist IV. In addition, (R)-10i and (R)-10r would
be conveniently obtained with the enantiomer of the ligand
(RC,SFc,Sax)-1a, which were the important intermediates of the
TRPM8 channel receptor antagonist V and AMPA receptor
antagonist I. Furthermore, the catalytic system was also applied
to the AH of 1-alkyl-3,4-DHIQs (9w, 9x), but the results were
disappointing. Lower enantioselectivities and yields were
obtained for both 1-methyl-6,7-dimethoxy-3,4-dihydroisoqui-
noline (47% ee, 56% yield) and 1-ethyl-6,7-dimethoxy-3,4-
dihydroisoquinoline (38% ee, 60% yield).
Encouraged by the remarkable enantioselectivity, catalytic
activity, and easily availability of these new ligands, we carried
out the application of this catalytic system in the large-scale
Figure 3. Probable transition state of hydrogenation.
C
DOI: 10.1021/acs.orglett.9b03251
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Letter
induction of this catalyst. This catalytic system provides an
atom-economic and efficient access to enantiomerically pure 1-
aryl-THIQs derivatives, including the substructure of the
pharmaceutical drug solifenacin. Further applications of these
diphosphine ligands are in progress and will be reported in due
course.
Scheme 3. Asymmetric Hydrogenation of 1-Aryl-3,4-DHIQs
by Ir-(RC,SFc,Sax)-1a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03251.
Procedures, NMR and HPLC spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: syzhang@fmmu.edu.cn.
ORCID
Huifang Nie: 0000-0002-6388-8620
Ru Jiang: 0000-0003-2583-5672
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21372259, 21472240) and Fourth Military Medical Uni-
versity (2018XA009) for financial support.
REFERENCES
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DOI: 10.1021/acs.orglett.9b03251
Org. Lett. XXXX, XXX, XXX−XXX