Enantioselective synthesis of 1-aryl tetrahydroisoquinolines by the rhodium-catalyzed reaction of 3,4-dihydroisoquinolinium tetraarylborates

Article abstract of DOI:10.1021/acs.orglett.1c00198

The 1-aryl tetrahydroisoquinolines (1-aryl THIQs) are omnipresent in biologically active molecules. Here we report on the direct asymmetric synthesis of these valuable compounds via the reaction of 3,4-dihydroisoquinolinium tetraarylborates. The dual roles of anionic tetraarylborates, which function as both prenucleophiles and stabilizers of 3,4-dihydroisoquinolinium cations, enable this rhodium(I)-catalyzed protocol to convergently provide enantioenriched 1-aryl THIQs in good yields (≤95%) with ≤97% ee, as demonstrated by the formal synthesis of (?)-solifenacin and the facile synthesis of (?)-Cryptostyline I.

Full text of DOI:10.1021/acs.orglett.1c00198

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Letter
Enantioselective Synthesis of 1‑Aryl Tetrahydroisoquinolines by the
Rhodium-Catalyzed Reaction of 3,4-Dihydroisoquinolinium
Tetraarylborates
Wei-Sian Li, Ting-Shen Kuo, Ping-Yu Wu, Chien-Tien Chen,* and Hsyueh-Liang Wu*
Cite This: Org. Lett. 2021, 23, 1141−1146
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ABSTRACT: The 1-aryl tetrahydroisoquinolines (1-aryl THIQs) are omnipresent in biologically active molecules. Here we report
on the direct asymmetric synthesis of these valuable compounds via the reaction of 3,4-dihydroisoquinolinium tetraarylborates. The
dual roles of anionic tetraarylborates, which function as both prenucleophiles and stabilizers of 3,4-dihydroisoquinolinium cations,
enable this rhodium(I)-catalyzed protocol to convergently provide enantioenriched 1-aryl THIQs in good yields (≤95%) with ≤97%
ee, as demonstrated by the formal synthesis of (−)-solifenacin and the facile synthesis of (−)-Cryptostyline I.
1,2,3,4-Tetrahydroisoquinolines (abbreviated as THIQs) with
a C1 stereogenic center make up a class of valuable molecules
with diverse bioactivities, ranging from bradycardia, central
nervous system (CNS) activation, and antidiabetic activities to
the reversal of multidrug resistance.1,2 Among these deriva-
tives, 1-aryl THIQs have a variety of biological and
pharmaceutical properties.2 For example, Cryptostyline I
(1a), isolated from Cryptostylis erythroglossa and Cryptostylis
fulva,3a and 1b have been used as probes for dopamine
receptor D1.3b 1c is a potent antagonist toward ionotropic
glutamate receptors (iGluRs).3c Solifenacin (Vesicare) (1d),
an antimuscarinic agent, is used to treat overactive bladders.3d,e
1e is clinically cytotoxic against L1210 murine leukemic cells
(Figure 1).3f
Consequently, optically pure 1-aryl THIQs are highly
sought-after molecular targets and have stimulated the
development of numerous synthetic methods.1,4,5 Prominent
Figure 1. Alkaloids and bioactive compounds bearing 1-aryl THIQ
moieties.
among the transition metal-catalyzed methods are those based
on the Ir-catalyzed enantioselective hydrogenation of 1-aryl
isoquinolinium salts (Scheme 1, eq a) and their 3,4-
dihydroisoquinoline analogues (eq b).4 However, handling
enediamine ligand to achieve a satisfactory asymmetric
the high H2 pressure and their linear-synthesis characteristic
induction, thus thwarting its synthetic potential (eq 1c). The
tend to be limiting factors. For these reasons, the development
shortcoming shown above combined with the lack of a more
of a convenient method for convergently producing 1-aryl
THIQs has attracted considerable interest. The asymmetric
Received: January 19, 2021
Published: January 25, 2021
addition of carbon-based nucleophiles to a vast collection of
readily available 3,4-dihydroisoquinolinium derivatives5a,6,7 has
emerged as an appealing alternative. Sato et al. published a
pioneering study on the enantioselective arylation of 3,4-
dihydroisoquinoline N-oxides.6b This Zn-mediated strategy,
however, required a stoichiometric excess of a chiral ethyl-
https://dx.doi.org/10.1021/acs.orglett.1c00198
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1141−1146
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Letter
unprecedented and challenging substrates for Rh catalysis. We
report herein on the synthesis of such molecules, in which a
Rh/chiral diene catalyst is used for the enantioselective
reaction of 3,4-dihydroisoquinolinium tetraarylborates (eq d).
At the outset, our initial intention was to identify a suitable
aryl-boron nucleophile for an addition reaction of 3,4-
dihydroisoquinolinium bromide (2a-Br) catalyzed by 1.5 mol
% [RhCl(COD)]2 (Table 1). While no reaction was observed
when using PhB(OH)2 (entry 1) and PhBF3K (entry 2),10 the
use of NaBPh4 gave a 23% yield of adduct 3aa (entry 3).11
This specific nucleophile led us to conceive of 2a-BPh4 as a
feasible substrate for this asymmetric reaction based on the
assumption that the tetraphenylborate anion would not only
serve as a source of a nucleophile but also enhance the stability
of the 3,4-dihydroisoquinolinium cation.12 The use of 2a-
BPh4, obtained via the anion exchange of 2a-Br with
NaBPh4,13 resulted in a substantial increase in the chemical
yield of 3aa to 88% (entry 4). This pleasing result led to the
subsequent optimization using a Rh catalyst comprised of a
series of known chiral ligands to achieve high enantioselectiv-
ity. In initial experiments,10 we observed the formation of 3aa
in 58% and 71% yields with 93% and 86% ee, respectively, in
the presence of 3 mol % Rh catalysts derived from chiral
bicyclo[2.2.1]heptadiene ligands L1 and L214 (entries 5 and 6,
respectively). A further examination of the chiral diene ligands
L3−L515 bearing a secondary amido group resulted in
relatively improved yields and selectivities (entries 7−9,
respectively), with L5 optimally giving rise to 3aa in 82%
yield with 92% ee (entry 9). Used in other Rh-catalyzed
Scheme 1. Synthetic Approaches to the Formation of 1-Aryl
THIQs
efficient method, therefore, triggered our efforts to develop a
more efficient approach.8
Our group, recently, employed the asymmetric arylation of
N-sulfonyl aldimines and ring cyclization reaction sequences to
efficiently prepare chiral 1-phenyl THIQ. The use of a Rh
catalyst comprised of a chiral bicyclo[2.2.1]heptadiene ligand
to establish the stereogenic center was instrumental in our
method prior to the sequential cyclization process.9 Building
upon this outcome, we envisioned a straightforward synthesis
of 1-aryl THIQs via the asymmetric reaction of aryl-boron
reagents with 3,4-dihydroisoquinolinium salts, which were
a
Table 1. Optimization of Reaction Conditions
b
c
entry
X
Ph-B
Rh catalyst
time (h)
yield (%)
ee (%)
d
1
2
3
4
5
6
7
8
Br
Br
Br
PhB(OH)2
PhBF3K
NaBPh4
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(C2H4)2]2/L1
[RhCl(C2H4)2]2/L2
[RhCl(C2H4)2]2/L3
[RhCl(C2H4)2]2/L4
[RhCl(C2H4)2]2/L5
[RhCl(C2H4)2]2/L6
[RhCl(C2H4)2]2/L7
[RhCl(C2H4)2]2/L8
36
36
36
15
9
4
12
6
12
48
48
48
nr
−
−
−
d
nr
23
88
58
71
74
56
82
BPh4
BPh4
BPh4
BPh4
BPh4
BPh4
BPh4
BPh4
BPh4
−
−
−
−
−
−
−
−
−
−
93
86
93
86
92
9
d
e
10
11
12
nr
nd
d
e
nr
nd
d
e
nr
nd
a
b
With 0.2 mmol of 2a-X in dioxane (1.0 mL) and [RhCl(COD)2]2 (1.5 mol %), or [RhCl(C2H4)2]2 (1.5 mol %) and L (3.6 mol %). Isolated
c
d
e
yield. Determined by chiral HPLC analysis. No reaction. Not determined.
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b
asymmetric reactions, chiral ligands L6−L8 failed to produce
the desired adduct (entries 10−12, respectively).
The scope of the reaction for various 3,4-dihydroisoquino-
linium tetraarylborates was then explored (Scheme 2). The
Scheme 3. Substrate Scope (II)
e
Scheme 2. Substrate Scope (I)
a
b
c
d
a
b
On a 2 mmol (1.14 g) scale. At 80 °C. At 120 °C. Using chiral
At 80 °C. Reaction conditions: 0.2 mmol of 2-BPh4 in dioxane (1.0
e
diene ligand L1. Reaction conditions: 0.2 mmol of 2-BAr4 in dioxane
(1.0 mL), [RhCl(C2H4)2]2 (1.5 mol %), L5 (3.6 mol %), stirred at
100 °C.
mL), [RhCl(C2H4)2]2 (1.5 mol %), and L5 (3.6 mol %), stirred at
100 °C.
afford adducts (3fa−3ha) in 84−95% yields with 70−90% ee.
Asymmetric phenylation with substrates containing substituted
aromatic rings, regardless of whether they contained alkyl,
electron-withdrawing, or electron-releasing substituents, of-
fered the desired adducts (3ia−3oa) in 64−94% yields with
85−97% ee. 3,4-Dihydroisoquinolinium salts with extended π-
conjugation or an analogue derived from 9-benzyl β-carboline
were also applicable to this enantioselective reaction, furnish-
ing 3pa in 53% yield with 91% ee and 3qa in 77% yield and
88% ee. The newly formed stereogenic center was unequiv-
ocally determined by a single-crystal X-ray crystallography
analysis of 3pa to possess an R configuration.
Although various 3,4-dihydroisoquinolinium tetraarylborates
are applicable, a further investigation of the addition reaction
of the 1-methyl-3,4-dihydroisoquinolinium analogue, 4-BPh4,
under the optimized reaction conditions, failed to furnish the
adduct bearing a quaternary stereogenic center (Scheme 4, eq
1). A diminishing asymmetric induction was observed in the
case of the reaction with the isoquinolinium substrate 5-BPh4,
providing 3ba, after a subsequent reduction, in a combined
75% yield with 55% ee. This outcome suggests the 3,4-
dihydroisoquinolinium ions are preferable substrates in this
asymmetric transformation (eq 2). A limitation was found in
the case of a tetra-heteroarylborate-containing substrate 2n-
B(2-furyl)4, which afforded the desired adduct 3nb in 46%
yield with 23% ee (eq 3). While the use of PhBF3K gave no
desired adduct (Table 1, entry 2), 2a-Br underwent
alkenylation with potassium octenyltrifluoroborate to afford
product 3ah in a 47% yield, but with no stereoselectivity (eq
enantioselective reactions of N-PMB 3,4-dihydroisoquinoli-
niums harboring diverse tetraarylborates afforded the corre-
sponding adducts (3aa−3ag) in 21−85% yields with 80−94%
ee. Notably, the reaction temperature was found to be a key
factor in influencing the reactivity and enantioselectivity of the
reaction. For the substrate containing tetra-4-MeO-phenyl
borate, adjusting the reaction temperature to 80 °C is
necessary for the corresponding product 3ae to be produced
in 81% ee, compared to the observed 67% ee at 100 °C,
suggesting that the use of a lower reaction temperature resulted
in a satisfactory ee for a prenucleophile containing a para-
electron-releasing aryl group. On the contrary, the reaction of
the tetraarylborate substrate harboring 4-Cl-phenyl substitu-
ents required a 120 °C reaction temperature to allow the
production of 3af in an optimal 39% yield. In addition, an
enhanced 80% ee of 3ag was observed when the reaction was
carried out in the presence of the Rh(I)/L1 catalyst for a
bulkier 2-naphthyl nucleophile as opposed to the value of 40%
ee when using L5. Asymmetric reactions with substrates
bearing various N substituents provided the corresponding
products (3ba16−3ea) in 30−90% yields along with 77−97%
ee. Conducting this asymmetric reaction on a larger scale (2.0
mmol), under optimal reaction conditions, furnished 3aa in
70% yield without the erosion of the high enantioselectivity.
Further investigations focused on substrates with varying
3,4-dihydroisoquinolinium motifs were carried out (Scheme
3). Substrates, bearing substituents on the N-containing
heterocyclic ring core, underwent phenylation smoothly to
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a
Scheme 4. Limitations
Table 2. Total Synthesis of (−)-Cryptostyline I [(−)-1a]
b
c
entry
ligand
temp (°C)
time (h)
yield (%)
ee (%)
1
2
3
4
5
L5
L5
L1
L2
L2
100
80
80
80
60
15
24
144
48
92
90
90
90
90
60
73
70
79
88
140
a
With 0.2 mmol of 2d-B(Ar)4 in dioxane (1.0 mL), [RhCl(C2H4)2]2
b
c
(1.5 mol %), and L5 (3.6 mol %). Isolated yield. Determined by
chiral HPLC analysis.
reaction was performed at a lower temperature (80 °C) as a
result of using a para-electron-releasing aryl prenucleophile.
The comparatively weaker asymmetric induction in the
formation of 1a prompted us to reinvestigate the reaction
conditions based on chiral diene ligands. Carrying out the
reaction in the presence of the Rh(I)/L1 catalyst at 80 °C for
144 h furnished 1a in a comparable yield and ee (entry 3).
Employing a Rh catalyst comprising L2 slightly increased the
enantioselectivity of 1a in a comparatively shorter reaction
time (48 h) (entry 4), and under such reaction conditions, the
reaction at 60 °C ultimately afforded 1a in a ≤88% ee (entry
5).
4), highlighting the stark difference in reactivity between aryl
and alkenyl trifluoroborates.
Using the models shown in Figure 2, we propose a reaction
pathway that explains the observed stereochemical outcomes.
In conclusion, we report on the development of a method
for providing enantioenriched 1-aryl THIQs based on
enantioselective reaction of 3,4-dihydroisoquinolinium tetraar-
ylborates. This protocol, in the presence of 3 mol % Rh/L5
catalyst, proceeds smoothly to afford 1-aryl THIQs in ≤97%
ee. The tetraarylborate anions not only function as stabilizers
of the highly reactive but unstable 3,4-dihydroisoquinolinium
countercations but also serve as readily available prenucleo-
philes for this asymmetric transformation to allow convenient
and rapid production of a wide variety of optically active 1-aryl
THIQs containing various substituents and structures. The
formal synthesis of (−)-solifenacin and asymmetric synthesis
of the alkaloid (−)-Cryptostyline I [(−)-1a] clearly confirm
the synthetic applicability of this protocol.
Figure 2. Proposed rationale for the stereochemical outcome of
phenylation of 3,4-dihydroisoquinolinium salt.
Transmetalation of the aryl group from tetraarylborate occurs,
yielding the corresponding [Rh]-Ar species to allow the
addition reaction to proceed more readily via the formation of
the re-face-coordinated transition structure (I) compared to
that with a si-face coordination (II), which is energetically
disfavored as a result of steric repulsion between the 3,4-
dihydroisoquinolinium ion and the ligand backbone, giving rise
to the observed R adducts.
Treatment of 3aa with ethyl chloroformate in toluene
provided the resulting 6aa in 61% without erosion of high ee,
enabling a one-pot formal synthesis of (−)-solifenacin
(Scheme 5).4e
ASSOCIATED CONTENT
■
Scheme 5. Formal Synthesis of (−)-Solifenacin
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00198.
Experimental procedures, complete characterization
data, HPLC chromatograms, and NMR spectra (PDF)
Although the successful production of 3ea paved the way for
the enantioselective synthesis of the naturally occurring
Cryptostyline I (1a) (Figure 1), which demonstrates the
synthetic utility of this reaction, the synthesis of 1a was not
encouraging at the early stage of the study. Under the optimal
reaction conditions, the desired 1a was produced in 92% yield
but with only 60% ee (Table 2, entry 1). In the ensuing
investigation, the ee of 1a was increased to 73% when the
Accession Codes
CCDC 2035808 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Discovery of a Novel and Highly Potent Noncompetitive AMPA
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AUTHOR INFORMATION
Corresponding Authors
■
Hsyueh-Liang Wu − Department of Chemistry, National
Taiwan Normal University, Taipei 11677, Taiwan;
orcid.org/0000-0001-7462-8536; Email: hlw@
ntnu.edu.tw
Chien-Tien Chen − Department of Chemistry, National
Tsing-Hua University, Hsinchu 30013, Taiwan;
orcid.org/0000-0001-8073-6007; Email: ctchen@
mx.nthu.edu.tw
(4) For representative examples of asymmetric hydrogenation, see:
(a) Chang, M.; Li, W.; Zhang, X. A Highly Efficient and
Enantioselective Access to Tetrahydroisoquinoline Alkaloids: Asym-
metric Hydrogenation with an Iridium Catalyst. Angew. Chem., Int. Ed.
Authors
Wei-Sian Li − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan
Ting-Shen Kuo − Department of Chemistry, National Taiwan
Normal University, Taipei 11677, Taiwan
Ping-Yu Wu − Oleader Technologies, Company, Ltd., Hsinchu
30345, Taiwan
̌
̌
̌
̌
2011, 50, 10679. (b) Ruzic, M.; Pecavar, A.; Prudic, D.; Kralj, D.;
Scriban, C.; Zanotti-Gerosa, A. The Development of an Asymmetric
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Res. Dev. 2012, 16, 1293. (c) Berhal, F.; Wu, Z.; Zhang, Z.; Ayad, T.;
Ratovelomanana-Vidal, V. Enantioselective Synthesis of 1-Aryl-
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Guo, R.; Cai, X.; Chen, M.; Shi, L.; Zhou, Y. Enantioselective Iridium-
Catalyzed Hydrogenation of 1- and 3-Substituted Isoquinolinium
Salts. Angew. Chem., Int. Ed. 2013, 52, 3685. (f) Wu, Z.; Perez, M.;
Scalone, M.; Ayad, T.; Ratovelomanana-Vidal, V. Ruthenium-
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Core via a Nonenzymatic Process. J. Am. Chem. Soc. 2015, 137,
10496. (h) Zhou, H.; Liu, Y.; Yang, S.; Zhou, L.; Chang, M. One-Pot
N-Deprotection and Catalytic Intramolecular Asymmetric Reductive
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00198
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and
Technology of the Republic of China (104-2628-M-003-001-
MY3 and 107-2113-M-003-014-MY3) is gratefully acknowl-
edged.
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Org. Lett. 2021, 23, 1141−1146