Enantioselective synthesis of tetrahydroisoquinoline derivatives via chiral-at-metal rhodium complex catalyzed [3+2] cycloaddition

Article abstract of DOI:10.1039/c8cc08275h

An asymmetric [3+2] cycloaddition of C,N-cyclic azomethine imines with α,β-unsaturated 2-acyl imidazoles catalyzed by a chiral-at-metal rhodium complex has been developed. The corresponding C-1-substituted tetrahydroisoquinoline derivatives were obtained in high yields (>90%) with excellent stereoselectivities (up to 99% ee and >20?:?1 dr). The reaction can be conducted on a gram-scale using a low catalyst loading (0.5 mol%) with high yield and selectivity.

Full text of DOI:10.1039/c8cc08275h

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Enantioselective synthesis of tetrahydroisoquinoline
derivatives via chiral-at-metal rhodium complex
catalyzed [3+2] cycloaddition†
a
Cite this:DOI: 10.1039/c8cc08275h
Received 16th October 2018,
Accepted 30th November 2018
Saira Qurban,‡ab Yu Du,‡a Jun Gong,ab Shao-Xia Lina and Qiang Kang
*
DOI: 10.1039/c8cc08275h
rsc.li/chemcomm
An asymmetric [3+2] cycloaddition of C,N-cyclic azomethine imines
C,N-Cyclic azomethine imines were discovered by Tamura7
with a,b-unsaturated 2-acyl imidazoles catalyzed by a chiral-at- in 1973 and developed by Maruoka as promising 1,3-dipoles to
metal rhodium complex has been developed. The corresponding undergo 1,3-dipolar cycloaddition8 with a,b-unsaturated alde-
C-1-substituted tetrahydroisoquinoline derivatives were obtained in hydes catalyzed by a BINOL–Ti (BINOL = 1,10-bi-2-naphthol)
high yields (490%) with excellent stereoselectivities (up to 99% ee complex, leading to the formation of a chiral tetrahydroisoquinoline
and 420 : 1 dr). The reaction can be conducted on a gram-scale scaffold.9a Since then, several catalytic asymmetric reactions of
using a low catalyst loading (0.5 mol%) with high yield and C,N-cyclic azomethine imines with different reagents, such as
selectivity.
vinyl ether,9b alkynes,9c cyclopropanes,10 d-substituted allenoates,11
aldehydes,12 Morita–Baylis–Hillman carbonates,13 unsaturated
Nitrogen-containing heterocycles are an attractive molecular nitriles14 and vinyl aziridines15, have been developed in the past
pool for bioactive natural alkaloids as well as significant few years, and C,N-cyclic azomethine imines have emerged as
structural units of pharmaceuticals.1 As an important branch, important precursors for the formation of various enantio-
chiral multifunctionalized tetrahydroisoquinolines, especially enriched C1-substituted tetrahydroisoquinoline derivatives.
those having a chiral stereocenter at the C1-position, have been However, despite these impressive achievements, there are some
identified as pharmacologically important molecules with drawbacks such as long reaction time, unsatisfactory stereo-
diverse biological activities2 (Fig. 1). For example, (S)-norcoclaurine selectivity and high catalyst loading. Therefore, the development
has been proven to be an effective b-1 and b-2 adrenergic agonist, of new efficient catalytic asymmetric methods to access chiral
which has been used in traditional Chinese medicine as extracts C1-substituted tetrahydroisoquinoline derivatives is still in
from natural plants.3 (S)-Coclaurine is a nicotinic acetylcholine high demand.
receptor antagonist, which has been isolated from a variety of plant
As a continuation of our interest in the development of
sources such as Nelumbo nucifera.4 Jamtine, which is isolated from chiral-at-metal Rh(III) complexes16 as chiral Lewis acids in catalytic
the climbing shrub Cocculus hirsutus, is one of the medicinal asymmetric reactions,17 herein we report an enantioselective [3+2]
alkaloids having significant antihyperglycemic activity.5 Canadine cycloaddition of C,N-cyclic azomethine imines with a,b-unsaturated
is a protoberberine alkaloid that can act as a calcium channel 2-acyl imidazoles catalyzed by a chiral-at-metal Rh(III) complex,
blocker.6 Considering such distinct biological and pharmacological affording enantio-enriched C1-substituted tetrahydroisoquinolines
properties and potential clinical values of chiral tetrahydroisoquino- with a fused five member ring, which contains three contiguous
line derivatives, the development of effective protocols for the tertiary stereocenters.
asymmetric synthesis of these valuable molecules and analogues
is desirable.
Key results in the search for a suitable chiral-at-metal
complex and optimal reaction conditions are shown in Table 1.
a Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for
Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou, 350002,
P. R. China. E-mail: kangq@fjirsm.ac.cn
b University of Chinese Academy of Sciences, Beijing, 100049, China
† Electronic supplementary information (ESI) available. CCDC 1837253. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c8cc08275h
‡ These authors contributed equally.
Fig. 1 Examples of important chiral tetrahydroquinoline derivatives.
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Table 1 Optimization of the reaction conditionsa
Entry Catalyst Solvent
Time (h) Yieldb (%) drc
eed (%)
1
2
3
4
5
6
7e
8
D-Rh1
D-Rh2
D-Rh3
D-Rh2
D-Rh2
D-Rh2
D-Rh2
None
DCE
DCE
DCE
DCM
THF
Toluene
DCE
DCE
3
3
3
3
3
3
7
—
94
99
93
96
91
95
95
NR
420 : 1 93
420 : 1 98
420 : 1 91
420 : 1 93
420 : 1 94
420 : 1 94
420 : 1 96
—
—
a
Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol) and a catalyst
b
(2.0 mol%) in a solvent (0.2 mL) under an argon atmosphere. Isolated
yield. Diastereomeric ratio, determined via the 1H NMR analysis of
c
d
the crude reaction mixture. Enantiomeric excess, determined via
chiral HPLC analysis. 1.0 mol% catalyst loading.
e
a,b-Unsaturated 2-acyl imidazole 1a and C,N-cyclic azomethine
imine 2a were chosen as the model substrates to react in the
presence of 2 mol% D-Rh1 developed by Meggers’ group16a in 1,2-
dichloroethane (DCE) at room temperature. To our delight, the
reaction proceeded smoothly for 3 hours to afford the corres-
ponding product 3a in 94% yield with 420 : 1 dr and 93% ee
(Table 1, entry 1). An evaluation of the chiral-at-metal complexes
(entries 1–3) showed that the catalyst D-Rh217a,c is the superior
one in terms of reactivity and stereoselectivity, mediating the
formation of 3a in 99% yield with 420 : 1 dr and 98% ee (entry 2).
Various solvents such as DCM, THF and toluene provided
comparable results (entries 4–6). A further decrease in the loading
of D-Rh2 to 1 mol% under similar reaction conditions (entry 2) led
to 3a with a prolonged reaction time (7 hours, entry 7). A control
experiment in the absence of the catalyst failed to provide any
product, thereby demonstrating that this reaction crucially
depends on the catalysis by chiral-at-metal Rh(III) complexes
(entry 8).
Scheme 1 Substrate scope of a,b-unsaturated 2-acyl imidazoles. Reaction
conditions: 1 (0.10 mmol), 2a (0.12 mmol) and D-Rh2 (2.0 mol%) in DCE
(0.2 mL) at room temperature under an argon atmosphere. All isolated
yields are based on substrate 1. The ee values were determined by HPLC
analysis using a chiral stationary phase. The dr values were detected by
crude 1H NMR.
With the optimal conditions in hand (Table 1, entry 2), the providing products 3n to 3q in high yields (490%) with excellent
scope of this chiral Rh(III) complex catalyzed [3+2] cycloaddition stereoselectivities (up to 99% ee and 420: 1 dr). The N-iso-
reaction was then examined. We first studied the cycloaddition propylimidazole group on substrate 1 was further replaced with
of C,N-cyclic azomethine imine 2a with a,b-unsaturated 2-acyl N-methylimidazole and 2-pyridyl, and no significant influence on
imidazoles 1 bearing a b-aryl substituent. The results are the reactivity and selectivity was observed, delivering the desired
summarized in Scheme 1. The use of substrate 1 with an electron- products (3r and 3s) in high yields (495%) with excellent
withdrawing moiety at the ortho, meta or para-position of the b-aryl stereoselectivities (dr 420 : 1, ee Z94%).
substituent led to high yields of the desired products (Scheme 1,
Cycloaddition of a,b-unsaturated 2-acyl imidazole 1a with
3b–h). Placing electron-donating groups on the b-aryl substituent substituted C,N-cyclic azomethine imines 2 was also investigated
was also well tolerated (3i–3j), and the b-naphthyl-substituted (Scheme 2). No matter electron-rich or -deficient phenyl substituted
substrate and heteroaryl (e.g., furyl, thienyl) analogues worked 1,3-dipoles 2, all substrates reacted smoothly to deliver the corres-
fine as well (3k–m). These reactions gave high yields (490%), ponding products (3t–v) in high yields (494%) with excellent
excellent values of diastereoselectivity (dr 420 : 1) and enantio- stereoselectivities (dr 420 : 1, up to 99% ee).
selectivity (up to 99% ee). a,b-Unsaturated 2-acyl imidazoles 1
To verify the synthetic potential of the current protocol, a
with a b-alkyl substituent (e.g., methyl, ethyl, trifluoromethyl and gram-scale reaction with 1a (3.0 mmol) was conducted at a lower
styryl) also worked well under the optimal reaction conditions, catalyst loading (0.5 mol%). The reaction completed in 24 hours,
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effectively shielded by one of the tert-butyl groups. Then C,N-
cyclic azomethine imines can attack in a highly selective approach
from the Re-face of the coordinated substrate, meanwhile, the exo-
selectivity should be adopted to minimize steric repulsion, leading
to the desired five member ring with (1S, 2S, 3R) configuration,
which is consistent with the observed absolute configuration of 3i
determined by X-ray crystallographic analysis (Fig. 2, for details,
see the ESI†).18 Other products were assigned by analogy.
In conclusion, we have developed a highly efficient asym-
metric [3+2] cycloaddition of a,b-unsaturated 2-acyl imidazoles
with C,N-cyclic azomethine imines catalyzed by chiral-at-metal
rhodium complexes, affording enantio-enriched C1-substituted
tetrahydroisoquinoline derivatives in high yields (490%) with
excellent stereoselectivities (up to 99% ee and 420 : 1 dr).
Remarkably, this protocol has extraordinary advantages in
terms of reactivity and stereoselectivity, given the fact that as
low as 0.5 mol% D-Rh2 can realize the title reaction on a gram
scale, yielding the desired product with high stereoselectivity.
This work was supported by the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant XDB20000000)
and the 100 Talents Program of the Chinese Academy of
Sciences. S. Qurban is thankful to the UCAS for providing the
UCAS scholarship for international students.
Scheme 2 Substrate scope of C,N-cyclic azomethine imines. Reaction
conditions: 1a (0.10 mmol), 2 (0.12 mmol) and D-Rh2 (2.0 mol%) in DCE
(0.2 mL) at room temperature under an argon atmosphere. All isolated
yields are based on substrate 1a. The ee values were determined by HPLC
analysis using a chiral stationary phase. The dr values were detected by
crude 1H NMR.
Conflicts of interest
There are no conflicts to declare.
Scheme 3 Gram-scale experiment and synthetic transformations.
Notes and references
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