Synthesis of Aristoquinoline Enantiomers and Their Evaluation at the α3β4 Nicotinic Acetylcholine Receptor

Article abstract of DOI:10.1021/acs.orglett.1c02057

The first synthesis of aristoquinoline (1), a naturally occurring nicotinic acetylcholine receptor (nAChR) antagonist, was accomplished using two different approaches. Comparison of the synthetic material's spectroscopic data to that of the isolated alkaloid identified a previously misassigned stereogenic center. An evaluation of each enantiomer's activity at the α3β4 nAChR revealed that (+)-1 is significantly more potent than (-)-1. This unexpected finding suggests that naturally occurring 1 possesses the opposite absolute configuration from indole-containing Aristotelia alkaloids.

Full text of DOI:10.1021/acs.orglett.1c02057

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Letter
Synthesis of Aristoquinoline Enantiomers and Their Evaluation at
the α3β4 Nicotinic Acetylcholine Receptor
Malaika D. Argade, Carolyn J. Straub, Lisa E. Rusali, Bernard D. Santarsiero, and Andrew P. Riley*
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ABSTRACT: The first synthesis of aristoquinoline (1), a naturally
occurring nicotinic acetylcholine receptor (nAChR) antagonist, was
accomplished using two different approaches. Comparison of the
synthetic material’s spectroscopic data to that of the isolated alkaloid
identified a previously misassigned stereogenic center. An evaluation
of each enantiomer’s activity at the α3β4 nAChR revealed that (+)-1
is significantly more potent than (−)-1. This unexpected finding
suggests that naturally occurring 1 possesses the opposite absolute
configuration from indole-containing Aristotelia alkaloids.
lants of the Aristotelia genus produce a family of alkaloids
1
Pthat feature indoles bonded to a monoterpene. In most
monoterpene indole alkaloids, the terpenoid portion is derived
from secologanin. In contrast, the Aristotelia alkaloids
incorporate tryptamine with a nonrearranged geranyl unit.1,2
The resulting Aristotelia indole alkaloids possess a character-
istic 3-azabicyclo[3.3.1]nonane architecture, as in hobartine
(Figure 1A).3 Additional family members such as peduncular-
ine and aristoteline arise through cyclization with and
rearrangements of the azabicyclic core.4−6 The related
quinoline alkaloid aristoquinoline (1) was isolated from the
leaves of Aristotelia chilensis in 1993.7,8 The biological activity
of 1 went uninvestigated for >25 years, but recently Arias et al.
determined that 1 is an antagonist of the nicotinic acetylcho-
line receptors (nAChRs).8 Notably, 1 demonstrated an
uncommon and desirable preference for the α3β4 subtype of
nAChRs, which have been proposed as targets to treat a variety
of substance use disorders.
Driven by this rare subtype selectivity and our group’s
interest in natural products to treat addiction,9 we sought an
efficient synthesis of 1 to characterize its biological activity.
However, unlike the indole-containing Aristotelia alkaloids,
whose absolute configurations have been confirmed by X-ray
crystallography and total synthesis,6,10 neither the absolute
configuration nor the specific rotation of 1 has been reported.
Moreover, the configuration of the C9 stereogenic center
reported by Arias differs from that originally proposed by
Cespedes.7,8 Thus, while the configuration of 1 depicted in
Figure 1A may be inferred from other Aristotelia alkaloids, we
elected to define the relative and absolute configurations of 1
by synthesizing and evaluating the activity of each of its
enantiomers.
Figure 1. Convergent Ritter-like reactions between monoterpenes
and nitriles are employed to synthesize the characteristic Aristotelia
azabicyclic scaffold.
Received: June 18, 2021
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© XXXX American Chemical Society
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A

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Several Aristotelia alkaloids have been synthesized by a
variety of methods.11−14 The earliest of these approaches
employed Hg(NO3)2-mediated Ritter-like reactions between
α- or β-pinene and alkyl nitriles to generate the 3-
azabicyclo[3.3.1]non-6-ene core (Figure 1B).11,12 When
(−)-β-pinene was employed, these reactions were highly
stereospecific, whereas (−)-α-pinene (2) yielded racemic
products. Applying this strategy to the synthesis of both
enantiomers of 1 is problematic, given the limited availability
of (+)-β-pinene. Later studies did establish that Brønsted acids
induced similar Ritter-like reactions, with both α- and β-pinene
producing optically active products.15−17 However, with
Brønsted acids, amides arising from a second Ritter reaction
were formed as the major products (Figure 1C). Moreover, the
enantiopurity of these products was not reported. In addition
to the stereochemical issues, the established Ritter-like
reactions have suffered from the need for large excesses of
the nitrile and have not been explored to introduce
heterocycles like quinolines to the monoterpene core. Thus,
we looked to overcome these limitations and leverage the
Ritter-like reaction to provide rapid access to both enantiomers
of 1 (Figure 1D).
Table 1. Optimization of the Ritter-Like Reaction
Conditions
a
a
entry
2:3
solvent
temp
rt
rt
rt
rt
% yield 4
% yield 5
1
2
3
4
5
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:4
4:1
4:1
4:1
benzene
toluene
AcOH
21
23 (20)
0
0
0
0
19
15
23
35
29
41
3
4 (4)
0
0
0
0
3
3
8
7
5
6
DMF
DMSO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
rt
b
6
7
8
9
−10 °C
110 °C
rt
rt
rt
rt
10
c
11
d
12
a
Yields determined by 1H NMR. Isolated yields in parentheses.
b
c
HBF4·OEt2, TFA, or polyphosphoric acid used instead of H2SO4. 7
d
used in place of 2. 8 used in place of 2.
with other Brønsted acids resulted in no observed product
formation (entry 6). Neither cooling nor heating the reactions
led to substantial changes in the product yields (entries 7−8).
Conducting the reactions with an excess of α-pinene 2 did
improve the yields of imine 4, whereas increasing the relative
amounts of nitrile 3 led to a slight increase in the undesired
product 5 (entries 9−10).
Finally, both 4 and 5 were produced in similar yields when
(−)-limonene (7) and (−)-α-terpineol (8) were used in place
of 2 (entries 11−12). Interestingly, under all the reaction
conditions tested, no evidence of products arising from a
Gratifyingly, the reaction of 2 and 4-cyanoquinoline (3) in
the presence of H2SO4 produced the intended product 4 as the
major product alongside an additional isomeric imine 5
1
(Scheme 1). A comparison of the corresponding H and 13C
Scheme 1. Synthesis of Aristoquinoline and
a
Isoaristoquinoline
1
second Ritter reaction was observed via LC/MS or H NMR
analysis of the crude reaction mixtures. With these optimized
conditions, the yield of 4 is comparable to that observed with
previous studies; however, these conditions avoid the use of
large excess of the nitrile and instead rely on an excess of the
abundant, inexpensive terpenes.
While these conditions allowed for a convergent synthesis of
1, the products from these reactions were nearly racemic.
Notably, terpenes 2, 7, and 8 all resulted in products with
similarly low levels of enantiopurity. Given this surprising
departure from previous Brønsted-acid-catalyzed Ritter reac-
tions,15 we looked to investigate the reaction mechanism in
hopes of being able to design a more stereoselective reaction.
The formation of 4 and 5 is consistent with the mechanism
proposed in Scheme 2A. In the presence of acid, 2, 7, and 8
generate the same carbocation intermediate 9. Nucleophilic
attack of the carbocation of intermediate 9 by 3 in a Ritter-like
reaction forms a nitrilium ion that is subsequently intercepted
by the endocyclic olefin, ultimately giving rise to 4. Conversely,
if 9 undergoes a 1,2-hydride shift to form 10 prior to attack by
the nitrile, imine 5 is produced. Intermediate 10 may also be
formed from the deprotonation of 9 to 11 and subsequent
reprotonation of the tetrasubstituted olefin. The low
enantiomeric ratio of 4 suggests that the conversion of 9 to
the achiral intermediates 10 or 11 is reversible. Alternatively,
the stereochemical scrambling of the products may arise from
the reversible protonation of the endocyclic olefin to generate
an achiral carbocation intermediate.
a
e.r. of 2 determined by optical rotation: [α]23 = −42.52, lit.18
D
[α]23 = −47.25.
D
NMR spectra revealed a striking similarity between the two
products, except for the geminal methyl groups, which
appeared as a pair of singlets in 4 and a pair of doublets in
5. COSY correlations in 5 indicated these methyl groups are
contained in an isopropyl group adjacent to a quaternary
carbon. Further analysis of the HMBC and COSY spectra
revealed the imine nitrogen of the minor product was bound to
the cyclohexene ring, consistent with the structure of 5.
Reduction of 4 with NaB(OAc)3H delivers a hydride to the
less hindered face of the imine, producing a single
diastereomer whose H and 13C spectra are consistent with
1
naturally occurring 1 and (−)-1 whose structure was
confirmed by X-ray crystallography (vide infra). A similarly
diastereoselective reduction of 5 yielded isoaristoquinoline (6).
Encouraged by these initial results, we looked to develop
reaction conditions that would favor the selective formation of
4 (Table 1). The yields of 4 and 5 were minimally impacted
when toluene was used in place of benzene, whereas the use of
polar solvents such as acetic acid, DMF, and DMSO proved
detrimental to the reaction (entries 1−5). Replacing H2SO4
To investigate these possible mechanisms, two isotopic
labeling studies were conducted. First, the reaction between 3
and 8 was conducted in the presence of D2SO4 (Scheme 2B).
If intermediate 11 is formed during the reaction, products 4
B
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aza-Prins reaction as the key cyclization event (Scheme 3).13
The tertiary alcohol of (−)-8 was first converted to the
Scheme 2. Mechanistic Studies Examining Racemization
and Product Formation
a
Scheme 3. Stereoselective Synthesis of (−)-Aristoquinoline
a
X-ray crystallography was performed on the dihydrochloride salt of
(−)-1. Ellipsoids in the ORTEP drawing indicate 50% probability.
corresponding azide 12.20 Subsequent reduction of 12 with
zinc provided the primary amine (−)-13. Condensation of
(−)-13 and 4-quinolinecarboxaldehyde (14) in the presence of
3 Å molecular sieves produced the imine 15. Although 15
proved difficult to isolate, the addition of a solution of 15
generated in situ to TFA led to the rapid and exclusive
formation of 1.
Excitingly, 1 formed through this route possessed consid-
erably improved enantiopurity (e.r. = 89(−):11(+)) compared
to the Ritter-like reaction product. A closer inspection of (−)-8
by optical rotation and (−)-13 by conversion to its
corresponding (R)-Mosher amide revealed the intermediates
possessed similar levels of enantiopurity, indicating the aza-
Prins reaction proceeds with complete stereospecificity. Using
this enantioenriched material, the configuration of the C9
stereogenic center and absolute configuration of (−)-1 was
determined through single-crystal X-ray diffraction.21 In this X-
ray crystal structure, the aromatic quinoline ring is positioned
directly over the C17 methyl group, accounting for its
and 5 would be expected to incorporate a deuterium atom at
C13. Indeed, under these conditions, compounds 4 and 5 are
34% and 95% deuterated at these positions, clearly showing
intermediate 11 is formed in the reaction. To confirm that a
concerted 1,2-hydride shift does not occur, deuterium-labeled
terpineol (d1-8) was synthesized from the reduction of
terpinolene oxide with LiAlD4.19 Reacting d1-8 with 3 in the
presence of H2SO4 produced 4 and 5 with 80% and 100% loss
of deuterium at C13, respectively (Scheme 2C). Taken
together, these studies reveal that the interconversion of 9
and 10 occurs through the generation of intermediate 11.
With these mechanistic understandings, it is likely the
modest yields of 4 are due to the poor nucleophilicity of 3,
particularly under the acidic reaction conditions that lead to
the protonation of the quinoline nitrogen. Notably, under
similar reactions aryl nitriles that lack a basic nitrogen do not
produce isomeric products like 5.15,16 This finding suggests
that the reduced nucleophilicity of 3 also contributes to the
formation of 5, by slowing the production of 4 such that the
conversion from 9 to 10 is competitive. The low nucleophil-
icity of 3 may also explain why products arising from the
second Ritter reaction were not observed. Regarding the
stereoselectivity of the transformation, the incorporation of
deuterium at C11 and C15 of 4 and 5 in the presence of
D2SO4 (Scheme 2B) indicates that protonation of the
endocyclic olefin also contributes to the racemization of the
products. This suggests that Brønsted-acid-promoted Ritter
reactions are unlikely to yield 4 with high levels of
enantiopurity.
1
considerable upfield shift in the H NMR spectrum (δ =
0.66 ppm).7 Notably, the structure proposed by Arias places
the quinoline distal to the C17 methyl group and is unlikely to
produce the observed anisotropic effect.8 Finally, adopting an
identical procedure, (+)-822 was successfully converted to
(+)-1 in 13% overall yield and high enantiopurity (e.r. ≤
1(−):99(+)).
With both enantiomers of 1 in hand, we turned our
attention to evaluating their activities at the rat α3β4 nAChRs
by employing a cell-based Ca2+ influx assay (Table 2). As
expected, neither the enantiomer of 1 nor racemic 6 produced
any activation of the nAChRs at concentrations up to 100 μM.
However, 1 and 6 effectively inhibited the action of
( )-epibatidine with similar potency to the pan-nAChR
channel blocker ( )-mecamylamine. Interestingly, (+)-1
antagonizes the α3β4 nAChRs more potently than (−)-1
and is nearly identical to the IC50 reported for 1 isolated from
A. chilensis,8 strongly implying that (+)-1 is the naturally
occurring enantiomer.
In light of these considerations, we reasoned that reversing
the roles of the nucleophile and electrophile could improve
both the yield and stereoselectivity of the reaction. To test this
hypothesis, we adopted an alternative approach employing an
In conclusion, we have investigated two approaches to 1,
resulting in the first synthesis of the alkaloid. By studying the
mechanism behind the Ritter-like reaction, we determined this
classical approach is unlikely to lead to enantioenriched 1. Our
C
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Authors
Table 2. Activity at the Rat α3β4 nAChRs Determined by
Calcium Influx Assay
Malaika D. Argade − Department of Pharmaceutical Sciences,
College of Pharmacy, University of Illinois at Chicago,
Chicago, Illinois 60612, United States
Carolyn J. Straub − Department of Pharmaceutical Sciences,
College of Pharmacy, University of Illinois at Chicago,
Chicago, Illinois 60612, United States; orcid.org/0000-
0002-8976-5039
Lisa E. Rusali − Department of Pharmaceutical Sciences,
College of Pharmacy, University of Illinois at Chicago,
Chicago, Illinois 60612, United States
Bernard D. Santarsiero − Department of Pharmaceutical
Sciences, College of Pharmacy, University of Illinois at
Chicago, Chicago, Illinois 60612, United States;
orcid.org/0000-0002-9032-9699
a
b
c
d
compound
e.r.
EC50 (μM)
--
--
--
--
--
Emax (%)
IC50 (μM)
( )-1
(−)-1
(+)-1
6
51:49
89:11
1:99
50:50
50:50
50:50
<5
<5
<5
<5
<5
3.5 0.9
3.4 1.2
0.89 0.36
3.4 0.6
e
MEC
EPI
1.1 0.1
f
0.028 0.006
100
0.012 0.001
a
Ratios of (−)-1:(+)-1 and (−)-6:(+)-6 determined by chiral HPLC.
Half maximal effective concentration. EC50 values are not reported
for compounds eliciting <5% receptor activation. Maximal effective
b
c
concentration relative to the maximal effect elicited by the agonist
d
( )-epibatidine. Half maximal inhibitory concentration for inhib-
e
ition of receptor activation evoked by 100 nM ( )-epibatidine. ( )-
Mecamylamine. ( )-Epibatidine.
f
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02057
Author Contributions
second strategy to form the 3-azabicyclo[3.3.1]non-6-ene via
an aza-Prins cyclization led to 1 with good enantiopurity,
which enabled us to unambiguously establish the absolute and
relative configuration via X-ray crystallography. With access to
both enantiomers of 1, we identified that (+)-1 possesses
considerably greater inhibitory activity at the α3β4 nAChR
than its antipode. While the activity observed is similar to that
reported for the isolated alkaloid, the configuration of (+)-1 is
opposite that reported for other Aristotelia alkaloids including
those found in A. chilensis. This unexpected result indicates
that in addition to being unique as the sole quinoline-
containing Aristotelia alkaloid 1 also appears to be the only
member of its enantiomeric series. In addition to these
naturally occurring alkaloids, the novel isoaristoquinoline 6
bearing a 6-azabicyclo[3.2.1]oct-2-ene scaffold reminiscent of
peduncularine was also shown to possess inhibitory activity
and thus represents the first entry into a previously unknown
class of nAChR ligands. The application of this step-economic
synthesis to the generation of aristoquinoline analogues to
elucidate structure−activity relationships is ongoing and will be
reported in due course.
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The rα3β4-HEK293 cells were kindly provided by Dr.
Kenneth Kellar (Georgetown University). Additionally, the
authors thank Dr. Lawrence Toll (Florida Atlantic University)
for assistance in establishing the receptor assay and Dr. Tom
Driver (University of Illinois at Chicago) for his helpful
discussion on the work. Epibatidine and mecamylamine were
provided by the National Institute of Drug Abuse (NIDA)
Drug Supply Program. This work was conducted in part by
funds awarded to A.P.R. by the National Center for Advancing
Translational Sciences (KL2TR002002) and the Advanced
Photon Source, a U.S. Department of Energy (DOE) Office of
Science User Facility operated for the DOE Office of Science
by Argonne National Laboratory under Contract No. DE-
AC02-06CH11357 for the X-ray studies. Use of the Life
Sciences Collaborative Access Team Sector 21 was supported
by the Michigan Economic Development Corporation and the
Michigan Technology Tri-Corridor (Grant 085P1000817).
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the NCATS,
NIDA, NIH, or DOE.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02057.
Experimental details, compound characterization data,
results of deuterium labeling experiments, representative
assay results, and concentration−response curves (PDF)
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Accession Codes
CCDC 2084820 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,
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AUTHOR INFORMATION
Corresponding Author
■
Andrew P. Riley − Department of Pharmaceutical Sciences,
College of Pharmacy, University of Illinois at Chicago,
Chicago, Illinois 60612, United States; orcid.org/0000-
0002-3878-0597; Email: apriley@uic.edu
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