Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols

Article abstract of DOI:10.1021/jacs.1c03923

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee). The obtained products are important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16 representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique profile and a clear morphological change.

Full text of DOI:10.1021/jacs.1c03923

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Article
Organocatalytic Asymmetric Multicomponent Cascade Reaction for
the Synthesis of Contiguously Substituted Tetrahydronaphthols
̌
Yidong Liu, Joseph A. Izzo, David McLeod, Sebastijan Ricko, Esben B. Svenningsen, Thomas B. Poulsen,
and Karl Anker Jørgensen*
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ABSTRACT: Isobenzopyrylium ions are unique, highly reactive,
aromatic intermediates which are largely unexplored in asymmetric
catalysis despite their high potential synthetic utility. In this study, an
organocatalytic asymmetric multicomponent cascade via dienamine
catalysis, involving a cycloaddition, a nucleophilic addition, and a
ring-opening reaction, is disclosed. The reaction furnishes chiral
tetrahydronaphthols containing four contiguous stereocenters in
good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93−98% ee). The obtained products are
important synthetic intermediates, and it is demonstrated that they can be used for the generation of frameworks such as
octahydrobenzo[h]isoquinoline and [2.2.2]octane scaffolds. Furthermore, mechanistic experiments involving oxygen-18-labeling
studies and density functional theory calculations provide a vivid picture of the reaction mechanism. Finally, the bioactivity of 16
representative tetrahydronaphthol compounds has been evaluated in U-2OS cancer cells with some compounds showing a unique
profile and a clear morphological change.
Compared to the number of reported transition-metal-
catalyzed asymmetric cascade reactions involving isobenzo-
pyrylium ions, organocatalytic approaches are rare6 even
though asymmetric organocatalysis has been extensively
applied in assembling chiral molecules.7 To date, there are
only two examples of catalytic asymmetric syntheses of
dihydronaphthalenes utilizing the ACDC strategy reported
independently by Sun and Schaus (Figure 1b).6a,b In these
novel approaches, the catalytically generated chiral counter-
anion also works as the nucleophile.
To expand the scope and synthetic applicability of
isobenzopyrylium ions, we present a novel catalytic regio-,
diastereo-, and enantioselective multicomponent cascade via
dienamine catalysis, consisting of first a cycloaddition, then a
nucleophilic addition, and finally a ring-opening reaction
affording contiguously substituted tetrahydronaphthols (Fig-
ure 1c). Through effective steric shielding by the organo-
catalyst, controlling the facial selectivity in the key carbon−
carbon bond forming event involving the dienamine
intermediate with the planar isobenzopyrylium ion, excellent
stereoselectivity was obtained for the tetrahydronaphthol
products. This important structural motif is central to many
INTRODUCTION
■
Catalytic asymmetric cascade reactions exhibit distinct
advantages in organic synthesis allowing for efficient
enantioselective preparation of complex molecules.1 Extensive
efforts have been devoted to the development of novel
reagents and the discovery of new activation modes for
cascade reactions in asymmetric catalysis.2
Isobenzopyrylium ions have emerged as a unique type of
reactive cyclic oxonium intermediates that have been shown
to participate in a range of cascade reactions affording natural
products and bioactive molecules.3 In contrast, catalytic
enantioselective cascade reactions with isobenzopyrylium ions
remain significantly less developed.4 The inherent challenges
in their use arises from the high reactivity, aromatic planar
structure, and the lack of a Lewis basic site needed for
interactions with a potential catalyst. Nevertheless, innovative
strategies to enable highly enantioselective transformations of
isobenzopyrylium ions have been demonstrated.5,6
Transition metal−isobenzopyrylium intermediates, gener-
ated by cyclization of alkynyl carbonyl compounds, can be
coupled either with electronically neutral chiral ligands,
thereby affording a chiral electrophile, or combined with
another transition-metal catalyst as a binary catalyst.5a−d,i,k By
use of an asymmetric counteranion-directed catalysis
(ACDC) strategy, metallo-isobenzopyrylium intermediates
have been incorporated with chiral counteranions, and high
enantioselectivities have been achieved through electrostatic
interactions (Figure 1a).5e−h,j
Received: April 14, 2021
Published: May 24, 2021
https://doi.org/10.1021/jacs.1c03923
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© 2021 American Chemical Society
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Figure 1. Generation and enantioselective reactions of isobenzopyrylium ions. (a) Activation by transition-metal complexes and reactions of the
metallo-isobenzopyrylium intermediate. (b) Asymmetric synthesis of dihydronaphthalenes applying asymmetric counteranion-directed catalysis.
(c) This work: organocatalytic formation of tetrahydronaphthols by enantioselective multicomponent cascade cycloaddition/nucleophilic
addition/ring-opening reaction via dienamine catalysis. (d) Biologically active natural products and APIs containing the tetrahydronaphthol
motif.
active pharmaceutical ingredients (API) and biologically
active natural products (Figure 1d).8 In addition, similar
polycyclic ring systems can be accessed through simple
transformations (vide infra).
Furthermore, we present mechanistic investigations based on
experimental and computational studies and finally cell
painting experiments demonstrating the bioactivity of the
scaffold.
Despite the intriguing scaffold of these molecules, the
catalytic enantioselective construction of enantioenriched
tetrahydronaphthols remains underdeveloped.9 In previous
studies, isobenzopyrylium ions displayed the ability to rapidly
generate chiral dihydronaphthalenes by taking advantage of a
cycloaddition reaction with alkenes as a key step.10 The
kinetic instability of the bridged oxonium intermediate,
generated in situ from the initial cycloaddition reaction, led
to an intramolecular elimination as the predominant pathway,
consequently producing the carbon−carbon double bond
present in the dihydronaphthalenes.
Alternatively, if the reactive oxocarbenium ion can be
trapped by introduction of an appropriate nucleophile, such
as H2O,11 tetrahydronaphthols might be accessed after ring-
opening of the in situ generated cyclic hemiacetal. Dienamine
catalysis can generate electron-rich olefins and has shown a
high degree of stereocontrol in cycloadditions and good
compatibility with water.12 We envisioned that this presented
an ideal strategy for a cascade sequence. Herein, we report
the first asymmetric organocatalytic multicomponent cascade
reaction involving isobenzopyrylium precursors, α,β-unsatu-
rated aldehydes, and H2O affording tetrahydronaphthols with
four contiguous stereogenic centers with excellent selectivity.
RESULTS AND DISCUSSION
■
Optimization of Reaction Conditions. We initiated an
investigation of the model reaction between 1-isopropoxy-3-
phenyl-1H-isochromene (1a) and (E)-4-(4-methoxyphenyl)-
but-2-enal (2a), in dichloromethane, at room temperature, in
the presence of 20 mol % diphenyl phosphate (DPP), to
examine the catalytic activities of various secondary amine
catalysts I−V. The reactions catalyzed by I−III only
delivered the dihydronaphthalene 3a′ in poor yield but
excellent enantiomeric excess (Table 1, entries 1−3). When
catalyst IV was employed in the reaction, the desired
tetrahydronaphthol 3a was obtained in low yield and
moderate enantiomeric excess, together with 3a′ as a
competing product (entry 4). No improvement in the yield
of 3a, or successful suppression of 3a′, could be achieved
from further screening of solvents (see the Supporting
Information).
Considering that the elimination process affording
dihydronaphthalene 3a′ may correlate with the Brønsted
basicity of the aminocatalyst, the gem-difluorinated catalyst V
was tested, and we were pleased that applying this catalyst
afforded tetrahydronaphthol 3a as the exclusive product in
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a
Table 1. Optimization of the Reaction Conditions for the Organocatalytic Formation of Tetrahydronaphthols
d
e
yield (%)
ee (%)
b
c
entry
cat.
acid
additives (mol %)
solvent (0.1 M)
T (°C)
3a
3a′
3a
3a′
1
2
3
4
5
6
7
8
I
DPP
DPP
DPP
DPP
DPP
DPP
DPP
DPP
DPP
DPP
DPP
DPP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
DME
DME
DME
DME
DME
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
−20
−20
19
29
29
22
92
96
96
97
II
III
IV
V
V
V
V
V
V
V
V
V
11
41
36
42
69
42
45
83
92
89
63
78
87
8
66
4
92
88
94
96
LiClO4 (100)
LiBF4 (100)
LiOTf (100)
H2O (240)
H2O (240)/LiBF4 (20)
H2O (240)/LiBF4 (30)
H2O (240)/LiBF4 (30)
9
10
11
12
DME
DME
DME
f
g
13
HCl
a
Reactions were performed with 1a (0.05 mmol), 2a (0.075 mmol), catalyst (20 mol %), acid (20 mol %), and additives in solvent (0.5 mL) at
b
c
d
specific temperature for 24 h. PMP = 4-methoxyphenyl. DPP = diphenyl phosphate. DME = 1,2-dimethoxyethane. Yields were determined by
e
1H NMR of the crude reaction mixture relative to an internal standard (tetraethylsilane). Enantiomeric excess determined by chiral stationary
f
g
phase UPCC after purification by FC. Reaction performed on a 0.10 mmol scale. HCl solution, 4 M in dioxane.
41% yield and 78% ee (entry 5). A survey of solvents
revealed that 1,2-dimethoxyethane (DME) was the best
choice (entry 6, see the Supporting Information). Additives
were found to have an impact on the reactivity and
stereoselectivity of the reaction (entries 7−9). Among
them, LiBF4 improved the yield significantly, but unfortu-
nately with concurrent erosion of the enantioselectivity. The
introduction of water (2.4 equiv) was shown to enhance the
yield and enantiomeric excess (entry 10). Delightfully,
product 3a was obtained in 83% yield and 88% ee when
water was present with a catalytic amount of LiBF4 (entry
11). Subsequently, other reaction parameters, including the
stoichiometry of additives and reaction temperature, were
further evaluated to afford 3a in 92% yield and 94% ee (entry
12 and the Supporting Information). Exchanging diphenyl
phosphate for HCl led to the optimized reaction conditions
(entry 13).
Scope of α,β-Unsaturated Aldehydes. With the
optimized reaction conditions in hand, we then evaluated
the substrate scope of this multicomponent cascade reaction
for the stereoselective formation of tetrahydronaphthols. As
shown in Table 2, α,β-unsaturated aldehydes 2 substituted
with γ-aryl rings react with 1-isopropoxy-3-phenyl-1H-
isochromene (1a) to afford the corresponding tetrahydro-
naphthols 3a−i in high yields and excellent regio-, diastereo-,
and enantioselectivities regardless of the electronic nature of
the aromatic ring and the position of the substituent(s). The
α,β-unsaturated aldehyde 2j containing a benzo[b]thiophene
group also provided product 3j in high yield and
enantioselectivity (93% ee). Crotonaldehyde proved to be
compatible with the developed reaction, albeit product 3k
was obtained in only moderate yield (62%), but with
excellent enantiomeric excess (93% ee). α,β-Unsaturated
aldehydes with different alkyl groups, including methyl,
propyl, and alkyl substituents bearing a 4-bromophenyl
group, did not impact yield or enantioselectivity but did
affect the diastereoselectivity (3l−n). Moreover, the reaction
of 1a with cyclopent-1-ene-1-carbaldehyde 2o provided the
tetrahydronaphthol product 3o with an additional stereo-
center, after increasing the temperature from −20 °C to
room temperature. The absolute configuration of 3j was
determined by X-ray crystallographic analysis; the config-
urations of all other products were assigned by analogy and
relevant 2D-NMR (see the Supporting Information).
Scope of Isochromenes. Next, we continued to
investigate the substrate generality with respect to isochro-
menes 1 (Table 3). A variety of isochromenes with
substituents on the 3-position were investigated. Electron-
rich, -poor, and -neutral phenyl groups on the 3-position of
the isochromenes uniformly gave excellent stereoselectivities
and high yields (4a−c). The 2-naphthyl-substituted iso-
chromene was also well tolerated, giving 4d. Isochromenes
carrying heteroaromatic substituents including furan and
thiophene were successfully employed in the reaction
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a
Table 2. Scope of α,β-Unsaturated Aldehydes for the Organocatalytic Enantioselective Formation of Tetrahydronaphthols
a
Reactions were performed with 1a (0.10 mmol), 2 (0.15 mmol), V (20 mol %), HCl (20 mol %, 4 M in dioxane), LiBF4 (30 mol %), and H2O
(2.4 equiv) in DME (1.0 mL) at −20 °C for 24 h. In all cases, isolated yields are indicated. Enantiomeric excess determined by chiral stationary
b
1
phase UPCC after purification by FC. The diastereomeric ratio was determined by H NMR analysis. Reaction was performed at rt.
sequence (4e,f). A TMS group could also be introduced,
giving 4g in relatively low yield but excellent stereoselectivity.
Intriguingly, the isochromene with no substituents at the 3-
position delivered hemiacetal 4h as a stable compound, which
could be isolated. Isochromenes having alkyl groups also
reacted smoothly and showed high reactivity and selectivity
regardless of being linear- or cycloalkyl-substituted (4i−k).
Isochromene with a methoxy group at the 7-position or a
fluoro group at the 6-position successfully formed the desired
products 4l or 4m, respectively. Benzofused isochromene was
also well tolerated, affording 4n in high yield and excellent
stereoselectivity. Interestingly, when employing benzothieno-
pyrylium precursor 1p, the eliminated compound 4o was the
only observed product. The exclusive formation of 4o is
probably due to the increased lability of the hydroxy group
granted by the electron-rich ring-system, though this was not
investigated further.
Oxygen-18-Labeling Studies.13 To elucidate which
oxygen atom is derived from the addition of H2O in the
tetrahydronaphthol adducts, 18O-isotope-labeling experiments
were performed with the intention of differentiating between
the nucleophilic addition to the bridged oxonium inter-
mediate by H2O (Scheme 1, top, path a) or an SN1 process
after ring-opening of the intermediate (Scheme 1, top, path
b).
The prototypical reaction between 1-isopropoxy-3-phenyl-
1H-isochromene (1a) and (E)-4-(4-methoxyphenyl)but-2-
enal (2a) was performed in the presence of 10 equiv of
H218O (Scheme 1a), which was intended to dilute the
concentration of advantageous H2O (natural isotopic
abundance) generated from the condensation of the α,β-
unsaturated aldehyde 2a and catalyst V. The 13C NMR of the
tetrahydronaphthol 3a showed an efficient 18O incorporation
at the ketone11c,d,f of 3a and no incorporation at the hydroxy
group.
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a
Table 3. Scope of Isochromenes for the Organocatalytic Enantioselective Formation of Tetrahydronaphthols
a
Reactions were performed with 1 (0.10 mmol), 2b (0.15 mmol), V (20 mol %), HCl (20 mol %, 4 M in dioxane), LiBF4 (30 mol %), and H2O
(2.4 equiv) in DME (1.0 mL) at −20 °C for 24 h. In all cases, isolated yields are indicated. Enantiomeric excess determined by chiral stationary
1
phase UPCC after purification by FC. The diastereomeric ratio was determined by H NMR analysis.
To further confirm that the oxygen atom at the hydroxy
group of the tetrahydronaphthol 3a originates from 1-
isopropoxy-3-phenyl-1H-isochromene (1a), 18O-labeled 1a
bearing 28% 18O at its isochromene ring was employed,
resulting exclusively in 18O incorporation at the hydroxy
group of 3a (Scheme 1b). These results support that the
oxygen atom of the ketone in tetrahydronaphthol 3a
originates from external H2O, and the oxygen atom of the
benzylic alcohol originates from isochromene 1a.
successful, and similar results to those observed with the full
system were achieved.
Catalytic Cycle and Computational Studies. With a
basic understanding of the mechanism, we turned to
modeling the reaction using density functional theory.
Because of computational resource considerations, the
theoretical investigation was performed on a model system.
To ensure applicability of the calculations to the larger
system, an experimental reaction was performed by using the
model system (eq 1). Gratifyingly, the experiment was
The model system was calculated by using the B3LYP
functional with a 6-31G(d) basis set and SMD solvent
continuum.14 The single-point energies of the optimized
structures were then calculated at the ωB97X-D/Def2-
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Scheme 1. Oxygen-18-Labeling Studies to Trace the Origin of the Oxygen Atoms in the Tetrahydronaphthol Adduct: (a)
the Reaction Was Performed in the Presence of H218O and (b) the Reaction Was Performed with 18O-Labeled 1a
Scheme 2. Proposed Catalytic Cycle
TZVPP/SMD level of theory.15 All calculations were
performed by using the Gaussian09 software package.16 The
free energies presented and discussed were calculated by
applying the free energy correction from the lower level of
theory optimization to the single point calculation.
The proposed catalytic cycle in Scheme 2 begins with the
condensation of (E)-4-phenylbut-2-enal (2b) with the catalyst
V to form dienamine intermediate A. After the isobenzo-
pyrylium ion intermediate B is generated by expulsion of the
isopropoxide leaving group from 1-isopropoxy-3-phenyl-1H-
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Figure 2. Free energy profile for the multicomponent cascade reaction between 1a and 2b; TS-CC for all possible diastereomeric outcomes and
the lowest four TS-ring energies leading to the theoretically preferred diastereomers; ωB97XD/Def2-TZVPP/SMD(THF)//B3LYP/6-31G(d)/
SMD(THF).
Figure 3. Geometries for optimized TS-CC for all possible stereochemical outcomes. Calculations performed by using ωB97X-D/Def2-TZVPP/
SMD//B3LYP/6-31G(d)/SMD; some atoms are not shown for clarity (distances in angstroms).
isochromene (1a), intermediate B is attacked by the γ-
position of dienamine A forming the initial carbon−carbon
bond via TS-CC to afford intermediate C. Ring-closure, via
TS-ring, then generates intermediate D. Addition of water at
the carbonyl carbon generates intermediate E. A series of
proton transfers, final C−O bond scission, and hydrolysis
yield product 3b and afford catalyst turnover.
Computational and NMR investigations into the nature of
dienamines have shown that the species tend to exist as a
mixture of isomers with rapidly converting double bonds
from protonation/deprotonation events and a mixture of s-cis
and s-trans conformers from rotating σ-bonds.17
A systematic search of transition-state structures corre-
sponding to TS-CC and TS-ring was performed exploring all
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Figure 4. Examples of transformations and relations to an API and a natural product. (a) Selective protection and elimination of 3a. (b)
Reductive amination of product 3a. (c) Reductive etherification of 3a to afford a bicyclo[2.2.2]octane framework. (d) Reductive allylation
protocol to afford bicyclo-ether 8.
possible stereoisomers and conformations (see the Support-
ing Information). After obtaining a basic understanding of the
potential energy surface, it became clear that TS-CC was
responsible for both the observed enantioselectivity as well as
the diastereoselectivity. The predicted barrier for the
transition state leading to the observed product is 9.0 kcal
mol−1 (Figure 2). The pathway leading to the enantiomer of
this product is 1.9 kcal mol−1 higher (10.9 kcal mol−1),
leading to a predicted enantiomeric excess of 96% ee, which
is in good agreement with experimental data (eq 1). The
lowest diastereomer is calculated to have a ΔG‡ of 10.2 kcal
mol−1. This leads to a predicted diastereomeric ratio of 11:1,
which again is in good agreement with the observed
selectivity (eq 1).
With the selectivity correctly predicted by our calculations,
we found it interesting to observe how dienamine A orients
itself in the reaction. It has been the argument with this type
of catalyst the incoming reacting partner prefers to approach
from the opposite face of the steric bulk of the catalyst.18 The
least sterically demanding conformation of A is to have the
C−N bond connecting the catalyst to the carbon−carbon
chain of the dienamine in an anti-conformation, the σ-bond
between the two π-systems of the dienamine in an s-trans-
conformation, and both double bonds in an E-conformation.
The E/Z nature of these systems has been well explored with
E-conformers being preferred.17
is pointed away from the bulk of the catalyst (Figure 3, top).
In the case of TS-CC(S,R) and TS-CC(S,S), with the Si-face
forming the initial carbon−carbon bond, one of the σ-bonds
was required to rotate. It was found that rotating the C−C
bond between the π-systems granted the lowest energy
transition-state structure, meaning that these products prefer
the s-cis conformation to minimize steric interaction with the
catalyst (Figure 3, bottom). As a consequence of this
conformation, the energies of these transition states increase,
thus leading to the observed stereoselectivity.
The observed selectivity between TS-CC(R,S) and TS-
CC(R,R) can be explained by the fact that the appended
phenyl ring of the isobenzopyrylium ion must be pointed
away from the catalyst to minimize steric interaction. As such,
in TS-CC(R,R), the π-system of A is not overlapping with that
of B. The lack of this interaction is proposed to be the major
contributor to the higher predicted energy as supported by
noncovalent interaction (NCI) analysis (see the Supporting
Information).
Computational investigation next turned to the nature of
the cycloaddition at hand. Previously, similar reactions have
been termed [4 + 2] cycloadditions,5c,g,6a,b but recent
investigation in our group has suggested that a system will
prefer to react with the most π-electrons available.19 For a
discussion of the possible number of π-electrons involved in
the cycloaddition, see the Supporting Information.
For TS-CC(R,S) and TS-CC(R,R), aligning the σ-bonds in
this anti- and s-trans-conformation was simple as the Re-face
Transformations. To demonstrate the synthetic utility of
the multicomponent cascade reaction, a 1 mmol scale
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Figure 5. Structures of compounds tested in the cell painting assay. The colored circles indicate the activity in the cell painting assay; see Figure
6 and the Supporting Information for details. *Compound 6 precipitated at the tested concentrations, causing unspecific cell death to a varying
degree.
synthesis of 1-isopropoxy-3-phenyl-1H-isochromene (1a) and
(E)-4-(4-methoxyphenyl)but-2-enal (2a) was performed with
a catalyst loading of 5 mol %. To our delight, the reaction
proceeded smoothly to give product 3a in 82% yield, without
erosion of enantioselectivity (96% ee, Figure 4, top). The
tetrahydronaphthol 3a obtained herein can be readily
converted into synthetically useful compounds in a facile
manner. The aldehyde functionality in 3a was selectively
protected by treatment with 1,3-propanediol and BF3·Et2O.
Concomitant elimination of the benzylic hydroxy group took
place as well as epimerization of the stereocenter at the α-
carbon of the carbonyl in 5 (Figure 4a). The sequential
reductive amination of 3a produced compound 6 in 58%
yield and maintained enantioselectivity (Figure 4b). The
octahydrobenzo[h]isoquinoline scaffold of 6 is the core
structure of many dopamine agonists like dinapsoline, an API
developed for the treatment of Parkinson’s disease.20
Treatment of 3a with TFA and nucleophilic reagents, such
as triethylsilane and allyltrimethylsilane (ATMS), resulted in
the formation of 7 and 8 bearing [2.2.2]octane frameworks
which are widely present in biologically active natural
products21 (Figure 4c,d).
facilitate the testing of bioactivity, we derivatized a number of
compounds providing 9a−9n (Figure 5; see the Supporting
Information), which, together with compounds 6 and 3o,
were submitted to the cell painting assay (Figure 6).22
Cell painting (Figure 6a) monitors the morphological
changes induced by compound treatment by fluorescence
microscopy. By performing quantitative image analysis, a large
number of morphological features can be extracted, yielding a
profile representing the bioactivity of the treatment (Figure
6a). The profile contains various information: From the
strength of a profile a bioactivity score (Mahalanobis
distance) can be calculated, and it can be determined if the
change is statistically significantly different from DMSO
treatment (mp value ≤0.01).23 Furthermore, the profile
encodes the mechanism, as a morphological fingerprint, by
which the compound induces morphological changes and can
thus be used to determine if compounds have similar or
different bioactivity. We tested the 16 compounds at 100, 20,
and 4 μM in U-2OS osteosarcoma cells. Of the 16
compounds, 63% (10 out of 16) induced significant
morphological changes, indicating that the scaffold is
enriched for biological activity (see Figure S9). Compounds
9k and 9l were toxic at 100 μM, reducing the cell viability to
<20%, while compound 6 was insoluble at the test
concentrations. The morphological profiles (Figure 6c) of
Bioactivity. As the tetrahydronaphthol scaffold is present
in various biologically active compounds, we set out to
investigate whether the compounds possessed bioactivity. To
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Figure 6. Bioactivity determination by morphological profiling. (a) Principle of morphological profiling via the cell painting assay. (b) Merge of
fluorescence microscopy images from the cell painting assay (see Figure S10 for individual channels). (c) Heatmap of morphological profiles
from nontoxic and significant active treatments. (d) Correlation matrix of nontoxic and significantly active profiles.
the active and nontoxic compounds were compared by
calculating the Pearson correlation coefficient and clustering
the compounds based on hierarchical clustering (Figure 6d).
Most compounds induced similar morphological changes
indicated by a large cluster with high cross-correlations
(0.77−0.95), which is unsurprising considering the structural
similarities between these compounds. The compounds in
this cluster induced subtle morphological changes, not readily
obvious by visible inspection (Figure 6b). Intriguingly, some
compounds such as 3o (100 μM) and 9c (100 μM) induced
a more unique profile, with compound 9c causing a clear
morphological change (Figure 6b), distinct from any other
compounds in this small collection. The mechanism of action
behind these compounds is subject to further investigations.
converted into synthetically useful compounds demonstrating
the power and importance of the development of a new
synthetic method utilizing isobenzopyrylium ions. 18O-
isotope-labeling experiments and theoretical studies provided
evidence for the reaction process and stereochemistry. We
finally show that a collection of tetrahydronaphthol
compounds possesses bioactivity in U-2OS cancer cells by
monitoring morphological changes.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03923.
Experimental procedures, characterization data, NMR
spectra, UPCC spectra, and theoretical calculations
(PDF)
CONCLUSION
■
In summary, we performed an organocatalytic asymmetric
multicomponent cascade reaction employing isobenzopyry-
lium precursors, α,β-unsaturated aldehydes, and water via
dienamine catalysis. Tetrahydronaphthols with up to five
contiguous stereocenters were prepared in high yield with
excellent diastereo- and enantioselectivity. The substrate
scope is broad, and the tetrahydronaphthols can be readily
Accession Codes
CCDC 2042817 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-
8217
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J. Am. Chem. Soc. 2021, 143, 8208−8220

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
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AUTHOR INFORMATION
Corresponding Author
■
Karl Anker Jørgensen − Department of Chemistry, Aarhus
University, DK-8000 Aarhus C, Denmark; orcid.org/
0000-0002-3482-6236; Email: kaj@chem.au.dk
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Joseph A. Izzo − Department of Chemistry, Aarhus
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0000-0002-2875-2138
David McLeod − Department of Chemistry, Aarhus
University, DK-8000 Aarhus C, Denmark
̌
Sebastijan Ricko − Department of Chemistry, Aarhus
University, DK-8000 Aarhus C, Denmark
Esben B. Svenningsen − Department of Chemistry, Aarhus
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Thomas B. Poulsen − Department of Chemistry, Aarhus
University, DK-8000 Aarhus C, Denmark; orcid.org/
0000-0002-0763-9996
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03923
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.A.J. thanks Villum Investigator Grant 25867, the Carlsberg
Foundation “Semper Ardens”, and Aarhus University. The
computational results presented in this work were obtained at
the Centre for Scientific Computing, Aarhus (http://phys.au.
dk/forskning/cscaa/). Thanks are expressed to Mathias Kirk
Thøgersen for performing the crystallographic work. S.R. was
supported by the European Union Horizon 2020 Research
and Innovation Programme under the Marie Skłodowska-
Curie Grant Agreement 754513 and by Aarhus University
Research Foundation (AIAS-COFUND). Financial support
from the Slovenian Research Agency through Grant P1-0179
is also gratefully acknowledged. T.B.P. acknowledges the
Carlsberg Foundation (Grant CF17-0800) for financial
support.
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