Bifunctional thiosquaramide catalyzed asymmetric reduction of dihydro-β-carbolines and enantioselective synthesis of (-)-coerulescine and (-)-horsfiline by oxidative rearrangement

Article abstract of DOI:10.1039/d0ra07705d

Tetrahydro-β-carboline (THBC) is a tricyclic ring system that can be found in a large number of bioactive alkaloids. Herein, we report a simple and efficient method for the synthesis of enantiopure THBCs through a chiral thiosquaramide (11b) catalyzed imine reduction of dihydro-β-carbolines (17a-f). The in situ generated Pd-H employed as hydride source in the reaction of differently substituted chiral THBCs (18a-f) afforded high selectivities (R isomers, up to 96% ee) and good isolated yields (up to 88%). Moreover, the chiral thiosquaramide used also afforded exceptional catalyst activity in the syntheses of (-)-coerulescine (5) and (-)-horsfiline (6) with excellent enantioselectivities up to 98% and 93% ee, respectively, via an enantioselective oxidative rearrangement approach.

Full text of DOI:10.1039/d0ra07705d

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PAPER
Bifunctional thiosquaramide catalyzed asymmetric
reduction of dihydro-b-carbolines and
enantioselective synthesis of (À)-coerulescine and
(À)-horsfiline by oxidative rearrangement†
a
Cite this: RSC Adv., 2020, 10, 38672
Manda Sathish,ab Fabiane M. Nachtigallc and Leonardo S. Santos
*
Tetrahydro-b-carboline (THBC) is a tricyclic ring system that can be found in a large number of bioactive
alkaloids. Herein, we report a simple and efficient method for the synthesis of enantiopure THBCs
through a chiral thiosquaramide (11b) catalyzed imine reduction of dihydro-b-carbolines (17a–f). The in
situ generated Pd–H employed as hydride source in the reaction of differently substituted chiral THBCs
(18a–f) afforded high selectivities (R isomers, up to 96% ee) and good isolated yields (up to 88%).
Moreover, the chiral thiosquaramide used also afforded exceptional catalyst activity in the syntheses of
(À)-coerulescine (5) and (À)-horsfiline (6) with excellent enantioselectivities up to 98% and 93% ee,
respectively, via an enantioselective oxidative rearrangement approach.
Received 8th September 2020
Accepted 15th October 2020
DOI: 10.1039/d0ra07705d
rsc.li/rsc-advances
framework with strong antileishmania activity. Few other
THBCs are competitive selective inhibitors of the monoamine
oxidase type A (MAO-A) enzyme12 and also potent reuptake
inhibitors of serotonin and epinephrine with greater selectivity
for serotonin.12 Not only because of their bioactivity, THBCs are
valuable intermediates in the production of potential drug
candidates. For example, the chiral THBCs like 18c and 18f are
key intermediates for the synthesis of active quinolactacin B13
(3) and the potent PDE5 inhibitor like pyrroloquinolone
RWJ387273 (4),14 respectively (Fig. 1).
Another synthon afforded by THBCs are spirooxindoles,
which show unique spiro-cyclic frameworks at the C3-position
of the oxindole core.15 The spirooxindole derivatives are play-
ing important role in the recent drug discovery.16 The struc-
turally rigid spiro-cyclic system may be a reason for the good
affinity towards three-dimensional proteins to exhibit
Introduction
Reduction of the C]N bond in cyclic systems is a fundamental
and important reaction in the area of modern organic
synthesis.1 Moreover, asymmetric reduction of the C]N bond
promoted by organocatalysts is a very valuable aspect in organic
stereoselective synthesis.2 Generally, transition metal
complexes with chiral bulky ligands are used for this type of
transformation3 and a few protocols are known in bio-
catalysis,2c,4 as well as for chiral auxiliary assisted reduction of
imines.5 The preparation of enantioselective secondary amines,
important chiral drug molecules and/or asymmetric reduction
of imines is an important topic in academic research as well as
from an industrial point of view.6 Nowadays, widespread
development has been witnessed in the asymmetric synthesis of
tetrahydro-b-carboline (THBC) skeletons.7 Furthermore, there is
a constant search in the development of new approaches for
asymmetric synthesis using chiral organocatalysis. Because the
unique tricyclic system, THBCs play key role in their bioactiv-
ities,8 for example: reserpine4a,9 is an indole alkaloid which is an
alternative drug for treating hypertension. The LY23728 (1)3d,10
a simple THBC has been reported as rst 5-HT2B-selective
antagonist and harmicine4a,11 (2) is a rare tetracyclic pyrrolidine
aLaboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources,
Universidad de Talca, Casilla 747, 3460000 Talca, Chile. E-mail: lssantos@utalca.cl
b
´
´
Nucleo Cientıco Multidisciplinario-DI, Universidad de Talca, Casilla 747, 3460000
Talca, Chile
c
´
´
Instituto de Ciencias Quımicas Aplicadas, Universidad Autonoma de Chile, Talca
3467987, Chile
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra07705d
Fig. 1 Representative examples of bioactive THBCs (1–4) and some
natural spirooxindoles (5–8).
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On the other hand, the chiral squaramides30 and thio-
squaramides31 have proven to be excellent catalysts in the
asymmetric organocatalysis. However, due to the high solubility
in non-polar solvents like toluene, DCM, DCE and THF, the
thiosquaramides have established as exceptional chiral orga-
nocatalysts.31 Whereas the squaramides are excellent catalysts
in polar solvents.31 Rawal group developed various squaramides
and thiosquaramides as chiral organocatalysts and witnessed
high enantioselectivities with thiosquaramides in Michael
additions of barbituric acids to nitroalkenes.31a Recently, ster-
eoselective double Michael addition of 2-(3H)-furanone to
nitroolens,32 as well as asymmetric Michael additions of
aldehydes to nitroolens for synthesis of chiral pyrrolidines
showed high enantio- and diastereoselectivities.33 Inspired by
Rawal's conclusions with chiral bifunctional thiosquaramides
and other consequences from recent articles, we have synthe-
sized a known squaramide and thiosquaramide based chiral
organocatalysts 11a–d (Fig. 2). In this work, the aim was to
establish chiral protocols to construct bioactive natural prod-
ucts from DHBCs to afford enantiopure THBCs using chiral
organocatalysts in asymmetric reduction reactions. The palla-
dium hydride11 (PdH) was generated in an in situ reaction of
catalytic PdCl2 with excess of Et3SiH and utilized as hydride
source in the asymmetric imine reduction. The chiral THBCs
18a–f were obtained with excellent selectivities (up to 96% ee)
and good yields (up to 88%). The catalytic efficiency of chiral
thiosquaramide in an oxidative rearrangement was also exam-
ined to produce (À)-coerulescine (5) and (À)-horsline (6).
Surprisingly, the products were observed with high enantiose-
lectivities reaching 98% and 93%, respectively. Moreover, the
chiral HPLC and polarimetry analyses proved the R congura-
tion of all the products (18a–f), 5 and 6.
Fig. 2 Few known chiral squaramides and thiosquaramides (9–11) and
the organocatalysts employed in this work (11a–d).
Scheme 1 Synthesis of chiral thiosquaramide (11a–d).
Results and discussion
We have synthesized the chiral squaramides 11a and 11c and
thiosquaramides 11b and 11d employing literature protocols31a
(Scheme 1), 17a–f and 20a–b were prepared as displayed in
Scheme 2. From our previous experience11 and other literature
reports,34 we choose the PdH as hydride source that showed
good enantioselectivity in similar approaches, which can be
generated in situ by treatment of catalytic PdCl2 (15 mol%) and
excess of Et3SiH. Initially, the asymmetric reduction of imine
17b employing 11a–d (10 mol%) was performed in 1,2-dichlo-
roethane (DCE) and THF for 2 h at 0 ꢀC. The reaction mixtures
were analyzed by chiral HPLC, which shown the chiral THBC
18b in 53%, 88%, 40%, and 62% ee in case of DCE, and 50%,
70%, 38% and 60% ee in THF with 11a, 11b, 11c and 11d
respectively in moderate yields (entries 1–8, Table 1). It is
observed that the thiosquaramide 11b catalyzed well compared
with 11a, 11c and 11d. Thiosquaramides seem to be good
catalysts for this reaction, it may be due to the poor solubility of
squaramides that afforded low catalysts activity. Further,
5 mol% of 11b was utilized to test the catalytic efficiency and
achieved only 85% ee with low yield (45%, entry 9, Table 1).
However, the selectivity and yield improved dramatically when
the reaction was performed up to 24 h at 0 ꢀC (entry 10, Table 1)
Scheme 2 Synthesis of (a) DHBCs 17a–f and (b) N-methyl THBCs
20a–b.
bioactivities.15,17–23 For example, the (À)-horsline (6) is used as
an intoxicating snuff,24 spirotryprostatin A25 inhibits G2M
progression of mammalian tsFT210 cells, rhynchophylline (8)
shows potency against various cancer cell lines,26 corynoxine
and corynoxine B show prominent activity in preventing or
treating Parkinson's disease.27 These bioactivities of spiroox-
indole derivatives have augmented attention in organic chem-
ists from academia as well as industry to develop various
synthetic routes,28 especially in the asymmetric manner for the
synthesis of chiral spirooxindoles.15,29
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Table 1 Chiral thiosquaramide (11a–d) catalyzed reduction of imine
(17b)a
load is sufficient for the asymmetric imine reduction. Further-
more, the reaction was also examined in other solvents such as
MeOH, DCM and water/DCM systems (entries 13–15, Table 1).
Moderate selectivities (73% ee and 80% ee) and good yields
(80% and 82%) were observed in aprotic solvents THF and DCM
(entries 12 and 14, Table 1). Whereas only traces of products
were observed in the protic solvents like MeOH as well as water/
DCM systems (entries 13 and 15, Table 1). Based on the above
methodology outcomes, the asymmetric imine reduction tool
was xed as 10 mol% of thiosquaramide catalyst (11b) in DCE as
Entry Catalyst Mol% Solvent
Time (h) Yieldb (%) eec (%)
ꢀ
solvent for 24 h at 0 C.
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11a
11b
11c
11d
11b
11b
11b
11b
11b
11b
11b
10
10
10
10
10
10
10
10
5
10
15
10
10
10
10
DCE
DCE
DCE
DCE
THF
THF
THF
THF
DCE
DCE
DCE
THF
MeOH
DCM
2
2
2
2
2
2
2
2
2
24
24
24
24
24
30d
60d
34d
55d
27d
55d
30d
53d
45d
85
85
80
Trace
82
Trace
53
88
40
62
50
70
38
60
85
92
92
73
—
80
—
With the proven reaction conditions in hand, a series of
DHBCs 17a–f with different substituents were explored (Table
2). Thus, DHBCs evenly undergone asymmetric reduction in
presence of catalytic chiral thiosquaramide (11b) and PdCl2/
Et3SiH, and we observed the chiral THBCs in good yields and
enantioselectivities (18a–f, Table 2). Typically, substituents at
C1 position of the DHBCs slightly altered the enantioselectiv-
ities. For example, the imine (17a) with methyl group gave the
chiral THBC (18a) with good selectivity (95% ee) and moderate
yield (73%). Moreover, chiral THBCs (18b and 18c) with ethyl
and isopropyl groups also shown signicant selectivities (92%
ee and 93% ee, respectively) and high yields (85% and 88%), as
depicted in Table 2. However, the 1-isobutyl THBC (18d) was
obtained with slightly low selectivity (86% ee, Table 2), which
may be explained due to an unfavorable transition state of
isobutyl DHBC (17d) with chiral catalyst as proposed in Fig. 3.
Despite, the chiral 1-phenyl THBC (18e) that displayed
moderate selectivity (91% ee, Table 2), gratifyingly the 2,3-
dihydrobenzofuranyl THBC (18f) demonstrated high enantio-
selectivity (96% ee, Table 2).
9
10
11
12
13
14
15
Water/DCM 24
a
Reactions were performed using 17b (1 mmol), 11 (mol%), PdCl2
b
(15 mol%) Et3SiH (4 mmol) solvent, for the given time. Isolated
c
yield. The enantiomeric excess (ee) was determined by chiral HPLC.
d
Imine 17b was recovered and the yield calculated by isolated
product amount.
Table 2 Chiral thiosquaramide (11b) catalyzed reduction of imine
17a–fa
Furthermore, we also explored an alternative enantiomeric
oxidative rearrangement of THBC. Several approaches for the
syntheses of chiral quinolactacins13 and RWJ387273 14 were
described. Quinolactacins shows activity against tumor necrosis
factor production, and RWJ387273 exhibited promising male
erectile dysfunction (MED) PDE5 inhibition. However, the key
step in both the syntheses approaches was the asymmetric
reduction of imine to corresponding amines. Generally, most of
the reports applied Noyori asymmetric transfer hydrogenation
of cyclic imine (17c and 17f) to the total synthesis of chiral
quinolactacin B (3) and potential PDE5 inhibitor RWJ387273
(4). Although the Noyori hydrogenation35 is an excellent meth-
odology, which includes Ru catalyst and extremely ammable
hydrogen gas, considering the cost effect, mildness of protocol
and environmental point of view, it is proposed a new formal
synthetic route for the R-quinolactacin B (3) and potential PDE5
inhibitor RWJ387273 (4), as depicted in Scheme 3.
Next following our interest in complex structures, it was
explored the conversion of N-methyl tetrahydro-b-carbolines to
spirooxindoles through a bifunctional activity of organocatalyst
11a–d. Thus, the conversion from N-methyl tetrahydro-b-car-
boline 20a to spirooxindole 5 have been carried out using N-
bromosuccinimide (NBS, 1 equiv., Scheme 2) and isolated
products with satisfactory yields (58–85%) aer 20 min reaction
time, as depicted in Table 3. In the catalytic activity optimiza-
tion, initially we tested 10 mol% of thiosquaramides 11a–d for
a
Reactions were performed using 17 (1 mmol), 11b (10 mol%), PdCl2
b
(15 mol%) Et3SiH (4 mmol) in DCE, for the 24 h. The enantiomeric
excess (ee) was determined by chiral HPLC. c Isolated yield.
with catalyst 11b (10 mol%). Further increment in catalyst load
(15 mol%) was ineffective on selectivity as well as yield (entry 11,
Table 1). These observations indicate just 10 mol% of catalyst
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reaction considerably (78%, 98%, 69% and 85% ee respectively,
entries 1–4, Table 3). However, reaction with 11b gave excellent
selectivity and good yield (98% ee and 85%, entry 2, Table 3). We
considered 11b as suitable catalyst for this reaction, further
tested with 5 mol% and we noticed only 68% ee (entry 9, Table
3). This reaction was found to be optimal with 10 mol% of 11b.
However, the asymmetric reactions without AcOH afforded only
racemic mixtures even aer 24 h (entries 5–8, Table 3). This may
be due to the low solubility of 20a in the absence of AcOH,
which may be needed to protonate the basic nitrogen to soluble
in the solvent mixture. It might indicate that the asymmetric
oxidative rearrangement may require protonation to the
nitrogen atom at b-position of carboline to form the stable
transition state with thiosquaramide catalyst leading to yield
the product in an enantioselective manner. Product 5 was not
observed without the use of aqueous solvent mixtures (entries
12 and 13, Table 3). Hence, we examined solvent mixtures such
as THF/water (1 : 1), DCE/water (1 : 1), THF/water/AcOH
(1 : 1 : 1), DCE/water/AcOH (1 : 1 : 1) and identied that the
chiral reaction was slightly efficient in THF/water/AcOH (98%
ee, entry 2, Table 3) than in DCE/water/AcOH (87% ee, entry 11,
Table 3). The reaction temperature also affected drastically the
enantioselectivities and witnessed good selectivity at 0 ꢀC, while
poor selectivities were observed at room temperature (entry 10,
Fig. 3 Plausible mechanism for the approach (major Si face and minor
Re face) of hydride to the DHBC 17 in the presence of chiral thio-
squaramide catalyst (11b), and the catalyzed oxidative rearrangement.
ꢀ
Table 3). Reactions carried out at temperatures below À10 C
Scheme 3 Formal synthesis of (R)-quinolactacin (3) and potential
PDE5 inhibitor RWJ387273 (4) through 11b catalyzed asymmetric
reduction of 17c and 17f.
ꢀ
(À20 to À78 C) did not give the desired product.
Based on above results, it was xed the protocol as 1 equiv-
alent of NBS, 10 mol% of thiosquaramide catalyst 11b, THF/
water/AcOH (1 : 1 : 1) as solvent system, and reaction tempera-
ture at 0 ꢀC for 20 min to give the key spirooxindole for the
asymmetric synthesis of (À)-coerulescine (5) in 98% ee and 85%
yield. Furthermore, aer reaching the optimal reaction
the asymmetric synthesis of spirooxindole 5 in THF/water/
AcOH (1 : 1 : 1). The reaction mixtures were analysed by chiral
HPLC and evidenced that all the catalysts 11a–d catalysed the
Table 3 Asymmetric oxidative rearrangement reaction optimizationa
Entry
Catalyst
Mol%
Solvents
Temp. (ꢀC)
Yield (%)
eeb (%)
1
2
3
4
11a
11b
11c
11d
11b
11b
11b
11b
11b
11b
11b
11b
11b
10
10
10
10
10
10
10
10
5
10
10
10
10
THF/water/AcOH (1 : 1 : 1)
THF/water/AcOH (1 : 1 : 1)
THF/water/AcOH (1 : 1 : 1)
THF/water/AcOH (1 : 1 : 1)
THF/water (1 : 1)
DCE/water (1 : 1)
THF/water (1 : 1)
DCE/water (1 : 1)
THF/water/AcOH (1 : 1 : 1)
THF/water/AcOH (1 : 1 : 1)
DCE/water/AcOH (1 : 1 : 1)
THF
0
0
0
0
rt
rt
0
0
0
rt
0
0
0
83
85
78
80
65
60
63
58
80
83
84
—
—
78
98
69
85
Racemic
Racemic
Racemic
Racemic
68
78
87
—
—
5c
6c
7c
8c
9
10
11
12
13
DCE
a
b
All the reactions were performed using tetrahydro-b-carboline 20a (1 equiv.), NBS (1 equiv.) for 20 min. The enantiomeric excess (ee) was
determined by chiral HPLC. c The reaction was stirred for 24 h.
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Scheme 4 Thiosquaramide 11b catalyzed asymmetric synthesis of
(À)-coerulescine (5) and (À)-horsfiline (6).
conditions, we also explored a short synthesis of (À)-horsline
(6) with 93% ee and 90% yield, as shown in Scheme 4.
Conclusions
In conclusion, we have synthesized four known squaramides
and thiosquaramide based organocatalysts (11a–d) and 11b was
identied as excellent organocatalyst for the asymmetric imine
reduction. Under the optimized conditions, considerable yields
(65–88%) and good enantioselectivities (88–96%) were observed
for the synthesis of chiral tetrahydro-b-carbolines (18a–f). All
THBCs were obtained with R conguration that could be
explained by Si face approach of hydride in the transition state,
as rationalized in Fig. 3. Moreover, formal syntheses of R-qui-
nolactacin (3) and potential PDE5 inhibitor RWJ387273 (4) via
asymmetric reduction of 17c and 17f, which can be avoided
through metal catalyst and hazardous reagents. Additionally,
we perform a chiral thiosquaramide 11b catalyzed enantiose-
lective synthesis of natural spirooxindoles (À)-coerulescine (5)
and (À)-horsline (6) through enantioselective rearrangement
in a short approach, which afforded good yield and high
enantioselectivities (up to 98% ee) in the direct oxidative
rearrangement.
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Conflicts of interest
There are no conicts to declare.
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Acknowledgements
L. L. S. and F. M. N. thank FONDECYT (Project #1180084)
´
´
´
and M. S. is grateful to Direccion de Investigacion Vicerrectorıa
´
Academica-Universidad de Talca, Talca, Chile for nancial
support for this work.
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