Organocatalytic Cascade Reactions for the Diversification of Thiopyrano-Piperidone Fused Rings Utilizing Trienamine Activation

Article abstract of DOI:10.1002/chem.202004553

An aminocatalytic privileged diversity-oriented synthesis (ApDOS) strategy utilizing trienamine catalysis for the construction of diverse and complex thiopyrans-piperidone fused rings through a thia-Diels–Alder/nucleophilic ring-closing sequence by using dithioamides as activated heterodienophiles is reported. Following this strategy, a super cascade reaction to assemble nine fused rings can be achieved by employing a bis-dithioamide. Additionally, by linking an indole moiety on the dithioamide, a Pictet–Spengler type reaction can be promoted once the cascade sequence has been achieved, leading to more complex penta- hexa- and heptacyclic fused ring derivatives in a one-pot process. This investigation opens new perspectives for the synthesis of a new class of complex and diverse thiopyrans that contribute to populate new relevant regions in the chemical space.

Full text of DOI:10.1002/chem.202004553

Accepted Article
Accepted Article
Title: Organocatalytic Cascade Reactions for the Diversification of
Thiopyrano-Piperidone Fused Rings via Trienamine Activation.
Authors: Suhas Balasaheb Mitkari, Alberto Medina-Ortíz, José Luis
Olivares-Romero, Miguel A. Vázquez, Eduardo Peña-
Cabrera, Clarisa Villegas Gómez, and David Cruz Cruz
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.202004553
Link to VoR: https://doi.org/10.1002/chem.202004553
01/2020

10.1002/chem.202004553
Chemistry - A European Journal
COMMUNICATION
Organocatalytic Cascade Reactions for the Diversification of
Thiopyrano-Piperidone Fused Rings via Trienamine Activation.
Suhas Balasaheb Mitkari,a Alberto Medina-Ortíz,a José Luis Olivares-Romero,b Miguel A. Vázquez,a
Eduardo Peña-Cabrera,a Clarisa Villegas Gómez,a* David Cruz Cruza*
[a]
[b]
Suhas Balasaheb Mitkari, Alberto Medina-Ortíz, Miguel A. Vázquez, Eduardo Peña-Cabrera, Clarisa Villegas Gómez, David Cruz Cruz.
Departamento de Química, División de Ciencias Naturales y Exactas.
Universidad de Guanajuato
Noria Alta S/N 36050 Guanajuato, Gto. México.
E-mail: clarisa.villegas@ugto.mx; david.cruz@ugto.mx
José Luis Olivares-Romero.
Red de Estudios Moleculares Avanzados.
Instituto de Ecología A.C.
Carretera Antigua a Coatepec 351, El Haya, Xalapa, Ver. 91070, México.
Abstract: We report an Aminocatalytic privileged Diversity-Oriented
Synthesis (ApDOS) strategy via trienamine catalysis for the
construction of diverse and complex thiopyrans-piperidone fused
rings through a thia-Diels–Alder/nucleophilic ring closing sequence
by using dithioamides as activated heterodienophiles. Following this
strategy, a super cascade reaction to assemble nine fused rings can
be achieved by employing a bis-dithioamide. Additionally, by linking
an indole moiety on the dithioamide, a Pictet-Spengler type reaction
can be promoted once the cascade sequence has been achieved,
leading to more complex penta- hexa- and heptacyclic fused ring
derivatives in a one-pot process. This investigation, open new
perspectives for the synthesis of a new class of complex and diverse
thiopyrans, which contribute to populate new relevant regions in the
chemical space.
the formal [4+2] cycloadducts of trienamine-mediated reactions
contain aldehyde moieties, which can undergo further
cyclizations.[13]
MeO
OMe
b)
a)
O2N
CO2H
Me
CO2H
O
N
O
S
MeO
O
N
HO
H
N
CF3
S
OMe
N
H
OH
OMe
OMe
Anti-hyperplasia
Antibacterial
Against IBD
Against Alzheimer disease
Figure 1. Some examples of biological active thiopyrans and piperidones.
Thiocarbonyls such as dithioesters, thioamides and
thioketones, constitute select group of sulfur-containing
a
The construction of chiral privileged structures of sulfur- and
compounds, which have been employed efficiently as
heterodienophiles for thia-Diels–Alder cycloadditions.[10a-b] In
2013, the organocatalytic version of this reaction was first
reported by Jørgensen et al. through a trienamine-mediated
cycloaddition using dithioesters as dienophiles.[14] Later, under
the same catalytic strategy, Albrecht and co-workers
demonstrated the dienophilic ability of aryl and hetaryl
thioketones.[15] In both cases, the reactions proceeded smoothly
and efficiently for the construction of diverse optically active
dihydro-2H-thiopyrans.
nitrogen-based heterocycles constitutes
a highly attractive
research topic in contemporary synthesis.[1] These relevant
frameworks are present in diverse natural and unnatural
biologically active molecules. Particularly, thiopyrans have
shown important biological properties such as analgesic,[2] anti-
cancer,[3] anti-hyperplasia,[4] antibacterial,[5] among others[6]
(Figure 1a). Meanwhile, piperidones have demonstrated to be
important therapeutic agents against different diseases such as
Alzheimer disease[7] anti-cancer[8] and inflammatory bowel
disease (IBD)[9] (Figure 1b). The constant demand of these
significant scaffolds has driven the development of new
synthetic methods, which have contributed to the diversification
of these skeletons.[10] However, the elaboration of effective
stereocontrolled protocols while maximizing atom economy is
In order to explore this relevant chemical design space and
contribute with reliable and efficient methodologies for the
Aminocatalytic
(ApDOS)[16] via trienamine catalysis, we envisioned an
organocatalytic cascade strategy through thia-Diels–
privileged
Diversity-Oriented
Synthesis
a
still
a challenge. In this context, aminocatalytic cascade
Alder/nucleophilic ring-closing sequence by using dithioamides
as activated heterodienophiles for the assembly of diverse
thiopyran-piperidone fused rings. Additionally, by linking an
indole moiety on the dithioamide, a Pictet-Spengler type reaction
can be performed once the first cascade sequence has been
achieved. Thus, high order polycyclic frameworks of greater
reactions have provided important protocols for the
enantioselective synthesis of simple and complex molecules
with high levels of structural diversity and atom economy.[11]
Particularly, trienamine catalysis has demonstrated the ability to
promote consecutive transformations to provide diverse
polycyclic frameworks.[12] One approach is to utilize the fact that
1
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10.1002/chem.202004553
Chemistry - A European Journal
COMMUNICATION
complexity can be prepared in a one-pot process. Finally, by
With the optimal conditions in hand, we explored the scope
of the cascade reaction with different 2,4-dienals as trienamine
precursors. As shown in Table 2, alkyl groups at γ- and δ-
positions were well tolerated, maintaining good yields and
stereoselectivities. An extra cyclohexane fused ring was also
generated by using the derivative 1e. Interestingly, an indole
moiety could be incorporated when the 2-methylindole
acrylaldehyde 1f was employed as masked 2,4-dienal, leading
to the corresponding tetracyclic adduct 4f in excellent yield
(96%) and stereoselectivity (96:4 dr, 98% ee). Next, we
investigated the protocol using different dithioamides.
considering
a
bis-dithioamide as hetero-dienophile, we
hypothesized a double cascade reaction for the construction of
two thiopyrano-piperidone cycloadducts at the same molecule,
in a simple process (Scheme 1).
Herein we present the results of this investigation, which
open new perspectives for the diversification of thiopyrans and
piperidones. To best of our knowledge, there are no reports
about the synthesis or natural occurrence of these fused cores.
Therefore, this strategy aims to populate relevant regions in the
chemical space.
Previous work:
Table 1. Screening of the thia-Diels–Alder/nucleophilic ring closing cascade
reaction.
OHC
R4OC
O
CHO
Ar1
Aminocatalytic
Trienamine
Activation
Aminocatalytic
Trienamine
Activation
R1
R2
R1
R2
R5S
R1
R2
Ar2
S
S
Ar1
Ar2
O
SR5
O
OH
R4
R3
S
R3
Cat. 3
20 mol%
O
Bn
N
R3
S
EtS
Bn
+
N
H
PhCO2H
20 mol%
O
SEt
Jørgensen et al.
Albrecht et al.
S
S
Solvent
r.t.
2a
4a
1a
This work:
R3
Ph
Ph
Ar
Ph
R2
R1
Ph
Ph
OMe
Ar
Ph
OSi(Ph)3
N
H
N
H
N
H
N
H
S
Aminocatalytic Trienamine
double-(Thio-Diels–Alder/
Nucleophilic ring closing)/
Elimination/Nucleophilic
ring closing cascade.
OTMS
OTMS
R7
SEt
O
OH
Ar = 3,5-(CF3)2C6H3
Aminocatalytic Trienamine
Thio-Diels–Alder/Nucleophilic
ring closing cascade.
3a
3d
3b
n
N
3c
N
drb
eec
(%)
R1
O
Entry
Cat. Solvent t (h) Conv. Yield
O
O
O
O
N
SR6
(%)
100
64
(%)a
93
62
70
78
57
61
---
R6S
S
NH HN
R2
n
N
H
O
R7
EtS
SEt
R1
R2
R3
S
SEt
S
S
1
2
3a
3b
3c
3d
3a
3a
3a
3a
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
THF
24
48
48
48
48
48
48
48
93:7
97:3
94:6
93:7
71:29
74:26
---
92
68
76
96
n.d.
82
---
S
One-pot process
R3
R7
3
74
n
N
Intramolecular
Pictet-Spengler reaction
4
100
61
R1
R2
O
SR6
5
S
R3
6
63
7
8d
dec.
64
Scheme 1. Thiocarbonyl compounds in aminocatalysis and our present
CHCl3
61
72:28
---
synthetic strategy.
The reactions were performed with 0.15 mmol of 1a, 0.1 mmol of 2a, 20 mol%
of catalyst and benzoic acid as additive in 0.5 ml of solvent at room
temperature. aYield of both diastereoisomers of 4a after chromatographic
purification on silica gel. bDetermined by 1H NMR of crude product. cMeasured
by chiral HPLC. dThe reaction was performed with 10% of the catalyst.
To proof the concept, we initiated our work by choosing the
2,4-dienal 1a and the dithioamide 2a as model substrates for the
cascade sequence thia-Diels–Alder/nucleophilic ring-closing.
Gratifyingly, when the reaction was carried out in presence of 20
mol% of Jørgensen-Hayashi catalyst 3a and benzoic acid as
additive in CHCl3, the desired product 4a was obtained after 24
To our delight, the reaction was also effective for
dithioamides carrying with aromatic or ester substituents
resulting in good to excellent yields (87-98%) and
stereoselectivities (90:10-95:5 dr, 93-97% ee). Only a small
difference was observed by changing the alkyl group at the
sulfur atom. Notably, an interesting polycyclic derivative with two
indole cores 4l was able to prepare through the reaction
between 1f and 2i.
h
at room temperature with excellent yield (93%) and
stereocontrol (93:7 dr, 92% ee) (Table 1, entry 1). In order to
improve the stereoselectivity, we tested different catalysts.
When the reaction was performed with the catalysts 3b-c, the
diastereoselectivity
was
slightly
improved
but
the
enantioselectivity and the yield were not satisfying (entries 2 and
3). By using the more sterically demanding O-Si(Ph)3 catalyst
3d, a better enantioselectivity was observed (96% ee) along with
the same diasteromeric ratio. However, the isolated yield
decreased less than 80% (entry 4). Therefore, we decided to
work with the readily available catalyst 3a. No further
improvement was observed by changing solvents such as
CH2Cl2, CH3CN and THF (entries 5, 6 and 7). Finally, the results
were not satisfying when the reaction was carried out with less
catalyst loading (entry 8).
Once we demonstrated the scope of the developed
methodology, we considered to extend the methodology towards
the construction of more complex frameworks. In this sense, we
focused our attention on the reactivity of the cycloadduct 4i,
which can undergo an intramolecular Pictet-Spengler type
reaction once an iminium ion intermediate is formed via hydroxyl
group elimination. To validate this hypothesis, the reaction was
promoted under acidic conditions. To our glad, when 4i was
treated with 1 equiv of TFA at room temperature, the thiopyrano-
piperidone-tetrahydrocarboline fused ring derivative 5i was
obtained as a mixture of two diastereoisomers in 22% of yield
(Scheme 2).
2
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10.1002/chem.202004553
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Table 2. Scope of the thia-Diels–Alder/nucleophilic ring closing cascade
Table 3. Scope of the thia-Diels–Alder/nucleophilic ring closing Pictet-
reaction.
Spengler one-pot reaction.
Ph
Ph
N
H
O
OH
3a
1)
OTMS
3a
HN
R5
20 mol%
PhCO2H
20 mol%
O
O
N
20 mol%
R1
R2
R4
S
R5
R1
R2
+
N
H
O
N
PhCO2H
20 mol%
CHCl3
r.t.
SR4
O
CHCl3
r.t. 24h
R1
R2
S
S
R1
R2
NH
O
EtS
+
2
N
H
R3
R3
SEt
2) TFA
20 mol%
S
S
R3
R3
4
1
2i
5
1
OH
OH
OH
OH
Bn
Bn
Bn
Bn
N
N
N
N
O
SEt
O
SEt
O
SEt
O
SEt
S
S
S
S
HN
HN
HN
4b
78% yield
93:7 dr, 91% ee
4c
90% yield
85:15 dr, 94% ee
4d
92% yield
89:11 dr, 94% ee
4a
93% yield
95:5 dr, 92% ee
N
N
N
O
OH
O
OH
OMe
O
OH
SEt
OH
SEt
S
Bn
S
SEt
Bn
N
N
S
O
N
N
N
Boc
O
O
O
5a
SEt
O
SEt
S
5b
74% (37%) yield
51:49 dr, 99% ee
5c
S
SEt
83% (41%) yield
51:49 dr, 97% ee
SEt
S
N
S
85% (41%) yield
51:49 dr, 98% ee
Boc
4h
98% yield
95:5 dr, 97% ee
4g
87% yield
4f
96% yield
96:4 dr, 98% ee
4e
72% yield
85:15 dr, 86% ee
The reactions were performed with 0.15 mmol of 1, 0.1 mmol of 2i, 20 mol% of
catalyst, and benzoic acid as additive in 0.5 ml of solvent at room temperature.
Then TFA (20 mol%) was added. The yield is for both diastereoisomers, the
yield in parenthesis is for single major diatereoisomer. The dr was determined
by 1H NMR of crude product. The ee was measured by chiral HPLC.
90:10 dr, 93% ee
OH
O
OH
OH
N
OH
NH
NH
Bn
N
OEt
N
N
O
O
O
SMe
O
SEt
SEt
S
S
SEt
S
S
N
Finally, driven by the access to more diverse and complex
molecules containing these attractive scaffolds we were
wondering if a double aminocatalytic cascade process would be
possible through the reaction with the bis-dithioamide 6 and
construct two cycloadducts connected by the amide moiety in
one process. Surprisingly, when the bis-dithioamide 6 was
reacted with three equiv of the aldehyde 1f under the standard
conditions, the nine fused ring compound 7 was directly
4j
4k
82% yield
92:8 dr, 90% ee
Boc
4i
90% yield
90:10 dr, 93% ee
93% yield
90:10 dr, 93% ee
4l
75% yield
96:4 dr, 86% ee
The reactions were performed with 0.15 mmol of 1, 0.1 mmol of 2, 20 mol% of
catalyst, and benzoic acid as additive in 0.5 ml of solvent at room temperature.
The yield is for both diastereoisomers of 4 after chromatographic purification
on silica gel. The dr was determined by 1H NMR of crude product. The ee was
measured by chiral HPLC.
obtained in
closing)/elimination/O-nucleophilic
a
double-(thia-Diels–Alder/N-nucleophilic ring
ring closing sequence
NH
NH
(Scheme 3). Notably, through this reaction, a separable mixture
of two diastereoisomers with six new stereocenters were
smoothly furnished in 41 and 39% of yield and 98% of ee for the
major diastereoisomer.
OH
HN
TFA
1 equiv.
N
N
N
CHCl3
r.t.
O
O
SEt
SEt
O
S
S
SEt
S
4i
5i
22% yield
50:50 dr
Boc
N
S
O
SEt
O
Scheme 2. Intramolecular Pictet-Spengler reaction to furnish 5i.
3a
O
O
N
20 mol%
NH HN
+
O
EtS
SEt
PhCO2H
20 mol%
N
N
S
S
Boc
CHCl3
r.t.
O
6
More importantly, when both, thia-Diels–Alder/nucleophilic
ring closing and Pictet-Spengler reactions were performed in a
one-pot fashion using catalytic amounts of TFA, the desired
product 5i was furnished in 83% overall yield and 97% ee.[17] In
order to prove the strategy, more complex hexa- and heptacyclic
compounds were successfully prepared following the same
conditions with good yields and excellent enantioselectivities
(Table 3).
1f
SEt
S
N
Boc
7
83% (41%)a yield
51:49 dr, 98% ee
Scheme 3. Aminocatalytic double-(thia-Diels–Alder/N-nucleophilic ring
closing)/elimination/O-nucleophilic ring closing cascade reaction. The reaction
was performed with 0.3 mmol of 1f, 0.1 mmol of 6, 20 mol% of catalyst 3a and
benzoic acid as additive in 0.5 ml of solvent at room temperature. The yield is
for both diastereoisomers. aThe yield is for a single major diastereoisomer.
The dr was determined by 1H NMR of crude product. The ee was measured by
chiral HPLC.
3
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products the configurations were assumed by analogy (Figure
2).
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Figure 2. X-ray structure of compounds 4f and 5c.
In conclusion, we have developed a new thia-Diels–
Alder/nucleophilic ring-closing cascade sequence for the
enantioselective synthesis of thiopyrano-piperidone fused ring
compounds through trienamine catalysis. The reaction proceeds
efficiently with high levels of stereocontrol. Additionally, by
promoting an intramolecular Pictet-Spengler reaction after the
cascade sequence, different thiopyrano-piperidone-carboline
fused ring compounds were constructed in a one-pot with good
yield and excellent enantiocontrol. Interestingly, by using a bis-
dithioamide as hetero-dienophile, a double-(thia-Diels–Alder/N-
nucleophilic ring closing)/elimination/O-nucleophilic ring closing
super cascade reaction was achieved, leading to a new type of
nine fused ring derivative with six new stereocenters. These
aminocatalytic cascade methodologies, open new perspectives
for the synthesis of a new class of complex and diverse
thiopyrans, which contribute to populate new relevant regions in
the chemical space.
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This work was made possible by grants from CONACYT (Project
supported by the Fondo Sectorial de Investigación para la
Educación, project: 253621) and DAIP-UG (project: 098/2020).
S.B.M. and A.M.O. thank to CONACYT for postgraduate
scholarships. National Laboratory of Molecular Spectroscopy of
the Universidad de Guanajuato is also gratefully acknowledged.
Thanks to Dr. Gerardo González García for X-ray
crystallography experiments and Dr. Hao Jiang for help
discussion.
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Keywords: aminocatalysis • trienamine catalysis• one pot
[17] For more screening conditions, see Supplementary Information.
reaction • dithioamide • bis-dithioamide.
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[2]
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4
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10.1002/chem.202004553
Chemistry - A European Journal
COMMUNICATION
Table of Contents
R3
S
R2
R1
Aminocatalytic Trienamine
R7
n
double-(Thio-Diels–Alder/
Nucleophilic ring closing)/
Elimination/Nucleophilic
ring closing cascade.
SEt
O
O
OH
Aminocatalytic Trienamine
Thio-Diels–Alder/Nucleophilic
ring closing cascade.
N
N
R1
R2
R1
R2
O
O
O
O
O
N
SR6
R6
S
S
NH HN
n
N
H
R7
O
R3
EtS
SEt
R1
R2
R3
12 examples
S
SEt
S
S
S
One-pot process
R3
1
example
R7
n
N
Intramolecular
Pictet-Spengler reaction
R1
R2
O
SR6
S
R3
examples
3
A highly enantioselective thio-Diels–Alder/nucleophilic ring closing cascade reaction via trienamine catalysis with dithioamides is
presented. Notably, by linking an indole moiety on the dithioamide, a Pictet-Spengler type reaction can be also promoted, leading to
more complex frameworks in a one-pot process. Additionally, a super cascade sequence to assemble nine fused rings can be
achieved by employing a bis-dithioamide.
Twitter: @DavidCr20916746
5
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