Stereoselectivity Enhancement During the Generation of Three Contiguous Stereocenters in Tetrahydrothiophenes

Article abstract of DOI:10.1002/cctc.202001583

Application of carefully designed Cinchona alkaloid based squaramides resulted in the formation of three contiguous stereocenters in enantio- and diastereoselective Sulfa-Michael/intramolecular aldol reactions cascade. Increase of the temperature to 333 K in reaction of mercaptoacetic aldehyde and various en-ynones allowed the rise of the reaction rate while not affecting the enantioselectivity nor diastereoselectivity. Stereoselectivity was dependent on the structure of the hydrogen-bonding unit, thus revealing the importance of weak interactions in the formation of the multifunctional tetrahydrothiophenes. Kohn-Sham Density Functional Theory results suggest that a perfect fit of the electrophile and squaramide via tailored (+)N?H hydrogen bonding and π–π stacking interactions were the main factors of the chirality transfer.

Full text of DOI:10.1002/cctc.202001583

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Stereoselectivity Enhancement During the Generation of Three
Contiguous Stereocenters in Tetrahydrothiophenes
Authors: Rafał Kowalczyk, Żaneta Anna Mała, Mikołaj Janicki, Natalia
Niedźwiecka, Robert Wiktor Góra, and Krzysztof Konieczny
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10.1002/cctc.202001583
ChemCatChem
FULL PAPER
Stereoselectivity Enhancement During the Generation of Three
Contiguous Stereocenters in Tetrahydrothiophenes
Żaneta A. Mała,[a] Mikołaj J. Janicki,[b] Natalia H. Niedźwiecka, Robert W. Góra,[b] Krzysztof A.
Konieczny,[c] Rafał Kowalczyk*[a]
[a]
M.Sc. Ż. A. Mała, Dr. R. Kowalczyk*
Bioorganic Chemistry, Faculty of Chemistry, ,
Wrocław University of Science and Technology
Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
E-mail: rafal.kowalczyk@pwr.edu.pl
[b]
[c]
M. Sc. M. J. Janicki, Dr. R. W. Góra
Physical and Quantum Chemistry, Faculty of Chemistry
Wrocław University of Science and Technology
Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
Dr. K. A. Konieczny
Faculty of Chemistry
Wrocław University of Science and Technology
Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Application of carefully designed Cinchona alkaloid based
Hence, the addition at either 4- or 6-position could afford the
synthesis of the chiral tetrahydrothiophenes bearing additional
reactive function in the molecule, thus enabling further
transformations into complex structures (eg. 3 and 5, Scheme 1).
The highly stereoselective formation of such heterocycles is
limited to the addition of 2-mercaptocarbonyl nucleophiles (1,
Scheme 1) rarely bearing aldehyde functionality. Therefore, in this
contribution we focus on the development of organocatalytic
strategy for the functionalization of variably decorated Michael
acceptors with additional double or triple bonds and another
electron-withdrawing group (Acc 1-3, Scheme 1) by applying a
convenient source of mercaptoaldehyde. The acceleration of the
reaction of 1,4-dithiane-2,5-diol (6) in the aqueous system by the
formation of hydrogen bonds or its decomposition by a base
indicates the bifunctional character of hydrogen bonding systems,
with the basic unit as the potential catalyst to the effective
formation of the sulfur-containing heterocycles. Hence, we also
studied the nature of the hydrogen bonding unit and its impact on
stereoselectivity of the transformation in which three contiguous
stereocenters were formed.
squaramides resulted in the formation of three contiguous
stereocenters
in
enantio-
and
diastereoselective
Sulfa-
Michael/intramolecular aldol reactions cascade. Increase of the
temperature to 333 K in reaction of mercaptoacetic aldehyde and
various en-ynones allowed the rise of the reaction rate while not
affecting
the
enantioselectivity
nor
diastereoselectivity.
Stereoselectivity was dependent on the structure of the hydrogen-
bonding unit, thus revealing the importance of weak interactions in the
formation of the multifunctional tetrahydrothiophenes. Kohn-Sham
Density Functional Theory results suggest that a perfect fit of the
electrophile and squaramide via tailored (+)N-H hydrogen bonding
and π-π stacking interactions were the main factors of the chirality
transfer.
Introduction
Chiral tetrahydrothiophenes are valuable scaffolds exhibiting
various biological activities.[1] The importance of such a structural
motif is demonstrated by a variety of synthetic approaches to the
formation of the tetrahydrothiophene ring. Among them, an
application of the dithiane diol as a source of low-weight building
block covering nucleophilic and electrophilic functionalities
deserves particular attention.[2] Decomposition of the stable dimer
of mercaptoacetaldehyde by a base or heating was the pillar of
the elaborated cascade Sulfa-Michael/aldol reaction or aldol
condensation resulting in the formation of the multi-decorated
tetrahydrothiophenes in a highly stereoselective fashion.[3] The
majority of transformations involve an initial addition to simple
Michael acceptors. However, the application of electrophiles with
additional π-electron conjugated system in β or δ position of
polyene may result in reaction at remote positions.[4]
Results and Discussion
The effective synthesis of the functionalized molecules with a few
stereocenters is prone to diastereoselection issues. The initial
reactions of dithiane diol 6 and enynone 11a[5], as a model
acceptor, suffered from the low selectivity when DABCO (4:1 d.r)
or chiral quinine (1:1 d.r.) were applied (Scheme 2), seriously
affecting the analysis of the reaction mixture. The essential
increase of the diastereomers ratio was noted when thiourea C1
was used, albeit the product 9a was formed with low
enantioselectivity. With the assumption that the stronger N-H
donor might be responsible for the diastereoselection
improvement, several squaramides were tested.[6]
1
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Scheme 2. Catalyst screen. For the C4-C15 20:1 d.r. was noted. Ees are given
for the crude product due to changes of enantiomeric composition affected by
column chromatography.
Among the tested, 3-iodo (C10) and 4-methoxy (C11) catalysts
provided the product but with lower ees than C4. Also, the
changes of the Cinchona core as 2’-phenyl-substituted catalyst
C1 had no distinct impact on stereoselectivity leading to an adduct
with 93% ee. Surprisingly, modification of the squaramide unit into
the more acidic analog of C3 like in thiosquaramide C14[8] resulted
in total loss of stereoselectivity. A flexible amine unit present in
squaramide C15 was also a probable factor of the lowering
enantioselectivity of the product. Besides providing the effective
chirality transfer, the role of the catalyst begins with the
decomposition of the stable 1,4-dithiane-2,5-diol (6) into the
reactive thiol 7[9] that is promoted also by the temperature
increase to 333 K.[3d] The amine unit is responsible for the
generation of dithiane anion, which then becomes unstable and
undergoes decomposition to thiolate. This process requires
energy for activation but provides a low concentration of
nucleophile formed upon the protonation. Reaction performed at
298 K required 48 h instead of only 6 h at 333 K. Although
enantioselectivity was satisfactory, such conditions led to
irreproducible results. Our KS-DFT calculations of a system
containing catalyst C3 and 6 indicate a readily accessible
molecular pathway allowing for the formation of the neutral and
Scheme 1. Addition of mercaptocarbonyls to functionalized enone-based π-
conjugated systems.
Achiral C2 offered the product with a bit higher d.r. than thiourea
C1. However, the application of chiral squaramide C3 led to the
product with high d.r. and 91% ee. Additional improvement was
observed for the reaction catalyzed by Cinchona-alkaloid based
squaramide C4, application of which led to the chiral
tetrahydrothiophene 9a with 96% ee and 20:1 d.r. Further studies
on the catalyst's structure-stereoselectivity of the product
revealed that as low as 2 mol% of squaramide C4 could efficiently
promote the studied reaction. The importance of the hydrogen-
bonding was demonstrated by the impact of the solvent (see SI
for details). The reaction catalyzed by C4 led to
enantioselectivities exceeding 90% only when chlorinated
alkanes and aromatics were applied, while the usage of 2-
propanol afforded adduct with only 40% of ee. No additional
improvement was observed for the congeners of C4 bearing
chlorine (C5), bromine (C6) or iodine (C7) atom in place of fluorine,
thus excluding the impact of the halogen-lone pair interaction with
carbonyl group in enynone.[7] Although product with up to 98% ee
was formed with the assistance of C5, it required four times more
of catalyst (8 mol% vs 2 mol%). In the case of large substituents
as in C6 and C7, the introduction of both trifuoromethyl (C8) and
methoxy (C9) groups instead of fluorine resulted in lowered
enantioselectivities. This was even more evident for catalyst C12,
that catalyzes the reaction but with only 78% of ee.
activated
nucleophile
(mercaptoacetaldehyde
7).
The
decomposition process is initiated by a proton abstraction from
dithiane diol by the basic unit of catalyst C3. This step,
characterized by a free energy barrier of 4.2 kcal/mol (cf. inset 1-
dithiane diol which is stabilized by three hydrogen bonds between
the oxygen atom of the anion and three N-H sites of C3 (the
structures of the relevant molecules are shown in the SI). Our
2
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calculations performed on the isolated anionic dithiane diol
indicate that it may decompose (cf. right panel of Figure 1).
by KS-DFT calculations is summarized in Figure 2, whereas in
Figure 3 the corresponding Gibbs energy profile is shown. The
stationary
points
were
located
at
the
ωB97X-
D/PCM(toluene)/def2-SVP level and the corresponding Gibbs
energies were computed assuming def2-TZVP basis set. Only in
the case of dithiane anion decomposition we employed
B2PLYP/PCM(toluene)/ma-def2-TZVP approach (cf. SI for
details).[10] According to our calculations the next step after
release of dithiane diol anion leads to mercaptoacetaldehyde
addition to en-ynone in the presence of C4 catalyst. The latter
starts with a deprotonation of mercaptoacetaldehyde by the
amine unit of chiral squaramide C4. This step (cf. Figure 3, 3-
Activation) seems to be readily available due to a low free energy
barrier of 4.4 kcal/mol. The activation process leads to the
formation
of
activated
nucleophile
(anion
of
mercaptoacetaldehyde, cf. 3-TS in Figure 2 and 3) having excess
negative charge located on the sulfur atom (reaching -0.54 e in
the 3-TS structure and -0.65 e in the 3-PC, Figure 2). Hence, it is
assumed that reaction underwent according to the specific base
catalysis. Moreover, our calculations indicate that the aldehyde
group forms hydrogen bonds with the squaramide unit which thus
assumes the appropriate position to attack the acceptor (2.48 Å).
According to the previous model involving organocatalyzed
addition to Michael acceptor[11], the ketone is believed to interact
with the protonated amine. In the alternative orientation of the
ketone, that would result in formation of the opposite stereogenic
center, the electron poor double bond is away of the reaction
center and thus becomes unreachable for the C-S bond formation.
Our KS-DFT results indicate that the 4-TS transition state is
formed, in which the nucleophile’s and en-ynone’s double bonds
are aligned with the assistance of advantageous aryl-aryl stacking
interactions (cf. 4-TS, Figure 2). Hence, the formed nucleophile
can attack the positively charged (+0.26 e) β-carbon atom of en-
ynone approaching the Si-face of the double bond and leading to
the formation of negatively charged intermediate (cf. Figure 3, 4-
PC). The free energy barrier for the addition step is merely 7.3
kcal/mol (cf. Figure 3, 4-Addition).
Figure 1. The computed Gibbs energy profile for the catalyst-supported
decomposition of 6 to mercaptoacetaldehyde 7 in the presence of C3 catalyst.
In the left panel the profile for proton abstraction is shown, leading to an anion
of dithiane diol, and in the right panel the profile for its decomposition is shown,
computed for isolated anion.. The abbreviations refer to -SC substrate complex,
-TS transition state, and -PC products.
Subsequently, a proton transfer from hydroxyl group to the sulfur
atom induces a C-S bond rupture (cf. Figure 2, 2-TS), that leads
to the formation of neutral and anionic forms of
mercaptoacetaldehyde (cf. Figure 2, 2-PC). The rate-limiting step
in the formation of nucleophile seems to be the release of an
anion of dithiane diol from the complex. A higher temperature of
the system should facilitate breaking of the hydrogen bonds
between anion of dithiane diol and C3 catalyst. Hence, at lower
temperatures, the aldehyde remained unconsumed and followed
self-condensation leaving Michael acceptor unreacted. The
results of our KS-DFT calculations are thus consistent with the
observed rates of performed reactions, which required elevated
temperature to be efficient. The complete mechanism elucidated
3
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Figure 2. The plausible reaction path including sulfa-Michael addition, intramolecular aldol reaction, the formation of the final product and X-ray of the product 9g
.
Then, the excess proton located in the basic unit of C4 catalyst is
spontaneously detached by the carbonyl group of the anionic
intermediate in a barrierless manner (cf. Figure 3, 5-Proton
Transfer), forming a neutral product and releasing the catalyst
thus providing a sulfa-Michael adduct. At this stage the topology
and stereochemistry of the final product is already established.
Further enolization of ketone generates a C-centered nucleophile
that could adopt the conformation in which both reactive centers
remain in proximity, separated by only 2.07 Å (cf. Figure 2, 6-TS).
The mutual orientation of the enol and aldehyde is organized by
the configuration of the C-S bond and an intramolecular hydrogen
bond, that enables formation of the next C-C bond in a highly
stereoselective manner. According to our KS-DFT calculations, in
which we assumed dissociation of en-ynone (requiring additional
29.6 kcal/mol) what is consistent with the use of elevated
temperature, the intramolecular aldol reaction resulted in
formation of the final product in a cyclization process (cf. 6-TS
inset in Figure 2), marked by the free energy barrier of 16.2
kcal/mol (cf. Figure 3, 6-Cyclization). Although the intermolecular
cyclization appears to be the overall rate limiting step this is also
a highly exoergic process, leading to the formation of (1S, 2S,
3R)-tetrahydrothiophene (cf. 6-PC inset in Figure 2) without the
assistance of a chiral catalyst and with high stereoselectivity.
Thus, the KS-DFT predictions are consistent with the observed
stereoselectivity of the investigated reaction (96% ee and >20:1
d.r.).
The absolute configuration observed in the final product was
supported by the X-ray analysis of the product 9g.[12] The
chemical absolute configuration of the compound was determined
on the grounds of the Flack parameter equal to 0.010(15) and was
assigned by analogy to other adducts 9a-9w (cf. Table 1).
According to the plausible mechanism revealed by our
calculations (Figure 2), only the precise arrangement of both
partners allows the activation of the electrophile, followed by the
stereoselective addition of sulfur nucleophile. The assumption
that only aromatic congeners of squaramides C3-C7 allow for the
4
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10.1002/cctc.202001583
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weak but crucial interactions with the aromatic unit of electrophile
could also be supported by a low yield and small enantioselectivity
when C15 was used instead (56%, 38% ee).
Figure 4. The ground-state minimum energy structures of C3 and the two
located conformers of C14 (C14-I and C14-II) obtained using
ωB97xD/PCM(Toluene)/def2-SVP method.
Further studies revealed that the formation of the
tetrahydrothiophene ring catalyzed by C4 performed well for a
variety of Michael acceptors 11 (Table 1). However, the structure
of the electrophile turned out to be crucial for the
stereoselectivities achieved. 2-Substituted ketones as in cases of
11b and 11c were transformed to products 9b and 9c,
respectively (Table 1), with poor to moderate enantioselectivities.
This observation is consistent with the proposed mechanism
(Figure 2) in which the formation of a hydrogen bond with
protonated amine and ketone (N-H and O=C) could be less
effective and thus allowing the reaction to occur without the
control of the catalyst. On the contrary, 3- and 4-substitution
Figure 3. The Gibbs energy profile for the sulfa-Michael addition of
mercaptoacetaldehyde to en-ynone in the presence of chiral squaramide C4
calculated at the ωB97xD/PCM(Toluene)/def2-TZVP level. The abbreviations
refer to -SC substrate complex, -TS transition state, and -PC product complex.
Furthermore, the profile for cyclization step calculated assuming earlier
dissociation of en-ynone is shown separately For further details, see SI.
patterns in Michael acceptors had
a modest impact on
enantioselectivity (products 9d-9g and 9i-j, 89-99% ee) except 4-
nitro-derivative (9h, 78% ee). The effects caused by the
surrounding of the triple bond in studied en-ynones to
stereoselectivities were found to be minor (Table 1, entries 12-22)
and only the 2-tiophene-derivative reacted to give the product 9u
with 77% ee albeit >20:1 d.r.
The minimum energy structures of both C3 and C14 catalysts
located in our KS-DFT calculations are shown in Figure 4. A
comparison of the structural features of these two squaramides
led to the conclusion that the aromatic unit of C14 could occupy
two conformations. Hence, on the contrary to C3, substitution of
the oxygen atom by sulfur does not allow to adopt the co-planar
alignment in C14. Therefore, in the latter the aromatic rings of the
acceptor are not able to fit nearby the hydrogen bond donor.[13]
Table 1. Influence of the substitution of en-ynone system in acceptors 11a-11w on the stereoselectivity[a]
Entry
R1
R2
Adduct
9a
Yield [%][b]
ee [%][c]
96
d.r.[d]
20:1
20:1
13:1
20:1
13:1
20:1
20:1
8:1
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
62
76
67
69
71
67
74
52
2-ClC6H4
2-BrC6H4
3-FC6H4
3-Cl6H4
4-BrC6H4
4-FC6H4
4-NO2C6H4
9b
68
9c
76
9d
94
9e
89
9f
93
9g
94
9h
78
5
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9
Ph
4-MeOC6H4
9i
73
77
90
90
84
83
83
81
61
99.5
72
92
78
84
52
95
99
93
94
93
94
90
91
93
93
94
94
77
92
70
20:1
18:1
20:1
20:1
20:1
20:1
20:1
15:1
20:1
20:1
20:1
17:1
20:1
20:1
20:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23[e]
Ph
4-PhC6H4
2-Npht
Ph
9j
Ph
9k
9l
2-FC6H4
2-ClC6H4
3-FC6H4
3-ClC6H4
3-BrC6H4
3-NO2C6H4
4-ClC6H4
2,4-Cl2C6H4
1-Npht
Ph
9m
9n
9o
9p
9q
9r
Ph
Ph
Ph
Ph
Ph
Ph
9s
9t
Ph
2-Tiophene
4-NO2C6H4
Ph
Ph
9u
9v
9w
Ph
CH3
[a] Unless otherwise stated, reactions were performed using 2 mol% of C4 in toluene at 60°C for 6h.
[b] Yield of isolated product. [c] Determined by HPLC on chiral stationary phases.
[d] Determined using 1H NMR. [e] Reaction was performed for 24h.
In general, products 9a, 9d-v (excluding 9h and 9u) were formed
with stereoselectivities ranged from 90 to 94% with little
dispersion of the ee values and regardless of structural variations
in the substrate. The aryl groups attached to triple bond in the
source en-ynones remained far apart from the reaction center and
did not affect the nucleophile’s approach. However, reaction
applying aliphatic en-ynone (R1 = 1-hexyne, Scheme in Table 1)
provided only a trace amount of product (up to 10% of yield). Even
more drastic impact on the reactivity was noted in case of reaction
involving acceptor (Z)-11a, that transformation in the optimized
conditions resulted in recovery of starting material without
changes of the double bond configuration. On the contrary,
methyl-ketone 11w reacted giving a product, with 52% of yield
and diminished enantioselectivity (up to 70%, Table 1, entry 23)
in comparison to aromatic ketones. In addition, reaction required
24h to proceed.
using mechanochemistry. However, application of ball-milling as
the technique to promote hydrogen-bonding catalysis and thus to
improve stereoselectivity of the transformation[17] resulted in
divergent conclusions. Among the tested substrates, reactions
performed in solution led to generally better enantioselectivities
than those obtained using mechanochemistry in all tested
transformations (Scheme 3) except for dienone (8, 89% vs. 92%
ee). The reaction performed in the biphasic (toluene/water)
system led to product 9a with lowered enantioselectivity in
comparison to standard conditions (toluene, 6h, 60°C). Moreover,
this transformation required 48h to reach 68% conversion.
Some attempts of further oxidative transformations of the product
9a were performed[18], but with no success. However, the catalytic
system based on C4 proved that reaction was scalable, resulting
in the formation of the desired product with slightly lower
enantioselectivities.
Extension of the catalyst’s system based on squaramide C4 to the
transformation of different Michael acceptors (Scheme 3)
provided tetrahydrothiophenes with enantioselectivities close to
91% in essentially one diastereomeric form. The studied
acceptors offered two potential paths of addition (Scheme 3,
framework). Due to construction of the unsaturated electron poor
system, the sulfa-Michael addition could potentially occur at the
end of conjugated system of en-ynones 11[14] and dienone Acc-
2[15] or both positions of benzylidene acrylate Acc-1.[16] However,
mercaptoaldehyde 7 reacted at the β-position of the π-systems
with accordance to the reported sulfa-Michael additions to acyclic
system of this type. Thus, formation of tetrahydrothiophenes 8, 9a,
10 and 12 was both stero- and regioselective. Bearing in mind that
the reaction outcome in terms of stereoselectivity was strongly
dependent on the conditions, including catalysts structure, solvent,
and temperature, some transformations were also performed
Conclusion
The carefully designed hydrogen-bond donor with tertiary amine
unit in Cinchona-alkaloid based squaramides provided the
effective catalytic system for the sulfa-Michael addition of the
reactive mercaptoaldehyde. Stereoselective addition of the
mercaptane to form a sulfide, followed by the intramolecular aldol
reaction, allowed for the synthesis of chiral tetrahydrothiophenes
in up to 99% ee and 20:1 d.r. Generation of the three contiguous
stereocenters required only 2 mol% of chiral bifunctional
squaramide. The reaction worked well for a variety en-ynones and
other Michael acceptors until the benzoyl moiety allowed a
suitable formation of the hydrogen bond with catalyst, limiting the
usage of sterically encumbered ketones. The KS-DFT
6
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calculations indicate the multiple functions of the catalyst
elucidating the plausible mechanism of chirality transfer and
explaining the observed stereochemical outcome. In particular,
the basic amine unit in the bifunctional catalyst C4 was found to
be responsible for the generation of a low concentration of
reactive thiol from the easily available 2,5-ditianediol. Thus, the
catalyst was involved in the formation of reactive nucleophile
(mercaptoaldehyde). The latter upon deprotonation, forms
hydrogen bonds via oxygen lone pairs of aldehyde and directs the
thiol to form C-S bond stereoselectively.
the factors hampering the stereoselectivity of the reaction
applying thiosquaramide C14. Based on the elaborated
stereochemical model it was devised that the application of the
latter in a catalytic cycle essentially reduces the interactions of the
catalyst with the ketone and directs the reaction to perform without
the assistance of catalyst.
Acknowledgements
National Science Center, Poland is acknowledged for financial
support (Grant No. 2016/22/E/ST5/00046). The allotment of
computer time at the Wrocław Centre of Networking and
Supercomputing (WCSS) is also acknowledged.
Keywords: Organocatalysis • Asymmetric catalysis •
Tetrahydrothiophenes • Squaramides • Density functional
calculations
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8
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Entry for the Table of Contents
Tetrahydrothiophenes with three contiguous stereocenters and contained three reactive functionalities were formed
with high stereoselectivities in sulfa-Michael/intramolecular aldol reactions cascade
9
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