Catalytic Enantioselective Synthesis of Protecting-Group-Free 1,5-Benzothiazepines

Article abstract of DOI:10.1002/chem.201700837

A one-pot enantioselective route to N-unprotected 2,3-dihydro-1,5-benzothiazepinones, by an organocatalyzed sulfa-Michael reaction of readily available α,β-unsaturated N-acyl pyrazoles with 2-aminothiophenols followed by silica-gel-catalyzed lactamization

Full text of DOI:10.1002/chem.201700837

DOI: 10.1002/chem.201700837
Communication
&
Asymmetric Catalysis
Catalytic Enantioselective Synthesis of Protecting-Group-Free 1,5-
Benzothiazepines
Sara Meninno, Chiara Volpe, and Alessandra Lattanzi*[a]
Abstract: A one-pot enantioselective route to N-un-
protected 2,3-dihydro-1,5-benzothiazepinones, by an
organocatalyzed sulfa-Michael reaction of readily available
a,b-unsaturated N-acyl pyrazoles with 2-aminothiophenols
followed by silica-gel-catalyzed lactamization, has been
developed. The method proceeds under mild conditions
at room temperature and it requires only 1 mol% catalyst
loading, to give 2-aryl/alkyl-substituted 1,5-benzothiaze-
pines in generally good to excellent yields and enantiose-
lectivities. The process, used for a short synthesis of anti-
depressant drug (R)-(À)-thiazesim, represents the first
method to access enantioenriched unprotected 1,5-benzo-
tiazepines, which are useful for rapid derivatization in
drug discovery.
Optically active 1,5-benzothiazepines are amongst the most
famous drugs in medicinal chemistry[1] and they have been
known and used since the 1960s. Depicted in Scheme 1 are
representative examples including the antidepressant agent
(R)-(À)-thiazesim marketed as its hydrochloride salt Altinil,[2]
Scheme 1. Asymmetric catalytic routes to 1,5-benzothiazepines.
diltiazem employed for the treatment of antihypertension and
angina,[3] and the ACE inhibitor CV-5975 .[4] Unsurprisingly, a va-
compounds, including pharmaceuticals.[10] Given the paucity of
riety of protocols have been developed for the racemic synthe-
sis of these compounds,[5] which are also endowed with anti-
methods to access optically active 2,3-dihydro-1,5-benzothiaze-
microbial, antifungal, anti-HIV, anticancer, and antiulcer activi-
ties.[1] Concerning their asymmetric synthesis, a limited number
of procedures relies on racemic resolution[2a,6] and occasional
examples have been reported in methodological studies.[7] To
date, only two catalytic enantioselective approaches to 2,3-di-
hydro-1,5-benzotiazepinones have been developed. In 2015,
Matsubara, Asano, and co-workers illustrated a formal [4+3]
pinones and our interest in developing stereoselective meth-
odologies to prepare heterocyclic compounds,[11] we embarked
on a study aimed at the development of a simple asymmetric
synthesis of this versatile and relevant class of pharmaco-
phores.
The elegant methods illustrated in Scheme 1, afforded N-
substituted-1,5-benzothiazepinones, the deprotection of which
was necessary to prepare analogs and drugs.[1] To circumvent
this additional step, the development of a direct asymmetric
methodology to access the core scaffold would be highly
desirable and advantageous from a sustainability point of view.
To this end, the combination of a sulfa-Michael reaction/lac-
tamization sequence, based on readily available reagents, was
considered the most expeditious route to achieve this goal
(Scheme 1c).[12] We envisioned bifunctional hydrogen-bonding
aminocatalysts could promote the sulfa-Michael reaction of
heteroatom-linked a,b-unsaturated ester equivalents. Indeed,
these compounds are good Michael acceptors, amenable to
replacement of the heterocyclic moiety by different nucleo-
philes.[13] To establish this approach, two challenging issues
had to be addressed: i) the identification of a suitable a,b-un-
cycloaddition reaction using
a chiral isothiourea catalyst
(Scheme 1a).[8] In 2016, Glorius and colleagues devised a differ-
ent approach based on the enantioselective ruthenium-N-
heterocyclic-carbene-catalyzed hydrogenation of heterocyclic
vinyl thioethers (Scheme 1b).[9]
One-pot multistep asymmetric procedures are highly attrac-
tive tools for the asymmetric synthesis of heterocyclic
[a] Dr. S. Meninno, C. Volpe, Prof. Dr. A. Lattanzi
Dipartimento di Chimica e Biologia “A. Zambelli”
Universitꢀ di Salerno
Via Giovanni Paolo II, 84084 Fisciano (Italy)
E-mail: lattanzi@unisa.it
Supporting information and the ORCID number(s) for the author(s) of this
article can be found under http://dx.doi.org/10.1002/chem.201700837.
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saturated ester equivalent able to undergo a regioselective
sulfa-Michael reaction by dinucleophilic 2-aminothiophenols;
and ii) setting up controlled conditions to foster lactamization,
while avoiding potential racemization of the adduct.
(entry 5). However, this finding indicated controlled timing was
necessary for the silica gel addition in the asymmetric version.
Cinchona-alkaloid-derived thiourea II and urea III, tested under
conditions reported in entry 3 (entries 6 and 7), proved to have
comparable efficiency, whereas squaramides gave better
results (entries 8–12). Pleasingly, hydroquinine-derived squar-
amide VII furnished 3a in excellent yield and 80% ee after
a short overall reaction time (entry 11). Upon solvent and reac-
tion parameter screening (see the Supporting Information for
optimization tables), Et2O was found to be the best medium in
which to conduct the first step, using 1 mol% of catalyst VII at
room temperature. Considering that the lactamization pro-
ceeded faster in toluene, after evaporation of Et2O at the end
of the first step, the crude mixture was charged with toluene
and silica gel to complete the process. To our delight, product
3a was isolated in 97% yield and 93% ee (Scheme 2).
A preliminary investigation was performed using 5 mol% of
Takemoto’s catalyst I in toluene at room temperature with
different a,b-unsaturated surrogate esters and 2-amino thio-
phenol (see the Supporting Information for optimization
table). We were pleased to find that trans-a,b-unsaturated N-
acylpyrazole 1a regioselectively afforded product 3a in good
yield and an encouraging 52% ee (enantiomeric excess), after
a prolonged reaction time (Table 1, entry 1). The lactamization
step was then studied under different conditions using catalyst
I. After the disappearance of 1a, warming the reaction mixture
to 408C helped to speed up the conversion and increase the
enantioselectivity (entry 2). Interestingly, the addition of silica
gel at room temperature rapidly yielded 3a with up to 76% ee
(entry 3).[14] Background catalysis was next investigated by per-
forming the reaction in absence of catalyst I (entries 4 and 5).
A modest formation of 3a was detected after prolonged reac-
tion time (entry 4), justifying a lower ee value observed in
entry 1, presumably affected by contribution of the racemic
pathway. Interestingly, the process was silica-gel-catalyzed,
providing a convenient way to obtain racemic products 3
Remarkably, working with 0.5 mol% of the catalyst guaran-
teed product formation in high yield and 90% ee, at the
Table 1. Catalyst screening.[a]
Entry
Catalyst
T [8C]
/Additive
t1(t2)
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
I
I
I
–
–
II
III
IV
V
VI
VII
VIII
rt
408C
92
85
81
82
30
85
85
81
80
75
95
97
71
52
66
76
–
–
À61
À61
À81
À76
À64
À80
66
14(11)
1.5(4)
72
rt/silica gel[d]
rt
rt/silica gel[d]
rt/silica gel[d]
rt/silica gel[d]
rt/silica gel[d]
rt/silica gel[d]
rt/silica gel[d]
rt/silica gel[d]
rt/silica gel[d]
5
1.5(4)
1.5(4)
2(4)
2.5(4)
14(4)
0.5(4)
4.5(4)
10
11
12
Scheme 2. Substrates scope of the one-pot reaction to 1,5-benzothiazepines.
Reaction conditions: 1 (0.3 mmol), 2 (0.39 mmol), and VII (0.003 mmol) in
Et2O were stirred at rt under nitrogen for the indicated times. After
removing Et2O (6 mL), toluene (3 mL) and silica gel (335 mg) were added
and stirring was maintained for 2–12 h. Yields of isolated products shown;
ee determined by HPLC on a chiral stationary phase. Absolute configuration
of (R)-3a was determined by comparison of the optical rotation with the
[a] Unless otherwise noted reactions were conducted with 1a (0.1 mmol),
2a (0.15 mmol), catalyst (0.005 mmol) in toluene (0.5 mL) under nitrogen.
[b] Determined by 1H NMR spectroscopy using 1,3,5-(MeO)3C6H3 as an inter-
nal standard. [c] Determined by HPLC on a chiral stationary phase. Negative
sign indicates the enantiomeric excess (ee) for the opposite enantiomer.
[d] Silica gel (111 mg) was added.
literature.[7a]
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expense of a longer reaction time (Scheme 2). With the
optimized conditions in hand, we explored the scope of the
process by using 1 mol% of catalyst VII (Scheme 2). Either elec-
tron-withdrawing and donating substituents at the para and
meta-positions in Michael acceptors 1 were tolerated, with
compounds 3b–g,i being isolated in high yield and enantio-
selectivity (87–96% ee). As expected, b-aryl a,b-unsaturated N-
acyl pyrazoles bearing electron-withdrawing groups, under-
went faster conversion (3d–g,i). The ortho-chloro-substituted
product 3h was obtained in 96% yield and with somewhat
lower ee value. Alkenes 1j–l, bearing naphthyl and hetero-
aromatic substituents, were smoothly converted into the prod-
ucts in fairly good to high ee values (83–93%ee). Pleasingly,
the protocol was successfully applied for the synthesis of linear
or branched 2-alkyl substituted benzotiazepines 3m–o,
obtained in good to high yield and high enantioselectivity
(92–94%ee). Other 2-aminothiophenols served as suitable
reagents to produce 2-aryl/alkyl derivatives 3p–s in good yield
and high level of enantiocontrol (89–95%ee).
a negligible but undesirable process because the catalyst
preferentially selected the (R)-adduct, eroding the enantio-
selectivity.
The robustness of the process was probed by carrying out
the model reaction at 3 mmol scale, maintaining high yield
and enantioselectivity (Scheme 4). The synthetic utility of the
Scheme 4. Scale up of model reaction and concise asymmetric synthesis of
antidepressant drug (R)-(À)-thiazesim.
To have a better understanding of the reversibility of the
first step,[11b,12d] and given the instability displayed by the
Michael adduct, 1a was treated with a substoichiometric
amount of 2a under the optimized conditions (Scheme 3).
methodology was demonstrated in a concise preparation of
the antidepressant drug (R)-(À)-thiazesim. The model process
was followed by filtration and the crude mixture was directly
treated with the alkylating reagent to give the product in 68%
overall yield and 93% ee. The absolute configuration of thiaze-
sim was assessed by comparison of optical rotation with the
literature.[7a,9]
In conclusion, we developed the first methodology to
prepare a variety of unprotected 1,5-benzothiazepinones in
good to excellent yields and enantioselectivities. Notable
features of the methodology include: i) low catalyst loading, ii)
general applicability, iii) mild reaction conditions, and iv) ready
availability of the reagents and the organocatalyst. The proto-
col expedites the entry to optically active 1,5-benzothiazepines
useful for bioassay testing. Further applications on the synthe-
sis of related heterocycles will be reported in due course.
Acknowledgements
Scheme 3. Mechanistic investigations on the reversibility of the sulfa-Michael
reaction.
We thank MIUR for financial support and Centro di Tecnologie
Integrate per la Salute (Project PONa3_00138), Universitꢁ di
Salerno. We also thank Dr. Rita Scarpelli (IIT, Genoa) and Dr.
Guido Furlotti (Angelini S.p.A., Rome) for helpful discussions.
After the disappearance of 2a, highly reactive alkene 1d was
added and left stirring for 96 hours, followed by lactamization.
1H NMR analysis of the crude mixture showed the presence of
3a/3d in a 82:18 ratio. When the same experiment was carried
out for 24 hours, only compound 3a was detected. Thus, the
catalyst promoted the retro-sulfa Michael reaction at a low
rate; however, according to reaction times in Scheme 2, these
observations did not affect the results. Additionally, we studied
the sulfa-Michael reaction of 1a using thiophenol 4. The (R)-
adduct 5 was regioselectively obtained in 76% yield and 88%
ee.[15] To check the reversibility of the sulfa-Michael reaction,
racemic 5 was stirred with catalyst VII for 90 hours. A small
amount of 1a was detected, whereas (S)-5 was recovered with
8% ee. The retro-sulfa Michael reaction was confirmed to be
Keywords: 1,5-benzothiazepine
·
asymmetric synthesis
·
enoate equivalent · michael addition · organocatalysis
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[15] Absolute configuration of 5 was determined by chemical derivatization
(see the Supporting Information for details).
Manuscript received: February 21, 2017
Accepted Article published: February 24, 2017
Final Article published: && &&, 0000
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COMMUNICATION
&
Asymmetric Catalysis
S. Meninno, C. Volpe, A. Lattanzi*
&& – &&
Catalytic Enantioselective Synthesis of
Protecting-Group-Free 1,5-
Benzothiazepines
Medicine made easy: The first method
to access optically active N-unprotected
1,5-benzothiazepinones has been devel-
oped under operational mild conditions
by using only 1 mol% loading of an
organocatalyst and readily available
reagents. These important pharmaco-
phores, isolated in good to excellent
yields and enantioselectivities (up to
96% ee), are useful for rapid derivatiza-
tion, as demonstrated in the synthesis
of antidepressant drug (R)-(À)-thiazesim.
Chem. Eur. J. 2017, 23, 1 – 5
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