Formal [3 + 4] Annulation of α,β-Unsaturated Acyl Azoliums: Access to Enantioenriched N-H-Free 1,5-Benzothiazepines

Article abstract of DOI:10.1021/acs.orglett.7b01457

An unprecedented formal [3 + 4] annulation of α,β-unsaturated acyl azoliums with 2-aminobenzenethiols has been utilized to synthesize enantioenriched N-H-free 1,5-benzothiazepines, which are recognized as privileged structures in numerous biologically active scaffolds. This protocol offers a rapid and direct pathway to access the target compounds with high enantioselectivities and has been applied in the concise synthesis of chiral drug (R)-thiazesim.

Full text of DOI:10.1021/acs.orglett.7b01457

Letter
pubs.acs.org/OrgLett
Formal [3 + 4] Annulation of α,β-Unsaturated Acyl Azoliums:
Access to Enantioenriched N−H‑Free 1,5-Benzothiazepines
Chao Fang, Tao Lu,* Jindong Zhu, Kewen Sun, and Ding Du*
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 210009, P.
R. China
S
* Supporting Information
ABSTRACT: An unprecedented formal [3 + 4] annulation of α,β-
unsaturated acyl azoliums with 2-aminobenzenethiols has been
utilized to synthesize enantioenriched N−H-free 1,5-benzothiaze-
pines, which are recognized as privileged structures in numerous
biologically active scaffolds. This protocol offers a rapid and direct
pathway to access the target compounds with high enantioselectiv-
ities and has been applied in the concise synthesis of chiral drug (R)-
thiazesim.
ver the past decade, N-heterocyclic carbenes (NHCs)
have emerged as powerful organocatalysts for a large
Scheme 2. Asymmetric synthesis of N-H-free 1,5-
benzothiazepines
O
number of chemical transformations that cannot be achieved by
traditional strategies.1 Particularly, the application of α,β-
unsaturated acyl azoliums as versatile 1,3-bielectrophilic
synthons in annulation reactions has attracted much attention
from organic chemists. The formal [3 + 3]2 and [3 + 2]3
annulations of α,β-unsaturated acyl azoliums have been
intensively investigated respectively for the synthesis of diverse
six-member or five-member heterocyclic compounds (Scheme
1a and 1b). However, the formal [3 + 4] annulations of α,β-
Scheme 1. Formal [3+m] annulations of α,β-unsaturated
acyl azoliums
discovery. Although a number of synthetic methods to
construct this framework have been documented,4b,5 catalytic
asymmetric synthesis is still challenging. Recently, Matsubara6
and Glorius7 developed two different efficient approaches to
enantioenriched N-substituted 1,5-benzothiazepines via an
organocatalytic [4 + 3] cycloaddition and transition-metal-
catalytic hydrogenation, respectively. These two elegant
methods afforded the target molecules which inevitably
underwent N-deprotection processes for further N-function-
unsaturated acyl azoliums for the synthesis of seven-member
ring systems are challenging and have not yet been explored
(Scheme 1c).
The 1,5-benzothiazepine heterocyclic motif is a fascinating
versatile pharmacophore frequently found in numerous bio-
logically active scaffolds such as thiazesim, diltiazem, and
clentiazem, which have been widely investigated in the area of
pharmaceutical drugs (Scheme 2).4 Thus, the development of
efficient and enantioselective synthetic approaches to diverse
1,5-benzothiazepine derivatives is of great importance for drug
Received: May 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01457
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Organic Letters
Letter
a
ality. Therefore, it is worthwhile to explore simple and efficient
methods to access optically active N−H-free 1,5-benzothiaze-
pines to circumvent the additional deprotection step for the
purposes of atom-economy and sustainability. To date, a few
asymmetric syntheses of N−H-free 1,5-benzothiazepines have
been achieved typically through two steps involving sequential
organocatalytic 1,4-addition of 2-aminobenzenethiols to diverse
Michael acceptors and cyclization (Scheme 2a).8 However, the
direct one-step asymmetric synthesis of N−H-free 1,5-
benzothiazepines remains very limited. There is only one
type of reaction very recently reported by Feng9 who applied a
chiral N,N′-dioxide-YbIII complex in the direct synthesis of the
optically active N−H-free 1,5-benzothiazepine derivatives
starting from α,β-unsaturated pyrazoleamides and 2-amino-
benzenethiols (Scheme 2b). In continuation of our studies on
the exploration of NHC-catalyzed formal [3 + m] annula-
tions,2k−m,3c,10 we envisioned a direct pathway to access
optically active N−H-free 1,5-benzothiazepines 3 via the formal
[3 + 4] annulation of α,β-unsaturated acyl azoliums with 2-
aminobenzenethiols 2 (Scheme 2b). It is noteworthy that
formal [3 + 4] annulations of homoenolates11 and dienolates12
with NHC catalysis have been successfully applied for the
synthesis of seven-membered cyclic compounds. Herein, we
report the first application of α,β-unsaturated acyl azoliums
derived from 2-bromoenals 1 in the formal [3 + 4] annulations.
Since α-bromoenals13 were frequently used as α,β-unsatu-
rated acyl azolium precursors, we commenced our study with
the reaction of α-bromoenal 1a with 2-aminobenzenethiol 2a in
the presence of 10 mol % of a carbene precursor and 2.0 equiv
of a base (Table 1). Initially, the efficiency of several commonly
used chiral NHC precursors A−E was evaluated in PhMe
employing NaOAc as the base (entries 1−5). To our delight,
these catalysts except D proved to be effective for this
transformation, while catalyst E was established as the optimal
one which afforded the desired product 3a with a moderate
yield and high enantioselectivity (entry 5). Unfortunately, we
did not obtain positive results when we tried to improve the
reaction yield by using different solvents and bases (entries 6−
12). However, increasing the catalyst loading to 20 mol % could
enhance the yield to 63% with a maintained enantioselectivity
(entry 13), which was finally established as the optimal
condition for the scope exploration. The absolute configuration
of 3a was assigned as (R) by comparing the optical rotation
with the literature value.8c,9
With the optimized conditions in hand, we focused our
attention to exploring the reaction scope (Table 2). Initially, a
series of α-bromoenals 1b−k with diverse substituents on the
phenyl ring were examined (entries 2−11). It seems that the
electronic nature and steric hindrance of the substituents had
little influence on the reaction yields and enantioselectivity
since the desired products 3b−k were all obtained in moderate
yields and high enantioselectivities. Additionally, 1-naphthyl-
and 2-heteroaromatic-substituted α-bromoenals 1l−n were also
suitable for this protocol, affording the desired products 3l−n
in 64−73% yields with 84−97% ee (entries 12−14). Gratify-
ingly, this protocol was also applicable for the synthesis of
styryl- and alkyl-substituted benzothiazepines 3o and 3p
although with somewhat decreased yields and enantioselectiv-
ities (entries 15 and 16). Then, the generality of this protocol
was further evaluated by using several substituted 2-amino-
benzenethiols 2b−d as the 1,4-bisnucleophiles (entries 17−19).
As expected, the reactions of these substrates worked equally
Table 1. Optimization of the Reaction Conditions
b
c
entry
cat.
solvent
PhMe
base
yield (%)
ee (%)
1
A
B
C
D
E
E
E
E
E
E
E
E
E
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
DIPEA
tBuOK
CsOAc
LiOAc
40
78
90
79
−
94
92
−
−
−
−
2
PhMe
PhMe
PhMe
PhMe
mesitylene
DCM
THF
22
3
18
4
trace
43
5
6
30
7
trace
trace
trace
trace
37
8
9
PhMe
PhMe
PhMe
PhMe
PhMe
10
11
12
93
93
94
31
d
13
NaOAc
63
a
Unless otherwise noted, all reactions were performed on a 0.1 mmol
scale with 1.0 equiv of 1a, 1.5 equiv of 2a, 10 mol % of a carbene
precursor, 2.0 equiv of a base, and 100 mg of 4 Å MS in an anhydrous
solvent (2 mL) at rt for 36 h under N2. Isolated yields based on 1a.
Ee values were determined by HPLC analysis. 20 mol % E was used.
Mes = 2,4,6-(CH3)3C6H2; DIPEA = N,N-diisopropylethylamine.
b
c
d
smoothly to give the desired products 3q−s in moderate yields
and high enantioselectivities.
We also tested the reactivity of (E)-1a that was found to be
inferior to (Z)-1a in terms of both reaction yield and
enantioselectivity (Scheme 3a). Therefore, it may be concluded
that the stereochemistry of 2-bromoenals 1 has great impact on
the reaction. As α,β-unsaturated acyl azoliums can be generated
from other precursors other than α-bromoenals, we applied
three activated esters 4a−c and ynal 5 as the precursors to test
their reactivity and feasibility for this formal [3 + 4]
annulations. It was disappointing that activated esters 4a−c
afforded the desired product 3a in 32−41% yields with poor
enantioselectivities (Scheme 3b).14 Ynal 5 was also unsuitable
for this transformation due to the formation of an imine
byproduct via the condensation of aldehyde 5 with 2a (Scheme
3c).
In order to further explore the synthetic utility of this
methodology, a scale-up synthesis of product 3a and a concise
one-step synthesis of the antidepressant drug (R)-thiazesim
from 3a were carried out as shown in Scheme 4. On one hand,
the reaction yield and enantioselectivity of the scale-up
synthesis were slightly decreased (Scheme 4a). It is noteworthy
that the scale-up reaction should be carried out under a lower
temperature to decrease the amount of imine byproduct
formed between aldehyde 1a and amine 2a. On the other hand,
natural product (R)-thiazesim was successfully synthesized
from 3a in 91% yield with 93% ee (Scheme 4b).
B
DOI: 10.1021/acs.orglett.7b01457
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Organic Letters
Letter
a
Table 2. Reaction Scope
Scheme 4. A Scale-up Synthesis of 3a and a Concise
Synthesis of (R)-Thiazesim from 3a
b
c
entry
R1, 1
C6H5, 1a
R2, 2
H, 2a
3
yield (%)
ee (%)
1
3a
3b
3c
3d
3e
3f
63
63
66
52
62
50
65
54
50
52
53
65
64
73
61
46
59
59
70
94
91
91
94
93
90
98
97
94
92
93
94
97
84
86
80
88
93
91
2
2-FC6H4, 1b
2-OMeC6H4, 1c
3-FC6H4, 1d
3-MeC6H4, 1e
3-OMeC6H4, 1f
4-ClC6H4, 1g
4-BrC6H4, 1h
4-CF3C6H4, 1i
4-MeC6H4, 1j
4-OMeC6H4, 1k
1-naphthyl, 1l
2-thienyl, 1m
2-furyl, 1n
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
H, 2a
4-Cl, 2b
5-Cl, 2c
5-Me, 2d
3
4
5
6
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
18
19
3j
ASSOCIATED CONTENT
* Supporting Information
3k
3l
■
S
3m
3n
3o
3p
3q
3r
3s
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01457.
styryl, 1o
n-propyl, 1p
C6H5, 1a
Experimental procedures and spectral data for all
compounds (PDF)
C6H5, 1a
C6H5, 1a
AUTHOR INFORMATION
Corresponding Authors
a
■
Unless otherwise noted, all reactions were performed on a 0.1 mmol
scale with 1.0 equiv of 1, 1.5 equiv of 2, 20 mol % of E, 2.0 equiv of
NaOAc, and 100 mg of 4 Å MS in anhydrous PhMe (2 mL) at rt for
36 h under N2. Isolated yields based on 1. Ee values were
determined by HPLC analysis.
*E-mail: lut163@163.com.
*E-mail: ddmn9999@cpu.edu.cn.
ORCID
b
c
Ding Du: 0000-0002-4615-5433
Notes
Scheme 3. Application of Other α,β-Unsaturated Acyl
Azolium Precursors for the Synthesis of 3a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is funded by the National Natural Science
Foundation of China (No. 21572270), the Qing Lan Project
of Jiangsu Province, and the Priority Academic Program
Development of Jiangsu Higher Education Institutions.
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In summary, we have demonstrated a direct and
enantioselective synthesis of N−H-free 1,5-benzothiazepine
derivatives via an NHC-mediated unprecedented formal [3 + 4]
annulation of α,β-unsaturated acyl azoliums with substituted 2-
aminobenzenethiols. This protocol offers an alternative and
rapid access to a broad range of N−H-free 1,5-benzothiazepines
with high enantioselectivities. Moreover, this protocol was
successfully applied in the concise synthesis of chiral drug (R)-
thiazesim. Further research and application of α,β-unsaturated
acyl azoliums in the construction of diverse seven-membered
heterocyclic systems are currently underway.
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DOI: 10.1021/acs.orglett.7b01457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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D
DOI: 10.1021/acs.orglett.7b01457
Org. Lett. XXXX, XXX, XXX−XXX