Catalytic asymmetric conjugate addition of thiols to α,β- unsaturated thioamides: Expeditious access to enantioenriched 1,5-benzothiazepines

Article abstract of DOI:10.1002/anie.201204365

Softly does it: The title reaction proceeded under proton transfer conditions with a catalyst prepared from commercially available reagents to afford the desired product in high enantioselectivity. The reaction was compatible with a free amino group, thus allowing for expeditious access to enantiomerically enriched 1,5-benzothiazepines, which are important chemical entities in medicinal chemistry.

Full text of DOI:10.1002/anie.201204365

Angewandte
Chemie
DOI: 10.1002/anie.201204365
Synthetic Methods
Catalytic Asymmetric Conjugate Addition of Thiols to a,b-
Unsaturated Thioamides: Expeditious Access to Enantioenriched 1,5-
Benzothiazepines**
Takanori Ogawa, Naoya Kumagai,* and Masakatsu Shibasaki*
Conjugate addition offers a general strategy for site-specific
reactions at carbon–carbon double bonds and is frequently
used in organic synthesis. Recent advances in this field have
rendered the transformation viable in both a catalytic and
asymmetric manner. Although a wide variety of carbon and
heteroatom nucleophiles are used in this process,[1–5] the range
of electrophiles used has been mostly limited to highly
electrophilic conjugate addition acceptors, such as enones,
Scheme 1. Catalytic asymmetric conjugate addition of thiols 2 to a,b-
unsaturated thioamides 1 and expeditious access to 1,5-benzothiaze-
pines.
enals, and nitroolefins. a,b-Unsaturated carboxylic acid
derivatives exhibit inherently lower electrophilicity at the b-
carbon atom and are thus less-common substrates in catalytic
asymmetric conjugate addition reactions. We recently found
that soft Lewis acids enhance the electrophilicity of a,b-
unsaturated thioamides 1, thus making them amenable to
conjugate addition with in situ generated carbon nucleo-
philes.[6] To expand the scope of conjugate additions using
a thioamide electrophiles, we envisioned that the use of a soft
Lewis basic heteroatom nucleophile would preferentially
produce an electrophile and nucleophile assembly in an
asymmetric environment at the transition state, thereby
affording the enantioenriched conjugate-addition product.
Herein, we report a catalytic asymmetric conjugate addition
(sulfa-Michael reaction) of thiols 2, as a soft nucleophile, to
a,b-unsaturated thioamides
1
(Scheme 1).[5,7,8] Optically
active sulfides have a wide range of applications in chemistry
and biology as chiral auxiliaries, ligands for asymmetric
catalysis, and biologically active compounds.[9] In particular,
the 1,5-benzothiazepine skeleton is an important structure
that is found in various pharmaceuticals and its efficient
construction is of considerable interest (Scheme 2).[10,11] We
envisioned that a conjugate addition reaction that involves
the use of thioamides, and is compatible with an amino
moiety, could be applied in the efficient synthesis of a 1,5-
benzothiazepine core bearing a stereogenic center.
Scheme 2. Therapeutics, therapeutic candidates, and biological tools
bearing a 1,5-benzothiazepine core.[11]
Our previous investigations revealed that a mesitylcop-
per/chiral bisphosphine catalyst forms an active copper
nucleophile with the liberation of mesitylene.[6b,d] An analo-
gous catalytic cycle can be delineated for the conjugate
addition of thiols 2 (Scheme 3). As the initial entry to the
catalytic cycle, proton exchange with mesitylcopper and 2
would produce copper thiolate 4, which activates the thio-
amide functionality as a soft Lewis acid to enable an
[*] T. Ogawa, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: nkumagai@bikaken.or.jp
À
enantioselective C S bond formation to afford 5. The
mshibasa@bikaken.or.jp
intermediary copper thioamide enolate 5 serves as a soft
Lewis acid/hard Brønsted base cooperative catalyst to
promote proton exchange with thiol 2 to regenerate copper
thiolate 4.[12] Mesitylcopper/(R)-DTBM-segphos (DTBM =
3,5-di-tert-butyl-4-methoxy) was quickly found to be a suitable
precatalyst for the conjugate addition reaction of a,b-
Homepage: http://www.bikaken.or.jp/research/group/shibasaki/
shibasaki-lab/index_e.html
[**] This work was financially supported by KAKENHI (No. 20229001
and 23590038).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204365.
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Communications
effect to the reactivity in the presence of the amine group
(Table 1, entry 2).[13] The amount of 2b and the catalyst
loading could be reduced to 1.2 equivalents and 0.25 mol%,
respectively, without any loss of enantioselectivity (Table 1,
entries 3–5). The reaction could be carried out on a 1 g scale
and an aqueous work-up was avoided by the addition of n-
hexane to the reaction mixture to form a suspension that was
then filtered; the recovered solid product had an enriched
ee value of up to > 99% ee (Table 1, entry 5).[14]
We then focused on the scope of this conjugate addition
protocol (Table 2). Irrespective of the electronic nature of the
ortho substituent of the thiophenols, the corresponding con-
jugate addition products were obtained with high enantiose-
lectivity (Table 2, entries 1–6). An ortho-hydroxy group had
no negative effects on reactivity and enantioselectivity
Table 2: Substrate generality.[a]
Scheme 3. Designed catalytic cycle using mesitylcopper/bisphosphine
precatalyst.
Entry Thioamide (1)
Thiophenol Product
T
t
Yield[b] ee
[8C] [h] [%] [%]
(2)
(3)
unsaturated thioamides 1a and thiophenol (2a); the corre-
sponding product 3aa was obtained in high yield and
enantioselectivity (Table 1, entry 1). However, the use of 2-
aminothiophenol (2b) as a nucleophile presented a challenge,
as both the amine and thiol functionalities are potentially
R1
X
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-ClC6H4
1a
H
2a 3aa
2b 3ab
2c 3ac
2d 3ad
0
0
0
0
0
0
0
0
0
0
0
0
24
6
93
88
92
83
64
47
85
86
90
81
78
71
94
98
93
93
97
95
98
98
98
97
97
95
1a NH2
1a OH
1a Me
1a OMe 2e 3ae
1a Cl
20
72
96
96
24
6
20
24
24
24
À
nucleophilic and the presence of the acidic N H protons
could compromise the proton transfer catalysis. Moreover, we
hypothesized that an amine functionality would decrease the
reactivity of the copper thiolate as a result of the formation of
a stable complex 6 (Scheme 3). Fortunately, 2b served as
suitable sulfur nucleophile and there was no detrimental
2 f 3af
2b 3bb
2b 3cb
2b 3db
2b 3eb
2b 3 fb
2b 3gb
1b NH2
1c NH2
4-MeOC6H4 1d NH2
10[c] 2-furyl
1e NH2
1 f NH2
1g NH2
11
12
2-thienyl
(E)-CH
CHCH3
Me
Me
=
Table 1: Initial screening.[a]
13
14
15
1h NH2
1h NH2
1i NH2
2b 3hb
2b 3hb
2b 3ib
0
1
2
6
85
90
93
88
97
99
À40
iPr
À40
[a] 1: 0.4 mmol; 2: 0.6 mmol. [b] Yield of the isolated product. [c] 1e:
1.0 mmol; 2b: 1.5 mmol.
(Table 2, entry 2). The reactions of a,b-unsaturated thioa-
mides 1b–f, which bear b-aryl or b-heteroaryl substituents,
produced the products with high enantioselectivity and were
accelerated by the presence of an electron-withdrawing
substituent on the aryl ring (Table 2, entries 7–11). The
reaction of diene-conjugated thioamide 1g led to the exclu-
sive formation of the 1,4-conjugate addition product (Table 2,
entry 12). b-Alkyl (Me) substituted thioamide exhibited
much higher reactivity, with the reaction reaching full
conversion after 1 h at 08C, albeit with lower enantioselec-
tivity (Table 2, entry 13). Even at À408C the reaction
proceeded rapidly, and the enantioselectivity was improved
to 97% ee (Table 2, entry 14). These modified reaction
conditions were applied to thioamides having a b-isopropyl
substituent to give the desired product with high enantiose-
Entry
x
y
R
t [h] Product Yield[b] [%] ee [%]
1
2
3
3
3
3
1
2
2
H
2a 24
3aa
3ab
3ab
3ab
3ab
quant.
quant.
quant.
quant.
82[d]
98
98
NH2 2b
6
1.2 NH2 2b 24
1.2 NH2 2b 48
98
98
4
5[c]
0.25 1.2 NH2 2b 40
>99
[a] Reactions were run at a 0.5m concentration. [b] Determined by
1H NMR analysis. [c] 1.0 g of 1a was used. [d] Yield of the isolated
product recovered by filtration after adding n-hexane to the reaction
mixture.
2
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lectivity (Table 2, entry 15). The catalytic system was also
applicable to a functionalized alkylthiol; the reaction of a,b-
unsaturated thioamide 1i and 2-mercaptoethanol (2g) pro-
ceeded smoothly at À408C without protection of the hydroxy
group, to afford the corresponding product 3ig with high
enantioselectivity [Eq. (1)].
Scheme 5. Transformation of the product into 1,5-benzothiazepin-4-
ones and the enantioselective synthesis of thiazesim. Tf=trifluorome-
thanesulfonyl, Ts=p-toluenesulfonyl.
The present conjugate addition reaction is highly chemo-
selective. A competition reaction of a,b-unsaturated carbox-
ylic acid derivatives, thioamide 1a, amide 7, ester 8, and
thioester 9, with 2-aminothiophenol resulted in the exclusive
formation of conjugate addition product 3ab with recovery of
unreacted 7–9 (Scheme 4). This result is presumably due to
the specific activation of the thioamide functionality in soft
Lewis acidic copper thiolate 4 to form the favorable six-
membered transition state (Scheme 3).
amino group and a suitable thioamide allowed for expeditious
access to the 1,5-benzothiazepine skeleton.
Received: June 5, 2012
Published online: && &&, &&&&
Keywords: 1,5-benzothiazepine · asymmetric catalysis ·
.
chemoselectivity · conjugate addition · synthetic methods
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4
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Chemie
Communications
Synthetic Methods
T. Ogawa, N. Kumagai,*
M. Shibasaki*
&&&& — &&&&
Catalytic Asymmetric Conjugate Addition
of Thiols to a,b-Unsaturated Thioamides:
Expeditious Access to Enantioenriched
1,5-Benzothiazepines
Softly does it: The title reaction pro-
ceeded under proton transfer conditions
with a catalyst prepared from commer-
cially available reagents to afford the
desired product in high enantioselectivity.
The reaction was compatible with a free
amino group, thus allowing for expedi-
tious access to enantiomerically enriched
1,5-benzothiazepines, which are impor-
tant chemical entities in medicinal
chemistry.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!