Asymmetric Hydrogenation of Vinylthioethers: Access to Optically Active 1,5-Benzothiazepine Derivatives

Article abstract of DOI:10.1002/anie.201512032

A novel asymmetric hydrogenation of vinylthioethers was developed using a ruthenium(II) NHC complex. This method provides an efficient approach to optically active 1,5-benzothiazepines featuring stereocenters with C-S bonds. Excellent enantioselectivities

Full text of DOI:10.1002/anie.201512032

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201512032
German Edition: DOI: 10.1002/ange.201512032
Asymmetric Hydrogenation
Asymmetric Hydrogenation of Vinylthioethers: Access to Optically
Active 1,5-Benzothiazepine Derivatives
Wei Li, Christoph Schlepphorst, Constantin Daniliuc, and Frank Glorius*
Dedicated to Professor Paul Knochel on the occasion of his 60th birthday
Abstract: A novel asymmetric hydrogenation of vinylthioeth-
ers was developed using a ruthenium(II) NHC complex. This
method provides an efficient approach to optically active 1,5-
important fraction (ca. 20%) of marketed pharmaceuticals,
with many of the top-selling drugs in 2012 containing at least
[4]
À
one C S bond. In 2007, Feringa and co-workers reported
À
benzothiazepines featuring stereocenters with C S bonds.
the first enantioselective hydrogenation of alkyl-
(vinyl)thioethers although ee values of only up to 60% were
obtained.[5] In 2008, the Pfaltz group reported the hydro-
genation of 2-phenyl-4H-thiochromene giving 73% conver-
sion and 91% ee.[6] Our group previously realized the hydro-
genation of thiophenes and benzothiophenes to the corre-
sponding reduced heterocycles with 32–99% yields and up to
98% ee.[7] One challenge observed during the reduction of
these sulfur-containing molecules is the catalyst deactivation
by coordination of the sulfur atom to the transition metal.[2,5]
Considering the widespread application of asymmetric hydro-
genation and the significance of organosulfur compounds, the
development of efficient and divergent asymmetric hydro-
genation processes applicable to vinylthioethers and other
sulfur-substituted alkenes to access chiral organosulfur com-
pounds is highly valuable.
Excellent enantioselectivities (up to 95% ee) and high yields
(up to 99%) were obtained for a variety of substrates bearing
a range of useful functional groups. Moreover, this method-
ology could be directly applied to the synthesis of the
antidepressant drug R-(À)-thiazesim.
A
symmetric hydrogenation of functionalized olefins is
a reliable and powerful method to access useful chiral
molecules and has been widely applied in both academia
and industry.[1] Compounds containing vinyl groups directly
connected to C, N, O, P, or B substituents such as a-
dehydroamino acids, acrylates, enamides, enamines, enols,
vinylphosphonates, or vinylboronates have been broadly used
À
as substrates in the construction of stereocenters bearing C X
bonds (Scheme 1a).[2] In stark contrast, much less success has
been achieved in the asymmetric hydrogenation of vinyl-
thioethers or other sulfur-functionalized alkenes, even though
this method would provide a straightforward approach to
Optically active 1,5-benzothiazepine, which contains
a seven-membered ring bearing a sulfur-substituted stereo-
center, is a versatile pharmacophore in the field of pharma-
ceutical research.[8] Thiazesim and diltiazem are representa-
tive drugs featuring this motif (Scheme 2a).[9] Although much
effort has been devoted to access this building block, methods
using asymmetric catalysis are quite limited. Typically multi-
step strategies are employed with an initial addition of a sulfur
nucleophile to a Michael acceptor or an epoxide constructing
the stereogenic center being followed by a cyclization to
afford the ring structure.[10] Recently, Matsubara and co-
À
access stereocenters bearing a C S bond which commonly
exists in natural products and synthetic molecules (Scheme
1b).[3] Particularly, organosulfur compounds make up an
Scheme 1. Construction of chiral X-substituted carbons by asymmetric
hydrogenation.
[*] Dr. W. Li, C. Schlepphorst, C. Daniliuc, Prof. Dr. F. Glorius
Westfälische Wilhelms-Universität Münster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
index.html
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201512032.
Scheme 2. a) Selected examples of drug molecules featuring the 2,3-
dihydro-1,5-benzothiazepinone core. b) Ru(NHC)2-catalyzed asymmet-
ric hydrogenation of 1,5-benzothiazepinones.
3300
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 3300 –3303

Angewandte
Communications
Chemie
workers reported a facile formal cycloaddition approach to
find that when the N-methyl-protected substrate 1c was used,
produce chiral 2,3-dihydro-1,5-benzothiazepinones catalyzed
by a benzotetramisole catalyst.[11] Undoubtedly, the explora-
tion of new catalytic strategies to construct diverse optically
active 1,5-benzothiazepine derivatives would be highly desir-
able for drug discovery. Based on our previous studies in the
field of asymmetric hydrogenation of heterocycles,[7,12] we
envisioned that an asymmetric hydrogenation of the vinyl-
thioether motif in 1,5-benzothiazepinones may provide
a direct method to access these important compounds through
the corresponding 2,3-dihydro-1,5-benzothiazepinone 2c
could be isolated in 70% yield with 92% ee (entry 3). The
use of the unsaturated NHC derivative (R,R)-INpEt·HCl
resulted in a similar yield but a lower enantioinduction
(entry 4). Reaction at a higher temperature (358C) led to both
lower yield and lower enantioselectivity, possibly due to the
enhanced poisoning propensity of sulfur-containing com-
pounds (entry 5). A reaction conducted at the lower temper-
ature of 108C afforded the product with a slightly better ee
but with lower conversion (entry 6). Other solvents such as
toluene and t-amyl alcohol led to lower enantioselectivities,
while ethereal solvents such as THF, Et2O, and DME led to
decomposition of the starting material. Better conversion was
observed when the reaction mixture was diluted (entry 7).
Finally, prolonging the reaction time could increase the yield
of the product to 99% while maintaining an ee value of 93%
(entry 8).
À
the construction of a stereocenter possessing a C S bond
(Scheme 2b). In addition to employing hitherto seldom
sulfur-containing compounds, this process would also repre-
sent a rare example of asymmetric hydrogenation of seven-
membered heterocycles.[2]
After a preliminary investigation, we found a straightfor-
ward route to rapidly access unsaturated 1,5-benzothiazepi-
none 1a from commercially available 2-aminothiophenol and
phenylpropiolic acid (see the Supporting Information for
details). An initial test reaction was then conducted with this
unprotected substrate (1a) under 100 bar H2 in n-hexane at
room temperature using our previously developed ruthenium
N-heterocyclic carbene (NHC) catalyst prepared in situ from
[Ru(cod)(2-methylallyl)2] (cod = cycloocta-1,5-diene), (R,R)-
SINpEt·HBF4, and KOtBu.[13] Unfortunately, no reduced
product was observed, presumably due to catalyst deactiva-
tion arising from the free amide group in 1a (Table 1, entry 1).
The N-Boc-protected substrate 1b (Boc = tert-butoxycar-
bonyl) was then submitted to the same hydrogenation
conditions but was still unreactive, possibly due to detrimen-
tal electronic bias (entry 2). We were, however, pleased to
With the optimized conditions in hand (Table 1, entry 8),
we examined the substrate scope of the reaction as shown in
Schemes 3 and 4. Hydrogenation of the N-4-methoxybenzyl-
protected substrate 1d gave the corresponding product in
70% yield with 93% ee (Scheme 3). The influence of
electronic nature of the substituents on the aminothiophenol
Table 1: Optimization of the reaction conditions.[a]
Entry
NHC·HX
R
T
[8C]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
(R,R)-SINpEt·HBF4
(R,R)-SINpEt·HBF4
(R,R)-SINpEt·HBF4
(R,R)-INpEt·HCl
(R,R)-SINpEt·HBF4
(R,R)-SINpEt·HBF4
(R,R)-SINpEt·HBF4
(R,R)-SINpEt·HBF4
H (1a)
25
25
25
25
35
10
25
25
0
0
–
–
Boc (1b)
Me (1c)
Me (1c)
Me (1c)
Me (1c)
Me (1c)
Me (1c)
70
73
60
45
93
99
92
85
85
95
93
93
7[d]
8[d,e]
Scheme 3. Substrate scope of unsaturated 1,5-benzothiazepinones 1c–
i. General conditions: [Ru(cod)(2-methylallyl)2] (0.02 mmol), KOtBu
(0.05 mmol), and (R,R)-SINpEt·HBF4 (0.04 mmol) were stirred at 708C
in n-hexane for 16 h, after which the mixture was added to 1c–i
(0.20 mmol) in n-hexane, and hydrogenation was then performed
under 100 bar H2 at 258C for 24–48 h. Yields of isolated products are
given. ee values were determined by HPLC analysis on a chiral sta-
tionary phase. PMB=4-methoxybenzyl.
[a] General conditions: [Ru(cod)(2-methylallyl)2] (0.01 mmol), KOtBu
(0.025 mmol), and NHC·HX (0.02 mmol) were stirred at 708C in n-
hexane (0.5 mL) for 16 h, after which the mixture was added to 1a–c
(0.10 mmol) in n-hexane (1.5 mL), and hydrogenation was performed at
100 bar H2 for 24 h. [b] Yield of isolated product. [c] Determined by
HPLC on a chiral stationary phase. [d] n-hexane (3.0 mL). [e] The reaction
time was prolonged to 36 h.
Angew. Chem. Int. Ed. 2016, 55, 3300 –3303
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3301

Angewandte
Communications
Chemie
desired 2,3-dihydro-1,5-benzothiazepinones 2j–o with excel-
lent enantioselectivities (87–95% ee) and in good yields (70–
93%). The halogenated substrates 1p–r were tolerated, giving
the corresponding products 2p–r in 86–92% ee and 56–82%
yield. Only trace amounts of dehalogenated products were
detected by NMR analysis for both substrates 1q and 1r.
Furthermore, the ester functionality in substrate 1s presented
no problems in this hydrogenation process, and the corre-
sponding product was produced in 94% yield and 89% ee.
These functional groups (OMe, F, Cl, Br, and ester groups)
provide an excellent opportunity for further modification of
the 1,5-benzothiazepinone products. The disubstituted sub-
strate 1t was successfully reduced to give 2t in 92% ee and
71% yield. Moreover, 2-naphthyl-substituted substrate 1u
was hydrogenated with excellent enantioselectivity and good
yield. We also tested several 1,5-benzothiazepinones derived
from aliphatic propiolic acids; however, poor results were
obtained under the current catalytic conditions.
To demonstrate the synthetic utility of this process, further
derivatization and application were carried out (Scheme 5).
Firstly, 2d was conveniently deprotected under strongly
Brønsted acidic conditions, affording the unprotected 2,3-
dihydro-1,5-benzothiazepinone 2a in almost quantitative
yield without any loss of enantiomeric excess (Scheme 5a).[15]
Scheme 4. Substrate scope of unsaturated 1,5-benzothiazepinones 1j–
u. General conditions: [Ru(cod)(2-methylallyl)2] (0.02 mmol), KOtBu
(0.05 mmol), and (R,R)-SINpEt·HBF4 (0.04 mmol) were stirred at 708C
in n-hexane for 16 h, after which the mixture was added to 1j–u
(0.20 mmol) in n-hexane, and hydrogenation was performed under
100 bar H2 at 258C for 24–48 h. Yields of isolated products are given.
ee values were determined by HPLC analysis on a chiral stationary
phase.
Scheme 5. Applications of the asymmetric hydrogenation reaction.
ring was investigated. Electron-rich substrates provided the
corresponding 2,3-dihydro-1,5-benzothiazepinones with
excellent enantioselectivities and yields (Scheme 3, 2e,f),
while the electron-poor substrate 1g provided 2g in compa-
ratively lower ee of 90% and 69% yield. Notably, fluoro- (1h)
and chloro-substituted substrates (1i) were also tolerated
under these conditions providing the corresponding products
with excellent enantioselectivities and good yields. In addi-
tion, the absolute configuration of 2i was determined to be S
by X-ray crystallographic analysis.[14] The configurations of
the other products were assigned by analogy.
We then further explored substrates derived from various
substituted propiolic acids as shown in Scheme 4. Introducing
electron-donating groups and electron-withdrawing groups at
the meta- or para-positions of the phenyl group had minimal
influence on the reactivity and selectivity, providing the
The remarkable functional group tolerance of this hydro-
genation methodology allowed us to directly apply the
unsaturated 1,5-benzothiazepinone 1v containing a tertiary
amine moiety, affording the seven-membered heterocyclic
antidepressant drug (R)-(À)-thiazesim 2v with 93% ee and
78% yield using (S,S)-SINpEt·HBF4 as the ligand precursor
(Scheme 5b). The absolute configuration of thiazesim 2v was
confirmed by comparing the optical rotation with the known
literature value (see the Supporting Information for details).
As far as we know, the present methodology provides the
most straightforward process for the asymmetric synthesis of
thiazesim to date.[10,11]
In summary, we have described a novel enantioselective
hydrogenation of cyclic vinylthioethers to access optically
active 2,3-dihydro-1,5-benzothiazepinones. Using a rutheni-
um(II) NHC catalyst, a series of unsaturated 1,5-benzothi-
3302
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 3300 –3303

Angewandte
Communications
Chemie
[8] For reviews on synthesis and applications of 1,5-benzothiazepine
azepinones were smoothly hydrogenated, producing the
desired products with excellent ee values (up to 95%), high
yields (up to 99%) and good functional group tolerance.
derivatives, see: a) A. LØvai, J. Heterocycl. Chem. 2000, 37, 199;
b) A. LØvai, A. Kiss-Szikszai, ARKIVOC 2008, 65; c) J. B.
Bariwal, K. D. Upadhyay, A. T. Manvar, J. C. Trivedi, J. S.
Singh, K. S. Jain, A. K. Shah, Eur. J. Med. Chem. 2008, 43, 2279.
[9] Thiazesim, an antidepressant drug: a) J. Krapcho, E. R. Spitz-
miller, C. F. Turk, J. Med. Chem. 1963, 6, 544; b) J. Krapcho, C. F.
Turk, J. Med. Chem. 1966, 9, 191; c) J. Krapcho, C. F. Turk, J. J.
Piala, J. Med. Chem. 1968, 11, 361. Diltiazem, used as Ca2+
channel blocker for the treatment of hypertension: d) T. Nagao,
M. Sato, H. Nakajima, A. Kiyomoto, Chem. Pharm. Bull. 1973,
21, 92; e) H. Inoue, S. Takeo, M. Kawazu, H. Kugita, Yakugaku
Zasshi 1973, 93, 729.
[10] a) Q.-L. Pei, H.-W. Sun, Z.-J. Wu, X.-L. Du, X.-M. Zhang, W.-C.
Yuan, J. Org. Chem. 2011, 76, 7849; b) T. Ogawa, N. Kumagai, M.
Shibasaki, Angew. Chem. Int. Ed. 2012, 51, 8551; Angew. Chem.
2012, 124, 8679; c) X. Fang, J. Li, C.-J. Wang, Org. Lett. 2013, 15,
3448; d) E. N. Jacobsen, L. Deng, Y. Furukawa, L. E. Martínez,
Tetrahedron 1994, 50, 4323.
Acknowledgements
We thank the Alexander von Humboldt Foundation (W.L.)
and the Deutsche Forschungsgemeinschaft (Leibniz Award)
for generous support. We also thank Dr. Matthew N. Hop-
kinson and Dr. Kathryn M. Chepiga for many helpful
discussions.
Keywords: 1,5-benzothiazepine · asymmetric hydrogenation ·
N-heterocyclic carbenes · ruthenium · vinylthioethers
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3300–3303
Angew. Chem. 2016, 128, 3361–3364
[11] Y. Fukata, K. Asano, S. Matsubara, J. Am. Chem. Soc. 2015, 137,
5320.
[12] a) S. Urban, N. Ortega, F. Glorius, Angew. Chem. Int. Ed. 2011,
50, 3803; Angew. Chem. 2011, 123, 3887; b) N. Ortega, S. Urban,
B. Beiring, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 1710;
Angew. Chem. 2012, 124, 1742; c) D. Zhao, B. Beiring, F. Glorius,
Angew. Chem. Int. Ed. 2013, 52, 8454; Angew. Chem. 2013, 125,
8612; d) N. Ortega, D.-T. D. Tang, S. Urban, D. Zhao, F. Glorius,
Angew. Chem. Int. Ed. 2013, 52, 9500; Angew. Chem. 2013, 125,
9678; e) J. Wysocki, N. Ortega, F. Glorius, Angew. Chem. Int. Ed.
2014, 53, 8751; Angew. Chem. 2014, 126, 8896.
[13] For the use of NHCs as ligands in transition-metal catalysis, see:
a) S. P. Nolan, N-Heterocyclic Carbenes in Synthesis, Wiley-
VCH, Weinheim, 2006; b) F. Glorius, N-Heterocyclic Carbenes
in Transition Metal Catalysis, Springer, Berlin, 2007; c) E. A. B.
Kantchev, C. J. OꢀBrien, M. G. Organ, Angew. Chem. Int. Ed.
2007, 46, 2768; Angew. Chem. 2007, 119, 2824; d) S. Díez-
Gonzµlez, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612;
e) S. Bellemin-Laponnaz, S. Dagorne, Chem. Rev. 2014, 114,
8747; f) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius,
Nature 2014, 510, 485. For reviews on the physicochemical
properties of NHCs, see: g) T. Drçge, F. Glorius, Angew. Chem.
Int. Ed. 2010, 49, 6940; Angew. Chem. 2010, 122, 7094; h) D. J.
Nelson, S. P. Nolan, Chem. Sco. Rev. 2013, 42, 6723.
[1] a) Catalysis in Asymmetric Synthesis (Eds.: V. Caprio, J. M. J.
Williams), Wiley VCH, Chichester, 2009; b) Modern Reduction
Methods (Eds.: P. G. Andersson, I. J. Munslow), Wiley-VCH,
Weinheim, 2008; c) Comprehensive Asymmetric Catalysis (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 2004;
d) Asymmetric Catalysis on Industrial Scale (Eds.: H. U. Blaser,
E. Schmidt), Wiley-VCH, Weinheim, 2004.
[2] For selected reviews, see: a) W. Tang, X. Zhang, Chem. Rev.
2003, 103, 3029; b) X. Cui, K. Burgess, Chem. Rev. 2005, 105,
3272; c) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111,
1713; d) D.-S. Wang, Q.-A. Chen, S.-M. Lu, Y.-G. Zhou, Chem.
Rev. 2012, 112, 2557; e) Z. Yu, W. Jin, Q. Jiang, Angew. Chem.
Int. Ed. 2012, 51, 6060; Angew. Chem. 2012, 124, 6164; f) B.
Zhao, Z. Han, K. Ding, Angew. Chem. Int. Ed. 2013, 52, 4744;
Angew. Chem. 2013, 125, 4844; g) J. J. Verendel, O. Pamies, M.
Dieguez, P. G. Andersson, Chem. Rev. 2014, 114, 2130.
[3] a) A. Nudelman, The Chemistry of Optically Active Sulfur
Compounds, Gordon and Breach, New York, 1984; b) Sulphur-
Containing Drugs and Related Organic Compounds (Ed.: L. A.
Damani), Wiley, New York, 1989; c) Organosulfur Chemistry in
Asymmetric Synthesis (Eds.: T. Toru, C. Bolm), Wiley-VCH,
Weinheim, 2008; d) J. Clayden, P. MacLellan, Beilstein J. Org.
Chem. 2011, 7, 582; e) P. Chauhan, S. Mahajan, D. Enders, Chem.
Rev. 2014, 114, 8807.
[14] CCDC 1441631 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] F. Hoffmann-Emery, R. Jakob-Roetne, A. Flohr, F. Bliss, R.
Reents, Tetrahedron Lett. 2009, 50, 6380.
[4] a) V. Tyagi, R. B. Bonn, R. Fasan, Chem. Sci. 2015, 6, 2488;
b) http://www.genengnews.com/insight-and-intelligenceand153/
top-20-best-selling-drugs-of-2012/77899775/?page = 2.
[5] A. F. Meindertsma, M. M. Pollard, B. L. Feringa, J. G. de Vries,
A. J. Minnaard, Tetrahedron: Asymmetry 2007, 18, 2849.
[6] A. Pfaltz, C. Valla, A. Baeza, F. Menges, Synlett 2008, 3167.
[7] S. Urban, B. Beiring, N. Ortega, D. Paul, F. Glorius, J. Am. Chem.
Soc. 2012, 134, 15241.
Received: December 30, 2015
Published online: February 5, 2016
Angew. Chem. Int. Ed. 2016, 55, 3300 –3303
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3303