Catalytic enantioselective synthesis of 3-substituted benzosultams via Corey-Bakshi-Shibata reduction of cyclic N-sulfonylimines

Article abstract of DOI:10.1055/s-0030-1259314

The catalytic asymmetric synthesis of 3-substituted benzo-fused sultams employing the Corey-Bakshi-Shibata reduction with catecholborane of the corresponding cyclic N-sulfonylimines is reported. Good to excellent yields (74-95%) and enantiomeric excesses

Full text of DOI:10.1055/s-0030-1259314

4
02
LETTER
Catalytic Enantioselective Synthesis of 3-Substituted Benzosultams via
Corey–Bakshi–Shibata Reduction of Cyclic N-Sulfonylimines
A
D
symmetric Synth
i
esis of
e
Sultam
s
ter Enders,* Matthias Seppelt
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 23 November 2010
6
7
Friedel–Crafts reactions, Heck couplings, ring-closing
Abstract: The catalytic asymmetric synthesis of 3-substituted ben-
zo-fused sultams employing the Corey–Bakshi–Shibata reduction
with catecholborane of the corresponding cyclic N-sulfonylimines
8
metathesis along with a number of cyclization reac-
tions.9 Beyond these methods a very convenient synthe-
,10
is reported. Good to excellent yields (74–95%) and enantiomeric sis of chiral sultams is the hydrogenation of cyclic N-
excesses (69–94%) are obtained.
sulfonylimines. Whilst various enantioselective metal-
catalyzed hydrogenations of such imines have been devel-
oped,11 to the best of our knowledge an enantioselective
organocatalytic reduction of cyclic N-sulfonylimines has
not been published so far. A transition-metal-free ap-
proach can be envisaged by utilizing the well-established
Corey–Bakshi–Shibata (CBS) reduction.12 While this is
known to provide easy access to a wide range of highly
enantioenriched alcohols by the reduction of ketones, rel-
atively few examples for the enantioselective reduction of
Key words: asymmetric synthesis, imine, reduction, catalysis, sul-
fonamide
Sultams can be seen as sulfur analogues of lactams and
represent an important class of heterocyclic compounds,
which can be found in many biologically active
1
compounds such as the anti-inflammatory agent A, the
carbonic anhydrase inhibitor B, and the herbicide C
13
2
imines are described in the literature. Difficulties in the
enantioselective borane reduction of ketimines stem from
the equilibrium between the E- and Z-isomers and their
(
Figure 1). In addition, the sultam D developed by
Oppolzer et al. has been used as a chiral auxiliary in many
3
asymmetric syntheses. This is also true for the 3-substi-
14
differentiation by the catalyst. Furthermore, oxazaboro-
lidines as Lewis acids may be trapped by the basic nitro-
gen of the imine moiety. However, there exist several
examples for the enantioselective reduction of imines
with catalytic amounts of chiral boron reagents. This
method has been applied to various aromatic and aliphatic
tuted benzosultam title compounds, which as N–F re-
agents can be used for electrophilic fluorinations.3d
Benzo-fused sultams have also received much attention as
potent HIV reverse-transcriptase inhibitors.
4
O
O
HN
15
16
17
imines and oximes as well as to stable N–H imines.
S
Me
N
A successful attempt to reduce a cyclic N-sulfonylimine
H
SO2NH2
N
N
MeO
N
by applying a CBS catalyst, however, has not been de-
S
S
18
3
scribed so far.
OH
O
O
O
A
B
Ph
H
Ph
F3C
Cl
O
O
N
B
R
O
O
O
(
10 mol%)
O
O
NH
S
O
S
3a R = Me
S
3
b R = o-tolyl
NH
S
N
NH
O
O
borane, solvent
*
O
1
a
2a
C
D
Scheme 1 Catalytic asymmetric synthesis of sultam 2a by CBS re-
duction of the cyclic N-sulfonylimine 1a
Figure 1 Selected compounds with biological activity A–C and the
Oppolzer sultam D
In continuation of our efforts in the asymmetric synthesis
Many protocols for the synthesis of sultams have been de-
1
0
of various sultams, we herein report the enantioselective
Corey–Bakshi–Shibata reduction of prochiral cyclic N-
sulfonylimines 1 to highly enantioenriched benzo-fused
sultams 2. Scheme 1 shows the model system for our in-
vestigation of the CBS reduction of cyclic N-sulfo-
nylimines.
scribed offering a broad substrate diversity. The formation
of the sultam structure can be realized by cycloadditions,5
SYNLETT 2011, No. 3, pp 0402–0404
x
x.
x
x.
2
0
1
1
Advanced online publication: 13.01.2011
DOI: 10.1055/s-0030-1259314; Art ID: G32810ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Synthesis of Sultams
403
For initial tests the cyclic N-sulfonylimine 1a was added Table 2 Optimization of the Reaction Conditions
slowly to a solution of the borane–THF complex and 10
Entry
Solventa
Catecholborane Yield
ee
mol% of oxazaborolidine 3a. When performed at room
temperature only a very low enantioselectivity was
achieved. The enantiomeric excess could be increased to
(
equiv)
(%)
60
58
73
90
74
(%)
79
90
89
91
94
1
2
3
THF
1.0
1.0
1.2
1.6
1.6
5
3% ee by lowering the temperature to –78 °C (Table 1,
THF–toluene 1:1
THF–toluene 1:1
THF–toluene 1:1
toluene
entry 1 and 2). Encouraged by these results we decided to
test catecholborane as a bulkier hydride source which led
to a significant improvement of the enantioselectivity
4
(
73–79%). Varying the order of addition of the reagents or
changing the catalyst to oxazaborolidine 3b did not im-
prove the reaction further (entry 5 and 6).
5b
a
Imine 1a was dissolved in the listed solvent and then added at 0 °C
via syringe pump as previously described.
Solid imine 1a was added in one portion.
Table 1 Evaluation of the Reaction Conditions for the Asymmetric
Synthesis of Sultam 2a (Scheme 2).
b
Entrya Catalyst Borane
Temp
Yield ee
However, a brominated sultam 2e is available in good
enantioselectivity and high yield with our protocol with
the option of further transformation at this position of the
aromatic ring.
b
(%)c
(
%)
1
3a
3a
3a
3a
3a
3b
BH ·THF
r.t.
63
21
3
2
BH ·THF
–78 °C to r.t. 72
53
3
Ph
3
catecholborane
catecholborane
catecholborane
catecholborane
r.t.
59
60
67
55
73
H
Ph
4
0 °C
r.t.
79
O
N
B
5d
76
H
O
O
O
B
Me
(0.1 equiv)
O
3
a
R2
R2
O
O
S
S
6
0 °C
56
N
+
NH
toluene, 0 °C
a
A solution of imine 1a (0.5 mmol) in THF (5 mL) was added by sy-
ringe pump addition over 1 h to a solution of catalyst 3 (0.1 equiv) and
R1
1.0 equiv)
R1
1
(S)-2
BH ·THF (0.6 equiv) or catecholborane (1.0 equiv) in THF (1 mL).
3
(
(1.6 equiv)
The reaction mixture was stirred overnight.
b
Yield of isolated product 2a.
Determined by chiral stationary phase HPLC analysis.
Instead of a slow addition of the imine 1a, a solution of catecholbo-
Scheme 2 Optimized reaction conditions for the enantioselective
synthesis of chiral sultams 2
c
d
rane in THF (1.0 mL) was added over 30 min to the THF solution of
Table 3 Substrate Scope for the Enantioselective Catalytic Synthe-
sis of Sultams 2 via CBS Reduction
1
a and 3a.
Entry
2a
R1
R2
H
Time (d) Yield (%) ee (%)
We assumed that a higher enantioselectivity could be
achieved by using a less polar solvent than THF. Since the
solubility of imine 1a was very low in nonpolar solvents a
1
2
3
4
2a
2b
2c
2d
2e
Me
Et
1
2
1
5
4
74
86
91
95
92
94
81
84
69
74
H
1
:1 mixture of THF and toluene was chosen, which led to
a very high selectivity of 90% ee. Unfortunately, the yield
did not increase (Table 2, entry 2). An increased amount
of catecholborane (1.6 equiv) delivered both a high enan-
tiomeric excess and yield (entry 4). The highest enantiose-
lectivity was obtained using toluene as the solvent in
combination with a direct addition of imine 1a in its solid
form (entry 5). This method provided sultam 2a in high
yield with an excellent enantiomeric excess of 94%. The
stereocenter of the sultam 2a possesses the S-configura-
n-Bu
Ph
H
H
5
Me
Br
a
Solid imine 1a (0.5 mmol) was added in one portion to a stirred so-
lution of catalyst 3a (0.1 equiv) and catecholborane (1.0 equiv) in tol-
uene (10 mL) at 0 °C.
tion, which was determined by comparison of its optical In conclusion we have developed an efficient catalytic
1
9
rotation with the value reported in the literature.
asymmetric synthesis of 3-substituted benzo-fused sultams
in high yields (74–95%) and very good enantiomeric ex-
cesses (69–94% ee). Thus, the substrate scope of the Co-
rey–Bakshi–Shibata reduction could be extended to cyclic
N-sulfonylimines opening a simple entry to the title com-
pounds.
Having identified the optimal reaction conditions a short
survey of the substrate scope for the CBS reduction of cy-
clic N-sulfonylimines 1 was examined (Scheme 2,
Table 3). Variation of the R group to ethyl and n-butyl
delivered the corresponding sultams in high yield and
enantioselectivity. Introducing a phenyl ring in this posi-
tion led to a considerable decrease of stereoselectivity.
2
0
1
Synlett 2011, No. 3, 402–404 © Thieme Stuttgart · New York

4
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D. Enders, M. Seppelt
LETTER
Supporting Information for this article is available online at
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