Dual Role of Vinyl Sulfonamides as N-Nucleophiles and Michael Acceptors in the Enantioselective Synthesis of Bicyclic δ-Sultams

Article abstract of DOI:10.1002/adsc.201800548

A new methodology for the synthesis of enantiomerically enriched bicyclic δ-sultams is described, involving an initial organocatalytic intramolecular aza-Michael reaction of vinyl sulfonamides bearing a conjugated ketone at a remote position. The resulting Michael adducts were then subjected to an intramolecular conjugate addition over the vinyl sulfone moiety, thus rendering the final bicyclic sultams containing two stereocenters. The key point of this strategy relies on the use of vinyl sulfonamides as both, nitrogen nucleophiles and Michael acceptors. The use of phosphazene-derived bases avoided the racemization of the intermediate derivatives, rendering 6-membered ring bicyclic δ-sultams in enantiomerically enriched manner with a small erosion of enantiopurity. Anyway, after recrystallization, final sultams were obtained in almost enantiomerically pure form. Nevertheless, the enantioselective synthesis of either 5-membered ring products or benzofused derivatives was found to be out of the scope of our strategy. (Figure presented.).

Full text of DOI:10.1002/adsc.201800548

Title: Dual Role of Vinyl Sulfonamides as N-Nucleophiles and Michael
Acceptors in the Enantioselective Synthesis of Bicyclic delta-
Sultams
Authors: Cristina Mulet, Marcos Escolano, Sebastián Llopis, Sergio
Sanz, Carmen Ramirez de Arellano, Maria Sanchez-Rosello,
Santos Fustero, and Carlos del Pozo
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800548
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Dual Role of Vinyl Sulfonamides as N-Nucleophiles and Michael
Acceptors in the Enantioselective Synthesis of Bicyclic -
Sultams
Cristina Mulet,a Marcos Escolano,a Sebastián Llopis,a Sergio Sanz,a Carmen Ramírez
de Arellano,a María Sánchez-Roselló,a Santos Fusteroa,b,* and Carlos del Pozoa,*
a
Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain
E-mail: carlos.pozo@uv.es or santos.fustero@uv.es
b
Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A new methodology for the synthesis of The use of phosphazene-derived bases avoided the
enantiomerically enriched bicyclic -sultams is described, racemization of the intermediate derivatives, rendering 6-
involving an initial organocatalytic intramolecular aza- membered ring bicyclic -sultams in enantiomerically
Michael reaction of vinyl sulfonamides bearing a conjugated enriched manner with a small erosion of enantiopurity.
ketone at a remote position. The resulting Michael adducts Anyway, after recrystallization, final sultams were obtained
were then subjected to an intramolecular conjugate addition in almost enantiomerically pure form. Nevertheless, the
over the vinyl sulfone moiety, thus rendering the final enantioselective synthesis of either 5-membered ring
bicyclic sultams containing two stereocenters. The key point products or benzofused derivatives was found to be out of
of this strategy relies on the use of vinyl sulfonamides as the scope of our strategy.
both, nitrogen nucleophiles and Michael acceptors.
Keywords: vinyl sulfonamides; intramolecular Michael
addition; bicyclic sultams; enantioselectivity;
organocatalysis
has attracted in the last decades.[9] Furthermore,
Introduction
sultam scaffolds have been employed as chiral
auxiliaries[10] and reagents to perform specific organic
transformations.[11] Specifically, the applications of
Oppolzer camphorsultam[12] have rapidly grown over
the past few years and nowadays it is considered one
of the most useful and suitable chiral auxiliaries for
asymmetric synthesis.[13]
From a structural point of view, benzofused
sultams are by far the most abundant ones, and a huge
amount of these derivatives have been described.[14]
However, fusion of the sultam scaffold with saturated
carbo- or heterocycles is quite scarce in the
literature.[15] Therefore, the development of
convenient methods to prepare these types of sultams
are highly desirable.
On the other hand, chiral sultams, beside their
utility as chiral auxiliaries, have also found potent
biological activities. For example, chiral sultams can
be found in RORc inverse agonists as potential
treatments of inflammatory diseases,[16] carbonic
anhydrase inhibitors such as Brinzolamide for the
treatment of glaucoma,[17] calpain I inhibitors
Since the discovery of the antibacterial activity of
sulfonamides in 1932,[1] this functional group has
become one of the most important pharmacophores in
medicinal chemistry,[2] being a commonly found
motif in drugs and agrochemicals. As mimics of the
amide functionality, sulfonamides are used to replace
amide groups in the design of novel peptidomimetics
and small molecule inhibitors due to their better
hydrolytic stability, low energy conformation and PK
properties.[3] Among the pool of sulfonamides,
sultams (cyclic sulfonamides) have emerged as
privileged structures in drug discovery due to their
diverse biological properties,[4] even though they do
not occur in Nature. Several marketed drugs contain
the sultam substructure such as the non-steroidal
antiinflamatory
agents
Ampiroxicam[5]
and
Piroxicam,[6] the antiepileptic Sulthiame,[7] or the
antidepressant Tianeptine,[8] among many others.
This huge assortment of bioactivities explains the
intense research activity that the synthesis of sultams
1
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
implicated in neurodegenerative processes,[18] HIV-1
inhibitors,[19] or MMP-2 inhibitors mainly targeted for
cancer[20] (Figure 1).
Scheme 1. Enantioselective synthetic strategies towards
chiral sultams.
Figure 1. Biologically relevant chiral sultams.
In spite of the importance of chiral sultams in
medicinal and synthetic chemistry, catalytic
enantioselective procedures for the synthesis of
optically active sultams are still limited and most of
them allow for the construction of benzofused sultam
derivatives. In this context, catalytic asymmetric
nucleophilic additions to cyclic N-sulfonyl ketimines
have been reported,[21] including transition metal-
catalyzed asymmetric arylation, allylation,[22]
alkenylation[23] or propargylation[24] reactions as well
as organocatalyzed Mannich type processes.[25]
Results and Discussion
Among the different cyclization protocols aimed at
the construction of the sultam skeleton,
intramolecular Michael-type processes have been
scarcely investigated.[30] On account of our interest in
the development of methodologies to perform the
IMAMR in an asymmetric organocatalytic fashion,[31]
we envisioned the possibility of employing
conveniently functionalized vinyl sulfonamides to
carry out an enantioselective synthesis of chiral
nonracemic bicyclic sultams by means of an
organocatalytic IMAMR as a key step. The starting
materials required to carry out the projected strategy
were assembled through a selective cross-metathesis
(CM) reaction between vinyl sulfonamides 1,
previously synthesized according to literature
procedures, and commercially available ,-
unsaturated ketones 2.[32] Due to the presence of two
different olefin moieties in compounds 1, three
possible scenarios should be considered, namely the
desired CM reaction through the isolated olefin to
yield compounds 3, a CM reaction with the vinyl
sulfonamide olefin, and a ring-closing metathesis
(RCM) cyclization pathway (Scheme 2), although the
last would be less favorable due to the slow formation
rate of an 8-membered ring. According to the general
model for predicting product selectivity in CM
reactions proposed by Grubbs and co-workers in
2003,[33] in the presence of second generation
ruthenium catalysts, we anticipated that a highly
selective CM reaction would be feasible between the
more reactive isolated olefin in compounds 1 (type I
olefin, rapid homodimerization and very reactive
homodimers) and conjugated ketones 2 (type II
olefins, slower homodimerization rate than type I)
just by employing an excess of the conjugated ketone
in order to avoid the homodimerization of the type I
Examples
of
metal-catalyzed
asymmetric
reductions[26] and organocatalytic asymmetric
annulations of cyclic sulfonyl ketimines leading to
chiral spirocyclic sultams have also been recently
developed.[27] Another synthetic strategy towards
chiral benzosultams involved an enantioselective
intramolecular C-H bond amination reaction[28]
(Scheme 1, Previous work). To the best of our
knowledge, there are no examples to date concerning
the enantioselective synthesis of non-benzofused
chiral bicyclic sultams.[29] Therefore, in the present
paper, a new methodology for the synthesis of
enantiomerically enriched bicyclic -sultams is
described, involving an initial organocatalytic
intramolecular aza-Michael reaction (IMAMR) of
vinyl sulfonamides bearing a conjugated ketone at a
remote position. The resulting intermediates will be
then subjected to an intramolecular conjugate
addition over the vinyl sulfone moiety, thus rendering
the desired -sultams containing two stereocenters
(Scheme 1, This work). The key point of this strategy
relies on the use of vinyl sulfonamides as both, N-
nucleophiles in the IMAMR and Michael acceptors.
Final products exemplify a very exclusive family of
chiral sultams, given the position of the sulfonamide
nitrogen at the ring juncture, not reported to date in
an asymmetric manner.
2
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
olefin counterpart. On the other hand, vinyl
sulfonamide would be a type III olefin, poorly
reactive in CM reactions and, therefore, unable to
react with unsaturated ketones 2.
In order to explore our planned strategy for the
synthesis of benzofused derivatives, compounds 3i-k
were also synthesized through the CM reaction of
conveniently functionalized vinyl sulfonamides 1f-h
(Table 2).
Table 2. Cross-metathesis reaction between benzofused
vinyl sulfonamides 1 and methyl vinyl ketone 2a.a)
Scheme 2. Classification of olefins and plausible
metathesis reactions between substrates 1 and 2.
Entry
1
n
1
2
1
m
1
3 [%]b)
3i [55]
3j [66]
3k [60]
1
2
3
1f
1g
1h
Second generation Hoveyda-Grubbs catalyst [HG-
II, Cl2(IMes)Ru=CH(o-iPrOC6H4)] was chosen in
order to optimize the desired transformation since it
was described to facilitate cross-coupling reactions
between olefins bearing electron-withdrawing groups
and terminal olefins.[34] Thus, the optimal conditions
to carry out the CM reaction between vinyl
sulfonamides 1 and conjugated ketones 2 involved
the addition of 24 mol% of catalyst HG-II in three
portions, 5 equiv of the ketone and titanium (IV)
isopropoxide (20 mol%) as a Lewis acid acid, which
avoids the basicity of the sulfonamide nitrogen.
Several vinyl sulfonamides 3 bearing a conjugated
ketone at a remote position were obtained in
moderate to good yields, as depicted in Table 1.
0
0
a)
Reactions were carried out with 1 (1 equiv) and 2a (5
equiv), catalyst HG-II (3 x 8 mol%) and Ti(i-PrO)4 (20
mol%) in dichloromethane (0.3M) at room temperature for
24h.b) Yields of compounds 3 after purification by flash
column chromatography.
With ,-unsaturated ketones 3 in hand, the next
step was the optimization of the organocatalytic
IMAMR, taking as starting point the results
previously obtained by our research group.[35]
Therefore, the first attempt was performed on model
compound 3a employing 9-amino-9-deoxy-epi-
hydroquinine (HQ-NH2, 20 mol%) as the
organocatalyst and trifluoroacetic acid (20 mol%) as
a co-catalyst in chloroform at room temperature. As
expected, the intramolecular conjugate addition took
place in 15 hours, giving rise to piperidine 4a in 57%
yield with a good 92:8 enantiomeric ratio (Table 3,
entry 1). When the reaction was carried out in THF or
dichloromethane, slightly lower yield and asymmetric
induction were observed (Table 3, entries 2, 3),
whereas the use of a more polar solvent (CH3CN)
completely inhibited the desired transformation
(Table 3, entry 4). Lowering the temperature to 0oC
led to enhanced er values (95:5 and 94:6 in CHCl3
and THF, respectively) at the expense of yields
(Table 3, entries 5, 6). We also tested the reaction
under microwave heating at 60oC, although both
yield and enantioselectivity became negatively
affected (Table 3, entry 7). Finally, the catalyst/co-
catalyst loading was evaluated. Therefore, decreasing
the amount of TFA from 20 to 10 mol% entailed a
drastic drop in yield and enantiocontrol (Table 3,
entry 8), while the use of a 1:2 ratio of catalyst/co-
catalyst led to the best er value (97:3) with a good
76% yield of compound 4a (Table 3, entry 9).
Table 1. Selective cross-metathesis reaction between vinyl
sulfonamides 1 and conjugated ketones 2.a)
Ent.
1
1
n
1
1
1
1
1
1
1
0
R
X
2
R1
R2
H
3 [%]b)
3a [86]
3b [81]
3c [70]
3d [45]
3e [93]
3f [88]
3g [58]
3h [65]
1a
1a
1a
1a
1b
1c
1d
1e
H
CH2 2a
CH2 2b
CH2 2c
CH2 2d
CH2 2a
CH2 2a
Me
Pr
2
H
H
3
H
Pent
Ph
H
4
H
Me
H
5
Me
Ph
H
Me
Me
Me
Me
6
H
7
O
2a
H
8
H
CH2 2a
H
a)
Reactions were carried out with 1 (1 equiv) and 2 (5
equiv), catalyst HG-II (3 x 8 mol%) and Ti(i-PrO)4 (20
mol%) in dichloromethane (0.3M) at room temperature for
24h.b) Yields of compounds 3 after purification by flash
column chromatography.
3
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
Table 3. Optimization of the organocatalytic IMAMR on ,-unsaturated ketone 3a.a)
Entry
HQ-NH2 (mol%)
TFA (mol%) Solvent
T (oC)
25
t (h)
15
15
15
120
48
48
2
% Yield b)
er c)
1
2
3
4
5
6
7
8
9
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
10
20
CHCl3
THF
57
47
58
NR
22
50
55
25
76
92:8
88:12
90:10
---
25
DCM
CH3CN
CHCl3
THF
25
25
0
95:5
94:6
87:13
60:40
97:3
0
60 d)
CHCl3
CHCl3
CHCl3
25
72
24
10
25
a)
NR= no reaction. Reactions were carried out with 3a (0.1 mmol), catalyst HQ-NH2 and TFA as a co-catalyst in
the specified solvent (1 mL), temperature and time. Yields of compound 4a after purification by flash column
chromatography. Enantiomeric ratios determined by HPLC analysis on a chiral stationary phase (see Supporting
Information).
b)
c)
d)
Heating
by
means
of
microwave
irradiation.
The optimal reaction conditions for the
organocatalytic IMAMR (Table 3, entry 9) were then
applied to the rest of ,-unsaturated ketones 3. In
this manner, a small family of enantioenriched N-
heterocycles was obtained in very good yields and
excellent enantioselectivities as determined by chiral
HPLC analysis (Figure 2). The assignment of the
absolute configuration at the stereocenter generated in
the IMAMR was made according to the mechanism
commonly invoked to rationalize the conjugate
additions of nitrogen nucleophiles to enones when
chiral primary amines are employed as catalysts,
previously described by our research group.[35
]
Furthermore, this stereochemical outcome was later
confirmed by X-ray analysis of a crystalline sultam
(see compound 5a in Table 5)
Figure 2. Scope of the organocatalytic IMAMR.
The next step in our study was the cyclization of
compounds 4 by means of a diastereoselective
intramolecular Michael addition (IMA) over the vinyl
sulfone moiety. In this manner, the skeleton of the
desired bicyclic or polycyclic -sultams would be
assembled. Initially, the cyclization was performed
under basic conditions with compound 4a as the
model substrate. The first attempt involved the use of
NaH (1 equiv) in a 5:1 THF/ DMF mixture (0.03M) at
4
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
room temperature, since these conditions had been not work under the same conditions (Table 4, entry
successfully employed in the racemic synthesis of our 12).
bicyclic and polycyclic sultams (see Supporting
Information). Unfortunately, even though the reaction
Table 4. Optimization of the IMA on sulfonamide 4a.a)
proceeded
in
good
yield
and
complete
diastereoselectivity, HPLC analysis showed
a
complete racemization of the final product 5a (Table
4, entry 1). This disappointing result can be explained
through a retro-aza-Michael reaction taking place in
the presence of NaH, thereby destroying the
stereochemical integrity of the stereocenter generated
during the organocatalytic IMAMR step (Scheme 3).
Ent. Base
Solvent
%
T (oC)
25
er c)
Yield b)
1
NaH
THF/
DMF
THF
76
--- d)
2
3
4
5
6
t-BuOK
80
25
25
25
25
25
--- d)
---
KHMDS THF
CM
NR
NR
CM
TBAF
DBU
THF
THF
DCM
---
---
Scheme 3. NaH-mediated retro-aza-Michael reaction.
Racemic synthesis of sultam 5a
trans-
---
2,5-DMP
7
8
L-Pro
MeOH NR
25
25
---
i-Pr-
Verkade
THF
THF
THF
93
61:39
In view of the above experiment, our next goal was
to find suitable conditions in order to carry out the
IMA avoiding the undesired retro-aza-Michael
reaction. In this context, several bases were screened,
with the results summarized in Table 4. Beside NaH,
the use of t-BuOK afforded the desired bicyclic
sultam in 80% yield as a single diastereoisomer,
although again with complete racemization (Table 4,
entry 2). Potassium hexamethyldisilazide led to a
mixture of non-identified products (Table 4, entry 3),
even at low temperature (40oC). Other bases such as
TBAF or DBU did not promote the cyclization
process and the starting piperidine 4a was recovered
(Table 4, entries 4, 5). We also tested chiral bases,
namely trans-2,5-dimethylpiperazine and L-proline,
without positive results (Table 4, entries 6, 7).[36]
Fortunately, the chirality was slightly kept with the
use of i-Pr-Verkade’s base, which allowed us to
isolate sultam 5a in 93% yield as a 61:39 mixture of
enantiomers (Table 4, entry 8). Lowering the
temperature to 78oC led to an enhanced er value
(75:25) with an excellent 95% yield (Table 4, entry 9),
whereas the i-Bu-Verkade’s base completely inhibited
the desired cyclization (Table 4, entry 10). Finally,
phosphazene base P2-Et, included in the superbases
family,[37] came up with an acceptable rate of chirality
and yield as bicyclic sultam 5a was obtained in 77%
yield and 93:7 er when the reaction was performed at
78oC in the presence of 4Å MS (Table 4, entry 11).
However, the bulkier phosphazene base P2-t-Bu did
9
i-Pr-
Verkade

R
78 to
40
78 to
40
78 e)
78 e)
75:25
---
10
i-Bu-
Verkade
11
12
P2-Et
THF
THF

R
93:7
---
P2-t-Bu
NR= no reaction. CM= complex mixture. DMP=
dimethylpiperazine. Reactions were carried out with 4a
a)
(0.1 mmol), base (1 equiv) in the specified solvent (1 mL)
and temperature for 4 hours.b) Yields of compound 5a after
c)
purification by flash column chromatography.
Enantiomeric ratios determined by HPLC analysis on a
chiral stationary phase (see Supporting Information).
Racemic product 5a was obtained. Reactions performed
d)
e)
in the presence of 4Å MS.
According to entry 11, the optimal conditions to
perform the intramolecular Michael addition with the
minimal erosion of enantiopurity were employed for
the synthesis of different bicyclic -sultams 5. In this
manner, non-benzofused bicyclic sultams 5a-g were
obtained as single diastereoisomers, in yields ranging
from 70 to 99% and high er values, as depicted in
Table 5 (entries 1-7). Interestingly, a single
recrystallization of these enantioenriched sultams 5a-
g from a mixture of n-hexanes: 2-propanol resulted in
5
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
a
significant enrichment in enantioselectivity, In conclusion, a two-step protocol for the synthesis of
exemplified by compounds 5f and 5g (Table 5, entries chiral bicyclic -sultams has been developed. These
6, 7), which were finally obtained with excellent er products constitute interesting scaffolds in medicinal
values (97:3 and >99:1, respectively). Unfortunately, chemistry due to their diverse biological activities,
the P2-Et mediated intramolecular Michael addition and their enantioselective synthesis has almost been
was found to be ineffective, in terms of limited to benzofused derivatives. Our synthetic
enantioselectivity, for the synthesis of the pyrrolidine- strategy
entails
a
highly
enantioselective
fused -sultam 5h (Table 5, entry 8) and the intramolecular aza-Michael reaction (IMAMR),
benzofused derivatives 5i-k (Table 5, entries 9-11). followed by a diastereoselective intramolecular
Although these sultams were obtained in good yields, Michael addition (IMA), taking advantage of the dual
it seems that the retro-aza-Michael reaction is faster ability of vinyl sulfonamides to act as nucleophilic
than the intramolecular Michael addition in these nitrogen sources and Michael acceptors. After careful
cases.
optimization of the second conjugate addition reaction
in order to avoid the epimerization of the stereocenter
initially generated in the IMAMR, we were able to
obtain non-benzofused bicylic -sultams in very good
yields and excellent enantioselectivities after a single
recrystallization process. However, our strategy did
not work for the enantioselective synthesis of either a
5-membered-fused bicyclic -sultam or benzofused
tricyclic sultams.
Table 5. Bicyclic and polycyclic -sultams 5 synthesized
through the base-mediated IMA.a)
Experimental Section
General procedure for the CM reaction: synthesis of
vinyl sulfonamides 3.
To a solution of vinyl sulfonamide 1 (1.0 equiv) in dry
DCM (0.3M) under nitrogen atmosphere, the
corresponding conjugated ketone 2 (3.0 equiv), titanium
isopropoxide (20 mol%) and an initial 8 mol% loading of
second generation Hoveyda-Grubbs catalyst were added.
After stirring for 2-3 h at room temperature, two more
portions of catalyst (2 x 8 mol%) were added as well as
ketone (2.0 equiv). The resulting mixture was stirred for 20
h at room temperature and then concentrated to dryness and
purified by means of flash column chromatography on
silica gel using mixtures of n- hexane and ethyl acetate as
eluents.
(E)-N-(7-oxo-5-octen-1-yl)ethenesulfonamide (3a): By
means of the general procedure described above,
compound 3a (211 mg, 86% yield) was obtained as a
brown oil starting from 200 mg (1.06 mmol) of 1a after
flash chromatography with 1:1 n-hexanes: ethyl acetate. 1H
NMR (300 MHz, CDCl3) δ 1.50-1.63 (m, 4H), 2.21-2.28
(m, 5H), 2.99-3.06 (m, 2H), 4.58 (br s, 1H), 5.94 (d, J = 9.9
Hz, 1H), 6.07 (dt, J = 15.9, 1.4 Hz, 1H), 6.23 (d, J = 16.5
Hz, 1H), 6.50 (dd, J = 16.5, 9.8 Hz, 1H), 6.76 (dt, J = 15.9,
6.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 24.7, 26.7, 29.1,
31.6, 42.5, 126.3, 131.3, 135.7, 147.6, 198.8. HRMS
(ESI/Q-TOF) m/z: [M++H] calcd. for C10H17NO3S
232.1002; found: 232.1005.
a) Reactions were carried out with 4 (1 equiv), phosphazene
base P2-Et (1 equiv) in THF (0.1M) at 78oC with 4Å MS
for 4h. b) Yields and enantiomeric ratios of sultams 5 after a
single recrystallization from a mixture of n-hexane:2-
propanol.
The absolute configuration of the final products
was assigned by X-ray analysis. Crystals of sultam 5a
suitable for single crystal X-ray diffraction were
grown from DCM/ Et2O solution and its structure was
unambiguously established (see structure in Table
5).[38] It revealed the anti relative configuration of the
two sterocenters and confirmed the expected (R)
configuration of the stereocenter generated in the
IMAMR. Identical stereochemical outcomes were
assumed for all other enantioenriched bicyclic sultams
5.
General procedure for the intramolecular aza-Michael
reaction. Synthesis of compounds 4.
In a 25 mL round bottomed flask, the corresponding vinyl
sulfonamide 3 (1.0 equiv) was dissolved in chloroform (0.1
M). Catalyst HQ-NH2 (10 mol%) and trifluoroacetic acid
(20 mol%) were added and the resulting solution was
stirred at room temperature for 24 h. Then, the crude
reaction mixture was subjected to flash column
chromatography on silica gel using mixtures of n-hexane:
ethyl acetate as eluents to afford the corresponding
products 4. The enantiomeric ratios were determined by
means of HPLC analysis with an appropriate chiral column.
Conclusion
6
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
(R)-N-(1-vinylsulfonyl)-2-(2-oxopropyl) piperidine (4a):
By means of the general procedure described above, 2-
substituted piperidine 4a (76 mg) was obtained as a
colorless oil from 3a in 76% yield and 97:3 er after flash
chromatography with 2:1 n-hexanes: ethyl acetate. The er
value was determined by HPLC analysis using a
Chiralpack AD column (hexane: isopropanol 90:10); flow
[2] For some reviews highlighting the importance of
sulfonamides, see: a) A. Ammazzalorso, B. De Filippis, L.
Giampietro, R. Amoroso, Chem. Biol. Drug Design 2017,
90, 1094; b) M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr.
Top. Med. Chem. 2016, 16, 1200; c) S. S. Shah, G. Rivera,
M. Ashfaq, Mini-Rev. Med. Chem. 2013, 13, 70; d) P. Jain,
S. Saravanan, S. K. Singh, Eur. J. Med. Chem. 2013, 60,
89; e) J.-Y. Winum, A. Scozzafava, J.-L. Montero, C. T.
Supuran, Med. Res. Rev. 2006, 26, 767; f) A. Scozzafava, T.
Owa, A. Mastrolorenzo, C. T. Supuran, Curr. Med. Chem.
2003, 10, 925; g) J. Drews, Science 2000, 287, 1960.
25
rate = 1.0 mL/min, tmajor= 21.1 min, tminor= 18.9 min. []D
1
+20.0 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3) δ 1.46-
1.70 (m, 6H), 2.19 (s, 3H), 2.81 (d, J = 7.2 Hz, 2H), 2.93-
3.03 (m, 1H), 3.62 (d, J = 14.1 Hz, 1H), 4.39-4.45 (m, 1H),
5.89 (d, J = 9.6 Hz, 1H), 6.21 (d, J = 16.5 Hz, 1H), 6.43
(dd, J = 16.4, 9.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
18.8, 25.3, 28.7, 30.4, 41.3, 44.7, 49.0, 126.2, 136.3, 206.1.
HRMS (ESI/Q-TOF) m/z: [M++H] calcd. for C10H17NO3S
232.1002; found: 232.0996.
[3] For representative examples of the use of
sulfonamides as amide mimics, see: a) K. Suthagar, A. J.
Fairbanks, Org. Biomol. Chem. 2016, 1748; b) K. Suthagar,
A. J. A. Watson, B. L. Wilkinson, A. J. Fairbanks, Eur. J.
Med. Chem. 2015, 102, 153; c) X. Lu, S. K. Olsen, A. D.
Capili, J. S. Cisar, C. D. Lima, D. S. Tan, J. Am. Chem. Soc.
2010, 132, 1748; d) S. Turcotte, S. H. Bouayad-Gervais, W.
D. Lubell, Org. Lett. 2012, 14, 1318; e) M. Benltifa, M. I.
García-Moreno, C. Ortiz-Mellet, J. M. García-Fernández,
A. Wadouachi, Bioorg. Med. Chem. Lett. 2008, 18, 2805; f)
F. Hanessian, H. Sailes, E. Therrien, Tetrahedron 2003,
7047.
General
procedure
for
the
base-mediated
intramolecular Michael addition. Synthesis of -sultams
5.
A microwave vial was filled with oven-dried 4Å MS and it
was heated at 120oC for 10 min under microwave
irradiation. Then,
a solution of the corresponding
compound 4 (1.0 equiv) in THF (0.1M) was added into the
vial. After immersing it into a 78oC bath, phosphazene
base P2-Et (1.0 equiv) was added and the resulting mixture
was stirred at that temperature for 4 hours. Then, the crude
reaction mixture was hydrolyzed with 1M HCl, extracted
with EtOAc and dried over anhydrous Na2SO4. Purification
of the crude mixture by flash column chromatography on
silica gel using mixtures of n-hexane: ethyl acetate as
eluents afforded the corresponding bicyclic sultams 5. The
enantiomeric ratios were determined by means of HPLC
analysis with an appropriate chiral column.
[4] See, for example: a) R. Silvestri, G. Marfè, M. Artico,
G. La Regina, A. Lavecchia, E. Novellino, M. Morgante, C.
Di Stefano, G. Catalano, G. Filomeni, E. Abruzzese, M. R.
Ciriolo, M. A. Russo, S. Amadori, R. Cirilli, F. La Torre, P.
S. Salimei, J. Med. Chem. 2006, 49, 5840; b) F.
Brzozowski, F. Saczewski, N. Neamati, Bioorg. Med.
Chem. Lett. 2006, 16, 5298; c) N. Lebegue, S. Gallet, N.
Flouquet, P. Carato, B. Pfeiffer, P. Renard, S. Leonce, A.
Pierre, P. Chavatte, P. Berthelot, J. Med. Chem. 2005, 48,
(4S,4aR)-4-(1-oxoethyl)octahydropyrido[1,2-
b][1,2]thiazine 1,1-dioxide (5a): By means of the general
procedure described above, bicyclic sultam 5a (38.5 mg)
was obtained as a white solid from 4a in 77% yield and 7363.
93:7 er after flash chromatography with 1:1 n-hexanes:
[5] X. Rabasseda, S. J. Hopkins, Drugs Today 1994, 30,
557.
ethyl acetate. The er value was determined by RID-HPLC
analysis using a Chiralcel OD-H column (hexane:
isopropanol 85:15); flow rate = 1.0 mL/min, tmajor= 26.0
25
[6] J. G. Lombardino, E. H. Wiseman, W. M. McLamore,
J. Med. Chem. 1971, 14, 1171.
min, tminor= 24.2 min. []D +1.9 (c 1.0, CHCl3). Mp= 34-
1
36oC. H NMR (300 MHz, CDCl3) δ 1.36-1.77 (m, 6H),
2.13-2.20 (m, 4H), 2.28-2.42 (m, 1H), 2.82-2.91 (m, 1H),
2.97-3.17 (m, 3H), 3.29-3.37 (m, 1H), 3.75-3.82 (m, 1H).
13C NMR (75 MHz, CDCl3) δ 20.9, 24.5, 25.9, 20.4, 29.7,
41.9, 45.0, 49.8, 58.3, 208.0. HRMS (ESI/Q-TOF) m/z:
[M++H] calcd. for C10H17NO3S 232.1002; found: 232.0996.
[7] H. Tanimukai, M. Inui, S. Harigushi, J. Kaneko,
Biochem. Pharmacol. 1965, 14, 961.
[8] S. Kasper, B. S. McEwen, CNS Drugs, 2008, 22, 15.
[9] For some reviews regarding the synthesis of sultams,
see: a) S. Debnath, S. Mondal, Eur. J. Org. Chem. 2018,
933; b) M. V. Popova, A. V. Dobrydnev, Chem. Het. Comp.
2017, 53, 492; c) K. C. Majumdar, S. Mondal, Chem. Rev.
2011, 111, 7749; d) Z. Liu, Y. Takeuchi, Heterocycles
2009, 78, 1387; e) M. I. Page, Acc. Chem. Res. 2004, 37,
297; f) Z. Liu, Y. Takeuchi, Heterocycles 2002, 56, 693.
Acknowledgements
We gratefully thank the Spanish Ministerio de Economía y
Competitividad (CTQ-2017-43310-P to C. P.). M. E. thanks the
Spanish Ministerio de Educación, Cultura y Deporte for a
predoctoral fellowship.
[10] a) A. W. M. Lee, W. H. Chan, S.-J. Zhang, H.-K.
Zhang, Curr.Org. Chem. 2007, 11, 213; b) O. Reiser in
Organic Synthesis Highlights IV (Ed.: H.-G. Schmalz),
Wiley-VCH: Weinheim, 2000, 11.
[11] F. A. Davis, B.-C. Chen, Chem. Rev. 1992, 92, 919.
References
[12] a) W. Oppolzer, C. Chauis, G. Bernardinelli, Helv.
Chim. Acta 1984, 67, 1397; b) W. Oppolzer, Pure Appl.
Chem. 1990, 62, 1241; c) B. H. Kim, D. P. Curran,
Tetrahedron 1993, 49, 293.
[1] For a history about the discovery of the first
sulfonamide, see: R. J. Bentley, Ind. Microbiol. Biotechnol.
2009, 36, 775.
7
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
[13] For a recent review, see: M. M. Heravi, V. Zadsirjan, Zhang, Angew. Chem. Int. Ed. 2013, 52, 7540; d) H. B.
Tetrahedron Asymm. 2014, 25, 1061.
Hepburn, H. W. Lam, Angew. Chem. Int. Ed. 2014, 53,
11605; e) T. Jiang, Z. Wang, M.-H. Xu, Org. Lett. 2015, 17,
528.
[14] For selected recent examples in the last two years,
see: a) S. Debnath, S. Mondal, Tetrahedron Lett. 2018, 59,
2260; b) N. Thrimurtulu, R. Nallagonda, C. M. R. Volla, [23] R.-R. Liu, D.-J. Wang, L. Wu, B. Xiang, G.-Q. Zhang,
Chem. Commun. 2017, 53, 1872; c) Z. Gong, G. Li, J. Wu, J.-R. Gao, Y.-X. Jia, ACS Catal. 2015, 5, 6524.
Org. Chem. Front. 2017, 4, 14; d) J. K. Laha, R. A.
[24] C. A. Osborne, T. B. D. Endean, E. R. Jarvo, Org.
Bhimpuria, A. M. Kumar, Org. Chem. Front. 2017, 4,
Lett. 2015, 17, 5340.
2170; e) T. B. Nguyen, P. Retailleau, Org. Lett. 2017, 19,
3879; f) V. A. Rassadin, M. Scholz, A. A. Klochkova, A.
de Meijere, Beilstein J. Org. Chem. 2017, 13, 1932; g) A. S.
Reddy, A. L. S. Kumari, K. C. K. Swamy, Tetrahedron
2017, 73, 2766; h) S. Mondal, S. Debnath, Synthesis 2016,
48, 710; i) Y. Xiang, Y. Kuang, J. Wu, Org. Chem. Front.
2016, 3, 901; j) W. D. Guerra, R. A. Rossi, A. B. Pierini, S.
M. Barolo, J. Org. Chem. 2016, 81, 4965; k) Q.-Q. Zhao,
X.-Q. Hu, M.-N. Yang, J.-R. Chen, W.-J. Xiao, Chem.
Commun. 2016, 52, 12749.
[25] a) S. Zhang, L. Li, Y. Hu, Z. Zha, Z. Wang, T.-P. Loh,
Org. Lett. 2015, 17, 1050; b) S. Nakamura, M. Sano, A.
Toda, D. Nakane, H. Masuda, Chem. Eur. J. 2015, 21,
3929.
[26] a) Y. Li, M. Lei, W. Yuan, E. Meggers, L. Gong,
Chem. Commun. 2017, 53, 8089; b) C.-B. Yu, D.-W. Wang,
Y.-G. Zhou, J. Org. Chem. 2009, 74, 5633.
[27] a) X. Yin, Y. Zheng, X. Feng, K. Jiang, X.-Z. Wei, N.
Gao, Y.-C. Chen, Angew. Chem. Int. Ed. 2014, 53, 6245; b)
C. Ma, J. Gu, B. Teng. Q.-Q. Zhou, R. Li, Y.-C. Chen, Org.
Lett. 2013, 15, 6206. For a Rh-catalyzed [3+2] annulation
leading to spirocyclic sultams, see: c) M. V. Pham, M.
Cramer, Chem. Eur. J. 2016, 22, 2270.
[15] For selected examples on the synthesis of non-
benzofused bicyclic or polycyclic sultams, see: a) M.
Ghandi, N. Zarezadeh, A. Abbasi, RSC Adv. 2016, 6, 6785;
b) N. Asad, T. B. Samarakoon, Q. Zang, J. K. Loh, S.
Javed, P. R. Hanson, Org. Lett. 2014, 16, 82; c) N. Lad, R.
Sharma, V. E. Marquez, M. Mascarenhas, Tetrahedron Lett.
2013, 54, 6307; d) V. A. Rassadin, D. S. Grosheva, A. A.
Thomasevskiy, V. V. Sokolov, D. S. Yufit, S. I.
Kozhushkov, A. de Meijere, Eur. J. Org. Chem. 2010,
3481; e) S. Merten, R. Fröhlich, O. Kataeva, P. Metz, Adv.
Synth. Catal. 2005, 347, 754; f) I. R. Greig, M. J. Tozer, P.
T. Wright, Org. Lett. 2001, 3, 369; g) U. Chiacchio, A.
Corsaro, A. Rescifina, M. Bkaithan, G. Grassi, A. Piperno,
T. Privitera, G. Romeo, Tetrahedron 2001, 57, 3425.
[28] a) J. A. McIntosh, P. S. Coelho, C. C. Farwell, J.
Wang, J. C. Lewis, T. R. Brown, F. H. Arnold, Angew.
Chem. Int. Ed. 2013, 52, 9309; b) M. Ichinose, H.
Suematsu, Y. Yasutomi, Y. Nishioka, T. Uchida, T.
Katsuki, Angew. Chem. Int. Ed. 2011, 50, 9884.
[29] For some examples regarding the synthesis of chiral
non-benzofused sultams employing chiral starting materials
or chiral auxiliaries, see: a) Ref. 15b; b) A. Zhou, P. R.
Hanson, Org. Lett. 2008, 10, 2951; b) M. Jiménez-Hopkins,
P. R. Hanson, Org. Lett. 2008, 10, 2223; c) D. Enders, A.
Moll, J. W. Bats, Eur. J. Org. Chem. 2006, 1271.
[16] B. P. Fauber, O. René, Y. Deng, J. DeVoss, C.
Eidenschenk, C. Everett, A. Ganguli, A. Gobbi, J. Hawkins,
A. R. Johnson, H. La, J. Lech, P. Lockey, M. Norman, W.
Ouyang, S. Summerhill, H. Wong, J. Med. Chem. 2015, 58,
5308.
[30] For one example regarding the synthesis of sultam
scaffolds through an intramolecular oxa-Michael reaction
see ref. 29b.
[17] a) R. E. Conrow, W. D. Dean, P. W. Zinke, M. E.
Deason, S. J. Sproull, A. P. Dantanarayama, M. T. DuPriest,
Org. Proc. Res. Dev. 1999, 3, 114; b) T. Wroblewski, A.
Graul, J. Castaner, Drugs Future 1998, 23, 365.
[31] M. Sánchez-Rosello, J. L. Aceña, A. Simón-Fuentes,
C. del Pozo, Chem. Soc. Rev. 2014, 43, 7430 and
references therein.
[32] For a review on the utility of the CM reaction
followed by intramolecular Michael additions, see: M.
Sánchez-Rosello, J. Miró, C. del Pozo, Synthesis 2017, 49,
2787.
[18] G. J. Wells, M. Tao, K. A. Josef, R. J. Bihovsky, J.
Med. Chem. 2001, 44, 3488.
[19] C.-B. Yu, D.-W. Wang, Z. Da-Wei, G. Yong, J. Org.
Chem. 2009, 74, 5633.
[33] A. K. Chatterjee, T.-L. Choi, D. P. Sanders, R. H.
[20] R. J. Cherney, R. Mo, D. T. Meyer, K. D. Hardman,
R.-Q. Liu, M. B. Covington, M. Qian, Z. R. Wasserman, D.
D. Christ, H. M. Trzaskos, R. C. Newton, C. P. Decicco, J.
Med. Chem. 2004, 47, 2981.
Gurbbs, J. Am. Chem. Soc. 2003, 125, 11360.
[34] For reviews regarding the CM reaction, see: a) M. B.
Herbert, R. H. Grubbs, Angew. Chem. Int. Ed. 2015, 54,
5058; b) K. Lafaye, C. Bosset, L. Nicolas, A. Guérinot, J.
Cossy, Beilstein J. Org. Chem. 2015, 11, 2223; c) Y.
Schrodi, R. L. Pederson, Aldrichimica Acta 2007, 40, 45;
d) S. J. Connon, S. Blechert, Angew. Chem. Int. Ed. 2003,
42, 1900; e) A. J. Vernall, A. D. Abell, Aldrichimica Acta
2003, 36, 93.
[21] The first catalytic enantioselective nucleophilic
addition to cyclic N-sulfonyl ketimines was reported by
Bode and co-workers: M. Rommel, T. Fukuzumi, J. W.
Bode, J. Am. Chem. Soc. 2008, 130, 17266.
[22] For examples of enantioselective addition of
organoboron reagents to cyclic N-sulfonyl imines, see: a) T.
Nishimura, A. Noishiki, G. C. T. Tsui, Hayashi, J. Am.
Chem. Soc. 2012, 134, 5056; b) H. Wang, T. Jiang, M.-H.
Xu, J. Am. Chem. Soc. 2013, 135, 971; c) G. Yang, W.
[35] S. Fustero, C. del Pozo, C. Mulet, R. Lázaro, M.
Sánchez-Roselló, Chem. Eur. J. 2011, 17, 14267.
8
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10.1002/adsc.201800548
Advanced Synthesis & Catalysis
[36] The cyclization reaction was also evaluated
employing BF3·OEt in THF at room temperature. However,
the reaction did not take place under these acidic conditions.
[37] Superbases for Organic Synthesis: Guanidines,
Amidines, Phosphazenes and Related Organocatalysts, Ed.
T. Ishikawa, 2009 John Wiley & Sons, Ltd.
[38] CCDC 1839885 contains the full supplementary
crystallographic data for compound 5a. These data are
provided free of charge by The Cambridge
Crystallographic Data Centre.
9
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Advanced Synthesis & Catalysis
FULL PAPER
Dual Role of Vinyl Sulfonamides as N-
Nucleophiles and Michael Acceptors in the
Enantioselective Synthesis of Bicyclic -Sultams
Adv. Synth. Catal. Year, Volume, Page – Page
Cristina Mulet, Marcos Escolano, Sebastián Llopis,
Sergio Sanz, Carmen Ramírez de Arellano, María
Sánchez-Roselló, Santos Fustero* and Carlos del
Pozo*
10
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