Access to Optically Pure Benzosultams by Superelectrophilic Activation

Article abstract of DOI:10.1021/acs.orglett.0c01301

Through superacid activation, N-(arenesulfonyl)-aminoalcohols derived from readily available ephedrines or amino acids undergo an intramolecular Friedel-Crafts reaction to afford enantiopure benzosultams bearing two adjacent stereocenters in high yields with fully controlled diastereoselectivity. Low-temperature NMR spectroscopy demonstrated the crucial role played by the conformationally restricted chiral dicationic intermediates.

Full text of DOI:10.1021/acs.orglett.0c01301

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Letter
Access to Optically Pure Benzosultams by Superelectrophilic
Activation
́
̂
Bastien Michelet,* Ugo Castelli, Emeline Appert, Maude Boucher, Kassandra Vitse, Jerome Marrot,
́
̂
̀
́
Jerome Guillard, Agnes Martin-Mingot, and Sebastien Thibaudeau*
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ABSTRACT: Through superacid activation, N-(arenesulfonyl)-aminoalcohols derived from readily available ephedrines or amino
acids undergo an intramolecular Friedel−Crafts reaction to afford enantiopure benzosultams bearing two adjacent stereocenters in
high yields with fully controlled diastereoselectivity. Low-temperature NMR spectroscopy demonstrated the crucial role played by
the conformationally restricted chiral dicationic intermediates.
enzosultams are prominent scaffolds in organic synthesis
to benzosultams.5 This process is promoted by the in situ
formation of superelectrophilic ammonium−carbenium dica-
tions that can react with very poor aromatic nucleophiles such
as arenesulfonamides despite the strong deactivating character
of the sulfamoyl group (Figure 2A).
B
and have found many applications, especially in medicinal
chemistry (Figure 1).1 In light of the growing demand for
Interestingly, starting from an N-aroyl derivative of
(−)-ephedrine, Trepanier demonstrated the formation of an
enantiopure dihydroisoquinolinone derivative after reaction in
concentrated sulfuric acid (Figure 2B).6 This reaction
suggested the implication of a strong electrophilic benzylic
carbocation and motivated this work. By taking advantage of
the stability of benzylic carbocations and of the benzylic strain,
Bach7 and others8 developed highly diastereoselective inter-
and intramolecular reactions that can be considered as guides
for further developments (Figure 2C). We envisioned that
starting from simple N-(arenesulfonyl)-ephedrine derivatives 1,
the conformationally restricted dicationic key intermediate A
could be generated under superacidic conditions. It would
react diastereoselectively to furnish enantiopure benzosultams
(Figure 2D). This strategy would also be amenable to a higher
level of complexity starting from amino acids in very few steps,
Figure 1. Selected examples of biologically active benzosultams.
enantioenriched benzosultam-based therapeutics, versatile
methodologies for their synthesis have been developed,
including metal-catalyzed asymmetric cyclization, enantiose-
lective addition to N-sulfonyl imines, reductive amination, or
C−H bond amination.2 Although demonstrated to be efficient
approaches to generate enantioenriched benzosultams exhibit-
ing one sterocenter, expeditious methods to control multiple
continuous stereocenters of enantiopure benzosultams are still
in demand.3
Received: April 14, 2020
One of the simplest routes to nitrogen-containing hetero-
cycles is probably the intramolecular Friedel−Crafts alkylation
of alkenes or alcohols.4 We previously demonstrated that
under superacid conditions, N-allyl-arenesulfonamides cyclize
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A

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Table 1. Optimization of the Acid-Promoted
Diastereoselective Synthesis of Benzosultam 2a
a
a
entry
acid
conditions
[2a] (%)
[2b] (%)
b
1
2
3
4
5
6
7
8
HF/SbF5 (7/1)
TfOH
−40 °C, 0.5 h
−40 °C, 0.5 h
−40 °C, 16 h
20 °C, 0.5 h
20 °C, 16 h
−40 °C, 16 h
20 °C, 0.5 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
20 °C, 16 h
10 °C, 16 h
−14 °C, 16 h
70
70
10
c
b
TfOH (2 equiv)
TfOH (2 equiv)
TfOH (2 equiv)
FeCl3 (2 equiv)
FeCl3 (2 equiv)
FeCl3 (2 equiv)
FeCl3 (1 equiv)
FeCl3 (0.1 equiv)
AlCl3 (2 equiv)
BF3OEt2 (2 equiv)
CeCl3 (2 equiv)
Ce(OTf)3 (2 equiv)
Bi(OTf)3 (2 equiv)
Sc(OTf)3 (2 equiv)
d
32
d
45
d
48
89
38
9
10
11
12
13
14
15
16
17
18
18
14
b
H2SO4 (95%)
CF3CO2H
14
b
Figure 2. (A) Previous work on the superacid-mediated synthesis of
racemic benzosultams. (B) Dihydroisoquinolinone derivative syn-
thesis in concentrated sulfuric acid. (C) Highly diastereoselective
intramolecular Friedel−Crafts alkylation induced by benzylic strain.
(D) Strategy envisioned for the diastereoselective synthesis of
optically pure benzosultams by superelectrophilic activation (this
work).
a
b
Yield of isolated product unless otherwise stated. Used as solvent.
c
d
Traces. Determined by 1H NMR analysis using p-anisaldehyde as an
internal standard.
the system by running the reaction in sulfuric acid or
trifluoroacetic acid was shown to be detrimental to the
reaction, a result that supports our initial hypothesis and the
necessity to use superelectrophilic activation to perform this
transformation (Table 1, entries 17 and 18). To avoid the
formation of any regioisomeric byproducts and for better
reproducibility, we selected the use of neat trifluoromethane-
sulfonic acid at −40 °C as the optimal conditions (Table 1,
entry 2).
making this method one of the rare examples of enantiopure
benzosultam synthesis from the chiral pool.9−12
First, our initial hypothesis was evaluated by testing the
reactivity of ephedrine derivative 1a, bearing a relatively
electron-rich tosyl group, to various acidic conditions (Table
1). Using neat HF/SbF5 superacid,5 we could obtain the
desired cyclized product 2a after only 30 min at −40 °C in a
good 70% yield with fully controlled diastereoselectivity (Table
1, entry 1). Delightfully, switching HF/SbF5 to the safer
trifluoromethanesulfonic acid afforded 2a in similar yield and,
again, as a single diastereomer (Table 1, entry 2). However,
any attempts at using lower amounts of trifluoromethanesul-
fonic acid in CH2Cl2 led to poor yields or the formation of the
regioisomer 2b when the reaction was carried out at a higher
temperature (Table 1, entries 3−5). Such isomerization is a
well-known drawback of Friedel−Crafts alkylations and can be
explained by intramolecular rearrangement within the arenium
ion generated by the subsequent protonation of the kinetic
product 2a to the most stable product 2b.13 Nevertheless, the
formation of byproduct 2b can be prevented by keeping the
reaction mixture at −40 °C, allowing the isolation of 2a as a
single regio- and stereoisomer.14 We next evaluated the
reactivity of 1a with an excess of Lewis acids. FeCl3 was
found to be inactive at −40 °C, and carrying out the
transformation at a higher temperature afforded, again, the
undesired regioisomer 2b (Table 1, entries 6−10). The use of
other Lewis acids from the main group, transition metal, or
lanthanide series led to poor yields or no conversion at all
(Table 1, entries 11−16). Decreasing the protonating ability of
The scope and functional group tolerance of this
diastereoselective intramolecular Friedel−Crafts cyclization
were next evaluated (Figure 3). Ephedrine derivatives 1a−e,
exhibiting alkyl electron-donating groups on the aromatic ring,
were smoothly converted to the corresponding enantiopure
benzosultams in good to excellent yields. The presence of
electron-donating group on the arenesulfonamide is not
essential for the cyclization, as shown by the clean conversion
of substrate 1f to its cyclic analogue 2f. Naphthalene and
indane derivatives 2g and 2h were also generated in very good
yields by exploiting this reaction. The reaction proceeded
equally well with electron-rich methoxy-substituted arenesul-
fonamides, affording compounds 2i and 2j in excellent yields.
It is noteworthy that the two regiosiomers 2jp and 2jo could be
separately isolated after flash column chromatography. Where-
as products 2k−m were generated in generally lower yields,
their formation, which must involve the nucleophilic addition
of the halogenated deactivated aromatic rings, further
reinforces the hypothesis of the transient formation of a highly
reactive cationic intermediate. However, strongly deactivating
substituents such as CF3, C(O)Me, or NO2 completely
inhibited the cyclization (Figure 3, bottom). Heteroarene
could also be used as a nucleophile, as exemplified by the
B
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Figure 4. Synthesis of benzosultam precursors 1p−s from amino
acids.
platform, successive tosylation/reductive amination/reduc-
tion/aryl Grignard addition led to the clean formation of
enantiomers 1p−r. A slightly modified procedure from proline
derivatives led to the formation of product 1s. The Grignard
addition was fairly diastereoselective (dr from 4.7:1 to >20:1),
and the major syn diastereomers 1p−s could be cleanly
isolated by flash chromatography on silica gel.15
The superacid-promoted cyclization applied to 1p and 1q
gratifyingly demonstrated the compatibility of the method with
halogenated ephedrine derivatives (Figure 5). However,
Figure 3. Reaction scope for the synthesis of enantiopure
a
benzosultams derived from ephedrines. A 63% yield was obtained
on a 1 g scale (see the SI for full details). bMajor regioisomer depicted
with solid bonds; minor regioisomer depicted with dashed bonds.
cEllipsoids are drawn at a 50% probability level, and hydrogen atoms
are represented as fixed-size spheres of radius 0.30 Å.
Figure 5. Reaction scope for the synthesis of enantiopure
benzosultams derived from amino acids.
preparation of benzosultam 2n, an analogue of the
antiglaucoma agent brinzolamide. Norephedrine derivative
1o, bearing no methyl group on the nitrogen atom, reacted
under the optimized conditions to afford benzosultams 2o,
albeit in moderate yield, opening new synthetic perspectives
through further N-functionalizations. The structure and
stereochemistry of these chiral compounds were confirmed
by X-ray analysis of the collected crystals of 2a generated after
the reaction of substrate 1a. To highlight the versatility of the
method and verify the enantiopurity of every products, the
reaction was carried out with each enantiomer of starting
material. With success, the corresponding cyclic products were
generated in the enantiopure form in similar yields.
substrates exhibiting vinyl or electronically enriched p-
methoxyphenyl substituents led to only a complex mixture of
compounds. In the latter case, the enhanced stability of the
postulated benzylic cation seems detrimental to the process,
leading to the formation of degradation byproducts upon
hydrolysis. Performing this reaction with FeCl3 (conditions
from Table 1, entry 8) afforded only N-(methyl)tosylamine in
97% yield, which confirms the lower reactivity of the cationic
intermediate toward Friedel−Crafts alkylation. As illustrated
by the transformation of 1r and 1s, respectively, synthesized
from leucine and proline the diastereoselectivity of the reaction
is maintained with bulkier α-substituted amines. Furthermore,
the formation of enantiomers 2s proves the efficiency of this
strategy to generate enantiopure conformationally rigid sultams
of interest.16
One step further in complexity, substrates bearing more
hindered alkyl substituents at the stereogenic center as well as
substitutents on the phenyl ring were selected (substrates 1p−
s, Figure 4). Using the corresponding amino acids as a chiral
C
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From a mechanistic point of view, this reaction most likely
proceeds through the formation of a benzylic carbocation.7d
The stereochemical information borne by the hydroxy-
substituted benzylic carbon should therefore play only a
minor role in the outcome of the transformation. When the
tosyl-pseudoephedrine 1a′ (diastereomer of 1a) was reacted
under the optimized conditions, benzosultam 2a was isolated
in a similar yield (83 vs 70−77%) as starting from 1a, thus
confirming our hypothesis (Figure 6A). Then, we explored the
Under these conditions, 1H, 13C, and HSQC NMR analyses of
the crude reaction mixture provided strong evidence of the
formation of the key dicationic species At (Figure 6B).18 The
1H NMR spectrum displays a doublet (J = 9.7 Hz) at 8.10 ppm
that is characteristic of a carbocationic benzylic C−H bond7d
as well as a broad signal at 6.37 ppm attributed to the
protonation of the sulfonamide moiety.19 The signal of the N-
methyl substituent is now a doublet (J = 4.6 Hz) slightly
shielded to 1.79 ppm (compared with a singlet at 2.79 ppm for
1t in CDCl3). This species is also characterized by a benzylic
carbenium ion at 198.4 ppm in the 13C NMR spectrum.7d,8d
Interestingly, both 1H and 13C NMR spectra show non-
equivalent signals for the phenyl substituent, indicating a
restriction of rotation around the phenyl−carbocation bond.7b
1
Luckily, the H NMR spectrum was sufficiently well-resolved
to allow a NOESY experiment, which showed a correlation
between the benzylic proton and an aromatic ortho proton as
well as a correlation between the proton at the stereogenic
center and another aromatic ortho proton. Altogether, these
NMR observations supported our initial hypothesis on the
generation of conformationally restricted superelectrophiles in
superacid. The carbon atom in the para position displays a
strong downfield shift to 168.1 ppm (compared with 128.1
ppm for 1t in CDCl3), indicating a strong delocalization of the
positive charge to this carbon atom. This observation might be
explained by the propensity of the aryl group to tackle the
destabilization of the benzylic carbocation induced by the
proximity of the second cationic charge located on the nitrogen
atom.8d Collectively, these data suggest that a right balance
between conformational stabilization and sufficient electro-
philic character must exist to favor the intramolecular
diasteroselective nucleophilic substitution.
To conclude, taking advantage of the chiral pool, a series of
optically active N-(arenesulfonyl)-aminoalcohols were effi-
ciently converted to enantiopure benzosultams exhibiting a
wide array of functions and substitution patterns. As
demonstrated by low-temperature NMR spectroscopy, this
process exploits the superelectrophilic character and the
privileged conformation of chiral benzylic dications in a
superacidic solution.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01301.
Figure 6. (A) Synthesis of benzosultam 2a from tosyl-pseudoephe-
drine 1a′. (B) Low-temperature 1H NMR (top) and 13C NMR
(bottom) analyses of ephedrine derivative 1t in HF/SbF5 (1/1) at
−40 °C. Acetone-d6 is used as the external standard.
General experimental procedures, reaction setup, char-
acterization data, low-temperature NMR spectra, and
spectra for all key compounds (PDF)
Accession Codes
hypothetical formation of any dicationic intermediate in
superacid solutions. To this end, preventing the substrate
from any cyclization by substituting the arenesulfonyl moiety
with a trifluoromethyl group, we initiated our investigation by
exploring the behavior of N-(arenesulfonyl)ephedrine 1t in
TfOH by a low-temperature in situ NMR analysis. Unfortu-
CCDC 1994486 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
nately, in TfOH, no clean H or 13C NMR spectra could be
collected from this experiment. Considering that the lifetime of
the generated cations under these conditions disallows any
observation on the NMR time scale, the same experiment was
conducted under weaker nucleophilic conditions17 by submit-
ting the same substrate to a HF/SbF5 superacid solution.
AUTHOR INFORMATION
■
Corresponding Authors
́
́
Sebastien Thibaudeau − Universite de Poitiers, UMR-CNRS
̀
7285, IC2MP, Equipe Synthese Organique, Poitiers 86073
D
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Cedex 9, France; orcid.org/0000-0002-6246-5829;
pubs.acs.org/OrgLett
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Email: sebastien.thibaudeau@univ-poitiers.fr
́
Bastien Michelet − Universite de Poitiers, UMR-CNRS 7285,
̀
IC2MP, Equipe Synthese Organique, Poitiers 86073 Cedex 9,
France; Email: bastien.michelet@univ-poitiers.fr
Authors
́
Ugo Castelli − Universite de Poitiers, UMR-CNRS 7285,
̀
IC2MP, Equipe Synthese Organique, Poitiers 86073 Cedex 9,
France
́
Emeline Appert − Universite de Poitiers, UMR-CNRS 7285,
IC2MP, Equipe Synthese Organique, Poitiers 86073 Cedex 9,
France
̀
́
Maude Boucher − Universite de Poitiers, UMR-CNRS 7285,
̈
hlthau, F.; Schuster, O.; Bach, T. J. Am. Chem. Soc. 2005,
hlthau, F.; Stadler, D.; Goeppert, A.; Olah, G. A.;
̀
IC2MP, Equipe Synthese Organique, Poitiers 86073 Cedex 9,
̈
France
Prakash, G. K. S.; Bach, T. J. Am. Chem. Soc. 2006, 128, 9668.
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Chem. 2009, 74, 312. (e) Rubenbauer, P.; Bach, T. Chem. Commun.
́
Kassandra Vitse − Universite de Poitiers, UMR-CNRS 7285,
̀
IC2MP, Equipe Synthese Organique, Poitiers 86073 Cedex 9,
France
́
̂
2009, 2130. (f) Stadler, D.; Muhlthau, F.; Rubenbauer, P.;
̈
Herdtweck, E.; Bach, T. Synlett 2006, 16, 2573−2576.
Jerome Marrot − Institut Lavoisier de Versailles, UMR CNRS
8180, Versailles 78035 Cedex, France
(8) (a) Chung, J. Y. L.; Mancheno, D.; Dormer, P. G.; Variankaval,
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L.; Alorati, A. D.; Brewer, S. E.; Scott, J. P. Org. Process Res. Dev. 2012,
́
̂
́
Jerome Guillard − Universite de Poitiers, UMR-CNRS 7285,
̀
IC2MP, Equipe Synthese Organique, Poitiers 86073 Cedex 9,
France
̀
́
Agnes Martin-Mingot − Universite de Poitiers, UMR-CNRS
7285, IC2MP, Equipe Synthese Organique, Poitiers 86073
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16, 1832. (c) Chenard, E.; Hanessian, S. Org. Lett. 2014, 16, 2668.
Cedex 9, France
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(15) See the SI for more information.
Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We great fully acknowledge the French Ministry of research
and education for the Ph.D. grant (for U.C.). We also
acknowledge the University of Poitiers, the Centre National de
la Recherche Scientifique, the European Union (ERDF), the
́
Region Nouvelle-Aquitaine, and the French Fluorine Network.
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