Synthesis and functionalization of cyclic sulfonimidamides: A novel chiral heterocyclic carboxylic acid bioisostere

Article abstract of DOI:10.1021/ml3000935

An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids. By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The compounds could be further derivatized in the aryl ring using standard cross-coupling reactions to yield highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique nonplanar shape in combination with the relatively strong acidity (pK_a 5-6) and the ease of modifying the chemical structure to fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available carboxylic acid isosteres.

Full text of DOI:10.1021/ml3000935

Letter
pubs.acs.org/acsmedchemlett
Synthesis and Functionalization of Cyclic Sulfonimidamides: A Novel
Chiral Heterocyclic Carboxylic Acid Bioisostere
Nils Pemberton,*,† Henrik Graden,† Emma Evertsson,† Emma Bratt,† Matti Lepisto,† Petra Johannesson,†
̈
and Per H. Svensson‡,§
†Medicinal Chemistry, AstraZeneca R&D, SE-431 83 Molndal, Sweden
̈
‡AstraZeneca Pharm. Dev., AstraZeneca R&D, SE-151 85 Sodertalje, Sweden
̈
̈
§Department of Applied Physical Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar
heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be
prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids.
By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The
compounds could be further derivatized in the aryl ring using standard cross-coupling reactions to yield
highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final
compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique
nonplanar shape in combination with the relatively strong acidity (pKa 5−6) and the ease of modifying the chemical structure to
fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available
carboxylic acid isosteres.
KEYWORDS: Carboxylic acid bioisostere, sulfonimidamide, bioisostere, acidic heterocycle, chiral heterocycle
he use of bioisosteres is a very important aspect of
modern medicinal chemistry and drug discovery.1
more planar motifs when optimizing drug−receptor inter-
actions. It has also been shown that disrupting the molecular
planarity is beneficial for aqueous solubility.7 In addition, the
possibility to modify and alternate the stereochemistry at S-1
and C-3 might allow optimization to minimize off-target
interactions, thus achieving greater selectivity. All these
properties suggested that this heterocycle could be an attractive
acid bioisostere, and we set out to synthesize this relatively
unexplored ring-system.
To date, only one report of a five membered cyclic
sulfonimidamide ring has been published.8 Cathers et al.
obtained compound 2 when they attempted to crystallize
sulfonimidamide 1 (Scheme 1), which had been prepared in six
steps starting from 2-phenylethanethiol. Even though the
literature on cyclic sulfonimidamides is scarce, there are some
reported preparations of noncyclic sulfonimidamides.9−18
These have mainly been explored as catalysts in asymmetric
synthesis13,14 but a few reports have also applied this
functionality in bioactive molecules,16,17 and recently, Arvids-
son and co-workers reported the use of noncyclic sulfonimi-
damides as a bioisostere for sulfonamides.18 Sulfonimidamides
are most commonly prepared from N-protected sulfinamides by
doing an oxidative chlorination to generate a sulfonimidoyl-
chloride, which can be further reacted with an amine to
generate the noncyclic sulfonimidamide. We envisioned that we
could apply a similar strategy to prepare the desired aryl
T
Introduction of a suitable bioisostere allows the medicinal
chemist to make relatively small structural modifications of a
lead structure to improve the compound's overall properties
without losing biological activity. Carboxylic acid bioisosteres
are one of the most frequently studied bioisosteric replace-
ments in drug discovery. This can be due to carboxylic acids
often having poor ADME properties, but also due to the fact
that carboxylic acids can be metabolized to reactive species such
as acyl glucuronides or CoA esters that can give rise to toxicity
effects.2,3 Some of the most commonly applied carboxylic acid
bioisosteres are heterocyclic motifs such as tetrazoles4 and
isoxazolones.5
In an ongoing medicinal chemistry program, we wanted to
explore new potential carboxylic acid isosteres attached directly
to an aromatic ring. One compound class that attracted our
attention was the five membered cyclic sulfonimidamide ring
system (Figure 1). This heterocycle has an acidic proton that
can be situated on either of the tautomeric nitrogens N-2 or N-
5 or on the oxygens at S-1 or C-4 (Figure 1a). Calculations
suggested that the lowest energy tautomer was the one with the
proton situated at N-2.6 Another important feature that drew
our attention to this heterocycle is that it contains a stereogenic
tetrahedral sulfur atom and a sp3-hybridized carbon, which
results in a twist of the heterocyclic ring (Figure 1b), thus
disrupting the molecular planarity compared to that of other
commonly used carboxylic acid isosteres, such as the
corresponding tetrazole and isoxazolone (see Figure 1b). This
structural differentiation can be beneficial compared to that of
Received: April 18, 2012
Accepted: May 30, 2012
Published: May 30, 2012
© 2012 American Chemical Society
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Figure 1. (a) Four different tautomeric forms can be adopted by the cyclic sulfonimidamide ring-system. Calculations show that the tautomer with
the acidic proton situated on N2 (left molecule depicted above) has the lowest energy. (b) Calculated structure of the 1S,3S stereoisomer of the
cyclic sulfonimidamide depicted in part a and also the corresponding tetrazole and isoxazol-3-one.6
The sulfonyl chloride 3 was first reduced to sulfinic acid 4 using
sodium sulfite, and 4 was then converted to the sulfinyl chloride
5 using thionyl chloride in DCM. Reacting 5 with trifluoro
acetamide in the presence of 2 equiv of n-BuLi yielded
trifluoroacetyl protected sulfinamide 6 in good yield.19 To
introduce the amino acid moiety and transform sulfinamide 6
to sulfonimidamide 7, an oxidative chlorination/amination step
was performed. This transformation was done by first
generating a sulfonimidoylchloride, which is then reacted with
a nucleophilic amine. The most commonly applied reagent to
perform this transformation is the explosive tert-butylhypo-
chlorite. However, recently Bolm and co-workers showed that
N-chlorosuccinimide can be used as a milder and more
convenient alternative.20
Scheme 1
substituted cyclic sulfonimidamideshence, by first preparing a
suitable N-protected sulfinamide and then performing the key
oxidative chlorination/amination step to introduce an ester
protected amino acid, which upon deprotection of the nitrogen
can ring-close to the desired five membered heterocycle in the
same way as observed by Cathers et al.8
We first set out to prepare the N-protected aryl substituted
sulfinamide 6, which also contains an aryl bromide that can
function as a handle to enable further functionalization of the
aromatic ring (Scheme 2). The synthesis of intermediate 6 was
relatively straightforward and could be prepared in three steps
starting from the commercially available sulfonyl chloride 3.
Initial attempts thus involved reacting 6 with N-chlorosucci-
1
nimide in MeCN. The reaction was monitored by H NMR,
and after 10 min at −10 °C, no remaining starting material
could be observed. A solution of L-alanine methyl ester
hydrochloride that had been stirred together with a tertiary
amine base (DIPEA or TEA) in acetonitrile to obtain the free
base was then added to this mixture. Initial attempts gave the
desired noncyclic sulfonimidamide 7 but also several by-
products and resulted in low isolated yields. However, with
further fine-tuning of the reaction conditions by varying the
amount of amino acid and amine base, the formation of
byproduct could be avoided, and using 2 equiv of amino acid
and 2 equiv of base proved to be the optimal conditions. The
crude sulfonimidamide 7 was then deprotected and ring-closed
using NaOMe in refluxing dry MeOH to yield the desired cyclic
sulfonimidamide 8ab as a diastereomeric mixture (ratio 1:1) in
73% over two steps. The diastereomers could be separated
using chiral HPLC, and the relative stereochemistry was
determined by single crystal X-ray analysis of diastereomer 8a
(Figure 2). The hydrogen bond pattern seen in the crystal
a
Scheme 2
a
Reagents and conditions: (a) Na2SO3, NaHCO3, H2O, THF, 75 °C;
(b) SOCl2, DCM; (c) n-BuLi, trifluoro acetamide, THF, −78 °C; (d)
NCS, MeCN, −10 °C then DIPEA, L-alanine methyl ester
hydrochloride, rt; (e) NaOMe, MeOH, reflux.
Figure 2. X-ray crystal structure of 8a.21
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a
structure is consistent with the most stable tautomer based on
calculations (see Figure 1). It was discovered that the quality of
NaOMe was important for the outcome, since some batches of
the commercially available reagent gave hydrolysis of the ester
and the generated acid did not ring-close to the desired
sulfonimidamide. This could be circumvented by instead using
commercially available sodium amylate in MeOH, and this also
proved more convenient from a practical point of view.
Scheme 3
With this methodology in hand, a small series of close
analogues were prepared. Using different commercially
available ester-protected amino acids, C-3 substituted analogues
8c−f were readily synthesized in moderate to good yields (40−
79%), starting from sulfinamide 6 (Table 1). We were now
Table 1. Synthesis of Cyclic Sulfonimidamides 8c−f from
a
Sulfinamide 6
a
Reagents and conditions: (a) arylboronic acid, PdCl2(dtbpf), K2CO3,
MeCN, H2O, 80 °C; (b) Pd(PPh3)4, (3-fluorobenzyl)zinc bromide,
THF, 60 °C.
acids 10a−b and tetrazoles 10c−d were also prepared and
evaluated22 (Table 2). The pKa's of cyclic sulfonimidamides 9a
and 9b were measured and found to be 6.0 and 5.8,
respectively. This was about two log units higher than those
of the corresponding acid 10a and tetrazoles 10c and 10d. The
calculated clogP for the cyclic sulfonimidamides was one unit
lower than the values for the corresponding matched pair
carboxylic acids and tetrazoles but the measured log D values
(at pH 7.4) were similar those of to the analogous carboxylic
acid and tetrazole. One of the reasons for using isosteric
replacements for carboxylic acids is to improve permeability,
and this prompted us to investigate and compare the
permability of these two acidic heterocycles. Permeability was
measured in a Caco-2 membrane assay at pH 7.4, and it was
found that the cyclic sulfonimidamides 9a and 9b had
considerably higher permeability and lower efflux ratio than
the matched-pair tetrazoles 10c and 10d.
In conclusion, we have developed an efficient synthetic
pathway to five membered aryl substituted cyclic sulfonimida-
mides 8a−f. The heterocyclic ring-system was constructed
starting from trifluoroacetyl protected sulfinamide 6, which was
first transformed to a sulfonimidamide by using an oxidative
chlorination/amination sequence using methyl ester protected
amino acids as the amine nucleophile. This was followed by
deprotection and ring-closure to the desired heterocycle under
basic conditions. The cyclic sulfonimidamides could be further
substituted on the aryl ring using standard Suzuki and Negishi
transition metal-catalyzed cross-coupling reactions. This
heterocyclic core was designed as a potential carboxylic acid
isostere. It is less acidic (pKa − 6) than the corresponding
carboxylic acid and tetrazole but has a similar log D at
physiological pH. Compared to the matched-pair tetrazoles,
this heterocycle has higher permeability and lower efflux ratio.
The substitution pattern of the sulfonimidamide ring can easily
be modified by starting from different amino acids. This gives a
straightforward way to decorate the scaffold and vary the
substitution pattern to tune physicochemical properties, as well
as giving access to different stereoisomers. It has also been
shown that this heterocycle has a nonplanar geometry which is
different from those of many of the frequently applied
carboxylic acid isosteres, such as tetrazoles and isoxazolones.
All this suggests that the cyclic sulfonimidamide can be a useful
addition to the range of available carboxylic acid isosteres, and
a
Typical conditions: (1) 6, MeCN, N-chlorosuccinimide, 15 min at 0
°C, then amino acid reagent and DIPEA, rt; (2) sodium amylate,
MeOH, reflux. Isolated yields over two steps given in parentheses.
b
interested to investigate the possibility to further derivatize the
compounds. As mentioned earlier, an aryl bromide had been
incorporated in the starting sulfonylchloride 3 to enable further
chemistry in this part of the molecule, and we were mainly
interested in performing cross-coupling chemistry to further
functionalize the scaffold. By applying standard Suzuki
conditions (PdCl2(dtbpf), K2CO3, MeCN/H2O), cyclic
sulfonimidamide 8b could be coupled with aryl boronic acids
to give biaryls 9a−c (Scheme 3). The reaction worked well
using both electron rich and electron poor boronic acids, and
9a−c were isolated in excellent yields (87−88%). To introduce
a benzyl substituent, a Negishi reaction using (3-fluorobenzyl)
zinc bromide was carried out. This more basic organometallic
reagent was also well tolerated and 9d was prepared in an
efficient manner using 2 equiv of the zinc reagent (Scheme 3).
Since our main interest in cyclic sulfonimidamides revolved
around using this heterocycle as a potential carboxylic acid
bioisostere, some physicochemical properties (log D, pKa, Papp
A-B, efflux ratio) were measured on compounds 9a and 9b, and
to be able to compare the data, the corresponding carboxylic
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Table 2. Physicochemical Properties (log D, pKa, Papp A-B, Efflux Ratio) for 9a, 9b, and 10a−d
a
b
c
Biobyte clogP. Experimental log D; see the Supporting Information for further details. pKa measured using pressure-assisted capillary
d
electrophoresis described in ref 23; see the Supporting Information for further details. Papp A-B is the permeability when applied to the apical side,
while Papp B-A is the permeability when applied to the basolateral side in a Caco-2 membrane assay (10−6 cm/s). The ratio of these two values is a
measure of the efflux ratio (Papp B-A/Papp A-B), while the Papp A-B value is a measure of permeability. The experimental protocol is described in the
Supporting Information.
it is currently being further studied and evaluated in our
laboratories.
ACKNOWLEDGMENTS
■
The authors wish to thank Eva-Lotte Lindstedt (AstraZeneca
R&D CVGI iMed) and Magnus Johansson (AstraZeneca R&D
CVGI iMed) for contributions and fruitful discussions.
ASSOCIATED CONTENT
■
S
* Supporting Information
REFERENCES
■
1
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Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*Fax: + 46-31-776 38 18. E-mail: Nils.Pemberton@astrazeneca.
com.
Notes
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