Water-Soluble Non-Classical Benzene Mimetics

Article abstract of DOI:10.1002/anie.202000548

A new generation of saturated benzene mimetics, 2-oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2-oxabicyclo[2.1.1]hexanes revea

Full text of DOI:10.1002/anie.202000548

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Accepted Article
Title: Water-soluble non-classical benzene mimics
Authors: Vadym Levterov, Yaroslav Panasyuk, Valentyna Pivnytska,
and Pavel Mykhailiuk
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000548
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Water-soluble non-classical benzene mimics
Vadym V. Levterov, Yaroslav Panasyuk, Valentyna O. Pivnytska and Pavel K. Mykhailiuk[a,c]*
[
a]
[a]
[b]
Abstract:
-oxabicyclo[2.1.1]hexanes, - was developed. These compounds
were designed as analogues of bicyclo[1.1.1]pentane with an
A new generation of saturated benzene mimics -
2
improved
water
solubility.
Crystallographic
analysis
of
2-oxabicyclo[2.1.1]hexanes revealed that they occupy
a
novel
chemical space, but at the same time resemble the fragment of
meta-disubstituted benzenes.
Introduction. The phenyl ring is one of the most popular
1
structural elements in bioactive compounds. Its motif is found in
the structures of over five hundred drugs.2 On the other hand,
the recently emerged concept escape from flatland,3 already
changed the way how medicinal chemists think – these days
3
small F(sp )-rich structures are especially popular in drug
discovery projects.4,5 In particular, replacing benzene rings with
saturated bioisosteres has become an important strategy to
obtain novel patent-free molecules with improved biological
activity and physico-chemical profile.6 Recently, Stepan and
colleagues replaced the substituted phenyl fragment in
a
ɣ-secretase inhibitor with the bicyclo[1.1.1]pentyl (BCP)
7
skeleton. The obtained analogue showed higher activity,
solubility and metabolic stability. Since then, bicyclo[1.1.1]pentyl-
containing derivatives have been often used in medicinal
chemistry, and have already been mentioned in more than one
hundred patents (Figure 1).
An increasing demand from pharmaceutical companies
initiated many academic research projects aimed at elaboration
of novel synthetic approaches to bicyclo[1.1.1]pentyl-substituted
building blocks and their analogues.8,9 For example, recently,
Merck chemists and our group developed difluoro-substituted
BCPs (Figure 1).10 The obtained molecules retained the planar
collinearity of exit vectors, but had lower solubility in water than
BCPs, unfortunately. In this work, therefore, we have designed,
synthesized and characterized a new generation of saturated
benzene mimics with improved solubility in water, and reduced
lipophilicity – 2-oxabicyclo[2.1.1]hexanes (Figure 1).
Design. In the design of a core that would have similar
structure to BCP, but much better solubility, we decided to
incorporate an oxygen atom into it. Replacing one methylene
group in BCP with an oxygen atom leads to core A (Scheme 1),
that should have similar geometrical characteristics, and much
better solubility than that of bicyclo[1.1.1]pentane. On the other
hand, core A is a conformationally constrained oxetane, and we
worried about its putative chemical (in)stability, because
oxetanes can be easily ring-opened by nucleophiles.11
Figure 1. Bicyclo[1.1.1]pentanes (BCPs) in medicinal chemistry. New
generation saturated benzene mimics – 2-oxabicyclo[2.1.1]hexanes.
Adding an additional oxygen atom to BCP, however, gives
core B (Scheme 1). It should have slightly different geometry,
indeed, but still better solubility than BCP. We also hoped, that
core B, being substituted tetrahydrofuran (no oxetane ring),
should be also chemically stable. Finally, we decided to develop
a practical route to mono- and disubstituted derivatives B,
suitable for the direct use in medicinal chemistry projects.
[a]
Mr. V. Levterov, Dr. Y. Panasyuk, Dr. Sci. P. K. Mykhailiuk
Enamine Ltd.; Chervonotkatska 78, 02094 Kyiv (Ukraine)
www.enamine.net; www.mykhailiukchem.org
Scheme 1. Design of analogues of bicyclo[1.1.1]pentanes with an enhanced
water solubility: cores A and B (2-oxabicyclo[2.1.1]hexane).
E-mail: Pavel.Mykhailiuk@gmail.com
[
[
b]
c]
Mrs. V. O. Pivnytska, Bienta, Chervonotkatska 78, Kyiv 02094
(Ukraine), www.bienta.net
Synthesis. Previously, we elaborated effective photochemical
Dr. P. K. Mykhailiuk; Taras Shevchenko National University of Kyiv;
Chemistry Department; Volodymyrska 64, 01601 Kyiv (Ukraine).
approaches to functionalized 2-azabicyclo[2.1.1]hexanes;12 but
unfortunately, we could not expand them onto the needed
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2
-oxabicyclo[2.1.1]hexanes (B). Therefore, we had to develop
acetate 10b. Phenyl-substituted product 11a and iodide 12a
were also synthesized.
13
alternative methods. Although the non-substituted or chain-
substituted 2-oxabicyclo[2.1.1]hexanes14 are well-documented,
the bridgehead-substituted structures remain unknown in a peer-
reviewed literature. In 2017, however, in a patent was described
a reaction of alkene L1 into product L2 and the subsequent
interesting transformations of functional groups (Scheme 2).15 In
our hands, unfortunately, only complex mixtures were formed
that according to GC-MS data contained traces of the needed
product. Presumably, non-selective oxidation of the primary
hydroxyl group took place. Nevertheless, this data gave us a
clue on how to optimize the described transformation. In
particular, we decided first to remove the labile hydroxyl group
and to run a reaction on a model substrate 1 (Scheme 2).
Indeed, the reaction smoothly took place, and the needed iodide
1
a was obtained in 67% yield (Scheme 2, entry 14). Quick
screen of the reaction conditions allowed increasing the isolated
yield of product 1a to 78% (Scheme 2, entry 1). Inorganic bases
(
(
(
entries 1-4) worked generally better than the organic ones
entries 5-8). Both iodine and N-iodosuccinimide worked well
entries 13, 14), but iodine gave better yields.
a
after the synthesis, unstable iodide 10a was treated with KOAc.
Scheme 3. Synthesis of 2-oxabicyclo[2.1.1]hexanes 1a-12a.
Mono-substituted cores. Two types of 2-oxabicyclo[2.1.1]-
hexanes mono-substituted at the bridgehead positions are
possible (A and B, Scheme 4). We started the synthesis of core
A by reacting iodide 8a with potassium acetate, followed by an
alkali hydrolysis to obtain alcohol 13 in 72% yield. Oxidation of
4 3
compound 13 with NaIO /RuCl (cat.) gave valuable acid 14, the
1
6
structure of which was confirmed by X-Ray analysis. Coupling
of acid 14 with N-hydroxyphtalimide (NHPI) afforded the redox-
active ester 15. Next, we performed a key nickel-catalysed
radical decarboxylation of substrate 15 - a transformation
recently developed by Baran and coworkers,17 - into ester 16.
The reaction was easily performed at room temperature with
catalytic amount of NiCl
No irradiation was needed in that transformation. Reduction of
the obtained ester 16 with LiAlH provided alcohol 17 that was
next converted into bromide 18 by a TosCl/LiBr sequence.
Reaction of bromide 18 with NaN under a heating, and the
reduction of the intermediate azide accomplished the needed
amine 19. On the other hand, hydrolysis of ester 16 with
potassium hydroxide provided an interesting acid 20 in 90%
yield. Curtius rearrangement of acid 20 led to amine 21 in 77%
yield.
2 2
*6H O that served as a redox-catalyst.
4
3
Scheme 2. a) Patent example L2. b) Optimization of the synthesis of
compound 1a.
With the optimized procedure in hand, we studied next its
scope (Scheme 3). Substituted at the bridgehead positions alkyl
(
(
2a-4a), benzyl (5a), methoxymethyl (6a) and benzyloxymethyl
7a) iodides were easily synthesized in 82-95% yield. The
For the synthesis of the second type of mono-substituted
2
1
-oxabicyclo[2.1.1]hexanes (B, Scheme 4), we converted iodide
a into alcohol 22, and oxidized it with NaIO /RuCl (cat.) into
transformation also worked with functionalized substrates - ester
a and nitrile 9a were obtained in 75-80% yield. CbzNH-
4
3
8
acid 23 - an isomer of acid 20. Reaction of iodide 1a with
potassium thioacetate, and oxidation of the intermediate
thioester with N-chlorosuccinimide gave an aliphatic sulfonyl
substituted iodide 10a was somewhat unstable, and after the
synthesis we immediately converted it with KOAc into the stable
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Scheme 5. Synthesis of bis-substituted 2-oxabicyclo[2.1.1]hexanes 26-41.
Martin reagent into aldehyde 30 (53% yield). Also, alcohol 29
was converted into bromide 31 by a two-step tosylation/LiBr
sequence. Treatment of bromide 31 with potassium cyanide and
Scheme 4. Synthesis of mono-substituted 2-oxabicyclo[2.1.1]hexanes 13-25.
chloride 24 – a class of compounds gaining popularity in recent
4
the subsequent reduction with LiAlH afforded amine 32 in 86%
1
8
years. Alkylation of iodide 1a with N-Boc piperazine, followed
by an acidic cleavage of N-Boc group gave amine 25 in 41%
yield.
yield. Alternatively, reaction of bromide 31 with sodium azide
and the hydrogenation using Pd/C as a catalyst gave amine 33
in 83% yield – a smaller homologue of amine 32.
Bis-substituted cores. Next, we synthesized several
Reaction of alkyl iodide 2a with potassium acetate, followed
by a hydrolysis provided alcohol 34 in 72% yield. Oxidation of
representative
bis-substituted
2-oxabicyclo[2.1.1]-hexanes
already having one smallest alkyl substituent - methyl group.
Hydrogenation of iodide 8a in methanol in the presence of
triethylamine over Pd/C as a catalyst produced compound 26 in
4 3
the alcohol group with NaIO /RuCl (cat.) gave acid 35 - an
isomer of acid 27. The structure of compound 35 was also
confirmed by X-Ray analysis.16 Oxidation of alcohol 34 with
Dess-Martin reagent led to aldehyde 36 in 52% yield. Reaction
of iodide 2a with sodium azide and the reduction gave amine 37
- an isomer of amine 33. Treatment of iodide 1a with potassium
thioacetate, and oxidation with NCS gave the methyl-substituted
sulfonyl chloride 38 in 81% yield.
8
2% yield (Scheme 5). Alkali hydrolysis of the ester group gave
16
acid 27, the structure of which was proven by X-Ray analysis.
Curtius rearrangement of 27 afforded the methyl-substituted
amine 28 in 78% yield. Reduction of ester 26 with LiAlH gave
alcohol 29 (71% yield) that was further oxidized with Dess-
4
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Indeed, these reactions described here for methyl-
substituted iodide 2a could also be performed with other alkyl-
containing iodides 3a-7a (Scheme 3).
hydrogenative cleavage of O-Bn group provided amino alcohol
44. N-protection of the amino group and oxidation of alcohol
moiety led to amino acid 45 - another intriguing linker.
Also, several key transformations were performed with iodides
1
a, 7a and 9a having a second functional group (Scheme 6). For
example, treatment of iodide 1a with KSAc in dimethyl sulfoxide
and the oxidation of the intermediate thioester gave bifunctional
linker
- sulfonyl chloride 46. Reaction of iodide 7a with
potassium acetate, hydrolysis of the ester group and the
cleavage of O-Bn group gave amino alcohol 47 - a homologue of
amino alcohol 44. Reaction of iodide 9a with sodium azide, and
the reduction of the intermediate nitrile afforded primary amine
4
8 in 75% yield. N-Boc-protection and reduction of the nitrile
moiety produced another interesting diamine 49 – a homologue
of diamine 41.
A standard two-step synthesis of additional alcohols 3b-6b,
1
2b and amines 3c-7c, 12c was also undertaken (Scheme 7).
Scheme 7. Synthesis of alcohols 3b-6b, 12b and amines 3c-7c, 12c.
Chemical stability. Indeed, because we suggest application
of 2-oxabicyclo[2.1.1]hexanes in medicinal chemistry projects,
we next checked a chemical stability of four representative
compounds – isomeric acids 27, 35 and isomeric amines 33, 37
(
Scheme 5). Treatment of them with aq. 1M hydrochloric acid, or
aq. 1M aq. sodium hydroxide at room temperature for 24 hours
did not lead to any decomposition of the starting materials. Also,
these compounds were stored on the shelf at room temperature,
and we did not observe any decomposition after at least three
months. These experiments indicate that described herein
products possess sufficient chemical stability to be used as
building blocks for further modifications.
Physico-chemical properties. In a next step, we wanted to
experimentally prove that incorporation of an oxygen atom into
the structure of bicyclo[1.1.1]pentane would indeed improve its
solubility. Therefore, we first synthesized two series of model
compounds – amides of aniline 50-53, and more lipophilic
amides of 2-naphthylamine 54-57 (Table 1).
Water solubility (Sol.). Indeed, replacement of the phenyl ring
in compounds 53, 57 by BCP motif (50, 54) increased the water
solubility in full agreement with the literature data:7 58 uM (53,
Ph) vs >350 uM (50, BCP); and 2 uM (57, Ph) vs 7 uM (54,
BCP). An influence of incorporation of an oxygen atom into BCP
model 50 onto the water solubility was not seen – all three
compounds 50-52 were well-soluble. However, this effect was
observed in amides of 2-naphthylamine 54-56. Incorporation of
an oxygen atom into model 54 close to the methyl group (55)
increased the water solubility by three times: 7 uM (54, BCP) vs
21 uM (55). The most unexpected result was measured with
model 56 – it was one magnitude of order (!) more soluble than
BCP 54, and three times more soluble than isomer 55: 7 uM (54,
BCP) vs 21 uM (55) vs 71 uM (56). Presumably, an
intramolecular hydrogen bonding between NH- and O-atoms in
compound 56 was responsible for this effect.
Scheme 6. Synthesis of bis-functionalized linkers 39-49.
Linkers. Finally, we performed the synthesis of bifunctinal
linkers for the direct use in medicinal chemistry projects
(
Scheme 6). Reaction of iodide 8a with sodium azide followed by
a reduction of the azido group gave amine 39 in 82% yield.
Standard N-Boc protection and the basic hydrolysis of the ester
moiety afforded the promising amino acid 40. Curtius
rearrangement of the carboxylic group and the hydrogenative
cleavage of the intermediate N-Cbz group gave the mono-
protected diamine 41 in 88% yield. Fluorinated acid 42 was
synthesized by tosylation of alcohol 13, reaction with TBAF, and
the alkali hydrolysis of the ester group. On the other hand,
alkylation of alcohol 13 with benzyl bromide, and the hydrolysis
gave acid 43. Curtius rearrangement of 43 and the
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Table 1. Experimental lipophilicity (logD), water solubility and metabolic
stability (CLint) data of model compounds 50-57.
Crystallographic analysis. We next studied an effect of
incorporation of an oxygen atom into BCP onto geometric
parameters, and compared the data with those of meta-/para-
disubstituted benzenes. Fortunately, crystallographic data for the
reference molecule 58 (BCP) and benzene derivatives 59, 60
were reported.19 Therefore, we compared geometric parameters
of five compounds 27, 35 and 58-60 (Table 2). The distance (r)
between two bridge-head carbon atoms in models 27, 35 was
somewhat longer than that in BCP 58, and slightly shorter than
that in meta-disubstituted benzene 60: 2.02-2.03 Å (27, 35) vs
a
b
c
Model compound
LogD(7.4) Sol(7.4) CLint
5
0
2
.6
>350 n.d.
(
BCP)
5
5
5
1
2
3
1.5
2.2
>350 n.d.
>350 n.d.
1
.87 Å (58, BCP) vs 2.42 Å (60, m-Ph). The distance (d)
between the substituents in compounds 27, 35 was very close to
that in both BCP 58 and meta-disubstituted benzene 60: 4.92-
4.94 Å (27, 35) vs 4.86 Å (58, BCP) vs 5.02 Å (60, m-Ph). On
the other hand, angle  between exit vectors in
3
4
.1
.2
58
7
n.d.d
(
Ph)
2
-oxabicyclo[2.1.1]hexanes 27, 35 (152-154) was significantly
5
4
106
deviated from those in both BCP 58 (180) and meta-
disubstituted benzene 60 (120).
(
BCP)
Overall, a full set of parameters r, d and  (Table 2) revealed
that 2-oxabicyclo[2.1.1]hexanes occupied a region of novel
chemical space, but at the same time, they resemble the
fragment of meta-disubstituted benzenes, as additionally
visualized on Figure 2a.
5
5
3.7
2.9
21
71
125
55
5
5
6
7
Table 2. Selected parameters of bicyclo[1.1.1]pentane 58, 2-oxabicyclo[2.1.1]-
hexanes 27, 35 and meta-/para-disubstituted benzenes 59, 60 according to X-
Ray crystal data: angle  (°), and distances r, d (Å).
4
.7
2
294
(
Ph)
a
b
Experimental n-octanol/water distribution coefficient (log) at pH 7.4; Kinetic aqueous
c
solubility (uM) in 50 mM phosphate buffer (pH 7.4). Intrinsic clearance rate CLint
d
(
mg/(min·μL)) measured in mouse liver microsomes. not determined.
Lipophilicity (logD7.4). Lipophilicity index (logD) of models 50-
Model compound
Angle  ()
r (Å)
1.87
d (Å)
4.86
5
7
correlated well with their solubility in water. Again,
replacement of the phenyl ring in models 53, 57 by BCP moiety
5
2
3
8
7
5
180
(
50, 54) decreased the lipophilicity in an agreement with the
7
previous data: 3.1 (53, Ph) vs 2.6 (50, BCP); and 4.7 (57, Ph)
vs 4.2 (54, BCP). Incorporation of an oxygen atom into BCPs
additionally decreased the lipophilicity by ca. one magnitude of
order, independently on the position of an oxygen atom: 2.6 (50,
BCP) vs 1.5 (51) vs 2.2 (52); and 4.2 (54, BCP) vs 3.7 (55) vs
152
154
2.02
2.03
4.92
4.94
2
.9 (56).
Metabolic stability (CLint). Model 55 was slightly less
metabolically stable (CLint (mg/(min·μL)) than BCP derivative 54,
while model 56 - more stable: 106 (54, BCP) vs 126 (55) vs 55
59
180
120
2.79
2.42
5.79
5.02
6
0
(
56). Importantly, all three saturated models 54-56 were more
metabolically stable than the benzene derivative 57.
In a brief summary, several conclusions from physico-chemical
data of models 50-57 can be made:
Virtual libraries. Similarity of geometric parameters of
-oxabicyclo[2.1.1]hexanes and meta-disubstituted benzenes
2
1
) 2-Oxabicyclo[2.1.1]hexanes are up to 10 times more water-
(
Table 2, Figure 2a) prompted us to generate two virtual mini-
soluble than BCPs; and up to 30 times more soluble than
benzene derivatives.
libraries on scaffolds 45 (Lib-1) and meta-amino benzoic acid
(
Lib-2) (Figure 2b). We used a free online software LLAMA.20
2
) 2-Oxabicyclo[2.1.1]hexanes are less lipophilic than both
BCPs and benzene derivatives.
2-Oxabicyclo[2.1.1]hexanes and BCPs have similar
The calculated principle moments of inertia (PMI) plots of both
libraries looked alike (please see SI), suggesting that
compounds from both libraries indeed had similar molecular
3
)
metabolic stability, and both are more stable than benzene
derivatives.
21
shape. However, compounds from library Lib-1 had better
lead-likeness index: 1.16 (Lib-1) vs 1.57 (Lib-2), and three-
3
times higher F(sp )-index: 0.51 (Lib-1) vs 0.18 (Lib-2).
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Figure 2. a) Visualized comparison of 2-oxabicyclo[2.1.1]hexane and meta-
disubstituted benzene. b) Characteristics of two virtual mini-libraries generated
by LLAMA software.20,21
Summary. Herein
characterized a new generation of saturated benzene mimics –
-oxabicyclo[2.1.1]hexanes. These compounds have much
we designed, synthesized and
2
higher solubility in water and lower lipophilicity than both
bicyclo[1.1.1]pentanes (BCPs) and meta-/para-disubstituted
benzenes. 2-Oxabicyclo[2.1.1]hexanes are also chemically and
3209-3226; g) M. L. J. Wong, J. J. Mousseau, S. J. Mansfield, E. A.
metabolically
stable.
Crystallographic
analysis
of
Anderson. Org. Lett. 2019, 21, 2408-2411; h) J. Nugent, C. Arroniz, B. R.
Shire, A. J. Sterling, H. D. Pickford, M. L. J. Wong, S. J. Mansfield, D. F.
J. Caputo, B. Owen, J. J. Mousseau, F. Duarte, E. A. Anderson. ACS
Catal. 2019, 9, 10, 9568-9574.
2
-oxabicyclo[2.1.1]hexanes revealed that they occupy a region
of novel chemical space, but at the same time resemble the
fragment of meta-disubstituted benzenes.
In summary, we do suggest the use of functionalized
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with the measurement of ADME parameters, to Prof. A. A.
Tolmachev for financial support, to Mrs. I. Sadkova for the help
with the preparation of the manuscript, and to Dr. Y. Moroz for
helpful discussions.
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Keywords: Bicyclo[1.1.1]pentanes • BCP • benzene mimetics •
bioisosteres • water solubility
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[
[
[
16] Reference codes for compounds 14, 27, 35 in Cambridge
Crystallographic Database Center (CCDC) are: 1971795 (14), 1971794
(27), 1971796 (35).
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21] For generation of both libraries L1, L2 (96 compounds), we a) used the
standard set of 44 decorating reagents (LLAMA Default); b) three
representative reactions – amide synthesis, urea synthesis, sulphonamide
synthesis; and c) selected only those molecules that “only have been
decorated twice.”
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COMMUNICATION
Benzene biois os ters . A new generation of saturated benzene mimics -
Vadym V. Levterov, Yaroslav Panasyuk,
Valentyna O. Pivnytska, Pavel K.
Mykhailiuk
2
-oxabicyclo[2.1.1]hexanes, - was developed. These compounds were
designed as analogues of bicyclo[1.1.1]pentane with an improved water
solubility. Crystallographic analysis of 2-oxabicyclo[2.1.1]hexanes revealed that
they occupy a novel chemical space, but at the same time resemble the
fragment of meta-disubstituted benzenes.
Water-soluble non-classical benzene
mimics
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