Investigation on the oxidation of aryl oxiranylmethanols and the synthesis of 2-aryl-N-thiazolyl-oxirane-2-carboxamides as glucokinase activators

Article abstract of DOI:10.1016/j.tetlet.2012.06.111

RuCl₃/NaIO₄-initiated oxidation of oxiranemethanols was investigated, and two products, oxirane-2-carboxylic acid and (5′-oxotetrahydrofuran-3-yl)acetic acid, were obtained in variant ratios. The product structures were determined and a tentative mechanism involving oxidation-rearrangement-oxidation process was proposed. Glucokinase enzymatic assay revealed that oxiranecarboxamides 4a-c retained moderate GK activation potency with amide 4a showing an EC₅₀ value of 584 nM and a high activation fold of 3.14. However, (5′-oxotetrahydrofuran-3-yl)acetamide 11a is inactive. This study not only provided an alternative protocol to access (5′-oxotetrahydrofuran-3-yl)acetic acid analogs, but also yielded nanomolar GA activators (esp. 4a) for further structure-activity relationship study.

Full text of DOI:10.1016/j.tetlet.2012.06.111

Tetrahedron Letters 53 (2012) 4738–4742
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Investigation on the oxidation of aryl oxiranylmethanols and the synthesis
of 2-aryl-N-thiazolyl-oxirane-2-carboxamides as glucokinase activators
Na Ye a, , Xiangtao Xu b, , Fuying Li a, Mengmeng Ning c, Zhiqing Liu a, Yuqing Cao b, , Ying Leng c,
⇑
⇑
,
Ao Zhang a,
⇑
a Synthetic Organic and Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
b College of Pharmacy, Hebei University, Baoding 071002, China
c State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
RuCl3/NaIO4-initiated oxidation of oxiranemethanols was investigated, and two products, oxirane-2-car-
boxylic acid and (50-oxotetrahydrofuran-3-yl)acetic acid, were obtained in variant ratios. The product
structures were determined and a tentative mechanism involving oxidation-rearrangement-oxidation
process was proposed. Glucokinase enzymatic assay revealed that oxiranecarboxamides 4a–c retained
moderate GK activation potency with amide 4a showing an EC50 value of 584 nM and a high activation
fold of 3.14. However, (50-oxotetrahydrofuran-3-yl)acetamide 11a is inactive. This study not only pro-
vided an alternative protocol to access (50-oxotetrahydrofuran-3-yl)acetic acid analogs, but also yielded
nanomolar GA activators (esp. 4a) for further structure–activity relationship study.
Received 15 May 2012
Revised 15 June 2012
Accepted 26 June 2012
Available online 29 June 2012
Keywords:
Arylacetamides
Glucokinase activators
Ruthenium-catalyzed
Oxo-rearrangement
Ó 2012 Elsevier Ltd. All rights reserved.
By catalyzing the first step of glycolysis and phosphorylation of
glucose to glucose 6-phosphate, glucokinase (GK), a unique iso-
form of the hexokinase enzymes, has emerged as a promising drug
target for the type-II diabetes.1 A growing number of small mole-
cule glucokinase activators (GKAs) have been developed with the
aim to activate this enzyme by interacting on its allosteric pocket
to achieve anti-hyperglycemic effects.2–7 Several such compounds
have already approached in clinic, including the arylpropanamide
1(PSN-GK1),8–10 which was reported by OSI Pharmaceuticals and
currently in phase I/II clinical trials (Fig. 1).
In the meantime, a strategy to develop conformationally con-
strained propanamides has been reported as well. This was repre-
sented by cyclopropanecarboxamide 33 (LY-2121260), a clinical
GKA developed by Lilly Research Laboratories. Similar to 1, this
compound can stimulate insulin secretion in a glucose-dependent
manner in pancreatic b-cells and increase glucose consumption in
rat hepatocytes.3 Encouraged by this result, we decided to explore
the synthesis and GK activation of compounds 4a–c containing an
oxirane-2-carboxamide scaffold (Fig. 1). Herein, we report our syn-
thesis and preliminary pharmacological investigations.
Based on the reported co-crystal structures of GK and its activa-
tors,2,11 it was postulated that in GKAs like 1, the backbone hydro-
gen and carbonyl oxygen of Arg63 anchor the thiazole nitrogen and
amide NH through H-bonding, respectively, whereas the tetrahy-
dro-2H-pryan-4-yl and the aryl are embedded in a lipophilic envi-
ronment created by Met235, Tyr214, and Val62. Therefore, much
effort in the development of new GKAs currently focuses on opti-
mization of these key pharmacophoric components.2,3,11 We have
also reported12 a series of new GKAs bearing the propanamide
skeleton by introducing diversified substituents to the aminothia-
zole C-4 or C-5 position, and identified several potent GKAs (e.g.,
2), with potency comparable to that of 1.
In the beginning, we decided to synthesize the target com-
pounds 4a–c by epoxidation of the key intermediate acrylic acid
5a,13,14 followed by amidation with appropriate aminothiaz-
oles12,15 (Scheme 1, path a). Although, this approach is straightfor-
ward, epoxidation of acid 5a using mCPBA in CH2Cl2 at either rt or
reflux only gave a complex mixture and no expected product was
obtained. Esterification of acid 5a followed by mCPBA-epoxidation
gave no product as well. Changing to other oxidants including
tBuOOH and H2O2, no reaction occurred. Based on these results, it
is apparent that the failure of the epoxidation reaction is due to
the electron-deficient property of acrylic acid 5a, therefore, an
alternative synthetic strategy was designed (path b, Scheme 1).
As described in Scheme 1, acid 5a was first converted into the
methyl ester and then subjected to reduction with DIBAL-H at
ꢀ78 °C to afford allylic alcohol 7a in 80% overall yield. Subsequent
epoxidation13 of alcohol 7a with mCPBA in CH2Cl2 at 0 °C–rt went
through smoothly, and the expected oxiran-2-ylmethanol 8a was
obtained in 90% yield. Oxidation of alcohol 8a to acid 6a was
⇑
Corresponding authors. Tel./fax: +86 21 50806035 (A.Z.); tel./fax: +86 21
50806059 (Y.L.); tel.: +86 0312 5071107 (Y.C.).
E-mail addresses: pharm_hbu123@yahoo.cn (Y. Cao), yleng@mail.shcnc.ac.cn
(Y. Leng), aozhang@mail.shcnc.ac.cn (A. Zhang).
These two authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.111

N. Ye et al. / Tetrahedron Letters 53 (2012) 4738–4742
4739
O
O
3
H
N
H
H
N
O
O
2
1
N
N
N
N
O
S
O
O
S
O
O
S
O
S
S
R
O
R
S
H3C
O
1 PSN-GK1
(
, R=5-F)
3 (LY-2121260)
Proposed new compounds 4a-c
i
2
(R=4-Pr , BMC-2010-3875)
Figure 1. Reported GK activators and our proposed new analogs.
O
O
O
H
N
i
O
O
ii
O
O
OH
N
OH
path a
O
S
O
O
S
O
O
S
O
O
S
R
5a
6a
4a-c
iii,iv
path b
vi
O
O
COOH
O
v
O
OH
OH
O
S
O
O
O
S
O
O
S
O
O
9a
7a
8a
Scheme 1. Reagents and conditions: (i) 30% H2O2, 5% NaOH, CH3CN, rt-60 °C or mCPBA, CH2Cl2, rt to reflux; (ii) an appropriate thiazole-2-amine, TBTU, Et3N, DCM, rt; (iii)
SOCl2, MeOH, reflux; (iv) DIBAL-H, THF, ꢀ78 °C-rt; (v) mCPBA, CH2Cl2, 0 °C-rt; (vi) NalO4, RuCl3ꢁH2O, rt, MeCN:CCl4:H2O = 2:2:3.
conducted by following a procedure reported by Panek et al16
using RuO4 as the oxidant. It was found that the oxidation of 8a
with RuO4, prepared in situ by mixing 5.0 equiv of NaIO4 and a cat-
alytic amount of RuCl3 (10%), occurred very slowly, and an elon-
gated time of 24 h was generally needed to complete the
conversion. Although with careful column chromatography, the
product obtained in 33% yield turned out to be a mixture on the ba-
sis of its NMR spectroscopic data with a ratio of 20:12. Fortunately,
repetitive preparative TLCs allowed us to separate each component
with sufficient amount for structural characterization.
The major component was confirmed to be the expected oxi-
rane-2-carboxylic acid 6a on the basis of its NMR spectra. Specifi-
cally, formation of the oxirane ring is ascertained by the existence
of a doublet peak with chemical shift of 3.33 ppm and coupling
constant of 9.0 Hz in the 300 M 1H NMR, and the existence of a ter-
tiary carbon at 67.3 ppm and a quaternary carbon at 61.7 ppm in
the 400 M 13C NMR. Quite surprisingly, all the diagnostical spectro-
scopic signals for the oxirane ring were not observed in the
corresponding NMR spectra of the minor product. Moreover, the
typical signals of tetrahydropyran ring, especially the two sets of
proton peaks at 3.84 and 3.21 ppm and two secondary carbon sig-
nals at 66.6 and 66.1 ppm (–CH2OCH2–), also disappeared. All these
results indicated that the second product does not contain the oxi-
rane ring, and the tetrahydropyran ring has been destroyed. How-
ever, the exact structure of the second product could not be
deduced at this time based on the available spectroscopic data,
although it was determined as 9a later.
In order to improve the yield and selectivity, we next optimized
the reaction conditions. First, we screened the loading of the oxi-
dant. With 10% ruthenium chloride hydrate (RuCl3ꢁxH2O) as the
catalyst, increasing (6.0 equiv) or decreasing (4.0 equiv) the oxi-
dant NaIO4 improved the yields of the products (Table 1, entries
2 and 3), but lower oxidant loading elevated the product ratio to
20:6 (entry 3). Higher temperature did not improve the reaction
except producing a complex (entry 4). Variant amount of the cata-
lyst was also explored (entries 5–7). It was found that higher
Table 1
Optimization of reaction conditions of oxiran-2-yl methanol 8aa
Entry
Oxidant
RuCl3 (%)
Solvent
T
6:9b
Yield (%)
1
2
3
4
5
6
7
8
9
5eq NaIO4
6eq NaIO4
4eq NaIO4
5eq NaIO4
5eq NaIO4
5eq NaIO4
5eq NaIO4
5eq NaClO
5eq KBrO3
5eq NMO
5eq Oxone
10
10
10
10
15
20
35
20 (py)
20 (py)
20
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
EA:MeCN:H2O = 1:1:2
EA:MeCN:H2O = 1:1:2
CCl4:MeCN:H2O = 2:2:3
CCl4:MeCN:H2O = 2:2:3
rt
rt
rt
60 °C
rt
20:12
20:12
20:6
—
20:14
20:17
20:13
rt
33
38
48
c
—
45
55
53
—
70
—
rt
rt
rt
rt
rt
1:0
—
1:0
10
11
20
61
a
b
c
The reaction was conducted on 0.1 mmol scale, and was reacted for 24 h before workup.
Determined by NMR spectra.
The reaction produced a complex.

4740
N. Ye et al. / Tetrahedron Letters 53 (2012) 4738–4742
Table 2
Ruthenium-catalyzed oxidation of oxiran-2-yl methanols 8a–j
O
O
O
COOH
O
5eq. NaIO4
20%RuCl3.H2O
O
O
O
O
+
OH
H
+
CCl4:MeCN:H2O
r.t, 24h
OH
O
O
6a-j
R
O
R
O
R
9a-j
8a-j
10
No.
R
Product
(6:9) or (6:10)a
Yieldb (%)
1 (8a)
2 (8b)
3 (8c)
4 (8d)
5 (8e)
6 (8f)
7 (8g)
8 (8h)
9 (8i)
10 (8j)
4-PrcSO2
4-MeSO2
4-F
4-I
4-H
2-OMe,5-Me
4-(4-F-Ph)
4-CN
4-Cl
4-Br
6a + 9a
6b + 9b
6c + 9c
6d + 9d
6e
6f + 10
6g
6h + 9h
6i + 9i
6j + 9j
20:17
20:12
20:29
20:5
1:0
20:24
1:0
20:19
20:20
20:10
55
50
40
71
36
56
68
19
62
73
a
Determined by the 1H NMR spectra.
Isolated yields.
b
O
S
O
O
H
2'
O
N
H
O
1'
3'
S
1 N
2
5'
O
H
H
H
11a (HMBC)
Figure 2. X-ray crystal of 9i and HMBC analysis of 11a.
loading of the catalyst generally increased the yield, but the ratios
of the products (6a:9a) were not significantly changed. Changing
NaIO4 to other oxidants, including NaClO (entry 8) and NMO (entry
10) did not promote the reaction, while using KBrO3 (entry 9) or
Oxone (entry 11) as the oxidant, oxirane 6a was obtained as the
major product in 70% and 61% yield, respectively.
From the results above, it is in general that by using 4.0 equiv of
NaIO4, or switching to other oxidants, the oxidation product 6a
could be obtained as the dominant product in moderate yield.
The lower yield is likely due to the existence of high amount of
inorganic salts and the difficulty in isolating the products. Since
the structure of the minor product 9a had not been settled yet,
we decided to choose 5.0 equiv NaIO4 and 20% of RuCl3ꢁxH2O with
the solvent mixture of CCl4/MeCN/H2O (2:2:3) as the optimal reac-
tion condition (Table 1, entry 5) to prepare both products for fur-
ther investigation.
As shown in Table 2, a small class of oxiran-2-ylmethanols 8b–j
were prepared following a similar procedure as that of preparation
of 8a, and subjected to the oxidation reaction subsequently. It was
found that all the oxiran-2-ylmethanol substrates went through
the oxidation and afforded two products in 19–73% yields, with
6a–j/9a–j ratios of nearly 1:1, except in cases of 4-iodophenyl-
(8d), non-substituted phenyl- (8e), and 4-fluorobiphenyl-(8g)
substituted oxiranemethanols where the corresponding oxirane
acids were produced as the major products. It is of note that in
the case of 2-methoxy-5-methyl substituted substrate (entry 6),
the oxidation intermediate oxiranecarbaldehyde 10 was obtained
as the side product.
Although most of side products 9a–j were obtained as powder,
we managed to achieve the X-ray crystals of 9i from the mixture of
chloroform and methanol, and secured its structure as 2-(2-(4-
chlorobenzoyl)-5-oxotetrahydrofuran-3-yl)acetic acid. As shown
in Figure 2, the benzoyl and acetamide moieties are in trans-con-
figuration. The structures of 9a–d, as well as 9h and 9j were de-
duced by analogy.
In spite of the wide use17 of ruthenium (VIII) tetroxide (RuO4),
in the oxidation of alkenes, alcohols, amines, amides, b-lactams,
O
O
O
3
1
O
O
O
oxid.
rearr.
H
OH
O
2
O
OH
O
OH
O
R
R
R
6a
-CO2
8a
I
O
H2O
O
O
O
O
oxid.
CH2OH
OH
9a
R
O
R
R
II
III
(R=SO2Prc)
Figure 3. Proposed mechanism.

N. Ye et al. / Tetrahedron Letters 53 (2012) 4738–4742
4741
Table 3
In vitro activation of GK by compounds 4a–c and 11a
Compound
Structure
EC50 (nM)
Activation fold⁄
1
2
—
—
62 (1302)
125
2.59
O
H
N
O
O
4a
584
3.14
N
O
S
S
O
O
O
H
N
N
4b
444
1.85
1.08
1.28
O
S
S
O
F
O
O
O
O
H
N
N
4c
1230
O
S
S
N
S
Ph
O
O
N
O
N
H
11a
>10,000
O
S
O
O
O
phenols, and inactivated hydrocarbons, oxidation of (3-(tetrahy-
dro-2H-pyran-4-yl)oxiran-2-yl)methanol to (50-oxotetrahydrofu-
ran-3-yl)acetic acid has never been reported before. Therefore, a
tentative oxidation-rearrangement-oxidation reaction mechanism
was proposed. Since both acids 6a and 9a were obtained in most
cases, we believed that acid 9 was produced from 6. As demon-
strated in Figure 3, oxirane-2-carboxylic acid 6a first underwent
decarboxylation, followed by oxirane ring-opening and nucleo-
philic attack of oxirane C-3 by the oxygen atom of tetrahydropyran
to form an oxonium intermediate II. Nucleophilic attack of species
II by water should generate tetrahydrofuran III. This intermediate
would readily undergo a second oxidation to afford acid 9a. It
should be mentioned that RuCl3-catalyzed oxidation of tetrahydro-
pyrans or tetrahydrofurans to corresponding lactones has been re-
ported in the literature long time ago.18–26 Although several other
mechanisms may exist, the key elements involving oxidation, rear-
rangement, and re-oxidation should be the same.
The structures of 9a–j are rare, and the available synthesis is very
limited. In 2005, Tomoda and co-workers27 reported the isolation of
two natural products, named as phenatic acids A and B, from the cul-
ture of Streptomyces sp. K03-0132. These are the earliest structural
examples containing (20-benzoyl-50-oxotetrahydrofuran-3-yl)ace-
tic acid scaffold, similar to that in compound 9i. Total synthesis of
these compounds was achieved recently by Fernandes et al28
through 11–12 steps. Therefore, our study provided an alternative
to access this class of compounds, although further work is needed
to improve the yield.
validate the effects of these new compounds, amides 4a–c and 11a
were prepared following a similar procedure we reported before by
coupling of acid 6a or 9a with an appropriate thiazole. Amide 11a
was further confirmed by all the spectroscopic data, especially by
its COSY, HSQC, and HMBC (Fig. 2).
All these new compounds were tested in an enzymatic glucoki-
nase (GK) assay using purified recombinant human islet GK follow-
ing a similar procedure as we reported earlier.12,15 The GK activity
of each compound was evaluated in six different concentrations
and was reported as EC50 value and maximum activation fold (ver-
sus control level). Clinical compound 1(PSN-GK1) and our earlier
lead 2 were also evaluated in current assays for side-by-side
comparison.
From the results in Table 3, conformationally constrained ary-
lacetamides 4a–c retained moderate GK potency with EC50 values
of 444–1230 nM, 4–10 fold less potent than our earlier lead 2
and much less potent than the clinical compound 1. The substitu-
ent in the aminothiazole component did not impact the EC50 values
significantly, whereas an appreciable discrepancy in activation fold
was observed. Compound 4a possesses an EC50 value of 584 nM
with a high activation fold of 3.14, while compound 4b has a
slightly higher potency (EC50, 444 nM) but with a much lower acti-
vation fold of 1.85. The piperidine-fused aminothiazole 4c showed
negligible activation potency. Quite disappointingly, amide 11a is
nearly invalid in GK activation, indicating that the 50-
oxotetrahydrofuran-3-yl)acetyl moiety in 11a may not interact
with the lipophilic environment proposed2,11 for the tetrahydopy-
ran moiety in 1 and 2.
Although glucokinase activators (GKAs) generally are benzam-
ide or arylacetamide analogs, we decided to convert both acids
6a–j and 9a–j into corresponding N-heteroaryl amides. To quickly
In summary, RuCl3-catalyzed oxidation of oxiranemethanols
was investigated, and two products, oxirane-2-carboxylic acid and

4742
N. Ye et al. / Tetrahedron Letters 53 (2012) 4738–4742
(50-oxotetrahydrofuran-3-yl)acetic acid, were obtained in variant
ratios. The product structures were determined and a tentative
mechanism was proposed involving oxidation-rearrangement-oxi-
dation process. Coupling of the resulting acids with aminothiazoles
produced amides 4a–c and 11a. Glucokinase enzymatic assay re-
vealed that oxirane-carboxamides 4a–c retained moderate GK acti-
vation potency with amide 4a showing an EC50 value of 584 nM and
a high activation fold of 3.14. However, (50-oxotetrahydrofuran-3-
yl)acetamide 11a is inactive. This study not only provided an alter-
native protocol to access (50-oxotetrahydrofuran-3-yl)acetic acid
analogs, but also yielded nanomolar GA activators (esp. 4a) for fur-
ther structure–activity relationship study.
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