Synthesis of 2-Thio-Substituted 1,6-Diazabicyclo[3.2.1]octane Derivatives, Potent β-Lactamase Inhibitors

Article abstract of DOI:10.1021/acs.joc.0c00980

Approval of avibactam by the FDA has led to the recognition of 1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds for β-lactamase inhibition. We achieved a concise and collective synthesis of 2-thio-substituted DBO derivatives. The synthesis involves diastereoselective photo-induced Barton decarboxylative thiolation, which can be applied to large-scale synthesis. The DBO analogues exhibited strong inhibitory activities against serine β-lactamases and acceptable solution stabilities for clinical development.

Full text of DOI:10.1021/acs.joc.0c00980

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Article
Synthesis of 2-Thio Substituted 1,6-Diazabicyclo[3.2.1]octane
Derivatives, Potent #-Lactamase Inhibitors
MOTOHIRO FUJIU, Katsuki Yokoo, Toshiaki Aoki, Satoru Shibuya, Jun Sato, Kazuo
Komano, Hiroki Kusano, Soichiro Sato, Masayoshi Ogawa, and Kenji Yamawaki
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00980 • Publication Date (Web): 08 Jul 2020
Downloaded from pubs.acs.org on July 8, 2020
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The Journal of Organic Chemistry
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Synthesis of 2-Thio Substituted 1,6-Diazabicyclo[3.2.1]octane
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Derivatives, Potent -Lactamase Inhibitors
Motohiro Fujiu*, Katsuki Yokoo, Toshiaki Aoki, Satoru Shibuya, Jun Sato, Kazuo
Komano, Hiroki Kusano, Soichiro Sato, Masayoshi Ogawa and Kenji Yamawaki
Shionogi Pharmaceutical Research Center, 3-1-1, Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan
ABSTRACT: Approval of avibactam by the FDA has led to the recognition of 1,6-diazabicyclo[3.2.1]octane
(DBO) derivatives as attractive compounds for β-lactamase inhibition. We achieved concise and collective
synthesis of 2-thio substituted DBO derivatives. The synthesis involves diastereoselective photo-induced Barton
decarboxylative thiolation, which can be applied to large-scale synthesis. The DBO analogues exhibited strong
inhibitory activities against serine β-lactamases and acceptable solution stabilities for clinical development.
INTRODUCTION
β-Lactam antibiotics have played an important to release people
serine of β-lactamase results in the formation of a relatively
stable carbamoyl-enzyme complex. This enables avibactam (1)
to inhibit serine β-lactamases and this mechanism is distinct
from other β-lactamse inhibitors such as clavulanic (5) acid and
tazobactam (6) (Figure 1b).
from bacterial infectious diseases since the discovery of
penicillin. In contrast with our expectation, however, a lot of
resistant strains to those drugs have emerged even though new
antibiotics have been approved by authorities in many
countries.1 One of the main mechanisms for resistance to β-
lactam is production of β-lactamase which catalyzes hydrolysis
of β-lactams.2 Fortunately another antibiotic, carbapenem, is
inert to most of β-lactamases and is used to treat β-lactam
resistant strains,3 but the emergence of carbapenem-resistant
enterobacteriaceae (CRE) producing “carbapenamase” has
been reported worldwide in recent year.4
For inhibitory activities against β-lactamases, DBO
derivatives need an electron-withdrawing group at the C2
position to increase the reactivity of the 2-imidazolone
backbone. Several DBOs utilize an amide electron withdrawing
group including avibactam (1), relebactam (2),7, 8 nacubactam
(3)9 and zidebactam (4).10 Other C2 electron-withdrawing
groups including nitrile and heterocycles have been reported as
well as a novel 2,3-ring-fused DBO. 5, 10a, 11 The structural strain
also enhances β-lactamase inhibitory activities. ETX2514 (7)12
and ETX1317 (8)13 have an unsaturated bond on the DBO
skeleton. However, introducing a double bond seems to be more
complex, and it is difficult to prepare these molecules. Herein,
we explore the synthetic route of DBO derivatives possessing a
sulfone, sulfoxide and sulfonamide as a strong electron-
withdrawing group and report their β-lactamase inhibitory
activity.
In order to cope with the emergence of CREs, a novel serine
β-lactamase inhibitor, avibactam (1),5, 6 was approved by the
FDA in 2015 as a combination with cephalosporin, ceftazidime.
Avibactam (1) has a unique 1,6-diazabicyclo[3.2.1]octane
(DBO) skeleton, unlike existing β-lactam-based β-lactamase
inhibitors such as clavulanic acid (5) and tazobactam (6). The
reaction between 2-imidazolone in DBO and an active center
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a) Structures of known -lactamase inhibitors
stable conformation shown in Figure 3. It is assumed that the
O
1
2
3
4
5
6
7
8
sterically less hindered lone pair on sulfur is preferentially
oxidized by m-CPBA to give the sulfoxide (16) with high
diastereoselectivity.
2
R
N
H
R =
R =
H2
R =
HN
HN
H
N
N
O
O
O
N
N
S
O
O
Na
O
O
1
2
3
4
)
Avibactam (
)
Relebactam (
)
Nacubactam (
)
Zidebactam (
R = H
In contrast to the case of sulfone (13), deprotection of the
benzyl group by Pd/C was not successful because the sulfoxide
presumably acted as a catalytic poison. Yasuda and coworkers
have reported that addition of a catalytic amount of DABCO
significantly accelerated Pd-catalyzed hydrogenolysis in the
synthesis of relebactam.8c We applied this procedure and the
result is shown in Table 2. The combination of DABCO and
Pd(OH)2 successfully gave the debenzylated intermediate (17)
(entry 4) although no improvement was observed in the case of
Pd(OH)2 alone and a combination of Pd/C and DABCO (entry
2, 3). Conversion to sulfate (19) using SO3-pyridine was also
unsuccessful and neither 19 was obtained nor 17 was recovered.
On the other hand, neopentyl chlorosulfate (20)
chemoselectively reacted with the hydroxyl amino group and
17 was successfully led to a neopenthyl sulfate (18).
Nucleophilic substitution at the neopentyl position released
sulfate (19) in good yield.
O
O
O
H
H2
N
O
H
O
S
H2N
OH
N
N
F
N
N
O
S
O
N
)
N
N
OH
N
O
O
N
O
O
O
O
COOH
Na
O
COOH
O
8
ETX1317 (
)
6
Tazobactam (
7
)
ETX2514 (
5
Clavulanic acid (
)
9
b) Mode of action of avibactam
H2NOC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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44
45
46
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50
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57
58
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H2NOC
N
O
N
OSO3H
N
H
O
OH
Ser
N
OSO3
H
O
Ser
carbamoyl-enzyme complex
Figure 1. a) Structures of known β-lactamase inhibitors. b) Mode
of action of avibactam.
RESULTS AND DISCUSSION
We attempted to convert carboxylic acid (9),6 a commercially
available starting material, into a sulfide (11) by photo-induced
Barton decarboxylative thiolation14 (Table 1). First, 2-
mercaptopyridine (12) was condensed onto 9 to form
intermediate N-hydroxy-2-thiopyridone ester (10) with EDC
hydrochloride. After an addition of diphenyl disulfide,
irradiation under white LED gave sulfide (11a) as a single
isomer (entry 1). The relative configuration of 11a was
determined by NOE correlations. We suppose the radical
intermediate stereoselectively reacted with diphenyl disulfide
from the convex side (Figure 2).
Table 1. Optimization of Reaction Conditions for Barton
Decarboxylative Thiolation
N
O
O
O
12
SH
S
N
R
HO
O
reagent (5 eq.)
EDC HCl
N
N
S
N
white LEDs
0 °C
CH2Cl2, rt
in the dark
N
N
N
OBn
OBn
OBn
O
O
O
10
11
(11a)
11b
9
R = Ph
Me
(
)
Subsequently, attempts were made to obtain a methyl sulfide
(11b) by the same method (Table 1). However, the yield was
low when dimethyldisulfide was used as a radical trapping
reagent (entry 2). Our investigation suggested that excess of
dimethyldisulfide was necessary to obtain the product in good
yield (entry 3). This result is consistent with the previous
report.14, 15 We speculated that dimethyl disulfide might be less
reactive. Then, methyl methanethiosulfonate (34) and
unsymmetrical disulfide PhSSMe (35) were tested to afford 11b
with acceptable yield (entry 4, 5). Interestingly, we observed
high chemoselectivity although both phenylthio and methylthio
groups might be introduced when PhSSMe (35) was used. The
unsymmetrical disulfide (35) is preferred because it is less polar
and easily removed by silica-gel column chromatography. To
the best of our knowledge, this is the first example of utilizing
an unsymmetrical disulfide to improve radical thiolation,
although the resulting sulfide (11) was unstable on silica-gel
column chromatography16 and the isolated yield was low.
yield (%)a
entry
reagent
PhSSPh
R
Ph
61 (50)b
30
1
2
3
4
5
MeSSMe
MeSSMec
Me
Me
Me
Me
52
34
MeSO2SMe (
)
47
48 (33)b
35
PhSSMe (
)
aYield was determined by 1H NMR using 1,1,2,2-tetrachloroethane as
an internal standard. bIsolated yield. c45 eq. of MeSSMe was used.
concave
OBn
convex
OBn
OBn
S
O
N
O
O
R
N
N
N
N
H
N
H
N
N
OBn
H
O
SR
S
R
R
S
The oxidation of sulfide (11) using 2.2 eq. of m-CPBA gave
sulfone (13) in a good yield (Scheme 1). Sulfone (13), after
catalytic hydrogenolysis of the benzyl group, led to sulfonate
(15) in a similar manner to the synthesis of avibactam.6
Figure 2. Proposed mechanism of diastereoselectivity.
Scheme 1. Synthesis of Sulfone (15)
The sulfide (11b) was also oxidized to sulfoxide (16) by using
1.1 eq. of m-CPBA at -78 ℃ (Scheme 2). Diastereoselective
oxidation was observed and the ratio was improved up to 31/1
after recrystallization from EtOAc at -30 ℃.17 The relative
configuration of sulfoxide (16) was established by X-ray
crystallography.18 The diastereoselectivity can be explained by
the conformation of the substrate (11b). Steric repulsion of the
methyl group and electric repulsion between the lone pair on
sulfur and that on nitrogen at the bridge-head would give the
2
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O
O
O O
O
S
H2 (1 atm)
Pd/C
S
S
R
O
S
m-CPBA (2.2 eq.)
CH2Cl2
R
R
N
1
2
CF3CONH2, Rh2(OAc)4
PhI(OAc)2, MgO
F3C
N O
S
N
N
,
THF/MeOH,
rt
N
0 °C, 1 h
N
N
OBn
O
OBn
OH
14a 14b
O
O
N
or
R = Ph (11a)
Me 11b
13a 91%
13b 90%
CH2Cl2, rt, overnight
78%
N
3
(
)
N
OBn
O
N
SO3-pyridine
pyridine, rt
4
5
OBn
16
O
22
O
O
6
7
8
9
S
R
The synthetic success of the sulfone and sulfoxide analogues
encouraged us to move onto synthesis of a sulfonamide
analogue. It is reported that a carboxylic acid was converted
into a sulfonamide via a thiosulfonate.21 We attempted a similar
synthetic route to access a sulfonamide (Scheme 4). In an
excess amount of liquid sulfur dioxide, the Barton ester (10),
prepared by reaction of carboxylic acid (9) with 36, was
irradiated with white LEDs. After sulfur dioxide trapped the
radical intermediate, the resulting sulfonyl radical reacted with
thiopyridone on the Barton ester (10) to propagate a radical
chain and gave a thiosulfonate (23). We attempted to transform
23 into a sulfonamide (25a) in the presence of 1,2-dibromo
tetrachloroethane and ammonia, however an epimer (25b) was
dominantly obtained in the crude mixture (25a/25b = 28/72)
and the isolated yield of 25b was poor (Route 1).
N
O
O
N
S
Na
O
O
O
15a
15b
13a
13b
78% (from
83% (from
)
)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Synthesis of Sulfoxide (19)
H2 (1atm)
Pd(OH)2
DABCO
O
O
S
O
S
S
SO3-pyridine
2,6-lutidine
S
m-CPBA (1.1 eq.)
N
N
N
N
O
S
O
CH2Cl2, -78 °C
2 h
N
MeOH, rt
89%
CH2Cl2, rt
N
OBn
N
N
O
O
O
OBn
OH
Na
O
O
O
11b
17
16
88%
19
d.r. = 91/9
O
O
S
Cl
O
20
DBU, DMF, 0 °C
54%
N
N
O
S
O
S
SNa
S
21
N
O
O
N
O
O
DMF, rt
76%
N
S
N
S
O
O
O
O
O
Na
O
19
18
Scheme 4. Synthesis of Sulfonamide (25a)
Table 2. Optimization of Debenzylation of Sulfoxide 16
Route 1
Cl
Cl
Br
Br
1) 36, Et3
CH2Cl2, rt,
in the dark
N
Cl
O
O
O
O O
entry
condition
Pd/C (5 mol%)
yield (%)
O
O
Cl
S
S
S
7M NH3 in MeOH
DMF, rt, 2 h
H2
N
H2N
HO
N
S
N
N
N
N
2) liquid SO2
white LEDs,
-10 °C
N
N
N
OBn
N
23
1
2
3
4
trace
trace
trace
89
OBn
O
OBn
O
OBn
O
O
9
25a
25b
6.5% isolated yield
37%
Pd(OH)2 (5 mol%)
PhSNa
THF/H2
rt, 3 h
25a 25b
/
= 28 / 72
Cl
O
O
N
Route 2
(determined by 1H NMR of the crude mixture)
O
S
Pd/C (5 mol%), DABCO (2 mol%)
Pd(OH)2 (5 mol%), DABCO (2 mol%)
36
O
S
O
O
H2NOSO3
NaOAc
H
S
O
H2
N
N
Na
N
THF/H2
0 C, 1 h
O
N
N
OBn
O
O
OBn
24
25a
46% (from 23)
electric replusion
Me
We hypothesized the mechanism of epimerization to be as
presented in Scheme 5. The sulfinate (26), derived from 23 after
cleavage of the sulfur-sulfur bond by ammonia, would be
oxidized by 1,2-dibromo tetrachloroethane to the corresponding
sulfonyl bromide (27). This sulfonyl bromide (27) would be
immediately deprotonated and converted into the sulfene (28).
After nucleophilic addition of ammonia to the sulfene (28), the
resulting anion (29) would receive protonation from the convex
side to afford the epimer (25b).
H
H
H
N
N
N
S
O
O
O
S
S
Me
N
N
N
OBn
OBn
OBn
steric replusion
mCPBA
favored
disfavored
disfavored
O
S
N
Scheme 5. Proposed Mechanism of Epimerization
N
OBn
O
16
O
O
O
O
S
S
N
S
H2
N
N
N
Figure 3. Presumable mechanism for diastereoselective
oxidation of 11b.
NH3
23
N
N
OBn
OBn
O
O
25b
The sulfoxide (16) was also led to a sulfoximine (22),19
a
Cl
Cl
Br
NH3
Br
Cl
functional group attracting attention in the field of medicinal
chemistry because its tetrahedral structure offers unique
properties such as favorable physicochemical properties,
hydrogen bond functionalities and structural diversity20
(Scheme 3).
O
O
S
O
O
H
OBn
Cl
S
S
O
N
Br
O
O
N
N
N
H2NO2
S
N
NH3
N
N
N
29
OBn
OBn
OBn
O
O
O
26
27
28
H
OBn
O
Scheme 3. Synthesis of Sulfoximine (22)
N
N
SO2NH2
In order to suppress the epimerization, we tried an alternative
route that circumvented the sulfonyl halide (Scheme 4, Route
3
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Reaaction set up for the large-scale synthesis
2). Electrophilic amination of a sulfinate (24), released from the
thiosulfonate (23), provided the desired sulfonamide (25a)
without the epimerization.
O
O
1
2
3
4
5
6
7
8
1) 12
EDC HCl
N
O
HO
S
N
N
CH2Cl2, rt
in the dark
N
N
OBn
OBn
O
O
9
10
600 g (2.17 mol)
We were able to successfully synthesize the sulfonamide
(25a), but the synthetic route required an excess amount of toxic
sulfur dioxide with an unsatisfactory yield. To work around this
issue, we continued our investigation and exploratory research
for another synthetic route (Scheme 6). Conversion of
acetoxymethyl sulfone into a sulfinate is known to be possible
by hydrolysis of an acetoxy group.22 We postulated that the
sulfonamide (25a) would be effectively obtained via an
acetoxymethyl sulfone (31). Compound 9 underwent Barton
decarboxylative radical thiolation utilizing a thiosulfonate (33)
to give a corresponding acetoxymethyl sulfide (30), which was
oxidized to a sulfone (31). Compared with the case of
thiosulfonate (23), the acetoxymethyl sulfone (31) could be
similarly prepared from 9 in better yield without using toxic
sulfur dioxide. The debenzylation of sulfonamide (25a), which
was derived from 31 via the sulfinate (24), followed by
sulfonation gave 32 in good yield.
light shielding solution
dropwise
O
S
1) column chromatograpyl
S
S
m-CPBA
2) recrystallization
S
N
N
CH2Cl2, 0 °C
white LEDs
CH2Cl2
-70 °C
N
11b
OBn
N
OBn
35
O
O
16
219 g (0.74 mol)
34% yield
d.r. = 31 / 1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the targeted 2-thio substituted DBO derivatives in hand,
their in vitro β-lactamase inhibitory activities against KPC,
CTX-M-15 and CMY-2 were evaluated using nitrocefin as a
substrate25 (Table 3). The inhibitory activities of sulfones (15a,
b) and sulfoxide (19) were comparable or better than those of
avibactam (1). On the other hand, sulfonamide (32) showed
weaker activities although it was expected to have activities
similar to avibactam because a sulfonamide is a bioisostere of
amide. These results suggest that an electron inductive effect of
the substituent at the C2 position would dominantly influence
the inhibitory activities.
Scheme 6. Improved Synthetic Route for Sulfonamide
12
1) , EDC HCl
O
O
S
O
Table 3. Inhibitory Activities against β-Lactamases
AcO
S
CH2Cl2, rt,
in the dark
AcO
m-CPBA
CH2Cl2, rt
47% (from
HO
N
N
N
Ts
N
2)
IC50 (M)
N
N
AcO
S
33
OBn
O
OBn
OBn
O
O
30
9
)
white LEDs, 0 °C
9
31
-lactamase
15a
15b
19
32
1
Avibactam ( )
NaOH
0.052
0.031
0.004
0.017
0.003
0.006
0.012
0.041
0.044
0.140
0.116
0.072
0.013
0.059
KPC-2
THF/H2
O
CTX-M-15
CMY-2
0 C, 1 h
<0.001
O
O
O
O
O
1) H2, Pd/C
THF/MeOH
H2NOSO3
NaOAc
H
S
S
S
H2
N
O
H2
N
The introduction of a strong electron withdrawing group, such
as a sulfone, enhances the reactivity of the 2-imidazolone
backbone in DBO and consequently improves the inhibitory
activity against β-lactamase. On the other hand, it also means
that 2-thio substituted DBO analogues might be readily
hydrolyzed in an aqueous solution. Therefore, we assessed the
solution stability of 15a, b and 32 (Table 4). Their stability fell
slightly short of avibactam (1) at pH 7, but they were stable at
pH 2 and 5. These results led us to the conclusion that 2-thio
substituted DBO derivatives offer the potential for clinical use
as a β-lactamase inhibitor in terms of physical stability.
N
N
N
Na
O
O
2) SO3-pyridine
pyridine, rt
N
THF/H2O
0 C, 1 h
N
N
S
OBn
O
OBn
O
O
O
Na
O
25a
24
32
25a
31
)
77% (from
)
86% (from
Following our synthetic studies, we tried the scaling up of the
synthesis for 16 (Scheme 7). It is generally difficult to scale up
a photochemical reaction with respect to photo-efficiency.
However, the Barton decarboxylative reaction is a radical chain
reaction offering a high quantum yield in contrast to a catalytic
photoredox reaction.23 Thus, we assumed that the scaling up of
this step would be possible without the need for a special
apparatus or technique such as a flow reactor.24 On the other
hand, a radical chain reaction involves the risk of becoming a
runaway reaction. To prevent this, we added the Barton ester
(10) at an appropriate rate by a liquid feeding pump. The light
shielding solution of 10 was added dropwise to the solution of
35 under white LED irradiation, maintaining the inner
temperature under 10 ℃. The reaction proceeded safely and the
resulting 11b, unstable on silica-gel, was oxidized to 16 without
purification by silica-gel column chromatography. The
sulfoxide (16) was obtained with a yield and diastereo-ratio
comparable to those of the small-scale synthesis.
Table 4. Solution Stability
recovery rate at 40 °C after 16 h
pH
1
15a
15b
32
Avibactam ( )
pH 2
pH 5
pH 7
85%
86%
66%
81%
79%
44%
78%
87%
51%
3%
95%
89%
CONCLUSIONS
In summary, we have presented the synthesis and bio- and
physical evaluation of 2-thio substituted DBO derivatives,
which could be efficiently prepared from commercially
available carboxylic acid (9) by Barton decarboxylative
thiolation. They exhibited significant β-lactamase inhibitory
activities and acceptable solution stabilities. These findings
indicate that 2-thio substituted DBO derivatives have the
potential to be clinically valuable β-lactamase inhibitors.
Scheme 7. Scale-up Synthesis of 16
EXPERIMENTAL SECTION
Materials and Methods
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Unless otherwise noted, reactions were performed under After the solvent was removed, the crude product was distilled
1
2
3
4
5
6
7
8
nitrogen atmosphere. Solvents and commercial reagents were
used without purification. Carboxylic acid 9, methyl
methanethiosulfonate 34 and salt 36 were purchased from
PharmaBlock R&D Co., Ltd., Leap Labchem Co., Ltd. and
Tokyo Chemical Industry Co., Ltd. Analytical thin-layer
chromatography (TLC) was run on silica gel F254 precoated
plates. Visualization of the developed chromatogram was
performed by fluorescence quenching or Vaughn’s reagent.
Column chromatography was carried out using silica gel.
Reverse phase column chromatography was performed using
HP20SS and octadecylsilyl Silica Gel (YAMAZEN ULTRA
under reduced pressure (10 mmHg, 105 ~ 115 ℃) to afford 35
(1710 g, 90%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3)
δ: 7.53-7.54 (2H, m), 7.34 (2H, t, J = 7.6 Hz), 7.24 (1H, t, J =
7.4 Hz), 2.45 (3H, s).
S
N
N
O
OBn
11b
9
(2R,5R)-6-(Benzyloxy)-2-(methylthio)-1,6-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
diazabicyclo[3.2.1]octan-7-one (11b). To
a solution of
1
PACK). H and 13C NMR spectra were recorded on a Bruker
carboxylic acid 9 (300 mg, 1.09 mmol) and 2-mercaptopyridine
1-oxide 12 (145 mg, 1.14 mmol) in CH2Cl2 (3.0 mL) was added
EDC HCl (219 mg, 1.14 mmol). The solution was stirred for
1.5 hours at room temperature in the dark. PhSSMe 35 (848 mg,
5.43 mmol) was added and stirred under white light irradiation
using two LED lamps (A 160WE Tuna Blue, Kessil®) for 30
min at 0 ℃. The reaction mixture was poured into water and the
layers were separated. The organic layer was dried over MgSO4
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography to obtain 11b
(99.3 mg, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ: 7.44-7.36 (5H, m), 5.06 (1H, d, J = 11.5 Hz), 4.91 (1H, d, J
= 11.5 Hz), 4.58 (1H, d, J = 7.3 Hz), 3.74 (1H, d, J = 11.5 Hz),
3.33-3.31 (1H, br m), 2.82 (1H, d, J = 11.5 Hz), 2.34-2.24 (1H,
m), 2.11 (3H, s), 1.97-1.94 (1H, m), 1.68-1.53 (2H, m). 13C{1H}
NMR (100 MHz, CDCl3) δ: 169.4, 136.0, 129.2, 128.7, 128.5,
78.2, 65.6, 59.2, 43.4, 24.4, 20.7, 13.9. HRMS (ESI) m/z: [M
+ H]+ Calcd for C14H19N2O2S 279.1162; Found 279.1160.
AV400 spectrometer or a Varian INOVA. Chemical shifts (δ)
are reported in parts per million (ppm) from trimethylsilane (in
CD3Cl) or the solvent residual peak (in D2O δ 4.79) as an
internal reference. High-resolution mass spectral data were
acquired on Orbitrap Q Exactive Plus (ESI). Elemental analysis
was performed by MICRO CORDER JM11 (J-SCIENCE LAB
CO., Ltd.). Melting points were measured with a Yanagimoto
melting point apparatus and were uncorrected. Light promoted
reactions were carried out using a Kessil A 160WE Tuna Blue
40 W lamp with the white light mode. LED lamps were placed
2-10 cm away from the reaction vessel without any filters.28 The
number of lamps we employed depended on the scale of
reaction and the specific number is presented in the
experimental detail of each compound.
S
N
N
O
11a
OBn
O
O
S
(2R,5R)-6-(Benzyloxy)-2-(phenylthio)-1,6-
N
diazabicyclo[3.2.1]octan-7-one (11a). To
a solution of
N
O
13a
OBn
carboxylic acid 9 (300 mg, 1.09 mmol) and 2-mercaptopyridine
1-oxide 12 (145 mg, 1.14 mmol) in CH2Cl2 (3.0 mL) was added
EDC HCl (219 mg, 1.14 mmol). The solution was stirred for
1.5 hours at room temperature in the dark. Diphenyldisulfide
(1.19 g, 5.43 mmol) was added and stirred under white light
irradiation using two LED lamps (A 160WE Tuna Blue,
Kessil®) for 30 min at 0 ℃. The reaction mixture was poured
into water and the layers were separated. The organic layer was
dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified by flash column
chromatography to obtain 11a (171 mg, 46%) as a white solid.
1H NMR (400 MHz, CDCl3) δ: 7.48-7.20 (10H, m), 5.06-5.04
(2H, m), 4.90 (1H, d, J = 11.5 Hz), 3.82 (1H, d, J = 11.5 Hz),
3.37-3.34 (1H, br m), 2.90 (1H, d, J = 11.5 Hz), 2.47-2.36 (1H,
m), 2.05-2.01 (1H, m), 1.78-1.69 (2H, m). 13C{1H} NMR
(100 MHz, CDCl3) δ: 168.6, 135.9, 133.8, 130.1, 129.2, 129.0,
128.7, 128.5, 127.0, 78.2, 66.3, 59.0, 44.0, 24.7, 20.9. HRMS
(ESI) m/z: [M + H]+ Calcd for C19H21N2O2S 341.1318; Found
341.1317.
(2R,5R)-6-(Benzyloxy)-2-(phenylsulfonyl)-1,6-
diazabicyclo[3.2.1]octan-7-one (13a). To a solution of 11a
(353 mg, 1.04 mmol) in CH2Cl2 (10 mL) was added m-CPBA
(72 wt%, 547 mg, 2.28 mmol) at 0 ℃. After stirred for 1 hour
at room temperature, the mixture was poured into aqueous
sodium thiosulfate solution and the layers were separated. The
aqueous layer was extracted with ethyl acetate (20 mL × 2) and
the combined organic layers were dried over Na2SO4. After the
solvent was removed under vacuum, the crude product was
purified by flash column chromatography (20-50%
EtOAc/hexane) to obtain 13a (353 mg, 91%) as a white solid.
1H NMR (400 MHz, CDCl3) δ: 7.91 (2H, J = 7.5 Hz), 7.67 (1H,
J = 7.4 Hz), 7.56 (2H, J = 7.8 Hz), 7.37-7.35 (5H), 4.94 (1H, J
= 11.5 Hz), 4.81 (1H, J = 11.5 Hz), 4.41 (1H, J = 7.5 Hz), 3.73
(1H, J = 11.8 Hz), 3.43-3.42 (1H), 3.02 (1H, J = 12.0 Hz), 2.48-
2.44 (1H), 2.22-2.09 (2H), 1.91-1.86 (1H). 13C{1H} NMR (100
MHz, CDCl3) δ: 167.2, 136.2, 135.5, 134.1, 129.2, 129.2, 129.0,
128.8, 128.6, 78.1, 74.2, 57.8, 43.2, 18.7, 15.6. HRMS (ESI)
m/z: [M + H]+ Calcd for C19H21N2O4S 373.1217; Found
373.1214.
S
S
35
1-Methyl-2-phenyldisulfane (35).26 To a solution of NaOH
(486 g, 12.1 mol) in H2O (1220 mL) was added benzenthiol
(1.25 L, 12.1 mol) at 0 ℃. After stirring for 10 minutes at room
temperature, methyl methanethiosulfonate 34 (1.25 L, 12.1
mol) was added at 0 ℃ and the mixture was stirred for 1 hour
at room temperature. The reaction mixture was extracted with
EtOAc (600 mL) and the organic layer was died over Na2S2O3.
O
O
S
N
N
O
OBn
13b
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(2R,5R)-6-(Benzyloxy)-2-(methylsulfonyl)-1,6- added 5% Pd/C (68.6 mg, 0.34 wt equiv). After stirred at room
1
2
3
4
5
6
7
8
diazabicyclo[3.2.1]octan-7-one (13b). To a solution of 11b
(1.00 g, 3.59 mmol) in CH2Cl2 (20 mL) was added m-CPBA (72
wt%, 2.16 g, 9.00 mmol) at 0 ℃. After stirred for 1 hour at 0 ℃,
the mixture was poured into a mixture of aqueous sodium
thiosulfate solution and sodium bicarbonate solution and the
layers were separated. The aqueous layer was extracted with
dichloromethane (20 mL × 1) and the combined organic layers
were dried over MgSO4. After the solvent was removed under
reduced pressure, the crude product was purified by flash
column chromatography (33-67% EtOAc/hexane) to obtain
13b (1.01 g, 90%) as a white amorphous. 1H NMR (400 MHz,
CDCl3) δ: 7.39 (5H, t, J = 5.5 Hz), 5.01 (1H, d, J = 11.5 Hz),
4.88 (1H, d, J = 11.3 Hz), 4.33 (1H, t, J = 7.8 Hz), 3.60 (1H, d,
J = 12.0 Hz), 3.45-3.44 (1H, m), 3.06-3.02 (4H, m), 2.36-2.26
(1H, m), 2.15-2.03 (2H, m), 1.84-1.79 (1H, m). 13C{1H} NMR
(100 MHz, CDCl3) δ: 167.3, 135.4, 129.2, 128.9, 128.6, 78.3,
72.7, 57.7, 43.0, 37.3, 18.2, 13.8. HRMS (ESI) m/z: [M + H]+
Calcd for C14H19N2O4S 311.1060; Found 311.1058.
temperature under H2 (1 atm) atmosphere for 1 hour, the
mixture was filtered. The solvent was removed in vacuo. The
crude product was dissolved to pyridine (4 mL) and SO3-
pyridine (514 mg, 3.23 mmol) was added. After stirred for 3.5
hours, 8.4% NaHCO3 aq (20 mL) was added at 0 ℃ and the
aqueous layer was washed with CH2Cl2 (20 mL × 3). To the
aqueous layer was added CH2Cl2 (20 mL) and
tetrabutylammonium hydrogen sulfate (183 mg, 0.54 mmol) at
0 ℃. After stirred at room temperature for 15 minutes, the
aqueous layer was extracted with CH2Cl2 (20 mL × 3) and the
solvent was removed under reduced pressure. The crude
product was applied onto a Dowex® sodium form column
(Dowex® 50WX8 hydrogen form treated with 1N NaOH aq and
washed until neutral pH with H2O) and subjected to ODS
column chromatography (H2O only). The fractions containing
the desired compound were combined, frozen and lyophilized
to afford 15b (172 mg, 83%) as a white amorphous. 1H NMR
(400 MHz, D2O) δ: 4.77 (1H, t, J = 8.3 Hz), 4.31-4.31 (1H, br
m), 3.69 (1H, d, J = 12.3 Hz), 3.42 (1H, dd, J = 12.4, 2.6 Hz),
3.19 (3H, s), 2.38-2.28 (1H, m), 2.21-2.07 (3H, m). 13C{1H}
NMR (100 MHz, D2O) δ: 168.2, 73.1, 59.4, 43.3, 36.5, 17.4,
14.5. Anal. Calcd for C7H11N2O7S2Na(H2O)1.9: C, 23.58; H,
4.18; N, 7.86; S, 17.99; Na, 6.45. Found: C, 23.64; H, 4.27; N,
7.89; S, 17.88; Na, 6.64.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
S
N
O
O
N
S
O
O
O
Na
15a
Sodium
(2R,5R)-7-oxo-2-(phenylsulfonyl)-1,6-
diazabicyclo[3.2.1]octan-6-yl sulfate (15a). To a solution of
13a (200 mg, 0.54 mmol) in THF/MeOH (v/v = 2/1, 6 mL) was
added 5% Pd/C (57.1 mg, 0.29 wt equiv). After stirred at room
temperature under H2 (1 atm) atmosphere for 1 hour, the
mixture was filtered. The solvent was removed in vacuo. The
crude product was dissolved to pyridine (4 mL) and SO3-
pyridine (514 mg, 3.23 mmol) was added. After stirred for 3.5
hours, 8.4% NaHCO3 aq (20 mL) was added at 0 ℃ and the
aqueous layer was washed with CH2Cl2 (20 mL × 3). To the
aqueous layer was added CH2Cl2 (20 mL) and
tetrabutylammonium hydrogen sulfate (183 mg, 0.54 mmol) at
0 ℃. After stirred at room temperature for 15 minutes, the
aqueous layer was extracted with CH2Cl2 (20 mL × 3) and the
solvent was removed under reduced pressure. The crude
product was applied onto a Dowex® sodium form column
(Dowex® 50WX8 hydrogen form treated with 1N NaOH aq and
washed until neutral pH with H2O) and subjected to ODS
column chromatography (H2O only). The fractions containing
the desired compound were combined, frozen and lyophilized
to afford 15a (162 mg, 78%) as a white amorphous. 1H NMR
(400 MHz, D2O) δ: 7.99 (2H, d, J = 7.8 Hz), 7.85 (1H, t, J = 7.5
Hz), 7.72 (2H, t, J = 7.8 Hz), 4.84-4.80 (1H, m), 4.26-4.26 (1H,
m), 3.56 (1H, d, J = 12.5 Hz), 3.32 (1H, dd, J = 12.4, 2.6 Hz),
2.39-2.33 (1H, m), 2.18-2.03 (3H, m). 13C{1H} NMR (100
MHz, D2O) δ: 167.9, 135.4, 133.8, 129.7, 129.1, 75.0, 59.3,
43.4, 17.7, 16.3. Anal. Calcd for C12H13N2O7S2Na(H2O)1.3: C,
35.35; H, 3.86; N, 6.87; S, 15.72; Na, 5.64. Found: C, 35.48; H,
4.13; N, 6.84; S, 15.88; Na, 5.48.
O
S
N
N
O
OBn
16
(2R,5R)-6-(Benzyloxy)-2-((R)-methylsulfinyl)-1,6-
diazabicyclo[3.2.1]octan-7-one (16). To a solution of 11b (2.47
g, 8.89 mmol) in CH2Cl2 (25 mL) was added m-CPBA (72 wt%,
2.34 g, 9.78 mmol) at -78 ℃. After stirred for 2 hour at -78 ℃,
the mixture was poured into aqueous sodium thiosulfate
solution and the layers were separated. The aqueous layer was
extracted with ethyl acetate (30 mL × 3) and the combined
organic layers were dried over Na2SO4. After the solvent was
removed under reduced pressure, the crude product was
purified by flash column chromatography (0-10%
MeOH/EtOAc) to obtain 16 (2.31 g, 88%, d.r. = 91/9) as a white
1
solid. H NMR (400 MHz, CDCl3) δ: 7.43-7.37 (5H, m), 5.04
(1H, d, J = 11.3 Hz), 4.90 (1H, d, J = 11.5 Hz), 4.02 (1H, dd, J
= 7.5, 4.3 Hz), 3.39-3.39 (1H, m), 3.18 (1H, d, J = 11.8 Hz),
3.03 (1H, d, J = 11.8 Hz), 2.68 (3H, s), 2.39-2.36 (1H, m), 2.17-
2.11 (2H, m), 1.80-1.77 (1H, m). 13C{1H} NMR (100 MHz,
CDCl3) δ: 166.9, 135.5, 129.3, 128.9, 128.6, 78.4, 76.3, 57.5,
45.7, 37.2, 19.6, 15.9. HRMS (ESI) m/z: [M + H]+ Calcd for
C14H19N2O3S 295.1111; Found 295.1108. Melting point: 96-99
℃.
O
S
O
O
N
S
N
O
OH
17
N
O
O
N
S
(2R,5R)-6-Hydroxy-2-((R)-methylsulfinyl)-1,6-
O
O
O
Na
diazabicyclo[3.2.1]octan-7-one (17). To a solution of 16 (1.53
g, 5.20 mmol) in MeOH (15 mL) were added 10% Pd(OH)2 on
carbon (365 mg, 0.24 wt equiv) and DABCO (11.7 mg, 0.10
mmol). After stirred at room temperature under H2 atmosphere
15b
Sodium
(2R,5R)-2-(methylsulfonyl)-7-oxo-1,6-
diazabicyclo[3.2.1]octan-6-yl sulfate (15b). To a solution of
13b (200 mg, 0.54 mmol) in THF/MeOH (v/v = 1/1, 4 mL) was
6
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(1 atm) for 1 hour, the mixture was filtered. The solvent was D2O) δ: 4.34-4.31 (2H, m), 3.47 (1H, d, J = 12.0 Hz), 3.39 (1H,
1
2
3
4
5
6
7
8
removed in vacuo to afford 17 (941 mg, 89%) as a white solid,
which was used to the next step without any purification. H
d, J = 12.3 Hz), 2.79 (3H, s), 2.38-2.34 (1H, m), 2.20-2.16 (2H,
m), 2.05-2.01 (1H, m). 13C{1H} NMR (100 MHz, D2O) δ: 167.9,
75.3, 59.2, 45.3, 34.8, 18.5, 15.5. Anal. Calcd for
C7H11N2O6S2Na(H2O)1.3: C, 25.50; H, 4.16, N, 8.50; S, 19.45;
Na, 6.97. Found: C, 25.86; H, 4.02; N, 8.25; S, 18.95; Na, 7.24.
O
1
NMR (400 MHz, D2O) δ: 4.20 (1H, t, J = 5.9 Hz), 3.95-3.94
(1H, m), 3.34-3.31 (2H, m), 2.77 (3H, s), 2.39-2.29 (1H, m),
2.19-2.14 (2H, m), 1.98-1.94 (1H, m). 13C{1H} NMR (100
MHz, D2O) δ: 166.4, 74.4, 58.9, 46.3, 34.9, 18.6, 15.2. HRMS
(ESI) m/z: [M + H]+ Calcd for C7H13N2O3S 205.0641; Found
205.0642.
F3C
N O
S
O
S
O
N
9
Cl
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
22
OBn
20
Neopentyl chlorosulfate (20).27 To a solution of sulfuryl
chloride (2.00 mL, 24.6 mmol) in Et2O (2 mL) was added a
solution of neopentyl alcohol (2.39 g, 27.1 mmol) and pyridine
(1.99 mL, 24.6 mmol) in Et2O (3 mL) at -78 ℃. After stirred at
room temperature for 2 hours, the mixture was diluted with
Et2O (30 mL) and the organic phase was washed with 10%
citric acid aq, water and brine and dried over Na2SO4. The
solvent was removed under reduced pressure to afford 20 (3.96
g, 86%) as a colorless oil, which was used without a further
purification. 1H NMR (400 MHz, CDCl3) δ: 4.18 (2H, s), 1.05
(9H, s).
N-((1R)-((2R,5R)-6-(Benzyloxy)-7-oxo-1,6-
diazabicyclo[3.2.1]octan-2-yl)(methyl)(oxo)-λ6-
sulfaneylidene)-2,2,2-trifluoroacetamide (22). To a solution of
16 (592 mg, 2.01 mmol) in CH2Cl2 (10 mL) were added 2,2,2-
trifluoroacetamide (445 mg, 4.02 mmol), magnesium oxide
(324 mg, 8.04 mmol), Rh2(OAc)4 (44.4 mg, 0.101 mmol) and
PhI(OAc)2 (971 mg, 3.02 mmol). After stirred overnight, the
reaction mixture was filtered and the solvent was removed in
vacuo. The crude product was purified by flash column
chromatography (20-50% EtOAc/hexane) to obtain 22 (632
mg, 78%) as a white amorphous. 1H NMR (400 MHz, CDCl3)
δ: 7.39 (5H, s), 4.99 (1H, d, J = 11.5 Hz), 4.87 (1H, d, J = 11.5
Hz), 4.49-4.47 (1H, m), 3.70 (1H, d, J = 12.3 Hz), 3.55 (3H, s),
3.47-3.46 (1H, m), 3.06 (1H, d, J = 12.0 Hz), 2.55-2.50 (1H,
m), 2.21-2.08 (2H, m), 1.95-1.90 (1H, m). 13C{1H} NMR (100
MHz, CDCl3) δ: 166.6, 164.4 (q, 3JC-F = 38.1 Hz), 135.1, 129.3,
129.1, 128.7, 115.9 (q, 2JC-F = 288.1 Hz), 78.4, 75.2, 57.7, 42.6,
35.7, 17.9, 14.4. 19F NMR (377 MHz, CDCl3) δ: -76.12 (3F, s).
HRMS (ESI) m/z: [M + H]+ Calcd for C16H19F3N3O4S
406.1043; Found 406.1039.
O
S
N
O
O
N
S
O
O
O
18
(2R,5R)-2-((R)-Methylsulfinyl)-7-oxo-1,6-
diazabicyclo[3.2.1]octan-6-yl neopentyl sulfate (18). To a
solution of 17 (300 mg, 1.47 mmol) in DMF (3 mL) were added
DBU (0.288 mL, 1.91 mmol) and chlorosulfate 20 (274 mg,
1.47 mmol) at 0 ℃ and stirred for 15 minutes. The reaction
mixture was poured into 10% aqueous citric acid solution and
the aqueous layer was extracted with ethyl acetate (20 mL × 4).
The combined organic layers were washed with water, dried
over MgSO4 and the solvent was removed in vacuo. The crude
product was purified by flash column chromatography (0-10%
MeOH/EtOAc) to afford 18 (281 mg, 54%) as a white
amorphous solid. 1H NMR (400 MHz, CDCl3) δ: 4.42 (1H, d, J
= 8.8 Hz), 4.26-4.26 (1H, br m), 4.18 (1H, d, J = 8.8 Hz), 4.11
(1H, t, J = 6.3 Hz), 3.45 (1H, d, J = 12.3 Hz), 3.34 (1H, d, J =
12.3 Hz), 2.69 (3H, s), 2.52-2.43 (1H, m), 2.29-2.12 (2H, m),
2.06-2.01 (1H, m), 1.00 (9H, s). 13C{1H} NMR (100 MHz,
CDCl3) δ: 166.4, 85.2, 76.9, 59.9, 44.9, 37.1, 31.9, 25.8, 19.3,
15.9. HRMS (ESI) m/z: [M + H]+ Calcd for C12H23N2O6S2
355.0992; Found 355.0989.
O
O
S
N
S
N
N
O
23
OBn
S-(Pyridin-2-yl)
(2R,5R)-6-(benzyloxy)-7-oxo-1,6-
diazabicyclo[3.2.1]octane-2-sulfonothioate (23). To a solution
of the carboxylic acid 9 (2.00 g, 7.24 mmol) in CH2Cl2 (20 mL)
were added Et3N (1.51 mL, 10.9 mmol) and salt 36 (1.65 g, 8.69
mmol). The reaction mixture was stirred at room temperature
for 1 hour in the dark (solution A). To another flask was added
CH2Cl2 (20 mL) and cooled to -78 ℃. After liquid sulfur
dioxide (20 mL, 7.24 mmol) was added, an inner temperature
was raised to -15 ℃. Under white light irradiation using four
LED lamps (A 160WE Tuna Blue, Kessil®), the solution A was
slowly added by a syringe wrapped in aluminum foil while
maintaining the inner temperature under -10 ℃. After the
reaction mixture was stirred at 0 ℃ for 2 hours, the solvent was
removed and water was added. The aqueous layer was extracted
with EtOAc (30 mL × 2) and the combined organic layers were
washed with NaHCO3 aq and brine. After dried over MgSO4,
the solvent was removed in vacuo. The crude product was
purified by flash column chromatography (10-70%
EtOAc/hexane) to obtain 23 (1.07 g, 37%) as a white
amorphous. 1H NMR (400 MHz, CDCl3) δ: 8.67 (1H, d, J = 4.0
Hz), 7.78-7.75 (2H, m), 7.41-7.35 (6H, m), 5.09 (1H, t, J = 8.2
Hz), 5.00 (1H, d, J = 11.5 Hz), 4.88 (1H, d, J = 11.5 Hz), 3.53
(1H, d, J = 12.3 Hz), 3.48-3.47 (1H, m), 3.13 (1H, d, J = 12.0
O
S
N
O
O
N
S
O
O
O
Na
19
Sodium
(2R,5R)-2-((R)-methylsulfinyl)-7-oxo-1,6-
diazabicyclo[3.2.1]octan-6-yl sulfate (19). To a solution of 18
(286 mg, 0.807 mmol) in DMF (3 mL) was added sodium
thiolate 21 (187 mg, 1.21 mmol). After stirred overnight, the
solvent was removed in vacuo. The crude product was applied
onto the HP20SS resin and subjected to ODS column
chromatography (H2O only) to afford 19 (188 mg, 76%) as a
1
white amorphous after lyophilization. H NMR (400 MHz,
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Hz), 2.37-2.31 (1H, m), 2.25-2.08 (2H, m), 1.88-1.80 (1H, m).
CH2Cl2 (200 mL) at 0 ℃ over 20 minutes by a liquid feeding
13C{1H} NMR (100 MHz, CDCl3) δ: 166.8, 151.2, 150.7, 138.0,
135.4, 131.1, 129.3, 128.9, 128.6, 124.8, 79.6, 78.2, 57.8, 43.6,
18.5, 17.4. HRMS (ESI) m/z: [M + H]+ Calcd for C18H20N3O4S2
406.0890; Found 406.0885.
1
2
3
4
5
6
7
8
pump. After the reaction mixture was stirred at 0 ℃ for 20
minutes, the organic layer was washed with water (300 mL) and
dried over MgSO4. After the solvent was removed in vacuo, the
crude product was purified by flash column chromatography (0-
40% EtOAc/hexane) to obtain 30 in a mixture with
thiosulfonate 33 (25.6 g, 49 wt% purity). The product was used
without any further purification. To a solution of 30 (25.6 g, 49
wt% purity) in CH2Cl2 (256 mL) was added m-CPBA at 0 ℃.
After stirred at room temperature for 2 hours, an aqueous
solution of Na2S2O3 and NaHCO3 was added at 0 ℃ and the
organic solvent was removed under reduced pressure. The
aqueous layer was extracted with EtOAc (200 mL × 2) and the
combined organic layers were washed with NaHCO3 aq and
dried over MgSO4. After the solvent was removed in vacuo, the
crude product was purified by flash column chromatography
(25-50% EtOAc/hexane) to obtain 31 as a white amorphous
O
O
S
H2N
N
N
O
OBn
25b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2S,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-
2-sulfonamide (25b). To a solution of 23 (40.0 mg, 0.099
mmol) in DMF (0.40 mL) were added 1,2-dibromo-1,1,2,2-
tetrachloroethane (257 mg, 0.789 mmol) and 7 M methanol
solution of ammonia (42.3 μL, 0.296 mmol). After stirred for 2
hours, 0.5 N HCl aq was added. The aqueous layer was
extracted with EtOAc (10 mL × 2) and the combined organic
layers were washed with water and brine. After dried over
MgSO4, the solvent was removed in vacuo. The crude product
was purified by flash column chromatography (0-60%
EtOAc/hexane) to obtain 25b (2.00 mg, 6.5%) as a pale yellow
oil. 1H NMR (400 MHz, CDCl3) δ: 7.40-7.38 (5H, m), 5.12 (2H,
s), 5.04 (1H, d, J = 11.5 Hz), 4.91 (1H, d, J = 11.3 Hz), 4.20
(1H, dd, J = 12.9, 4.1 Hz), 3.44 (1H, d, J = 11.5 Hz), 3.38-3.38
(1H, br m), 2.89 (1H, d, J = 11.5 Hz), 2.31-2.28 (2H, m), 2.14-
2.07 (1H, m), 1.80-1.75 (1H, m). 13C{1H} NMR (100 MHz,
CDCl3) δ: 166.3, 135.1, 129.4, 129.1, 128.7, 78.5, 78.3, 58.2,
54.8, 23.2, 21.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C13H18N3O4S 312.1013; Found 312.1010.
1
(12.6 g, 47%). H NMR (400 MHz, CDCl3) δ: 7.39-7.38 (5H,
m), 5.57 (1H, d, J = 12.0 Hz), 5.00 (2H, dd, J = 11.7, 2.6 Hz),
4.87 (1H, d, J = 11.5 Hz), 4.61 (1H, t, J = 8.3 Hz), 3.52 (1H, d,
J = 12.3 Hz), 3.44-3.43 (1H, m), 3.06 (1H, d, J = 12.0 Hz), 2.31-
2.28 (1H, m), 2.23 (3H, s), 2.17-2.03 (2H, m), 1.88-1.81 (1H,
m). 13C{1H} NMR (100 MHz, CDCl3) δ: 168.7, 166.9, 135.3,
129.3, 129.0, 128.7, 78.3, 70.1, 69.4, 57.6, 42.9, 20.4, 18.0, 13.3.
HRMS (ESI) m/z: [M + H]+ Calcd for C16H21N2O6S 369.1115;
Found 369.1113.
O
O
S
H2N
N
N
O
OBn
O
O
25a
S
S
OAc
(2R,5R)-6-(Benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-
2-sulfonamide (25a). Method A (Scheme 4): To a solution of
thiosulfonate 23 (75.9 mg, 0.187 mmol) in THF/H2O (v/v =
10/1, 0.84 mL) was added NaSPh (27.5 mg, 0.187 mmol). After
the mixture was stirred at room temperature for 3 hours, H2O
(10 mL) was added and the aqueous layer was washed with
EtOAc (10 mL × 2). The aqueous solvent was partially removed
under reduced pressure, the resulting aqueous sodium sulfinate
24 solution was equally divided into two flasks and one of the
solution was used to the next step. To the aqueous solution of
24 (ca. 1.5 mL) were added NaOAc (19.2 mg, 0.23 mmol) and
(aminooxy)sulfonic acid (13.2 mg, 0.12 mmol). After stirred at
room temperature overnight, Na2S2O3 aq was added and the
aqueous layer was extracted with EtOAc (10 mL × 2). The
combined organic layers were washed with 1 N HCl aq,
NaHCO3 aq, water and brine. After dried over MgSO4, the
solvent was removed under reduced pressure. The crude
product was purified by flash column chromatography (0-60%
EtOAc/hexane) to obtain 25a as a white amorphous (13.3 mg,
46%). Method B (Scheme 6): To a solution of sulfone 31 (1.24
g, 3.37 mmol) in THF/H2O (v/v = 1/1, 25 mL) was added 1 N
NaOH aq (6.74 mL, 6.74 mmol) at 0 ℃. After stirred at 0 ℃ for
1 hour, NaOAc (1.11 g, 13.5 mmol) and (aminooxy)sulfonic
acid (1.22 g, 10.8 mmol) were added and the mixture was stirred
at room temerature for 6 hours. After the organic solvent was
removed under reduced pressure, the aqueous layer was
extracted with EtOAc (20 mL × 2) and the combined organic
layers were dried over MgSO4. After the solvent was removed
in vacuo, the crude product was purified by flash column
chromatography (0-60% EtOAc/hexane) to obtain 25a as a
33
(Tosylthio)methyl acetate (33). To a white suspension of
potassium 4-methylbenzenesulfonothioate (5.00 g, 22.1 mmol)
in MeCN (20 mL) were added chloromethyl acetate (3.36 g,
30.9 mmol), NaI (3.31 g, 22.1 mmol) and DMF (15 mL). After
stirred overnight, water was added and the mixture was
extracted with EtOAc (40 mL × 2). The combined organic
layers were dried over MgSO4 and the solvent was removed
under reduced pressure. The crude product was purified by
flash column chromatography (0-33% EtOAc/hexane) to obtain
33 (4.86 g, 85%) as a white solid. 1H NMR (400 MHz, CDCl3)
δ: 7.84 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 5.58 (2H,
s), 2.46 (3H, s), 1.87 (3H, s). 13C{1H} NMR (100 MHz, CDCl3)
δ: 169.6, 145.1, 142.9, 129.8, 127.2, 67.0, 21.7, 20.4. HRMS
(ESI) m/z: [M + Na]+ Calcd for C10H12O4S2Na 283.0069;
Found 283.0066.
O
O
AcO
S
N
N
O
31
OBn
(((2R,5R)-6-(Benzyloxy)-7-oxo-1,6-
diazabicyclo[3.2.1]octan-2-yl)sulfonyl)methyl acetate (31). To
a solution of carboxylic acid 9 (20.0 g, 72.4 mmol) and 2-
mercaptopyridine 1-oxide 12 (9.20 g, 7.24 mmol) in CH2Cl2
(200 mL) was added EDC HCl (13.9 g, 7.24 mmol). The
solution was stirred for 1 hours at room temperature in the dark
(solution A). Under white light irradiation using four LED
lamps (A 160WE Tuna Blue, Kessil®), solution A was slowly
added to a solution of thiosulfonate 33 (56.5 g, 217 mmol) in
1
white amorphous (0.90 g, 86%). H NMR (400 MHz, CDCl3)
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δ: 7.39-7.38 (5H, m), 5.00 (1H, d, J = 11.5 Hz), 4.96 (2H, s), mixture was poured into a stirring aqueous solution (4.3 L) of
1
2
3
4
5
6
7
8
4.87 (1H, d, J = 11.5 Hz), 4.39 (1H, t, J = 8.2 Hz), 3.55 (1H, d,
J = 12.0 Hz), 3.45-3.44 (1H, m), 3.07 (1H, d, J = 11.8 Hz), 2.32-
2.07 (3H, m), 1.84-1.77 (1H, m). 13C{1H} NMR (100 MHz,
CDCl3) δ: 167.7, 135.3, 129.3, 129.0, 128.7, 78.3, 74.0, 57.9,
43.3, 18.2, 17.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C13H18N3O4S 312.1013; Found 312.1010.
NaHCO3 (225 g) and Na2S2O3•5H2O (350 g). After the organic
layer was separated, NaCl (675 g) was added and the aqueous
phase extracted with EtOAc (4.5 L × 2). The combined organic
layers were dried over MgSO4 (750 g) and the solvent was
removed under reduced pressure. The crude product was
purified by flash column chromatography (0-10%
MeOH/EtOAc) using 3.0 kg of silica-gel. To the purified
product (553 g) was added EtOAc (97 mL) and the slurry was
stirred at -30 ℃ for 20 minutes before filtering, washing with
EtOAc (480 mL × 2) and IPE (480 mL × 2), and drying to afford
16 (219 g, 34%, dr = 31/1) as a white crystalline solid.
O
O
S
H2N
N
O
O
9
N
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
Na
32
O
S
Sodium
(2R,5R)-7-oxo-2-sulfamoyl-1,6-
diazabicyclo[3.2.1]octan-6-yl sulfate (32). To a solution of 25a
(168 mg, 0.54 mmol) in MeOH (6.7 mL) was added 5% Pd/C
(115 mg, 0.68 wt equiv). After stirred at room temperature
under H2 atmosphere (1 atm) for 1 hour, the mixture was
filtered. The solvent was removed in vacuo. The crude product
was dissolved to pyridine (6 mL) and SO3-pyridine (514 mg,
3.23 mmol) was added. After stirred for 3.5 hours, 8.4%
NaHCO3 aq (20 mL) was added at 0 ℃ and the aqueous layer
was washed with CH2Cl2 (20 mL × 3) and the solvent was
removed under reduced pressure. The crude product was
applied onto the HP20SS resin and subjected to ODS column
chromatography (H2O only) to afford 32 (133 mg, 77%) as a
N
N
O
OBn
epi-16
(2R,5R)-6-(benzyloxy)-2-((S)-methylsulfinyl)-1,6-
diazabicyclo[3.2.1]octan-7-one (epi-16).
After
recrystallization of 16, the crude mixture of 16 and epi-16 was
obtained from the mother liquid. The crude was purified by
preparative supercritical fluid chromatography (SFC) to afford
epi-16 as a white solid.30 1H NMR (400 MHz, CDCl3) δ: 7.40-
7.38 (5H, m), 5.02 (1H, d, J = 11.5 Hz), 4.88 (1H, d, J = 11.5
Hz), 3.75 (1H, t, J = 7.8 Hz), 3.70 (1H, d, J = 11.8 Hz), 3.43-
3.43 (1H, br m), 3.12 (1H, d, J = 11.8 Hz), 2.71 (3H, s), 2.45-
2.41 (1H, m), 2.22-2.13 (2H, m), 1.90-1.85 (1H, m). 13C{1H}
NMR (100 MHz, CDCl3) δ: 169.0, 135.6, 129.2, 128.8, 128.6,
78.2, 71.3, 58.1, 45.3, 34.9, 19.4, 19.3. HRMS (ESI) m/z: [M +
H]+ Calcd for C14H19N2O3S 295.1111; Found 295.1108.
1
white amorphous after lyophilization. H NMR (400 MHz,
D2O) δ: 4.60 (1H, t, J = 8.1 Hz), 4.32-4.29 (1H, br m), 3.72 (1H,
d, J = 12.3 Hz), 3.41 (1H, dd, J = 12.0, 2.1 Hz), 2.30-2.24 (2H,
m), 2.10-2.04 (2H, m). 13C{1H} NMR (100 MHz, D2O) δ: 168.7,
74.2, 59.6, 55.4, 43.4, 17.7. Anal. Calcd for
C6H10N3O7S2Na(H2O)2.0(NaHCO3)0.3: C, 19.68; H, 3.75; N,
10.93; S, 16.68; Na, 7.77. Found: C, 19.52; H, 3.75; N, 11.10;
S, 16.89; Na, 7.72.
β-Lactamase inhibitory assay. The inhibition of β-lactamase
was determined by hydrolysis of nitrocefin. The hydrolysis of
nitrocefin was recorded as absorbance at 492 nm by
Envision2013 (Perkin Elmer. US). The concentration of β-
lactamase enzyme (KPC-2, CTX-M-15, and CMY-2) used was
determined by measurement of hydrolysis of nitrocefin (50
g/mL) where the change of the absorbance was approximately
0.2 from negative control (no enzyme). The enzyme was added
to sample solution including nitrocefin (final concentration 50
g /mL) and inhibitor at the volume ratio of 1:3 (final 80 L).
The absorbance was measured at 35 ℃ after 20 min incubation.
The concentration of inhibitor needed to reduce the hydrolysis
of substrate by 50% (IC50) was calculated using XLfit (IDBS,
UK).
Large-scale synthesis of 16.29 To a solution of carboxylic acid
9 (600 g, 2.17 mol) in CH2Cl2 (3.0 L) were added 2-
mercaptopyridine 1-oxide 12 (290 mg, 2.28 mol) and EDC HCl
(437 g, 2.28 mol) maintaining the inner temperature 10 ~ 20 ℃,
with CH2Cl2 (600 mL) for rinsing apparatuses. The reaction
mixture was stirred at room temperature for 1.5 hours in the
dark (solution A). A solution of PhSSMe 35 (1.20 kg, 6.52 mol)
in CH2Cl2 (1.2 L) was cooled to 0 ℃ under white light
irradiation using ten LED lamps (A 160WE Tuna Blue,
Kessil®). The solution A was added over 1 hour by a liquid
feeding pump, with a CH2Cl2 (600 mL) linewash while
maintaining the inner temperature under 10 ℃. After stirred at
0 ℃ for 1.5 hours, CO2 gas evolution stopped and the reaction
mixture was poured into water (10 L). The organic phase was
separated and the aqueous layer was extracted with CH2Cl2 (300
mL). After dried over MgSO4 (400 g), the solvent was removed
under reduced pressure to afford 1.86 kg of the crude product.
To a slurry of silica-gel (1.0 kg) in hexane/EtOAc (v/v = 2/1,
3.0 L) was slowly added a hexane (2.0 L) solution of the crude
product while keeping the inner temperature under 10 ℃. After
stirred for 15 minutes, the mixture was filtered and the silica-
gel was washed with hexane/EtOAc (v/v = 2/1, 3.0 L× 3). The
solvent was removed under reduced pressure to afford a roughly
purified sulfide 11b (1.57 kg) containing PhSSMe 35. To a
solution of the roughly purified sulfide 11b (1.57 kg) in CH2Cl2
(2.4 L) was slowly added a solution of m-CPBA (72 wt%, 448
g, 1.87 mol) in CH2Cl2 (4.8 L) over 1.5 hours while maintaining
the inner temperature under -55 ℃. After stirred for 15 minutes,
the inner temperature was raised to -30 ℃ and the reaction
ASSOCIATED CONTENT
SUPPORTING INFORMATION
This material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental details and copies of NMR spectra of all new
compounds (PDF)
X-ray crystallographic data of compound 16 (CIF)
AUTHOR INFOMATION
Corresponding Author
*E-mail: motohiro.fujiu@shionogi.co.jp
ORCID
Motohiro Fujiu: 0000-0002-5976-7041
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Page 10 of 11
Metzger, L.; Nocito, S.; Ossola, F.; Phizackerley K.; Rasper, D.; Shaul,
ACKNOWLEDGMENTS
J.; Shen, X.; Simmons, R. L.; Tang, D.; Tashiro K.; Yue, Q.; IID572:
A New Potentially Best-In-Class -Lactamase Inhibitor. ACS Infect.
Dis. 2019, 5, 1045-1051.
1
2
3
4
5
6
7
8
We appreciate the kind support for the large-scale synthesis by
Shinichiro Hara and Dr. Akihiro Takada. The β-lactamase
inhibitory assay was supported by Shuhei Matsumoto and Dr.
Naoki Kohira and the solution stability study was conducted by Dr.
Daiki Nagamatsu. We thank Dr. Yukiko Kan for the NMR
spectroscopy data, Dr. Hirotoshi Morita for the HRMS, and
Yumiko Takagi for the element analysis data.
(12) Durand-Réville, T. F.; Guler S.; Comita-Prevoir, J.; Chen, B.;
Bifulco, N.; Huynh, H.; Lahiri, S.; Shapiro, A. B.; McLeod, S. M.;
Carter, N. M.; Moussa, S. H.; Velez-Vega, C.; Olivier, N. B.;
McLaughlin, R.; Gao, N.; Thresher, J.; Palmer, T.; Andrews, B.;
Giacobbe, R. A.; Newman, J. V.; Ehmann, D. E.; Jonge, R. d.;
O’Donnell, J.; Mueller, J. P.; Tommasi, R. A.; Miller A. A. ETX2514
is a broad-spectrum -lactamase inhibitor for the treatment of drug-
resistant Gram-negative bacteria includine Acinetobacter baumannii.
Nat. Microbiol. 2017, 2, 17104.
(13) Miller, A. A.; Shapiro, A. B.; McLeod, S. M.; Carter, N. M.;
Moussa, S. H.; Tommasi, R.; Mueller J. P. In Vitro Characterization of
ETX1317, a Broad-Spectrum -Lactamase Inhibitor That Restores and
Enhances -Lactam Activity against Multi-Drug-Resistant
Enterobacteriales, Including Carbapenem-Resistant Strains. ACS
Infect. Dis. 2020, 6, 1389-1397.
(14) Barton, D. H. R.; Bridon, D.; Zard, S. Z. THE INVENTION OF
NEW RADICAL REACTIONS. PART XIII. HIGH YIELDING
DECARBOXYLATIVE CHALCOGENATION OF ALIPHATIC
AND ALICYCLIC ACIDS. Heterocycles 1987, 25, 449-462.
(15) Ashton, M. J.; Lawrence, C.; Karlsson, J. A.; Stuttle, K. A. J.;
Newtin, C. G.; Vacher, B. Y.; Webber, S.; Withnall, M. J. Anti-
inflammatory 17β-Thioalkyl-16α,17α-ketal and -acetal Androstanes: A
New Class of Airway Selective Steroids for the Treatment of Asthma.
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(16) 2D developed TLC showed that 11b decomposed on silica-gel. A
picture of TLC is in Supporting Information. See Figure S1.
(17) The minor isomer (epi-16) was also isolated. The procedure for
isolation is described in the Experimental Section.
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(28) Typical set up for light-promoted reaction is described in
Supporting Information. See Figure S2.
(29) Reaction set up for the large-scale synthesis is described in
Supporting Information. See Figure S4.
(30) SFC condition and chromatogram are presented in Supporting
Information.
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