Synthesis and structure-activity relationships of novel lincomycin derivatives part 3: Discovery of the 4-(pyrimidin-5-yl)phenyl group in synthesis of 7(S)-thiolincomycin analogs

Article abstract of DOI:10.1038/ja.2016.114

Novel lincomycin derivatives possessing an aryl phenyl group or a heteroaryl phenyl group at the C-7 position via sulfur atom were synthesized by Pd-catalyzed cross-coupling reactions of 7(S)-7-deoxy-7-thiolincomycin (5) with various aryl halides. This reaction is the most useful method to synthesize a variety of 7(S)-7-deoxy-7-thiolincomycin derivatives. On the basis of analysis of structure-activity relationships of these novel lincomycin derivatives, we found that (a) the location of basicity in the C-7 side chain was an important factor to enhance antibacterial activities, and (b) compounds 22, 36, 42, 43 and 44 had potent antibacterial activities against a variety of Streptococcus pneumoniae with erm gene, which cause severe respiratory infections, even compared with our C-7-modified lincomycin analogs (1-4) reported previously. Furthermore, 7(S)-configuration was found to be necessary for enhancing antibacterial activities from comparison of configurations at the 7-position of 36 (S-configuration) and 41 (R-configuration).

Full text of DOI:10.1038/ja.2016.114

The Journal of Antibiotics (2016), 1–13
2016 Japan Antibiotics Research Association All rights reserved 0021-8820/16
www.nature.com/ja
&
ORIGINAL ARTICLE
Synthesis and structure–activity relationships
of novel lincomycin derivatives part 3: discovery of
the 4-(pyrimidin-5-yl)phenyl group in synthesis
of 7(S)-thiolincomycin analogs
Yoshinari Wakiyama, Ko Kumura, Eijiro Umemura, Satomi Masaki, Kazutaka Ueda, Yasuo Sato,
Takashi Watanabe, Yoko Hirai and Keiichi Ajito
Novel lincomycin derivatives possessing an aryl phenyl group or a heteroaryl phenyl group at the C-7 position via sulfur atom
were synthesized by Pd-catalyzed cross-coupling reactions of 7(S)-7-deoxy-7-thiolincomycin (5) with various aryl halides.
This reaction is the most useful method to synthesize a variety of 7(S)-7-deoxy-7-thiolincomycin derivatives. On the basis of
analysis of structure–activity relationships of these novel lincomycin derivatives, we found that (a) the location of basicity in the
C-7 side chain was an important factor to enhance antibacterial activities, and (b) compounds 22, 36, 42, 43 and 44 had
potent antibacterial activities against a variety of Streptococcus pneumoniae with erm gene, which cause severe respiratory
infections, even compared with our C-7-modified lincomycin analogs (1–4) reported previously. Furthermore, 7(S)-configuration
was found to be necessary for enhancing antibacterial activities from comparison of configurations at the 7-position of
36 (S-configuration) and 41 (R-configuration).
The Journal of Antibiotics advance online publication, 5 October 2016; doi:10.1038/ja.2016.114
INTRODUCTION
resistant bacteria with erm and mef genes, causing respiratory
Macrolide antibiotics, which are protein-synthesis inhibitors, have infections, and have some problems in safety or taste in clinical site.
Lincomycin (LCM)13–16 was isolated as a secondary metabolite
effective antibacterial activity against bacterial strains, for example,
from the fermentation broth of Streptomyces lincolnensis. Clindamycin
(CLDM)17 was synthesized by chemical modification of LCM and
possessed a chlorine atom at the C-7 position with 7(S)-configuration.
CLDM exhibited improved antibacterial activities compared with
LCM, but it was also not effective against resistant pathogens with
erm gene as in the case of LCM (Figure 1, Table 1).
LCM and CLDM inhibit protein synthesis of bacteria in a similar
manner to macrolide antibiotics. X-ray crystallographic analysis18–20
indicated that CLDM had several major interactions by hydrogen
bonding in 23S rRNA, and its binding site was closely located to that
of macrolide antibiotics. Furthermore, they are effective against
pathogens with mef gene in clinical isolate (Table 1). As an overview,
CLDM exhibited the following positive characters: (1) availability of
p.o. and i.v. administrations (switch therapy is possible), (2) good
distribution to tissue and cells, (3) suppression21 of toxin production
by Streptococcal strains and (4) expected reasonable production cost
of CLDM derivatives. Thus, LCM derivatives might be more clinically
valuable than macrolide antibiotics, if they are effective against
pathogens with erm gene.
Streptococcus pneumoniae, Streptococcus pyogenes, Haemophillus
influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Neisseria
gonorrhoeae and so on, and have been used in clinical site over
many years. Recently, resistant bacteria, especially S. pneumoniae with
erm gene, have markedly increased,1–3 which cause serious problems
in bacterial respiratory infections. Although clarithromycin4 and
azithromycin5 are currently available in clinical site, they are partially
influenced by efflux pumps produced by S. pneumoniae mef gene and
are not effective enough against resistant bacteria such as
S. pneumoniae and S. pyogenes with erm gene (Figure 1, Table 1).
Telithromycin (TEL)6 is effective enough against S. pneumoniae with
erm gene, but has potential to cause a serious liver damage7,8 and loss
of consciousness.9,10 So, TEL has scarcely been used in Japan.
Furthermore, the production cost of TEL is assumed to be
relatively high owing to its complicated structure. Novel azalides11
were generated starting from 16-membered macrolides, and several
optimized 16-membered azalides12 were effective against resistant
S. pneumoniae and S. pyogenes with erm gene. These analogs are,
however, still under research process and have not been developed yet.
Chemical modifications at the C-7 position of LCM have been
Currently available oral antibiotics are not effective enough against investigated by several research groups.16,17,22–34 One of their reports
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan
Correspondence: Dr K Ajito, Pharmaceutical Research Center, Meiji Seika Pharma Co., LTD., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.
E-mail: keiichi.ajito@meiji.com
Received 28 June 2016; revised 31 July 2016; accepted 5 August 2016

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
2
N
N
Me
N
Me
Me
O
N
Me
HO
Me
Me
Me
O
N
O Me
OMe
Me
HO
Me
OH
Me
O
R2
R1
O
OH
OH
Me
Me
Me
Me
OMe
NMe2
Me
NMe2
Me
Me
N
HO
HN
H
HO
HO
O
O
O
O
O
Me
Me
Me
NMe2
O
Me
O
SMe
O
O
O
O
O
OMe
Me
OMe
Me
HO
O
Me
Me
O
Me
Me
Me
OH
Me
HO
OH
Me
OH
O
O
O
O
Me
Lincomycin (LCM): R1 = OH, R2 = H
Clindamycin (CLDM): R1 = H, R2 = Cl
Clarithromycin (CAM)
Azithromycin (AZM)
Telithromycin (TEL)
Figure 1 Chemical structures of clarithromycin, azithromycin, telithromycin, lincomycin and clindamycin.
Table 1 Antibacterial activities (MIC, μg ml− 1) of the representative macrolides, LCM, CLDM and previously reported LCM derivatives (1–4)
Test organisma
Characteristicsb
CAM
AZM
LCM
CLDM
1
2
3
4
Streptococcus pneumoniae DP1 typeI
S. pneumoniae-2
susceptible
0.03
0.03
0.015
4128
4128
4128
4128
4128
0.5
0.06
0.03
0.03
4128
4128
4128
4128
4128
0.5
1
1
0.06
0.12
0.06
4128
4128
4128
128
128
0.12
0.06
128
0.12
16
0.06
0.06
0.03
8
0.06
0.06
0.03
8
0.06
0.06
0.06
8
0.03
0.03
0.06
2
susceptible
S. pneumoniae-3
susceptible
0.25
4128
4128
4128
128
128
1
S. pneumoniae-4
ermAM methylase (c)
ermAM methylase (c)
ermAM methylase (c) + mefE
ermAM methylase (i)
ermAM methylase (i)
mefE efflux
S. pneumoniae-5
32
8
2
2
S. pneumoniae-6
64
64
8
4
S. pneumoniae-7
16
8
2
1
S. pneumoniae-8
8
8
1
N.T.
0.03
0.03
2
S. pneumoniae-9
0.03
0.03
4
0.06
0.06
2
0.03
0.06
4
Streptococcus pyogenes cook
S. pyogenes-2
susceptible
0.015
4128
8
0.06
4128
8
0.12
4128
0.25
8
ermAM methylase (c)
mefE efflux
S. pyogenes-3
0.06
8
0.12
16
0.06
4
0.25
8
Haemophilus influenzae
H. influenzae-2
susceptible
2
0.25
1
susceptible
4
16
8
4
8
4
16
H. influenzae-3
susceptible
8
2
16
16
32
32
16
0.25
64
H. influenzae-4
Δacr
0.5
0.5
4
1
0.25
0.5
0.25
Abbreviations: AZM, azithromycin; CAM, clarithromycin; CLDM, clindamycin; LCM, lincomucin; MIC, minimum inhibitory concentration; N.T., not tested.
Gray shading indicates target strains.
aAll strains except standard organisms were clinically isolated.
bʽc’ indicates constitutive and ʽi’ indicates inducible.
mentioned that 7(S)-7-O-methyllincomycin had stronger activities an additional moiety around the C-7 position. So, we hypothesized
than 7(R)-7-O-methyllincomycin (7(S)-7-OMe47(R)-7-OMe)27,28 that antibacterial activities may be improved by filling the above space
and it possessed 3.5 times stronger activities against Sarcina lutea with an appropriate substituent. We have reported synthesis and
than LCM. Derivatives possessing a larger alkoxy group or a biological evaluation of several 7(S)-7-arylthio-7-deoxylincomycin
substituted alkoxy group exhibited weaker antibacterial activities derivatives so far.35–41 As far as we know, we reported LCM analogs
compared with LCM. On the other hand, 7(S)-7-alkylthio-7- possessing antibacterial activities against resistant pathogens with erm
deoxylincomycin and 7(S)-7-deoxy-7-(substituted-alkylthio)lincomy- gene for the first time.35 We recently reported 7(S)-thiolincomycin
cin were stronger than LCM against Gram-positive or Gram- analogs as the first-generation derivatives in our research. Compounds
negative organisms in vitro.29,31 7(R)-7-Deoxy-7-(imidazol-2-yl-thio) 1 and 2 (Figure 2) exhibited improved antibacterial activities against
lincomycin34 had similar antibacterial activities as LCM. According to resistant S. pneumoniae with erm and mef genes compared with CAM,
AZM, LCM and CLDM39 as shown in Table 1. Furthermore, we also
the accumulated SAR information so far, a sulfur atom may
be preferable to an oxygen atom to improve antibacterial activities reported novel derivatives 3 and 4,40 which had stronger activities than
compounds
1 and 2. Comparing with compounds 1–4, we
in chemical modifications at the C-7 position of LCM. Furthermore,
antibacterial activities are influenced by both configuration and
structure of a substituent at the C-7 position.
newly hypothesized that a benzene ring and a hetero ring with basicity
are important to enhance antibacterial activities against resistant
X-ray crystallographic analyses18,20 between bacterial ribosomal bacteria with erm and mef genes. In this article, we report synthesis
RNA and bacterial peptide-synthesis inhibitors, including CLDM and biological evaluation of novel LCM analogs possessing a
and macrolide antibiotics, have already been reported. According to benzene ring and a hetero ring with basicity via sulfur atom with
their reports, CLDM had enough three-dimensional empty space for the 7(S)-configuration.
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
3
O
NH2
Me
R
N
N
N
Me
Me
O Me
7(S)
O Me
7(S)
O Me
7(S)
S
S
S
S
S
N
N
N
HN
H
HN
H
HN
Me
Me
Me
O
O
H
O
HO
SMe
HO
SMe
HO
SMe
HO
OH
HO
OH
HO
OH
1
2
N
O
N
3: R =
4: R =
NMe2
Figure 2 Previously reported LCM analogs modified at the C-7 position.
NMe2
b
c
d
R
8
R =
R =
R =
Me
O Me
7(S)
9
SH
O
Me
a
O Me
MeO
N
HN
HO
S
Me
N
H
N
HN
H
HO
30
22
SMe
Me
O
SMe
31
NH
HO
OH
Me
N
5
HO
OH
e
R =
6-8, 10-30, 32-36, 44
=
R
Br
Ar Br
42
43
R
N
N
N
6
7
8
10
18
11
12
13
14
22
N
NMe
N
NMe2
N
NMe2
NMe2
NMe
N
N
N
N
S
S
15
16
17
N
19
20
21
29
N
N
N
N
S
MeO
OMe
NH2
CN
N
N
N
Br
23
24
25
34
26
35
27
28
44
30
N
CN
F
OMe
N
N
N
NMe
N
N
N
32
OMe 33
36
NH2
N
N
Scheme 1 Synthesis of 7(S)-7-arylphenylthio-7-deoxylincomycin, 7(S)-7-deoxy-7-heteroarylphenylthiolincomycin or 7(S)-7-aminoalkylphenylthio-7-deoxylin-
comycin derivatives. Conditions were as follows: (a) Ar-Br, Xantphos, Pd2(DBA)3, iPr2NEt, dioxane, reflux, 2–21 h, (b) Pd/C, H2, MeOH, r.t., overnight, (c)
(2-methoxypyridin-3-yl)boronic acid, Pd(PPh3)4, Na2CO3, DMF, H2O, 80 °C, 8 h, (d) Pt black, H2, MeOH, 1 N HCl, r.t., 11 days, (e) HCHO, AcOH, NaBH
(OAc)3, MeOH, r.t., 30 min.
RESULTS AND DISCUSSION
Synthesis of 7(S)-7-deoxy-7-(substituted-phenylthio)lincomycin
derivatives
compared with Mitsunobu reaction or an SN2 reaction in application
of a methanesulfonyl intermadiate.35–37,40,42 In this reaction, aryl
halides such as aryl bromide, aryl iodide and aryl triflate can be used.42
Synthesis
of
7(S)-7-deoxy-7-(substituted-phenylthio)lincomycin Compounds 6–8, 10–30, 32–36 and 44 were synthesized by the
derivatives is shown in Scheme 1. We have already reported synthetic cross-coupling reaction to investigate the antibacterial activities of
route of compound 5.35–37,40 We applied a different synthetic route for aliphatic and aromatic amine compounds having a benzene ring and a
compound 5 from the previously reported route by Magerlein et al.25 basic moiety via sulfur atom at the C-7 position of LCM. Compound 9
We first prepared a key intermediate 5 derived from LCM in six was synthesized by reduction of a triple bond in compound 8 to
steps in order to construct the same configuration at the C-7 position evaluate its antibacterial activity compared with that of compound 6
as CLDM in the final target molecules. A palladium-catalyzed or 7 focusing on the distance between a phenyl group and a
cross-coupling reaction using 5 with various aryl halides is a widely dimethylamino group. Compound 31 was also prepared in application
applicable method to synthesize novel LCM derivatives in our research of Suzuki-Miyaura cross-coupling reaction from 30. This type of
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
4
reaction, the palladium-catalyzed cross-coupling reaction of with erm gene and H. influenzae compared with 9. Next, we fixed the
arylboronic acid with a LCM intermediate (30) possessing an aryl number of carbon atom(s) between the phenyl group and the basic
bromide moiety via sulfur at the C-7 position, was reported for the functionality as one or two, and we replaced the dimethylamino group
first time. The pyridine ring of compound 22 was reduced to give the with a hetero ring such as pyrrolidine, mono-N-methylpiperazine and
corresponding piperidin-3-yl derivative (42). Then, compound 42 was piperidine. Consequently, compounds 10, 11 and 14 had similar
converted to the desired N-methyl derivative (43) by reductive antibacterial activities as compounds 6 and 7. On the other hand, we
aminoalkylation. Compounds 42 and 43 were isolated as a mixture reported40 that
a 2-(methoxymethyl)pyrrolidine group was an
of each diastereoisomer.
important moiety to enhance antibacterial activities against resistant
bacteria with erm gene. Then, we introduced the 2-methoxymethyl
group on the pyrrolidine ring of 10 to afford 15. Consequently, the
desired product 15 exhibited four times potent activities against
S. pneumoniae and S. pyogenes with erm gene compared with 10.
These results suggest that a phenyl group and a basic moiety
(especially, a hetero ring with a substituent) are important to enhance
antibacterial activities against resistant bacteria with erm gene, and the
number of carbon atoms between the phenyl group and the basic
functionality might be optimized with one or two.
Synthesis of 7(R)-7-deoxy-7-(4-(pyrimidin-5-yl)phenylthio)
lincomycin
Synthesis of 7(R)-7-deoxy-7-(4-(pyrimidin-5-yl)phenylthio)lincomy-
cin (41) is shown in Scheme 2. We prepared compound 41 possessing
a 4-(pyrimidin-5-yl)phenyl group with 7(R)-configuration via sulfur
atom at the C-7 position of LCM in order to evaluate its activity
compared with that of compound 36 with the 7(S)-configuration.
Preparation of 41 began with protection of all hydroxyl groups of
CLDM. The protected compound 37 was reacted with potassium
thioacetate by an SN2 reaction to give the corresponding thioacetate
(38). Compound 39 was prepared by removing all TMS groups of
compound 38 under the acidic condition and followed by the removal
of the acetyl group to give a key intermediate 40. The desired
pyrimidinylphenylthio derivative (41) with 7(R)-configuration was
synthesized in application of 5-(4-bromophenyl)pyrimidine.
SAR analysis of LCM derivatives possessing a heteroaryl group as a
substituent on the phenyl group at the C-7 position
Novel aromatic derivatives possessing a phenyl or a heteroaryl group
as a substituent on the phenyl group at the C-7 position via sulfur
atom were synthesized and their antibacterial activities are shown in
Table 3. Consequently, the heterocyclic substituent on the phenyl
group at the C-7 position also improved antibacterial activities against
resistant pathogens. Especially, compounds 19 and 22 had potent
activities against resistant Streptococcus strains with erm gene and
H. influenzae. Moreover, antibacterial activities of 22, when compared
with those of 21 or 23 suggested that the location of the nitrogen atom
was an important factor to enhance antibacterial activities.
SAR analysis of LCM derivatives possessing an aliphatic amine as a
substituent on the phenyl group at the C-7 position
Antibacterial activities of LCM derivatives possessing an aliphatic
amine as a substituent on the phenyl group at the C-7 position via
sulfur atom are shown in Table 2. As described above, we newly
hypothesized that a benzene ring and a hetero ring with basicity were
important to enhance antibacterial activities against resistant bacteria
with erm gene. So, we first evaluated the distance between the phenyl
group and the dimethylamino group in the C-7 substituent. As a
SAR analysis of LCM derivatives possessing a substituted phenyl or
pyridinyl group as a substituent on the phenyl group at the C-7
position
result, compounds 6 and 7, which possessed one or two carbon atom Antibacterial activities of alternative biaryl derivatives possessing a
(s) between the phenyl group and the dimethylamino group, exhibited substituted phenyl or pyridinyl group as a substituent on the
relatively potent antibacterial activities against resistant S. pneumoniae phenyl group at the C-7 position are shown in Table 4. As a
Me
a
Me
b
O Me
O Me
7(S)
Cl
O
SAc
O
N
N
HN
HN
Me
Me
TMSO
H
H
CLDM
TMSO
SMe
SMe
TMSO
OTMS
TMSO
OTMS
37
38
N
N
Me
O Me
Me
SR
O
O Me
N
HN
7(R)
S
c
e
Me
H
N
HN
Me
HO
SMe
H
O
HO
SMe
HO
OH
HO
OH
39: R = Ac
40: R = H
d
41
Scheme 2 Synthesis of 7(R)-7-deoxy-7-thiolincomycin 40 and compound 41. Conditions were as follows: (a) TMSCl, HMDS, Py, r.t., 1 h, (b) KSAc, DMF,
100 °C, 18 h, (c) 1 N HCl, MeOH, r.t., 10 min, (d), NaOMe, MeOH, r.t., 20 min, (e) Xantphos, Pd2(DBA)3, iPr2NEt, dioxane, reflux, 6 h.
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
5
Table 2 Antibacterial activities (MIC, μg ml− 1) of dimethylamino derivatives and cyclicaminoalkyl derivatives
Abbreviations: MIC, minimum inhibitory concentration; N.T., not tested.
Gray shading indicates target strains.
aAll strains except standard organisms were clinically isolated.
bʽc’ indicates constitutive and ʽi’ indicates inducible.
result, the 5-methoxypyridin-3-yl derivative (29) exhibited signifi- CONCLUSION
We were interested in LCM analogs possessing a phenyl ring and a
cantly stronger activities against resistant bacteria than the
3-methoxyphenyl derivative (25) or the 6-methoxypyridin-3-yl
derivative (32). The pyridine analog (29) was shown to be
the most potent among substituted pyridine analogs. However,
it was less potent when compared with non-substituted pyridine
analog (22).
hetero ring with basicity via sulfur atom focusing on the 7(S)-
configuration at the C-7 position. We synthesized a variety of LCM
analogs in application of the Pd-catalyzed cross-coupling reaction35–37,40
of 7(S)-7-deoxy-7-thiolincomycin (5) with an aryl bromide or an aryl
iodide. This methodology was very useful to synthesize various 7(S)-7-
thio-modified LCM analogs. Antibacterial activities of LCM analogs
with a linear moiety, which possessed one or two carbon atom(s)
between the phenyl group and the dimethylamino group, were relatively
effective against resistant bacteria. Furthermore, we found that the
location of the nitrogen atom was important to improve antibacterial
activities based on the results of compounds 21–23. Consequently, we
found that compounds 22, 36 and 42–44 had potent antibacterial
activities against S. pneumoniae and S. pyogenes with erm gene and H.
influenzae. On the other hand, we confirmed that the 7(S)-configura-
tion was important to enhance antibacterial activities in the comparison
results of potency between compound 36 (7(S)-configuration) and
compound 41 (7(R)-configuration). Antibacterial activities against
S. pneumoniae with erm gene of our novel derivatives reported in this
article were catching up with those of TEL, and the activities against
S. pyogenes with erm gene and Streptococcus strains with mef gene of our
selected derivative were stronger than those of TEL as shown in Table 5.
We selected the 4-(pyrimidin-5-yl)phenyl group in compound 36 as the
C-7 substituent for further medicinal chemistry toward generation of
candidates, because it exhibits physicochemical stability without addi-
tional stereochemistry. In order to investigate other possibilities of novel
semi-synthetic LCM antibiotics, alternative modifications of LCM
SAR analysis of optimized LCM derivatives possessing a
six-membered hetero ring as a substituent on the phenyl group
at the C-7 position
Antibacterial activities of optimized LCM derivatives possessing a
six-membered hetero ring as a substituent on the phenyl group at the
C-7 position are shown in Table 5. A pyrimidine analog (36)
exhibited slightly improved antibacterial activities compared with the
pyridine-3-yl analog (22) against S. pneumoniae and H. influenzae.
Moreover, non-aromatic derivatives 42–44 also exhibited potent
antibacterial activities against S. pneumoniae with erm gene and
markedly improved activities against both S. pyogenes with erm
gene and H. influenzae. We have already reported the importance of
7(S)-configuration to enhance antibacterial activities.39 Then, we
also investigated the importance of 7(S) stereochemistry in
pyrimidinylphenyl analogs. As a result, we could reconfirm that 7
(S)-configuration was important to improve antibacterial activities
based on the comparison results of potency between compound 36
(7(S)-configuration) and compound 41 (7(R)-configuration). Accord-
ing to the previously reported docking simulation analysis40 of
7(S)-7-deoxy-7-(4-morpholinocarbonylphenylthio)lincomycin,
it
analogs possessing
a 7-thiothiadiazolyl group are in progress.
was supposed that steric hindrance occurs between the 8-methyl
group and a carbohydrate moiety in compound 41, and its
three-dimensional structure is not appropriate for antibacterial
activity.
On the basis of the information stated in this article, we will continually
explore novel chemical modifications focusing on clinically promising
LCM derivatives which exhibit potent antibacterial activities against
resistant S. pneumoniae and S. pyogenes with erm and mef genes.
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
6
Table 3 Antibacterial activities (MIC, μg ml− 1) of a variety of heteroaromatic derivatives and compound 20
Test organisma
Characteristicsb
16
0.03
0.03
0.03
4
17
0.015
0.015
0.015
4
18
0.015
0.015
0.015
2
19
0.008
0.008
0.015
1
20
0.25
0.25
0.25
32
21
0.03
0.06
0.03
8
22
0.008
0.008
0.015
0.5
23
0.03
0.03
0.03
8
Streptococcus pneumoniae DP1 TypeI susceptible
S. pneumoniae -2
S. pneumoniae -3
S. pneumoniae -4
S. pneumoniae -5
S. pneumoniae -6
S. pneumoniae -7
S. pneumoniae -8
S. pneumoniae -9
Streptococcus pyogenes Cook
S. pyogenes -2
susceptible
susceptible
ermAM methylase(c)
ermAM methylase(c)
ermAM methylase(c) + mefE
ermAM methylase(i)
ermAM methylase(i)
mefE efflux
8
4
8
N.T.
4
>64
>64
16
16
1
16
16
16
32
>64
4
2
>64
4
4
1
1
0.5
0.25
0.25
0.008
0.015
0.5
1
2
2
0.12
0.008
0.008
0.5
16
4
4
0.015
0.015
4
0.008
0.015
1
0.008
0.015
4
0.25
0.25
16
0.03
0.03
8
0.03
0.03
8
susceptible
ermAM methylase(c)
mefE efflux
S. pyogenes -3
0.03
16
0.015
8
0.03
16
0.008
4
0.25
>64
32
0.03
32
0.015
4
0.06
16
Haemophilus influenzae
H. influenzae -2
susceptible
susceptible
8
4
8
2
16
2
16
H. influenzae -3
susceptible
>64
0.25
16
32
8
>128
4
>64
0.25
16
>64
0.25
H. influenzae -4
acr
0.12
0.25
0.03
0.06
Abbreviations: MIC, minimum inhibitory concentration; N.T., not tested.
Gray shading indicates target strains.
aAll strains except standard organisms were clinically isolated.
bʽc’ indicates constitutive and ʽi’ indicates inducible.
EXPERIMENTAL PROCEDURE
General methods
1H NMR spectra were measured with
spectrometer (BRUKER, Coventry, UK) for 400 MHz, JEOL JNM-GSX 400
NMR spectrometer (JEOL,Tokyo, Japan) for 400 MHz or a Varian Gemini 300
NMR spectrometer (Varian, Palo Alto, CA, USA) for 300 MHz in CDCl3 or
CD3OD. TMS (0 p.p.m.) in CDCl3 or CD3OD was used as an internal reference
1.95–2.05 (m, 1 H), 1.97 (s, 3 H), 2.06–2.13 (m, 1 H), 2.13–2.22 (m, 1 H), 2.26
(s, 6 H), 2.41 (s, 3 H), 3.00 (dd, J = 10.6, 4.6 Hz, 1 H), 3.25 (dd, J =8.1, 5.6 Hz,
1 H), 3.49 (s, 2 H), 3.58 (dd, J = 10.2, 3.3 Hz, 1 H), 3.72–3.78 (m, 1 H), 3.87
(dq, J = 6.9, 2.6 Hz, 1 H), 4.10 (dd, J = 10.2, 5.6 Hz, 1 H), 4.34 (br dd, J = 9.7,
0.5 Hz, 1 H), 4.42 (dd, J = 9.7, 2.6 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.26–7.32
(m, 2 H), 7.37–7.43 (m, 2 H).
a BRUKER Ascend 400 NMR
standard. Mass spectra (MS) were obtained on
a JEOL JMS-700
7(S)-7-Deoxy-7-(4-(2-(dimethylamino)ethyl)phenylthio)lincomycin (7)
Compound 5 (106 mg, 0.251 mmol), 2-(4-bromophenyl)-N, N-dimethylethan-
1-amine (124.9 mg, 0.547 mmol), Xantphos (15.8 mg, 0.027 mmol), Pd2(dba)3
(12.9 mg, 0.014 mmol) and N,N-diisopropylethylamine (64.0 μl, 0.368 mmol)
in 1,4-dioxane (3 ml) were treated for 14 h according to the similar procedure
as described for the preparation of 6 to afford 7 (85.7 mg, 60%) as a colorless
mass spectrometer (JEOL) or Agilent Technologies 6530-Q-TOF LC/MS mass
spectrometer (Agilent Technologies, Santa Clara, CA, USA). The optical
rotations were recorded with Jasco P-2300 digital polarimeter (Jasco, Tokyo,
Japan). Column chromatography was performed with silica gel (Wakogel C200,
Wako Pure Chemical Industries, Osaka, Japan). Preparative thin-layer
chromatography was performed with silica gel (Merck, Darmstadt, Germany:
TLC plates Silica gel 60 F254). All organic extracts were dried over anhydrous
MgSO4, and the solvent was removed with a rotary evaporator under reduced
pressure.
solid. [α]D +102° (c 0.64, MeOH); ESI-MS (m/z) 570 (M+H)+ as
24
C28H47N3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C28H47N3O5S2: 570.3035,
found: 570.3034; 1H NMR (400 MHz, CD3OD) δ 0.88–0.98 (m, 3 H), 1.26
(d, J = 6.8 Hz, 3 H), 1.30–1.42 (m, 4 H), 1.79–1.91 (m, 1 H), 1.95–2.04 (m, 1
H), 2.01 (s, 3 H), 2.05–2.12 (m, 1 H), 2.12–2.23 (m, 1 H), 2.31 (s, 6 H), 2.39
(s, 3 H), 2.52–2.60 (m, 2 H), 2.74–2.82 (m, 2 H), 2.98 (dd, J = 10.7, 4.6 Hz,
1 H), 3.24 (dd, J = 8.0, 5.6 Hz, 1 H), 3.58 (dd, J = 10.2, 3.3 Hz, 1 H), 3.74
(m, 1 H), 3.81 (dq, J = 6.8, 2.6 Hz, 1 H), 4.10 (dd, J = 10.2, 5.5 Hz, 1 H), 4.33
(br dd, J = 9.8, 0.5 Hz, 1 H), 4.39 (dd, J = 9.8, 2.6 Hz, 1 H), 5.26 (d, J = 5.5 Hz,
1 H), 7.17–7.24 (m, 2 H), 7.34–7.41 (m, 2 H).
7(S)-7-Deoxy-7-(4-((dimethylamino)methyl)phenylthio)lincomycin
(6)
To a solution of 1-(4-bromophenyl)-N, N-dimethylmethanamine (23.2 mg,
0.108 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)
(10.4 mg, 0.018 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Pd2
(dba)3) (8.3 mg, 9.6 μmol) in 1,4-dioxane (1 ml) were added to compound 5
(38.2 mg, 0.090 mmol) and N,N-diisopropylethylamine (31.4 μl, 0.180 mmol) 7(S)-7-Deoxy-7-(4-(3-(dimethylamino)prop-1-yn-1-yl)phenylthio)
and refluxed for 3 h. The mixture was filtrated by either Chromatodisc
(0.45 μm) (KURABO INDUSTRIES, Osaka, Japan) or celite. The filtered solid
were washed with MeOH three times and then the assembled solution was
concentrated under reduced pressure. The resulting residue was purified by
preparative TLC (CHCl3/MeOH/28% aq. NH4OH= 10/1/0.1) to obtain the
lincomycin (8)
Compound 5 (66.2 mg, 0.157 mmol), 3-(4-bromophenyl)-N, N-dimethyl-
prop-2-yn-1-amine (42.3 mg, 0.178 mmol), Xantphos (9.8 mg, 0.017 mmol),
Pd2(dba)3 (6.5 mg, 7.1 μmol) and N,N-diisopropylethylamine (38.9 μl,
0.224 mmol) in 1,4-dioxane (0.75 ml) were treated for 14 h according to the
similar procedure as described for the preparation of 6 to afford 8 (59.4 mg,
65%) as a colorless solid. FAB-MS (m/z) 580 (M+H)+ as C29H45N3O5S2; FAB-
HRMS (M+H)+ calcd. for C29H45N3O5S2: 580.2879, found: 580.2878; 1H NMR
(400 MHz, CD3OD) δ 0.85–1.00 (m, 3 H), 1.26–1.42 (m, 4 H), 1.34
24
title compound as an off-white solid (39.4 mg, 78%). [α]D +98.0° (c 1.94,
MeOH); ESI-MS m/z 556 (M+H)+ as C27H45N3O5S2; TOF-ESI-HRMS (M+H)
+
calcd. for C27H45N3O5S2: 556.2879, found: 556.2883; 1H NMR (400 MHz,
CD3OD) δ 0.89–0.98 (m, 3 H), 1.29 (d, J = 6.9 Hz, 3 H), 1.31–1.41 (m, 4 H),
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
7
Table 4 Antibacterial activities (MIC, μg ml− 1) of substituted phenyl derivatives and substituted pyridinyl derivatives
Abbreviations: MIC, minimum inhibitory concentration; N.T., not tested.
Gray shading indicates target strains.
aAll strains except standard organisms were clinically isolated.
bʽc’ indicates constitutive and ʽi’ indicates inducible.
(d, J = 6.9 Hz, 3 H), 1.78–1.90 (m, 1 H), 1.92–2.03 (m, 1 H), 1.94 (s, 3 H), 1 H), 2.40 (s, 3 H), 2.48–2.58 (m, 4 H), 2.99 (dd, J = 10.6, 4.6 Hz, 1 H), 3.24
2.03–2.11 (m, 1 H), 2.11–2.22 (m, 1 H), 2.37 (s, 6 H), 2.38 (s, 3 H), 2.97 (dd, J =8.1, 5.6 Hz, 1 H), 3.59 (dd, J = 10.2, 3.2 Hz, 1 H), 3.61 (s, 2 H),
(dd, J = 10.6, 4.7 Hz, 1 H), 3.24 (dd, J = 8.2, 5.7 Hz, 1 H), 3.48 (s, 2 H), 3.58 3.72–3.76 (m, 1 H), 3.86 (dq, J = 6.9, 2.6 Hz, 1 H), 4.11 (dd, J = 10.2, 5.6 Hz,
(dd, J = 10.2, 3.2 Hz, 1 H), 3.75 (br dd, J = 3.2, 0.6 Hz, 1 H), 3.89 (dq, J = 6.9, 1 H), 4.30–4.36 (m, 1 H), 4.42 (dd, J = 9.7, 2.6 Hz, 1 H), 5.28 (d, J = 5.6 Hz,
2.8 Hz, 1 H), 4.10 (dd, J = 10.2, 5.6 Hz, 1 H), 4.36 (br dd, J = 9.8, 0.6 Hz, 1 H), 1 H), 7.28–7.34 (m, 2 H), 7.36–7.42 (m, 2 H).
4.45 (dd, J = 9.8, 2.8 Hz, 1 H), 5.26 (d, J =5.6 Hz, 1 H), 7.35–7.42 (m, 4 H).
7(S)-7-Deoxy-7-(4-(2-(pyrrolidin-1-yl)ethyl)phenylthio)lincomycin
7(S)-7-Deoxy-7-(4-(3-(dimethylamino)propyl)phenylthio)
(11)
lincomycin (9)
Compound
5 (83.0 mg, 0.196 mmol), 1-(4-bromophenethyl)pyrrolidine
To a solution of compound 8 (21.4 mg, 0.037 mmol) in MeOH (2 ml) was (50.0 mg, 0.197 mmol), Xantphos (11.0 mg, 0.019 mmol), Pd2(dba)3 (9.0 mg,
added Pd/C (10.4 mg) and then vigorously stirred in hydrogen atmosphere at 0.010 mmol) and N,N-diisopropylethylamine (172.5 μl, 0.990 mmol) in
room temperature for 14 h. The mixture was filtrated with celite. The filtered 1,4-dioxane (3 ml) were treated for 3 h according to the similar procedure as
solid was washed with MeOH three times and then the assembled solution was described for the preparation of 6 to afford 11 (82.0 mg, 70%) as a colorless
concentrated under reduced pressure. The resulting residue was purified by solid. [α]D +68.0° (c 0.25, MeOH); ESI-MS (m/z) 596 (M+H)+ as
25
preparative TLC (CHCl3/CH3OH/28% aq. NH4OH= 10/1/0.1) to obtain C30H49N3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C30H49N3O5S2: 596.3192,
23
the title compound (9) (13.7 mg, 64%) as a colorless solid. [α]D +87.1° found: 596.3171; 1H NMR (400 MHz, CD3OD) δ 0.89–0.97 (m, 3 H), 1.27
(c 0.22, MeOH); ESI-MS (m/z) 584 (M+H)+ as C29H49N3O5S2; TOF-ESI- (d, J = 6.9 Hz, 3 H), 1.31–1.42 (m, 4 H), 1.82–1.92 (m, 5 H), 1.95–2.04
HRMS (M+H)+ calcd. for C29H49N3O5S2: 584.3192, found: 584.3192; 1H NMR (m, 1 H), 2.01 (s, 3 H), 2.05–2.12 (m, 1 H), 2.12–2.25 (m, 1 H), 2.39 (s, 3 H),
(400 MHz, CD3OD) δ 0.90–0.97 (m, 3 H), 1.26 (d, J = 7.0 Hz, 3 H), 1.31–1.41 2.66–2.75 (m, 4 H), 2.75–2.89 (m, 4 H), 2.98 (dd, J = 10.6, 4.6 Hz, 1 H), 3.24
(m, 4 H), 1.76–1.91 (m, 3 H), 1.95–2.04 (m, 1 H), 2.01 (s, 3 H), 2.05–2.12 (dd, J =8.0, 5.6 Hz, 1 H), 3.58 (dd, J = 10.2, 3.3 Hz, 1 H), 3.71–3.76 (m, 1 H),
(m, 1 H), 2.12–2.23 (m, 1 H), 2.28 (s, 6 H), 2.39 (s, 3 H), 2.37–2.44 (m, 2 H), 3.81 (dq, J =6.9, 2.5 Hz, 1 H), 4.10 (dd, J = 10.2, 5.6 Hz, 1 H), 4.33 (br dd,
2.62 (t, J = 7.7 Hz, 2 H), 2.98 (dd, J =10.6, 4.6 Hz, 1 H), 3.24 (dd, J = 8.1, J = 9.8, 0.5 Hz, 1 H), 4.39 (dd, J = 9.8, 2.5 Hz, 1 H), 5.26 (d, J = 5.6 Hz, 1 H),
5.5 Hz, 1 H), 3.57 (dd, J =10.3, 3.3 Hz, 1 H), 3.73 (m, 1 H), 3.80 (dq, J = 7.0, 7.18–7.24 (m, 2 H), 7.34–7.41 (m, 2 H).
2.4 Hz, 1 H), 4.10 (dd, J = 10.3, 5.6 Hz, 1 H), 4.33 (br dd, J = 9.8, 0.6 Hz, 1 H),
4.38 (dd, J = 9.8, 2.4 Hz, 1 H), 5.26 (d, J = 5.6 Hz, 1 H), 7.15–7.21 (m, 2 H),
7.34–7.39 (m, 2 H).
7(S)-7-Deoxy-7-(4-((4-methylpiperazin-1-yl)methyl)phenylthio)
lincomycin (12)
Compound 5 (100.2 mg, 0.237 mmol), 1-(4-bromobenzyl)-4-methylpiperazine
(144.3 mg, 0.536 mmol), Xantphos (14.6 mg, 0.025 mmol), Pd2(dba)3
(11.0 mg, 0.012 mmol) and N,N-diisopropylethylamine (119.9 μl, 0.689 mmol)
7(S)-7-Deoxy-7-(4-(pyrrolidin-1-ylmethyl)phenylthio)lincomycin
(10)
Compound 5 (97.5 mg, 0.231 mmol), 1-(4-bromobenzyl)pyrrolidine (90.1 mg, in 1,4-dioxane (2 ml) were treated for 4 h according to the similar procedure as
0.375 mmol), Xantphos (14.6 mg, 0.025 mmol), Pd2(dba)3 (11.1 mg, described for the preparation of 6 to afford 12 (132.7 mg, 92%) as a colorless
0.012 mmol) and N,N-diisopropylethylamine (119.9 μl, 0.689 mmol) in solid. [α]D +93.2° (c 2.52, MeOH); ESI-MS (m/z) 611 (M+H)+ as
25
1,4-dioxane (2 ml) were treated for 3 h according to the similar procedure as C30H50N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C30H50N4O5S2: 611.3301,
described for the preparation of 6 to afford 10 (115.5 mg, 86%) as an off-white found: 611.3285; 1H NMR (400 MHz, CD3OD) δ 0.88–0.97 (m, 3 H), 1.28
solid. [α]D +102° (c 3.96, MeOH); ESI-MS (m/z) 582 (M+H)+ as
(d, J = 6.8 Hz, 3 H), 1.28–1.41 (m, 4 H), 1.80–1.91 (m, 1 H), 1.95–2.04
23
C29H47N3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C29H47N3O5S2: 582.3035, (m, 1 H), 1.98 (s, 3 H), 2.04–2.12 (m, 1 H), 2.12–2.23 (m, 1 H), 2.27 (s, 3 H),
found: 582.3027; 1H NMR (400 MHz, CD3OD) δ 0.88–0.97 (m, 3 H), 1.28 2.30–2.92 (m, 8 H), 2.40 (s, 3H), 2.99 (dd, J = 10.7, 4.6 Hz, 1 H), 3.25 (dd,
(d, J = 6.9 Hz, 3 H), 1.30–1.41 (m, 4 H), 1.75–1.83 (m, 4 H), 1.83–1.91 J = 8.1, 5.7 Hz, 1 H), 3.51 (s, 2 H), 3.58 (dd, J = 10.2, 3.3 Hz, 1 H), 3.71–3.77
(m, 1 H), 1.98 (s, 3 H), 1.94–2.04 (m, 1 H), 2.05–2.11 (m, 1 H), 2.12–2.23 (m, (m, 1 H), 3.85 (dq, J = 6.8, 2.6 Hz, 1 H), 4.10 (dd, J = 10.2, 5.6 Hz, 1 H),
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
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Table 5 Antibacterial activities (MIC, μg ml− 1) of optimized derivatives with a heterocycle and TEL
Abbreviations: MIC, minimum inhibitory concentration; TEL, telithromycin.
Gray shading indicates target strains.
aAll strains except standard organisms were clinically isolated.
bʽc’ indicates constitutive and ʽi’ indicates inducible.
4.29–4.35 (m, 1 H), 4.41 (dd, J = 9.8, 2.6 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H),
7.26–7.33 (m, 2 H), 7.36–7.43 (m, 2 H).
4.11 (dd, J = 10.2, 5.6 Hz, 1 H), 4.30–4.36 (m, 1 H), 4.41 (dd, J = 9.7, 2.6 Hz,
1 H), 5.28 (d, J =5.6 Hz, 1 H), 7.25–7.32 (m, 2 H), 7.35–7.41 (m, 2 H).
7(S)-7-Deoxy-7-(4-(2-(4-methylpiperazin-1-yl)ethyl)phenylthio)
lincomycin (13)
7(S)-7-Deoxy-7-(4-((2(S)-(methoxymethyl)pyrrolidin-1-yl)methyl)
phenylthio)lincomycin (15)
Compound 5 (90.0 mg, 0.213 mmol), 1-(4-bromophenethyl)-4-methylpipera-
zine (60.0 mg, 0.212 mmol), Xantphos (12.0 mg, 0.021 mmol), Pd2(dba)3
(9.7 mg, 0.011 mmol) and N,N-diisopropylethylamine (184.6 μl, 1.060 mmol)
in 1,4-dioxane (3 ml) were treated for 2 h according to the similar procedure as
described for the preparation of 6 to afford 13 (89.0 mg, 67%) as an off-white
Compound 5 (70.0 mg, 0.166 mmol), (S)-1-(4-bromobenzyl)-2-(methoxy-
methyl)pyrrolidine (96.5 mg, 0.340 mmol), Xantphos (9.7 mg, 0.017 mmol),
Pd2(dba)3 (7.6 mg, 8.3 μmol) and N,N-diisopropylethylamine (87.6 μl,
0.503 mmol) in 1,4-dioxane (2 ml) were treated under microwave irradiation
for 30 min according to the similar procedure as described for the preparation
solid. [α]D +90.7° (c 2.05, MeOH); ESI-MS (m/z) 625 (M+H)+ as
23
23
of 6 to afford 15 (61.0 mg, 59%) as a colorless solid. [α]D +72.0° (c 1.52,
C31H52N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C31H52N4O5S2: 625.3457,
found: 625.3461; 1H NMR (400 MHz, CD3OD) δ 0.88–0.98 (m, 3 H), 1.26
(d, J = 6.9 Hz, 3 H), 1.30–1.40 (m, 4 H), 1.79–1.92 (m, 1 H), 1.94–2.04
(m, 1 H), 2.00 (s, 3 H), 2.05–2.12 (m, 1 H), 2.12–2.23 (m, 1 H), 2.31 (s, 3 H),
2.39 (s, 3 H), 2.41–2.88 (m, 8 H), 2.58–2.64 (m, 2 H), 2.75–2.84 (m, 2 H), 2.99
(dd, J = 10.6, 4.6 Hz, 1 H), 3.24 (dd, J = 8.0, 5.6 Hz, 1 H), 3.58 (dd, J = 10.2,
3.3 Hz, 1 H), 3.71–3.76 (m, 1 H), 3.80 (dq, J = 6.9, 2.4 Hz, 1 H), 4.10
(dd, J =10.2, 5.6 Hz, 1 H), 4.31–4.35 (m, 1 H), 4.38 (dd, J = 9.8, 2.4 Hz, 1 H),
5.26 (d, J = 5.6 Hz, 1 H), 7.17–7.23 (m, 2 H), 7.34–7.40 (m, 2 H).
MeOH); ESI-MS (m/z) 626 (M+H)+ as C31H51N3O6S2; TOF-ESI-HRMS
(M+H)+ calcd. for C31H51N3O6S2: 626.3298, found: 626.3297;
1H NMR (400 MHz, CD3OD) δ 0.88–0.98 (m, 3 H), 1.28 (d, J = 6.9 Hz, 3
H), 1.31–1.40 (m, 4 H), 1.54–1.63 (m, 1 H), 1.64–1.75 (m, 2 H), 1.80–2.05 (m,
3 H), 2.00 (s, 3 H), 2.05–2.12 (m, 1 H), 2.12–2.22 (m, 1 H), 2.22–2.31 (m, 1
H), 2.40 (s, 3 H), 2.69–2.79 (m, 1 H), 2.84–2.91 (m, 1 H), 2.99 (dd, J =10.6,
4.6 Hz, 1 H), 3.24 (dd, J = 8.1, 5.6 Hz, 1 H), 3.32–3.36 (m, 1 H), 3.33 (s, 3 H),
3.37–3.46 (m, 2 H), 3.58 (dd, J = 10.2, 3.2 Hz, 1 H), 3.72–3.76 (m, 1 H),
3.85 (dq, J = 6.9, 2.5 Hz, 1 H), 4.04–4.14 (m, 2 H), 4.31–4.37 (m, 1 H),
4.40 (dd, J =9.8, 2.5 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.28–7.34 (m, 2 H),
7.36–7.41 (m, 2 H).
7(S)-7-Deoxy-7-(4-(piperidin-1-ylmethyl)phenylthio)lincomycin
(14)
Compound 5 (98.1 mg, 0.232 mmol), 1-(4-bromobenzyl)piperidine (95.3 mg,
0.375 mmol), Xantphos (14.7 mg, 0.025 mmol), Pd2(dba)3 (10.8 mg,
0.012 mmol) and N,N-diisopropylethylamine (119.9 μl, 0.689 mmol) in
1,4-dioxane (2 ml) were treated for 3.5 h according to the similar procedure
as described for the preparation of 6 to afford 14 (123.4 mg, 89%) as an off-
7(S)-7-Deoxy-7-(4-(thiazol-4-yl)phenylthio)lincomycin (16)
Compound
5
(100.0 mg, 0.237 mmol), 4-(4-bromophenyl)thiazole
(100.0 mg, 0.416 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3
(10.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (82.6 μl, 0.474 mmol)
in 1,4-dioxane (2 ml) were treated for 6 h according to the similar procedure as
described for the preparation of 6 to afford 16 (93.6 mg, 68%) as a colorless
white solid. [α]D +97.7° (c 4.26, MeOH); ESI-MS (m/z) 596 (M+H)+ as
23
C30H49N3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C30H49N3O5S2: 596.3192,
found: 596.3184; 1H NMR (400 MHz, CD3OD) δ 0.86–0.97 (m, 3 H), 1.29
(d, J = 6.9 Hz, 3 H), 1.31–1.40 (m, 4 H), 1.40–1.50 (m, 2 H), 1.52–1.64
(m, 4 H), 1.79–1.91 (m, 1 H), 1.93–2.04 (m, 1 H), 1.98 (s, 3 H), 2.04–2.12
(m, 1 H), 2.12–2.23 (m, 1 H), 2.30–2.48 (m, 4 H), 2.39 (s, 3 H), 2.99
solid. [α]D +98.1° (c 0.62, MeOH); ESI-MS (m/z) 582 (M+H)+ as
19
C27H39N3O5S3; TOF-ESI-HRMS (M+H)+ calcd. for C27H39N3O5S3: 582.2130,
found: 582.2131; 1H NMR (400 MHz, CD3OD) δ 0.89–0.96 (m, 3 H),
1.27–1.36 (m, 4 H), 1.36 (d, J = 6.9 Hz, 3 H), 1.81–1.91 (m, 1 H), 1.95–2.04
(m, 1 H), 2.00 (s, 3 H), 2.05–2.13 (m, 1 H), 2.13–2.24 (m, 1 H), 2.40 (s, 3 H),
(dd, J = 10.6, 4.6 Hz, 1 H), 3.24 (dd, J = 8.1, 5.7 Hz, 1 H), 3.46 (s, 2 H), 3.59 3.02 (dd, J = 10.5, 4.8 Hz, 1 H), 3.23 (dd, J =8.2, 5.6 Hz, 1 H), 3.60
(dd, J = 10.2, 3.2 Hz, 1 H), 3.72–3.77 (m, 1 H), 3.86 (dq, J =6.9, 2.6 Hz, 1 H), (dd, J =10.2, 3.3 Hz, 1 H), 3.74–3.79 (m, 1 H), 3.90 (dq, J = 6.9, 2.6 Hz,
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
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1 H), 4.11 (dd, J = 10.2, 5.6 Hz, 1 H), 4.37–4.42 (m, 1 H), 4.45 (dd, J = 9.7, 4.6 Hz, 1 H), 3.21 (dd, J =8.3, 5.8 Hz, 1 H), 3.60 (dd, J = 10.2, 3.3 Hz, 1 H),
2.6 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.48–7.54 (m, 2 H), 7.88–7.95 (m, 3 H), 3.73–3.80 (m, 1 H), 3.88 (dq, J = 6.9, 2.5 Hz, 1 H), 4.12 (dd, J = 10.2, 5.5 Hz, 1
9.05 (d, J = 2.0 Hz, 1 H).
H), 4.36–4.41 (m, 1 H), 4.42 (dd, J = 9.7, 2.5 Hz, 1 H), 5.28 (d, J =5.5 Hz, 1
H), 7.31–7.36 (m, 1 H), 7.39–7.46 (m, 2 H), 7.48–7.54 (m, 2 H), 7.56–7.64
(m, 4 H).
7(S)-7-Deoxy-7-(4-(1H-imidazol-1-yl)phenylthio)lincomycin (17)
Compound
5 (100.0 mg, 0.237mmol), 1-(4-bromophenyl)-1H-imidazole
7(S)-7-Deoxy-7-(4-(pyridin-2-yl)phenylthio)lincomycin (21)
(70.0 mg, 0.314 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3
(10 mg, 0.011 mmol) and N,N-diisopropylethylamine (82.6 μl, 0.474 mmol) Compound 5 (70.6 mg, 0.167 mmol), 2-(4-bromophenyl)pyridine (77.8 mg,
in 1,4-dioxane (5 ml) were treated for 4 h according to the similar procedure as 0.332 mmol), Xantphos (11.4 mg, 0.020 mmol), Pd2(dba)3 (7.9 mg, 8.6 μmol)
described for the preparation of 6 to afford 17 (56.5 mg, 42%) as a
and N,N-diisopropylethylamine (58.0 μl, 0.333 mmol) in 1,4-dioxane (1 ml)
colorless solid. [α]D +97.8° (c 1.40, MeOH); ESI-MS (m/z) 565 (M+H)+ as were treated for 3 h according to the similar procedure as described for the
C27H40N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C27H40N4O5S2: 565.2518, preparation of 6 to afford 21 (87.9 mg, 91%) as a colorless solid. [α]D25 +86.7°
found: 565.2522; 1H NMR (400 MHz, CD3OD) δ 0.89–0.96 (m, 3 H), (c 2.58, MeOH); ESI-MS (m/z) 576 (M+H)+ as C29H41N3O5S2; TOF-ESI-
1.26–1.41 (m, 4 H), 1.34 (d, J = 6.9 Hz, 3 H), 1.81–1.92 (m, 1 H), 1.96–2.06 HRMS (M+H)+ calcd. for C29H41N3O5S2: 576.2566, found: 576.2558; 1H NMR
(m, 1 H), 2.01 (s, 3 H), 2.06–2.14 (m, 1 H), 2.14–2.25 (m, 1 H), 2.43 (s, 3 H), (400 MHz, CD3OD) δ 0.88–0.95 (m, 3 H), 1.28–1.37 (m, 4 H), 1.37
3.04 (dd, J = 10.6, 4.8 Hz, 1 H), 3.25 (dd, J = 8.3, 5.7 Hz, 1 H), 3.59 (d, J = 6.9 Hz, 3 H), 1.95–2.04 (m, 1 H), 1.95–2.05 (m, 1 H), 1.97 (s, 3 H),
(dd, J = 10.2, 3.2 Hz, 1 H), 3.78 (br dd, J = 3.2, 0.5 Hz, 1 H), 3.91 (dq, 2.05–2.11 (m, 1 H), 2.11–2.22 (m, 1 H), 2.41 (s, 3 H), 3.02 (dd, J = 10.6,
J = 6.9, 2.8 Hz, 1 H), 4.11 (dd, J = 10.2, 5.5 Hz, 1 H), 4.37 (br dd, J = 9.7, 4.8 Hz, 1 H), 3.23 (dd, J =8.3, 5.6 Hz, 1 H), 3.61 (dd, J = 10.2, 3.2 Hz, 1 H),
0.5 Hz, 1 H), 4.48 (dd, J =9.7, 2.8 Hz, 1 H), 5.27 (d, J = 5.5 Hz, 1 H), 7.14–7.17 3.76–3.82 (m, 1 H), 3.95 (dq, J = 6.9, 2.6 Hz, 1 H), 4.13 (dd, J = 10.2, 5.5 Hz,
25
(m, 1 H), 7.53–7.60 (m, 5 H), 8.13–8.17 (m, 1 H).
1 H), 4.37–4.43 (m, 1 H), 4.49 (dd, J = 9.7, 2.6 Hz, 1 H), 5.29 (d, J = 5.5 Hz,
1 H), 7.34 (ddd, J = 6.9, 5.0, 1.7 Hz, 1 H), 7.49–7.56 (m, 2 H), 7.81–7.91
(m, 2 H), 7.91–7.96 (m, 2 H), 8.61 (ddd, J = 4.9, 1.6, 1.0 Hz, 1 H).
7(S)-7-Deoxy-7-(4-(1,3,4-thiadiazol-2-yl)phenylthio)lincomycin (18)
Compound 5 (100.0 mg, 0.237 mmol), 2-(4-bromophenyl)-1,3,4-thiadiazole
(100.0 mg, 0.415 mmol), Xantphos (20.0 mg, 0.035 mmol), Pd2(dba)3
7(S)-7-Deoxy-7-(4-(pyridin-3-yl)phenylthio)lincomycin (22)
(20.0 mg, 0.022 mmol) and N,N-diisopropylethylamine (82.6 μl, 0.474 mmol) Compound
5
(109.3 mg, 0.259 mmol), 3-(4-bromophenyl)pyridine
in 1,4-dioxane (2 ml) were treated for 6 h according to the similar procedure as (89.7 mg, 0.383 mmol), Xantphos (15.2 mg, 0.026 mmol), Pd2(dba)3
described for the preparation of 6 to afford 18 (88.3 mg, 64%) as a colorless (12.5 mg, 0.014 mmol) and N,N-diisopropylethylamine (88.9 μl, 0.511 mmol)
solid. [α]D +71.9° (c 0.40, MeOH); ESI-MS (m/z) 583 (M+H)+ as
in 1,4-dioxane (1.8 ml) were treated for 5.5 h according to the similar
20
C26H38N4O5S3; TOF-ESI-HRMS (M+H)+ calcd. for C26H38N4O5S3: 583.2083, procedure as described for the preparation of 6 to afford 22 (131.0 mg,
found: 583.2089; 1H NMR (400 MHz, CD3OD) δ 0.90–0.96 (m, 3 H), 88%) as a colorless solid. [α]D +83.9° (c 0.37, MeOH); ESI-MS (m/z)
24
1.28–1.41 (m, 4 H), 1.41 (d, J = 6.9 Hz, 3 H), 1.82–1.94 (m, 1 H), 1.91 (s, 3 576 (M+H)+ as C29H41N3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for
H), 1.98–2.08 (m, 1 H), 2.09–2.25 (m, 2 H), 2.45 (s, 3 H), 3.09 (dd, J = 10.3, C29H41N3O5S2: 576.2566, found: 576.2573; 1H NMR (400 MHz, CD3OD) δ
4.7 Hz, 1 H), 3.29 (dd, J = 7.9, 5.4 Hz, 1 H), 3.59 (dd, J =10.2, 3.2 Hz, 1 H), 0.89–0.96 (m, 3 H), 1.26–1.41 (m, 4 H), 1.36 (d, J = 6.9 Hz, 3 H), 1.80–1.91
3.79 (br dd, J = 3.2, 0.5 Hz, 1 H), 4.03 (dq, J = 6.8, 2.8 Hz, 1 H), 4.10 (m, 1 H), 1.96–2.05 (m, 1 H), 1.98 (s, 3 H), 2.05–2.12 (m, 1 H), 2.12–2.23
(dd, J =10.2, 5.6 Hz, 1 H), 4.39 (br dd, J = 9.7, 0.5 Hz, 1 H), 4.54 (dd, J = 9.7, (m, 1 H), 2.41 (s, 3 H), 3.00 (dd, J = 10.6, 4.6 Hz, 1 H), 3.24 (dd, J = 8.1,
2.8 Hz, 1 H), 5.26 (d, J = 5.6 Hz, 1 H), 7.52–7.57 (m, 2 H), 7.93–7.99 (m, 2 H), 5.7 Hz, 1 H), 3.59 (dd, J = 10.2, 3.3 Hz, 1 H), 3.76–3.80 (m, 1 H), 3.94
9.43 (s, 1 H).
(dq, J = 6.9, 2.7 Hz, 1 H), 4.11 (dd, J =10.2, 5.6 Hz, 1 H), 4.38 (br dd, J = 9.7,
0.4 Hz, 1 H), 4.47 (dd, J = 9.7, 2.7 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.51
(ddd, J = 8.0, 4.9, 0.7 Hz, 1 H), 7.54–7.58 (m, 2 H), 7.62–7.68 (m,2 H), 8.09
(ddd, J = 8.0, 2.3, 1.6 Hz, 1 H), 8.52 (dd, J = 4.9, 1.6 Hz, 1 H), 8.77–8.82
(m, 1 H).
7(S)-7-Deoxy-7-(4-(1,2,3-thiadiazol-4-yl)phenylthio)lincomycin (19)
Compound 5 (100.0 mg, 0.237 mmol), 4-(4-bromophenyl)-1,2,3-thiadiazole
(100.0 mg, 0.415 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3
(10.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (82.6 μl, 0.474 mmol)
in 1,4-dioxane (3 ml) were treated for 6 h according to the similar procedure as
7(S)-7-Deoxy-7-(4-(pyridin-4-yl)phenylthio)lincomycin (23)
described for the preparation of 6 to afford 19 (71.7 mg, 52%) as a colorless Compound 5 (61.9 mg, 0.146 mmol), 4-(4-bromophenyl)pyridine (67.5 mg,
solid. [α]D +71.8° (c 0.35, MeOH); ESI-MS (m/z) 583 (M+H)+ as
0.288 mmol), Xantphos (8.8 mg, 0.015 mmol), Pd2(dba)3 (6.9 mg, 7.5 μmol)
20
C26H38N4O5S3; TOF-ESI-HRMS (M+H)+ calcd. for C26H38N4O5S3: 583.2083, and N,N-diisopropylethylamine (50.0 μl, 0.287 mmol) in 1,4-dioxane (1 ml)
found: 583.2085; 1H NMR (400 MHz, CD3OD) δ 0.89–0.96 (m, 3 H), were treated for 6.5 h according to the similar procedure as described for the
25
1.26–1.38 (m, 4 H), 1.39 (d, J = 6.9 Hz, 3 H), 1.82–1.93 (m, 1 H), 1.96–2.06 preparation of 6 to afford 23 (72.6 mg, 86%) as an off-white solid. [α]D
(m, 1 H), 1.98 (s, 3 H), 2.07–2.24 (m, 2 H), 2.44 (s, 3 H), 3.06 (dd, J = 10.6, +87.3° (c 2.15, MeOH); ESI-MS (m/z) 576 (M+H)+ as C29H41N3O5S2;
4.8 Hz, 1 H), 3.26 (dd, J = 8.3, 5.6 Hz, 1 H), 3.60 (dd, J =10.2, 3.2 Hz, 1 H), TOF-ESI-HRMS (M+H)+ calcd. for C29H41N3O5S2: 576.2566, found:
3.78 (br dd, J = 3.2, 0.6 Hz, 1 H), 3.96 (dq, J = 6.9, 2.7 Hz, 1 H), 4.11 576.2562; 1H NMR (400 MHz, CD3OD) δ 0.87–0.97 (m, 3 H), 1.26–1.40
(dd, J =10.2, 5.6 Hz, 1 H), 4.41 (br dd, J = 9.8, 0.6 Hz, 1 H), 4.49 (dd, J = 9.8, (m, 4 H), 1.38 (d, J = 6.9 Hz, 3 H), 1.80–1.92 (m, 1 H), 1.95 (s, 3 H), 1.97–2.07
2.7 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.55–7.60 (m, 2 H), 8.05–8.09 (m, 2 H), (m, 1 H), 2.07–2.14 (m, 1 H), 2.14–2.24 (m, 1 H), 2.43 (s, 3 H), 3.04
9.25 (s, 1 H).
(dd, J = 10.6, 4.8 Hz, 1 H), 3.25 (dd, J = 8.2, 5.6 Hz, 1 H), 3.61 (dd, J = 10.2,
3.2 Hz, 1 H), 3.77–3.82 (m, 1 H), 3.97 (dq, J = 6.9, 2.7 Hz, 1 H), 4.13
(dd, J =10.2, 5.6 Hz, 1 H), 4.35–4.43 (m, 1 H), 4.51 (dd, J = 9.8, 2.7 Hz, 1 H),
5.28 (d, J = 5.6 Hz, 1 H), 7.51–7.58 (m, 2 H), 7.68–7.78 (m, 4 H), 8.54–8.60
(m, 2 H).
7(S)-7-([1,10-Biphenyl]-4-ylthio)-7-deoxylincomycin (20)
Compound
0.363 mmol), Xantphos (10.8 mg, 0.019 mmol), Pd2(dba)3 (8.1 mg, 8.8 μmol)
and N,N-diisopropylethylamine (60.0 μl, 0.344 mmol) in 1,4-dioxane (1 ml)
were treated for 4 h according to the similar procedure as described for the
5
(72.3 mg, 1.71 mmol), 4-bromo-1,10-biphenyl (84.7 mg,
7(S)-7-(30-Cyano-[1,10-biphenyl]-4-ylthio)-7-deoxylincomycin (24)
preparation of 6 to afford 20 (90.0 mg, 92%) as a colorless solid. [α]D26 +101° Compound 5 (85.2 mg, 0.202 mmol), 4'-bromo-[1,1'-biphenyl]-3-carbonitrile
(c 1.16, MeOH); ESI-MS (m/z) 575 (M+H)+ as C30H42N2O5S2; TOF-ESI- (104.0 mg, 0.403 mmol), Xantphos (12.7 mg, 0.022 mmol), Pd2(dba)3
HRMS (M+H)+ calcd. for C30H42N2O5S2: 575.2613, found: 575.2608; 1H NMR (10.4 mg, 0.011 mmol) and N,N-diisopropylethylamine (69.9 μl, 0.402 mmol)
(400 MHz, CD3OD) δ 0.88–0.95 (m, 3 H), 1.25–1.40 (m, 4 H), 1.34 in 1,4-dioxane (1 ml) were treated for 4 h according to the similar procedure as
(d, J = 6.9 Hz, 3 H), 1.79–1.90 (m, 1 H), 1.95–2.03 (m, 1 H), 2.02 (s, 3 H), described for the preparation of 6 to afford 24 (49.4 mg, 41%) as a colorless
2.03–2.09 (m, 1 H), 2.10–2.21 (m, 1 H), 2.39 (s, 3 H), 2.99 (dd, J = 10.6, solid. [α]D +91.6° (c 1.97, MeOH); ESI-MS (m/z) 600 (M+H)+ as
24
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
10
C31H41N3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C31H41N3O5S2: 600.2566, 7(S)-7-(4-(5-Cyanopyridin-3-yl)phenylthio)-7-deoxylincomycin (28)
found: 600.2559; 1H NMR (400 MHz, CD3OD) δ 0.88–0.97 (m, 3 H),
1.27–1.39 (m, 4 H), 1.35 (d, J =6.9 Hz, 3 H), 1.80–1.91 (m, 1 H), 1.95–2.05
(m, 1 H), 1.98 (s, 3 H), 2.06–2.21 (m, 1 H), 2.13–2.24 (m, 1 H), 2.42 (s, 3 H),
3.02 (dd, J = 10.6, 4.6 Hz, 1 H), 3.24 (dd, J = 8.1, 5.7 Hz, 1 H), 3.61
(dd, J = 10.2, 3.3 Hz, 1 H), 3.76–3.81 (m, 1 H), 3.93 (dq, J = 6.9, 2.7 Hz, 1
H), 4.12 (dd, J = 10.2, 5.6 Hz, 1 H), 4.36–4.42 (m, 1 H), 4.48 (dd, J = 9.7,
2.7 Hz, 1 H), 5.28 (d, J = 5.6 Hz, 1 H), 7.50–7.55 (m, 2 H), 7.60–7.66 (m, 3 H),
7.67–7.71 (m, 1 H), 7.90–7.96 (m, 1 H), 7.96–8.00 (m, 1 H).
Compound 5 (66.0 mg, 0.156 mmol), 5-(4-bromophenyl)nicotinonitrile
(50.0 mg, 0.193 mmol), Xantphos (20.0 mg, 0.035 mmol), Pd2(dba)3
(10.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (60.0 μl, 0.344 mmol)
in 1,4-dioxane (1.5 ml) were treated for 6 h according to the similar procedure
as described for the preparation of 6 to afford 28 (55.0 mg, 59%) as a colorless
solid. [α]D +87.4° (c 0.81, MeOH); ESI-MS (m/z) 601 (M+H)+ as
25
C30H40N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C30H40N4O5S2: 601.2518,
found: 601.2512; 1H NMR (400 MHz, CD3OD) δ 0.88–0.97 (m, 3 H),
1.29–1.41 (m, 4 H), 1.37 (d, J = 6.8 Hz, 3 H), 1.83–1.92 (m, 1 H), 1.95
(s, 3 H), 1.98–2.08 (m, 1 H), 2.08–2.25 (m, 2 H), 2.44 (s, 3 H), 3.05 (dd,
J = 10.6, 4.8 Hz, 1 H), 3.27 (dd, J =8.1, 5.6 Hz, 1 H), 3.59 (dd, J = 10.1, 3.2 Hz,
1 H), 3.79 (br dd, J = 3.2, 0.6 Hz, 1 H), 3.98 (dq, J = 6.8, 2.7 Hz, 1 H), 4.11
(dd, J = 10.1, 5.6 Hz, 1 H), 4.39 (br dd, J = 9.7, 0.6 Hz, 1 H), 4.50 (dd, J = 9.7,
2.7 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.53–7.60 (m, 2 H), 7.68–7.73 (m, 2 H),
8.45–8.49 (m, 1 H), 8.87 (d, J = 1.8 Hz, 1 H), 9.08 (d, J = 2.2 Hz, 1 H).
7(S)-7-Deoxy-7-(30-methoxy-[1,10-biphenyl]-4-ylthio)lincomycin
(25)
Compound
5 (56.1 mg, 1.33 mmol), 4'-bromo-3-methoxy-1,1'-biphenyl
(45.6 mg, 0.173 mmol), Xantphos (8.1 mg, 0.014 mmol), Pd2(dba)3 (6.3 mg,
6.9 μmol) and N,N-diisopropylethylamine (46.0 μl, 0.264 mmol) in 1,4-dioxane
(1 ml) were treated for 6 h according to the similar procedure as described for
24
the preparation of 6 to afford 25 (69.0 mg, 86%) as a colorless solid. [α]D
7(S)-7-Deoxy-7-(4-(5-methoxypyridin-3-yl)phenylthio)lincomycin (29)
Compound 5 (70.2 mg, 0.166 mmol), 3-(4-bromophenyl)-5-methoxypyridine
(70.1 mg, 0.265 mmol), Xantphos (10.2 mg, 0.018 mmol), Pd2(dba)3 (8.1 mg,
8.8 μmol) and N,N-diisopropylethylamine (57.5 μl, 0.330 mmol) in 1,4-dioxane
+100° (c 2.76, MeOH); ESI-MS (m/z) 605 (M+H)+ as C31H44N2O6S2;
TOF-ESI-HRMS (M+H)+ calcd. for C31H44N2O6S2: 605.2719, found:
605.2712; 1H NMR (400 MHz, CD3OD) δ 0.87–0.95 (m, 3 H), 1.24–1.37
(m, 4 H), 1.33 (d, J = 6.9 Hz, 3 H), 1.79–1.89 (m, 1 H), 2.01 (s, 3 H), 1.95–2.09 (1 ml) were treated for 6 h according to the similar procedure as described for
26
the preparation of 6 to afford 29 (78.0 mg, 78%) as a colorless solid. [α]D
+86.8° (c 2.82, MeOH); ESI-MS (m/z) 606 (M+H)+ as C30H43N3O6S2;
TOF-ESI-HRMS (M+H)+ calcd. for C30H43N3O6S2: 606.2672, found:
606.2660; 1H NMR (400 MHz, CD3OD) δ 0.83–0.99 (m, 3 H), 1.27–1.39
(m, 4 H), 1.35 (d, J = 7.0 Hz, 3 H), 1.80–1.91 (m, 1 H), 1.95–2.05 (m, 1 H),
1.99 (s, 3 H), 2.06–2.13 (m, 1 H), 2.13–2.24 (m, 1 H), 2.42 (s, 3 H), 3.03
(dd, J = 10.6, 4.7 Hz, 1 H), 3.24 (dd, J = 8.2, 5.6 Hz, 1 H), 3.61 (dd, J = 10.1,
3.3 Hz, 1 H), 3.77–3.82 (m, 1 H), 3.90–3.98 (m, 1 H), 3.94 (s, 3 H), 4.13
(dd, J = 10.1, 5.5 Hz, 1 H), 4.36–4.42 (m, 1 H), 4.49 (dd, J = 9.8, 2.7 Hz, 1 H),
5.29 (d, J = 5.5 Hz, 1 H), 7.50–7.56 (m, 2 H), 7.59 (br dd, J = 2.7, 1.7 Hz, 1 H),
7.61–7.67 (m, 2 H), 8.21 (d, J = 2.7 Hz, 1 H), 8.39 (d, J = 1.7 Hz, 1 H).
(m, 2 H), 2.09–2.20 (m, 1 H), 2.38 (s, 3 H), 3.00 (dd, J = 10.6, 4.8 Hz, 1 H),
3.20 (dd, J = 8.3, 5.7 Hz, 1 H), 3.61 (dd, J = 10.2, 3.3 Hz, 1 H), 3.74–3.79
(m, 1 H), 3.83 (s, 3 H), 3.88 (dq, J = 6.9, 2.6 Hz, 1 H), 4.13 (dd, J = 10.2,
5.5 Hz, 1 H), 4.36–4.42 (m, 1 H), 4.44 (dd, J = 9.8, 2.6 Hz, 1 H), 5.29
(d, J = 5.5 Hz, 1 H), 6.91 (ddd, J =8.2, 2.5, 0.9 Hz, 1 H), 7.11–7.14 (m, 1 H),
7.14–7.19 (m, 1 H), 7.30–7.37 (m, 1 H), 7.46–7.51 (m, 2 H), 7.54–7.59
(m, 2 H).
7(S)-7-(30-Amino-[1,10-biphenyl]-4-ylthio)-7-deoxylincomycin (26)
Compound
5
(66.9 mg, 0.158 mmol), 40-bromo-[1,1'-biphenyl]-3-amine
(75.9 mg, 0.306 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3 (7.3 mg,
8.0 μmol) and N,N-diisopropylethylamine (53.5 μl, 0.307 mmol) in 1,4-dioxane
(1 ml) were treated for 6 h according to the similar procedure as described for
7(S)-7-(4-Bromophenylthio)-7-deoxylincomycin (30)
Compound 5 (100.0 mg, 0.237 mmol), 1-bromo-4-iodobenzene (133.8 mg,
0.473 mmol), Xantphos (27.4 mg, 0.047 mmol), Pd2(dba)3 (21.7 mg,
0.024 mmol) and N,N-diisopropylethylamine (82.6 μl, 0.474 mmol) in
1,4-dioxane (1 ml) were treated for 3 h according to the similar procedure as
described for the preparation of 6 to afford 30 (100.2 mg, 73%) as a colorless
solid. 1H NMR (400 MHz, CD3OD) δ 0.87–0.98 (m, 3 H), 1.27–1.40 (m, 4 H),
1.31 (d, J =6.9 Hz, 3 H), 1.76–1.90 (m, 1 H), 1.93–2.03 (m, 1 H), 1.98 (s, 3 H),
28
the preparation of 6 to afford 26 (47.6 mg, 51%) as a colorless solid. [α]D
+142° (c 0.51, MeOH); ESI-MS (m/z) 590 (M+H)+ as C30H43N3O5S2;
TOF-ESI-HRMS (M+H)+ calcd. for C30H43N3O5S2: 590.2722, found:
590.2713; 1H NMR (400 MHz, CD3OD) δ 0.89–0.95 (m, 3 H), 1.25–1.40
(m, 4 H), 1.33 (d, J = 6.9 Hz, 3 H), 1.80–1.91 (m, 1 H), 1.95–2.05 (m, 1 H),
2.01 (s, 3 H), 2.05–2.21 (m, 2 H), 2.40 (s, 3 H), 3.02 (dd, J =10.5, 4.6 Hz, 1 H),
3.23 (dd, J = 8.1, 5.6 Hz, 1 H), 3.60 (dd, J = 10.2, 3.3 Hz, 1 H), 3.74–3.79 2.06 (dd, J = 10.1, 8.6 Hz, 1 H), 2.10–2.22 (m, 1 H), 2.37 (s, 3 H), 2.98 (dd,
J = 10.6, 4.6 Hz, 1 H), 3.22 (dd, J =8.1, 5.7 Hz, 1 H), 3.60 (dd, J = 10.2, 3.2 Hz,
1 H), 3.72–3.79 (m, 1 H), 3.85 (dq, J =6.9, 2.7 Hz, 1 H), 4.12 (dd, J = 10.2,
5.6 Hz, 1 H), 4.31–4.37 (m, 1 H), 4.42 (dd, J = 9.7, 2.7 Hz, 1 H), 5.28
(d, J = 5.6 Hz, 1 H), 7.31–7.37 (m, 2 H), 7.44–7.50 (m, 2 H).
(m, 1 H), 3.86 (dq, J = 6.9, 2.3 Hz, 1 H), 4.11 (dd, J = 10.2, 5.6 Hz, 1 H),
4.36–4.41 (m, 1 H), 4.43 (dd, J = 9.7, 2.3 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H),
6.71 (ddd, J = 7.9, 2.2, 0.9 Hz, 1 H), 6.92 (ddd, J = 7.7, 1.7, 1.0 Hz, 1 H),
6.96–7.00 (m, 1 H), 7.13–7.19 (m, 1 H), 7.45–7.50 (m, 2 H), 7.52–7.57
(m, 2 H).
7(S)-7-Deoxy-7-(4-(2-methoxypyridin-3-yl)phenylthio)lincomycin
(31)
7(S)-7-Deoxy-7-(4-(5-fluoropyridin-3-yl)phenylthio)lincomycin (27)
Compound 5 (66.0 mg, 0.156 mmol), 3-(4-bromophenyl)-5-fluoropyridine
(50.0 mg, 0.198 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3
(10.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (13.5 μl, 0.077 mmol)
in 1,4-dioxane (1.5 ml) were treated for 3 h according to the similar procedure
as described for the preparation of 6 to afford 27 (72.0 mg, 73%) as a colorless
To a solution of compound 30 (100.2 mg, 0.173 mmol) in DMF (1 ml)
and water (0.25 ml) were added Pd(PPh3)4 (12.5 mg, 0.011 mmol),
2-methoxypyridine-3-boronic acid (62.6 mg, 0.409 mmol) and Na2CO3
(37.6 mg, 0.355 mmol) and then stirred at 80 °C for 10 h. The solution were
diluted with ethyl acetate and water, and then filtrated with celite. The filtered
solid was washed with ethyl acetate three times. The obtained solution was
extracted with ethyl acetate and then the organic layer was dried over Na2SO4,
filtrated and concentrated under reduced pressure. The resulting residue was
purified by preparative TLC (CHCl3/MeOH/28% aq NH4OH=10/1/0.1) to
solid. [α]D +88.5° (c 1.78, MeOH); ESI-MS (m/z) 594 (M+H)+ as
25
C29H40FN3O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C29H40FN3O5S2:
594.2472, found: 594.2473; 1H NMR (400 MHz, CD3OD) δ 0.88–0.96 (m, 3
H), 1.26–1.40 (m, 4 H), 1.36 (d, J = 7.0 Hz, 3 H), 1.79–1.92 (m, 1 H), 1.93–2.06
(m, 1 H), 1.97 (s, 3 H), 2.07–2.14 (m, 1 H), 2.14–2.24 (m, 1 H), 2.43 (s, 3 H),
3.04 (dd, J = 10.5, 4.6 Hz, 1 H), 3.22–3.29 (m, 1 H), 3.60 (dd, J = 10.1, 2.8 Hz, 1
H), 3.76–3.82 (m, 1 H), 3.93–4.01 (m, 1 H), 4.12 (dd, J =10.1, 5.5 Hz, 1 H),
4.36–4.41 (m, 1 H), 4.47–4.53 (m, 1 H), 5.28 (d, J = 5.5 Hz, 1 H), 7.51–7.58
(m, 2 H), 7.64–7.71 (m, 2 H), 7.87–7.94 (m, 1 H), 8.41–8.47 (m, 1 H), 8.69
(s, 1 H).
24
obtain the title compound as an off-white solid (74.1 mg, 71%). [α]D +97.8°
(c 3.63, MeOH); ESI-MS (m/z) 606 (M+H)+ as C30H43N3O6S2;
TOF-ESI-HRMS (M+H)+ calcd. for C30H43N3O6S2: 606.2672, found:
606.2670; 1H NMR (400 MHz, CD3OD) δ 0.87–0.96 (m, 3 H), 1.27–1.39
(m, 4 H), 1.35 (d, J = 6.9 Hz, 3 H), 1.79–1.90 (m, 1 H), 1.96–2.04 (m, 1 H),
1.99 (s, 3 H), 2.06 (dd, J = 10.2, 8.5 Hz, 1 H), 2.11–2.24 (m, 1 H), 2.39 (s, 3 H),
2.99 (dd, J = 10.6, 4.6 Hz, 1 H), 3.23 (dd, J =8.3, 5.7 Hz, 1 H), 3.60 (dd,
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
11
J = 10.1, 3.2 Hz, 1 H), 3.74–3.79 (m, 1 H), 3.89 (dq, J =6.9, 2.5 Hz, 1 H), 3.93 1.22–1.37 (m, 4 H), 1.39 (d, J =6.8 Hz, 3 H), 1.79–1.90 (m, 1 H), 1.93–2.07
(s, 3 H), 4.12 (dd, J = 10.1, 5.6 Hz, 1 H), 4.35–4.40 (m, 1 H), 4.42 (dd, J = 9.7, (m, 2 H), 1.94 (s, 3 H), 2.07–2.23 (m, 1 H), 2.39 (s, 3 H), 3.00 (dd, J = 10.6,
2.5 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.03 (dd, J = 7.3, 5.0 Hz, 1 H), 7.44–7.55 4.7 Hz, 1 H), 3.20 (dd, J =8.3, 5.9 Hz, 1 H), 3.63 (dd, J = 10.2, 3.4 Hz, 1 H),
(m, 4 H), 7.69 (dd, J = 7.3, 1.8 Hz, 1 H), 8.11 (dd, J = 5.0, 1.8 Hz, 1 H).
3.75–3.82 (m, 1 H), 3.99 (dq, J = 6.8, 2.6 Hz, 1 H), 4.14 (dd, J = 10.2, 5.5 Hz,
1 H), 4.38–4.43 (m, 1 H), 4.51 (dd, J = 9.8, 2.6 Hz, 1 H), 5.30 (d, J = 5.5 Hz,
1 H), 7.33 (t, J = 4.9 Hz, 1 H), 7.47–7.54 (m, 2 H), 8.31–8.39 (m, 2 H), 8.82
(d, J = 4.9 Hz, 2 H).
7(S)-7-Deoxy-7-(4-(6-methoxypyridin-3-yl)phenylthio)lincomycin (32)
Compound 5 (41.1 mg, 0.0973 mmol), 5-(4-bromophenyl)-2-methoxypyridine
(38.6 mg, 0.146 mmol), Xantphos (11.3 mg, 0.0195 mmol), Pd2(dba)3 (8.9 mg,
0.0097 mmol) and N,N-diisopropylethylamine (33.9 μl, 0.195 mmol) in
7(S)-7-Deoxy-7-(4-(pyrimidin-5-yl)phenylthio)lincomycin (36)
1,4-dioxane (0.82 ml) treated for 6 h according to the similar procedure as Compound 5 (69.5 mg, 0.164 mmol), 5-(4-bromophenyl)pyrimidine (74.6 mg,
described for the preparation of 6 to afford 32 (53.4 mg, 91%) as a colorless 0.317 mmol), Xantphos (10.1 mg, 0.017 mmol), Pd2(dba)3 (7.8 mg, 8.5 μmol)
solid. [α]D +96.1° (c 2.60, MeOH); ESI-MS (m/z) 606 (M+H)+ as
and N,N-diisopropylethylamine (55.0 μl, 0.316 mmol) in 1,4-dioxane (1 ml)
29
C30H43N3O6S2; TOF-ESI-HRMS (M+H)+ calcd. for C30H43N3O6S2: 606.2672, were treated for 6 h according to the similar procedure as described for the
found: 606.2664; 1H NMR (400 MHz, CD3OD) δ 0.87–0.96 (m, 3 H), preparation of 6 to afford 36 (74.7 mg, 79%) as an off-white solid. [α]D28 +142°
1.27–1.37 (m, 4 H), 1.33 (d, J = 6.8 Hz, 3 H), 1.79–1.91 (m, 1 H), 1.96–2.04 (c 0.51, MeOH); ESI-MS (m/z) 577 (M+H)+ as C28H40N4O5S2; TOF-ESI-
(m, 1 H), 2.01 (s, 3 H), 2.04–2.10 (m, 1 H), 2.11–2.22 (m, 1 H), 2.40 (s, 3 H), HRMS (M+H)+ calcd. for C28H40N4O5S2: 577.2518, found: 577.2508; 1H NMR
3.01 (dd, J = 10.6, 4.7 Hz, 1 H), 3.22 (dd, J = 8.1, 5.7 Hz, 1 H), 3.61 (dd, (400 MHz, CD3OD) δ 0.88–0.96 (m, 3 H), 1.27–1.42 (m, 4 H), 1.37
J = 10.2, 3.3 Hz, 1 H), 3.75–3.80 (m, 1 H), 3.89 (dq, J =6.8, 2.6 Hz, 1 H), 3.93 (d, J = 6.9 Hz, 3 H), 1.81–1.91 (m, 1 H), 1.96 (s, 3 H), 1.97–2.06 (m, 1 H),
(s, 3 H), 4.13 (dd, J = 10.2, 5.6 Hz, 1 H), 4.36–4.40 (m, 1 H), 4.45 (dd, J = 9.8, 2.06–2.13 (m, 1 H), 2.12–2.24 (m, 1 H), 2.43 (s, 3 H), 3.02 (dd, J = 10.6,
2.6 Hz, 1 H), 5.29 (d, J = 5.6 Hz, 1 H), 6.86 (dd, J = 8.6, 0.6 Hz, 1 H), 7.46–7.58 4.8 Hz, 1 H), 3.25 (dd, J =8.3, 5.7 Hz, 1 H), 3.60 (dd, J = 10.1, 3.2 Hz, 1 H),
(m, 4 H), 7.92 (dd, J = 8.6, 2.6 Hz, 1 H), 8.37 (br dd, J = 2.6, 0.6 Hz, 1 H).
3.77–3.82 (m, 1 H), 3.98 (dq, J = 6.9, 2.8 Hz, 1 H), 4.12 (dd, J = 10.1, 5.6 Hz,
1 H), 4.35–4.42 (m, 1 H), 4.50 (dd, J = 9.7, 2.8 Hz, 1 H), 5.28 (d, J = 5.6 Hz, 1
H), 7.54–7.60 (m, 2 H), 7.68–7.73 (m, 2 H), 9.07 (s, 2 H), 9.13 (s, 1 H).
7(S)-7-(4-(6-Aminopyridin-3-yl)phenylthio)-7-deoxylincomycin (33)
Compound 5 (100.0 mg, 0.237 mmol), 5-(4-bromophenyl)pyridin-2-amine
(100.0 mg, 0.401 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3
7(S)-7-Chloro-7-deoxy-2,3,4-tris-O-(trimethylsilyl)lincomycin (37)
(10.0 mg, 0.011 mmol) and N,N-diisopropylethylamine (10.0 μl, 0.057 mmol) To a solution of CLDM (1.0 g, 2.353 mmol) in pyridine (5 ml) were added
in 1,4-dioxane (5 ml) were treated for 6 h according to the similar procedure as trimethylchlorosilane (1.19 ml, 9.389 mmol), hexamethyldisilazane (1.97 ml,
described for the preparation of 6 to afford 33 (18.0 mg, 13%) as a colorless 9.42 mmol) and stirred at room temperature for 2 h, then the solution was
solid. [α]D +101° (c 0.33, MeOH); ESI-MS (m/z) 591 (M+H)+ as
added to the saturated aqueous NaHCO3. The desired compound was extracted
25
C29H42N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C29H42N4O5S2: 591.2675, with hexane and then the organic phase was dried over Na2SO4, filtrated and
found: 591.2678; 1H NMR (400 MHz, CD3OD) δ 0.89–0.96 (m, 3 H), concentrated under reduced pressure to obtain the title compound (1.47 g,
1.25–1.40 (m, 4 H), 1.33 (d, J = 6.9 Hz, 3 H), 1.80–1.91 (m, 1 H), 1.95–2.05 97%) as a colorless solid. ESI-MS (m/z) 641 (M+H)+ as C27H57ClN2O5SSi3; 1H
(m, 1 H), 2.03 (s, 3 H), 2.05–2.12 (m, 1 H), 2.12–2.21 (m, 1 H), 2.40 (s, 3 H), NMR (400 MHz, CDCl3) δ 0.13 (s, 9 H), 0.14 (s, 9 H), 0.18 (s, 9 H), 0.84–0.94
3.01 (dd, J = 10.6, 4.6 Hz, 1 H), 3.23 (dd, J = 8.1, 5.4 Hz, 1 H), 3.59 (dd, (m, 3 H), 1.22–1.35 (m, 4 H), 1.44 (d, J = 6.8 Hz, 3 H), 1.78–1.91 (m, 1 H),
J = 10.2, 3.3 Hz, 1 H), 3.73–3.78 (m, 1 H), 3.85 (dq, J =6.9, 2.4 Hz, 1 H), 4.11 1.92–2.10 (m, 3 H), 2.16 (s, 3 H), 2.41 (s, 3 H), 3.00 (dd, J =10.8, 3.7 Hz, 1 H),
(dd, J = 10.2, 5.6 Hz, 1 H), 4.36–4.40 (m, 1 H), 4.43 (dd, J = 9.8, 2.4 Hz, 1 H), 3.18 (dd, J = 7.3, 5.4 Hz, 1 H), 3.62 (dd, J = 9.5, 2.4 Hz, 1 H), 3.74
5.27 (d, J = 5.6 Hz, 1 H), 6.66 (dd, J = 8.7, 0.7 Hz, 1 H), 7.46–7.55 (m, 4 H), (d, J = 2.4 Hz, 1 H), 4.02 (d, J = 9.9 Hz, 1 H), 4.16 (dd, J = 9.5, 5.6 Hz, 1 H),
7.75 (dd, J = 8.7, 2.4 Hz, 1 H), 8.17 (br dd, J = 2.4, 0.7 Hz, 1 H).
4.46–4.54 (m, 1 H), 4.56–4.64 (m, 1 H), 5.26 (d, J = 5.6 Hz, 1 H), 7.67
(d, J = 10.5 Hz, 1 H).
7(S)-7-Deoxy-7-(4-(pyrazin-2-yl)phenylthio)lincomycin (34)
7(R)-7-Acetylthio-7-deoxylincomycin (39)
Compound 5 (100.0 mg, 0.237 mmol), 2-(4-bromophenyl)pyrazine (70.0 mg,
0.298 mmol), Xantphos (10.0 mg, 0.017 mmol), Pd2(dba)3 (10.0 mg, To a solution of compound 37 (1.47 g, 2.29 mmol) in DMF (10 ml) was
0.011 mmol) and N,N-diisopropylethylamine (82.6 μl, 0.474 mmol) in added potassium thioacetatate (1.31 g, 11.4 mmol) and stirred at 100 °C for
1,4-dioxane (2 ml) were treated for 4 h according to the similar procedure as 18 h to give 7(R)-7-acetylthio-7-deoxy-2,3,4-tris-O-(trimethylsilyl)lincomycin
described for the preparation of 6 to afford 34 (65.0 mg, 48%) as a colorless (38). Compound 38 was dissolved with 1 N HCl and MeOH, and it was stirred
solid. [α]D +85.2° (c 1.01, MeOH); ESI-MS (m/z) 577 (M+H)+ as
at room temperature for 10 min. After the reaction mixture was washed with
19
C28H40N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C28H40N4O5S2: 577.2518, diethyl ether, ethyl acetate and the saturated aqueous NaHCO3 were added to
found: 577.2515; 1H NMR (400 MHz, CD3OD) δ 0.88–0.96 (m, 3 H), the aqueous layer. The desired compound was extracted with ethyl acetate and
1.27–1.38 (m, 4 H), 1.39 (d, J = 6.9 Hz, 3 H), 1.82–1.92 (m, 1 H), 1.95 then the organic layer was dried over Na2SO4, filtrated and concentrated under
(s, 3 H), 1.97–2.07 (m, 1 H), 2.07–2.14 (m, 1 H), 2.14–2.24 (m, 1 H), 2.43 reduced pressure. The resulting residue was purified by silica gel column
(s, 3 H), 3.05 (dd, J = 10.6, 4.8 Hz, 1 H), 3.26 (dd, J = 8.1, 5.6 Hz, 1 H), 3.60 chromatography (CHCl3/CH3OH= 50/1→ 10/1) to obtain the title compound
(dd, J = 10.2, 3.3 Hz, 1 H), 3.76–3.81 (m, 1 H), 3.99 (dq, J = 6.9, 2.7 Hz, 1 H), (187.2 mg, 18%) as
a
colorless solid. ESI-MS (m/z) 465 (M+H)+ as
0.85–0.99 (m, H),
4.12 (dd, J = 10.2, 5.6 Hz, 1 H), 4.40 (br dd, J = 9.8, 0.6 Hz, 1 H), 4.51 C20H36N2O6S2; 1H NMR (400 MHz, CD3OD)
δ
3
(dd, J = 9.8, 2.7 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H), 7.53–7.58 (m, 2 H), 1.26–1.42 (m, 4 H), 1.32 (d, J =7.1 Hz, 3 H), 1.75–1.88 (m, 1 H), 1.92–2.25
8.04–8.08 (m, 2 H), 8.52 (d, J = 2.5 Hz, 1 H), 8.66 (dd, J = 2.5, 1.5 Hz, 1 H), (m, 3 H), 2.16 (s, 3 H), 2.29 (s, 3 H), 2.38 (s, 3 H), 2.94 (dd, J =10.5, 5.1 Hz, 1
9.10 (d, J = 1.5 Hz, 1 H).
H), 3.21 (dd, J = 8.6, 6.1 Hz, 1 H), 3.51 (dd, J = 10.3, 3.3 Hz, 1 H), 3.72–3.77
(m, 1 H), 4.04 (dq, J = 7.1, 3.7 Hz, 1 H), 4.08–4.13 (m, 1 H), 4.14–4.19
(m, 1 H), 4.44 (dd, J = 9.4, 3.7 Hz, 1 H), 5.27 (d, J = 5.6 Hz, 1 H).
7(S)-7-Deoxy-7-(4-(pyrimidin-2-yl)phenylthio)lincomycin (35)
Compound
5
(105.7 mg, 0.250 mmol), 2-(4-bromophenyl)pyrimidine
7(R)-7-Deoxy-7-mercaptolincomycin (40)
(116.3 mg, 0.495 mmol), Xantphos (15.0 mg, 0.026 mmol), Pd2(dba)3
(11.6 mg, 0.013 mmol) and N,N-diisopropylethylamine (86.0 μl, 0.494 mmol) To a solution of compound 39 (187.2 mg, 0.403 mmol) in MeOH (2 ml) was
in 1,4-dioxane (1.5 ml) were treated for 6 h according to the similar procedure added 4.1 M sodium methoxide in MeOH solution (0.295 ml, 1.209 mmol)
as described for the preparation of 6 to afford 35 (134.0 mg, 93%) as a colorless and stirred at room temperature for 20 min. The mixture was diluted with
solid. [α]D +83.6° (c 4.97, MeOH); ESI-MS (m/z) 577 (M+H)+ as
saturated aqueous NH4Cl and concentrated under reduced pressure. The
26
C28H40N4O5S2; TOF-ESI-HRMS (M+H)+ calcd. for C28H40N4O5S2: 577.2518, resulting residue was diluted with ethyl acetate and 10% aqueous NaHCO3.
found: 577.2512; 1H NMR (400 MHz, CD3OD) δ 0.86–0.95 (m, 3 H), Then, the desired compound was extracted with ethyl acetate, dried over
The Journal of Antibiotics

Synthesis of novel lincomycin derivatives
Y Wakiyama et al
12
Na2SO4 and concentrated under reduced pressure. The resulting residue was 7(S)-7-Deoxy-7-(4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)
purified by silica gel column chromatography (CHCl3/CH3OH= 50/1 → 10/1)
to obtain the title compound (35.6 mg, 20%) as a colorless solid. ESI-MS (m/z)
423 (M+H)+ as C18H34N2O5S2; TOF-ESI-HRMS (M+H)+ calcd. for
phenylthio)lincomycin (44)
Compound 5 (162.6 mg, 0.385 mmol), 5-(4-bromophenyl)-1-methyl-1,2,3,
6-tetrahydropyridine
(114.9 mg,
0.456 mmol),
Xantphos
(22.8 mg,
C18H34N2O5S2: 423.1987, found: 423.1982; 1H NMR (400 MHz, CD3OD) 0.039 mmol), Pd2(dba)3 (17.7 mg, 0.019 mmol) and N,N-diisopropylethyla-
mine (130.1 μl, 0.747 mmol) in 1,4-dioxane (2.5 ml) were treated for 6 h
according to the similar procedure as described for the preparation of 6 to
afford 44 (175.9 mg, 77%) as a colorless solid. [α]D +89.1° (c 1.63, MeOH);
δ 0.88–0.97 (m, 3 H), 1.25–1.40 (m, 4 H), 1.33 (d, J = 7.0 Hz, 3 H), 1.77–1.88
(m, 1 H), 1.95–2.09 (m, 2 H), 2.11 (s, 3 H), 2.16–2.27 (m, 1 H), 2.41 (s, 3 H),
2.97 (dd, J = 10.5, 4.8 Hz, 1 H), 3.21 (dd, J = 8.4, 6.1 Hz, 1 H), 3.33–3.41 (m, 1
H), 3.55 (dd, J = 10.2, 3.3 Hz, 1 H), 3.80–3.85 (m, 1 H), 4.09 (dd, J = 10.2,
5.6 Hz, 1 H), 4.20–4.30 (m, 2 H), 5.24 (d, J = 5.6 Hz, 1 H).
17
ESI-MS (m/z) 594 (M+H)+ as C30H47N3O5S2; TOF-ESI-HRMS (M+H)+ calcd.
for C30H47N3O5S2: 594.3035, found: 594.3039; 1H NMR (400 MHz, CD3OD)
δ 0.89–0.97 (m, 3 H), 1.30 (d, J = 6.9 Hz, 3 H), 1.30–1.41 (m, 4 H), 1.80–1.91
(m, 1 H), 1.94–2.03 (m, 1 H), 1.98 (s, 3 H), 2.04–2.10 (m, 1 H), 2.11–2.22
(m, 1 H), 2.37 (s, 3 H), 2.41 (dt, J =6.1, 3.0 Hz, 2 H), 2.48 (s, 3 H), 2.62–2.69
(m, 2 H), 2.98 (dd, J = 10.7, 4.7 Hz, 1 H), 3.22 (dd, J = 8.1, 5.7 Hz, 1 H),
3.33–3.38 (m, 2 H), 3.58 (dd, J = 10.2, 2.6 Hz, 1 H), 3.72–3.76 (m, 1 H), 3.84
(dq, J = 6.9, 2.6 Hz, 1 H), 4.10 (dd, J = 10.2, 5.6 Hz, 1 H), 4.32–4.37 (m, 1 H),
4.41 (dd, J =9.7, 2.6 Hz, 1 H), 5.26 (d, J = 5.6 Hz, 1 H), 6.20–6.25 (m, 1 H),
7.33–7.37 (m, 2 H), 7.38–7.42 (m, 2 H).
7(R)-7-Deoxy-7-(4-(pyrimidin-5-yl)phenylthio)lincomycin (41)
Compound 40 (35.6 mg, 0.084 mmol), 5-(4-bromophenyl)pyrimidine
(23.8 mg, 0.101 mmol), Xantphos (9.7 mg, 0.017 mmol), Pd2(dba)3 (7.7 mg,
8.4 μmol) and N,N-diisopropylethylamine (29.4 μl, 0.169 mmol) in 1,4-dioxane
(1 ml) were treated for 6.5 h according to the similar procedure as described for
the preparation of 6 to afford 41 (21.8 mg, 45%) as a colorless solid.
[α]D +142° (c 1.05, MeOH); ESI-MS (m/z) 577 (M+H)+ as C28H40N4O5S2;
24
TOF-ESI-HRMS (M+H)+ calcd. for C28H40N4O5S2: 577.2518, found: 577.2510;
1H NMR (400 MHz, CD3OD) δ 0.88–0.96 (m, 3 H), 1.27–1.37 (m, 4 H), 1.38
(d, J = 7.1 Hz, 3 H), 1.79–1.90 (m, 1 H), 1.95–2.05 (m, 1 H), 2.08 (dd, J = 10.1,
8.7 Hz, 1 H), 2.14 (s, 3 H), 2.16–2.27 (m, 1 H), 2.46 (s, 3 H), 3.01 (dd, J = 10.5,
5.0 Hz, 1 H), 3.24 (dd, J =8.4, 6.1 Hz, 1 H), 3.53 (dd, J = 10.2, 3.3 Hz, 1 H),
3.74–3.78 (m, 1 H), 3.84 (dq, J = 7.1, 3.8 Hz, 1 H), 4.08 (dd, J = 10.2, 5.7 Hz, 1
H), 4.22 (d, J = 9.4 Hz, 1 H), 4.45 (dd, J = 9.4, 3.8 Hz, 1 H), 5.26 (d, J = 5.7 Hz,
1 H), 7.54–7.61 (m, 2 H), 7.65–7.72 (m, 2 H), 9.06 (s, 2 H), 9.12 (s, 1 H).
In vitro antibacterial activity
Minimum inhibitory concentration (μg ml− l) was determined by the agar
dilution method, which was described in Clinical and Laboratory Standards
Institute (M7-A5 in 2000). Test strains of S. pneumoniae and S. pyogenes were
subjected to seed culture using brain heart infusion agar (Becton Dickinson and
Company, Tokyo, Japan) and 5% defibrinated horse blood. Test strains of
H. influenzae were subjected to seed culture using sensitivity disk agar-N
‘Nissui’ (Nissui, Tokyo, Japan), 5% defibrinated horse blood, 5 μg ml− l Hemin
and 15 μg ml− l nicotinamide adenine dinucleotide. A 5 μl portion of cell
suspension of the test strains having about 106 CFU per ml was inoculated into
sensitivity disk agar-N supplemented with 5% defibrinated horse blood,
5 μg ml− l Hemin and 15 μg ml− 1 NAD, and incubated at 37 °C for 18–22 h.
Then, the minimum inhibitory concentration was measured.
7(S)-7-Deoxy-7-(4-(piperidin-3-yl)phenylthio)lincomycin (42)
To a solution of compound 22 (12.4 mg, 0.022 mmol) in MeOH (1 ml) were
added 1 N HCl (0.1 ml) and Pt black (12.8 mg) and stirred at room
temperature for 22 h under the hydrogen gas atmosphere. Then, Pt black
(12.4 mg) was added to the solution and stirred at room temperature for 3 days
under the hydrogen gas atmosphere. The mixture was filtrated with celite and
concentrated under reduced pressure. The resulting residue was purified by
preparative TLC (CHCl3/MeOH/28% aq. NH4OH= 4/1/0.1) to obtain the title
CONFLICT OF INTEREST
The authors declare no conflict of interest.
29
compound (4.2 mg, 34%) as a colorless solid. [α]D +97.9° (c 0.74, MeOH);
ACKNOWLEDGEMENTS
ESI-MS (m/z) 582 (M+H)+ as C29H47N3O5S2; TOF-ESI-HRMS (M+H)+ calcd.
for C29H47N3O5S2: 582.3035, found: 582.3028; 1H NMR (400 MHz, CD3OD)
δ 0.88–0.99 (m, 3 H), 1.27 (d, J = 6.9 Hz, 3 H), 1.30–1.41 (m, 4 H), 1.61–1.70
(m, 2 H), 1.77–1.90 (m, 2 H), 1.92–2.04 (m, 2 H), 1.98 (s, 3 H), 2.05–2.12 (m,
1 H), 2.12–2.23 (m, 1 H), 2.38 (s, 3 H), 2.59–2.78 (m, 3 H), 2.98 (dd, J = 10.6,
4.7 Hz, 1 H), 3.40–3.12 (m, 2 H), 3.24 (dd, J = 8.2, 5.6 Hz, 1 H), 3.58
(dd, J = 10.2, 3.3 Hz, 1 H), 3.74 (br dd, J = 3.3, 0.5 Hz, 1 H), 3.81 (dq, J = 6.9,
2.6 Hz, 1 H), 4.10 (dd, J = 10.2, 5.6 Hz, 1 H), 4.29–4.35 (m, 1 H), 4.38
(dd, J =9.8, 2.6 Hz, 1 H), 5.26 (d, J = 5.6 Hz, 1 H), 7.18–7.24 (m, 2 H),
7.35–7.41 (m, 2 H).
We thank Mr A. Tamura, Dr E. Shitara and Dr T. Yoshida for encouragement
and valuable discussion. We are grateful to Professor Emeritus Dr M. Konno
for supervision through our in-house drug-discovery program in lincomycin
field. We also thank Ms M. Ishii for direction in intellectual properties,
Ms T. Miyara, Ms R. Hiruta Ms S. Miki and Ms K. Kaneda for analytical and
synthetic chemistry, Mr Y. Takayama and Ms K. Yamada for biological studies,
and Ms M. Takagi for English manuscript.
1
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added acetic acid (0.0175 ml, 0.306 mmol), 37% aqueous formaldehyde
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3
4
5
6
18
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1 H), 4.10 (dd, J =10.2, 5.6 Hz, 1 H), 4.30–4.35 (m, 1 H), 4.39 (dd, J = 9.8,
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7
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