A facile synthesis of (+)/(?)-pentenomycin I and analogs, and their antimicrobial evaluation

Article abstract of DOI:10.1016/j.tetlet.2019.04.026

This study reported a stereoselective synthesis of (+)/(+)-pentenomycin I in 4–5 steps through regioselective silylation, optical resolution and dihydroxylation, followed by an olefin formation, from a known racemic cyclopentenone prepared from 2-deoxy-D-

Full text of DOI:10.1016/j.tetlet.2019.04.026

Accepted Manuscript
A facile synthesis of (+)/(−)-pentenomycin I and analogs, and their antimicro-
bial evaluation
Takaaki Kamishima, Masato Suzuki, Shigenobu Aoyagi, Toshihiro Watanabe,
Yoshitaka Koseki, Hitoshi Kasai
PII:
S0040-4039(19)30363-6
https://doi.org/10.1016/j.tetlet.2019.04.026
TETL 50741
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 February 2019
11 April 2019
15 April 2019
Please cite this article as: Kamishima, T., Suzuki, M., Aoyagi, S., Watanabe, T., Koseki, Y., Kasai, H., A facile
synthesis of (+)/(−)-pentenomycin I and analogs, and their antimicrobial evaluation, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.04.026
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A facile synthesis of (+)/(−)-pentenomycin I
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Takaaki Kamishima, Masato Suzuki, Shigenobu Aoyagi, Toshihiro Watanabe, Yoshitaka Koseki and Hitoshi
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1
Tetrahedron Letters
A facile synthesis of (+)/(−)-pentenomycin I and analogs, and their antimicrobial
evaluation
Takaaki Kamishimaa,b , Masato Suzukic, Shigenobu Aoyagid, Toshihiro Watanabea, Yoshitaka Kosekia and
Hitoshi Kasaia
aInstitute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan
bFromseeds Corporation, 6-6-40 Aramaki, Aoba-ku, Sendai, Miyagi, 980-0845, Japan
cAntimicrobial Resistance Research Center, National Institute of Infectious Diseases, 4-2-1 Aobamachi, Higashimurayama, Tokyo,189-0002, Japan
d Ouchi Shinko Chemical Industrial Co., Ltd., Research and Development Center, 111 Shimojyukumae, Sukagawa, Fukushima, 962-0806, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This study reported a stereoselective synthesis of (+)/(+)-pentenomycin I in 4−5 steps through
regioselective silylation, optical resolution and dihydroxylation, followed by an olefin
formation, from a known racemic cyclopentenone prepared from 2-deoxy-D-glucose. We also
accomplished the transformation of a common intermediate into a variety of analogs. In
addition, the antimicrobial activities of the pentenomycin analogs were evaluated, which
revealed important structural factors of pentenomycins for the antimicrobial activities.
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Pentenomycin
Total synthesis
Antimicrobial susceptibility testing
Structure-activity relationships
Introduction
and enantioselective. The shortest process for the synthesis of
(+)-1 were reported by Elliott group.20 In this case, however, the
In general, the molecules having a cyclopentenone framework
also possess an important function as the Michael acceptors for a
variety of cellular nucleophiles, due to their highly reactive α,β-
unsaturated carbonyl centers.1 Thus, the cyclopentenone
framework is usually used as a basic core to prepare natural and
unnatural products.2,3 In addition, highly oxygenated
cylopentenoids are known to exhibit promising antimicrobial
activity.4 In particular, pentenomycins exhibit moderate activity
against both Gram-positive and Gram-negative bacterial species
(Figure 1).5–7 Pentenomycin I (1) was isolated by Umino et al. in
1973 from a culture strain of Streptomyces eurythermus. The
unique structures of pentenomycins having various reactive
functional groups and quaternary chiral center are especially
interesting for its synthesis. Furthermore, pentenomycins with
biological properties have also attracted attention in recent years.
Various methods have been reported for the total syntheses, both
enantioselective and racemic, of pentenomycins.8–19 In recently,
total synthesis of (−)-pentenomycin I (1), a natural product, from
D-mannose, and (+)-1 from D-ribose were reported by Rao
group.18 In later years, Pal group reported the the syntheses of
both enantio isomers of 1 from D-ribose as the single starting
material, via stereoselective hydroxymethylation, Grignard
reaction and ring-closing metathesis as key reactions.19 While the
synthetic methods reported to date are very interesting, many of
required starting material was prepared from quinic acid in more
than ten steps.21,22 In addition, pentenomycin analogs could not
be efficiently synthesized from pentenomycin (1) because multi-
hydroxy groups inhibit selective modification of functional
groups. Despite numerous efforts on the synthesis of 1, there are
few reports of antimicrobial evaluation. Therefore, the
development of synthetic routes of pentenomycin analogs and
investigation of their antimicrobial activities would be beneficial.
Herein, we report the enantioselective synthesis of (+)/(−)-
pentenomycin I (1) and their analogs prepared from a key
intermediate in a short overall process, and their antimicrobial
evaluation.
Figure 1. Structures of pentenomcyins
t—ho—se r—equire multiple steps, especially the ones that are stereo-
 Corresponding author. Tel.: +81-22-217-5612; fax: +81-22-217-5614; e-mail: kasai@tohoku.ac.jp

2
Tetrahedron
Results and discussion
Recently, we reported a facile method for the preparation of
cyclopentenone from 2-deoxy-D-glucose (2-DG) by a
4
hydrothermal reaction under mild condition,23 and 4 could be
replaced with the starting material used by Elliott et al. The
synthetic plan of (+)/(−)-pentenomycin I (1) is shown in Scheme
1. At the beginning, the primary hydroxy group in 4 is protected
regioselectively, then the optical resolution by enzymes results in
the separation of the (+)/(−)-enantiomers. After that, the basic
pentenomycins skeleton is formed by dihydroxylation and
formation of the olefin by E1cb elimination. Finally, protective
group is removed to produce 1. According to the synthetic plan,
the synthesis of (+)/(−)-1 were achieved as follows (Scheme 2).
The regioselective silylation of primary hydroxy group was
carried out by a non-nucleophilic base under catalyst-free
conditions.24 In this case, with the presence of the catalyst, 4-
dimethylaminopyridine (DMAP), the major product in which
both hydroxy groups protected was produced and also, the
regioselectivity was reduced when nucleophilic bases were
used.25 Subsequent optical resolution was succeeded by using
Lipase amano series.26,27 When 5 was treated with vinyl acetate
and Lipase AK amano, 6 and (S)-5 were obtained in equivalent
yield. The absolute configuration of each compound was
determined by comparing to the optical resolution of the chiral
compounds prepared from the (R)-4 (99% ee) and (S)-4 (99% ee)
(both were supplied by the FromSeeds Corporation). After that,
the olefination and the subsequent dihydroxylation were
proceeded in one-pot in which 6 was treated with osmium
catalyst and N-methylmorpholine oxide at room temperature.
Scheme 2. Syntheses of (+)/(−)-pentenomycin I (1). Reagents and
conditions: (a) TBSCl (tert-butyldimethylsilyl), Et3N, THF, room
temperature (r.t.), overnight, 82%; (b) Lipase AK amano,
vinlyacetate-acetone (1:1), r.t., overnight, 48% for 6, 50% for (S)-5;
(c) Ac2O, pyridine, 4-Dimethylaminopyridine (DMAP), r.t.,
overnight, 72%; (d) K2OsO2(OH)2, N-methylmorpholine oxide
(NMO), acetone-H2O (2:1), r.t., 2 h, 61% for (−)-7, 55% for (+)-7;
(e) 3 M HCl, THF, r. t., 0.5 h, 48 % for (−)-1, 57% for (+)-1.
However, compound 6 has not consumed completely and
recovered in 28% yield. In this case, we found that compound 7
decomposed and a lower yield was obtained when the reaction
time exceeded 2 h. The pentenomycin skeleton could be
constructed at once, however the enatiopurity of 7 was moderate
(56% ee, determined by chiral-phase high performance liquid
chromatography (HPLC)). In addition, the enatiopurity of (–)-7
prepared from (R)-4 (99% ee) was also moderate. Therefore, the
stereoselective formation of the osmate ester intermediate was
not completely controlled due to the less steric hindrance of the
acetoxy group.20 Finally, desilylation through treatment with
aqueous 3 M HCl produced (–)-pentenomycin I (1). Under the
same conditions, (+)-1 was produced from (S)-5. The
spectroscopic properties of 1 were identical to those reported
previously. The optical rotation of synthetic (+)-1, [α]D23 = + 13.2
(c = 0.36, EtOH), matched with the literature value of [α]D
=
+30.1 (c 0.1, EtOH)19. And also, the optical rotation of (–)-1,
23
[α]D = –19.6 (c = 0.35, EtOH) matched with a previous report
of [α]D = −30.2 (c 0.29, EtOH)19.
Previously, Umino et al. reported that several pentenomycin
analogs were produced from an isolated 1, however the overall
yield was very low. On the other hand, we believe that the
intermediate 7 is suitable to promote to analogs. We have also
demonstrated the syntheses of several analogs of natural type
from (−)-7, as shown in Scheme 3. Initially, the secondary
hydroxyl group of (−)-7 was modified with benzoic ester 8
Scheme 1. Retrosynthesis of (+)/(−)-pentenomycin I (1). PG:
protective group.

3
through treatment with benzoic anhydride under basic condition,
pyridine and DMAP. The reaction was required longer time to
reach completion when benzoyl chloride was used instead of
benzoic anhydride. Benzoic pentenomycin 9 was prepared by
treatment of 8 with 6 M HCl, because the starting material 9 was
not completely consumed under 3 M HCl. I2 in the presence of
pyridine provided the α-iodide derivatives 10 and 11.
Hydrogenation of 9 over Pd/C catalyst subjected compound
12.Compound 13 could be obtained in 64% yield from 11 in two
steps: Suzuki-Miyaura coupling reaction which was carried out
with PhB(OH)2, K2CO3, and a catalytic amount of Pd(PPh3)2Cl2,
followed by desilylation.17 We have succeeded in synthesizing
several pentenomycin analogs, so as the next target, we
attempted their antimicrobial evaluation. The synthesized analogs
9, 10, 12 and 13 were tested for their antimicrobial activity.
Antimicrobial susceptibility was tested by broth microdilution
method according to the Clinical and Laboratory Standards
Institute (CLSI) recommendations. It was performed on seven
bacterial species of the most common pathogens in the clinical
settings, and the minimum inhibitory concentration (MIC) values
are summarized in Table 1. Compound 9 and 10 had moderate
antimicrobial activities for either organisms. On the other hand,
the activities of compound 11 and 13 were remarkably decreased.
These results suggested that the cyclopentenone framework, α,β-
unsaturated carbonyl, in pentenomycins would be responsible for
the pronounced antimicrobial activity. In addition, it was
revealed that when there is bulky and non-liberating substituent,
such as phenyl group, in α position of cyclopentenone, its
antimicrobial activity was remarkably attenuated. To the best of
our knowledge, the antimicrobial activity of compound 10, 11
and 13 has not been previously reported in literature; while the
MIC value of compound 9 was reported elsewhere.7
Table 1. Antimicrobial evaluation of pentenomycin
analogs
These findings provide new knowledge for designing new
pentenomycin derivatives, more active synthetic antimicrobial
compounds.
Conclusion
We have achieved the enantioselective synthesis of (+)/(−)-
Pentenomycin I (1) in a liner sequence of four steps, starting
from cyclopentenone 4 which could be prepared from 2-DG. In
addition, the analogs could be obtained successfully in a less
complicated method from intermediate 7.
A preliminary
antibiological activity of pentenomycin analogs 10, 11 and 13
was also investigated, which provided some structure-activity
relationship insight. We believe that these findings will be useful
for the design and development of new pentenomycins for
antimacrobial agents. Now we are promoting the syntheses of the
highly enantioselective pentenomycin analogs.
Acknowledgments
We would like to thank Emeritus Profs. Kunio Arai, Dr.
Hideo Hattori and Dr. Toshiyuki Nonaka of FromSeeds Co., who
provided fruitful discussion and supplied materials. We are very
grateful to Prof. Fumi Nagatsugi, Prof. Hidetoshi Oikawa and
Assistant Prof. Anh T. N. Dao of Tohoku University for their
help on the compounds measurements. This work was performed
under the Cooperative Research Program of "Network Joint
Research Center for Materials and Devices. This work was
supported by a Grant-in-Aid for Research Program on Emerging
and Re-emerging Infectious Diseases (JP18fk0108020 for M.S.)
from Japan Agency for Medical Research and Development
(AMED), Japan.
Scheme 3. Syntheses of pentenomycin analogs. Reagents and
Conditions: (a) (PhCO)2O, pyridine, 4-Dimethylaminopyridine
(DMAP), THF, room temperature (r.t.), 1 h, 95%; (b) 6 M HCl,
THF, r.t., 1 h, 100 %; (c) I2, CH2Cl2-pyridine (2:1), 1 h, r.t., 47% for
10; (d) H2 (balloon), Pd/C, MeOH, r.t., 1 h, 100 %; (e) K2CO3,
PhB(OH)2, Pd(PPh3)2Cl2, THF-H2O (2:1), 60 °C, overnight; (f) 3 M
HCl, THF, r.t., 1 h, 64 % (2 steps from 11).

4
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5
A facile synthesis of (+)/(−)-
pentenomycin I and analogs, and their
antimicrobial evaluation
Takaaki Kamishimaa,b , Masato Suzukic, Shigenobu
Aoyagid, Toshihiro Watanabea, Yoshitaka Kosekia
and Hitoshi Kasaia
Highlight
・ New pentenomycin analogs scaffolds.
・ Short process synthesis.
・ Natural product from deoxy sugar.
・ Antimicrobial evaluation for the development of novel
antiracial agents.
———
 Corresponding author. Tel.: +81-22-217-5612; fax: +81-22-217-
5614; e-mail: kasai@tohoku.ac.jp