7-Phenylplatensimycin and 11-methyl-7-phenylplatensimycin: More potent analogs of platensimycin

Article abstract of DOI:10.1016/j.bmcl.2010.02.037

Carbonyl ylide cycloaddition strategy was employed in the synthesis of platensimycin analogs. 7-Phenylplatensimycin and 11-methyl-7-phenylplatensimycin are more potent analogs of platensimycin.

Full text of DOI:10.1016/j.bmcl.2010.02.037

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2156–2158
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
7-Phenylplatensimycin and 11-methyl-7-phenylplatensimycin: More potent
analogs of platensimycin
Ki Po Jang a, Chan Hyuk Kim a, Seong Wook Na a, Dong Seok Jang a, Hiyoung Kim b, Heonjoong Kang b,
Eun Lee a,
*
a Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea
b School of Earth and Environmental Sciences, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Carbonyl ylide cycloaddition strategy was employed in the synthesis of platensimycin analogs. 7-Phenyl-
platensimycin and 11-methyl-7-phenylplatensimycin are more potent analogs of platensimycin.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 4 January 2010
Revised 2 February 2010
Accepted 9 February 2010
Available online 13 February 2010
In memory of Professor Chi Sun Hahn
Keywords:
Platensimycin
7-Phenylplatensimycin
11-Methyl-7-phenylplatensimycin
Antibiotic
Platensimycin (1a, R = Me, X = Y = H) is a broad spectrum antibi-
otic (against Gram-positive bacteria) recently discovered from
Streptomyces platensis by Merck scientists: it inhibits bacterial
growth by selectively inhibiting the condensing enzyme FabF of
the bacterial fatty acid synthesis pathway.1 Platensimycin (1a)
shows no cross-resistance to methicillin-resistant Staphylococcus
aureus, vancomycin-intermediate S. aureus, and vancomycin-resis-
tant enterococci. Due to the remarkable biological activities, in-
tense activities were directed to the synthesis of platensimycin
(1a)2 and its analogs.3
Recently, we reported an efficient and concise synthetic route
towards 1a, in which the key tricyclic intermediate 2a (R = Me,
X = I) was prepared via intramolecular dipolar cycloaddition of
the carbonyl ylide generated from the halogen-substituted olefinic
intermediate 3a (R = Me, X = I).2h In the absence of halogen substi-
tution, regioselectivity in this key step is reversed, and an isomeric
tricycle 4a (R = Me) was obtained from 3f (R = Me, X = H) (Scheme
1). The tricycle 4a was used in the synthesis of isoplatensimycin
(5), a novel analog of 1a with subtle structural differences.4
A wide variety of analogs may easily be prepared using the
method described in Scheme 1. In this Letter, we wish to report
the synthesis of 15-phenyl-17-norplatensimycin (1b), 11-methyl-
platensimycin (1c), 11-bromoplatensimycin (1d), 11-chloroplaten-
simycin (1e), 7-methylplatensimycin (1f),5 7-phenylplatensimycin
(1g), and 11-methyl-7-phenylplatensimycin (1h).
First, the key tetracyclic intermediates 11b–e were prepared
according to the known route from 6 to 11a (R = Me, X = H) as
X
11
1a
1b
1c
1d
1e
1f
R=Me, X=Y=H
15
OH
R=Ph, X=Y=H
H
N
R
R
O
R=Me, X=Me, Y=H
R=Me, X=Br, Y=H
R=Me, X=Cl, Y=H
R=Me, X=H, Y=Me
R=Me, X=H, Y=Ph
R=Me, X=Me, Y=Ph
1
CO2H
O
7
Y
O
HO
1g
1h
1a Platensimycin
R
O
N2
X
Rh2(OAc)4
Rh2(OAc)4
O
O
R
O
NC
(a)
(f)
O
O
CN
CN
X
3a
3f
R=Me, X=I
4a R=Me
2a R=Me, X=I
R=Me, X=H
O
OH
H
N
CO2H
O
O
HO
5 Isoplatensimycin
* Corresponding author. Tel.: +82 2 880 6646; fax: +82 2 889 1568.
E-mail address: eunlee@snu.ac.kr (E. Lee).
Scheme 1. Platensimycin and analogs.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.037

K. P. Jang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2156–2158
2157
shown in Scheme 2. For synthesis of 15-phenyl-17-norplatensimy-
cin (1b), -chloroacetophenone was used in the alkylation of 6 in
produced a new tetracycle 12f. For optimal introduction of a phe-
nyl group at C7, a different route was adopted. The hydrosilylation
intermediate from enone 9a was allowed to react with phenyllithi-
um to form 10g after hydrolysis. The product 10g was converted
into the tetracycles 11g under the acidic conditions. The known
procedures as described in Scheme 2 were followed for the conver-
sion of 11g into 12g. Synthesis of the intermediate 12h also fol-
lowed the same sequence of reactions starting from enone 9c
(Scheme 3).
Conversion of 12a–h into the carboxylic acids 13a–h was
accomplished under alkaline conditions (Scheme 4). Platensimycin
(1a) was prepared via amide coupling of 13a with amine 14a in the
presence of HATU and TEA and subsequent basic hydrolysis. More
generally, amide coupling of 13b–h with (trimethylsilyl)ethyl ester
14b and then treatment with TASF led to analogs 1b–h as
expected.
In vitro bioassay for testing analogs 1b–h was carried out using
strains of S. aureus and Enterococcus faecalis and Enteroccocus
faecium. Oxacillin (15) and vancomycin (16) were also tested as ref-
erence compounds for comparison (Table 1). Analogs 1b–h dis-
played different levels of activities against S. aureus and
enterococci. Substitution of the 15-methyl group (C17) with a phenyl
group (i.e., 1b) did not help to enhance the antibacterial activity, nor
did 11-methyl-, 11-bromo-, 11-chloro-, and 7-methyl substitution
(i.e., 1c, 1d, 1e, 1f) comparing with 1a. Conspicuously, 7-phenylpla-
tensimycin (1g) displayed higher activities than 1a against methicil-
lin-resistant S. aureus and vancomycin-insensitive S. aureus. 11-
Methyl-7-phenylplatensimycin (1h) also showed similar activity
a
place of chloroacetone in Scheme 2. In the alkylation of 7a, E/Z mix-
tures of crotyl bromide, 1,3-dibromopropene, and 1,3-dichloropro-
pene were used as alkylating agents. The product 8c was isolated
as a mixture of E/Z mixture, but 8d and 8e were isolated as pure
E isomers. Diazoketones 3b–e were prepared from 8b–e following
the known procedure. The rhodium-catalyzed dipolar cycloaddi-
tion of 3b–e proceeded uneventfully to produce tricycles 2b–e.
The preparation of enone 9b from 2b involved radical-mediated
dehalogenation and Horner–Emmons reaction. Conversion of 2c–
e into 9c–e required only the Horner–Emmons reaction. Rh(I)-cat-
alyzed hydrosilylation of enones 9b–e, DIBAL reduction, and care-
ful imine hydrolysis was carried out under one-pot reaction
conditions, and keto aldehydes 10b–e were obtained after silyl
enol ether hydrolysis. As noted in the preparation of 11a, purifica-
tion of ketoaldehyde intermediates 10b–e was important for prep-
aration of 11b–e (Scheme 2). Conversion of 11a–e to 12a–e
involved the use of acrylonitrile as used in the synthesis of isopla-
tensimycin (5).4
For introduction of a methyl group at C7, tetracycle 12a was re-
acted with lithium dimethylcuprate in the presence of trimethyl-
silyl chloride. DDQ oxidation of the resulting silyl enol ether then
CO2Me
CN
6
a
X
R
O
R
O
R
O
N2
O
b
c, d
a, b
CO2Me
CO2Me
CN
O
O
12a
CN
CN
NC
NC
O
O
Ph
X
X
97% R=Me, X=I
66% R=Ph, X=I
80% R=Me, X=Me
39% R=Me, X=Br
30% R=Me, X=Cl
88%
7a 88%
7b 81%
8a
3a
3b
3c
3d
3e
12f 51%
12g 55%
12h 35%
R=Me
R=Ph
86%
89%
59%
69%
8b
8c
8d
8e
f, g
X
X
e
e
c, d
O
O
9a
9c
O
X
X
X
f, g
(2a-b)
O
O
h, i
Ph
Ph
R
O
R
O
O
R
O
O
11g 97%
g
10g
10h
57% X=H
68% X=Me
O
CN
CN
O
11h 100%
(2c-e)
H
10a
10b
10c
10d
10e
83%
65%
55%
82%
90%
59%
63%
53%
44%
64%
85% R=Me, X=H
71% R=Ph, X=H
49% R=Me, X=Me
73% R=Me, X=Br
80% R=Me, X=Cl
2a
9a
9b
9c
9d
9e
Scheme 3. Introduction of 7-substituents. Reagents and conditions: (a) Me2CuLi,
TMSCl, ether–THF, À78 °C; (b) DDQ, HMDS, benzene, reflux; (c) Me2PhSiH, 2 mol %
(Ph3P)3RhCl, benzene, 60 °C; PhLi, ether, À40 °C; AcOH–H2O (1:1), 0 °C; (d) 2 N HCl,
THF, 0 °C; (e) p-TsOH, toluene, reflux; (f) KHMDS, THF–HMPA (5:1), À78 °C; MeI,
À10 °C; (g) KOH, acrylonitrile, t-BuOH, 60 °C.
2b
2c
2d
2e
j
X
X
k, l
1a
1b
1c
1d
1e
1f
12a
12b
12c
12d
12e
12f
49%
43%
41%
40%
35%
44%
56%
59%
X
R
O
R
O
b, c
CN
(13a)
a
O
O
R
O
Y
OH
d, e
(13b-h)
11a 96%
11b 96%
11c 83%
11d 93%
11e 76%
61%
23%
65%
54%
11%
12a
12b
12c
12d
12e
O
O
1g
1h
12g
12h
R=Me, X=Y=H
R=Ph, X=Y=H
R=Me, X=Me, Y=H
13a 98%
13b 71%
13c 98%
OH
13d 79% R=Me, X=Br, Y=H
H2N
HO
CO2R'
Scheme 2. Synthesis of tetracyclic intermediates. Reagents and conditions: (a)
NaOMe, MeCOCH2Cl or PhCOCH2Cl, MeOH; (b) NaH, (E)-ICHCHCH2I or MeCH-
CHCH2Br (E/Z = 5:1) or BrCHCHCH2Br (E/Z = 1:1), THF or NaH, ClCHCHCH2Cl (E/
Z = 1:1), DMF; (c) 1 N KOH, MeOH; (d) ClCO2i-Bu, TEA, THF, À20 °C; CH2N2, ether,
0 °C; (e) 3 mol % Rh2(OAc)4, CH2Cl2; (f) 1-ethylpiperidine, H3PO2, Et3B, MeOH, 0 °C;
(g) MeCOCH2PO(OMe)2, DIPEA, LiCl, MeCN; (h) Me2PhSiH, 2 mol % (Ph3P)3RhCl,
toluene, 60 °C; DIBAL, toluene, À40 °C; AcOH–H2O (1:1), 0 °C; (i) 2 N HCl, THF, 0 °C;
(j) p-TsOH, toluene, reflux; (k) KHMDS, THF–HMPA (5:1), À78 °C; MeI, À10 °C; (l)
KOH, acrylonitrile, t-BuOH, 60 °C.
R=Me, X=Cl, Y=H
R=Me, X=H, Y=Me
R=Me, X=H, Y=Ph
13e 81%
13f 94%
13g 99%
R'=Me
R'=TMSE
14a
14b
13h 67% R=Me, X=Me, Y=Ph
Scheme 4. Synthesis of platensimycin and analogs. Reagents and conditions: (a) aq.
KOH, MeOH, reflux; (b) 13a, HATU, TEA, DMF; (c) 2 N KOH, 1,4-dioxane, 35 °C; (d)
13b–g, HATU, TEA, DMF; (e) TASF, DMF, 40 °C.

2158
K. P. Jang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2156–2158
Table 1
Bioassay of platensimycin (1a) and analogs
No.
Strain name
Drug sensitivity
MICs (
1e
l
g/ml)
1af
1b
1c
1d
1f
1g
1h
15g
16h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
S. aureus
E. faecalis
E. faecalis
E. faecalis
E. feacium
E. feacium
MSSAa
MSSA
MSSA
MSSA
MRSAb
MRSA
MRSA
MRSA
VISAc
VISA
1
2
8
2
8
8
1
1
2
2
4
16
16
60.5
16
16
8
0.25
1
8
<0.25
0.25
0.5
0.5
1
2
8
1
32
64
2
1
8
32
1
1
2
1
4
8
16
4
128
>128
4
1
8
8
0.5
0.25
0.5
0.25
4
8
8
2
64
64
8
0.5
4
2
0.5
1
0.5
0.25
2
4
4
60.5
8
16
2
0.25
0.5
2
<0.25
<0.25
<0.25
<0.25
0.5
1
1
60.5
8
16
<0.25
0.5
0.5
<0.25
<0.25
<0.25
<0.25
<0.25
1
4
8
16
8
<0.25
<0.25
<0.25
<0.25
>32
>32
>32
>32
>32
>32
NT
NTi
NT
NT
NT
NT
NT
NT
NT
NT
NT
2
<0.25
0.25
0.25
0.25
1
2
2
60.5
8
8
VSEd
VREe
VRE
VRE
VRE
NT
NT
NT
NT
64
64
>128
>128
60.5
60.5
2
60.5
2
60.5
60.5
1
16
2
60.5
a
b
c
d
e
f
MSSA: methicillin-sensitive Staphylococcus aureus.
MRSA: methicillin-resistant Staphylococcus aureus.
VISA: vancomycin-insensitive Staphylococcus aureus.
VSE: vancomycin-sensitive Enterococcus.
VRE: vancomycin-resistant Enterococcus.
1a Platensimycin.
15 Oxacillin.
16 Vancomycin.
NT: not tested.
g
h
i
951; (f) Singh, S. B.; Herath, K. B.; Wang, J.; Tsou, N.; Ball, R. G. Tetrahedron Lett.
2007, 48, 5429; For recent report compromising the use of FASII-based
antimicrobials for treating sepsis caused by Gram-positive pathogens, see: (g)
Brinster, S.; Lamberet, G.; Staels, B.; Trieu-Cuot, P.; Gruss, A.; Poyart, C. Nature
2009, 458, 83.
profile. The present results are in contrast with those obtained for
isoplatensimycin (5), which showed little activities against all
strains of S. aureus and weak activities against vancomycin-resistant
E. faecium.4
a
2. For the first total synthesis, see: (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew.
Chem., Int. Ed. 2006, 45, 7086; For asymmetric total synthesis, see: (b) Nicolaou,
K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem., Int. Ed. 2007, 46, 3942; (c)
Ghosh, A. K.; Xi, K. J. Org. Chem. 2009, 74, 1163; (d) Nicolaou, K. C.; Li, A.;
Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J. Am. Chem. Soc. 2009, 131, 16905; For
asymmetric formal synthesis, see: (e) Li, P.; Payette, J. N.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 9534; (f) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921; (g)
Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.; Gibe, R.; Chen, D. Y.-K. Angew. Chem., Int.
Ed. 2008, 47, 944; (h) Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E.
Angew. Chem., Int. Ed. 2008, 47, 4009; (i) Yun, S. Y.; Zheng, J.-C.; Lee, D. J. Am.
Chem. Soc. 2009, 131, 8413; (j) Nicolaou, K. C.; Li, A.; Ellery, S. P.; Edmonds, D. J.
Angew. Chem., Int. Ed. 2009, 48, 6293; For racemic formal synthesis, see: (k) Zou,
Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org. Lett. 2007, 9, 1825;
(l) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem. Commun. 2007, 1922; (m)
Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2007, 46, 8074; (n) Matsuo,
J.-i.; Takeuchi, K.; Ishibashi, H. Org. Lett. 2008, 10, 4049; (o) McGrath, N. A.;
Bartlett, E. S.; Sittihan, S.; Njardarson, J. T. Angew. Chem., Int. Ed. 2009, 48, 8543;
For a recent review on the synthesis of platensimycin, see: (p) Tiefenbacher, K.;
Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548; (q) Nicolaou, K. C.; Chen, J. S.;
Edmonds, D. J.; Estrada, A. A. Angew. Chem., Int. Ed. 2009, 48, 660.
It is worth noting that 7-phenylplatensimycin (1g) and 11-
methyl-7-phenylplatensimycin (1h) are the first analogs reported
with better antimicrobial activities than the parent platensimycin
(1a). From the present and previous studies, it may be concluded
that the skeletal conservation/substituents appendage would be
sensible future strategy for the development of useful analogs of
platensimycin.
Acknowledgments
This work was supported by a Grant from Marine Biotechnology
Program funded by Ministry of Land, Transport and Maritime Af-
fairs, Republic of Korea. BK21 graduate fellowship Grants to
K.P.J., C.H.K., and H.K., and Seoul Science Fellowship Grants to
C.H.K. and H.K. are gratefully acknowledged.
3. For some notable examples, see: (a) Nicolaou, K. C.; Lister, T.; Denton, R. M.;
Montero, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2007, 46, 4712; (b) Nicolaou, K.
C.; Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem. Soc. 2007, 129,
14850; (c) Nicolaou, K. C.; Stepan, A. F.; Lister, T.; Li, A.; Montero, A.; Tria, G. S.;
Turner, C. I.; Tang, Y.; Wang, J.; Denton, R. M.; Edmonds, D. J. J. Am. Chem. Soc.
2008, 130, 13110; (d) Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2008, 10, 3877; (e)
Krauss, J.; Knorr, V.; Manhardt, V.; Scheffels, S.; Bracher, F. Arch. Pharm. Chem.
Life Sci. 2008, 341, 386; (f) Shen, H. C.; Ding, F.-X.; Singh, S. B.; Parthasarathy, G.;
Soisson, S. M.; Ha, S. N.; Chen, X.; Kodali, S.; Wang, J.; Dorso, K.; Tata, J. R.;
Hammond, M. L.; MacCoss, M.; Colletti, S. L. Bioorg. Med. Chem. Lett. 2009, 19,
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.02.037.
References and notes
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5. This analog has already been reported in Ref. 3f.