Biomedical Engineering Reference
In-Depth Information
R
1
OH
Ref. [60]
O
R
1
O
O
139
Me
Ref
.
[60]
N
n
n
LiBr, DBU
R
2
CHO
MeCN
Chiral bis(oxazoline)
Cu(OTf)
2
, 3 Å MS
CH
2
Cl
2
, PhH
R
1
O
O
O
O
140
(
n
= 1, 3, 5)
O
Ref
.
[60]
Me
P
OEt
OEt
R
N
O
R
R
1
R
R
1
R
137
136
138
141
(
n
= 1, 2)
Ref. [60]
O
O
R
1
O
Ph
142
O
OsO
4
, NMO
acetone/H
2
O
R
=
R
BnO
OBn
Si O
N
N
OH
OH
143
NaIO
4
, THF/H
2
O
then R
3
NH
2
, NaB(OAc)
3
H
CH
2
Cl
2
Ref
.
[60]
Ref
.
[60]
Ref
.
[60]
Cl
R
1
R
1
O
O
S
O
R
1
O
O
R
1
R
R
R
R
HO
O
O
N
N
O
O
N(R
2
)
2
R
2
(R
2
)
2
N
NO
2
R
2
R
2
148
147
146
145
144
R
2
H
N
SCHEME 15.13
136
137
precursor
, itself subjected to
an Evans oxazoline-catalyzed cycloaddition with cyclopentadiene to afford
was reactedwith a series of aldehydes to produce
138
with
good enantio- and diastereoselectivities (ee
138
was then subjected to diversifying processes, which included an osmium tetroxide-
mediated dihydroxylation of the double bond to generate the corresponding
syn
-diols
143
¼
89-98%, de
¼
74%). Compounds
, followed by oxidative cleavage and reductive amination to produce the seven-
membered rings
. The library was designed in a way that no structural equivalent
existed in Nature, maximizing the chances to discover a small molecule antibiotic that
could act via a novel mechanism. After structural characterization of a representative
sample, the library was screened on penicillin- and erythromycin-resistant strains of
Staphylococcus aureus
.(
147
was shown to prevent growth of Gram-
positive strains
in vitro
with low antifungal activity and low mammalian cell toxicity,
illustrating the selectivity of the small molecule. Further investigation demonstrated
that gemmacin acts via a disruption of the cell membrane, a property rather unan-
ticipated owing to the low molecular weight of the compound (539 g/mol) in
comparison to other drugs acting via similar mechanisms (1700 g/mol). This study
demonstrates the relevance of diversity-oriented synthesis to the identification of
potent antibiotics.
)-Gemmacin
148
15.7. PERSPECTIVES
Over the past 20 years, small molecules have played a critical role in chemical biology
studies. While target-oriented synthesis remains an important area of research that
prompted the development of organic chemistry, diversity-oriented synthesis has set
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