Biomedical Engineering Reference
In-Depth Information
Boc
Cl
Msc
CN
Ph
O
O
N
O
O
S
O
O
PMB
O
O
N
Br
O
F-tag
O
O
O
O
C
6
F
13
(CH
2
)
n
Cbz
or
O
R
C
8
F
17
(CH
2
)
n
Cl
O
O
Br
O
O
Teoc
O
N
i
-Pr
Si
i
-Pr
O
Br
Ph
Cl
Fmoc
Ph
TIPS
Trityl
FIGURE 10.1
Representative fluorous protective linkers.
Light fluorous synthesis employs short fluorous tags, such as C
6
F
13
or C
8
F
17
,
and relies on fluorous solid-phase extraction (F-SPE) and fluorous high-performance
liquid chromatography (F-HPLC) for product purifications [13-16]. Light fluorous
synthesis offers the following advantages: (1) fluorous linker attachedmolecules have
reasonable solubility in common organic solvents and do not require fluorous solvents
for reaction or separation; (2) reactions can be monitored by conventional analytical
tools such as TLC, LC-MS, and NMR; (3) F-SPE is used to replace chromatography
for product purification, thus reducing the amount of solvent waste; (4) F-SPE
cartridges are reusable, which reduces the operation cost; and (5) microwave reactions
can be used to decrease reaction time and improve reproducibility.
Dozens of fluorous linkers have been developed in last decade and are classified
into three categories: protective linkers, displaceable linkers, and safety-catch
linkers [17,18]. Protective linkers are the most popular (Figure 10.1). They are
nonconvertible and structurally resemble the protecting groups such as TIPS, Boc,
Fmoc, PMB (
p
-methoxybenzyl), and Cbz for the protection of amino, hydroxyl,
carboxyl, and other groups. These linkers are suitable for the synthesis of complex
molecules that require functional group protections. Displaceable linkers, on the other
hand, are able to convert the attached functional group to a new group after linker
cleavage, which are useful for diversity-oriented synthesis (DOS). Finally, safety-
catch linkers are stable under common reaction conditions and cannot be cleaved until
activated by oxidation, photolysis, or other selective reactions. Examples of three
different linkers are highlighted in Scheme 10.1.
10.2. FLUOROUS PROTECTIVE LINKER FOR THE
SYNTHESIS OF NATURAL PRODUCT ANALOGUES
Sclerotigenin was isolated from the sclerotia of
Penicillium sclerotigenum
.Itis
structurally the simplest one in the natural alkaloid benzodiazepine-quinazolinone
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