Biomedical Engineering Reference
In-Depth Information
There are obvious advantages for the use of immobilized reagents in synthesis,
for instance, product isolation and separation can be made easier, since reagents can
be used in excess to drive reactions to completion. Furthermore, reaction quenching,
aqueous workups, and chromatographic purification are generally not necessary.
More often than not, products are obtained in a pure formdirectly following removal of
the resin by filtration and subsequent solvent evaporation. An additional advantage is
that the recovered spent reagents can often be recycled, which constitutes an attractive
feature especially when using expensive catalysts or precious materials. Supported
reagents often have improved safety profiles compared to their nonimmobilized
counterparts, meaning toxic, noxious, and flammable compounds become more
manageable when tethered to a heterogeneous support. In addition, site isolation
effects mean that mutually incompatible reagents such as immobilized acids and
bases can be used together in one reaction vessel. Similarly, immobilized scavenger
resins can be used during downstream purification processes to negate complicated
purification processes. These agents exploit ionic and covalent substrate interactions
and bind both organic and inorganic impurities, allowing them to be rapidly seques-
tered from crude reaction mixtures.
Although some immobilized reagents can react more slowly, reactions times
are often improved by using focused microwave heating methods [8]. Alternatively,
doping the solution with ionic liquids, which act as good thermal transfer agents in
the presence of microwaves, gives greatly improved heating when poor absorbing
solvents are used [9].
By seeking to challenge the prevailing dogma of using solid-phase synthesis
for the preparation of chemistry compound libraries in the 1990s, the combination of
solution-phase chemistry with the versatility and convenience of immobilized
reagents has led to a significant shift in improved practices and synthesis concepts.
Indeed, to illustrate how these reagents can be used best in multistep synthesis
sequences, a few examples are highlighted that demonstrate the breadth and utility
in conducting a multitude of chemical transformations. These include the preparation
of the amaryllidaceae alkaloids (
)-oxomaritidine and (
)-epimaritidine [10],
(
)-epibatidine [12], as well as a number of key pharmaceutical
compounds, including sildenafil (Viagra
) [13], the
b
2
adrenoceptor agonist
(
R
)-salmeterol [14],
g
-aminobutyric acid (GABA) analogues [15], carpanone [16],
and in more recent times the synthesis of the epothilones [17].
รพ
)-plicamine [11], (
11.2. MULTISTEP SYNTHESIS OF NATURAL PRODUCTS
AND BIOACTIVE MATERIALS USING IMMOBILIZED
REAGENTS
The first multistep synthesis of a natural product to be reported that used immobilized
reagents for each transformation was the preparation of the amaryllidaceae alkaloids
(
7
8
(Scheme 11.1) [10]. The six-step
synthesis route began with the oxidation of benzylic alcohol
)-oxomaritidine
and (
)-epimaritidine
to the corresponding
aldehyde using immobilized perruthenate [18]. The corresponding aldehydewas then
reacted with phenolic amine
2
under reductive amination conditions to generate the
1
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