Biomedical Engineering Reference
In-Depth Information
15.4. STRATEGIES TO CREATE STRUCTURALLY COMPLEX
AND DIVERSE SMALL MOLECULES
The complex nature of biologically active natural products suggests that structural
complexity of small molecule modulators may be correlated to their function and
specificity. The fundamental objective of DOS, as introduced by Schreiber [10], is
to generate unrelated complex structures to populate unexplored chemical space
with the view to selectively interacting with a wide variety of biomolecules and
altering biological processes. Structural complexity and molecular diversity can be
analyzed separately and are usually integrated in the final synthetic strategy that
will lead to a DOS library. This section will discuss several strategies that have
been implemented and developed to expand the scope of DOS, taking into account
both complexity and diversity.
15.4.1. Complexity-Generating Reactions
Schreiber and coworkers established a synthetic protocol involving the use of
complexity-generating reactions that can be carried out in a tandem manner, where
the product released after the first step is a direct substrate for the next. Diversity-
oriented synthesis has stimulated resurgence in interest for multicomponent reactions
because simple substrates can be combined and converted into a more complex
structure in a single step. The use of “pairwise” reactions is illustrated in Scheme 15.2
by an efficient tandemUgi four-component/Diels-Alder cycloaddition, followed by a
ring-opening/ring-closing olefin metathesis [25,26]. The success of this process was
due to the introduction of a diene and a dienophile as two of the four components
required for the Ugi, capable of entering an intramolecular Diels-Alder cycloaddi-
tion. (Triisopropylsilyloxy)methylbenzenyl-amine
1
, furfural
2
(the dienophile),
fumaric acid (3-bromobenzyl)monocarboxamide
3
(the diene), and benzyl isocyanide
4
were reacted in methanol to give the Diels-Alder adduct
5
as a single
endo
-isomer
O
OSi(
i
-Pr)
3
NH
2
O
OHC
HN
H
(
i
-Pr)
3
SiO
O
N
1
2
KHMDS
allyl bromide, rt
MeOH, THF, rt
O
H
N
H
HO
2
C
Ar
CN
67%
89%
HN
O
O
5
3
4
Br
OH
O
OSi(
i
-Pr)
3
N
H
O
1. Ru-cat., CH
2
Cl
2
, 40°C
(69%)
2. HF
.
Py
(95%)
O
N
H
N
N
O
O
H
H
O
O
N
O
Br
N
N
H
H
Mes
Mes
N
Br
Cat. =
Cl
Cl
Ru
6
Ph
7
Cy
3
P
SCHEME 15.2
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