Biomedical Engineering Reference
In-Depth Information
R
2
(
R
)-cat., LiClO
4
3 Å MS
CH
2
Cl
2
, rt
Phosphazene base
electrophile, Bu
4
NI
NMP, rt
OMe
CO
2
Me
CO
2
Me
OHC
O
N
N
4
4
100% conversion
5
100% conversion
5
H
R
1
O
O
Ar
Ar
Ar
R
2
R
1
17
R
1
15
16
18
Br
(dr > 94:6)
(ee > 95%)
(dr > 85:15)
1. PMe
3
/DBU
dioxane/H
2
O, rt
(>95% conversion)
2. Phosphazene base
PhCH
2
Br, NMP, rt
(100% conversion)
R
1
= H, N
3
, or CH
2
N
3
R
2
= H, N
3
, or CH
2
N
3
R
3
= CH
2
Ph
R
2
R
2
R
3
N
O
O
NR
3
NR
3
NR
3
O
N
N
N
N
O
O
O
O
O
Ar
Ar
Ar
Ar
1. TMSOK, THF, rt
2. R
4
R
5
NH, PyBroP
CH
2
Cl
2
/DMF, rt
(0-100%)
R
1
R
1
20
21
22
19
t-
Bu
t-
Bu
O
NR
4
R
5
i
-Pr
i
-Pr
N
O
O
N
N
Si
TfO
Al
Ar =
O
O
Ar
O
t-
Bu
23
(
R
)-cat.
t-
Bu
SCHEME 15.4
23
into a series of acyclic amides
, increasing themolecular diversity of the librarywith
more flexible analogues. This powerful method gave rise to a 529 small molecule-
containing library based on five structurally distinct molecular frameworks.
The implementation of an original strategy to force a
syn
-alkylation at C4 could
potentially provide additional skeletal diversity.
15.4.4. Implementation of Skeletal Diversity
Molecular diversity can be achieved by the introduction of appending functional
groups or by the variation of stereochemical elements within the molecular scaffold
itself. However, these approaches are incomplete with regard to the apparent skeletal
diversity produced. While the molecular diversity is usually represented by a large
number of small molecules, the skeletal diversity is usually unsubstantial, as it
remains restricted to products with similar molecular frameworks (Scheme 15.3). In
their seminal review, Burke and Schreiber emphasized the relevance of divergent
synthetic pathways that lead to collections of distinct molecular skeletons [15].
Structurally distinct substrates can be converted into collections of diverse molecular
scaffolds by use of a single set of reagents, where each starting material leads to a
single scaffold. Alternatively, a discrete molecular entity empowered by a pluripotent
reactivity can be transformed into a library of structurally unrelated products by
employing diverse reagents, each reagent determining the nature of the chemical
transformation. The quintessence of diversity-oriented synthesis lies in the systematic
application of these chemical pathways. This requires an accurate knowledge of
synthetic organic chemistry with the awareness of complexity-generating reactions,
their scope, and limitations.
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