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(dashed lines represent chemical bonds resulting from the cycloaddition). The
oxabicycloheptene containing a strained alkene was identified in the forward syn-
thetic planning as a potential partner for a second complexity-generating reaction
such as ring-opening metathesis (ROM)-ring-closing metathesis (RCM). Two mono-
substituted olefins were introduced prior to remodeling the molecular framework.
Compound
was then treated with a second-generation Grubbs catalyst in refluxing
dichloromethane [27] to give the [7-5-5-7]-fused tetracycle. Finally, the silyl moiety
was removed in the presence of HF
6
.
The silyl protecting group was initially used to mimic a solid support in order to adapt
the synthetic strategy to solid-phase chemistry. It was anticipated that the integration
of this synthetic scheme into a split-pool protocol would permit to implement
molecular diversity into the complex scaffold
Py, leading to the final complex product
7
with the generation of analogues.
This elegant example highlights the high value of complexity-generating reactions,
converting very simple substrates such as compounds
7
1
-
4
into a more complex
product in only four steps.
15.4.2. Appendage Diversity
Tan et al. reported the synthesis of a library containing over twomillion rigid tetracyclic
small molecules derived from shikimic acid (Scheme 15.3) [8,9]. Shikimic acid
8
was
9
first converted into both enantiomers of the epoxycyclohexenol
that were loaded onto
a photocleavable solid support. Both substrates were reacted with a variety of nitrone
carboxylic acids
, with absolute
control over regio- and stereoselectivities via a tandem acylation/1,3-dipolar cyclo-
addition previously reported by Tamura et al. [28,29]. The structures generated
contained several reactive centers that could be modified in an orthogonal manner
in order to introduce side appendages, virtually increasing the size of the library.
Initially, a collection of alkyne building blocks was introduced onto
10
, leading to the complex tetracyclic products
11
via a copper-
catalyzed Sonogashira coupling. All products differed from each other by newly
introduced appendages. However, they bore common functional features allowing
them to participate as a pool in the next step, using the same reaction conditions. A
library of diverse nucleophilic amines was reacted with
11
to promote lactone opening.
The introduction of a third appendage was realized via acylation of
12
13
, which after
O
R
H
O
O
N
10
, PyBroP, DIPEA
DMAP, CH2Cl2, rt
HO
HO
Ref
.
[8]
OH
O
O
N
N
H
H
O
O
H
HO
N
O
O
HO
R
OH
10
O
(-)-Shikimic acid
8
9
11
R = CH
2
Ar, Ar
>98%
R
1
Cu(I)/Pd(II), DIPEA
DMF, rt
90-95%
R
1
R
1
R
1
R
2
R
2
1. R
3
CO
2
H, DIPC
DMAP, CH
2
Cl
2
, rt
(>95%)
R
2
NH
2
2-Hydroxypyridine
THF, rt
NH
NH
O
H
n
n
n
O
N
O
N
N
2. Photocleavage
(80-90%)
H
N
(>95%)
H
N
R
3
O
O
O
O
O
HO
NH
2
H
H
H
H
O
O
O
O
O
O
O
14
13
12
(
n
= 0,1)
SCHEME 15.3
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