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Another example from the Schreiber group involves a 1,3-dipolar cycloaddition between an
indole dipolarophile and an in situ generated cyclic oxonium ylide to give skeletally different
products by varying the placement of the reactive functional groups around a common pyridone
core 8 (Scheme 1.3). 17
Scheme 1.3 Synthesis of skeletally distinct products by substrate-design.
HN
O O
8
OEt
O
O
MeN O
Me
O
Me
O
N2 O
N
N
N2 O
9
N
O
10
N2 O
N
H
N
TsN
O
( ) 4
OSi
OMe
OSi
O
O
NHtBu
N
( ) 4 PMB O
OSi
11
Rh(II)
O
O
O
N
Me H
O
Me
O
O
N
Ts
H N
O
N
Me
N OMe
H
O
O
( ) 4
OSi
12
N
H
O
H
N
CONHtBu
NPMB
Despite the fact that a high degree of skeletal diversity can be accessed via the substrate-based
approach, the efficiency of the overall process is compromised since all of the precursors need to
be synthesized independently.
- Therefore, a more efficient approach to skeletal diversity involves subjecting a common
synthetic precursor to different reaction conditions to give skeletally unique products (reagent-
based control, Scheme 1.1). Although there are some applications of this concept, it remains the
most difficult to achieve, particularly in the context of cyclic skeleton synthesis. 18 For example,
Schaus and Porco have shown that aryl-ether C-glycoside derivative 15 unveils phenol 16 via a
[3,3]-sigmatropic rearrangement under microwave irradiation, or furanyl alcohol 17 via a Au-
7
13
14
O
( ) 4
OSi
OSi