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stereocontrol elements can be used to access different diastereomers from a common precursor.
This form of diversity is important because it is well known that stereoisomeric compounds
(enantiomers, diastereomers or atropisomers) can have different biological activity by virtue of
displaying functional groups differently in three-dimensional space (stereochemical diversity,
Scheme 1.1). 15
(3) Skeletal diversity is arguably the most important but relatively difficult to achieve in
an efficient manner. There are at least two conceptually distinct ways it can be accomplished:
- The first one involves designing structurally similar substrates that under common reaction
conditions undergo diverging transformations affording skeletally distinct products. The
chemical information that leads to different products is therefore encoded in the substrates
(substrate-based control, Scheme 1.1). This is the most commonly utilized synthetic approach to
skeletal diversity. 16 For example, Schreiber demonstrated that substituted furans 1-3 containing
one, two or no alcohols in the side chain can undergo different transformations when treated to
oxidative acidic conditions (NBS and PPTS). 10c The reaction proceeds via an oxidative opening
of the furan to a cis-endione intermediate 4, which then is subject to nucleophilic attack by the
hydroxyl groups to give skeletally distinct products 5-7 (Scheme 1.2).
Scheme 1.2 Substrate-controlled skeletal diversity.
O
O
O
OH
1
OH
Bn
Me
N
OH
O
OAc O
O
2
Bn
Me
N
3
O
O
O
NHPh
NBS
PPTS
O O
4
6
O
O
O
O
O
N
Me
5 Bn
6
7
O
O
O
O
O
O
Me
NHPh
OAc O
Bn
N
O