Biomedical Engineering Reference
In-Depth Information
8.5.2 Diversification Strategies Based on Natural Macrolactones
Macrolactones represent an important segment of macrocyclic natural products pos-
sessing activity on numerous biological targets [10]. Schreiber and co-workers pio-
neered the synthesis of libraries of macrolactones based on scaffold
65
(Figure 8.8)
[82]. Macrocycles were assembled by first anchoring monomer 1 on resin via a TIPS
linker, followed by attachment of monomer 2 to give precursor
64
, which underwent
macrocyclization using Yamaguchi's procedure [9d]. This library provided excellent
stereochemical and conformational diversity; not surprisingly, yields varied widely
(0 to 75%).
The same group then reported the synthesis of a 2070-membered library of macro-
lactones based on scaffold
67
assembled by RCM from precursor
66
(Scheme 8.12).
Testing of this library for ligands of the Sonic Hedgehog N-terminal peptide identified
robotnikinin
68
, which demonstrated its ability to bind the extracellular Sonic Hedge-
hog (Shh) protein and block Shh signaling in human cancer lines [82b,83]. Ring size
and stereochemistry were found to greatly influence biological activity. This series
of compounds represents an eloquent example of how to take advantage of syn-
thetic diversification around natural structural motifs, which have been essentially
“validated” through natural selection, to discover novel bioactive compounds [10].
Several natural products and structural analogs have been synthesized using solid-
phase synthesis. Nicolaou et al. reported the synthesis of a library of analogs of the
epothilones (
19
, Figure 8.1) using solid-phase synthesis (Scheme 8.13) [84]. Strate-
gically, macrocycles were synthesized in microreactors on Merrifield resin function-
alized as phosphonium salt
67
. Three building blocks were then added sequentially:
aldehyde
68
(
n
=
3) via a Wittig reaction, ketone
69
(
n
=
3) via an aldol reaction,
and alcohol
70
(
n
5) bearing an epothilone side chain via an esterification reaction.
Macrocyclization was then performed as RCM-release, giving after side-chain depro-
tections epothilone analogs of general formula
71
. Subsequent epoxidation delivered
congeners
72
. Using this strategy,
=
100 stereochemically diverse analogs bearing a
variety of exocyclic appendages were synthesized. This library was used to probe the
SAR of the epothilones systematically using rapidly accessible analog generation.
The biological profile of analogs was tested in antitubulin polymerization and ovarian
and breast carcinoma cell growth assays, delivering several analogs with activities
similar or superior to those of natural products.
Using the fluorous mixture synthesis strategy developed in their labs [85], Cur-
ran and co-workers synthesized the 16 diastereomers of the natural macrolactone
Sch727654 (
79
, Scheme 8.14) [86]. Using only one fluorous and one nonfluorous
tag (T2 and T1, respectively), the authors synthesized four mixtures of isomers from
each enantiomer of alcohols
73
and
74
, following esterification with tagged car-
boxylic acids
75
and
76
in the cis and trans series. Subsequent RCM followed by
hydrogenation delivered four mixtures of isomers (
77
), which were independently
subjected to preparative fluorous HPLC that allowed tag identification. Final detag-
ging led to the 16 diastereomers (e.g.,
78
) of Sch727654. Additional applications of
the fluorous mixture synthesis to the synthesis of collections of macrocycles include
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