Biomedical Engineering Reference
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This emphasizes that diversity-oriented synthesis provides excellent opportunities for
identifying gaps in current synthetic methods, in addition to generating novel
molecular probes and drug candidates.
15.5.2. Biomimetic Diversity-Oriented Synthesis
Cells use genomic reprogramming, a mechanism analogous to combinatorial pro-
cesses, to generate libraries of antibodies and receptors required by the immune
system to overcome the intrusion of exogenous threats. Very little is known about
diversity-oriented synthetic processes occurring in Nature that lead to collections of
structurally diverse and complex nonpeptidic small molecules.
Baldwin, Adlington, and coworkers described a fascinating biomimetic syn-
thesis of polypropionate-derived natural products that supports a hypothesis whereby
Nature uses a combination of branching and folding pathways in addition to
functional group pairing to generate an entire collection of structurally diverse
metabolites from unique precursors. Indeed, structural features shared by all the
members of this family suggest a common origin. It was hypothesized that a fully
conjugated
g
-pyrone polyene could be subjected to a series of double bond isomer-
izations (dbi) driven by a 1,3-methyl steric strain, associated with diversifying
pericyclic processes catalyzed by metals, light, or heat to trigger the formation of
distinct molecular skeletons. To investigate this hypothesis, polyene precursors were
synthesized and their chemical transformation explored (Scheme 15.9). Boronic
esters
were assembled via a palladium-catalyzed
Suzuki coupling to provide the desired
g
-pyrone polyene
100
-
102
. Under thermal
conditions,
100
was converted into 9,10-deoxytridachione
103
and ocellapyrone A
104
94
-
96
and halogenoalkenes
97
-
99
, as a result of a 6
p
-dis electrocyclization and an
E
/
Z
dbi/8
p
-con/6
p
-dis cascade,
respectively [51,52]. It is noteworthy that the authors had synthesized
prior to its
isolation from the natural source. In the presence of palladium salts, which presum-
ably acted as a Lewis acid,
104
101
underwent a similar transformation involving 2
E
/
Z
dbi/8
p
-con/6
p
-dis to provide
was converted by an
analogous sequence of isomerization and electrocyclization into a mixture of
products containing
105
. Under thermal conditions,
101
103
,
104
, and
106
[53]. It is likely that a dbi first afforded
100
, itself thermally converted into
103
and
104
, while compound
106
was formally
obtained from a 3
E
/
Z
dbi/8
p
-con/6
p
-dis cascade. Photodeoxytridachione
107
arose
either from a photocatalyzed 2
E
/
Z
dbi followed by the rarely observed [
p
4
s
þ
p
2
a
]
photocycloaddition or alternatively from a 2
E
/
Z
dbi/6
p
-con/[
s
2
a
þ
p
2
a
] rearrange-
ment, whereas
iso
-9,10-deoxytridachione
originated from a photocatalyzed
E
/
Z
dbi/6
p
-con cascade. Moses and coworkers completed this work with an elegant
synthesis of tridachiahydropyrone
108
109
, phototridachiahydropyrone
110
, and oxytri-
dachiahydropyrone
111
obtained from the photochemical transformation of polyene
102
through
a suprafacial photoinduced [1,3]-sigmatropic shift of the 2-hexenyl fragment.
Finally, compound
[54]. Compound
109
resulted from a 6
p
-con and was converted into
110
111
was obtained from a photocatalyzed cycloaddition of singlet
109
oxygen with
.
These incredibly diverse chemical pathways led to the synthesis of six natural
products (
103
,
104
,
107
-
109
, and
111
) and three related analogues, most likely
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