Progress in the Chemistry of Cytochalasans
95
Besides the cytochalasans mentioned above, Zhang and coworkers reported a
series of merocytochalasans of considerable complexity [4, 193, 196]. The representative compounds included heterotrimers (455–467) and heterotetramers (468),
which are all hybrid molecules of cytochalasan and epicoccine moieties (Scheme 5).
A hypothetical biosynthesis was proposed to involve a Diels–Alder reaction and [3 +
2] cycloaddition as key steps, as shown in Scheme 5. The intermolecular Diels–Alder
reaction between aspochalasin D (346) and an oxidized epicoccine moiety (D1) led
to the linkages of C-19/C-8
and C-20/C-1
with a β-oriented oxygen bridge, giving
two products, D4 and D5, with different epicoccine orientations. After this, the trihydroxy benzene parts of D4 and D5 are oxidized to give D6 and D7, respectively.
The [3 + 2] cycloaddition occurred between two merocytochalasan intermediates,
which led to the new cytochalasan heterotetramer, asperflavipine A (468), bearing two
moieties of cytochalasans and two moieties of epicoccines. Intermediate D6, instead
of reacting with D7, also may accept an additional oxidized epicoccine molecule (D2
or D3) to give D9 or D8 through a [3 + 2] cycloaddition reaction. These heterotrimer
intermediates would undergo additional nucleophilic additions to generate the carbon
cage scaffolds. Finally, epicochalasines A and B (461 and 462) would be formed after
keto-enol tautomerization.
Asperchalasine A (455), a heterotrimer with two cytochalasan moieties and
one epicoccine moiety, represents another assembly mode. Aspochalasin B (344),
rather than aspochalasin D (346), participates in the DA cycloaddition to give D10.
After oxidization to D11, it couples with the second molecule of 344 to furnish
asperchalasine A (455).
The above pathways are proposed based on the structures of related intermediates
isolated from the producing strain. Several obvious uncertainties remain. One is
on the origin of the polyketide compound epicoccine, inclusive of the location of
its synthetic gene in the genome of the producing strain, and its relation to the
cytochalasan BGC in terms of the genome position or expression time. Second, the
addition of epicoccine needs to undergo oxidation and [3 + 2] cyclization. It is not
known if these processes are spontaneous or enzymatic, or, if enzymes are required,
whether they are pathway-specific or non-specific. Currently, the search for the genes
involved in epicoccine formation is underway by the present author group, and these
points remain to be answered. However, as reviewed in the total synthesis part of
this chapter (Sect. 5), the cycloaddition between D11 and aspochalasin B (344)
proceeds when directly exposed to the air [198]. It may be suggested that the [3 +
2] cycloaddition is a non-enzymatic reaction in the fungal cell.
The assembly of various forms of merocytochalasans reveals unparalleled plasticity in their biosynthesis and may provide new insight into the broad chemical
diversity of the merocytochalasan family. It is worth noting that most of these
assembled molecules are biologically active (Sect. 3), implying that these are functional metabolites produced by fungi during evolution. It will be interesting to study
the metabolic regulation and molecular evolution mechanisms of these compounds
during biosynthesis work.
95
Besides the cytochalasans mentioned above, Zhang and coworkers reported a
series of merocytochalasans of considerable complexity [4, 193, 196]. The representative compounds included heterotrimers (455–467) and heterotetramers (468),
which are all hybrid molecules of cytochalasan and epicoccine moieties (Scheme 5).
A hypothetical biosynthesis was proposed to involve a Diels–Alder reaction and [3 +
2] cycloaddition as key steps, as shown in Scheme 5. The intermolecular Diels–Alder
reaction between aspochalasin D (346) and an oxidized epicoccine moiety (D1) led
to the linkages of C-19/C-8
and C-20/C-1
with a β-oriented oxygen bridge, giving
two products, D4 and D5, with different epicoccine orientations. After this, the trihydroxy benzene parts of D4 and D5 are oxidized to give D6 and D7, respectively.
The [3 + 2] cycloaddition occurred between two merocytochalasan intermediates,
which led to the new cytochalasan heterotetramer, asperflavipine A (468), bearing two
moieties of cytochalasans and two moieties of epicoccines. Intermediate D6, instead
of reacting with D7, also may accept an additional oxidized epicoccine molecule (D2
or D3) to give D9 or D8 through a [3 + 2] cycloaddition reaction. These heterotrimer
intermediates would undergo additional nucleophilic additions to generate the carbon
cage scaffolds. Finally, epicochalasines A and B (461 and 462) would be formed after
keto-enol tautomerization.
Asperchalasine A (455), a heterotrimer with two cytochalasan moieties and
one epicoccine moiety, represents another assembly mode. Aspochalasin B (344),
rather than aspochalasin D (346), participates in the DA cycloaddition to give D10.
After oxidization to D11, it couples with the second molecule of 344 to furnish
asperchalasine A (455).
The above pathways are proposed based on the structures of related intermediates
isolated from the producing strain. Several obvious uncertainties remain. One is
on the origin of the polyketide compound epicoccine, inclusive of the location of
its synthetic gene in the genome of the producing strain, and its relation to the
cytochalasan BGC in terms of the genome position or expression time. Second, the
addition of epicoccine needs to undergo oxidation and [3 + 2] cyclization. It is not
known if these processes are spontaneous or enzymatic, or, if enzymes are required,
whether they are pathway-specific or non-specific. Currently, the search for the genes
involved in epicoccine formation is underway by the present author group, and these
points remain to be answered. However, as reviewed in the total synthesis part of
this chapter (Sect. 5), the cycloaddition between D11 and aspochalasin B (344)
proceeds when directly exposed to the air [198]. It may be suggested that the [3 +
2] cycloaddition is a non-enzymatic reaction in the fungal cell.
The assembly of various forms of merocytochalasans reveals unparalleled plasticity in their biosynthesis and may provide new insight into the broad chemical
diversity of the merocytochalasan family. It is worth noting that most of these
assembled molecules are biologically active (Sect. 3), implying that these are functional metabolites produced by fungi during evolution. It will be interesting to study
the metabolic regulation and molecular evolution mechanisms of these compounds
during biosynthesis work.