2
H. Zhu et al.
3.3
Antiparasitic Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.4
Anti-inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.5
Antiviral Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.6
Phytotoxic Effects and Ecological Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3.7
Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4
Biosynthesis of Cytochalasans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.1
Cytochalasan Gene Clusters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.2
Investigations into the Biosynthesis of Cytochalasans . . . . . . . . . . . . . . . . . . . . . . 86
4.3
Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
5
Chemical Syntheses of Cytochalasans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
5.1
Synthesis of Periconiasin G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.2
Syntheses of Cytochalasin B and L-696,474 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.3
Total Syntheses of Periconiasins A–E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.4
Total Synthesis of Aspochalasins D and B and (+)-Aspergillin PZ . . . . . . . . . . . 108
5.5
Total Synthesis of Asperchalasine A and Related Derivatives . . . . . . . . . . . . . . . 111
5.6
Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1 Introduction
Cytochalasans are a group of fungal-derived natural products characterized by the
presence of a perhydro-isoindolone core fused with a macrocyclic ring, with these
compounds exhibiting high structural diversity and a broad-spectrum of bioactivities. From the standpoint of biosynthesis, cytochalasans are generated via a hybrid
polyketide synthase–non-ribosomal peptide synthetase (PKS–NRPS) biosynthesis
pathway with certain amino acids. Cytochalasans have attracted significant attention
from the chemical and pharmacological scientific communities and have already
been reviewed in recent years from different vantage points, such as their chemistry
and biology [1], biosynthesis [2], and total synthesis [3]. There is continued interest
in cytochalasans and relevant investigations on these compounds are growing rapidly,
as noted from the fact that only 100 cytochalasans were reported by 2009 [1], but by
2020, this number had grown to 500.
The present contribution provides a general view of the isolation, structural determination, biological activities, biosynthesis, and total synthesis of cytochalasans. In
all, 477 cytochalasans are described: some “unnatural” cytochalasans obtained by
feeding or genetic manipulation and a new sub-group named “merocytochalasans”
are also included. Merocytochalasans are a class of cytochalasans arising from the
dimerization or polymerization of one or more cytochalasan molecules with one or
more other natural product units. The term “merocytochalasan” was put forward
initially in 2017 by Zhang and coworkers [4], but the first isolation and characterization of merocytochalasans may be traced back to the isolation of aspochalamins
A–D (439–442) from Aspergillus niveus LU 9575 in 2004 [5, 6]. Merocytochalasans
are found mainly as a group of aspochalasins, generally with an additional epicoccine moiety or peptide (amino acid). Due to their intriguing structures and potential
H. Zhu et al.
3.3
Antiparasitic Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.4
Anti-inflammatory Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.5
Antiviral Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.6
Phytotoxic Effects and Ecological Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3.7
Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4
Biosynthesis of Cytochalasans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.1
Cytochalasan Gene Clusters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.2
Investigations into the Biosynthesis of Cytochalasans . . . . . . . . . . . . . . . . . . . . . . 86
4.3
Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
5
Chemical Syntheses of Cytochalasans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
5.1
Synthesis of Periconiasin G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.2
Syntheses of Cytochalasin B and L-696,474 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.3
Total Syntheses of Periconiasins A–E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
5.4
Total Synthesis of Aspochalasins D and B and (+)-Aspergillin PZ . . . . . . . . . . . 108
5.5
Total Synthesis of Asperchalasine A and Related Derivatives . . . . . . . . . . . . . . . 111
5.6
Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1 Introduction
Cytochalasans are a group of fungal-derived natural products characterized by the
presence of a perhydro-isoindolone core fused with a macrocyclic ring, with these
compounds exhibiting high structural diversity and a broad-spectrum of bioactivities. From the standpoint of biosynthesis, cytochalasans are generated via a hybrid
polyketide synthase–non-ribosomal peptide synthetase (PKS–NRPS) biosynthesis
pathway with certain amino acids. Cytochalasans have attracted significant attention
from the chemical and pharmacological scientific communities and have already
been reviewed in recent years from different vantage points, such as their chemistry
and biology [1], biosynthesis [2], and total synthesis [3]. There is continued interest
in cytochalasans and relevant investigations on these compounds are growing rapidly,
as noted from the fact that only 100 cytochalasans were reported by 2009 [1], but by
2020, this number had grown to 500.
The present contribution provides a general view of the isolation, structural determination, biological activities, biosynthesis, and total synthesis of cytochalasans. In
all, 477 cytochalasans are described: some “unnatural” cytochalasans obtained by
feeding or genetic manipulation and a new sub-group named “merocytochalasans”
are also included. Merocytochalasans are a class of cytochalasans arising from the
dimerization or polymerization of one or more cytochalasan molecules with one or
more other natural product units. The term “merocytochalasan” was put forward
initially in 2017 by Zhang and coworkers [4], but the first isolation and characterization of merocytochalasans may be traced back to the isolation of aspochalamins
A–D (439–442) from Aspergillus niveus LU 9575 in 2004 [5, 6]. Merocytochalasans
are found mainly as a group of aspochalasins, generally with an additional epicoccine moiety or peptide (amino acid). Due to their intriguing structures and potential