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Review
. 2012 Apr 27;75(4):812-33.
doi: 10.1021/np200954v. Epub 2012 Apr 15.

Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids

Jennifer M Finefield  1 , Jens C Frisvad, David H Sherman, Robert M Williams
Affiliations
Review

Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids

Jennifer M Finefield et al. J Nat Prod. .

Abstract

Over eight different families of natural products consisting of nearly 70 secondary metabolites that contain the bicyclo[2.2.2]diazaoctane ring system have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy.

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Figures

Figure 1
Figure 1
Structures of several secondary metabolites that contain the core bicyclo[2.2.2]diazaoctane ring system.
Figure 2
Figure 2
Anti- and syn- relationship of the bicyclo[2.2.2]diazaoctane core.
Figure 3
Figure 3
Structures of the brevianamides and related metabolites.
Figure 4
Figure 4
The marcfortine family of natural products.
Figure 5
Figure 5
Structures of the paraherquamides and related compounds.
Figure 6
Figure 6
Structure of 2-deoxyparaherquamide A (derquantel).
Figure 7
Figure 7
Structures of the stephacidins and related compounds.
Figure 8
Figure 8
Structures of the notoamides and related compounds.
Figure 9
Figure 9
Structures of the enantiomeric metabolites produced by Aspergillus sp. MF297-2 and A. versicolor.
Figure 10
Figure 10
Notoamide (not) biosynthetic gene cluster from Aspergillus sp. MF297-2.
Figure 11
Figure 11
Possible biosynthetic precursor of citrinadins.
Scheme 1
Scheme 1
The classical mevalonic acid pathway showing the labeling pattern via 1,2-doubly labeled acetate (note the change in carbon numbering).
Scheme 2
Scheme 2
Proposed biosynthetic Diels-Alder reaction.
Scheme 3
Scheme 3
Proposed biosynthesis of the malbrancheamides.
Scheme 4
Scheme 4
Precursor incorporation studies with M. aurantiaca.
Scheme 5
Scheme 5
Birch's proposed biosynthesis of the brevianamides.
Scheme 6
Scheme 6
Alternative biosynthetic pathway for the brevianamides.
Scheme 7
Scheme 7
Biosynthetic derivatives of marcfortine A.
Scheme 8
Scheme 8
Two biogenetic routes from l-lysine to pipecolic acid.
Scheme 9
Scheme 9
(A) 13C-labeled amino acid incorporation into paraherquamide A in Penicillium cf. canescens. (B) Proposed biosynthetic pathway for the conversion of l-isoleucine to 3(S)-methyl-l-proline.
Scheme 10
Scheme 10
Relevant coupling patterns observed in the 13C NMR spectrum of paraherquamide A. Thick lines represent intact acetate units.
Scheme 11
Scheme 11
Proposed biosynthetic mechanism of reverse prenylation in paraherquamide A to explain the scrambling of the geminal methyl 13C labels observed during the precursor incorporation study.
Scheme 12
Scheme 12
Incorporation of 13C-labeled pre-paraherquamide into paraherquamide A in P. cf. canescens.
Scheme 13
Scheme 13
Asperparaline A precursor incorporation study.
Scheme 14
Scheme 14
Proposed unified biosynthetic pathway with branch-point to generate paraherquamides or asperparalines.
Scheme 15
Scheme 15
Currently postulated biosynthetic pathway of the stephacidins and notoamides in Aspergillus sp. MF297-2 and A. versicolor.
Scheme 16
Scheme 16
(±)-[13C]2-stephacidin A precursor incorporation study with A. versicolor and Aspergillus sp. MF297-2.
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