Structural and stereochemical diversity in prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system from marine and terrestrial fungi

Abstract

Covering: up to February 2017 Various fungi of the genera Aspergillus, Penicillium, and Malbranchea produce prenylated indole alkaloids possessing a bicyclo[2.2.2]diazaoctane ring system. After the discovery of distinct enantiomers of the natural alkaloids stephacidin A and notoamide B, from A. protuberus MF297-2 and A. amoenus NRRL 35660, another fungi, A. taichungensis, was found to produce their diastereomers, 6-epi-stephacidin A and versicolamide B, as major metabolites. Distinct enantiomers of stephacidin A and 6-epi-stephacidin A may be derived from a common precursor, notoamide S, by enzymes that form a bicyclo[2.2.2]diazaoctane core via a putative intramolecular hetero-Diels-Alder cycloaddition. This review provides our current understanding of the structural and stereochemical homologies and disparities of these alkaloids. Through the deployment of biomimetic syntheses, whole-genome sequencing, and biochemical studies, a unified biogenesis of both the dioxopiperazine and the monooxopiperazine families of prenylated indole alkaloids constituted of bicyclo[2.2.2]diazaoctane ring systems is presented.

Fig. 1

Structures of representative prenylated indole alkaloids isolated from fungi of the genera Aspergillus, Penicillium, and Malbranchea.

Fig. 2

Structures of several prenylated indole alkaloids isolated from fungi and their stereochemical relationships.

Fig. 3

Early suggestions of Sammes and Birch concerning the biogenesis of the bicyclo[2.2.2]diazaoctane ring system in the brevianamides.

Fig. 4

Stereochemical outcomes of the oxidative isoprene cyclization across the two amino acid a-carbons in the construction of the bicyclo [2.2.2]diazaoctane.

Fig. 5

Precursor incorporation results of [¹³C]₂–notoamide E in A. protuberus MF297-2.^–

Fig. 6

Structures of notoamides L and N–P.^,,

Fig. 7

Results of the incorporation experiment of [¹³C]₂–[¹⁵N]₂–notoamide S in A. amoenus NRRL 35660.

Fig. 8

Results of the incorporation experiments of [¹³C]₂–(±)-notoamide T in a trace element solution (A), [¹³C]₂–(±)-6-epi-notoamide T in a trace element solution (B), and (±)-6-epi-notoamide T on trace element agar plates (C) in A. protuberus MF297-2.^,

Fig. 9

Prenylated indole alkaloids illustrating the syn- and anti-diastereomeric relative configurations isolated from A. protuberus MF297-2 and A. amoenus NRL 35660.^,,,

Fig. 10

Structures of the taichunamides isolated from A. taichungensis IBT19404.

Fig. 11

Mining and annotation of biosynthetic gene clusters of fungal indole alkaloids. Brevianamide (Aspergillus versicolor MF030, brn); chrysogenamide (Penicillium. alligativum, chr); notoamide A (A. protuberus MF297-2, not); malbrancheamide (Malbranchea aurantiaca RRC1813, mal); waikialoid A (Aspergillus sp., wai); 3-epi-notoamide C (A. taichungensis IBT 19404, tai); oxaline (P. oxalicum F30, oxa); citrinalin (P. citrinum F53, cit); parahequamide A (P. fellutanum ATCC20841, phq); citrinadins (P. citrinum IBT 29821, cnd).^,

Fig. 12

Comparison of the biosynthetic gene clusters of the (+)-notoamide (Aspergillus amoenus) and ( )-notoamide (Aspergillus protuberus) producing fungi.

Scheme 1

Alternative brevianamide biogenesis proposed by Williams.

Scheme 2

Putative IMDA reactions in the oxidative enzymatic transformation from notoamide S.

Scheme 3

Structures of prenylated indole alkaloids isolated from A. protuberus MF297-2 and initial proposal regarding their possible biogenetic relationships.^,,,–

Scheme 4

Possible biosynthetic pathways to notoamide E4 from notoamide E.

Scheme 5

Structures of notoamides M and Q and possible formation of the bicyclo[2.2.2]diazaoctane ring system, theoretically through notoamides M and Q.^,,

Scheme 6

Possible biosynthetic pathways to notoamides L (A) and O (B).

Scheme 7

Initial proposal for the enantiodivergent biogenesis of enantiomeric prenylated indole alkaloids with a bicyclo[2.2.2]diazaoctane core in A. protuberus MF297-2 and A. amoenus NRRL 35660.^,

Scheme 8

Possible biosynthetic pathways from deoxybrevianamide E to stephacidin A and potential precursors for IMDA reactions.^–

Scheme 9

Possible biosynthetic pathways to 6-epi-notoamide T3 and 6-epi-notoamide T4 from 6-epi-notoamide T.^,

Scheme 10

Possible biosynthetic pathways of an enantiomeric mixture of 6-epi-stephacidin A and (+)-versicoclamide B in A. amoenus NRRL 35660.^,

Scheme 11

Possible biogenesis of taichunamides B and E and versicolamide B from 6-epi-stephacidin A.

Scheme 12

Proposed facial specificities of IMDA reactions for metabolites in A. protuberus MF297-2 (blue circles), A. amoenus NRRL 35660 (red triangles), and A. taichungensis IBT 19404 (green squares). Major and minor metabolites in each fungus are represented with large and small symbols, respectively.

Scheme 13

Current understanding of (+)- and (−)-notoamide biogenesis in Aspergillus sp.

Scheme 14

Role of NotB in the conversion of notoamide E into notoamides C and D.

Scheme 15

First-generation biomimetic total synthesis of _D,L-brevianamide B.

Scheme 16

Second generation biomimetic total synthesis of _D,L-brevianamide B.

Scheme 17

Third-generation biomimetic total synthesis of _D,L-brevianamide B.^,

Scheme 18

Theoretical calculations predicting transition state energies and predicted product diastereoselectivities at the B3LYP/6-31G* level.

Scheme 19

Synthesis of the reverse-prenylated tryptophan moiety.^,,–

Scheme 20

Biomimetic total synthesis of stephacidin A and notoamide B.^,

Scheme 21

Biomimetic total syntheses of notoamide C, C3-epi-notoamide C and notoamide D.

Scheme 22

Biomimetic total syntheses of notoamide J.^,

Scheme 23

Biomimetic total synthesis of the malbrancheamides.

Scheme 24

Biomimetic total synthesis of _D,L-marcfortine C.

Scheme 25

Biomimetic total synthesis of (+)-versicolamide B and (−)-versicolamide B.^,

Scheme 26

Biomimetic total synthesis of _D,L-notoamide T and _D,L-6-epi-notoamide T.

Scheme 27

Biomimetic total synthesis of (−)-VM55599.

Scheme 28

Biomimetic total synthesis of _D,L-VM55599 and _D,L-pre-paraherquamide.^,

Scheme 29

Results of precursor incorporation studies in Penicillium fellutanum with isotopically labeled dioxopiperazine and monooxopiperazine substrates.

Scheme 30

Results of precursor incorporation studies in Malbranchea aurantiaca with isotopically labeled dioxopiperazine and monooxopiperazine substrates.

Scheme 31

Molecular architecture of the monooxopiperazine NRPS module and a hypothetical biogenetic pathway to pre-paraherquamide and pre-malbrancheamide.

Scheme 32

Unified biogenetic hypothesis for prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane nucleus.