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. 2011 Apr;51(3):442-452.
doi: 10.1002/ijch.201100016.

Studies on the Biosynthesis of the Stephacidin and Notoamide Natural Products: A Stereochemical and Genetic Conundrum

James D Sunderhaus  1 , David H Sherman, Robert M Williams
Affiliations

Studies on the Biosynthesis of the Stephacidin and Notoamide Natural Products: A Stereochemical and Genetic Conundrum

James D Sunderhaus et al. Isr J Chem. 2011 Apr.

Abstract

The stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a bicyclo[2.2.2]diazaoctane core. Biosynthetically, this bicyclic core is believed to be the product of an intermolecular Diels- Alder (IMDA) cycloaddition of an achiral azadiene. Since all of the natural products in this family have been isolated in enantiomerically pure form to date, it is believed that an elusive Diels-Alderase enzyme mediates the IMDA reaction. Adding further intrigue to this biosynthetic puzzle is the fact that several related Aspergillus fungi produce a number of metabolites with the opposite absolute configuration, implying that these fungi have evolved enantiomerically distinct Diels-Alderases. We have undertaken a program to identify every step in the biogenesis of the stephacidins and notoamides, and by combining the techniques of chemical synthesis and biochemical analysis we have been able to identify the two prenyltransferases involved in the early stages of the stephacidin and notoamide biosyntheses. This has allowed us to propose a modified biosynthesis for stephacidin A, and has brought us closer to our goal of finding evidence for, or against, the presence of a Diels-Alderase in this biosynthetic pathway.

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Figures

Figure 1
Figure 1
Representative notoamide alkaloids and the enantiomeric forms of stephacin A, notoamide B, and veriscolamide B.
Figure 2
Figure 2
The notoamide (not) biosynthetic gene cluster
Scheme 1
Scheme 1
Representative prenylated alkaloids and their proposed biosynthesis.
Scheme 2
Scheme 2
The proposed biogenesis of the both enantiomers of stephacidin A.
Scheme 3
Scheme 3
Originally proposed biosynthetic route to stephacidin A via notamide E.
Scheme 4
Scheme 4
Synthesis of notoamide E.
Scheme 5
Scheme 5
Incorporation studies with doubly 13C-labeled notoamide E.
Scheme 6
Scheme 6
Potential biosynthetic pathways to stephacidin A.
Scheme 7
Scheme 7
The synthesis of 6-hydroxydeoxybrevianamide E (41).
Scheme 8
Scheme 8
The total synthesis of notoamide S (42).
Scheme 9
Scheme 9
The synthesis of substrate 43.
Scheme 10
Scheme 10
The Synthesis of substrate 44.
Scheme 11
Scheme 11
Reaction of 13C-labeled brevianamide F with NotF.
Scheme 12
Scheme 12
The prenylation of 6-hydroxydeoxybrevianamide E by NotC.
Scheme 13
Scheme 13
The revised biosynthesis of stephacidin A.
Scheme 14
Scheme 14
Some possible biogeneses of versicolamide B.
See this image and copyright information in PMC

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