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. 2015 Aug 1;2(8):978-984.
doi: 10.1039/C5QO00165J.

Syntheses of Sceptrins and Nakamuric Acid and Insights into the Biosyntheses of Pyrrole-Imidazole Dimers

Xiaolei Wang  1 , Yang Gao  2 , Zhiqiang Ma  1 , Rodrigo A Rodriguez  3 , Zhi-Xiang Yu  4 , Chuo Chen  1
Affiliations

Syntheses of Sceptrins and Nakamuric Acid and Insights into the Biosyntheses of Pyrrole-Imidazole Dimers

Xiaolei Wang et al. Org Chem Front. .

Abstract

Sceptrins and nakamuric acid are structurally unique antibiotics isolated from marine sponges. Recent studies suggest that the biosynthesis of these dimeric pyrrole-imidazole alkaloids involves a single-electron transfer (SET)-promoted [2+2] cycloaddition to form their cyclobutane core skeletons. We describe herein the biomimetic syntheses of racemic sceptrin and nakamuric acid. We also report the asymmetric syntheses of sceptrin, bromosceptrin, and dibromosceptrin in their natural enantiomeric form. We further provide mechanistic insights into the pathway selectivity of the SET-promoted [2+2] and [4+2] cycloadditions that lead to the divergent formation of the sceptrin and ageliferin core skeletons. Both the [2+2] and [4+2] cycloadditions are stepwise reactions, with the [2+2] pathway kinetically and thermodynamically favored over the [4+2] pathway. For the [2+2] cycloaddition, the dimerization of pyrrole-imidazole monomers is rate-limiting, whereas for the [4+2] cycloaddition, the cyclization is the slowest step.

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Figures

Fig. 1
Fig. 1
Sceptrins (1) and ageliferins (3) are formally the [2+2] and [4+2] cycloaddition products of hymenidin/oroidin (4). Nakamuric acid (2) is a pseudo-symmetric [2+2]-type pyrrole–imidazole dimer.
Fig. 2
Fig. 2
Design and proof-of-concept of our biomimetic synthetic strategy.
Fig. 3
Fig. 3
Preparation of the [2+2] cycloaddition precursor.
Fig. 4
Fig. 4
Construction of the cyclobutane core skeleton.
Fig. 5
Fig. 5
Synthesis of rac-nakamuric acid (2).
Fig. 6
Fig. 6
Synthesis of rac-sceptrin (1a).
Fig. 7
Fig. 7
Construction of the core skeleton of nat-sceptrins (1).
Fig. 8
Fig. 8
Synthesis of nat-sceptrin (1a).
Fig. 9
Fig. 9
Comparison of the CD spectra of sceptrins in water. Red, natural sceptrin•TFA in methanol; Blue, synthetic sceptrin•TFA from L-glutamic acid in water; Green, synthetic sceptrin•TFA from D-glutamic acid in water; Grey, synthetic dibromosceptrin•TFA from D-glutamic acid in water.
Fig. 10
Fig. 10
Energy diagram for the [2+2] and [4+2] cycloadditions of 4c•+/4c.
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