Total Synthesis, Structure, and Biological Activity of Adenosylrhodibalamin, the Non-Natural Rhodium Homologue of Coenzyme B12.

Florian J Widner,Klaus Wurst,Stefanie Frank,Karl Gruber,Bernhard Kräutler,Evelyne Deery,Andrew D Lawrence,Martin J Warren,Dana Heldt

doi:10.1002/anie.201603738

Abstract

B12 is unique among the vitamins as it is biosynthesized only by certain prokaryotes. The complexity of its synthesis relates to its distinctive cobalt corrin structure, which is essential for B12 biochemistry and renders coenzyme B12 (AdoCbl) so intriguingly suitable for enzymatic radical reactions. However, why is cobalt so fit for its role in B12‐dependent enzymes? To address this question, we considered the substitution of cobalt in AdoCbl with rhodium to generate the rhodium analogue 5′‐deoxy‐5′‐adenosylrhodibalamin (AdoRbl). AdoRbl was prepared by de novo total synthesis involving both biological and chemical steps. AdoRbl was found to be inactive in vivo in microbial bioassays for methionine synthase and acted as an in vitro inhibitor of an AdoCbl‐dependent diol dehydratase. Solution NMR studies of AdoRbl revealed a structure similar to that of AdoCbl. However, the crystal structure of AdoRbl revealed a conspicuously better fit of the corrin ligand for RhIII than for CoIII, challenging the current views concerning the evolution of corrins.

Highlights

B12 is unique among the vitamins as it is biosynthesized only by certain prokaryotes
The complexity of its synthesis relates to its distinctive cobalt corrin structure, which is essential for B12 biochemistry and renders coenzyme B12 (AdoCbl) so intriguingly suitable for enzymatic radical reactions
Why is cobalt so fit for its role in B12dependent enzymes? To address this question, we considered the substitution of cobalt in AdoCbl with rhodium to generate the rhodium analogue 5’-deoxy-5’-adenosylrhodibalamin (AdoRbl)

Summary

Introduction

B12 is unique among the vitamins as it is biosynthesized only by certain prokaryotes. AdoRhbad was synthetically accessible when contained resonances for all carbon-bound H atoms, includrhodibyrinic acid a,c-diamide was isolated as the dichloro- ing the characteristic doublet- and triplet-like signals at high substituted RhIII corrinoid (DCRhbad), which was character- field for the Rh-bound CH2 group of the Ado ligand ized by UV/Vis spectroscopy and mass spectrometry.

Results

Conclusion