Harnessing the Substrate Promiscuity of Dioxygenase AsqJ and Developing Efficient Chemoenzymatic Synthesis for Quinolones

Nature
has developed complexity-generating reactions within natural
product biosynthetic pathways. However, direct utilization of these
pathways to prepare compound libraries remains challenging because
of limited substrate scopes, involvement of multiple-step reactions,
and moderate robustness of these sophisticated enzymatic transformations.
Synthetic chemistry offers an alternative approach to prepare natural
product analogues. However, because of complex and diverse functional
groups appended on the targeted molecules, dedicated design and development
of synthetic strategies are typically required. Herein, by leveraging
the power of chemoenzymatic synthesis, we report an approach to bridge
the gap between biological and synthetic strategies in the preparation
of quinolone alkaloid analogues. Leading by in silico analysis, the predicted substrate analogues were chemically synthesized.
The AsqJ-catalyzed asymmetric epoxidation of these substrate analogues
was followed by a Lewis acid-triggered ring contraction to complete
the viridicatin formation. We evaluated the robustness of this method
in gram-scale reactions. Lastly, through chemoenzymatic cascades,
a library of quinolone alkaloids is effectively prepared.