New molecular strategy achieves complete synthesis of anti-MRSA natural product (new antibiotics)

Good news! Amazing stuff! With machine learning & AI this will only get better!

Interesting: Most of the researchers involved in this study are from the Shanghai University of Traditional Chinese Medicine.

"Spiroaspertrione A is a complex polycyclic compound naturally produced by the fungus Aspergillus sp. TJ23. First isolated in 2017, it quickly drew scientific attention for its promising ability to combat drug-resistant bacteria and restore their sensitivity to existing antibiotics.

Scientists have now found a way to carry out the total synthesis of the molecule in 16 steps, starting from a chiral pool building block called (+)-enoxolone that costs less than one euro per gram. ..."

From the editor's summary and abstract:

"Editor’s summary

Spiroaspertrione A is a complex, polycyclic fungal natural product that has garnered interest in antibiotics research. Huang et al. now report a total synthesis of the compound in its natural stereoconfiguration starting from readily available precursors.

Key steps included a Diels-Alder reaction to set the compound’s characteristic spiro stereocenter, as well as a divinylcyclopropane rearrangement to establish an additional out-of-plane ring. The synthesis required 16 steps from a reported precursor and proceeded in an overall yield of 2.3%. ...

Abstract

The rise of multidrug-resistant pathogens poses a major threat to global health, with methicillin-resistant Staphylococcus aureus (MRSA) among the most challenging. One promising approach to overcoming resistance is using small molecules that resensitize MRSA to existing drugs.

Here, we report the enantioselective total synthesis of one such promising candidate, (−)-spiroaspertrione A, a complex meroterpenoid of the andiconin family. This natural product has long eluded synthesis because of its densely functionalized polycyclic backbone.

Our route features a stereoselective Diels-Alder cycloaddition, followed by a key divinylcyclopropane rearrangement forming the spirobicyclo[3.2.2]nonane core, which proved to be reversible and was further investigated by density functional theory calculations. Strategic late-stage functionalization of the compact cage architecture enabled access to the natural product and provided evidence for a plausible biosynthetic relationship with (−)-aspermerodione."

New molecular strategy achieves complete synthesis of anti-MRSA natural product

The total synthesis of (−)-spiroaspertrione A: A divinylcyclopropane rearrangement approach (no public access)

A new 16-step process enables total synthesis of (−)-spiroaspertrione A from a known intermediate.