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

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

Scientists have now found a way to complete the synthesis of the molecule in 16 steps, starting with a chiral pool building block called (+)-enoxolone, which costs less than one euro per gram. Synthesis technology is presented V Science.

Staphylococcus aureus (staphylococcus) is a type of bacteria that lives quietly on our skin and nose. It usually causes no harm, but when it becomes invasive, it causes dangerous infections such as sepsis, pneumonia and many hospital-acquired infections. What makes it truly alarming is its growing antibiotic resistance, which can turn treatable infections into deadly threats.

Methicillin-resistant staphylococcus, or MRSA, has caused 130,000 deaths worldwide in 2021 alone. One promising way to fight antibiotic resistance by using small molecules for example (-)-spiroaspetrion A, which can make MRSA again sensitive to existing drugs.

Since the discovery of its therapeutic properties, scientists have been trying to develop effective strategies for synthesizing this molecule in the laboratory.

The main bottleneck was the formation of the spirobicyclo molecule.[3.2.2]nonane core. To build the spirobicyclic framework, quaternary centers must be formed at C8 and C2'. However, the highly functionalized nature of the polycyclic backbone that makes up the molecule forms a tight cage structure that prevents further modifications. It blocks chemical groups from accessing reactive sites and starting a reaction.

To overcome the structural obstacles, the researchers performed a Diels–Alder cycloaddition followed by a key divinylcyclopropane rearrangement (DVCPR). Instead of adding groups to an already crowded backbone, they created a flexible precursor molecule and heated it to 180°C. This heating caused the atoms to rearrange themselves and form a spirobicyclic-like cage.[3.2.2]nonane core in a single step, and this mechanism is further supported by density functional theory (DFT) calculations.

Once the basic structure of the target molecule was created, the researchers carefully added oxygen and other substances. functional groups in precise positions. Through a series of oxidation reactions, they obtained an aldehyde, which was then converted to (-)-aspermerodione. When this compound was heated with a base, it underwent a molecular rearrangement that closed the ring and formed the final product, (-)-spiroaspetrion A.

Although the yield was 2.3%, which is quite low, the study was able to completely synthesize the anti-MRSA compound starting from an inexpensive, commercially available precursor.

The researchers noted that through this process, they were able to gain a deeper understanding of the structures of other molecules in the natural product family. These results may help develop new compounds that can sensitize antibiotic-resistant bacteria to existing drugs.

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