How a Chemical Reaction Transformed Molecular Design
50 Years of Application in Organic Synthesis
In the intricate world of organic synthesis—where chemists craft complex molecules atom by atom—certain reactions stand out as particularly elegant tools. Among these is the Achmatowicz rearrangement, a chemical transformation that has quietly revolutionized how scientists build complex natural compounds and medicines. First reported fifty years ago by Polish chemist Osman Achmatowicz Jr., this reaction transforms simple furan-based molecules (readily available from agricultural waste) into sophisticated pyranones—key building blocks for many biological compounds 1 3 .
The rearrangement performs a skeletal transformation, elegantly rearranging atoms to create new architectures with perfect control over stereochemistry.
From its conception in a Warsaw laboratory to becoming an indispensable tool for chemists worldwide, enabling breakthroughs in medicine and biology.
At its core, the Achmatowicz rearrangement is an oxidative ring expansion that converts furfuryl alcohols into highly functionalized dihydropyranones 2 5 . The reaction elegantly rearranges the simple five-membered furan ring into a more complex six-membered pyran structure—a transformation that has been compared to a molecular dance where atoms gracefully reposition themselves into new configurations.
The furan ring in furfuryl alcohol is activated through electrophilic attack, typically using bromine or other oxidants
This creates a reactive 2,5-dihydrofuran intermediate
Under acidic conditions, this intermediate rearranges to form the valuable 6-hydroxy-2H-pyran-3(6H)-one structure
The resulting pyranone can be readily transformed into various sugar derivatives or complex natural product frameworks
| Step | Process | Key Transformation |
|---|---|---|
| 1 | Oxidation | Furan ring activation via electrophilic attack |
| 2 | Intermediate formation | Creation of 2,5-dihydrofuran structure |
| 3 | Acid-catalyzed rearrangement | Ring expansion to dihydropyranone |
| 4 | Functionalization | Conversion to sugars or natural product precursors |
Table 1: Key Steps in the Classical Achmatowicz Reaction 1 5
Furan Alcohol → Oxidation → Dihydrofuran Intermediate → Rearrangement → Pyranone Product
Achmatowicz's original protocol utilized bromine in methanol to achieve the initial oxidation, followed by treatment with dilute sulfuric acid to effect the rearrangement 5 .
Chemists developed numerous improved oxidation methods including singlet oxygen, m-CPBA, N-bromosuccinimide (NBS), metal-catalyzed oxidations, and electrochemical methods 6 .
Researchers discovered an enzymatic approach combining glucose oxidase and chloroperoxidase, operating under mild conditions using atmospheric oxygen 7 .
Bromine/methanol system with sulfuric acid treatment
m-CPBA, NBS, singlet oxygen, metal catalysts
GOx/CPO system with atmospheric oxygen
The development of a fully enzymatic Achmatowicz rearrangement represents one of the most significant advances in the field. This section details the groundbreaking experiment that demonstrated the feasibility of using biological catalysts for this traditionally chemical transformation 7 .
The research team designed an elegant biocatalytic system comprising two enzymes working in concert:
The enzymatic system demonstrated remarkable efficiency and selectivity:
| Method | Oxidizing System | Typical Yield (%) | Key Advantages | Limitations |
|---|---|---|---|---|
| Classical | Brâ‚‚/MeOH, then Hâ‚‚SOâ‚„ | 60-75 | Reliable, well-established | Bromine handling issues, moderate yields |
| m-CPBA | meta-chloroperbenzoic acid | 70-85 | Consistent results | Acid-sensitive groups incompatible |
| Singlet Oxygen | Photosensitizer + light | 65-80 | Very mild conditions | Requires special equipment |
| Enzymatic | GOx/CPO system | 75-90 | Green chemistry, excellent compatibility | Limited to certain substrate types |
This experiment demonstrated for the first time that complex synthetic rearrangements could be achieved using purely biological catalysts, opening new possibilities for sustainable chemistry. The research proved that enzymes could be recruited for transformations not found in natural metabolism, expanding the toolbox of biocatalysis far beyond traditional biochemical reactions 7 .
Moreover, the system's ability to use atmospheric oxygen as the ultimate oxidant and glucose as a cheap sacrificial reagent established a new paradigm in green chemistry for the valorization of biogenic furans—compounds derived from plant biomass 7 .
The experimental advances in Achmatowicz chemistry have been enabled by specialized reagents and materials. Here we detail the key components of the modern synthetic toolkit for this transformation:
| Reagent/Material | Function | Notes on Application |
|---|---|---|
| Furfuryl alcohols | Starting materials | Readily available from biomass; can be enantiomerically pure |
| N-Bromosuccinimide (NBS) | Bromine source | Safer alternative to elemental bromine |
| m-CPBA | Peroxide oxidant | Reliable for acid-stable substrates |
| Singlet oxygen systems | Photooxidant | Rose Bengal or tetraphenylporphyrin as photosensitizers |
| Glucose oxidase (GOx) | Hâ‚‚Oâ‚‚ generation | From Aspergillus niger; enables enzymatic oxidation |
| Chloroperoxidase (CPO) | Oxygen transfer | From Caldariomyces fumago; key to enzymatic rearrangement |
| Terf-butanol | Cosolvent | Enhves product stability in enzymatic system |
Table 3: Essential Research Reagents for Achmatowicz Chemistry 2 5 6
The rearrangement has played a pivotal role in the synthesis of numerous complex natural products with biological activity 1 :
Beyond natural product synthesis, the rearrangement has enabled access to medicinally relevant compounds:
Originally developed for the total synthesis of monosaccharides, the rearrangement continues to be valuable for preparing 1 3 :
Drug discovery and development
Probing biological systems
Sustainable synthesis methods
Conversion of renewable resources
Over fifty years, the Achmatowicz rearrangement has evolved from a specialized carbohydrate synthesis method to a versatile synthetic tool with applications across chemical biology, medicinal chemistry, and natural product synthesis. Its enduring value lies in its ability to efficiently construct molecular complexity from simple starting materials, often with exquisite control over stereochemistry.
Developing methods to create single enantiomer products with high selectivity
Creating new reaction variants for different molecular architectures
Designing improved biocatalysts for enhanced efficiency and substrate range
Developing continuous flow systems for industrial applications
The Achmatowicz rearrangement continues to be taught in advanced organic chemistry courses worldwide, inspiring new generations of chemists to explore creative synthetic solutions to complex molecular challenges.
The story of the Achmatowicz rearrangement exemplifies how a fundamental chemical discovery can grow and adapt over decades, continually finding new applications and improved methodologies. It stands as a testament to the creativity and persistence of the chemistry community—and a reminder that even after fifty years, important reactions still have new secrets to reveal and new contributions to make to science and society.
As we celebrate this golden anniversary, the Achmatowicz rearrangement continues to inspire chemists to explore new molecular frontiers, building ever more complex and functional structures from the simple beauty of a furan ring.