Catalytic Asymmetric Polyene Cyclization of Homofarnesol to Ambrox: A Challenging Synthetic Transformation Achieved

Concetti Chiave

Chemists have achieved a diastereoselective and enantioselective synthesis of the valuable natural product (−)-ambrox and (+)-sclareolide through a catalytic asymmetric polyene cyclization using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols.

Sintesi

The content discusses the significant challenge of achieving precise control over product distribution and stereochemistry in polyene cyclizations, a complex and challenging transformation in biology. The authors report a diastereoselective and enantioselective synthesis of the valuable naturally occurring ambergris odorant (−)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide through a catalytic asymmetric polyene cyclization.

The key aspects of the synthesis are:

• The use of a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols.
• Deuterium-labelling studies suggest the reaction predominantly proceeds through a concerted pathway in line with the Stork–Eschenmoser hypothesis.
• Mechanistic studies highlight the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Statistiche

Polyene cyclizations are among the most complex and challenging transformations in biology.
The polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (−)-ambrox is recognized as a longstanding challenge in chemical synthesis.

Citazioni

"Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists."
"Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations."

Approfondimenti chiave tratti da

The catalytic asymmetric polyene cyclization of homofarnesol to ambrox - Nature

by Na Luo,Mathi... alle www.nature.com 07-31-2024

https://www.nature.com/articles/s41586-024-07757-7

Domande più approfondite

What other complex natural products could be synthesized using this catalytic asymmetric polyene cyclization approach?

The catalytic asymmetric polyene cyclization approach described in the context could potentially be applied to synthesize a wide range of complex natural products. For instance, molecules with intricate ring systems and multiple stereocenters, such as sesquiterpenes, diterpenes, and polyketides, could be targeted using this methodology. Compounds like artemisinin, taxol, and gibberellins, known for their biological activities and structural complexity, could be potential candidates for synthesis through this approach.

How do the selectivity and efficiency of this synthetic approach compare to enzymatic polyene cyclizations in nature?

The selectivity and efficiency of the catalytic asymmetric polyene cyclization approach described in the context can be comparable to enzymatic polyene cyclizations in nature. Enzymes in biological systems exhibit remarkable selectivity and efficiency in catalyzing complex transformations, including polyene cyclizations. The synthetic approach mimics the enzyme-like microenvironment through the use of a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst, leading to exceptionally high selectivities. While enzymatic reactions in nature are highly evolved and specific to their substrates, the synthetic approach demonstrates the potential to achieve similar levels of selectivity and efficiency in challenging organic transformations.

What insights from this work could be applied to improve the design of artificial enzymes or other catalysts for challenging organic transformations?

The insights gained from this work on catalytic asymmetric polyene cyclization can be instrumental in improving the design of artificial enzymes or other catalysts for challenging organic transformations. By understanding the importance of the enzyme-like microenvironment in achieving high selectivities, researchers can focus on developing catalysts that provide a similar confined and tailored reaction environment. Additionally, the use of fluorinated alcohols in the reaction system highlights the significance of solvent effects on catalysis, which could be further explored in designing artificial enzymes. Furthermore, the mechanistic studies emphasizing the concerted pathway and the Stork–Eschenmoser hypothesis offer valuable information for designing catalysts that operate through similar mechanisms, paving the way for more efficient and selective synthetic transformations.