Ladder polyether synthesis via epoxide-opening cascades using a disappearing directing group

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Synthetic Methodology

Background:

• Ladder polyether natural products are a significant class of complex molecules with diverse biological activities.
• Their intricate structures, characterized by multiple tetrahydropyran rings, present considerable synthetic challenges.
• Understanding and emulating biosynthetic pathways is crucial for efficient synthesis.

Purpose of the Study:

• To develop a novel synthetic strategy for constructing the tetrad of tetrahydropyran rings common in ladder polyether natural products.
• To emulate the final steps of Nakanishi's proposed biosynthetic pathway.
• To achieve the synthesis of ladder polyether subunits devoid of directing groups.

Main Methods:

• A cascade reaction involving a trimethylsilyl group, a Brønsted base, and a fluoride source in a hydroxylic solvent.
• Utilizing a series of epoxide-opening events.
• Employing conditions that lead to the disappearance of the trimethylsilyl group during the reaction.

Main Results:

• The first successful construction of the tetrad of tetrahydropyran rings, a key structural motif in ladder polyether natural products.
• Demonstration of a cascade of epoxide-opening events that effectively mimics a proposed biosynthetic pathway.
• Generation of ladder polyether subunits lacking any directing groups, a significant advancement in synthetic efficiency.

Conclusions:

• The developed cascade reaction provides an efficient and novel route to key subunits of ladder polyether natural products.
• This method successfully emulates a proposed biosynthetic pathway, offering insights into natural product formation.
• The absence of directing groups in the final products simplifies further synthetic elaborations.