Halichondrin Macrolide Synthesis via Macrocyclization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for synthesizing halichondrin B and its analogs are limited by inefficient macrocyclization reactions, which hinder the production of pharmaceutically active macrolide compounds.
Innovation Solution
The method involves performing macrocyclization reactions on non-macrocyclic intermediates using organic bases and Lewis acids, or olefin metathesis catalysts, to form specific bonds in the halichondrin macrolide structure, such as C.2-C.3, C.3-C.4, C.12-C.13, C.15-C.16, C.19-C.20, or C.26-C.27 bonds, employing compounds like DBU, triethylamine, ruthenium-carbene complexes, and Cr(II) or Ni(II) salts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional macrocyclization methods are used in the synthesis of halichondrin B, then the synthesis process can proceed, but the reaction efficiency is low and the yield is limited
Solution Approach 1:
The patent employs multiple parameter changes including using different bases (DBU, triethylamine, pyridine), various Lewis acids (LiCl, ZnCl2, BF3·OEt2), and different solvents to optimize the macrocyclization reaction conditions. These parameter adjustments enable efficient formation of macrocyclic intermediates with improved yields compared to conventional methods
Solution Approach 2:
The patent uses specific intermediates with predetermined structures (compounds of formula I with various protecting groups and functional groups) that facilitate the macrocyclization reaction. These intermediates act as mediators that enable controlled bond formation at specific positions (C.2-C.3, C.3-C.4, C.12-C.13, etc.) to produce the macrocyclic structure with high efficiency
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables the efficient synthesis of macrocyclic intermediates, facilitating the production of halichondrin macrolides and its analogs, thereby overcoming the limitations of previous synthesis methods and enhancing the yield of these potent anticancer agents.
Implementation Method 1
contacting the non-macrocyclic intermediate with an organic base and a Lewis acid
Implementation Method 2
macrocyclization reaction producing the macrocyclic intermediate by forming C.2-C.3, C.3-C.4, C.12-C.13, C.15-C.16, C.19-C.20, or C.26-C.27 bond
Implementation Method 3
contacting the non-macrocyclic intermediate with an olefin metathesis catalyst (e.g., a ruthenium-carbene complex)
Implementation Method 4
contacting the non-macrocyclic intermediate with a Cr(II) salt and a Ni(II) salt
Data Source
AI summary
The invention provides methods for the synthesis of a halichondrin macrolides through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic macrolide. The invention also provides compounds useful as intermediates in the synthesis of a halichondrin macrolides and methods for preparing the same.