A total synthesis of spirastrellolide A methyl ester

Area of Science:

• Organic Chemistry
• Marine Natural Products
• Total Synthesis

Background:

• Spirastrellolides are marine macrolides known for high cytotoxicity.
• Previous synthesis efforts focused on related compounds like spirastrellolide F methyl ester.
• A flexible synthesis plan was previously established by the group.

Purpose of the Study:

• To achieve a concise total synthesis of spirastrellolide A methyl ester.
• To expand the utility of a previously developed synthesis strategy.
• To investigate the structural requirements for cytotoxicity.

Main Methods:

• Strategic masking of the Δ(15,16)-bond as a C16-carbonyl group.
• Highly selective hydrogenation of a C24 exo-methylene precursor.
• Conformational control for stereochemical direction during reduction.
• Alkenyl triflate formation and palladium-catalyzed hydride delivery for double bond formation.
• Key coupling reactions: alkyl-Suzuki and Yamaguchi lactonization.
• Modified Julia-Kocienski olefination for lateral chain attachment.
• Methodological advancements in N-O-bond cleavage and ozonolysis.

Main Results:

• Successful concise total synthesis of spirastrellolide A methyl ester.
• Demonstrated flexibility of the established synthesis plan.
• Stereogenic center at C24 set via selective hydrogenation.
• Macrocyclic core and lateral chain assembled efficiently.
• Identified novel synthetic methodologies for specific transformations.

Conclusions:

• The total synthesis of spirastrellolide A methyl ester was achieved.
• The developed strategy is adaptable for related marine macrolides.
• Preliminary data suggest the entire carbon framework is crucial for cytotoxicity.