Chemical Studies Toward the Total Synthesis of Lagunamide A Incorporating the Application of Diastereoselective Vinylogous Mukaiyama Aldol Reaction via Kinetic Resolution Methodology
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Chemical Studies Toward the Total Synthesis of Lagunamide A Incorporating the Application of Diastereoselective Vinylogous Mukaiyama Aldol Reaction via Kinetic Resolution Methodology

  • Author(s): Singh, Simranjeet
  • Advisor(s): Bergdahl, Mikael
  • et al.
No data is associated with this publication.
Abstract

Lagunamide A is a cyclic depsipeptide isolated from marine cyanobacterium Langbya majuscula from deep oceans of Pulau Hantu Besar, Singapore. Upon isolation it was revealed to be a potent antimalarial, cytotoxic against leukemia and colon cancer. Latest Structure Activity Relationship research shows Lagunamide A to be active against various cancer cells including A549, HeLa, U2OS, HepG2, BEL-7404, BGC-823, HCT116, MCF-7, HL-60, and A375; with IC50 values ranging from 4.7 nM to 19.8 nM. The diversity exemplifies the natural products potential for future therapeutics as other cyclic depsipeptides have in the past. The investigation of various Vinylogous Mukaiyama Aldol Reactions (VMAR) of β-oxyaldehydes led to the efficient construction of the polyketide carbon framework of Lagunamide A. Solution state synthesis of multiple peptides fragments of Lagunamide A were achieved to avoid epimerization of crucial stereocenters. The peptide portion and the polyketide framework were converged leading to precious intermediates. HR-MS data shows the detection of Lagunamide A although a modified synthetic route would be needed for larger quantities of the natural product. An investigation of Vinylogous Mukaiyama Aldol Reaction was done to test if kinetic resolution could be achieved using Kobayashi’s protocol. An unexplored territory of VMAR is reacting vinylketene N,O-acetal with a racemic mixture of aldehydes to produce stereotriades. Differences in selectivity were observed depending on the size of α-substitutions. Single diastereomers of stereotriades can be produced using this platform of VMAR.

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This item is under embargo until April 20, 2023.