Lagunamide A is a novel cyclic depsipeptide obtained from the marine cyanobacterium Lyngbya majuscula that shares structural elements with known potential therapeutics. Expressing impressive IC₅₀ values against leukemia (6.4 nM) and Ileocecal colon cancer (1.6 nM) cell lines, as well as antimalarial activity (0.19-0.91μM), lagunamide A is a highly desired, potent, cytotoxic, structurally complex natural product in need of a streamlined, efficient, economical total synthesis. The crucial C27-C45 chiral fragment of the molecule contains a δ-hydroxy-α,γ- dimethyl-α,β-unsaturated carbonyl unit that is seen in similar biologically-active polyketide natural products. Synthesis of the southern hemisphere of the molecule, the C27-C45 segment, was completed in two efficient asymmetric routes. Two highly asymmetric vinylogous Mukaiyama aldol reactions (VMAR) were used in order to set the contiguous stereocenters with excellent diastereomeric and enantiomeric ratio. The total synthesis of the 26-membered macrocyclic depsipeptide was proposed and an optimized route converging the northern and southern hemispheres of the molecule was performed. The synthesis employed solid phase peptide synthesis, N-methylation of both L and D forms of amino acids, inversion of stereochemistry using Mitsunobu technology, and two iterative VMAR’s. The VMAR is a highly diastereoselective, asymmetric method that incorporates a Lewis acid-activated electrophilic carbonyl in the presence of a vinyl silyl enol ether (VSEE) carbon nucleophile to deliver an aldol fragment, a framework that is found in countless natural products. Incorporation of a chiral directing group afforded an unprecedented degree of remote (1,7- and 1,6,7-) asymmetric induction to this robust reaction. Results from the investigation of the effects of varying Lewis acids, achiral and chiral auxiliaries, silyl enol ethers, aldehydes of varying complexity, and diastereomeric studies of racemic mixtures of a-substituted and unsubstituted aldehydes led to a proposed transition state model for the VMAR, a powerful technique widely employed in the synthesis of biologically active natural products.