Marshall and his co-workers used their asymmetric allenylmetal-homoaldol tactic to construct polypropionate frameworks of (+)-discodermolide. The novelty of the Marshall approach is that the three stereotriad subunits are assembled through addition of non-racemic allenylmetal reagents to (S)-3-silyloxy-2-methylpropanal to generate both syn/syn and syn/anti adducts. The central feature for the synthesis of the alkyl iodide fragment was the treatment of aldehyde to allenyltributylstannane in the presence of BF3-etherate to get the syn/syn isomer. Syn/anti methyl-hydroxyl-methyl stereotriads were obtained through the reaction between aldehyde and homochiral allenylzinc reagent.
In the Marshall synthesis, the coupling between the alkyne fragment to the aldehyde fragment proceeded in 92% yield, with 85:15 diastereoselectivity. The condensation of aldehyde with iodoethylidene triphenylphosphorane was the most challenging step, which produce 40% yield and an 85:15 inseparable mixture of (Z) and (E) isomers. The last coupling was performed via a Suzuki union of vinyl iodide with the boronate derived of alkyl iodide. The Marshall synthesis of (+)-discodermolide has an overall yield of 1.3% with a longest linear sequence of 30 steps and 48 total steps.