In 1995, Smith and his co-workers reported the second total synthesis of (-)-discodermolide. Smith adapted the triply convergent strategy of the Schreiber synthesis. In Smith's strategy, all three fragments shared a common precursor, which was the product of a highly efficient 50g scale five-step conversion from 3-hydroxy-2-methylpropionate with 59% yield. An Evans syn aldol reaction was utilized to obtain the desired stereochemical outcome.
The synthesis of fragment A, alkyl iodide, applied the Evans' acyl oxazolidinone method. After hydroxyl protection and reductive removal of the chiral auxiliary, an iodination was carried out to afford fragment A. The preparation of fragment B began with TBS protection and DIBAL reduction. The resulting aldehyde can be converted to desired Z-trisubstituted vinyl halide with 6:1 selectivity. The key feature of the synthesis of fragment C was the addition of the anion derived from dithiane to benzyl glycidyl ether.
Palladium(0)-mediated crosscoupling of vinyl iodide with the organozinc derivative of alkyl iodide afford product in 66% yield. After a two-step conversion to the corresponding phosphonium salt, Wittig union of phosphonium salt with aldehyde, fragment C, proceeded in 76% yield and good selectivity. The last feature of this synthesis was the titanium-mediated installation of the diene. The smith synthesis of (-)-discodermolide has an overall yield of 2.0% with a longest linear sequence of 29 steps and 42 total steps.