In 2003, Paterson and co-workers  reported a strategy that relies heavily on substrate-derived stereocontrol. Instead of a reagent-controlled aldol reaction in Paterson first-generation synthesis, a dicyclohexylboron-mediated anti-aldol was used to connect C(5)-C(6), which leads to a significant increase in diastereoselectivity from 4:1 to 92:8. Notably, Still–Gennari modified Horner–Wadsworth–Emmons reaction was also used to construct the C(13)-C(14) trisubstituted olefin in early stage of this synthesis. The Paterson second-generation synthesis of (+)-discodermolide has an overall yield of 7.8% with a longest linear sequence of 24 steps and 35 total steps.
In 2004, Paterson and his co-workers disclosed the third-generation total synthesis of (+)-discodermolide. The stepwise method used in previous generations to incorporate the C(1)–C(8) subunit was replaced by a late-stage Still-Gennari olefination, which leads to a notable improvement in convergence. The Paterson third-generation synthesis of (+)-discodermolide has an overall yield of 11.1% (highest reported to date) with a longest linear sequence of 21 steps and 37 total steps.