To highlight the advantage of the modular approach outlined above, the first total synthesis of neoSTX (4) was pursued. This natural product has been known since 1977 and has even been utilized in topical indications for pain in a phase 1 clinical study . The only means to access 4 is from natural sources or cell cultures. To our knowledge, no successful synthetic route (total or semi) to 4 has been disclosed. In our hands, attempted chemical oxidations of various intermediates towards 1 proved fruitless and reports of direct oxidative biocatalytic experiments on 1 were not promising . Scheme 2B illustrates how small permutations of the approach outlined in Scheme 1 could be enlisted to access both 4 and the related natural product dc-neoSTX (5). The key hurdle that needed to be overcome was the site-specific incorporation of oxygen onto one of the three nitrogen atoms within STXintermediate 33 (Scheme 1). This was accomplished by removal of the Fmoc group and in situ exchange with a PMB group through reductive amination to afford secondary amine 45.