A stereoselective synthesis of the bis-guanidinium toxin (+)-saxitoxin (STX), the agent infamously associated with red tides and paralytic shellfish poisoning, is described. Our approach to this unique natural product advances through an unusual nine-membered ring guanidine intermediate 39 en route to the tricyclic skeleton that defines STX. The effectiveness of this strategy is notable, as only four steps are needed to transform 39 into the target molecule, including a four-electron alkene oxidation catalyzed by OsCl3. Construction of the critical monocyclic guanidine has been achieved through two channels, the first of which makes use of Rh-catalyzed C-H amination and highlights a novel class of heterocyclic N,O-acetals as iminium ion equivalents for crafting functionalized amines. A second route to 39 relies on a stereoselective acetylide dianion addition to a serine-based nitrone, thereby facilitating the preparation of STX in just 14 linear steps from commercial material.

An asymmetric synthesis of the bis-guanidinium poison, (+)-saxitoxin (STX), is described. Commencing from an N,O-acetal starting material made readily available through sulfamate ester C-H amination, the completed route to STX showcases the utility of oxathiazinane dioxide heterocycles for the assembly of polyfunctionalized amine derivatives. In the final preparative stages, an unusual nine-membered ring guanidine intermediate is oxidized selectively and made to undergo dehydrative cyclization to afford the tricyclic core of the natural product. Access to STX and related structures will provide unique pharmacological tools for the study of voltage-regulated Na+ ion channel proteins.

A new strategy for the synthesis of Buckybowls is presented and initial attempts to implement it are reported. This involves annulation of further rings onto polycyclic aromatic systems that prefer to be planar but have been "pre-bent" by the installation of a tether. Pyrenophane 2b reacts with TCNE and PTAD to give 1:1 and 1:2 adducts, respectively. The less strained pyrenophane 2c is unreactive toward TCNE but gives a 1:2 adduct with PTAD. Attempted electrophilic aromatic brominations of pyrenophane 2e under a variety of conditions were unsuccessful, as were attempts to brominate cyclophanediene 1c, the direct synthetic precursor of 2c. Tether cleavage and addition reactions occurred rather than substitution. In an effort to circumvent tether cleavage problems, [7]-, [8]- and [9](2,7)pyrenophanes 22b-d were prepared. However, attempted bromination and Friedel-Crafts acylations failed. Evidence for the fleeting existence of [6](2,7)pyrenophane 22a was also obtained. Comparison of structural data (X-ray and AM1 calculations) for the pyrenophanes 22a-d with their 1,n-dioxa analogues 2a-d indicates that the nature of the tether has a strong effect on the degree of bend in the pyrene moiety and this led to the identification of trioxapyrenophane 28 as the next target in the quest for increasingly bent pyrenes.

We report here the photophysical, electrochemical, and electrogenerated chemiluminescent studies of four new pyrenophanes. Comparison with the cyclic voltammogram obtained using the planar parent compound, pyrene, showed these bent-pyrene-containing cyclophanes have a shift in the thermodynamic reduction potentials to more negative values. AM1 semiempirical calculations support such findings in which the LUMO energy increased with the degree of nonplanarity. The HOMO energy, however, remained essentially unchanged for all the compounds in this study. The nonplanarity in these compounds resulted in a substantial decrease in fluorescence quantum yield as well as a slight red shift in both the absorption and emission spectra. In addition, unlike pyrene, no excimer emission was evident in the fluorescence spectra even at concentrations as high as 1 mM. However, the ECL spectra of all four pyrenophanes, produced by generating the anion radical in the presence of benzoyl peroxide as a coreactant, showed broad “excimer-like” emission in addition to the monomer emission observed at shorter wavelengths.