SYNTHETIC APPROACHES TO TETRODOTOXIN Controlling Diastereoselectivity with a cis-Decalin Ring System: Highlights of Kishi’s Synthesis Kishi’s racemic synthesis of tetrodotoxin began with a Lewis acid catalyzed Diels-Alder cycloaddition

INTRODUCTION Tetrodotoxin (Figure 1) is a naturally occurring compound isolated from the liver and ovaries of puffer fish. Due to its potent toxicity as a selective blocker of voltage-gated Na ion channels and the high regard for puffer fish as a culinary delicacy, tetrodotoxin has become a molecule of general, as well as scientific, interest. Structural determination revealed a densely functionalized dioxa-adamantane core containing an ortho-acid and a pendant guanidine. The challenging architecture, as well as a demand for structural analogues to study the mechanism of its action, make tetrodotoxin a synthetic target. The first total synthesis of racemic tetrodotoxin was accomplished by Kishi and co-workers in 1972. Since then, though recent attempts from many labs have been disclosed, the work of Du Bois and Isobe have provided the only two completed syntheses, each within the past year. This review will briefly summarize the Kishi synthesis and highlight recent approaches to the natural product.