SmI2‐induced cyclizations and their applications in natural product synthesis

Since the isolation of brevetoxin‐B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans‐fused polycyclic ether ring systems have been reported. We have developed SmI₂‐induced cyclization of β‐alkoxyacrylate with aldehyde, affording 2,6‐syn‐2,3‐trans‐tetrahydropyran (THP) or 2,7‐syn‐2,3‐trans‐oxepane with complete stereoselection, as a key reaction of efficient iterative and bi‐directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3‐, 5‐, and 6‐methyl‐THPs and 3,5‐dimethyl‐THP. The synthesis of 2‐methyl‐ and 2,6‐dimethyl‐THPs was accomplished by means of a unique methyl insertion. Recently, the SmI₂‐induced cyclization was extended to similar reactions using β‐alkoxyvinyl sulfone and sulfoxide. Reaction of (E)‐ and (Z)‐β‐alkoxyvinyl sulfone‐aldehyde afforded 2,6‐syn‐2,3‐trans‐ and 2,6‐syn‐2,3‐cis‐ THPs, respectively. Reaction of (E)‐β‐alkoxyvinyl (R)‐ and (S)‐sulfoxides gave 2,6‐anti‐2,3‐cis‐ and 2,6‐syn‐2,3‐trans‐THPs, respectively. Reaction of (Z)‐β‐alkoxyvinyl (R)‐sulfoxides gave 2,6‐syn‐2,3‐cis‐THP and an olefinic product, while that of (Z)‐β‐alkoxyvinyl (S)‐sulfoxide afforded a mixture of many products. These SmI₂‐induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin‐B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 159–172; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900027