The total synthesis of mandelalide A and its ring-expanded macrolide isomer isomandelalide A has been achieved. Unexpected high levels of cytotoxicity were observed with the ring-expanded isomandelalide A with a rank order of potency: mandelalide A > isomandelalide A > mandelalide B. Key aspects of the synthesis include Ag-catalyzed cyclizations (AgCC's) to construct both the THF and THP rings present in the macrocycle, diastereoselective Sharpless dihydroylation of a cis-enyne, and lithium acetylide coupling with a chiral epoxide.

Highly tractable 1-aryl-1-propynes, which are readily accessible via Sonogashira coupling, serve as chiral allylmetal pronucleophiles in ruthenium-JOSIPHOS-catalyzed anti-diastereoand enantioselective aldehyde (α-aryl)allylations with primary aliphatic or benzylic alcohol proelectrophiles. This method enables convergent construction of homoallylic sec-phenethyl alcohols bearing tertiary benzylic stereocenters. Both steric and electronic features of aryl sulfonic acid additives were shown to contribute to the efficiency with which a more selective and productive iodidebound ruthenium catalyst is formed. As corroborated by isotopic labeling studies, a dual catalytic process is operative in which alkyneto-allene isomerization is followed by allene-carbonyl reductive coupling via hydrogen auto-transfer. Crossover of ruthenium hydrides emanating from these two discrete catalytic events is observed. The utility of this method is illustrated by conversion of selected reaction products to the corresponding phenethylamines and the first total syntheses of the neolignan natural products (−)-crataegusanoids A−D.

Minireviews 684 www.angewandte.org Scheme 9. Vanderwal et al.:C 20 quaternary stereocenter and bicycle construction.T IPS = Triisopropylsilyl. Scheme 10. Vanderwal et al.:C7quaternary stereocenter and THP construction. m-CPBA = meta-chloroperoxybenzoic acid. Angewandte Chemie Minireviews Scheme 19. Zhao et al.:s ynthesis of (AE)-gelsedilam. LHMDS = lithium bis(trimethylsilyl)amide, TBAB = tetrabutylammonium bromide, AIB-N = a,a'-azobisisobutyronitrile. Angewandte Chemie Minireviews 693

The exploration into the scope of a silver-catalyzed cyclization (AgCC) of propargyl benzoates for accessing pyran ring systems has been reported. The impact of the degree of substitution, nature of the substitution on the carbon backbone/benzoate moiety, and stereochemistry has been evaluated. The application of this methodology to the synthesis of the C1-C12 southern fragment of madeirolide A is disclosed.

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