The First Total Synthesis of a Macrocyclic Anti-protozoan, LL-Z1640-2

Abstract

Anti-protozoan, LL-Z1640-2 has been stereoselectively synthesized from d-ribose through Sonogashira coupling, Tsuji hydrogenolysis, and Mukaiyama lactonization.

Resorcylic acid lactones as new lead structures for kinase inhibition

“…The first total synthesis of a cis-enone-containing resorcylic acid lactone was reported by Tatsuta and co-workers in 2001 for LL-Z1640-2 (1) [31]. As illustrated in Scheme 1, the key elements of the retrosynthesis conceived by Tatsuta for this target structure included the Mukaiyama macrolactonization reaction of a protected seco acid LL-I, introduction of the E double bond between C1 0 and C2 0 through reductive double bond isomerization of the Z-configured allylic carbonate LL-II, and the construction of the aliphatic/aromatic bond connection between C6 and C1 0 through Sonogashira coupling between L-III and LL-IV.…”

“…This was followed by pivaloylation of the primary hydroxyl group and removal of the TMS group with TBAF to provide propargylic alcohol 9 in 48% overall yield (from 8). Although the stereochemical outcome of the acetylide addition remains inconsequential, due to the reductive removal of the propargylic hydroxyl group later in the synthesis, it should be noted that the reaction proceeded with high selectivity (only ''traces'' of a second isomer were observed [31]). Alkyne 9 underwent smooth Sonogashira coupling with iodide 10 in the presence of Pd(OAc) 2 , CuI, and Ph 3 P to furnish, after ethoxycarbonylation of the free hydroxyl group, compound 11 in excellent overall yield (83%).…”

Total syntheses of bioactive natural products from carbohydrates

“…The lactone 84 was methylated stereoselectively by Michael addition with MeMgBr [112,113] in the presence of CuBr Á Me 2 S and TMSCl to give 102 as a single isomer. Reduction with LiAlH 4 afforded acyclic diol 103, which was transformed to give the segment 104 in several steps.…”

Acetylenosaccharides

“…Intramolecular substitution then provided (with inversion of configuration) the b-d-mannofuranosylacetylene 74. Although additions to pyranoses have also been described (see, for example, [60,120,121]), the ring-closing reaction has only been used for the preparation of glycofuranosylacetylenes. The glucopyranosyl hydroxylamine 75 was transformed via the tautomeric hydroxynitrone into the propargylic hydroxylamines 76a and 76b [122], and the 2-hydroxypyrrolidine 77 was selectively converted into the hydroxy tosylamide 78 [123].…”

“…Sonogashira coupling of acetylenosaccharides with iodo-and (triflyloxy)benzenes gave mono-to tetraalkynylated benzenes (see 81 in Scheme 5.18, and 237 and 238 in Scheme 5.53) [121,131,268,269]. Enynes were obtained by Sonogashira coupling of iodoalkenes with acetylenosaccharides [270,271].…”