Synthesis of macrocyclic precursors of lankacidins using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure

Christopher T. Brain, Anqi Chen, Adam Nelson, Nongluk Tanikkul, Eric J. Thomas

    Research output: Contribution to journalArticlepeer-review

    Abstract

    In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones and their participation in Stille coupling reactions have been investigated. 1-tert-Butyldimethylsilyl-4-(2-iodoethenyl) azetidinone was found to undergo a Stille coupling reaction with a 3-hydroxy-1-tributylstannylhepta-1,5-diene to give an acceptable yield of the corresponding conjugated diene but the analogous reaction with a 3-tert-butyldimethylsilyloxy-1-tributylstannylhepta-1,5-diene was unsuccessful. A series of 4-[(E)-2-iodoprop-1-enyl]azetidinones, a ring-opened ester and a lactone were also found to undergo Stille reactions with 3-tributylstannylprop- 2-enol albeit with variable yields. Asymmetric syntheses of methyl (2R,3R,5S)-3-tert-butyldimethylsilyloxy-2-methyl-5-(2-trimethylsilylethoxy) methoxy-6-oxohexanoate, (3R,4S)-1-tert-butyldimethylsilyl-4-[(E)-2-iodoprop-1- enyl]-3-methylazetidin-2-one, and (5S,2E,6E)-5-tert-butyldimethylsilyloxy-2- methyl-1-phenylsulfonyl-7-tributylstannylhepta-2,6-diene and their incorporation into macrocyclic precursors of the lankacidins were then investigated. Key reactions were a Julia reaction between the aldehyde and the sulfone to form the 12,13-double-bond, a stereoselective acylation of the azetidinone, and formation of macrocycles using intramolecular Stille reactions in the presence of a free hydroxyl group at C(8) (lankacidin numbering). Intramolecular Stille reactions have been used to prepare advanced intermediates for a proposed synthesis of lankacidin C. © 2010 Elsevier Ltd.
    Original languageEnglish
    Pages (from-to)6613-6625
    Number of pages12
    JournalTetrahedron
    Volume66
    Issue number33
    DOIs
    Publication statusPublished - 14 Aug 2010

    Keywords

    • Chemoselectivity
    • Macrocyclization
    • Natural products
    • Palladium catalyzed coupling
    • Stereoselectivity
    • Total synthesis

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