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Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7 R DesTHP‐Peloruside A
Author(s) -
Wullschleger Christoph W.,
Gertsch Jürg,
Altmann KarlHeinz
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201301796
Subject(s) - stereoselectivity , stereochemistry , tetrahydropyran , chemistry , bicyclic molecule , aldehyde , moiety , ether , diastereomer , prins reaction , ring (chemistry) , organic chemistry , catalysis
The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐ syn and ‐ anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐ syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC 50 values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for n M biological activity.