1466415-04-2Relevant articles and documents
Synthesis and biological activity of 7,8,9-trideoxy- and 7R DesTHP-peloruside A
Wullschleger, Christoph W.,Gertsch, Jürg,Altmann, Karl-Heinz
supporting information, p. 13105 - 13111 (2013/10/01)
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 IC50 values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity. I need the THP ring: Convergent stereoselective syntheses of mono- and bicyclic analogues 2 and 3 of the natural product mitosis inhibitor peloruside A (1) have been developed based on macrocyclization by ring-closing metathesis (2) or macrolactonization (3). Both analogues are less potent than natural 1, but the activity difference is distinctly less pronounced for bicyclic analogue 3. The bicyclic core structure of peloruside A thus appears to be a necessary, but not sufficient provision for peloruside A-like activity (IC50 = 2: 1-5 μM, 3: 100-300 nM). Copyright
