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. 2010 Nov 19;75(22):7505-13.
doi: 10.1021/jo1010203. Epub 2010 Jul 29.

Total synthesis and evaluation of phostriecin and key structural analogues

Christopher P Burke  1 , Mark R Swingle, Richard E Honkanen, Dale L Boger
Affiliations

Total synthesis and evaluation of phostriecin and key structural analogues

Christopher P Burke et al. J Org Chem. .

Abstract

Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, both inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12-C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective).

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Figures

FIGURE 1
FIGURE 1
Natural product structures
FIGURE 2
FIGURE 2
Assignment of relative and absolute stereochemistry
FIGURE 3
FIGURE 3
Retrosynthetic plan for sultriecin (1)
FIGURE 4
FIGURE 4
Diagnostic region of 1H NMR of 1 and 2
FIGURE 5
FIGURE 5
Protein phosphatase activity (IC50,μM)
SCHEME 1
SCHEME 1
SCHEME 2
SCHEME 2
SCHEME 3
SCHEME 3
SCHEME 4
SCHEME 4
SCHEME 5
SCHEME 5
Synthesis of sultriecin (1)
SCHEME 6
SCHEME 6
Synthesis of phostriecin (2)
SCHEME 7
SCHEME 7
Synthesis of analogues 45 and 48
SCHEME 8
SCHEME 8
Synthesis of analogues 55 and 58
SCHEME 9
SCHEME 9
Synthesis of analogue 65
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