Artem Kireev - Synthesis of Structurally Simplified Analogues of Pancratistatin: Truncation of the Cyclitol Ring

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      Publication Details (including relevant citation   information):

      J. Org. Chem. 2009, 74, 7122.

      Abstract:

      Pancratistatin is a phenanthridone-type natural product isolated   from  several plants of the Amaryllidaceae family. Its   potent  antiproliferative, antivascular, antiviral, and   antiparasitic properties  have attracted the attention of   synthetic, biological, and medicinal  chemists.   Pancratistatin’s low natural availability and complex    structure have steered many of these research projects toward   the  preparation of its simplified synthetic analogues with   useful levels of  activity. In this work we have developed   synthetic chemistry aimed at  the preparation of   pancratistatin analogues with a truncated cyclitol  portion   of the molecule. The described synthetic pathways are based on   a  highly anti-diastereoselective arylcuprate   conjugate addition to γ-alkoxy-α,β-enoates and   syn-selective  azidation at the α-position of ester   enolates. Analogues with the  formally cleaved C3−C4 bond,   and thus containing an open ring C, as well  as a compound   containing a truncated lactol moiety in lieu of the    cyclitol, were prepared. Several of the analogues exhibited   weak  antiproliferative activity, with the highest potency   observed in the  case of the lactol analogue. From these   results implications for the  design of future   pancratistatin analogues are discussed. Furthermore,  the   synthetic pathways can be used to construct   pancratistatin-mimetic  libraries, in which the cyclitol   moiety is replaced by other cyclic  motifs.

      Address (URL): http://pubs.acs.org/doi/abs/10.1021/jo901494r