Studies towards the total synthesis of the spongistatins

• Main Author: Hodgson, A.
• Published: University of Cambridge 2001
• Subjects: 547.7
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604132

The spongistatins are a novel class of recently isolated marine macrolides exhibiting potent activity against a series of cancer cell lines, through inhibition of microtubule assembly. Progress towards the total synthesis of the spongistatins is described. In particular, the stereocontrolled syntheses of two fragments A and B are described, which employs boron-mediated aldol reactions and allylations. (Fig. 2890A) Fragment A incorporates the AB-spiroacetal ring system of the spongistatins and was derived from acetone and two chiral aldehydes, C and D. Selective deprotection of E occurred with concomitant spiroacetalisation. Oxidation of the C<SUB>9</SUB> alcohol followed by methyl addition to the resulting ketone and subsequent C<SUB>9</SUB>-hydroxyl protection led to A. (Fig. 2890B) Aldehydes C and D were obtained by a protection/oxidation sequence performed on the homoallylic alcohols F and G, which were obtained <I>via </I>Brown asymmetric allylation reactions (Fig. 2890C) Fragment B contains the chlorodiene sidechain of spongistatin 1 and a glucopyranose model F-ring system. Horner-Wadsworth-Emmons methodology was employed to synthesise chlorodiene aldehyde H <I>via</I> ester I (Fig. 2890D) Methyl ketone J was formed <I>via</I> enol ether addition to the trichloroacetimidate of benzyl protected D-glucose K, followed by equilibration to the desired anomer. 1,5-Stereoinduction in the boron-mediated aldol coupling of J with aldehyde H was explored using (+)- and (-)-Ipc<SUB>2</SUB>BC1 and (<I>c</I>C<SUB>6</SUB>H<SUB>5</SUB>)<SUB>2</SUB>BC1. Protection of the C<SUB>47</SUB> hydroxyl of aldol product L followed by methylenation completed fragment B (Fig. 2890E).