Complex aldol reactions for polyketide synthesis: I. Total synthesis of callipeltoside A. II. Synthesis of the carbon(27)-carbon(48) subunit of Aflastatin A

I. The enantioselective total synthesis of the marine macrolide callipeltoside A is described. The convergent synthesis strategy divided the macrolide into three main fragments: a chlorocyclopropanecontaining enyne phosphonate, a highly functionalized deoxyamino sugar and a 14-membered macrolactone. A diastereoselective cyclopropanation of a vinyl reactive carbenoid developed by Shi was pivotal in the construction of chloride using a the phosphonate fragment. An anti-Felkin-selective aldol addition of an oxygenated enolate to a methyl ketone was used to prepare the sugar fragment in an expedient manner. A second-generation synthesis of the macrolactone fragment was highlighted by an enantioselective vinylogous aldol reaction to define the C10--C 11 olefin geometry and the C13 stereochemistry. An anti-selective beta-ketoimide aldol reaction, influenced by remote induction, and a Felkin-selective Mukaiyama aldol addition completed the stereoarray of this fragment, which was macrolactonized with inversion using an SN2 displacement of a mesylate at C 13. A mild glycosylation was used to join the sugar and macrolactone fragments, and a trans-selective Horner-Wadsworth Emmons reaction with the phosphonate sidechain completed the synthesis. The relative and absolute stereochemistry of callipeltoside A were confirmed by coupling with both enantiomers of the phosphonate and comparison with published data for the natural material.*; II. A convergent synthesis of the C27--C 48 fragment of the polyketide natural product aflastatin A is described. This subunit contains two polyol regions, where oxygenation is present on contiguous atoms: C27--C31 and C32--C 36. An anti-selective anti-Felkin aldol addition of an oxygenated enolate to an alpha,beta-oxygenated aldehyde was used to generate the anti-syn-anti stereotetrad of the C32--C36 region. The synthesis of the C27--C35 subfragment was highlighted by a diastereoselective [3+2] cycladdition of a nitrile-oxide to an allylic alcohol to set the C31 stereocenter. The C28--C30 stereotriad was constructed using an auxiliary-controlled aldol addition of a glycolate enolate to an alpha-oxygenated aldehyde.*; *Please refer to dissertation for diagrams.