Mechanistic Investigation of 1,5-Anti Stereoinduction in Aldol Reactions

Peloruside A (+)-1 is a novel secondary metabolite isolated from a New Zealand marine sponge (Mycale hentscheli) by Northcote and West of Victoria University. Because it has a polyketide backbone, aldol reactions have been widely employed for its total synthesis. Aldol reactions displaying 1,5-anti stereoinduction mediated by the C₁₅ stereocenter (according to peloruside A numbering) have proven useful for the synthesis of the C₁₁–C₁₂ bond of peloruside A and analogues. This project is the continuation of Stocker's and Turner's studies on the excellent stereoinduction of 2 in boron-mediated aldol reactions. The relative stereochemistry of the corresponding aldol product is consistence with the expectations of Kishi's C database for a 1,5-anti product. Furthermore, the diphenylsilyl acetal tethered eight-membered ring of 2 has proven to be essential for its stereoinduction, while the homoallylic oxygen does not appear to play a significant role.  Although 1,5-anti aldol reactions have been used frequently in the syntheses of polyketidederived natural products, the underlying mechanism for the 1,5-anti-stereoinduction remains inconclusive. Three models have been proposed, including Hoberg's π-stacking model, Goodman's hydrogen-bonding model, and a modification of Abiko's diborylated model. The underlying mechanism for the stereoinduction of 2 was investigated using variable temperature NMR, 1D NOESY and 1D ROESY experiments. It was found that Hoberg's and Abiko's models are not able to explain the stereoinduction of 2 and that Goodman's model used for explaining the transition states of the aldol reaction of β-trimethylsilyloxy methyl ketones is also not suitable.  A modification of Goodman's model has been proposed to explain the excellent 1,5-anti stereoinduction of 2. While attempts to couple 2 and 3 to a variety of bulky aldehydes bearing groups with different steric and electronic factors in boron-mediated aldol reactions were unsuccessful, the reaction of 3 with 4-bromobenzaldehyde using TiCl₄ and DIPEA afforded an excellent yield (>99%) of the aldol product. This revealed the six-membered ring in the TS of the boron-mediated aldol reaction is too compact for 2 and 3. However, it was found that 2 is incompatible with TiCl₄. Key questions regarding the 1,5-anti-stereoinduction of 2 have been answered and a modified procedure for the NMR investigation of an aldol reaction is described in this thesis.