Natural products Mukaiyama aldol reaction, diastereoselective

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

The directed aldol reaction in the presence of TiC found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anft-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47]. 

While substantial utility has been demonstrated for the Mukaiyama aldol reaction in diastereoselective natural product syntheses, more recent research efforts have been focused on the development of catalytic enantioselective variants of the reaction. These enantioselective variants of the reaction have provided creative solutions to problems associated with stereocontrolled syntheses of molecules of polyacetate origin. A wide range of chiral Lewis acid and Lewis base catalysts have been developed that exhibit high levels of enantioselectivity in the Mukaiyama aldol reaction. While the list is certainly not exhaustive, some such catalysts are shown below (65-72). 

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