The Mukaiyama Aldol Reaction (MAR) has been an invaluable tool in the field of synthetic organic chemistry since it’s discovery in 1973.  The MAR produces a carbon-carbon bond which forms an aldol fragment, often a crucial chiral motif found in a plethora of biologically active natural products. The MAR adds structural complexity to molecules via the use of a Lewis acid activated electrophilic aldehyde in the presence of a silyl enol ether carbon nucleophile to induce carbon-carbon bond formation. Introducing “vinylogy” affords the reaction to take place at the highly desirable terminal position of the double bond system, giving rise to the Vinylogous Mukaiyama Aldol Reaction (VMAR). When this reaction is used in combination with a chiral auxiliary, the VMAR is a highly diastereoselective asymmetric method that delivers an aldol fragment framework found in countless natural products.  The precision of the VMAR allows for high functional group tolerance and variability. Thus, the stereoselective VMAR has become a benchmark reaction in the synthesis of natural products with interesting bioactivity.<br/> <br/>Extensive studies have been done on the MAR in regards to diastereoselectivity, Lewis acid effectiveness, and substituent effects.  However, there is a lack of detailed knowledge about the VMAR, which has the capability to produce the highly desired δ-hydroxy-α,γ-dimethyl-α,β-unsaturated carbonyl unit that is seen in many polyketide natural products. We will present our results into the VMAR methodology exploring the effects of varying Lewis acids, VMAR substrates, and the reaction with various aldehydes of different complexity. We will describe newly developed VMAR methods to produce the critical carbon backbones common in biologically active target molecules. This crucial work on the widely used VMAR paves the way for the more streamlined, stereoselective construction of highly substituted, polyoxygenated natural products.<br/>

New developments of the asymmetric vinylogous Mukaiyama aldol reactions

251st National Meeting (2016)

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