The development of synthetic methodology using enantioselective organocatalysis promises the efficient generation of structurally diverse and functionally versatile molecules. The applications of the methodology are wide-ranging and this proposal aims to use enantioselective organocatalysis to address problems in both synthesis and chemical biology. This will offer a multi-disciplinary aspect to the proposed research and in particular we will use the molecular functionality to design cascade reactions for the innovative and rapid synthesis of bioactive natural products. Furthermore enantioselective catalysis can provide ideal building blocks the synthesis of structurally unbiased libraries that can be used to probe biological function or mode of action.
Alternatively, a more focussed approach using chemical genetics can be used to investigate biological function through the synthesis of natural product like libraries. We propose to develop an organocatalytic and enantioselective variant of this transformation that precludes the use of strong bases and avoids the competing 1,2-rearrangement and is mediated through the generation of a transient enamine motif via secondary amine catalysis. The use of homochiral substituted secondary amines should lead to the first catalytic enantioselctive sigmatropic rearrangement reaction. The potential applications of this reaction are widespread as the ability to install 2-vicinal stereo-centres embedded amongst up to 3-orthogonally reactive functional groups represents a powerful transformation. Applications to the synthesis of architecturally complex natural products will be investigated that exploit efficacy of the proposed new transformation.
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