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Dissymmetrical Double-Chain Elongation Approach to the Asymmetric Synthesis of Long-Chain Polypropionates

By Claudia Jana Exner


Polyketides show interesting biological activities and therefore represent an important class of natural products. The necessity of their diastereo- and enantioselective synthesis led to the development of numerous methodologies. A brief overview of this topic is presented. The research carried out in our group has led to the development of a C-C-bond forming reaction involving Umpolung of a chiral, electron rich 1,3-dioxy-1,3-diene due to hetero-Diels-Alder reaction with sulphur dioxide. The so-formed six-membered sultines (6-alkoxy-3,6-dihydro-1,2-oxatiin-2-oxides) can be ionized into a zwitterion in the presence of a Lewis acid promoter, which can be trapped by nucleophiles, e.g. enoxy- or allylsilanes, to generate the corresponding alkenylsulfinates. Protolysis of the latter to sulfinic acids initiates retro-ene desulfitation to produce polyketide- or polypropionate fragments. Studies towards the influence of electronic and steric effects on the diastereoselectivity of the SO2-reaction cascade between 1,3-dioxy-1,3-dienes and enoxysilanes have been performed. A novel series of chiral, p-substituted 1-arylethoxy-3-acyloxy-1,3-dienes has been synthesised and their reactivity and diastereoselectivity in the SO2-cascade has been studied. Enoxysilanes and silyl-based Lewis acid promoters of different steric bulk have been employed in the SO2-cascade with the aim to improve the diastereoselectivity of the reaction. The utility of the SO2-methodology is demonstrated by the short and selective synthesis of several natural and unnatural δ-lactones with various relative configurations from the same starting materials (stereodiversity). The stereoselectivity of the reaction cascade has been verified to be governed exclusively by the chiral auxiliary, even in the presence of additional stereocentres. The methodology has been extended to the synthesis of pseudo-C2- or -CS-symmetrical, long-chain polyketide precursors via bidirectional elongation strategy, either through multistep or one-pot operations employing 1,3-dienes of the novel series and allylsilanes in the first case or allylbissilanes in the second. The so-obtained products are readily desymmetrised and have been shown to undergo selective chain elongations in both directions, which allow for the selective formation of advanced polyketide fragments

Publisher: Lausanne, EPFL
Year: 2010
DOI identifier: 10.5075/epfl-thesis-4756
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