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Methodology for and Synthesis of Highly Congested Molecules

Final Report Summary - VICQUAT (Methodology for and Synthesis of Highly Congested Molecules)

The aim of this project was to develop a reaction between two achiral molecules which generates high levels of molecular complexity by forming up to two carbon-carbon bonds, one carbon-oxygen bond and four stereocentres including three adjacent quaternary stereocentres and vicinal all carbon quaternary stereocentres in one pot. The applied methodologies were to be used in complex molecule synthesis, in particular in the synthesis of the core of of a highly complex terpenoid natural product.

In phase 1 of the project methodologies were developed involving a conjugate addition onto an alkylidene malonate, followed by an oxidative radical cyclisation, in the presence of a single electron oxidant, while the second method was a cascade anionic reaction. Several strategies to have access to the necessary cyclic substrate required for a polycyclisation were developed without success. Due to the synthetic route to the original cyclic substrates proving to be more challenging than expected, it was deemed prudent to investigate and develop the conjugate addition/cyclisation methodology with readily prepared acyclic substrates and then further investigate the preparation of cyclic substrates. The cascade sequence of reactions has therefore been applied to several substituted alkenes using a number of Grignard and organolithium reagents in the presence of copper(I) for the conjugate addition step. A large number of bicyclic lactones have been synthesized with good yield and good diastereocontrol. These results are currently being prepared for publication.

In phase 2 of the project, and having completed the modified substrate study, the preparation of the cyclic cyclisation substrates was reinvestigated according to a modified cyclopentene annulation strategy. The cyclic substrate could be synthesized using this strategy, however the last step allowing the introduction of the alkylidene malonate by a Knoevenagel condensation did not work efficiently despite several conditions being evaluated. The synthesis of the target substrate was therefore not achieved but a new strategy is under investigation starting from a linear precursor. The conjugate addition/ iodine-mediated cyclisation will then be investigated on this substrate which we aim to use in the synthesis of the tetracyclic core of terpenoid natural product and we will then aim to complete a formal synthesis of this complex polycyclic molecule.
Given the testing nature of the substrate synthesis, the synthesis of highly congested cis-fused THF lactones by radical oxidative cyclisation in presence of Mn(III) and Cu(II) was developed. This methodology, which may also be utilized in the synthesis of the core of the natural product, led to the synthesis of more than 20 examples of THF-lactones with good yield and good diastereocontrol. A manuscript describing this work has been submitted to Org. Biomol. Chem.

The development of novel methodologies for the synthesis of complex molecules is an important goal that has relevance to the pharmaceutical, fine chemicals and materials sectors. The project was basic science, and as such it is difficult to predict the societal impact of the work will be. Nevertheless in the project two complexity-generating methodologies were developed, which could be of use to those working in the listed sectors.