Zusammenfassung
Olefin metathesis is a highly effective method for the formation of cyclic alkenes. However, in the case of macrocycles, it often suffers from low stereoselectivity. Consequently, synthetic tools need to be developed for the stereoselective formation of large cycloalkenes. Alkyne metathesis arose as a powerful method to overcome this selectivity issue. Indeed, Ring Closing Alkyne Metathesis (RCAM) followed by cis-selective Lindlar hydrogenation generate (Z)-cycloalkenes in good yields and excellent stereoselectivity. However, the formation of the corresponding (E)-cycloalkene from the cycloalkyne under practical and mild conditions remained difficult until Trost and Fürstner reported independently a two-step procedure of ruthenium-catalysed trans-hydrosilylation / desilylation offering an excellent entry into this series.
Following this lead, a large series of (E)-cycloalkenes of different ring size and bearing various functionalities were prepared in good yield and excellent selectivity.
Stereoselective formation of large cycloalkadienes via olefin metathesis is even more challenging because problems of chemoselectivity may also arise. It was therefore interesting to extend the method to the formation of (E,E)-cycloalkadienes.
In this context, the formation of cyclic 1,3-enynes via the first examples of ring closing enyne-yne metathesis have been successfully implemented in high yields. The tungsten alkylidyne catalyst (t- BuO)3 WC≡Ct-Bu turned out to be well suited for this purpose. Due to the strain imposed by the formed enyne, however, the method is limited to rings greater than 16-membered.
The ruthenium-catalysed hydrosilylation of alkynes could not be directly extended to conjugated enynes due to the formation of numerous by-products and the insufficient reactivity of the catalyst. A scrupulous screening of the reaction conditions showed that the nature of the solvent has a significant impact on the reaction. We found that the ruthenium-catalysed hydrosilylation of conjugated alkynes occurs in excellent yields and selectivity when carried out under neat conditions. Thus, numerous cyclic and acyclic dienylsilanes were prepared through a highly stereoselective process.
Silver fluoride turned out to be very effective for the desilylation of conjugated dienylsilanes and enabled the formation of cyclic and linear (1E,3E)-dienes in good yields and excellent selectivity. Importantly, this transformation can be performed with catalytic amounts of silver in the presence of a fluoride source (TBAF). This catalytic desilylation proceeds with the same yields and selectivity as the stoichiometric method. Furthermore, the procedure was compatible with both conjugated and non-conjugated vinylsilanes.
In order to demonstrate the potential of the developed methodologies, their application to a more complex synthetic setting was envisaged. To this end, the potent antibiotic Myxovirescin A1 was chosen as biologically active target. Since the formation of the 1,3-diene unit in this compound represents a challenging extension of our methodology, it was decided to initially focus on the synthesis of the simplified but closely related structure 147.
The synthesis of this model was successfully completed via ring closing enyne-yne metathesis and the stereoselective semi-reduction of the resulting conjugated enyne as the key steps. Furthermore, many issues that occurred during preparation of the fragments and their interconnections were solved, offering an excellent basis for the envisaged total synthesis of Myxovirescin A1.
