UHLE’S KETONE-DERIVED N-SULFONYL HYDRAZONES: TOWARDS A DIVERGENT TOTAL SYNTHESIS OF CLAVINE ALKALOIDS

N-Sulfonyl hydrazones have been widely exploited as safer alternative precursors for hazardous diazo and carbene compounds. Over the years, they have enabled access to numerous novel transformations. Moreover, they can be readily prepared from the corresponding aldehydes or ketones, ubiquitous functional groups in organic molecules, in combination with suitable commercially available aryl-sulfonyl hydrazides. This PhD project aims to utilise N-sulfonyl hydrazones as key intermediates in the development of a divergent total synthesis of representative ergot alkaloids spanning different structural subclasses: tricyclic and rearranged clavines. The plan was to generate a key N-sulfonyl hydrazone from 4-amino Uhle’s ketone by condensation and then combine it with an appropriate four-carbon synthon to furnish representative members of both subclasses. The first part of the thesis is focused on the total synthesis of a representative example of tricyclic clavines: (-)- 6,7-secoagroclavine. In particular, the natural product (-)- 6,7-secoagroclavine and its unnatural epimer (+)-5-epi-6,7-secoagroclavine have been achieved in an overall concise, convergent and asymmetric total synthesis. The key step consists of a metal-free reductive coupling between N-tosylhydrazone and an alkenyl boronic acid, which served as the four-carbon synthon. This method enables a regioselective Csp2–Csp3 and Csp3–H bond formation on the same carbon, where the new double bond is not conjugated with the aromatic ring. In the second part of the thesis, a novel total synthesis of a representative example of rearranged clavines, (+)-cycloclavine, is disclosed. After evaluating several synthetic strategies, including intermolecular and intramolecular cyclopropanation approaches as pivotal steps, we report a concise, asymmetric and divergent total synthesis of the natural product (+)-cycloclavine and its unnatural analogue (-)-5-epi-cycloclavine. The strategy relies on a metal-free intramolecular cyclopropanation of N-tosylhydrazone bearing a preinstalled four-carbon synthon. The reaction yields two diastereomers, which have been isolated and individually advanced through the following steps to provide the final products. Although the yield of this transformation is low and will require further optimization, it is noteworthy that, in a single metal-free process, a [3.1.0] bicyclic system containing a highly challenging tetrasubstituted cyclopropane moiety is generated. Finally, the project carried out during my period abroad in the Morandi group at ETH-Zurich is illustrated. Here, a new catalytic shuttle system is described, in which a formyl unit is transferred from a donor to an acceptor under mild conditions. This single bond metathesis enables the synthesis of valuable aldehydes, which are appreciated building blocks in both academic and industrial fields. Remarkably, the method does not rely on an external source of CO and unactivated alkanes, typically considered inert, are employed as CO acceptors, being activated through a photocatalytic hydrogen atom transfer (HAT), with inexpensive TBADT used as photocatalyst. After extensive optimization of the reaction conditions, a range of inexpensive CO donors has been evaluated. In addition, a preliminary scope of accessible alkanes as acceptors is reported.