Alkyne Metathesis: a new tool for the self-assembly of complex molecular architectures

Abstract

Macrocyclic scaffolds have attracted considerable attention over the past two decades because of their unique properties and promising potential in a wide range of applications in drug discovery, material science and supramolecular chemistry. Recent approaches to accessing complex macrocyclic architectures from simple precursors include metathesis-based cyclooligomerisations, which are described as one-pot alkyne/alkene cross-metathesis/ ring-closing metathesis reactions (CM/RCM or ACM/RCAM) in this thesis. The collection of vignettes presented in Chapter 1, clearly exemplifiesthat one-pot iterative metathesis reactions provide a powerful and versatile set of tools for the rapid construction of highly decorated architectures of variable ring sizes with a wide range of properties and applications. Since the utility of alkyne metathesis-based synthetic methodologies such as the one-pot ACM/RCAM reaction is limited by the availability of well-defined and user-friendly alkyne metathesis catalysts. In Chapter 2, the development of a new alkyne metathesis catalyst was investigated. The newly developed catalyst (I) also termed “canopy catalyst” is endowed with the privileged tripodal silanolate ligand framework. The unrivaled catalytic performance of this complex is illustrated by its broad functional group tolerance. The catalyst works well in the presence of unprotected primary alcohols and even tolerates substrates having multiple donor sites, including basic nitrogen and heterocycles.

Moreover, the ease of formation of key intermediates in the total synthesis of marine natural products including amphidinolide F and nor-cembranoid sinulariadiolide further highlights the unrivalled catalytic activity of this catalyst. The total synthesis of cytotoxic marine-derived bis(lactone) disorazole C1 (II), discussed in Chapter 1, reported by our group in 2015, features the first example of an alkyne-metathesis-based homodimerization approach applied to the synthesis of natural products.

Capitalising on this synthetic methodology in Chapter 3, the first total synthesis of C2-symmetric antimalarial samroiyotmycin A (III) is described (9 steps longest linear sequence with an overall 6%). The convergent synthetic strategy used, involves a bisalkyne fragment-assembly via an unprecedented Schöllkopf-type condensation on a substituted β-lactone and a late-stage one-pot ACM–RCAM reaction.

The demanding alkyne metathesis sequence was successfully achieved using the newly developed alkyne metathesis catalyst, discussed in Chapter 2. Contemporary ruthenium catalysed hydrometallation chemistry enabled the final elaboration into the required E-alkenes.