Gold-Catalyzed Late-Stage Diversification of Prenylated Pharmaceuticals and Biomolecules with Acetylene Gas
Final Report Abstract
Acetylene is the smallest alkyne and an important base chemical in different industrial processes. Although it has been known for several decades that Au(I)-complexes can selectively activate alkynes, the reactivity of cationic Au(I)-complexes with acetylene has scarcely been investigated. In general, intermolecular Au(I)-catalyzed reactions of alkynes with alkenes are less studied and more difficult to control due to oligomerizations and unwanted reactivity of the resulting cyclopropyl gold(I) carbenes. This is especially true for reactions with acetylene, as control of exact stoichiometry is difficult, and the resulting Au(I)- acetylene complexes are highly electrophilic. Aim of this project was the stereoselective insertion of one acetylene unit into double bonds leading to (Z,Z)-butadienes, which are difficult to synthesize by common methodologies. This reaction should then be applied to late-stage functionalization of prenylated pharmaceuticals and biomolecules. During this project, the very bulky cationic Au(I)-catalyst containing a tris(biphenyl)phosphineligand was observed to be highly reactive in the planned reaction, giving the desired (Z,Z)-butadiene from α-methyl styrene even at temperatures below 0 ºC. However, the catalyst and all other catalysts tested were not able differentiate between product and starting material, resulting in considerable amounts of oligomerization and thus only moderate yields of the desired single-insertion product. To circumvent those problems, an insertion of acetylene into cyclobutenes was envisioned, which was thought to give more selective reactions, because a) cyclobutenes have considerably more ring-strain then the cyclohexadiene products, favoring single insertion; b) installation of a leaving-group in these cyclobutenes would lead to less nucleophilic alkenes, but elimination would directly give an aromatic ring which makes further insertion impossible. Indeed, based on these assumptions a formal Au(I)-catalyzed C2- ring expansion of cyclobutenyl acetates was developed leading to the formation of biphenyls. DFT-calculations gave insights into the mechanism which consists of acetate assisted ringexpansion of a bicyclo[2.1.0]pentyl gold(I) carbene and Au(I)-catalyzed acetate elimination. In an unrelated side project, the total synthesis of Monomarginine was explored. Monomarginine is a Sampangine type 2,7-naphthyridine alkaloid that presents a surprisingly tricky synthetic challenge because of its substitution. Key step of this synthesis was planned to be a Au(I)-catalyzed hydroarylation of a diyne to synthesize a key dihydropyridine.
Publications
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Towards the Total Synthesis of Monomarginine, ICIQ School 2023, Tarragona/Spain.
M. P. Beller, G. Ogalla & E. García-Padilla
