Organometallic NucleosideAnalogues: An Adenine-Analogue Fischer Carbene­ Complex

Abstract

A six-step synthesis of a nucleoside analogue Fischer carbene complex has been developed starting from D-ribono-1,4-lactone. The key steps involve a stoichiometric metathesis of exoglycal 3 with pentacarbonyl[(diphenyl)carbene]chromium to give chromium furanosylidene 4, its ring-opening aminolysis with the nucleobase adenine and a Mitsunobu recyclisation leading to imino-L-lyxo-furanosylidene complex 6 with inversion of configuration.Saccharides play a central role in the chemistry of life. 2 They are involved in structural backbones, in energy storage as well as in intercellular molecular recognition processes such as infection, tumor-cell growth and cell adhesion. The monosaccharides ribose and desoxyribose, when attached to N-heterocyclic nucleobases, serve as building blocks for the nucleosides adenosine, cytidine, thymidine, uridine and guanosine, which form nucleotides upon phosphorylation. On the other hand, organometallic chemistry has received increasing interest directed towards biological and pharmaceutical targets which has been referred to as 'bioorganometallic chemistry'; in some cases organometallic functionalities have been shown to improve the performance of drugs. 3 Following our ongoing interest in the organometallic -and in particular metal carbene 4 -chemistry of sugars 5 we turned our attention to the incorporation of nucleobases into glycosylidene complexes. Now we report the first example of a nucleoside analogue Fischer carbene complex.The synthesis starts from the commercially available D-ribono-1,4-lactone 1 which was protected as 5-benzyl-2,3-isopropylidene derivative 2 (steps a,b) 6 (Scheme 1). Olefination with the Petasis reagent 7 afforded the exo-glycal 3 as a colourless waxy solid in 50-70% yield depending on the quality of the Petasis reagent (step c). Freshly prepared Cp 2 TiMe 2 increases the yield by 10-20%.The transformation of exo-glycal 3 into furanosylidene complex 4 has been achieved by a stoichiometric metathesis reaction using pentacarbonyl(diphenylcarbene)chromium (step d), a strongly electrophilic carbene complex handled at temperatures £ 30°C. Its modification into the a-heteroatom-stabilized oxacyclopentylidene complex provides the thermodynamic driving force for the metathesis reaction. 8 Heptane solutions of exo-glycal 3 and pentacarbonyl(diphenylcarbene)chromium were prepared at -45°C and combined. The mixture was stirred and allowed to warm to room temperature while the progress of the reaction was monitored using FT-IR and TLC. 9 After flash chromatography ribosylidene complex 4 was obtained in 47% yield as an orange oil and was characterized by a down-field 13 C NMR-signal at 341.5 (carbene-C).Alkoxycarbene complexes readily undergo aminolysis upon reaction with amines. 10 The rate of the reaction depends on the nature of the amine and significantly decreases with increasing steric bulk of the amine. Based on this experience we expected the primary amino group in the nucleobase adenine to be more reactive than the secondary amino functionality. In contrast to ...

A Novel Field of Research: Bioorganometallic Chemistry, Origins, and Founding Principles

“…Subsequently, metal carbene complexes of carbohydrates were synthesized [238][239][240][241][242]. In a series of papers, Dötz and coworkers [12,243] introduced the "Fischer-type carbene functionality" into carbohydrates by using a number of different synthetic methodologies; these complexes can be used for the modification of sugars. Cyclopentadienyl-titanium complexes with chiral σ-coordinated ligands derived from glucose are stereoselective reagents in organic synthesis [244,245].…”