Synthesis of (S)-2-(1,4,7-tritosyl-1,4,7-triazonan-2-yl) ethanol, a chiral triazacyclononane

Research work has proven some novel and flexible routes in the synthesis of chiral annulet of triazacyclononane and their derivatives possessing one or more stereo centers on the macro cyclic structure. In this project work, using the standard Richman-Atkins cyclisation, (S)-2-(1,4,7tritosyl-1,4,7-triazonan-2-yl) ethanol, is synthesized despite low yield, by coupling “racemic” 1,2-ditosamide (6) to tritosyl diethanol amine. Triazacyclononanes are well known to posses rich chelation chemistry and form structurally rigid metal ligand in synthesis. They are also known to be able to stabilize both high and low oxidation state of different metal ions. With base placed in silico modeling, a proposed complex structure (figure 2), that can be formed by this cyclononane with a chiral lithium amide base can be used to test catalytically for asymmetric enolate alkylation and aldol reactions. Synthesis of (S)-2-(1, 4, 7-tritosyl-1, 4, 7-triazonan-2-yl) ethanol, a chiral triazacyclononane. Master’s level degree project in Chemistry, August 2011. Emmanuel Nwachuwku. 2 Table of contents Abstract 1 Table of contents 2 List of abbreviations 3 Introduction 4 Aim of Project 8 Results and discussions 9 Reaction mechanisms 13 Experimental part 15 Acknowledgement 21 Spectra analyses 22 References 25 Synthesis of (S)-2-(1, 4, 7-tritosyl-1, 4, 7-triazonan-2-yl) ethanol, a chiral triazacyclononane. Master’s level degree project in Chemistry, August 2011. Emmanuel Nwachuwku. 3 List of abbreviations Aq. Aqueous COSY Corelation spectroscopy DMF Dimethylformamide DMAP 4-(Dimethylamino)pyridine LiHMDS Lithium bis(trimethylsilyl)azanide mw Microwave M Mesomeric NMR Nuclear magnetic resonance. r.t. Room temperature. Refl. Reflux SN2 Substitution nucleophilic bimolecular TLC Thin layer chromatography. Ts p-Toluenesulfonyl. THF Tetrahydrofuran. TBDPSCl Tert-butyldiphenylsilyl chloride. TBAF Tetra-n-butylammonium fluoride. Synthesis of (S)-2-(1, 4, 7-tritosyl-1, 4, 7-triazonan-2-yl) ethanol, a chiral triazacyclononane. Master’s level degree project in Chemistry, August 2011. Emmanuel Nwachuwku. 4 Introduction: Asymmetric products can be obtained by; 1 the use of natural stereo chemically enriched starting materials to induce chirality to achiral molecules, resolution of racemic mixture or by designing and using asymmetric route to the desired product. The last method usually requires the use of a chiral reagent e.g. (-)-sparteine (Z), a chiral auxiliary (can be reuse after reaction since need not to be consume in the reaction process e.g. Enders SAMP (Y)) or a chiral base (X), to get to the desired stereochemistry. However, it is advantageous using a chiral ligand instead of auxiliary in chiral induction in that; despite the fact that the auxiliary can be reuse after reaction, they cannot be use directly as the case of chiral ligands since they often require modification before reuse due to the effect they get during the cleavage stage. Also, the fact that chiral ligands can be used in catalytic amount, offers environmentally friendly atmosphere and are less costly compared to chiral auxiliaries that needs to be used in stoichiometric amount. Recently, chiral bases e.g. chiral lithium amide bases have successively been use catalytically for some enantioselective deprotonation reactions. 6 The fact that catalytic deprotonation depends on the structure of the chiral lithium amide and also the kind of ligands formed with metals, taken the substituted prochiral cyclic ketone below as an example, it is noted that as bases for deprotonation, bidentate lithium amides are superior to both tridentate and tetra dentate lithium amides. This results due to drop down in Lewis acidity of the lithium metal as a result of extra intramolecular coordination. In this scenario, proposals were achieved successively by using catalytic amount of chiral bidentate amine with stoicheometric amount of achiral tridentate (or tetra dentate) lithium amide to form chiral bidentate lithium amide as a result of lithium-hydrogen interchange. 4 This chiral lithium amide base formed are able to deprotonate catalytically, 4-substituted cyclohexanones. X y z Synthesis of (S)-2-(1, 4, 7-tritosyl-1, 4, 7-triazonan-2-yl) ethanol, a chiral triazacyclononane. Master’s level degree project in Chemistry, August 2011. Emmanuel Nwachuwku. 5 The catalytic cycle below by Koga illustrates these results. Scheme 1: Catalytic cycle showing catalytic asymmetric deprotonation, depicted by Koga. The concept of using chiral bases in asymmetric synthesis appeared with the emergence of the chemistry of chiral lithium amide. For the past few years, there have been great focuses and steady increase in the use of chiral lithium bases by different research groups with focus based on structure elucidation of these bases, to induce chirality to achiral molecules. Based on asymmetric desymmetrization, extensive use of chiral lithium amide bases on reactions involving; enantioselective deprotonation of conformationally locked prochiral cyclic ketones, enantioselective rearrangement of epoxide to allylic alcohols. 7 and also reactions involving enantioselective aromatic functionalisation of (arene)-tricarbonylchromium(0)complexes, 7 have been noted. O