Graduate Thesis Or Dissertation


Cis-2,5-diaminobicyclo[2.2.2]octane : a novel C₂-symmetric scaffold for asymmetric catalysis Public Deposited

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  • This thesis describes the development of a new enantioselective synthetic method employing chiral cis-2,5-diaminobicyclo[2.2.2]octane-based organometallic catalysts. The significance of this new method to organic synthesis is illustrated with preparation of enantioenriched products that are transformed to important pharmaceutical agents. Chapter 1 provides a brief historical overview of asymmetric catalysis, especially the development of salen-ligands and salen-metal complexes. Focus is placed on salen frameworks derived from chiral 1,2-diamines and their application in asymmetric synthesis. Chapter 2 introduces the concept of increasing nitrogen-nitrogen separation in a salen framework and the associated enlargement of chiral space. This leads to our proposition that the 1,4-diamine motif present in a cis-2,5-diaminobicyclo[2.2.2]octane scaffold would provide a superior chiral framework for the salen ligand in asymmetric induction via a metal-salen catalyst. This chapter describes the synthesis and characterization of the new salen ligand and its complexes with various transition and pblock metals. Chapter 3 describes the enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky diene with a large number of aldehydes catalyzed by our new chromium(III)-salen complex. The reaction provides 5,6-dihydro-4-pyranones in high yield and with enantiomeric excess up to 96%. These results compare favorably with those obtained with other chiral catalyst systems. The HDA adducts are rich in functionality and stand ready for conversion into useful chiral building blocks. Chapter 4 further illustrates an application of our chromium(III)-salen complex in catalysis of the enantioselective Nozaki-Hiyama-Kishi (NHK) reaction of allyl halides with aromatic aldehydes. The reaction affords homoallylic alcohols in high yield and enantiomeric excess. Extension of this reaction to vinylic halides using the same catalyst is probed but further studies are needed to find optimal conditions for the synthesis of enantioenriched allylic alcohols by this method. In chaper 5, a tetrahydrosalen derivative generated by reduction of our salen ligand in combination with copper(I) triflate was found to be an efficient catalyst for the enantioselective Henry reaction of aldehydes with nitromethane, affording β-nitro alcohols in high enantiomeric excess. The enantioenriched Henry adducts were transformed to important organic materials including beta-adrenergic receptor blocking agents. The catalyst system when used with nitropropane was shown to give a syn-nitro alcohol in high diastereomeric and enantiomeric excess. Chapter 6 describes an iron(III) complex derived from our salen ligand and shows that it is an efficient catalyst for enantioselective sulfa-Michael addition (SMA) of thiols to acyclic α,β-unsaturated ketones. β-Thiaketones are produced by this method in high enantiomeric excess. This protocol was used to synthesize (R)-Montelukast, an anti asthma agent, from commercially available starting materials in four steps. With asubstituted acyclic enones as SMA substrates, the method was shown to give syn product in high diastereomeric and enantiomeric excess. Chapter 7 shows that a novel iron(III)-salen catalyst bearing our bicyclo[2.2.2]octane scaffold leads to enantioselective intramolecular Conia-ene cyclization of a β-keto ester bearing an unactivated terminal alkyne. The product, a chiral polyfunctionalized cyclopentane derivative, constitutes a useful platform for further structural elaboration. In chapter 8, it was demonstrated that a cobalt(II)-salen catalyst induces a high degree of diastereo- and enantioselectivity in the cyclopropanation of a 1,1'-disubstituted alkene with ethyl diazoacetate as co-reactant. A formal synthesis of the dual serotonin and norepinephrine reuptake inhibitor Synosutine was accomplished using this protocol.
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