Graduate Thesis Or Dissertation
 

Catalytic desymmetrization of D₂d̳-symmertic proprochiral tetrasubstituted biphenyl compounds: a novel approach to the synthesis of axially chiral C₂-symmetric molecules

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/9w032739h

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  • Many D2d-symmetric 2,2',6,6'-tetrasubstituted biphenyls are readily prepared via net oxidative dimerization of appropriate 1,3-disubstituted benzenes. Conversion of such proprochiral compounds to useful C2-symmetric chiral biphenyls requires formal replacement of two substituents on opposing aryl ring units with alternate groups. This under exploited desymmetrization tactic has been demonstrated for the generation of scalemic biaryls using stoichiometric chiral reagent control, but no reports concerning its realization by a (potentially) more efficient asymmetric catalytic approach have appeared. Accordingly, two different possible strategies for achieving a catalytic enantioselective biaryl synthesis based on D2d to C2 desymmetrization were investigated: (a) enzyme catalyzed hydrolysis of tetraester derivatives of 2,2'-biresorcinol, and (b) transition metal catalyzed substitution from 2,2',6,6'- tetrabromobiphenyl. In pursuit of the first approach, 2,2'- biresorcinol was prepared from 1,3-dimethoxybenzene via nbutyllithium initiated ortho-directed lithiation, followed by iron(III) chloride mediated oxidative coupling of the aryllithium, and then (in a separate step) demethylation of the resulting 2,2',6,6'-tetramethoxybiphenyl with excess boron tribromide. Tetraacetate and tetravalerate esters of 2,2'-biresorcinol were subsequently synthesized and their hydrolysis with the following four distinct esterases was examined: Pseudomonas cepacia lipase (PCL), porcine liver esterase (PLE), Candida antarctica lipase B (CAL B), and bovine pancreas acetone powder (a source of bovine cholesterol esterase). Turn-over was not observed in any case; however, a majority of the enzymes studied successfully hydrolyzed model test substrates such as phenyl valerate, phenyl acetate, and mono- and diesters of resorcinol. For the second approach, a significant new one-pot synthesis of 2,2',6,6'-tetrabromobiphenyl was realized from 1,3- dibromobenzene via lithium diisopropylamide mediated ortholithiation followed again by oxidative coupling with iron(III) chloride (66% yield). Palladium catalyzed cross-coupling reactions (comprising Kumada, Negishi, and Sonogashira subtypes) were evaluated from 2,2',6,6'-tetrabromobiphenyl and 1,3- dibromobenzene. The latter model substrate revealed that a degree of control was possible, in that monosubstitution could be readily achieved; however, reactions from the pivotal D2d-symmetric 2,2',6,6'-tetrasubstituted substrate typically gave either no reaction (reflecting the high steric hindrance of the starting material) or else complex intractable mixtures of various polysubstituted products.
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