The study of the asymmetric synthesis of lignans

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Chee, Gaik-Lean.
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The work in this thesis focuses on the asymmetric synthesis of lignans by approaches such as Diels-Alder reactions, asymmetric alkylation reactions, and intramolecular oxidative coupling reactions. In addition to developing asymmetric synthetic methodologies for chiral lignans, an investigation of chirality in arylnaphthalene lignans which lack stereogenic centers has also been carried out. In the first project, a bis-(methyl (S)-lactyl) ester of acetylenedicarboxylic acid (ADA) was used in asymmetric Diels-Alder reactions with dienes such as ortho-quinodimethanes (o-QDMs) and isobenzofurans to produce aryltetralin lignans. As part of this study, a general and versatile method was developed for the preparation of ADA esters and applied to the synthesis of both chiral and achiral esters.$$\eqalign{ &1)\rm Br\sb2\cr &2)\rm PCl\sb5\cr\rm HO\sb2C{\qquad\qquad\over\qquad\qquad}CO\sb2H\qquad&\rm \longrightarrow\qquad R\sp*O\sb2C{\qquad\qquad\over\qquad \qquad}CO\sb2R\sp*\cr &\rm3)R\sp*OH\cr\rm ADA\qquad\qquad&\rm4)Zn\qquad \qquad\qquad ADA\ ester\cr}$$Moderate asymmetric induction was observed in Diels-Alder reactions of the bis-(methyl (S)-lactyl) ester o ADA with $\alpha$-hydroxy-o-QDMs. In one case, an unusual solvent-induced reversal of asymmetric induction was observed. An approach to the synthesis of optically active lignans via asymmetric alkylation of a chiral benzylbutyrolactone was undertaken. The key intermediate was synthesized by employing a highly diastereoselective alkylation of a chiral imide enolate of a dihydrocinnamic acid.$\sp*$ The resulting enantiomerically pure $\beta$-benzyl-$\gamma$-butyrolactone was subsequently transformed into the benzylidenebenzylbutyrolactone lignans gossypifan and savinin via aldol condensation/dehydration reactions, and to the dibenzylbutyrolactone lignan 4$\sp\prime$-demethylyatein through alkylation. A study of intramolecular oxidative coupling reactions of phenylpropanoid dimers and a monophenolic dibenzylbutyrolactone lignan was also undertaken. Oxidations of sinapic acid ester dimers were attempted using metal and nonmetal oxidants, but were unsuccessful. The focus on oxidative coupling reactions of diol disinapates was redirected to oxidative cyclization of $\sp\prime$-demethylyatein, using DDQ as oxidant. Aryltetralin lignan 4$\sp\prime$-demethylisodeoxypodophyllotoxin was formed, as well as cis- and trans-benzylidenebenzylbutyrolactones, in good to excellent yield. 1-Arylnaphthalenes, prepared by aromatization of the Diels-Alder products from o-QDM and acetylenedicarboxylates, were found to exhibit hindered rotation about the phenyl-naphthalene (C1-C1$\sp\prime$) bond. To test if hindered rotation in naturally occurring arylnaphthalene lignans might give rise to isolable enantiomeric rotamers, eleven arylnaphthalene lignans and analogs were synthesized and the barriers to rotation about the phenyl-naphthalene bonds were measured. The barriers to rotation ranged from 16.9 to 21.5 kcal/mol, which translated to half-lives for individual rotamers of less than 15 min at room temperature. The experimental rotational barriers of these compounds were compared to those obtained from molecular orbital calculations. (Abstract shortened by UMI.) ftn$\sp*$Please refer to the dissertation for diagram.