Graduate Thesis Or Dissertation
 

Atropisomeric 8,8'-biquinolyl derivatives : synthesis, properties and applications

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  • 7,7'-Dihydroxy-8,8'-biquinolyl (azaBINOL) was prepared from 7-hydroxyquinoline via N,N-dimethyl O-quinol-7-yl carbamate by directed ortho-metallation followed by FeCl₃-mediated oxidative coupling of the 8-lithioquinoline intermediate. Saponification of the resulting dicarbamate provided crystalline (±)-azaBINOL in 56% overall yield. 6,6'-Bis(dimethylaminocarbonyl)-7,7'-dihydroxy-8,8´-biquinolyl was prepared from the same dicarbamate by a double anionic-Fries rearrangement in 43% yield. 7,7'-Bis(diethylamino-carbonyloxy)-6,6'-diiodo-8,8´-biquinolyl was synthesized from 7-(diethylaminocarbonyloxy)-8-iodoquinoline in 54% yield by a tandem halogen-dance/oxidative coupling process. The diiodide was converted to 6,6'-bis[(methylamino)-sulfonyl]-7,7'-dihydroxy-8,8´-biquinolyl by a three-step sequence in 91% overall yield. Resolution of (±)-azaBINOL into its atropisomeric enantiomorphs was accomplished in two ways: (a) via chromatographic (HPLC) separation of diastereomeric bismenthylcarbonates generated from the racemic diol and homochiral menthylchloroformate, and (b) via hydrolytic enzymatic kinetic resolution of the (±)-azaBINOL dipentanoate ester derivative with bovine pancreas acetone powder. Method (b) was superior and afforded the unreacted (+)-(aR)-diester (46%, ≥99%ee) accompanied by (–)-(aS)-azaBINOL (30%, 92%ee after recrystallization). 2,2'-Di-tert-butyl-azaBINOL was prepared in enantioenriched form from scalemic samples of azaBINOL-dipentanoate by addition of t-BuLi followed by saponification in the presence of air. First-order rate constants for the enantiomerization of azaBINOL in H₂O were measured (over 316-366 K) and activation parameters determined as ΔH‡ = 34.0 kcal mol–1 and ΔS‡ = 18.7 cal mol⁻¹ K⁻¹ by Eyring plot analysis. The further functionalized 2,2'-di-tert-butyl-azaBINOL was found to be configurationally labile and showed racemization half-lives of 30.5 h and 1.9 h at 23 °C in MeOH and CHCl₃, respectively. A series of cyclic diethers were prepared from azaBINOLs and dihalides X(CH₂)nX' (n = 1-6) and their pKa values determined by potentiometric titration in MeOH. Biquinolyl basicity was dependent on interannular dihedral angle (IDA; assessed by X-ray crystallography and UV spectroscopy), the methylene diethers (IDA ≤60°) exhibited single pKa points of exceptionally low magnitude (2.7-3.1). 6,6'-Bis[(methylamino)sulfonyl]-7,7'-dihydroxy-8,8´-biquinolyl, resolved via an HPLC based method, catalyzed the enantioselective addition of TMSCN to aldehydes in the absence of additives. Resulting cyanohydrins were obtained in ≥ 90% yield and up to 20%ee. Control experiments established the requirement of sulfonamide functionality, free hydroxyl groups, quinoline nitrogen atoms and the dimeric manifold for catalytic activity.
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  • Only .pdf document created from the original Word form. Some figures were scanned using Epson Stylus Photo RX600. For formulas used ChemDraw files.
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