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

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.;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.;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 DeltaH‡ = 34.0 kcal mol-1 and DeltaS‡ = 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.