Graduate Thesis Or Dissertation


Scaffold reactivity and large scale Synthesis of organocatalyzed Yamada-Otani Condensation product and investigation of the synthesis and properties of axially chiral 8,8'-biquinolyls and 8-(naphtha-1-yl)quinolines Public Deposited

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  • In Part I, (4S,5R)-4,5-dimethyl-4-phenylcyclohex-2-enone (19a) was prepared in 73% yield with high enantio- and diastereo-selectivity (er > 98:2, dr > 20:1) on a multigram scale by a Yamada-Otani condensation between (E)-pent-3-en-2-one and 2-phenylpropanal catalyzed by a sulfonimide derivative of (S)-proline (18, HuaCat®). Synthetically useful transformations of the cyclohexenone product 19a were demonstrated, as follows: (a) alpha-alkylation via Li-enolate formation (e.g., LDA, DMPU, MeI, THF, –78 °C, 2 h; 86% yield, dr > 20:1), (b) 1,2-addition of organolithiums (e.g., PhLi, THF, –78 °C, 2 h; 82% yield, dr > 20:1), and (c) 1,4-addition of cyanocuprates (e.g., n-BuLi, CuCN, THF, –78 °C, 2 h; 90% yield, dr > 20:1). In Part II, an azaanalog of 1,1´-bi-2-naphthol (BINOL, 38), 7-hydroxy-8-(2-hydroxynaphth-1-yl)quinoline (8-azaBINOL, 67), was prepared in 3 steps and 49% yield from N,N-diethyl O-(7-hydroxy-8-iodoquinolyl) carbamate via Suzuki coupling with 1-naphthyl-boronic acid followed by Sanford oxidation and saponification. 8- AzaBINOL (67) was resolved into (–)-(aS) and (+)-(aR) atropisomers by enzymatic hydrolysis of its racemic divalerate derivative with bovine pancreas acetone powder. The configurational stability of 8-azaBINOL (67) was found to be intermediate to that of 7,7´-dihydroxy-8,8´-biquinolyl ('8,8´-diazaBINOL', 50, least stable) and BINOL (38, most stable). Eyring plot analysis of the enantiomerization kinetics of 50, 67, and 38, in DMSO solution revealed activation parameters of ΔH‡ = +27.4, +19.9, +23.2 kcal mol–1, and ΔS‡ = +3.8, –27.9, –25.3 cal mol–1 K–1, respectively. The unique character of ΔH‡ and ΔS‡ values for biquinolyl 50 suggests that the enantiomerization mechanism for 50 is distinct to that for naphthalenes 67 and 38. Monohydroxy analogs of 67, 7-hydroxy-8-(naphth-1-yl)quinoline (71) and 8-(2-hydroxynaphth-1-yl)quinoline (75), were similarly prepared and their racemization half-lives at rt were determined; τ1/2(rac.) was strongly dependent on solvent for naphthol 75 (τ1/2(rac.) at 24 °C: in CHCl3 = 2.7 h, in MeOH = 89 h) but not for the quinol 71 (τ1/2(rac.) at 24 °C: in CHCl3 = 106 h, in MeOH = 120 h). 8-AzaBINOL (67) and its tosylic acid salt (67•TsOH) were evaluated as potential hydrogen-bonding / Brønsted acid organocatalysts for enantioselective carbon-carbon bond forming processes. Neither form of the compound was an effective catalyst for the Henry reaction between nitromethane and benzaldehyde nor the conjugate addition of acetylacetone to beta-nitrostyrene; however, these quinols did promote the addition of nucleophilic arenes to pyruvate esters (albeit with low enantioselectivity). For example, addition of indole to ethyl trifluoropyruvate (Et2O, –78 °C) gave the expected beta-substituted indole product [(S)-87] in 98% yield and with 5% ee in the presence of free base (S)-67 (10 mol%). The same organocatalyst did not promote addition of indole to ethyl pyruvate (Et2O, –40 °C) but its more reactive tosylate salt (S)-67•TsOH did, resulting in an 82% yield of the addition product with 3% ee. In a collaborative study (with R. Overacker and S. Loesgen), a 45-member library of 8-azaBINOL and 8,8´-diazaBINOL derivatives was evaluated for biological activity in cytotoxicity/cell viability and HIV viral entry inhibition assays. The isopropyl ether of 7-hydroxy-8-(naphth-1-yl)quinoline (92) and the analogous N,N-diethyl carbamate (69) exhibited the most significant bioactivity with respective IC50 = 4.74 μM and 5.18 μM for inhibition of HIV-1 entry into TZM-b1 cells. Comparable 8,8´-diazaBINOLs did not inhibit viral entry. Specific binding of isopropyl ether 92 to purified and immobilized HIV-1 glycoprotein 120 with a KD = 22 ± 2.9 μM was established using biolayer interferometry.
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