- Synthesis and Stereodynamics of Highly Constrained 1,8.Bis(2,2′ -dialkyl-4,4′-diquinolyl)naphthalenes
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The syn and anti isomers of axially chiral 1,8-diquinolylnaphthalenes have been synthesized via Pd-catalyzed Stille coupling of 1,8-dibromonaphthalene and 2-alkyl-4-trimethylstannylquinolines. Optimization of the cross-coupling reaction allowed the preparation of highly constrained 1,8-bis(2,2′ -dimethyl-4,4′-diquinolyl)naphthalene, 2, and 1,8-bis(2,2′ -diisopropyl-4,4′-diquinolyl)naphthalene, 3, in 42% and 41% yield, respectively. Employing Pd(PPh3)4 and CuO as the cocatalysts in the coupling reaction of 1,8-dibromonaphthalene and 2-alkyl-4-trimethylstannylquinolines proved to be superior over other catalysts such as PdCl2(dppf), Pd2(dba)3/P(t-Bu) 3, and POPd. The C2-symmetric anti isomers of 2 and 3 were found to be more stable than the corresponding meso syn isomer. The ratio of the two enantiomeric anti conformers to the syn conformer was determined as 7.9:1 for 2 and 8.6:1 for 3 by NMR and HPLC analysis. The atropisomers of 2 and 3 were found to be stable to rotation about the chiral axis at room temperature and all three stereoisomers of 2 were isolated by semipreparative HPLC on a Chiralpak AD column. The diastereoisomers of 3 were separated via preferential crystallization of the anti isomers from diethyl ether. Slow syn/anti interconversion was observed for both atropisomers at enhanced temperature, and the diastereomerization and enantiomerization processes were monitored by NMR and HPLC. The Gibbs activation energy, ΔG?, for the isomerization of 2 was determined as 116.0 (112.1) kJ/mol for the conversion of the anti (syn) to the syn (anti) isomer at 71.0 °C. The rotational energy barrier of 3 was determined as 115.2 (111.1) kJ/mol for the conversion of the anti (syn) to the syn (anti) isomer at 66.2 °C.
- Tumambac, Gilbert E.,Wolf, Christian
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- NEW TARGETED CYTOTOXIC ISOCOMBRETAQUINOLINE DERIVATIVES AND CONJUGATES THEREOF
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The present invention is directed to novel natural product-derived combretastatin- based compounds useful as payloads in drug-conjugates constructs with cell target binding moieties (CTBM) and payload-linker compounds useful in connection with drug conjugates. The present invention further relates to new isoNH2CombretaQuinoline compositions including the aforementioned payloads, payload-linkers and drug conjugates, and methods for using these payloads, payload-linkers and drug conjugates, to treat pathological conditions including cancer.
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- One-pot iodination of hydroxypyridines
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(Chemical Equation Presented) A one-pot, high-yielding iodination of hydroxypyridines and hydroxyquinolines is described. The iodination proceeds under mild conditions, and the products are obtained in high yield without the need for chromatographic purif
- Maloney, Kevin M.,Nwakpuda, Emily,Kuethe, Jeffrey T.,Yin, Jingjun
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supporting information; experimental part
p. 5111 - 5114
(2009/10/24)
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- Acid-Mediated Halogen Exchange in Heterocyclic Arenes: A Highly Effective Iodination Method
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Heterocyclic arenes including pyridyl, quinolyl, and isoquinolyl chlorides have been converted to their corresponding iodides in good to high yields via acid-mediated nucleophilic halogen exchange with sodium iodide. This procedure avoids the use of transition metals, harsh reaction conditions, and affords highly regioselective halide exchange. Chloride substituents in position 2 and 4 of pyridines and quinolines are readily substituted by iodide in 75-91% and conversion of 1-chloroisoquinoline to its iodide derivative was found to proceed with 90% yield. Positions that are not activated for nucleophilic aromatic substitution proved to be inert to halide exchange. Regioselective chloride/iodide exchange in 4,7-dichloroquinoline hydrochloride gave 7-chloro-4-iodoquinoline, an important precursor of anti-malaria drugs, in almost 90% yield.
- Wolf, Christian,Tumambac, Gilbert E.,Villalobos, Cristina N.
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p. 1801 - 1804
(2007/10/03)
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