A novel bifunctional catalyst derived from BINOL has been developed that promotes the highly enantioselective bromolactonizations of a number of structurally distinct unsaturated acids. Like some known catalysts, this catalyst promotes highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzes the highly enantioselective bromolactonizations of 5-alkyl-4(Z)-pentenoic acids. These reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceed via 5-exo mode cyclizations to give lactones in which new carbon–bromine bonds are formed at a stereogenic center with high enantioselectivity. We also disclose the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization.
A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4(Z)-olefinic acids via 5-exo mode cyclizations to give lactones in which new carbon–halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5(Z)-olefinic acids also occur via 6-exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.
Purpose
To determine the maximum tolerated dose of a single intravitreal
injection of aminoguanidine and 1400W, two inhibitors of inducible nitric
oxide synthase, in rabbit eyes.
Methods
Groups of four New Zealand white rabbits were injected with balanced
salt solution in the right eye and a single dose of either aminoguanidine (5
mg, 1 mg, 0.25 mg) or 1400W (2 mg, 0.4 mg) in the left eye. Toxicity was
assessed by slit lamp and fundus examination, intraocular pressure and
pachymetric measurements, and electrophysiologic and histologic
analysis.
Results
Eyes injected with high doses of aminoguanidine (5 mg) or 1400W (2
mg) demonstrated severe retinal vascular attenuation and infarction. Lower
doses of intravitreal aminoguanidine (1 mg) and 1400W (0.4 mg) caused no
significant toxic ocular effects in rabbit eyes.
Conclusions
If the difference in vitreal volume between rabbit eyes and human
eyes is taken into account, aminoguanidine (2.7 mg) and 1400W (1 mg) would
be reasonable intravitreal doses to test for safety and efficacy in early
clinical trials.
Translational Relevance
Inhibition of inducible nitric oxide synthase has already been shown
to be beneficial in various animal models of diabetic eye disease. Dosing
information is needed for preliminary testing in humans.
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