Two synthetic routes towards the construction of the aminocyclohexitol moiety of hygromycin A have been developed based on palladium-catalyzed asymmetric alkylation of conduritol derivatives. A protocol has been established whereby this biologically relevant molecule is formed from benzoquinone. A conduritol A derivative is synthesized in eight steps from benzoquinone and is then subjected to the palladium reaction. From this flexible intermediate, four epimers of the aminocyclitol, including the natural one, can be obtained with complete stereoselectivity. Racemic conduritol B derivatives are available in four steps from benzoquinone, and these are then made enantiomerically pure by a palladium-catalyzed dynamic kinetic resolution. From the chiral conduritol B, the aminocyclitol is available in six steps. Excellent levels of enantio- and diastereoselectivity highlight these strategies.
Nitro-1-(phenylsulfonyl)ethane sodium salt 8 SO 2 Ph NO 2 Na 1-Nitro-1-(phenylsulfonyl)ethane 1 (4 g, 18.6 mmol) is dissolved in dry THF (20 mL), and at 0 C is added sodium hydride (60% in oil) (0.744 g, 18.6 mmol). After one hour of stirring at room temperature, the mixture is evaporated in vacuo, then dissolved and triturated in dichloromethane. The solid is filtrated and washed 3 times with dichloromethane to give 1-nitro-1-(phenylsulfonyl)ethane sodium salt 6 (4.4 g, 18.6 mmol) with a quantitative yield.
A strategy for stereocontrolled syntheses of furanoside type of natural products is developed for a glycosyl aryl ether. This strategy resolves the issue of low diastereoselectivity typical of normal glycosidation methods for furanosides. All the stereochemistry ultimately derives from a desymmetrization of a 2,5-diacyloxy-2,5-dihydrofuran using Pd catalyzed asymmetric allylic alkylation which sets both the absolute stereochemistry and 1,4-relative stereochemistry. Diastereo-controlled elaboration of the 3,4-double bond then completes the synthesis. A new conjunctive reagent, 1-nitro-1-phenylsulfonyl-ethane, is developed to serve as an acyl anion equivalent. The utility of a phenol as a nucleophile in the Pd catalyzed glycosylation is demonstrated. From this strategy emerged a short, practical synthesis of C-2-epi-hygromycin A.
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