ABSTRACT
A chiral pool based synthetic strategy that leads from the readily available and inexpensive C(2)-symmetric tartaric acids to the chiral O-isopropylidenebenzooxazole--a convenient precursor to the aminocyclitol core of hygromycin A as well as the chiral γ-disilyloxybutyrolactone--a pivotal intermediate to approach to the furanoside of hygromycin A.
Subject(s)
Cinnamates/chemical synthesis , Hygromycin B/analogs & derivatives , Catalysis , Cinnamates/chemistry , Combinatorial Chemistry Techniques , Cyclization , Hygromycin B/chemical synthesis , Hygromycin B/chemistry , Molecular Structure , StereoisomerismABSTRACT
Concise and efficient syntheses of the aminocyclitol cores of hygromycin A (HMA) and methoxyhygromycin (MHM) have been achieved starting from readily available myo-inositol. Reductive cleavage of myo-inositol orthoformate to the corresponding 1,3-acetal, stereospecific introduction of the amino group via the azide, and resolution of a racemic cyclitol derivative as its diastereomeric mandelate esters are the key steps in the synthesis. Synthesis of the aminocyclitol core of hygromycin A involved chromatography in half of the total number of steps, and the aminocyclitol core of methoxyhygromycin involved only one chromatography.
Subject(s)
Cinnamates/chemical synthesis , Cyclitols/chemistry , Hygromycin B/analogs & derivatives , Inositol/chemistry , Carbohydrate Conformation , Cinnamates/chemistry , Hygromycin B/chemical synthesis , Hygromycin B/chemistry , Inositol/analogs & derivatives , StereoisomerismABSTRACT
Novel hygromycin A derivatives bearing a variety of functionalized aminocyclitol moieties have been synthesized in an effort to increase the antibacterial activity and drug-like properties of this class of agents. A systematic study of the effect of alkylation and removal of the hydroxyls of the aminocyclitol directed us to a series of alkylated aminocyclitol derivatives with improved gram-positive activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cinnamates/chemical synthesis , Cinnamates/pharmacology , Hygromycin B/analogs & derivatives , Hygromycin B/chemical synthesis , Hygromycin B/pharmacology , Microbial Sensitivity TestsABSTRACT
[reaction: see text] Stereoselective aminohydroxylation and dihydroxylation using osmium(VIII) oxidants enabled the short and efficient synthesis of the aminocyclitol core of hygromycin A. In addition to allowing the selective introduction of the heteroatoms N and O, the use of osmium (via an osmate ester) as a protecting group for a 1,2-glycol is also reported. This tactic allowed efficient differentiation of otherwise equivalent hydroxyl groups and allowed us to complete the synthesis in short order (14 steps) and excellent overall yield (12%).
Subject(s)
Cinnamates/chemical synthesis , Hygromycin B/analogs & derivatives , Inositol/chemical synthesis , Cinnamates/chemistry , Crystallography, X-Ray , Hygromycin B/chemical synthesis , Hygromycin B/chemistry , Inositol/chemistry , Molecular Structure , Stereoisomerism , Streptomyces/chemistryABSTRACT
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.
Subject(s)
Biological Factors/chemical synthesis , Furans/chemistry , Hygromycin B/analogs & derivatives , Hygromycin B/chemical synthesis , Streptomyces/chemistry , Aldehydes/chemistry , Benzoates/chemistry , Biological Factors/chemistry , Catalysis , Chromatography, High Pressure Liquid , Cinnamates/chemistry , Fermentation/physiology , Glycosylation , Hygromycin B/chemistry , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Palladium/chemistry , Phenols/chemistry , Stereoisomerism , Sulfones/chemistryABSTRACT
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.
