ABSTRACT
The C-8 position of the tetracyclines has been largely underexplored because of limitations in traditional semisynthetic techniques. Employing a total synthetic approach allowed for modifications at the C-7 and C-8 positions, enabling the generation of structure-activity relationships for overcoming the two most common tetracycline bacterial-resistance mechanisms: ribosomal protection (tet(M)) and efflux (tet(A)). Ultimately, several compounds were identified with balanced activity against both Gram-positive and Gram-negative bacteria, including pathogens bearing both types of tetracycline-resistance mechanisms. Compounds were screened in a murine systemic infection model to rapidly identify compounds with oral bioavailability, leading to the discovery of several compounds that exhibited efficacy when administered orally in murine pyelonephritis and pneumonia models.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Tetracyclines/chemical synthesis , Tetracyclines/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Bacterial Infections/complications , Female , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Models, Chemical , Molecular Structure , Pneumonia/etiology , Pneumonia/prevention & control , Pyelonephritis/etiology , Pyelonephritis/prevention & control , Structure-Activity Relationship , Tetracycline Resistance/drug effects , Tetracyclines/chemistry , Treatment OutcomeABSTRACT
The tricyclic core of the cylindricine or lepadiformine families of alkaloid natural products was assembled via a Prins addition/intramolecular Schmidt rearrangement under Lewis acid conditions. Both single-pot and two-stage variations of this process were examined, with particular attention to the stereochemical outcome of the processes. This technology has been applied to a formal total synthesis of lepadiformine A and a total synthesis of lepadiformine C.
Subject(s)
Alkaloids/chemical synthesis , Alkaloids/chemistry , Molecular Structure , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/chemistry , StereoisomerismABSTRACT
A series of domino reactions in which the intramolecular Schmidt reaction is combined with either a Sakurai reaction, an aldol reaction, or both is reported. The Sakurai reaction of an allylsilane with an azido-containing enone under Lewis acidic conditions followed by protonation of the resulting titanium enolate species allowed for a subsequent intramolecular Schmidt reaction. Alternatively, the intermediate titanium enolate could undergo an aldol reaction followed by the intramolecular Schmidt reaction to form lactam products with multiple stereogenic centers. The stereochemical features of the titanium enolate aldol reaction with several 3-azidoaldehyde substrates during this domino process is discussed.
Subject(s)
Lactams/chemical synthesis , Aldehydes/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Lactams/chemistry , Molecular StructureABSTRACT
The influence of attractive, nonbonded interactions on the reactions of 1,2- and 1,3-hydroxyalkyl azides with ketones has been investigated through experimental and computational means. A series of 1,3-hydroxyalkyl azides bearing electronically tuned aromatic groups at the 2 position were prepared and reacted along with several derivatives designed to conformationally restrict the rotational orientation of the aromatic substituent. These studies showed that a cation-pi interaction between an aryl moiety and an N2(+) leaving group plays a role in determining the stereoselectivity of these reactions. A series of ab initio calculations supported this hypothesis. A computational and experimental analysis suggested a primarily steric model for the analogous reactions of substituted 2-azido-1-ethanol analogues.
Subject(s)
Azides/chemistry , Alkylation , Carbon/chemistry , Cations/chemistry , Cyclization , Ethanol/chemistry , Gases/chemistry , Hydroxylation , Molecular Structure , Propane/chemistry , Solvents , StereoisomerismABSTRACT
The Lewis acid-promoted reactions of chiral 2-aryl-3-azido-1-propanols with 4-substituted cyclohexanones lead to iminium ethers and ultimately caprolactams (following a hydrolysis step). In this study, it is shown that these reactions afford variable ratios of products, depending on the electronic nature of the phenyl group. These results are interpreted in the context of a cation-pi stabilizing effect in the product-determining reaction intermediate. Remarkably, the best selectivity was obtained when an azidopropanol reagent containing a quaternary center was used; a control experiment showed that the high selectivity observed in this result depended upon the free rotation of the pseudoaxial aromatic group in the intermediate that affords the major product.
Subject(s)
Azides/chemistry , Cyclohexanones/chemistry , Lactams/chemical synthesis , Azides/chemical synthesis , Lactams/chemistry , Molecular Conformation , StereoisomerismABSTRACT
An asymmetric equivalent of the Schmidt reaction permits stereocontrol in ring expansions of symmetrical cyclohexanones. The procedure involves the reaction of chiral 1,2- and 1,3-hydroxyalkyl azides with ketones under acid catalysis; the initial reaction affords an iminium ether that can be subsequently opened with base. A systematic study of this reaction is reported, in which ketone substrates, chiral hydroxyalkyl azides, and reaction conditions are varied. Selectivities as high as ca. 98:2 are possible for the synthesis of substituted caprolactams, with up to 1,7-stereoselection involved in the overall process. The fact that either possible migrating carbon is electronically identical provides an unusual opportunity to study a ring-expansion reaction controlled entirely by stereoelectronic factors. The mechanism of the reaction and the source of its stereoselectivity are also discussed.