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Gentamicin C1a and the minor isomer C2b have been reported to have favorable properties in terms of antibacterial activity and toxicity compared to the commercial mixture from which they have previously been isolated by preparative high-performance liquid chromatography. We report straightforward syntheses of both compounds from readily available sisomicin by selective oxidation of the side chain in ring I, hydrogenation of the double bond in ring I to give the 5'-epi series, inversion of configuration at position 5' under thermodynamic conditions, and installation of the 6'-amino group by reductive amination.

Metaperiodate cleavage of the glycerol side chain from an N-acetyl neuraminic acid-derived thioglycoside and condensation with the two enantiomers of the Ellman sulfinamide affords two diastereomeric N-sulfinylimines from which bacterial sialic acid donors with the legionaminic, and acetaminic acid configurations and their 8-epi-isomers are obtained by samarium iodide-mediated coupling with acetaldehyde and subsequent manipulations. A variation on the theme, with inversion of configuration at C5, similarly provides two differentially-protected pseudaminic acid donors.

[Image: see text] The influence of substitution of an N,N,O-trisubstituted hydroxylamine (−NR–OR′−) unit for a hydrocarbon (−CHR–CH(2)−), ether (−CHR–OR′−), or amine (−NR–CHR′−) moiety on lipophilicity and other ADME parameters is described. A matched molecular pair analysis was conducted across five series of compounds, which showed that the replacement of carbon–carbon bonds by N,N,O-trisubstituted hydroxylamines typically leads to a reduction in logP comparable to that achieved with a tertiary amine group. In contrast, the weakly basic N,N,O-trisubstituted hydroxylamines have greater logD(7.4) values than tertiary amines. It is also demonstrated that the N,N,O-trisubstituted hydroxylamine moiety can improve metabolic stability and reduce human plasma protein binding relative to the corresponding hydrocarbon and ether units. Coupled with recent synthetic methods for hydroxylamine assembly by N–O bond formation, these results provide support for the re-evaluation of the N,N,O-trisubstituted hydroxylamine moiety in small-molecule optimization schemes in medicinal chemistry.

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.

Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of gluco and manno iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the gauche,gauche side chain conformations are 6- to 10-fold more potent than isosteric compounds with the gauche,trans conformation; a manno-configured iminosugar with the gauche,gauche conformation is a 27-fold better inhibitor than 1-deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.

Low-temperature NMR studies with a 4-C-methyl-4-O-benzoyl galactopyranosyl donor enable the observation and characterization of a bridged bicyclic dioxacarbenium ion arising from participation by a distal ester. Variable-temperature NMR studies reveal this bridged ion to decompose at temperatures above ≈-30 °C. In the absence of the methyl group, the formation of a bicyclic ion is not observed. It is concluded that participation by typical secondary distal esters in glycosylation reactions is disfavored in the ground state conformation of the ester from which it is stereoelectronically impossible. Methylation converts the secondary ester to a conformationally more labile tertiary ester, removes this barrier, and renders participation more favorable. Nevertheless, the minor changes in selectivity in model glycosylation reactions on going from the secondary to the tertiary esters at both low and room temperature argue against distal group participation being a major stereodirecting factor even for the tertiary system.

An intramolecular hydrogen bond between the protonated equatorial 7'-methylamino group of apramycin and the vicinal axial 6'-hydroxy group acidifies the 6'-hydroxy group leading to a strong hydrogen bond to A1408 in the ribosomal drug binding pocket in the decoding A site of the small ribosomal subunit. In 6'-epiapramycin, the trans-nature of the 6'-hydroxy group and the 7'-methylamino group results in a much weaker intramolecular hydrogen bond, and a consequently weaker cooperative hydrogen bonding network with A1408, resulting overall in reduced inhibition of protein synthesis and antibacterial activity.

Super-armed glycosyl donors, whose substituents are predominantly held in pseudoaxial positions, exhibit strongly increased reactivity in glycosylation through significant stabilization of oxocarbenium-like transition states. Examination of X-ray crystal structures reveals that the GH47 family of glycoside hydrolases have evolved so as to distort their substrates away from the ground state conformation in such a manner as to present multiple C-O bonds in pseudoaxial positions and so benefit from conformational super-arming of their substrates, thereby enhancing catalysis. Through analysis of literature mutagenic studies, we show that a suitably placed aromatic residue in GHs 6 and 47 sterically enforces super-armed conformations on their substrates. GH families 45, 81, and 134 on the other hand impose conformational super-arming on their substrates, by maintaining the more active ring conformation through hydrogen bonding rather than steric interactions. The recognition of substrate super-arming by select GH families provides a further parallel with synthetic carbohydrate chemistry and nature and opens further avenues for the design of improved glycosidase inhibitors.

The preparation of four per-O-benzyl-d- or l-glycero-d-galacto and d- or l-glycero-d-gluco heptopyranosyl sulfoxides and the influence of their side-chain conformations on reactivity and stereoselectivity in glycosylation reactions are described. The side-chain conformation in these donors is determined by the relative configuration of its point of attachment to the pyranoside ring and the two flanking centers in agreement with a recent model. In the d- and l-glycero-d-galacto glycosyl donors, the d-glycero-d-galacto isomer with the more electron-withdrawing trans,gauche conformation of its side chain was the more equatorially selective isomer. In the d- and l-glycero-d-gluco glycosyl donors, the l-glycero-d-gluco isomer with the least disarming gauche,gauche side-chain conformation was the most equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triflates at -80 °C in all cases, were inconclusive owing to a change in the decomposition mechanism with the change in configuration. It is suggested that the equatorial selectivity of the l-glycero-d-gluco isomer arises from H-bonding between the glycosyl acceptor and O6 of the donor, which is poised to deliver the acceptor antiperiplanar to the glycosyl triflate, resulting in a high degree of SN2 character in the displacement reaction.

With a view to reducing the notorious complexity and irreproducibility of glycosylation reactions, 12 guidelines for the choice of concentration, temperature, and counterions are adumbrated.

The reaction of magnesium amides with tert-butyl 2,6-dimethyl perbenzoate in tetrahydrofuran at 0 °C provides a method for the synthesis O-tert-butyl-N,N-disubstituted hydroxylamines by direct N-O bond formation with a broad functional group tolerance. Less sterically hindered magnesium amides require ortho,ortho-disubstitution on the perester electrophile component, whereas sterically encumbered magnesium amides perform comparably with either tert-butyl perbenzoate or tert-butyl 2,6-dimethyl perbenzoate. A reaction mechanism is presented to account for the observed reactivity.

In order to further investigate the importance of the conformation of the ring I side chain in aminoglycoside antibiotic binding to the ribosomal target several derivatives of paromomycin were designed with conformationally locked side chains. By changing the size of the appended ring between O-4′ and C-6′ used to restrict the motion of the side chain, the position of the C-6′ hydroxy group was fine tuned to probe for the optimal conformation for inhibition of the ribosome. While the changes in orientation of the 6′-hydroxy group cannot be completely dissociated from the size and hydrophobicity of the conformation-restricting ring, overall, it is apparent that the preferred conformation of the ring I side chain for interaction with A1408 in the decoding A site of the bacterial ribosome is an ideal gt conformation, which results in the highest antimicrobial activity as well as increased selectivity for bacterial over eukaryotic ribosomes.

Carbohydrate chemistry is an essential component of the glycosciences and is fundamental to their progress. This perspective takes the position that carbohydrate chemistry, or glycochemistry, has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author’s and other laboratories. The first of these potential inflexion points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the experimental evidence supports bimolecular S(N)2-like mechanisms for typical glycosylation reactions over unimolecular ones involving stereoselective attack on naked glycosyl oxocarbenium ions. Similarly, it is argued that the experimental evidence does not support long range stereodirecting participation of remote esters through bridged bicyclic dioxacarbenium ions in organic solution in the presence of typical counterions. Rational design and improvement of glycosylation reactions must take into account the role of the counterion and of concentration. A second crossroads is that between mainstream organic chemistry and glycan synthesis. The case is made that the only real difference between glycan and organic synthesis is the formation of C-O rather than C-C bonds, with diastereocontrol, strategy, tactics and elegance being of critical importance in both areas: mainstream organic chemists should feel comfortable taking this fork in the road, just as carbohydrate chemists should travelling in the opposite direction. A third crossroads is that between carbohydrate chemistry and medicinal chemistry, where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the last decade or so, but the creativity, input and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.

The influence on glycosyl selectivity of substituting oxygen for sulfur at the 3-position of 4,6-O-benzylidene-protected mannopyranosyl thioglycosides is reported and varies considerably according to the protecting group employed at the 3-position. The substitution of a thioether at the 3-position for the more usual 3-O-benzyl ether results in a significant loss of selectivity. The installation of a 3-S-picolinyl thioether results in a complex reaction mixture, from which a stable seven-membered bridged bicyclic pyridinium ion is isolated, while the corresponding 3-O-picolinyl ether affords a highly α-selective coupling reaction. A 3-O-picolyl ester provides excellent β-selectivity, while the analogous 3-S-picolyl thioester gives a highly α-selective reaction. The best β-selectivity is seen with a 3-deoxy-3-(2-pyridinyldisulfanyl) system. These observations are discussed in terms of the influence of the various substituents on the central glycosyl triflate – ion pair equilibrium.

The preparation of glycosyl dibutyl phosphates in the 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) and pseudaminic acid series and their application to the formation of C-glycosides are described. Both donors were obtained from the corresponding thioglycosides by treatment with dibutylphosphoric acid and N-iodosuccinimide. As with the thioglycosides, both donors adopted very predominantly the strongly electron-withdrawing tg conformation of their side chains, which is reflected in the excellent equatorial selectivity of both donors in the formation of exemplary O-glycosides. With respect to C-glycoside formation on the other hand, contrasting results were observed: the KDO donor was either relatively unselective or selective for the formation of the axial C-glycoside, while the pseudaminic acid donor was selective for the formation of the equatorial C-glycoside. These observations are rationalized in terms of the greater electron-withdrawing ability of the azides in the pseudaminic acid donor compared to the corresponding acetoxy groups in the KDO series, resulting in a reaction through tighter ion pairs even at the SN1 end of the general glycosylation mechanism. The contrast in the axial versus the equatorial selectivity between C- and O-glycosylation cautions against the extrapolation of models for SN1-type glycosylation with weak nucleophiles for the explanation of O-glycosylation.

Carbohydrate side chain conformation confers a significant influence on reactivity during glycosylation and anomeric bond hydrolysis due to stabilization of the oxocarbenium intermediate or oxocarbenium-like transition state. By analysis of 513 pyranoside-bound glycoside hydrolase (GH) crystal structures, we determine that most glucosidases and β-mannosidases preferentially bind their substrates in the most reactive gauche,gauche (gg) conformation, thereby maximizing stabilization of the corresponding oxocarbenium ion-like transition state during hydrolysis. α-Galactoside hydrolases mostly show a preference for the second most activating gauche,trans (gt) conformation to avoid the energy penalty that would arise from imposing the gg conformation on galacto-configured ligands. These preferences stand in stark contrast to the side chain populations observed for these sugars both in free solution and bound to non-hydrolytic proteins, where for the most part a much greater diversity of side chain conformations is observed. Analysis of sequences of GH-ligand complexes reveals that side chain restriction begins with the enzyme-substrate complex and persists through the transition state until release of the hydrolysis product, despite changes in ring conformation along the reaction coordinate. This work will inform the design of new generations of glycosidase inhibitors with restricted side chains that confer higher selectivity and/or affinity.

Magnesium dialkylamides react with alcohol-derived 2-methyl-2-tetrahydropyranyl alkyl peroxides (MTHPs) in tetrahydrofuran at 0 °C to give N,N,O-trisubstituted hydroxylamines suitable for medicinal...

We describe the synthesis of 10-aza-9-oxakalkitoxin, an N,N,O-trisubstituted hydroxylamine-based analog, or hydroxalog, of the cytotoxic marine natural product kalkitoxin in which the -NMe-O- moiety replaces a -CHMe-CH2- unit in the backbone of the natural product. 10-Aza-9-oxakalkitoxin displays potent and selective cytotoxicity (IC50 2.4 ng mL-1) comparable to that of kalkitoxin itself (IC50 3.2 ng mL-1) against the human hepato-carcinoma cell line HepG2 over both the human leukemia cell line CEM and the normal hematopoietic CFU-GM. Like kalkitoxin, and contrary to the common expectation for hydroxylamines, 10-aza-9-oxakalkitoxin is not mutagenic.

To facilitate the synthesis of paromomycin and/or neomycin analogues, we describe a cleavage of ring I from paromomycin that proceeds in the presence of azides and affords a glycosyl acceptor for the installation of a modified ring I. A paromomycin 4',6'-diol is oxidized by the Dess-Martin periodinane followed by m-chloroperoxybenzoic acid. Base treatment then affords a protected pseudodisaccharide, which functions as a glycosyl acceptor. The method should also apply to the cleavage of pyranosyl 4,6-diols from oligosaccharides and glycoconjugates.

The pseudosymmetric relationship of the bacterial sialic acid, pseudaminic acid, and 3-deoxy-d-manno-oct-2-ulosonic acid (KDO) affords the hypothesis that suitably protected KDO donors will adopt the trans, gauche conformation of their side chain and consequently be highly equatorially selective in their coupling reactions conducted at low temperature. This hypothesis is borne out by the synthesis, conformational analysis, and excellent equatorial selectivity seen on coupling of per-O-acetyl or benzyl-protected KDO donors in dichloromethane at -78 °C. Mechanistic understanding of glycosylation reactions is advancing to a stage at which predictions of selectivity can be made. In this instance, predictions of selectivity provide the first highly selective entry into KDO equatorial glycosides such as are found in the capsular polysaccharides of numerous pathogenic bacteria.

We describe a formal synthesis of 10-aza-9-oxakalkitoxin, the hydroxalog of the cytotoxic marine natural product kalkitoxin, that features Mukaiyama Markovnikov silyl peroxidation of a terminal alkene and N-O bond formation as the central enabling steps.

We describe the synthesis of the unusual bicyclic sugar bradyrhizose in 14 steps and a 6% overall yield from d-glucose. The synthesis involves the elaboration of a trans-fused carbocyclic ring onto the preexisting glucopyranose framework followed by adjustment of the oxidation levels. Key steps include radical extension of the glucopyranose side chain, ring closing metathesis, allylic oxidation, Luche reduction, hydroxy-directed epoxidation, and acid-catalyzed epoxide opening at the more substituted position.

Apramycin is a structurally unique member of the 2-deoxystreptamine class of aminoglycoside antibiotics characterized by a monosubstituted 2-deoxystreptamine ring that carries an unusual bicyclic eight-carbon dialdose moiety. Because of its unusual structure, apramycin is not susceptible to the most prevalent mechanisms of aminoglycoside resistance including the aminoglycoside-modifying enzymes and the ribosomal methyltransferases whose widespread presence severely compromises all aminoglycosides in current clinical practice. These attributes coupled with minimal ototoxocity in animal models combine to make apramycin an excellent starting point for the development of next-generation aminoglycoside antibiotics for the treatment of multidrug-resistant bacterial infections, particularly the ESKAPE pathogens. With this in mind, we describe the design, synthesis, and evaluation of three series of apramycin derivatives, all functionalized at the 5-position, with the goals of increasing the antibacterial potency without sacrificing selectivity between bacterial and eukaryotic ribosomes and of overcoming the rare aminoglycoside acetyltransferase (3)-IV class of aminoglycoside-modifying enzymes that constitutes the only documented mechanism of antimicrobial resistance to apramycin. We show that several apramycin-5-O-β-d-ribofuranosides, 5-O-β-d-eryrthofuranosides, and even simple 5-O-aminoalkyl ethers are effective in this respect through the use of cell-free translation assays with wild-type bacterial and humanized bacterial ribosomes and of extensive antibacterial assays with wild-type and resistant Gram negative bacteria carrying either single or multiple resistance determinants. Ex vivo studies with mouse cochlear explants confirm the low levels of ototoxicity predicted on the basis of selectivity at the target level, while the mouse thigh infection model was used to demonstrate the superiority of an apramycin-5-O-glycoside in reducing the bacterial burden in vivo.

We describe the synthesis and side chain conformational analysis of a series of four 6-deoxy-2,3,5-tri-O-benzyl hexofuranosyl donors with the D-gluco, L-ido, D-altro, and L-galacto configurations. The conformation of the exocyclic bond of these compounds depends on the relative configuration of the point of attachment of the side chain to the ring and of the two flanking centers and can be predicted on that basis analogously to the heptopyranose analogs. Variable-temperature nuclear magnetic resonance (VT NMR) spectroscopy of the activated donors reveals complex, configuration-dependent mixtures of intermediates that we interpret in terms of fused and bridged oxonium ions arising from participation by the various benzyl ethers. The increased importance of ether participation in the furanoside series compared to the pyranosides is discussed in terms of the reduced stabilization afforded to furanosyl oxocarbenium ions by covalent triflate formation. The stereoselectivities of the four donors are discussed on the basis of the benzyl ether participation model.

We describe the novel oxidative fragmentation of methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-5-deoxy-3-O-trifluoromethanesulfonyl-β-d-erythro-l-gluco-2-nonulopyranos)onate 2 on stirring with sodium nitrite in DMF to give the novel 3-acetamido-2,5,6,7-tetra-O-acetyl-d-glycero-d-galacto-heptono-1,4-lactone 3 in excellent yield. Stirring of the same triflate with sodium carbonate on the other hand affords the novel methyl (5-acetamido-7,8,9-tri-O-acetyl-3,6-anhydro-5-deoxy-d-manno-3-ene-2-nonulos)onate 19 also in excellent yield. Reduction of the heptono lactone with sodium borohydride followed by acetylation gives a peracetylated aminodeoxyheptitol 6 that adopts the zig zag conformation of its carbon backbone.

Background The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Graphical abstract, Although scientists around the world have put lots of effort into the development of new treatments for COVID-19 since the outbreak, no drugs except Veklury (remdesivir) have been approved by FDA. There is an urgent need to discover some alternative antiviral treatment for COVID-19. Because polyphenols have been shown to possess antiviral activities, here we conducted a large-scale virtual screening for more than 400 polyphenols. Several lead compounds such as Petunidin 3-O-(6''-p-coumaroyl-glucoside) were identified to have promising binding affinities and convincing binding mechanisms. Analyzing the docking results and ADME properties sheds light on the potential efficacy of the top-ranked drug candidates and pinpoints the key residues on the target proteins for the future of drug development.

Carbohydrate side chain conformation is an important factor in the control of reactivity at the anomeric center, ie, in the making and breaking of glycosidic bonds, whether chemically or, for hydrolysis, by glycoside hydrolases. In nature glycosidic bond formation is catalyzed out by glycosyltransferases (GTs), glycoside phosphoryases, and transglycosidases. By analysis of 118 crystal structures of sugar nucleotide dependent (Leloir) GTs, 136 crystal structures of glycoside phosphorylases, and 54 crystal structures of transglycosidases bound to hexopyranosides or their analogs at the donor site (-1 site), we determined that most enzymes that catalyze glycoside synthesis, be they GTs, glycoside phosphorylases or transglycosidases, restrict their substrate side chains to the most reactive gauche,gauche (gg) conformation to achieve maximum stabilization of the oxocarbenium ion-like transition state for glycosyl transfer. The galactose series deviates from this trend, with α-galactosyltransferases preferentially restricting their substrates to the second-most reactive gauche,trans (gt) conformation, and β-galactosyltransferases favoring the least reactive trans,gauche (tg) conformation. This insight will help progress the design and development of improved, conformationally-restricted GT inhibitors that take advantage of these inherent side chain preferences.

The preparation of four per-O-benzyl-d- or l-glycero-d-galacto and d- or l-glycero-d-gluco heptopyranosyl sulfoxides, and the influence of their side chain conformations on reactivity and stereoselectivity in glycosylation reactions are described. The side chain conformation in these donors is determined by the relative configuration of its point of attachment to the pyranoside ring and the two flanking centers in agreement with a recent model. In the d- and l-glycero-d-galacto glycosyl donors the d-glycero-d-galacto isomer with the more electron-withdrawing trans,gauche conformation of its side chain was the more equatorially-selective isomer. In the d- and l-glycero-d-gluco glycosyl donors, the l-glycero-d-gluco isomer with the least disarming gauche,gauche side chain conformation was the most equatorially selective donor. Variable temperature NMR studies, while supporting the formation of intermediate glycosyl triflates at −80 °C in all cases, were inconclusive owing to a change in decomposition mechanism with the change in configuration. It is suggested that the equatorial selectivity of the l-glycero-d-gluco isomer arises from H-bonding between the glycosyl acceptor and O6 of the donor which is poised to deliver the acceptor antiperiplanar to the glycosyl triflate resulting in a high degree of S(N)2 character in the displacement reaction.

The reaction of magnesium amides with

Low-temperature NMR studies with a 4-C-methyl-4-O-benzoyl galactopyranosyl donor enable the observation and characterization of a bridged bicyclic dioxacarbenium ion arising from participation by a distal ester. Variable temperature NMR studies reveal this bridged ion to decompose at temperatures above ~−30 °C. In the absence of the methyl group, the formation of a bicyclic ion is not observed. It is concluded that participation by typical secondary distal esters in glycosylation reactions is disfavored in the ground state conformation of the ester from which it is stereoelectronically impossible. Methylation converts the secondary ester to a conformationally more labile tertiary ester, removes this barrier, and renders participation more favorable. Nevertheless, the minor changes in selectivity in model glycosylation reactions on going from the secondary to the tertiary esters at both low and room temperature argue against distal group participation being a major stereodirecting factor even for the tertiary system.

The role of ortho esters in the formation of 2,3,4-tri

Propylamycin (4'-deoxy-4'-propylparomomycin) is a next generation aminoglycoside antibiotic that displays increased antibacterial potency over the parent, coupled with reduced susceptibility to resistance determinants and reduced ototoxicity in the guinea pig model. Propylamycin nevertheless is inactivated by APH(3')-Ia, a specific aminoglycoside phosphotransferase isozyme that acts on the primary hydroxy group of the ribofuranosyl moiety (at the 5''-position). To overcome this problem, we have prepared and studied the antibacterial and antiribosomal activity of various propylamycin derivatives carrying amino or substituted amino groups at the 5''-position in place of the vulnerable hydroxy group. We find that the introduction of an additional basic amino group at this position, while overcoming the action of the aminoglycoside phosphoryltransferase isozymes acting at the 5''-position as anticipated, results in a significant drop in selectivity for the bacterial over the eukaryotic ribosomes that is predictive of increased ototoxicity. In contrast, 5''-deoxy-5''-formamidopropylamycin retains the excellent across-the-board levels of antibacterial activity of propylamycin itself, while circumventing the action of the offending aminoglycoside phosphotransferase isozymes and affording even greater selectivity for the bacterial over the eukaryotic ribosomes. Other modifications to address the susceptibility of propylamycin to the APH(3')-Ia isozyme including deoxygenation at the 3'-position and incorporation of a 6',5''-bis(hydroxyethylamino) modification offer no particular advantage.