Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade.

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,ß-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.

Nine-Step Stereoselective Synthesis of Islatravir from Deoxyribose.

A stereoselective nine-step synthesis of the potent HIV nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (EfdA, MK-8591) from 2-deoxyribose is described. Key findings include a diastereodivergent addition of an acetylide nucleophile to an enolizable ketone, a chemoselective ozonolysis of a terminal olefin and a biocatalytic glycosylation cascade that uses a unique strategy of byproduct precipitation to drive an otherwise-reversible transformation forward.

Origins of cell selectivity of cationic steroid antibiotics.

A key factor in the potential clinical utility of membrane-active antibiotics is their cell selectivity (i.e., prokaryote over eukaryote). Cationic steroid antibiotics were developed to mimic the lipid A binding character of polymyxin B and are shown to bind lipid A derivatives with affinity greater than that of polymyxin B. The outer membranes of Gram-negative bacteria are comprised primarily of lipid A, and a fluorophore-appended cationic steroid antibiotic displays very high selectivity for Gram-negative bacterial membranes over Gram-positive bacteria and eukaryotic cell membranes. This cell selectivity of cationic steroid antibiotics may be due, in part, to the affinity of these compounds for lipid A.

Synthesis and characterization of peptide-cationic steroid antibiotic conjugates.

[reaction: see text] New cationic steroid antibiotics have been prepared by conjugating tripeptides to a triamino analogue of cholic acid. These compounds were synthesized on a solid phase in an indexed library that was screened for antibacterial activity against Gram-negative and Gram-positive bacteria. Selected compounds were synthesized on a larger scale, and minimum inhibition concentrations were measured. These results correlated very well with the screening of the indexed library of antibiotics. The most active antibiotics demonstrate a marked improvement over a related and well characterized cationic steroid antibiotic.

Detection of VX contamination in soil through solid-phase microextraction sampling and gas chromatography/mass spectrometry of the VX degradation product bis(diisopropylaminoethyl)disulfide.

A solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS) sampling and analysis method was developed for bis(diisopropylaminoethyl)disulfide (a degradation product of the nerve agent VX) in soil. A 30-min sampling time with a polydimethylsiloxane-coated fiber and high temperature alkaline hydrolysis allowed detection with 1.0 microg of VX spiked per g of agricultural soil. The method was successfully used in the field with portable GC-MS instrumentation. This method is relatively rapid (less than 1 h), avoids the use of complex preparation steps, and enhances analyst safety through limited use of solvents and decontamination of the soil before sampling.

Trimethyl phosphite as a trap for alkoxy radicals formed from the ring opening of oxiranylcarbinyl radicals. Conversion to alkenes. Mechanistic applications to the study of C-C versus C-O ring cleavage.

Trimethyl phosphite, (MeO)(3)P, is introduced as an efficient and selective trap in oxiranylcarbinyl radical (2) systems, formed from haloepoxides 8-13 under thermal AIBN/n-Bu(3)SnH conditions at about 80 degrees C. Initially, the transformations of 8-13, in the absence of phosphite, to allyl alcohol 7 and/or vinyl ether 5 were measured quantitatively (Table 1). Structural variations in the intermediate oxiranylcarbinyl (2), allyloxy (3), and vinyloxycarbinyl (4) radicals involve influences of the thermodynamics and kinetics of the C-O (2 --> 3, k(1)) and C-C (2 --> 4, k(2)) radical scission processes and readily account for the changes in the amounts of product vinyl ether (5) and allyl alcohol (7) formed. Added (MeO)(3)P is inert to vinyloxycarbinyl radical 4 and selectively and rapidly traps allyloxy radical 3, diverting it to trimethyl phosphate and allyl radical 6. Allyl radicals (6) dimerize or are trapped by n-Bu(3)SnH to give alkenes, formed from haloepoxides 8, 9, and 13 in 69-95% yields. Intermediate vinyloxycarbinyl radicals (4), in the presence or absence of (MeO)(3)P, are trapped by n-Bu(3)SnH to give vinyl ethers (5). The concentrations of (MeO)(3)P and n-Bu(3)SnH were varied independently, and the amounts of phosphate, vinyl ether (5), and/or alkene from haloepoxides 10, 11, and 13 were carefully monitored. The results reflect readily understood influences of changes in the structures of radicals 2-4, particularly as they influence the C-O (k(1)) and C-C (k(2)) cleavages of intermediate oxiranylcarbinyl radical 2 and their reverse (k(-1), k(-2)). Diversion by (MeO)(3)P of allyloxy radicals (3) from haloepoxides 11 and 12 fulfills a prior prediction that under conditions closer to kinetic control, products of C-O scission, not just those of C-C scission, may result. Thus, for oxiranylcarbinyl radicals from haloepoxides 11, 12, and 13, C-O scission (k(1), 2 --> 3) competes readily with C-C cleavage (k(2), 2 --> 4), even though C-C scission is favored thermodynamically.

Radical-induced formation of some siloles and diazasiloles.

The Bu(3)Sn radical-induced reaction of o-iodobenzylvinylsilanes and o-iodoallylsilanes leads to cyclic products in yields of 40-60%. These regioselective cyclizations occur with high preference for a 5-exo and a 7-endo mode with a 6-exo mode being absent. An example for ring closure via a 7-exo mode is described.

Antibacterial properties of cationic steroid antibiotics.

Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activity. These compounds are comprised of steroids appended with amine groups arranged to yield facially amphiphilic morphology. Examples of these antibiotics are highly bactericidal, while related compounds effectively permeabilize the outer membranes of Gram-negative bacteria sensitizing these organisms to hydrophobic antibiotics. Cationic steroid antibiotics exhibit various levels of eukaryote vs. prokaryote cell selectivity, and cell selectivity can be increased via charge recognition of prokaryotic cells. Studies of the mechanism of action of these antibiotics suggest that they share mechanistic aspects with cationic peptide antibiotics.

Correlation of the antibacterial activities of cationic peptide antibiotics and cationic steroid antibiotics.

The antibacterial activities of cationic steroid antibiotics and cationic peptide antibiotics have been compared. Depolarization of bacterial membranes, activation of bacterial stress-related gene promoters, and changes in bacterial morphologies caused by these antibiotics suggest that cationic steroid and peptide antibiotics share mechanistic aspects. Modified cationic steroid antibiotics display improved selectivity for prokaryotic cells over eukaryotic cells presumably due to increased charge recognition.

First Synthesis and Structure of a Tetraazasilafenestrane.

A shift from the computational to the synthetic side has taken place in the quest for compounds containing planar-tetracoordinate silicon: The first tetraazasilaspiro[4.4]nonane with two alkylene bridges has been prepared [Eq. (1)]. According to the X-ray structure analysis, the angle between the two diazasilacyclopentene rings is 84.7°. AIBN=azobisisobutyronitrile, X=Br.