C1-CBP-vancomycin: Impact of a Vancomycin C-Terminus Trimethylammonium Cation on Pharmacological Properties and Insights into Its Newly Introduced Mechanism of Action.

C1-CBP-vancomycin (3) was examined alongside CBP-vancomycin for susceptibility to acquired resistance upon serial exposure against two vancomycin-resistant enterococci strains where its activity proved more durable and remarkably better than many current therapies. Combined with earlier studies, this observation confirmed an added mechanism of action was introduced by incorporation of the trimethylammonium cation and that C1-CBP-vancomycin exhibits activity against vancomycin-resistant organisms through two synergistic mechanisms of action, both independent of d-Ala-d-Ala/d-Lac binding. New insights into this added mechanism of action, induced cell membrane permeabilization, can be inferred from studies that show added exogenous lipoteichoic acid reduces antimicrobial activity, rescues bacteria cell growth inhibition, and blocks induced cell permeabilization properties of C1-CBP-vancomycin, suggesting a direct binding interaction with embedded teichoic acid is responsible for the added mechanism of action and enhanced antimicrobial activity. Further studies indicate that the trimethylammonium cation does not introduce new liabilities in common pharmacological properties of the analogue and established that 3 is well tolerated in mice, displays substantial PK improvements over both vancomycin and CBP-vancomycin, and exhibits in vivo efficacy against a challenging multidrug-resistant and vancomycin-resistant S. aureus strain that is representative of the resistant pathogens all fear will emerge in the general population.

Total Synthesis and Stereochemical Assignment of Streptide.

Streptide (1) is a peptide-derived macrocyclic natural product that has attracted considerable attention since its discovery in 2015. It contains an unprecedented post-translational modification that intramolecularly links the ß-carbon (C3) of a residue 2 lysine with the C7 of a residue 6 tryptophan, thereby forming a 20-membered cyclic peptide. Herein, we report the first total synthesis of streptide that confirms the regiochemistry of the lysine-tryptophan cross-link and provides an unambiguous assignment of the stereochemistry (3R vs 3S) of the lysine-2 C3 center. Both the 3R and the originally assigned 3S lysine diastereomers were independently prepared by total synthesis, and it is the former, not the latter, that was found to correlate with the natural product. The approach enlists a powerful Pd(0)-mediated indole annulation for the key macrocyclization of the complex core peptide, utilizes an underdeveloped class of hypervalent iodine(III) aryl substrates in a palladium-catalyzed C-H activation/ß-arylation reaction conducted on a lysine derivative, and provides access to material with which the role of streptide and related natural products may be examined.

N-Terminus Alkylation of Vancomycin: Ligand Binding Affinity, Antimicrobial Activity, and Site-Specific Nature of Quaternary Trimethylammonium Salt Modification.

A series of vancomycin derivatives alkylated at the N-terminus amine were synthesized, including those that contain quaternary trimethylammonium salts either directly at the terminal amine site or with an intervening three-carbon spacer. The examination of their properties provides important comparisons with a C-terminus trimethylammonium salt modification that we recently found to improve the antimicrobial potency of vancomycin analogues through an added mechanism of action. The N-terminus modifications disclosed herein were well-tolerated, minimally altering model ligand binding affinities (d-Ala-d-Ala) and antimicrobial activity, but did not induce membrane permeabilization that was observed with a similar C-terminus modification. The results indicate that our earlier observations with the C-terminus modification are sensitive to the site as well as structure of the trimethylammonium salt modification and are not simply the result of nonspecific effects derived from introduction of a cationic charge.

Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics.

Subsequent to binding pocket modifications designed to provide dual d-Ala-d-Ala/d-Ala-d-Lac binding that directly overcome the molecular basis of vancomycin resistance, peripheral structural changes have been explored to improve antimicrobial potency and provide additional synergistic mechanisms of action. A C-terminal peripheral modification, introducing a quaternary ammonium salt, is reported and was found to provide a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of d-Ala-d-Ala/d-Ala-d-Lac binding. This modification, which induces cell wall permeability and is complementary to the glycopeptide inhibition of cell wall synthesis, was found to provide improvements in antimicrobial potency (200-fold) against vancomycin-resistant Enterococci (VRE). Furthermore, it is shown that this type of C-terminal modification may be combined with a second peripheral (4-chlorobiphenyl)methyl (CBP) addition to the vancomycin disaccharide to provide even more potent antimicrobial agents [VRE minimum inhibitory concentration (MIC) = 0.01-0.005 µg/mL] with activity that can be attributed to three independent and synergistic mechanisms of action, only one of which requires d-Ala-d-Ala/d-Ala-d-Lac binding. Finally, it is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by VRE and that their durability against such challenges as well as their antimicrobial potency follow now predictable trends (three > two > one mechanisms of action). Such antibiotics are expected to display durable antimicrobial activity not prone to rapidly acquired clinical resistance.

Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues.

A review of efforts that have provided total syntheses of vancomycin and related glycopeptide antibiotics, their agylcons, and key analogues is provided. It is a tribute to developments in organic chemistry and the field of organic synthesis that not only can molecules of this complexity be prepared today by total synthesis but such efforts can be extended to the preparation of previously inaccessible key analogues that contain deep-seated structural changes. With the increasing prevalence of acquired bacterial resistance to existing classes of antibiotics and with the emergence of vancomycin-resistant pathogens (VRSA and VRE), the studies pave the way for the examination of synthetic analogues rationally designed to not only overcome vancomycin resistance but provide the foundation for the development of even more powerful and durable antibiotics.

Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis.

Given the huge dependence on dipolar, aprotic solvents such as DMF, DMSO, DMAc, and NMP in nucleophilic aromatic substitution reactions (SNAr), a simple and environmentally friendly alternative is reported. Use of a "benign-by-design" nonionic surfactant, TPGS-750-M, in water enables nitrogen, oxygen, and sulfur nucleophiles to participate in SNAr reactions. Aromatic and heteroaromatic substrates readily participate in this micellar catalysis, which takes place at or near ambient temperatures.

Dehalogenation of Functionalized Alkyl Halides in Water at Room Temperature.

Alkyl bromides and chlorides can be reduced to the corresponding hydrocarbons utilizing zinc in the presence of an amine additive. The process takes place in water at ambient temperatures, enabled by a commercially available designer surfactant. The reaction medium can be readily recycled, and the amount of organic solvent invested for product isolation is minimal, leading to very low E Factors.

Copper-catalyzed hydrophosphinations of styrenes in water at room temperature.

Copper-catalyzed hydrophosphinations of styrenyl systems in water, at room temperature is herein reported, enabled by our 'designer' surfactant TPGS-750-M. This is an attractive alternative to the more common Pd and Pt catalyzed versions.

Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis.

A single set of conditions consisting of a palladium catalyst, a commercially available ligand, and a base, allow for several types of C-N bond constructions to be conducted in water with the aid of a commercially available "designer" surfactant (TPGS-750-M). Products containing a protected NH2 group in the form of a carbamate, sulfonamide, or urea can be fashioned starting with aryl or heteroaryl bromides, iodides, and in some cases, chlorides, as substrates. Reaction temperatures are in the range of room temperature to, at most, 50 °C, and result in essentially full conversion and good isolated yields.

Leveraging the micellar effect: gold-catalyzed dehydrative cyclizations in water at room temperature.

The first examples of gold-catalyzed cyclizations of diols and triols to the corresponding hetero- or spirocycles in an aqueous medium are presented. These reactions take place within nanomicelles, where the hydrophobic effect is operating, thereby driving the dehydrations, notwithstanding the surrounding water. By the addition of simple salts such as sodium chloride, reaction times and catalyst loadings can be significantly decreased.

Transforming Suzuki-Miyaura cross-couplings of MIDA boronates into a green technology: no organic solvents.

New technology has been developed that enables Suzuki-Miyaura couplings involving widely utilized MIDA boronates to be run in water as the only medium, mainly at room temperature. The protocol is such that no organic solvent is involved at any stage; from the reaction through to product isolation. Hence, using the E factor scale as a measure of greenness, the values for these cross-couplings approach zero.

On the way towards greener transition-metal-catalyzed processes as quantified by E factors.

Transition-metal-catalyzed carbon-carbon and carbon-heteroatom bond formations are among the most heavily used types of reactions in both academic and industrial settings. As important as these are to the synthetic community, such cross-couplings come with a heavy price to our environment, and sustainability. E Factors are one measure of waste created, and organic solvents, by far, are the main contributors to the high values associated, in particular, with the pharmaceutical and fine-chemical companies which utilize these reactions. An alternative to organic solvents in which cross-couplings are run can be found in the form of micellar catalysis, wherein nanoparticles composed of newly introduced designer surfactants enable the same cross-couplings, albeit in water, with most taking place at room temperature. In the absence of an organic solvent as the reaction medium, organic waste and hence, E Factors, drop dramatically.

C-C bond formation via copper-catalyzed conjugate addition reactions to enones in water at room temperature.

Conjugate addition reactions to enones can now be done in water at room temperature with in situ generated organocopper reagents. Mixing an enone, zinc powder, TMEDA, and an alkyl halide in a micellar environemnt containing catalytic amounts of Cu(I), Ag(I), and Au(III) leads to 1,4-adducts in good isolated yields: no organometallic precursor need be formed.

Rhodium-Catalyzed Asymmetric 1,4-Additions, in Water at Room Temperature, with In-Flask Catalyst Recycling.

Using the newly introduced designer surfactant polyethyleneglycol ubiquinol sebacate (PQS), as the platform for micellar catalysis, nonracemic BINAP has been covalently attached and rhodium(I) inserted to form PQS-BINAP-Rh. This species, the first example of a nonracemically-ligated transition metal catalyst-tethered amphiphile, can be utilized for Rh-catalyzed asymmetric conjugate addition reactions of arylboronic acids to acyclic and cyclic enones. These are performed in water at room temperature, while the catalyst can be recycled without its removal from water in the reaction vessel.

Alkoxide-catalyzed reduction of ketones with pinacolborane.

The reduction of ketones with pinacolborane (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) is catalyzed by 5 mol % NaOt-Bu at ambient temperature. The reaction is high yielding and general, providing complete conversion of aryl and dialkyl ketones. Although spectroscopic studies of the active hydride source in benzene-d(6) were complicated due to poor solubility, the data are consistent with the active hydride source being the trialkoxyborohydride, which is believed to be present in low concentration under the reaction conditions. Performing analogous studies in tetrahydrofuran resulted in a complex equilibrium between several different boron-containing species in which the trialkoxyborohydride compound was the major species.

Synthesis of Ruthenium Boryl Analogues of the Shvo Metal-Ligand Bifunctional Catalyst.

Metal boryl complexes have received significant attention in the literature in recent years due to their role as key intermediates in a number of metal-catalyzed borylation reactions. The ligand scaffold is known to have a significant impact on the observed reactivity of these metal boryl complexes. A synthetic strategy to access ruthenium boryl analogues of the Shvo metal-ligand catalysts is described. Heating a precursor to Shvo's catalyst (1) with bis(catecholato)diboron at 50 °C provided ruthenium boryl complex 3 [2,5-Ph(2)-3,4-Tol(2)(η(5)-C(4)COBcat)Ru(CO)(2)Bcat] (Bcat = catecholatoboryl). Addition of bis(catecholato)diboron to complex 1 in the presence of a phenol results in ruthenium boryl complex5 [2,5-Ph(2)-3,4-Tol(2)(η(5)-C(4)COH)Ru(CO)(2)Bcat] at 22 °C in 30% isolated yield. A single crystal X-ray analysis of complex 5 confirmed the assigned structure. An improved synthesis of ruthenium boryl complex 5 was developed by the in situ formation of complex 3 [2,5-Ph(2)-3,4-Tol(2)(η(5)-C(4)COBcat)Ru(CO)(2)Bcat] followed by addition of the phenol, resulting in a 51% yield.