Designer oxazolidinones

Wang, D., Sherer, E., Duffy, E. A computational suite for the discovery of designer oxazolidinones suitable for IV and oral usage, in 45th Interscience Conference on Antimicrobial Agents and... 

Oxazolidinones and dihydrofuranones as inactivators and substrates of monoamine oxidase B, approaches to the design of antiparkinsonian agents 97F343. 

With Chiral Bis(oxazoline)/metal Complexes Several research groups have developed chiral Lewis acids by using chiral 1,3-bis(oxazoline) ligands for asymmetric Diels-AIder reactions. Evans designed C2-symmetric bis(oxazoline)/Cu(II) complexes derived from chiral bis(oxa-zoline)and Cu(OTf)2, and applied them to asymmetric cycloadditions of acryloyl oxazolidinones and thiazolidine-2-thione analogues. Attractive features of this catalyst system include a clearly interpretable geometry for the catalyst-dienophile complex, which rationalizes the sense of asymmetric induction for the cycloaddition process [26] (Eq. 8A.14). 

As has been well documented elsewhere (3, 4), there was roughly a 25-year gap between the introduction of the qninolone antibiotics and the next new chemical class of antibiotics, the oxazolidinones. During this interval, innovation in antibiotic drug design and discovery was focused on the semisynthetic tailoring of natnral prodnct antibiotic scaffolds to improve pharmacologic properties and, most importantly, to overcome resistance to existing antibiotics. 

Dermac SR-38 is one of a series of oxazolidinones, cyclic urethane compounds, evaluated as transdermal enhancers. The compound was designed to mimic natural skin lipids (such as ceramides), to be nonirritating, and to be rapidly cleared from the systemic circulation following absorption. In animal and human safety studies, Dermac SR-38 demonstrated a good skin tolerance (no observed irritancy or sensitization at levels of 1-10 wt% moderate to severe irritation in rabbit at 100%), and a low degree of acute toxicity (LD50(rat oral) > 5.0g/kg). The compound was evaluated for its ability to enhance the human skin permeation of diverse drugs from dermal and transdermal delivery systems. Data for minoxidil indicated an enhancer concentration-dependent effect for permeation enhancement. Dermac SR-38 was also found to enhance the skin retention of both retinoic acid when applied in Retin A cream, and dihydroxyacetone when applied in a hydrophilic cream. ... 

Keywords ribosome antibiotics RNA drug design molecular modeling crystallography docking QSAR Macrolides Oxazolidinones aminoglycosides molecular properties... 

This new family of oxazolidinones was described and shown to effectively displace compounds that bind the ribosomal 50S A-site (linezolid site), including chloramphenicol and Puromycin [80]. The structures of several family members (16-20) are depicted in Scheme 3. The reader is referred to the primary citations for tables of antibacterial activity data (as is the case for all case studies). Compounds such as 17 and 19 were compounds predicted to have good oral bioavailability in the QSAR model [79]. Compounds such as 16 were predicted to have good Haemophilus influenzae activity in that QSAR activity model [79]. The computational and crystallographically inspired design of novel oxazolidinones eventually led to Rib-X Pharmaceuticals clinical candidate, Radezolid (20), currently in Phase II clinical trials [31]. 

A recently new designed Wang resin supported Evans chiral auxiliary (52) has been shown to perform Evans asymmetric alkylation on solid support (Scheme 12.19) [34, 35], Preparation of the auxiliary started with coupling of Fmoc-piperidine-4-carboxylic acid to Wang resin. Subsequent removal of the Fmoc protection was followed by coupling to N-protected (2J ,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid. After deprotection, the amino-alcohol moiety was converted into the oxazolidinone auxiliary 52 using carbonyldiimidazole (CDI). 

Ahmed, S., S. Adat, A. Murrells, C.R Owen, and Y. Amanuel (2002). Design, synthesis, and evaluation of 4-(4 )-aminobenzyl)-2-oxazolidinones as novel inhibitors of the cytochrome P-450 enzyme aromatase. Bioorg. Chem. 30, 315-331. 

The abihties of the tube-in-tube design was further expanded by Buba et al. (2013EJOC4509). For the synthesis of the oxazolidinone 36, formaldehyde was used in the gaseous state by heating paraformaldehyde to 80 °C. The tube-in-tube reactor needs to be kept at a temperature higher than 80 °C to prevent polymerization and subsequent precipitation of paraformaldehyde onto the membrane surface. Formaldehyde reacted with Fmoc-protected alanine 35 in the presence of a catalytic amount ofp-tolue-nesulfonic acid in acetonitrile to achieve N-Fmoc-L-4-methyl-oxazohdin-5-one 36 in excellent yield (91% Scheme 9) (2013EJOC4509). 

Several routes to the hydroxyoxazolidinones, 1, were designed. The route which proved most successful was based on the approach used for the hydroxypyrrolidinones 2. The key step in this approach was the ozonolysis of the double bond to yield the 5-hydroxy-oxazolidinone ring, 1 (3). With this as the anchoring reaction in the process, two routes to the double bond carbamate 9 were envisioned. 

A number of chiral auxiliaries has been designed for enantioselective 1,4-addition to a, -unsaturated carbonyl compounds. Chiral oxazolidinones are among the most efficient, affording the Michael-adducts with up to 99% ee. Asymmetric conjugate addition of an arylmagnesium reagent to cinnamoyloxazolidinone 151 is the key step in the synthesis of (+)-tolterodine 152, an important muscarinic receptor agonist (Scheme 2-58). 

To circumvent this problem, asymmetric 1,3-dipolar cycloaddition catalyzed by a metallic Lewis acid catalyst was designed to use electron-deficient alkene as a dipolarophile that has a chelating ligand structure, such as A-acyl oxazolidinone (Figure 11.2). The incorporation of a Lewis acid was expected to be equilibrating between 1,3-dipole and dipolarophile in the reaction and the reaction rate acceleration of cycloaddition occurs only in the Lewis acid/dipolarophile complex [4]. 

In addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

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