Noteworthy Chemistry

November 21, 2011

MRSA strains respond to a neomycin analogue. The appearance and proliferation of multidrug-resistant Staphylococcus aureus (MRSA) strains have caused a serious health scare. Reliance on the potent antibiotic vancomycin led to the appearance of vancomycin-resistant strains and increased mortality rates in infected individuals.

In a quest to overcome MRSA, S. Hanessian and coauthors at the University of Montreal and Achaogen Inc. (South San Francisco, CA) selected the class of 4,5-disubstituted 2-deoxystreptamine aminoglycosides—which includes neomycin B (1) and paromomycin—for structural modification studies. The strategy for making analogues of 1 involves a deoxygenation of diols in two rings and an amide substitution at the N-1 position. These structural enhancements provide efficient access to the highly potent aminoglycoside 2 in six steps.

So that the structure can tolerate the subsequent deoxygenation step, neomycin B is initially protected with six N-carbobenzoxy (Cbz) groups to form intermediate 3 (see Figure 1). The sole hydroxymethyl group in 3 is protected as a triphenylmethyl (Tr) ether, then deoxygenated at the two trans-diol sites to form intermediate 4. (DMAP is p-dimethylaminopyridine.)

The authors note that the antibiotic butirosin contains the (l)-γ-amino-α-hydroxybutyramide group, which enhances and broadens the antibacterial spectrum compared with its simple congener that lacks this structure. They incorporated this side chain into intermediate 4 at its N-1 site by first treating it with mild base to deprotect the C-3-amino groups (see Figure 2). The chiral side chain is introduced via acylation under standard peptide coupling conditions. Hydrogenation of 4 followed by deprotecting the remaining amine groups results in the target amide 2. [EDC is 1-ethyl-3-(3-dimethylaminopropyl)dicyclohexylcarbodiimide; DIPEA is diisopropylethylamine.]

A series of in vitro evaluations supported the potent activity of 2. Perhaps most importantly, 2 has significant activity against at least three aminoglycoside-resistant strains of S. aureus.

The authors then tested 2 against a series of 50 MSRA clinical isolates and measured a >64-fold increase in activity compared with amikacin and gentamicin, two antibiotics now used against resistant strains. This study provides evidence that antibiotics with specifically targeted structural modifications can be useful against multidrug-resistant S. aureus. (ACS Med. Chem. Lett. 2011, 2, Article ASAP DOI: 10.1021/ml200202y; W. Jerry Patterson)


Are we defeating cancer? In a question-and-answer article titled “Cancer research: Past, present, and future”, Y. Cao at Central South University (Changsha, China), R. A. DePinho at M. D. Anderson Cancer Center (Houston), M. Ernst at the Ludwig Institute Melbourne–Parkville Branch (Australia), and K. Vousden at the Beatson Institute of Cancer Research (Glasgow, UK) sum up what has been learned from cancer research in the past decade and predict where progress will be made in the next.

In the past 10 years, our understanding of cancer has progressed significantly, and cancer research has resulted in many new treatments. However, our knowledge of the disease and the technology available to learn more about it still are far from adequate. In the next decade, the focus will be on basic research to find effective, feasible, cost-efficient treatment methods. In the long run, prevention of new types of cancer, early detection of pathological changes, and the development of comprehensive treatment methods will be the basic strategies for controlling cancer. (Nat. Rev. 2011, 11, 749−754; Sally Peng Li)


A simplified celecoxib synthesis features direct arylation. Celecoxib (1) is a selective cyclooxygenase (COX-2) inhibitor used as a nonsteroidal anti-inflammatory agent against osteoarthritis, rheumatoid arthritis, menstrual discomfort, and other painful conditions. Current synthesis of celecoxib involves the hydrazination of a diketone or an α,β-unsaturated ketone or cycloaddition with a hydrazonyl sulfonate. These processes, however, produce regioisomeric pyrazole byproducts. S. M. Gaulier*, R. McKay, and N. A. Swain at Pfizer Global Research and Development (Sandwich, UK) developed a synthesis of the celecoxib that uses copper-mediated Ullmann coupling and palladium-mediated C–H bond arylation.

In the first step of the sequence, commercially available sulfonyl chloride 2 is aminated to produce N-protected iodosulfonamide 3 in 92% yield. Then trifluoropyrazole 4, also commercially available, is treated with 3 under Ullmann conditions to form compound 5 in 73% yield. No chromatographic purification is required because 5 in the sole regioisomer, as indicated by NMR spectroscopy. The reaction fails in the absence of the protecting group.

C–H bond arylation of intermediate 5 with p-bromotoluene produces compound 6, and removing the benzyl groups with strong acid gives 1 in ≈50% yield over the two steps. (PBuAd2 is butyldiadamantylphosphine; DMA is N,N-dimethylacetamide.) Again, NMR shows that no regioisomers are formed. (Tetrahedron Lett. 2011, 52, 6000–6002; JosÉ C. Barros)


Use a DABCO salt in an amide coupling reaction. In the synthesis of MK-0941, a potent glucokinase inhibitor, N. Yoshikawa, F. Xu, and co-workers at Merck Research Laboratories (Rahway, NJ) produced a differentially substituted 3,5-dihydroxybenzoate–1,4-diazabicyclo[2.2.2]octane (DABCO) salt as an intermediate. The salt was then subjected to an amide coupling with 1-methyl-3-aminopyrazole.

Originally, the free 3,5-dihydroxybenzoic acid was generated in advance of the amide coupling, but further studies showed that this step is unnecessary. The slow addition of 1 equiv aq HCl to an aq MeCN solution of the DABCO salt, the aminopyrazole, coupling agent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and a catalytic amount of pyridine cleanly produces MK-0941. The product can be isolated as the methanesulfonate salt in 90% yield and >99% purity. The authors scaled up the reaction to industrial quantities (>1 t) with no loss of yield or purity. (Org. Process Res. Dev. 2011, 15, 824–830; Will Watson)


An amphiphile exhibits polymorphic self-assembly and reversible vapochromism. Mechanistic understanding of self-assembly and organization processes of π-conjugated molecules is important for designing, preparing, and manipulating organic electronic and sensory systems. M. Kumar and S. J. George* at the Jawaharlal Nehru Center for Advanced Scientific Research (Bangalore, India) used spectroscopic techniques to probe the self-assembly processes of amphiphilic naphthalenediimide derivative 1 and showed that 1 undergoes reversible vapochromism.

The dynamic self-assembly of 1 in aqueous mixtures produces numerous polymorphic aggregate structures with differing optical properties that depend on the solvent composition. In thin films or the J-aggregated state in solution, molecules of 1 undergo reversible vapochromism with rapid, enhanced fluorescence responses to vapors of volatile organic compounds such as CHCl3. Spectroscopic monitoring of this enhanced fluorescence suggests a dynamic molecular reorganization of the J-type assembly to a preassociated H-type aggregate with excimer emission. (Chem.–Eur. J. 2011, 17, 11102–11106; Ben Zhong Tang)


Confine hierarchically structured materials in porous polyethylene. B. H. Jones and T. P. Lodge* at the University of Minnesota (Minneapolis) studied the confinement-induced assembly of polystyrene-b-polyisoprene (PS-b-PI), polyisoprene-b-poly(dimethylsiloxane) (PI-b-PDMS), polyisoprene-b-poly(2-vinylpyridine) (PI-b-P2VP), and blends of PI-b-P2VP with homopolymeric PI or P2VP. They conducted the assemblies within hard nanoporous polyethylene (PE) templates with a poly(ethylene-alt-polypropylene) (PEP) skin layer generated from bicontinuous microemulsions.

The authors filled 60–70 vol% of the templates with a THF solution of the block copolymers (BCPs) or BCP–homopolymer blends, then slowly removed the solvent to form bulk equilibrium morphologies. Transmission electron microscopy images of templated PI-b-P2VP and PS-b-PI showed significant contrast levels in the hierarchically assembled materials with interconnected BCP and PE networks and nanoscale assembly within the BCP phases.

For example, in the confined PI-b-P2VP (fPI = 0.18) system, a thin wetting layer of PI was seen next to the PE–PEP template, followed by a thicker P2VP region; fPI is the volume fraction of PI in the copolymer. The core of this material contained mainly dispersed cylindrical, helical, and disklike PI nanostructures in a P2VP matrix with dimensions similar to those observed in the bulk.

The authors used blends to examine confined morphologies as a function of variations in composition. In PI-b-P2VP–PI blends that contained an effective PI volume fraction of 0.40, the wetting layers were similar to those in pure PI-b-P2VP. The core, however, exhibited a range of self-assembled structures, from a pure PI core to multiple concentric PI and P2VP phases, depending upon the pore size of the tortuous PE template pathway. At the highest PI content, 71 vol%, the P2VP wetting layer was absent; but assorted dispersed P2VP nanostructures were present.

By using a selective solvent extraction strategy, the authors obtained porous, mechanically stable PI-b-P2VP systems that preserved the confined self-assembly nanostructure. These results mark an advance in hierarchically assembled porous materials. (ACS Nano 2011, 5, Article ASAP DOI: 10.1021/nn203096x; LaShanda Korley)


Make diastereopure products from α-trifluoromethyl carbonyls. Synthetic transformations that selectively incorporate the trifluoromethyl group are important in the pharmaceutical industry. The presence of CF3 groups can promote changes in molecular properties such as solubility, lipophilicity, metabolic stability, and bioavailability.

A. Togni, D. Cahard, and coauthors at the Swiss Federal Institute of Technology (Zurich) and the University and National Institute of Applied Sciences of Rouen (Mont-Saint-Aignan, France) noted previous studies on the strategic placement of CF3 groups by the diastereoselective functionalization of chiral imide enolates by radical trifluoromethylation. They now describe a synthetic strategy that promotes trifluoromethylation of the enolate intermediate by using an electrophilic CF3 transfer reagent instead of radical trifluoromethylation.

In a typical reaction sequence, an oxazolidinone substrate such as 1 is converted with lithium hexamethyldisilazide (LiHMDS) to the corresponding enolate, which is treated in situ with CF3–I reagent 2 to yield the α-trifluoromethyl carbonyl derivative 3 with as high as 97:3 dr.

A benzyl-substituted variant of structure 3 provides a versatile scaffold for mild, simple conversion to trifluoromethylated alcohol 4 or carboxylic acid 5, both in enantiopure form. The authors emphasize the use of electrophilic CF3 transfer reagents such as 2 that promote CF3 substitution with high diastereoselectivity. They also note that products 4 and 5 form without racemization. (Org. Lett. 2011, 13, 5762–5765; W. Jerry Patterson)


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