Noteworthy Chemistry

April 15, 2013

Detect ATP in water with a self-assembled host. One of the attractive features of self-assembly is that it opens a way to design sensors for biological systems without the problems associated with molecule-based sensors . A. J. H. M. Meijer, J. A. Thomas, and coauthors at the University of Sheffield (UK) and the University of Putra Malaysia (Serdang) devised a water-soluble, stable Ru2Re2 macrocycle that selectively recognizes adenosine triphosphate (ATP).

The authors synthesized three self-assembled heterometallic Ru2Re2 macrocycles (13) from ReCl(CO)5 and ruthenium bipyridine complexes. All three complexes have large cavity widths (≈15 Å) and emit red-light λmax values of ≈650 nm in MeCN and water. UV–vis absorption studies showed that the macrocycles form relatively stable (Ks ≈ 104–105) 1:1 host–guest complexes with adenine, ATP, and guanosine triphosphate (GTP).

Unexpectedly, binding with adenine does not change the emission of 13. The luminescence of macrocycle 3 increases when ATP is added, but the emission of 1 and 2 is quenched in the presence of ATP.

GTP emission is also quenched by 1 and 2, but it does not change the emission profile of 3. Computational studies indicate that the ATP frontier orbitals are significantly altered in its complex with 3, but there is little change in the GTP orbitals in the equivalent complex. Therefore, 3 can be used as a selective sensor for ATP that is free of interference from adenine and GTP. (Chem.—Eur. J. 2013, 19, 5081–5087; Xin Su)

Sometimes the original substituent works best. A. N. Campbell and co-workers at Eli Lilly (Indianapolis) developed an alternative route to a key intermediate in the synthesis of a Janus kinase 2 inhibitor. In one reaction, they used a vanadium catalyst to attach a benzylic morpholine substituent to the 8-position of an imidazopyridazine core.

In the original synthesis, the imidazopyridazine core contained an acyl group at the 3-position. The authors examined alternative less-functionalized substrates for this reaction as part of a program to improve the overall synthesis. With a hydrogen or benzyl substituent at the 3-position, the conversion of starting material in the oxidative alkylation was incomplete. With an ester or an acyl group, conversion is complete. This finding suggests that an electron-withdrawing group is required at the 3-position for the reaction to proceed efficiently.

The impurity profile with the ester is slightly different from the acyl starting material. With the ester, greater quantities of an endo-isomer are produced—as much as 25%, depending on the reaction conditions. As a result, the authors used the acyl group in the upgraded synthesis. (Org. Process Res. Dev. 2013, 17, 273–281; Will Watson)

Streamline the synthesis of atorvastatin. Atorvastatin (Lipitor, 1) is a blockbuster drug that is widely used for lowering low-density lipid serum cholesterol. N. Kumagai, M. Shibasaki, and coauthors at the Institute of Microbial Chemistry, Tokyo, and the University of Tokyo report a short, scalable synthesis of this active pharmaceutical ingredient.

The authors’ route consists of eight steps (Figures 1 and 2):

  1. a direct asymmetric aldol reaction between thione 2 and aldehyde 3 catalyzed by copper and a biphosphine ligand {Tr is trityl; (R,R)-Ph-BPE is 1,2-bis[(2R,5R)-2,5-diphenylphospholano]ethane};
  2. reduction of thiocarbamide 4 and filtration over silica gel to recover the catalyst;
  3. acidic deprotection of the trityl group in amino alcohol 5 to produce amino dialcohol 6;
  4. oxidation of 6 to the aldehyde and a subsequent Wittig reaction to form unsaturated ester 7;
  5. an intramolecular oxy-Michael reaction followed by protection with benzylidene to make cyclic ether 8;
  6. deprotection of the diallylamine to produce primary amine 9 [dba is dibenzylideneacetone; dppb is 1,4-bis(diphenylphosphino)butane];
  7. conversion of 9 and diketone 10 to precursor 11 via a Paal–Knorr pyrrole synthesis, followed by recrystallization to increase the enantiomeric excess of 11; and
  8. acidic, then basic hydrolysis to produce target molecule 1.

The scaled-up synthesis began with 30.6 g of aldehyde 3 and had an overall yield of 10%. This route is an improvement over an 11-step sequence developed by the same researchers, and it has the potential to be used for atorvastatin manufacture. (Chem. Eur. J. 2013, 19, 3802–3806; José C. Barros)

Use risk assessment to evaluate genotoxic impurities. A. Teasdale and colleagues at AstraZeneca (Macclesfield, UK), GlaxoSmithKline (Ware, UK), Abbott Laboratories (Abbott Park and North Chicago, IL), Amgen (Thousand Oaks, CA), and Takeda Global Research & Development Center (Deerfield, IL) describe a way to deal with genotoxic impurities (GTIs) that may contaminate a drug substance.

A purge factor for each GTI is calculated from its reactivity, solubility, volatility, ionizability, and chromatography properties. The purge factor is cumulative if the GTI has to pass through several chemical and isolation steps between the introduction or formation of the GTI and the production of the drug substance. The calculated purge factor determines whether monitoring the GTI is required. (Org. Process Res. Dev. 2013, 17, 221–230; Will Watson)

Use a magnetic nanopowder catalyst for Friedel–Crafts acylations. Friedel–Crafts acylation has many applications in the chemical and pharmaceutical industries. Traditionally, the reaction requires an acidic catalyst, usually AlCl3, that is moisture-sensitive and converts to a byproduct [Al(OH)3] that is difficult to separate from the crude reaction mixture.

S. A. Babu and co-workers at the Indian Institute of Science Education and Research (Punjab) developed a Friedel–Crafts synthesis that is catalyzed by moisture-insensitive, magnetic CuFe2O4 nanopowder with a ≈50-nm particle size.

The researchers began with the reaction of neat anisole (1) and p-toluoyl chloride (2) at room temperature and obtained ketone product 3 in 86% and 98% yields with 15 and 20 mol% catalyst, respectively. The reaction workup requires only adding EtOAc, stirring, magnetically removing the catalyst, and decanting the supernatant liquid. After the workup is repeated three times, the solution is evaporated, and the product was purified by using flash chromatography.

The authors expanded the method to several substituted arenes and acid chlorides with good yields. The reaction can be scaled up to 3 g of starting arene, and the catalyst can be used twice without loss of efficiency. High-resolution transmission electron microscopy showed that the nano-CuFe2O4 maintains its morphology during the reaction. (Tetrahedron Lett. 2013, 54, 1738–1742; JosÉ C. Barros)

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