Noteworthy Chemistry

February 10, 2014

“Green” the valsartan synthesis with a sol–gel-trapped catalyst. Valsartan (trade name Diovan) is an angiotensin receptor blocker that has been used since the 1980s to combat hypertension. The synthesis of this active pharmaceutical ingredient goes through biphenyl intermediate 1, which is prepared via a Suzuki–Miyaura coupling reaction. The reaction is mediated by palladium catalysts that generate large amounts of toxic metal byproducts. 

Suzuki–Miyaura coupling to form a valsartan intermediate

F. Béland, M. Pagliaro, and coauthors at SiliCycle (Quebec City) and the Institute for the Study of Nanostructured Materials (Palermo, Italy) optimized the preparation of 1 by using the sol–gel-entrapped catalyst SiliaCat DPP-Pd. The catalyst consists of an organosilica matrix functionalized with diphenylphosphine ligands bound to Pd(II).

Starting from the standard valsartan synthesis, the authors conducted experiments at the 6-mmol scale. They optimized the production of 1 by

  • replacing the EtOH–H2O solvent with pure EtOH to avoid decomposing the catalyst matrix;
  • setting the substrate mol ratio at 1:1.01 aryl halide/boronic acid; and
  • using 1.5 equiv K2CO3 as the base and 0.7 mol% catalyst.

With this method, the authors scaled up the synthesis to 720 mmol (100 g) halide. The yield of 97% pure 1 was 98%. The palladium concentration in the product was <0.5 ppm, an acceptable value for a commercial pharmaceutical.

The catalyst can be filtered from the reaction mixture and washed before reusing it. Catalyst performance, however, is significantly lower after the second run. The authors expanded their method to several halides, with most yields >90%. (Org. Process Res. Dev. 2013, 17, 1492–1497; José C. Barros)

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A biomimetic matrix traps and releases bioactive compounds. A. Bandiera and colleagues at the University of Trieste (Italy) describe the induced-release characteristics of bioactive elements trapped in hydrogels that were made from enzymatically cross-linked human elastin–like polypeptides (HELPs). HELPs are similar to tropoelastin and contain hydrophobic units and residues that can be cross-linked. Their degradation kinetics vary with the type of elastolytic proteases they contain.

To examine the induced-release profile, the authors loaded HELPs with enhanced green fluorescent protein (EGFP). They formed a hydrogel network by adding an enzyme. When they monitored the fluorescence intensity, they observed that proteolytic promoters induce a significant release EGPF. They believe that this process not only entraps bioactive molecules in the HELP matrix, but it also can conjugate them to the matrix. (Biomacromolecules 2014, 15, 416–422; LaShanda Korley)

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Twistane has a new twist. Tricyclo[4.4.0.0]decane, also known as twistane, is a D2-symmetrical molecule that has three twisted boat rings interwoven with one another. First prepared by H. W. Whitlock in 1962, twistane has unusual stereochemical properties that have enticed chemists to work on functionalizing it and modifying its structure.

M. Olbrich, P. Mayer, and D. Trauner* at Ludwig Maximilian University Munich and the Munich Center for Integrated Protein Science extended the twistane skeleton by threefold. They synthesized a tritwistane molecule (5) that has C2-symmetry,

Four-step synthesis of tritwistane

The authors began with tetrachlorotriene 1, which they converted to tetracyclic diene 2 by adding ethylene under high pressure. When it is treated with sodium, 2 dechlorinates to give laticyclic hydrocarbon 3. Brominating 3 leads to dibromotritwistane 4 via an “N”-type cyclization that bridges the two double-bond–containing rings. Dibromo compound 4 is dehalogenated with Chatgilialoglu’s reagent [tris(trimethylsilyl)silane (TTMSS)– azoisobutyronitrile (AIBN)] in toluene to yield the target C2-tritwistane as a racemic mixture.

This study produced a new hydrocarbon skeleton and may provide insight for designing and synthesizing more complicated oligo- and polytwistanes that could be potential building blocks for chiral carbon nanowires and ultrasmall carbon nanotubes. (Org. Biomol. Chem.2014, 12, 108–112Xin Su)

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Telescoping the reactions improves an anti-HIV-1 drug yield.D. K. Leahy* and S. K. Pack at Bristol-Myers Squibb (New Brunswick, NJ) optimized the synthesis of a phosphonooxymethyl prodrug for HIV-1 attachment inhibitors. They isolated the intermediate di-tert-butyl phosphonate ester by crystallizing it from n-butyl acetate. After aqueous workup, the yield was 84% with >98% HPLC area purity.

The authors found, however, that 11% of the phosphonate remained in the mother liquors. Because the next step involved deprotection with CF3CO2H in CH2Cl2, they developed an alternative protocol. After aqueous workup, the phosphonate ester was extracted into CH2Cl2 and treated directly with CF3CO2H. This step was followed by a solvent switch to MeOH. The phosphonic acid was produced in 93–96% yield and 97.4% HPLC area purity. In the final step, the acid was converted to the lysine salt, which, after crystallization, upgraded the purity to 99.7%. (Org. Process Res. Dev. 2013, 17, 1440–1444Will Watson)

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Protease inhibitors block cell-to-cell spread of HIV-1. HIV-1 can spread between CD4+ T lymphocytes by cell-free viral diffusion or by direct cell-to-cell transfer through virological synapses. HIV-1 infection can be effectively managed by using combination antiretroviral therapy (cART), which controls viral replication and prevents disease progression.

But it is unclear whether cART can effectively block both modes of HIV-1 dissemination. The large quantity of viral particles transmitted during cell-to-cell transfer may cause the reverse transcriptase inhibitor (RTI) component of cART to become saturated and allow HIV-1 to replicate at low levels despite ongoing therapy.

Protease inhibitors (PIs) are potent for suppressing viral replication, are effective against multiple drug–resistant viral variants, and can be used for monotherapeutic HIV treatment or included in cART. PIs inhibit viral maturation by preventing the cleavage of viral polyproteins into functional subunits, which results in the formation of noninfectious immature virus particles. PIs can affect entry and postentry events, but their effect on cell-to-cell transmission has not been studied. C. Jolly and co-workers at University College London and the University of KwaZulu-Natal (South Africa) investigated and compared the efficacy of PIs and RTIs during cell-free and cell-to-cell spread of HIV-1 between T lymphocytes.

The authors determined that two PIs, lopinavir and darunavir, effectively block both modes of HIV-1 spread at similar IC50 values. PI treatment inhibits viral DNA synthesis and prevents the spread of infection. The nucleoside or nucleotide RTIs nevirapine, tenofovir, and zidovudine, however, are less able to inhibit cell-to-cell HIV-1 spread, although these effects vary in a drug-class–dependent manner.

In addition, varying the coculture ratios of uninfected and infected cells influences the degree of RTI efficiency, demonstrating that multiplicity of infection determines the relative efficacy of cART. The authors conclude that the efficacy against different modes of HIV-1 dissemination depends on the class of antiretroviral drugs used. (Retrovirology2013, 10, No. 161; Abigail Druck Shudofsky)

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[Jenny: Please group the following two items; both involve HIV-1 drugs.]



Telescoping the reactions improves an anti-HIV-1 drug yield.D. K. Leahy* and S. K. Pack at Bristol-Myers Squibb (New Brunswick, NJ) optimized the synthesis of a phosphonooxymethyl prodrug for HIV-1 attachment inhibitors. They isolated the intermediate di-tert-butyl phosphonate ester by crystallizing it from n-butyl acetate. After aqueous workup, the yield was 84% with >98% HPLC area purity.

The authors found, however, that 11% of the phosphonate remained in the mother liquors. Because the next step involved deprotection with CF3CO2H in CH2Cl2, they developed an alternative protocol. After aqueous workup, the phosphonate ester was extracted into CH2Cl2 and treated directly with CF3CO2H. This step was followed by a solvent switch to MeOH. The phosphonic acid was produced in 93–96% yield and 97.4% HPLC area purity. In the final step, the acid was converted to the lysine salt, which, after crystallization, upgraded the purity to 99.7%. (Org. Process Res. Dev. 2013, 17, 1440–1444Will Watson)

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Protease inhibitors block cell-to-cell spread of HIV-1. HIV-1 can spread between CD4+ T lymphocytes by cell-free viral diffusion or by direct cell-to-cell transfer through virological synapses. HIV-1 infection can be effectively managed by using combination antiretroviral therapy (cART), which controls viral replication and prevents disease progression.

But it is unclear whether cART can effectively block both modes of HIV-1 dissemination. The large quantity of viral particles transmitted during cell-to-cell transfer may cause the reverse transcriptase inhibitor (RTI) component of cART to become saturated and allow HIV-1 to replicate at low levels despite ongoing therapy.

Protease inhibitors (PIs) are potent for suppressing viral replication, are effective against multiple drug–resistant viral variants, and can be used for monotherapeutic HIV treatment or included in cART. PIs inhibit viral maturation by preventing the cleavage of viral polyproteins into functional subunits, which results in the formation of noninfectious immature virus particles. PIs can affect entry and postentry events, but their effect on cell-to-cell transmission has not been studied. C. Jolly and co-workers at University College London and the University of KwaZulu-Natal (South Africa) investigated and compared the efficacy of PIs and RTIs during cell-free and cell-to-cell spread of HIV-1 between T lymphocytes.

The authors determined that two PIs, lopinavir and darunavir, effectively block both modes of HIV-1 spread at similar IC50 values. PI treatment inhibits viral DNA synthesis and prevents the spread of infection. The nucleoside or nucleotide RTIs nevirapine, tenofovir, and zidovudine, however, are less able to inhibit cell-to-cell HIV-1 spread, although these effects vary in a drug-class–dependent manner.

In addition, varying the coculture ratios of uninfected and infected cells influences the degree of RTI efficiency, demonstrating that multiplicity of infection determines the relative efficacy of cART. The authors conclude that the efficacy against different modes of HIV-1 dissemination depends on the class of antiretroviral drugs used. (Retrovirology2013, 10, No. 161; Abigail Druck Shudofsky)

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Weak thermal force directs chirality. Chirality is a topic that never fails to intrigue scientists, especially chemists. For example, the homochirality (single-handedness) of life forms on Earth is an important phenomenon that has not been explained. Enantioselection, the process that leads to homochirality, is usually caused by mirror-symmetry breaking through biased external inputs such as polarized light or chiral templates.

P. Mineo, V. Villari, and coauthors at the University of Catania and CNR-IPCF Institute for Chemical and Physical Processes (Messina, both in Italy) induced chirality in porphyrin aggregates by applying small temperature gradients. This process may provide another way to achieve enantioselection.

Porphyrin derivative that forms chiral aggregates when heat is applied

The authors studied the aggregation behavior of a noncharged porphyrin (1) modified with four peripheral poly(ethylene glycol) chains. Aggregates formed by 1 in aqueous solution had a 200-nm average hydrodynamic radius and a 600-nm radius of hydration. The aggregates produced a circular dischroism signal with an intensity that correlates positively with temperature changes.

The authors attribute the origin of this supramolecular chirality to the thermal force of temperature gradients, a form of asymmetric physical perturbation, that may cause the thermophoretic motion of the aggregates of 1. Chirality can be generated or dissipated by modulating the thermal force. (Soft Matter 2014, 10, 44–47; Xin Su)

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