Noteworthy Chemistry

October 10, 2011

Control biological and mechanical function in peptide gels. J. Z. Gasiorowski and J. H. Collier* at the University of Chicago explored the co-assembly of multicomponent β-sheet–forming Q11 (QQKFQFQFEQQ)–derived peptides. They used two strategies to direct the separate assembly of individual fibrillar soluble peptide species or to intermix the soluble peptides prior to gel cross-linking to form protofibrils.

Cross-linking in the presence of phosphate-buffered saline (PBS) led to denser packing of larger diameter fibrils. By using particle labeling with the separate assembly technique, the authors confirmed that distinct peptide populations existed. Predominantly intermixed peptide domains were generated via co-assembly.

Incubation time played an important role in stiffness modulation. For example, the modulus increased 2.5–3.5-fold when the incubation time with the PBS buffer was increased from 2 to 24 h.

The authors incorporated a bifunctional initiator with thiol- and amine-reactive functional groups into the intermixed and the separately assembled Q11-based peptides. The separately assembled functionalized peptides had a higher storage modulus than the intermixed peptides. The authors also demonstrated control of biological function via the assembly process; the intermixed peptide gels exhibited increased cell growth. (Biomacromolecules 2011, 12, Article ASAP DOI: 10.1021/bm200763y; LaShanda Korley)

Use a one-pot method to make chiral tetrahydro-γ-carbolines. The tetrahydro-β-carboline heterocyclic scaffold is present in many bioactive compounds. In contrast, the tetrahydro-γ-carboline analogue is unknown in natural products, but it is a valuable template for drug discovery.

Y. Lee, R. S. Klausen, and E. N. Jacobsen* at Harvard University (Cambridge, MA) report an unusually mild, efficient method that leads to optically pure 4-substituted tetrahydro-γ-carbolines, exemplified by structure 4 in the figure. Their synthetic strategy uses a catalytic “iso-Pictet–Spengler reaction” that features a one-pot condensation and cyclization of indolylethylamines and carbonyl compounds such as 1 and 2, respectively.

The unusual chiral thiourea 3—together with cocatalyst benzoic acid—effectively promotes this asymmetric reaction. The final treatment of the crude reaction mixture with Boc2O produces 4 as the N-Boc derivative; Boc is tert-butoxycarbonyl. The enantiomeric composition of 4 can be upgraded to optically pure (>99%) form by direct crystallization or trituration. This process reduces the requirement for commercially available catalyst 3 and supplies the product in a form that is readily adaptable to preparative scale.

The authors transformed the tetrahydro-γ-carboline scaffold into a structurally complex alkaloid by converting 4 in one step to spirocyclic oxindole 5. This cyclization proceeds with almost complete retention of enantiopurity. They stress that the structural skeleton in 5 is frequently observed in bioactive compounds. (Org. Lett. 2011, 13, Article ASAP DOI: 10.1021/ol202300t; W. Jerry Patterson)

Reversibly bend plastic with light. Photochromic compounds change color when exposed to light. They may be considered solar dyes—colored molecules that use the sun’s energy to change their physical properties. They often change shape when irradiated.

Y. Jin, S. I. M. Paris, and J. J. Rack* at Ohio University (Athens) hypothesized that the structural changes in certain photochromic solar dyes might be amplified to induce macroscopic changes in a polymer environment. When they incorporated a ruthenium photochromic solar dye into a plastic, they discovered that at low photochrome/plastic monomer loadings (1:60), the plastic can be bent reversibly by light from a laser pointer.

The authors coupled the amine-functionalized ruthenium dye with 5-norbornene-2-carboxylic acid and copolymerized the product with unsubstituted norbornene. Films formed from the copolymer were alternately irradiated with UV (370 nm) and blue (470 nm) light. UV light caused the films to deform in one direction, and the blue-light irradiation bent them in the opposite direction. These effects continued for >10 UV–blue light irradiation cycles.

Polymers that transduce light energy to mechanical energy are exceptionally rare. Plastics formed from photoactive polymers such as these may one day be used in ophthalmic lenses or in visual prosthetic devices. They may also help direct objects toward a light source, much as the leaves of plants orient themselves toward the sun. (Adv. Mater. 2011, 23, 4312–4317; Gary A. Baker)

Fluorescent nanomicelles act as tumor-targeting bioprobes. Although many organic fluorophores emit efficiently in organic solvents, their applications for bioimaging are limited because of their intrinsic immiscibility with biological media. Most organic fluorophores are subject to aggregation-induced fluorescence quenching: Their light emission decreases when they aggregate in physiological mixtures.

S. He and coauthors at Zhejiang University (Hangzhou, China), South China Normal University (Guangzhou), and Hannam University (Daejeon, Korea) developed nanomicelles that contain fluorogenic aggregates and are highly emissive in aqueous buffers. They operate as excellent in vivo biosensors.

The researchers produced the nanomicelles with an average size of <30 nm by mixing fluorogen 1 with poly‍(ethylene glycol) end-capped by phospholipids. Whereas 1 fluoresces weakly, its aggregates in the nanomicelles are highly emissive because of their unique aggregation-enhanced emission. The nanomicelles are stable in biological environments and can be readily conjugated with bioactive molecules such as arginine-glycine-aspartic acid (RGD) peptide.

The fluorescent nanomicelles work well as bioprobes for in vivo sentinel lymph-node mapping of mice. Their RGD conjugates perform well as biomarkers for in vivo diagnosis of subcutaneously xenografted tumors in mice. (Biomaterials 2011, 32, 5880–5888; Ben Zhong Tang)

A hurdle to using two solvents in drug synthesis is removed. 2-Methyltetrahydrofuran and cyclopentyl methyl ether are potentially “greener” solvent alternatives to THF and methyl tert-butyl ether, but their use in the later stages of drug candidate syntheses is limited by a lack of toxicity data. J. P. Scott and colleagues at Merck (Rahway and Summit, NJ; West Point, PA; and Hoddesdon, UK) generated toxicity data that show that 2% of either of these solvents in a drug candidate would not be expected to contribute to any potential toxicity exhibited by the active ingredient.

The authors carried out three studies: the Ames test for mutagenicity, a chromosomal aberration test for genotoxicity, and a 3-month repeat-dose oral toxicity study on rats. The results were negative in all three tests for both solvents. (Org. Process Res. Dev. 2011, 15, 939–941; Will Watson)

Use benzodipyrrolidone-based polymers in optoelectronic devices. W. Cui, J. Yuen, and F. Wudl* at the University of California, Santa Barbara, note that the previously studied pyrrolo‍[3,4-c]‍pyrrole-1,4-dione chromophoric system exhibits several structural characteristics that are useful for electronic applications (Farnum, D. G., et al. Tetrahedron Lett. 1974, 15, 2549–2552). These features include a planar, highly conjugated lactam structure that provides strong π‍–‍π interactions and electron-withdrawing effects. This type of material has been integrated into such devices as organic thin-film transistors and organic photovoltaics.

The authors observe that appealing benzodipyrrolidone-based molecules such as 1 in Figure 1 are structurally similar to pyrrolo‍[3,4-c]‍pyrrole-1,4-dione. Their strategy uses 1 as a scaffold for making potentially useful polymers. The synthesis of 1 involves the initial reaction of p-phenylenediamine with 4-bromomandelic acid (2) to give dibromide 3.

The terminal bromine atoms in 3 are key functionalities that later provide coupling sites for the desired polymer-forming reaction. The cyclization of 3 proceeds in the presence of strong acid to form 4, which is oxidized by persulfate to give 5. This completes the conjugation pathway throughout the molecule.

N-Alkylation of 5 incorporates large alkyl groups that confer important solubility characteristics to 1. The authors prepared several analogues of 1 with different alkyl groups. Polymerization of monomer 1 with benzenebis‍(boronic acid) 6 or thiophenebis‍(boronate ester) 7 was carried out by Suzuki coupling mediated by a palladium catalyst complex to give completely conjugated polymers 8 and 9 (Figure 2).

The molecular weight (Mn) of 8 is as high as 20 kDa, and 8 is highly soluble in common solvents such as CHCl3. This allows thin films to be deposited from solution for device production.

The maximum absorption wavelengths of polymers 8 and 9 are 524 and 579 nm, respectively. The polymers’ absorption is greatly red-shifted from that of the monomers, indicating extended conjugation of the polymer chain. The polymer optical band gaps are 1.9 eV for 8 and 1.68 eV for 9, which suggests that the benzodipyrrolidone scaffold will be an effective unit to form low–band gap polymers.

Field-effect transistor devices made with 8 and 9 show electron mobilities of 10‍–‍3 cm2/‍(V·s). These values ensure effective charge transport for organic optoelectronic applications. (Macromolecules 2011, 44, Article ASAP DOI: 10.1021/a2017293; W. Jerry Patterson)

Introducing DABSO, a new source of sulfur dioxide. SO2 is an important chemical in organic synthesis. It takes part in pericyclic reactions; the synthesis of sulfonyl chlorides, sulfinates, and sulfones; alkene isomerizations and copolymerizations; and multicomponent reactions. Because SO2 is a gas, however, it has drawbacks for laboratory use.

M. C. Willis and co-workers at the University of Oxford (UK) report a bench-stable SO2 source. DABCO (1,4-diazabicyclo[2.2.2]octane) forms a crystalline 1:2 charge-transfer complex with SO2 that the authors call DABSO. DABCO·2SO2 is reported in the literature, but it has not been used as a SO2 source in organic reactions.

The authors first tested DABSO in the preparation of sulfonamides from Grignard reagents (see figure). The Grignard intermediate is treated with SO2Cl2 and then with an amine to form the sulfonamide. Aryl, benzyl, and alkyl Grignard reagents can be used, and the nitrogen nucleophile can be a primary, secondary, or allylic amine or a hydrazine.

The yields are comparable with traditional reactions that use gaseous SO2. DABSO also can be used to prepare sulfamides from anilines and in the cheletropic addition of SO2 to 2,3-dimethylbutadiene to produce dimethylsulfolene. This new reagent may have many additional applications in organic synthesis. (Org. Lett. 2011, 13, 4876–4878; JosÉ C. Barros)

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