Noteworthy Chemistry

April 13, 2015


Make four chiral centers at once. Organic reactions that can form multiple chiral centers in a single step with high stereoselectivity are desirable because they reduce the workload for synthesizing complex molecules. This result is often achieved through domino reactions in the presence of chiral catalysts or catalyst combinations.

In a spectacular example of this strategy, L. Pu and co-workers at University of Virginia (Charlottesville) discovered a highly chemo- and stereoselective domino cycloaddition that simultaneously forms four stereogenic carbon centers in a tetracyclic framework from an acyclic starting material with one chiral center. They started with simple terminal alkynes that they converted to chiral propargylic alcohols via addition to aldehydes. The alcohols were then etherified to form tripodal propargylic ether–based dienediynes centered at the chiral carbon (e.g., 1 in the figure). In the presence of a rhodium carbonyl chloride catalyst, the tripodal precursors were annulated into fused tetracyclic products (2) under 1 atm of carbon monoxide. 

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Reaction that creates four fused rings with four new chiral centers

The reaction that forms 2 is a domino Pauson–Khand, Diels–Alder cycloaddition cascade. This single step creates four fused rings with four new chiral carbon atoms in a controlled manner with chemo- and stereoselectivity.

This method can be used to prepare enantiopure chiral polycyclic systems from easily accessible starting materials in as few as three steps. Given its efficiency for creating multiple chiral centers in complex fused ring systems, it is likely to become a widely used tool in natural-product synthesis and drug development. (J. Org. Chem. DOI: 10.1021/acs.joc.5b00150; Xin Su)

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Adjust reactant stoichiometry to reaction conditions. X. Shi and coauthors at Biogen Idec (Cambridge, MA) and Dottikon Exclusive Synthesis AG (Switzerland) developed a two-step route to an N-benzylated purine, a potent heat shock protein 90 inhibitor. In the first step, 6-chloro-9H-purin-2-amine reacts with 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride in the presence of base. The product is converted to its methanesulfonate salt in the second step.

In the original process, the authors used potassium carbonate as the base with dimethylformamide or dimethyl sulfoxide solvent. A slight excess of 1.1 equiv of the pyridine salt was used; the excess reactant was easily removed when the intermediate was isolated and purified.

Problems with filtering the intermediate, however, led to the development of a telescoped process in dimethylacetamide solvent. The researchers changed the purine/pyridine stoichiometry to 1:0.95 because excess pyridine was difficult to purge. Excess purine presented no significant downstream problems. (Org. Process Res. Dev. DOI: 10.1021/op5003903; Will Watson)

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Chameleons use photonic crystals to change color. Most species that change color rapidly do so by dispersing or aggregating pigment-containing organelles to modify skin brightness. Only a few species, including chameleons, actually change their skin hue. This usually requires cellular structures that modify light wave reflectance and interference, rather than pigment cells.

J. Teyssier, S. V. Saenko, and co-workers at the University of Geneva (Switzerland) used electron microscopy, photometric videography, and photonic band-gap modeling to show that panther chameleons from Madagascar change color by tuning a lattice of guanine nanocrystals. The researchers examined biopsied skin samples 2 mm in diameter. They used Raman spectroscopy to identify two types of dark chromatophores that contain melanin and an unidentified dark blue pigment that panther chameleons of both sexes and all ages use to modulate skin color in response to stress (see video).

Adult males can produce more extreme color shifts when they encounter a male competitor or a receptive female. They have a thick upper skin layer with iridophores (reflective or iridescent cells) that contain close-packed lattices of small guanine crystals. The crystal arrays and surrounding cytoplasm behave as photonic crystals, similar to those that generate bright colors in some birds and insects. Transmission electron microscope images of skin samples show that the distance between guanine crystals is 30% smaller in the resting state (blue to green) than in the excited state (yellow to white).

A deeper skin layer contains iridophores with larger guanine crystals that reflect a substantial portion of sunlight, especially in the near-infrared range, which may protect the chameleons from overexposure to the sun in their native hot, dry habitats. (Nat. Commun. DOI: 10.1038/ncomms7368; Nancy McGuire)

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“See” the self-assembly of block copolymer nanostructures. Realizing the full potential of nanotechnology relies on making robust nanodevices with well-defined nanostructures. Block copolymers can self-assemble into nanostructures, but the structures are usually characterized with electronic microscopes that require high vacuum, which may cause distortion. Optical microscopy can be used under ambient conditions, but its resolution is limited by light diffraction.

M.-Q. Zhu and colleagues at Huazhong University of Science and Technology (Wuhan, China) developed a fluorescent nanoimaging system for characterizing the nanostructures generated by polymer self-assembly. They used amphiphilic polystyrene-b-poly(ethylene oxide) (PS-b-PEO) as a model block copolymer system.

The researchers visualized micelles formed by PS-b-PEO macromolecules by staining the polystyrene block of the copolymer with spiropyran. The fluorophores, localized in the polystyrene phases of the copolymer micelles, reversibly switched on and off when the micelles were alternately irradiated with ultraviolet and visible light.

Phase-selective distribution of the spiropyran fluorophores in the micelles allowed optical nanoimaging of the microphase structures of the block copolymer self-assembly with high (50-nm) resolution. The authors believe that this fluorescent nanoimaging system can be developed into a versatile tool for characterizing nanostructures assembled from various copolymers. (J. Am. Chem. Soc. DOI: 10.1021/ja512189a; Ben Zhong Tang)

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This 3-D process makes parts at a rapid CLIP. Additive manufacturing, or 3-D printing, has captured the imagination of parts manufacturers and do-it-yourselfers alike. The process, however, is very slow; it requires the sequential deposition of hundreds of thin layers. A new process, continuous liquid interface production (CLIP), produces monolithic polymeric shapes with dimensions of tens of centimeters and resolved features <100 μm across in minutes rather than hours.

E. T. Samulski, J. M. DeSimone, and coauthors at Carbon 3D (Redwood City, CA), the University of North Carolina (Chapel Hill), and North Carolina State University (Raleigh) formed complex solid shapes by projecting a continuous sequence of ultraviolet (UV) images through an oxygen-permeable window located below a liquid polymer resin bath. The oxygen inhibits free-radical polymerization by creating a “dead zone”, or continuous liquid interface, several tens of micrometers thick on the lower surface of the resin.

As the part is continuously drawn out of the resin bath, the UV-exposed regions (which contain residual free radicals) move out of the oxygen-rich zone, polymerize, and harden; and a new liquid layer forms underneath. The sequence of the UV images determines the shape of the part’s cross-section at each level. The speed of the process, which can reach 500 mm/h, is limited by the polymer’s cure rate and viscosity rather than by stepwise layer formation.

The authors experimented with various dead-zone thicknesses, polymerization rates, and feature resolutions to establish optimum conditions and limitations of the technique. An amorphous fluoropolymer, Teflon AF 2400, makes a good oxygen-permeable window. Pure oxygen forms a thicker dead zone than air; pure nitrogen produces no dead zone at all.

Increasing the incident photon flux or the reactivity of the polymer resin reduces the thickness of the dead zone. Dye loading can increase feature resolution by inhibiting print-through effects. Because the dyes absorb UV light that would otherwise produce free radicals, however, the parts must be elevated more slowly to increase light exposure and solidify the polymer adequately.

Other recently published preliminary studies show that the CLIP process can be used to produce parts from soft elastic materials, ceramics, and biomaterials. (Science DOI: 10.1126/science.aaa2397; Nancy McGuire)

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How easily do isolated retinal chromophores isomerize? Animals’ vision is largely based on the photoisomerization of highly conjugated retinal protonated Schiff base (RPSB) chromophores (e.g., all-trans 1 in the figure) in which rhodopsin proteins convert light signals to electric signals. This process holds the key for understanding the color-tuning mechanism of vision proteins, but the basic isomerization parameters for RPSBs are still unknown. 

All-trans RPSB

Using ion-mobility spectrometry (IMS) coupled with mass spectrometry (MS), Y. Toker at Bar-Ilan University (Ramat-Gan, Israel) and colleagues in the United States, Israel, Denmark, and Russia isolated four RPSB isomers. Their experiments measured the isomerization energy barriers of these RPSBs in the gas phase.

The researchers’ technique, called IMS-IMS-MS, uses two IMS drift tubes. The first separates the isomers; the second determines isomer distributions after activation. Then, they used time-of-flight MS to identify the isomer fragments. For each RPSB reaction pathway, they established the threshold voltage that triggers isomerization. With the measured fragmentation threshold voltages, they determined the relative energies and isomerization barriers of all of the separated RPSB isomers.

For a single cis–trans isomerization in an isolated RPSB, the energy barrier is 0.64 eV, significantly lower than the observed value for RPSBs in opsin proteins. These results suggest that counterions and steric constraints in proteins contribute to the increased isomerization barrier and ensure efficient vision reactions that are not disrupted by thermal noise. (Angew. Chem., Int. Ed. DOI: 10.1002/anie.201411894; Xin Su

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