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Noteworthy Chemistry

April 2, 2012

Common milkweed yields cytotoxic cardiac glycosides and other compounds. Asclepias syriaca L. (common milkweed) has been used for centuries by Native Americans for medicines and foods. Today manufacturers use the silky seed floss as a hypoallergenic filling for pillows and comforters and also in insulating fibers. Typically, they discard the remaining biomass.

Researchers at the University of Kansas (Lawrence) have been studying the chemical diversity and medicinal potential of various Kansas flora. J. J. Araya, K. Kindscher, and B. N. Timmermann* investigated common milkweed to identify bioactive molecules with potential medical uses.

After a series of extraction and separation steps, the researchers isolated and identified five new compounds (cardiac glycoside 1, quercetin triglycoside 2, neolignin 3, phenylethanoid 4, and megastigmane glycoside 5) and 19 known compounds.


The researchers screened all of the isolates against the human breast cancer cell line Hs578T. Compounds 1 and 69 had IC50 values that ranged from 0.59 to >40 μM. (IC50 is the drug concentration needed for 50% cell inhibition in vitro.) They then compared these compounds with four known cardiac glycosides: digoxin, digitoxegenin, ouabain, and doxorubicin. Compound 6 (0.59 μM IC50) was comparable to the positive controls doxorubicin (0.55 μM) and digoxin (0.25 μM).

The authors compared data for cancerous Hs578T cells and normal Hs578Bst cells and showed that the toxicity percentage for all five test compounds was significantly higher in the cancer cells. Although additional research is needed to explain this behavior, the authors say that it may be attributable to differences between the growth rates of cancer cells and normal cells. (J. Nat. Prod. 2012, 75, 400–407; Beth Ashby Mitchell)

What is the absolute configuration of a venerable antimalarial? The antimalarial drug Lariam is a racemic mixture of erythro-mefloquine hydrochloride enantiomers (1). The (+)-enantiomer is the active antimalarial, but the (–)-enantiomer may cause side effects such as depression and psychosis. Although a patent for the (+)-enantiomer was issued in 2003 (Fletcher, A.; Shepherd, R. US Patent 6,664,397), researchers have assigned conflicting stereochemical structures to the compounds.

C. Griesinger, U. M. Reinscheid, and coauthors at the Max Planck Institute for Biophysical Chemistry (Göttingen), the European Euroscience Institute Göttingen, the DFG Research Center (Göttingen), and the University of Jena (all in Germany) used a combination of NMR spectroscopy, optical rotary dispersion (ORD), circular dichroism (CD), and density functional theory (DFT) calculations to assign the configurations of the enantiomers.

The authors measured 3JH–H and 3JH–C NMR coupling constants and concluded that the conformational freedom of 1 relies on three rotatable bonds and the position of the chloride ion. They then used DFT to calculate the chiroptical properties of both enantiomers and compared them with experimental values. Analysis of ORD spectra indicated that the (11R,12S) configuration corresponds to the (–)-antipode (2). CD spectra agreed with the ORD conclusions.

The researchers conclude that the compound with antimalarial activity is the (11S,12R) enantiomer (3). This work should pave the way for new enantioselective syntheses of this important molecule. (J. Am. Chem. Soc. 2012, 134, 3080–3083; JosÉ C. Barros)

Is DMSO a safe solvent for a lithium acetylide addition reaction? To prepare (1R,2R)-2-pent-4-ynylcyclopropanol, C. A. Baxter, G. L. Beutner, K. M. Emerson, and co-workers at Merck (Rahway, NJ, and Hoddesdon, UK) introduced the terminal acetylene group by treating 2-(3-chloropropyl)cyclopropanol with a lithium acetylide–ethylenediamine complex. Their initial screening identified DMSO as a good solvent, but safety testing showed that the reaction mixture decomposed at the elevated temperature (50 °C) required for an efficient reaction with the chloride substrate. The decomposition caused an adiabatic temperature rise of ≈170 °C, at which point a second decomposition involving DMSO led to a violent, uncontrollable runaway reaction.

When the researchers changed the solvent to 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU), the reaction mixture was somewhat more stable. The initial slow decomposition began at 70 °C, with an adiabatic temperature rise about half that of the DMSO reaction and no secondary decomposition. The authors further improved the conditions by using a sacrificial base to deprotonate the cyclopropanol before adding the acetylide to reduce the amount of byproduct acetylene gas. (Org. Process Res. Dev. 2012, 16, 87–95; Will Watson)

Here’s the first asymmetric synthesis of 1,3-difluoroallenes. Although almost four decades have passed since the synthesis of 1,3-difluoroallene (1)—the simplest molecule apart from isotopologues to have axial chirality—its physical and chemical properties are still virtually known. The original bromofluorocarbon starting materials are now banned, which makes synthetic access difficult. D. Lentz and coauthors at the Free University of Berlin, Albert Ludwig University (Freiburg, Germany), and the University of MÁlaga (Spain) report synthesizing an enantiomer of 1 via C–F bond activation by zirconium metallocene complexes.

The authors first hydrodefluorinated tetrafluoroallene (2) in the presence of 1 equiv chiral zirconium hydride complex 3 to produce trifluoroallene 4. When they treated 2 with 2.3 equiv 3, it was converted to the desired optically active 1,3-difluoroallen 5 in 24% yield with a smaller amount (3.5%) of 1,1-difluoroallene.


Inspired by these results, the authors designed a Brintzinger-type ansa-metallocence zirconium hydride that features a rigid backbone and strong chiral induction ability. (S,S)-Diastereomer 6 was prepared in 92% yield with >98% ee. Treating 4 with 6 selectively gave the (S)-enantiomer 5 in 76% yield and 29% ee; the reaction of 4 with the (R,R)-hydride produced the opposite enantiomer. The authors used a chiral solvating reagent and 19F NMR spectroscopy to determine the ee values from the ratio of diastereomeric inclusion complexes formed by 5 or its enantiomer.

The crystal structure of 5 showed a slightly bent (4.6°) carbon backbone. The authors attribute this configuration to the repulsion between nonbonding electrons on the fluorine atoms and the Cβ–Cγ π-bonding orbitals. The torsion angle between the two F–C–H planes in 5 is 91.9°, in contrast with previously reported angles measured by microwave spectroscopy. (Angew. Chem., Int. Ed. 2012, 51, 2218–2220; Xin Su)

Use norbornene end-caps to make robust conjugated polymers. T. M. Swager and co-workers at MIT (Cambridge, MA) developed a simple strategy for end-capping conjugated triblock copolymers with strained bicyclic alkenes. They copolymerized dihaloarenes with conjugated comonomers and used norbornadiene to end-cap the chains under reductive hydroarylation conditions.

Key considerations for this high-yielding reaction pathway are the relief of ring strain and lack of orientation in the synthetic intermediates. High–molecular-weight triblock copolymers were obtained via ring-opening metathesis polymerization of the norbornene caps. In addition to acting as copolymer units, the norbornene end groups form a ruthenium-based macroinitiator with a third-generation Grubbs catalyst.

The authors cite two drawbacks of high–molecular-weight (24–131 kDa) macroinitiators. First, their low solubility and slow diffusion rates increase the polydispersity of the resulting triblock copolymers. Second, in some cases, the high metathesis reactivity of norbornene causes the macroinitiator to oligomerize.

An advantage of this synthetic method is that it can lead to elastomeric materials formed via UV- or ambient-light cross-linking of the end-capped norbornadiene copolymers and norbornene monomers. These cross-linked systems also can be used for sensing volatile organic compounds, which swell the copolymers to cause shifts in photoluminescence. This research opens opportunities for developing conjugated materials with robust mechanical properties and tunable optical responses. (ACS Macro Lett. 2012, 1, 334–337; LaShanda Korley)

Applying force changes the emission of a pyrenyl fluorophore. Mechanochromism is a photophysical process in which the color of a chromophore changes in response to a mechanical force. The emission colors of some fluorophores are switchable by mechanical grinding, but mechanochromic systems with tunable emission color and intensity are rare.

X.-R. Jia and coauthors at Peking University and Tsinghua University (both in Beijing) developed a “smart” mechanochromic system with dual-mode manipulability. The emission color and intensity of pyrene-based fluorophore 1 are easily modulated in the solid state by controlling its molecular microstructure with external stimuli.


The as-prepared powder of 1 emits blue light when it is excited by 345-nm UV irradiation. The emission has a λmax of 412 nm and a shoulder at 480 nm. When the authors sheared the powder with a spatula, the emission color changed from blue to green. The two bands coalesced into one at λmax 480 nm with an intensity slightly greater than that of the original 412 nm band. Wetting with MeOH restored the green emission to the initial blue state, indicating that the mechanochromic process is reversible.

The authors believe that the blue fluorescence of the as-prepared powder is caused by emission from the pyrene excimers with a partially overlapped stacking structure. The green fluorescence of the sheared powder is associated with the sandwich pyrene excimers in the amorphous state. (Adv. Mater. 2012, 24, 1255–1261; Ben Zhong Tang)