Noteworthy Chemistry
January 19, 2009
- Generate novel stimulus-induced network dissociation
- Ring-closing metathesis uses substrate encapsulation to form lactones
- Crystallization activates fluorescence of a biogenic chromophore
- Make tertiary alcohols with high enantioselectivity
- Layer and click to assemble biodegradable capsules
- Synthesize functionalized oxazines with high stereocontrol
The weak link: Generate novel stimulus-induced network dissociation. Researchers at the University of Shizuoka (Japan) used a weak covalent bond to develop a stimulus-dependent, reversible dissociation scheme to generate linear macromolecular chains from cross-linked polymer networks.
Using established techniques, T. Iwamura* and M. Sakaguchi introduced a hexaarylbiimidazole (HABI) functional unit—which reverts to an imidazoyl radical in the presence of visible light or under moderate pressure—as a cross-linking moiety in vinyl monomer 1. This monomer could not be homopolymerized under standard free-radical reaction conditions because of steric hindrance. However, the HABI-based monomer could be copolymerized with methyl methacrylate (MMA) at 60 °C for 24 h using a 2,2’-azobis(isobutyronitrile) (AIBN) initiator to give polymer 2 (Mn 9900, polydispersity 3.69).
The authors cross-linked the linear copolymer in solution with a KOH–1% K3[Fe(CN)6] aqueous mixture at low temperature to form an insoluble network. They report that characterization of the cross-linked polymer was challenging because of the overlap of the spectral bands for MMA and the HABI dimer. The network could be de-cross-linked by exposure to visible light or by pressure induced by manual grinding.
The authors used electron spin resonance (ESR) experiments to determine that light irradiation (23 min) of a CHCl3 solution of the cross-linked polymer dissociates the HABI dimer linkage in the network to generate the imidazoyl radical; this allows recovery of the soluble linear copolymer. Longer irradiation times produce a stronger ESR radical signal (2.41 × 1017 spins/mg vs 1.56 × 1017 spins/mg at the shorter time). Pressure induced by grinding with a mortar and pestle also initiated the de-cross-linking phenomenon, which the authors confirmed by using gel permeation chromatography. Grinding produced longer radical lifetimes because of hindered radical diffusion in the solid state. (Macromolecules 2008, 41, 8995–8999; LaShanda Korley)
Ring-closing metathesis uses substrate encapsulation to form lactones. Ring-closing metathesis (RCM) is the premiere technique for synthesizing difficult-to-make cyclic molecules. However, RCM often must be carried out under highly dilute conditions to suppress competing acyclic diene metathesis oligomerizations. RCM substrates such as α,ω-dienyl esters (e.g., 1) also exhibit conformational biases that severely limit the usefulness of this technique.
E. B. Pentzer, T. Gadzikwa, and S. T. Nguyen* at Northwestern University (Evanston, IL) developed a strategy that helps circumvent this problem. They used a bulky Lewis acid, aluminum tris(2,6-diphenylphenoxide) (2), to overcome the conformational bias of the α,ω-dienyl ester by coordination-based “encapsulation” of this substrate, thus preventing intermolecular reactivity and promoting the desired RCM even at concentrations much higher than normally used.
Under these conditions, the RCM of 1 led to high yields of the seven-membered unsaturated lactone 3. In the presence of 2, 3 can be obtained from 1 in reaction mixtures 200 times more concentrated than for conventional RCM reactions. The encapsulation effects of 2 on α,ω-dienyl esters are easily seen in the crystal structure of a complex of 1 and 2. The binding pocket of the complex extends around the ester moiety and forces the two olefins closer than would be expected in the unbound state to produce a conformation that promotes the RCM reaction.
The authors extended their substrate-encapsulated RCM strategy to form several β,γ- and γ,δ-unsaturated ε-lactones in excellent yields, regardless of the substitution pattern. Whereas the second-generation Grubbs catalyst is better for making all β,γ-unsaturated ε-lactones, a second-generation Hoveyda–Grubbs catalyst is preferred for the γ,δ-unsaturated isomers to avoid rearrangement to the more thermodynamically stable γ-lactones. Practical features of this procedure are the convenient preparation of Lewis acid 2 in situ and its direct use in RCM in a one-pot method. (Org. Lett. 2008, 10, 5613–5615; W. Jerry Patterson)
Crystallization activates fluorescence of a biogenic chromophore. Green fluorescence protein (GFP) is widely used as a bioprobe. Its chromophore is a p-hydroxybenzylideneimidazolinone group that is covalently bound to the middle of an internal α-helix directed along a rigid β-barrel axis. The emission of denatured protein chromophores is greatly quenched in solution at room temperature, suggesting that the β-barrel plays a critical role in imparting steric hindrance to the free rotation around the exo-methylene double bond in the excited state.
J. Dong, K. M. Solntsev*, and L. M. Tolbert* at Georgia Tech (Atlanta) synthesized a group of O-alkyl-substituted analogues of the GFP chromophore by replacing the protein side chains with alkyl groups (1–3) and investigated their fluorescence behavior in the solution and solid states. They expected that crystal packing would significantly affect their photophysical properties.
The synthetic analogues of the GFP chromophore are nonfluorescent in solution, but they emit in the crystalline state. As the size of the O-alkyl substituent increases from methyl (1) to hexyl (2) to dodecyl (3), the interaction between the aromatic moieties in the lattice becomes weaker, leading to a hypsochromic shift in the crystal emission.
The authors believe that the fluorescence of the GFP chromophore analogues is activated by crystal packing and finely tuned by the subtle balance among intermolecular forces. According to them, “An application of the GFP fluorophores as model compounds that are quenched due to free intramolecular rotation in solutions and are bright in the solid state could be extrapolated to a much wider class of organic fluorophores.” (J. Am. Chem. Soc. 2009, 131, 662–670; Ben Zhong Tang)
Make tertiary alcohols with high enantioselectivity. Chiral tertiary alcohols are usually prepared by the face-selective addition of nucleophiles to ketones. The efficacy of this method, however, relies on a steric difference between the ketone substituents.
V. K. Aggarwal and co-workers at the University of Bristol (UK) developed a method based on a 1,2-metallate rearrangement of boronate complexes. They convert readily available chiral secondary alcohols to carbamates (OCb in the figure) and deprotonate them with s-BuLi. The subsequent addition of a borane or a boronic ester gives tertiary alcohols in good yield and high optical purity.
The choice of borane or boronic ester directs the selectivity of the reaction. In boronic ester–mediated reactions, the complexation of boronate oxygen and lithium induces boron attack from the lithium side of the stereogenic center. In the absence of complexation, as in the case of boranes, the reaction is driven from the side opposite the metal by the presence of electron density in the partially flattened carbanion. Thus it is possible to obtain both tertiary alcohol enantiomers from a single secondary alcohol enantiomer.
The compounds prepared by the new reactions are not easily accessible by alternative routes. The number of commercially available boranes and boronic esters enhances the usefulness of this protocol. (Nature 2008, 456, 778–782; José C. Barros)
Layer and click to assemble biodegradable capsules. F. Caruso and colleagues at the University of Melbourne (Australia) use a combination of click chemistry and layer-by-layer (LbL) assembly to design biodegradable capsules based on poly(L-lysine) (PLL) and poly(glutamic acid) (PGA) functionalized with alkyne (Alk) or azide (Az) groups.
Using planar silica supports coated with 3-aminopropyltriethoxysilane (APTS) and PGA, the authors assembled five bilayers of PLL-Az–PLL-Alk at various pH and salt concentrations. LbL assembly at pH 5–9 with no salt present resulted in stable structures, but further investigation showed that PGA click–LbL assembly is optimal at pH 4 and 0.5 M NaCl. Fluorescence labeling confirmed that assembly of PLL click films (six bilayers) on 5-μm colloidal templates (pure silica or APTS–PGA modified) could be achieved in the presence of copper catalyst. Similarly, PGA click multilayers were deposited on APS-coated colloidal silica with the addition of copper. Biodegradable capsules were produced by removing the silica core in the core–shell particles (PGA or PLL click films).
PLL capsules swelled to 8.4 ± 0.2 μm when they were exposed to buffered HF solution because of the repulsion between the protonated amine groups. Only slight shrinkage (to 4.3 ± 0.4 μm) of the PGA click capsules occurred in HF buffer as result of lesser protonation (i.e., less-repulsive forces) of the carboxylic acid moieties. Upon drying, layer thickness and integrity were maintained in collapsed and folded PLL capsules. The uniformity of the PGA shell was preserved in the dry state, but indentations were seen in the PGA click capsules.
The authors report that the PGA and PLL LbL capsules were stable (no degradation or aggregation) at 4 °C in water for >4 weeks. They also studied the pH-responsive behavior of the click capsules and found that the PLL capsules exhibited reversible swelling (53% diam change) between pH 11 and 2. This reversible switching also occurred to a lesser extent (28% diam change) in the PGA click capsules. They demonstrated that these click containers can be postfunctionalized with biotin- or OMe-terminated polyethylene glycol (PEG) using surface lysine groups. These PEGlyated capsules displayed low-fouling properties (PEG-OMe) or specific binding sites (PEG-biotin). (Biomacromolecules 2008, 9, 3389–3396; LaShanda Korley)
Synthesize functionalized oxazines with high stereocontrol. New methods for producing enantiopure 1,2-oxazines are desirable because these structures appear frequently in complex natural products and provide potential scaffolds for medicinal targets. The scope of current asymmetric routes to 1,2-oxazines is limited, but G. Zhong and co-workers at Nanyang Technological University (Singapore) report a novel strategy that uses acyclic nitroalkenals (e.g., 1) and nitrosobenzenes (2) to “build in” the C–O and C–N bonds in one reaction. Their method leads to highly functionalized tetrahydro-1,2-oxazines (3) that contain as many as three stereogenic centers. This organocatalytic process can be visualized as a domino α-aminoxylation–aza-Michael reaction.
The authors added the organic salt Et4NBr to enhance the solubility of the L-proline catalyst. The homogeneous reaction is run under mild conditions and produces a variety of oxazines with high enantiomeric excesses and similarly high diastereomeric ratios. For most of the variants of 1 studied, the products were essentially optically pure. The course of the reaction is easily followed by a change in color of the solution from green to orange.
The domino reaction generates as many as three stereogenic centers, yet forms only one out of eight possible stereoisomers—an impressive feat. The authors suggest that the high stereoselectivity derives from the α-aminoxylation reaction, which proceeds with high enantioselectivity. Following the α-aminoxylation reaction, the aza-Michael addition and protonation appear to be promoted by hydrogen bonding provided by a water molecule.
This method illustrates another in a growing list of synthetic processes that are mediated by the simple chiral catalyst L-proline and lead to highly efficient stereocontrol of the products. (Angew. Chem., Int. Ed. 2008, 47, 10187–10191; W. Jerry Patterson)