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Noteworthy Chemistry

March 11, 2013

Use a three-enzyme system to prepare a chiral piperidine. L.-C. Campeau and co-workers at Merck (Kirkland, QU, and Rahway, NJ) developed a kilogram-scale synthesis of an orexin receptor analyst that is in clinical trials for treating insomnia. In a key step, (6R)-methylpiperidine-3-methanol is prepared from dimethyl 2-(3-oxobutyl)malonate, which was synthesized by a Michael addition of dimethyl malonate to methyl vinyl ketone.

The synthesis of the chiral piperidine is a three-enzyme biocatalytic transamination–cyclization–reduction sequence. The authors used a transaminase enzyme as the catalyst, D-alanine as the amine donor, and pyridoxal-5’-phosphate as a cofactor to transfer the amine to the malonate substrate. The product spontaneously cyclizes to a piperidone ester.

Two additional enzymes help drive the reaction: Lactate dehydrogenase, with NADH as a cofactor, reduces the lactate byproduct; and glucose dehydrogenase recycles the NAD coproduct back to NADH. Reducing the methyl ester to a hydroxymethyl group with NaBH4 and CaCl2, followed by LiAlH4 reduction of the piperidone, completes the synthesis of the piperidine building block. (Org. Process Res. Dev. 2013, 17, 61–68; Will Watson)

Get past steric hindrance in Suzuki–Miyaura coupling reactions. Sterically hindered biaryl structures occur widely in natural products and are useful building blocks for ligands in numerous catalysts. Although they are in great demand, the synthesis of sterically hindered biaryls—especially tetra-ortho-substituted biaryls with large functional groups—is a challenge.

To overcome this problem, W. Tang and coauthors at the Shanghai Institute of Organic Chemistry and Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT) developed an efficient method for synthesizing sterically hindered biaryls: Suzuki–Miyaura coupling that uses palladium catalysts with biaryl monophosphorus ligands 1 and 2.


When they optimized the conditions for the model reaction between 2-bromo-1,3-dimethoxybenzene (3) and 2,4,6-triisopropylphenylboronic acid (4), the authors found that strong bases effectively promote the reaction. Whereas very little product forms with weak inorganic bases (NaHCO3 and KF) or organic bases (1,8-diazabicyclo[5.4.0]undec-7-ene [DBU] and 1,4-diazabicyclo[2.2.2]octane [DABCO]), using NaO-t-Bu as the base gives a 97% yield.

Commercially available phosphorus ligands such as S-Phos, Ru-Phos, and X-Phos give disappointingly low yields (1−22%). Ligands 1 and 2 are efficient for cross-coupling sterically hindered aryl halide and boronic acid substrates; yields are >80% in most cases. The authors’ ligands are compatible with functional groups such as aldehydes, nitriles, and phosphonates. They required catalyst loadings as low as 1 mol%.

An example of overcoming extreme steric hindrance is the synthesis of a biphenyl derivative with four o-isopropyl groups in 48% yield.

The X-ray diffraction crystal structure of {Pd(0)[(S)-1]2} showed that the complex has a large P–Pd–P angle (167.9°), which indicates that 1 is unusually bulky. The authors believe that the ligand’s size drives the formation of a monoligated palladium active species.

The bulky base NaO-t-Bu promotes the formation of an active monoaryl palladium alkoxide complex. The more active ligand 2 shows unusual π-coordination in the crystal structure of {Pd(0)[(R)-2]2}, which the authors believe stabilizes the monoligated palladium intermediates. (Chem.—Eur. J. 2013, 19, 2261–2265; Xin Su)

Controlling polymer shape allows surface chemistry modification. S. M. Brosnan, A. H. Brown, and V. S. Ashby* at the University of North Carolina at Chapel Hill synthesized a poly(octylene adipate)–poly(octylene diazidoadipate) thermoset copolymer with shape-memory properties that can be surface-functionalized. By varying the diazide monomer content up to 38 mol%, the melting temperature can be tuned to >40 °C.

At 19 mol% diazide, the authors reported high strain fixity and strain recovery in these shape-memory thermosets. They developed a patterning technology to transfer micro- and nanoscale features to the surface of the materials. The shape-memory response induces structural changes in the patterned features.

The authors also used click chemistry on the azide units to functionalize the surfaces of the hydrophobic thermosets with a range of reactive groups. The dynamic shape-memory response induces an unusual reversible shift in the azide content on the surface, which makes it possible to modify the surface while it is in a temporary configuration. The authors’ methods emphasize the effect of responsive architectures for designing reconfigurable surfaces. (J. Am. Chem. Soc. 2013, 135, 3067–3072; LaShanda Korley)

Make the invisible visible—“see” a greenhouse gas with the naked eye. Invisible carbon dioxide (CO2) is well known as the greenhouse gas that is primarily responsible for global warming. Conventional methods for detecting and quantifying CO2 are time-consuming and require expensive instruments. These methods are also susceptible to such interferents as water and carbon monoxide.

Y. Wang, L. Guo, and coworkers at Beihang University and the Chinese Academy of Sciences (both in Beijing) developed a fluorescence system that can be used to visualize CO2 without interference by other gases present.

When a gas stream that contains CO2 is bubbled through a 1:1 v/v mixture of 1,8-diazabicyclo-[5,4,0]-undec-7-ene (DBU, 1) and 5-amino-1-pentanol (2), an ionic liquid (IL, 3) is formed. The IL salt consists of protonated DBU and carbonate and carbamate anions formed from CO2 and the alcohol.


IL 3 increases the viscosity of the medium and restricts the intramolecular rotation of tetraphenylethylene (4), which is also in the mixture. The authors believe that the alcohol and amine groups in 2 act synergistically to enhance the viscosity of 3.

The rotation restriction causes 4 to fluoresce when it is irradiated. In effect, the fluorescence makes CO2 visible to the naked eye. The emission of 4 intensifies with increasing CO2 concentration in the gas and makes quantitative monitoring of CO2 feasible. (Analyst 2013, 138, 991–994; Ben Zhong Tang)

Mass spectrometry helps identify brain tumors during surgery. The correct delineation of tumor boundaries during brain surgery is difficult because tumors resemble normal tissue. The neurosurgeon is typically guided by histopathological images. More recently, intraoperative magnetic resonance imaging (MRI) has been used, but it has limited ability to distinguish residual tumor tissue from the surrounding normal brain.

N. Y. R. Agar, G. Cooks, and colleagues at Purdue University (West Lafayette, IN) and Harvard Medical School (Boston) developed a mass spectrometric method to differentiate brain tumors from normal tissue. They chose desorption electrospray ionization mass spectrometry (DESI-MS), in which the sample is examined in the ambient environment with minimal pretreatment, to analyze normal-tissue and brain-tumor lipids; they then compared the results with histopathological results from a sample bank. The sample is subjected to a spray of charged droplets to ionize the lipids, which are then transferred to the mass spectrometer and identified. The results are shown as a 2-D image that shows the relative abundances and spatial distribution of lipid ions.

Comparison with data bank information indicated that the technique correctly assigns normal tissue, several types of brain tumors (e.g., gliomas and meningiomas), tumor-cell concentration, and subtypes or grades by lipid distribution. The authors also successfully applied the technique to five samples obtained from surgeries (ex vivo analysis).

The method can be used to identify samples that have heterogeneous cell concentrations as the result of infiltration by neoplastic cells into neighboring normal brain tissue and even into bone tissue. Results of 2-D analyses were combined with preoperative MRI data to construct 3-D tumor models. Efforts are under way to develop small mass spectrometers that can guide surgical resections of brain and other tumors. (Proc. Nat. Acad. Sci. U.SA. 2013, 110, 1611–1616; José C. Barros)

Make aromatic azides from anilines in one pot. Aromatic azides are an important class of building blocks in organic chemistry and biochemistry, but they are conventionally prepared from hazardous and/or expensive reagents. To respond to the need for more efficient, safer methods, V. M. Telvekar and co-workers at the Institute of Chemical Technology (Mumbai) developed a one-pot protocol for synthesizing aromatic azides from the corresponding amines under mild conditions in good yield.


The authors treated aniline, their model substrate, with NaNO2, AcOH, and NH2NH2·H2O in CH2Cl2 solvent under ambient conditions for 30 min. Phenyl azide is produced in 90% yield. Yields are lower and reaction times longer when other solvents (e.g., CHCl3, toluene, and DMSO) are used.

This method is compatible with several functional groups on the phenyl ring and can be applied to heteroaromatic amines. Although deactivating groups lower the yield and require longer reaction times, the highly deactivated 2-amino-6-nitrobenzoic acid is converted to the azide in 50% yield in 9 h.

In the authors’ proposed mechanism, one mole of NaNO2 reacts with one mole of the aniline to give a diazonium salt. Another mole of NaNO2 reacts with one mole of NH2NH2·H2O to form an azide ion. N3 displaces the diazonium group to produce the azide. (Tetrahedron Lett. 2013, 54, 1294–1297; Xin Su)

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