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Advancing Chiral Chemistry in Pharmaceutical Synthesis
Chiral chemistry plays an important role in pharmaceutical development and manufacturing. Strategies in asymmetric synthesis to produce single-enantiomer drugs as well as methods for detecting and quantifying chirality are important tools for pharmaceutical chemists. Some recent developments involve stereoretentive cross-coupling for producing libraries of single enantiomers, an approach in enantioselective alcohol silylation, strategies for amplifying signals in circular dichroism spectroscopy, and a synthetic route to the natural product ingenol.
The use of nanoparticles to amplify the signal was done to overcome the weak signal when applying circular dichroism spectroscopy in the ultraviolet range for chiral molecules. The researchers were guided by experimental work that showed that coupling certain molecules with metallic nanoparticles would increase their response to light (4) as well as theoretical work that suggested that the plasmonic particles, which induce a collective oscillation of the material’s conductive electrons to create stronger absorption of a particular wavelength, could move the signal into the visible spectrum, where it would be easier to measure, according to the BNL release.
The researchers experimented with different shapes and compositions of nanoparticles and found that cubes with a gold center surrounded by a silver shell are not only able to show a chiral optical signal in the near-visible range, but also were effective signal amplifiers. For their test biomolecule, they used synthetic strands of DNA. When DNA was attached to the silver-coated nanocubes, the signal was approximately 100 times stronger than it was for free DNA in the solution, according to the BNL release. The observed amplification of the circular dichroism signal is a consequence of the interaction between the plasmonic particles and the energy absorbing-electrons within the DNA-nanocube complex, according to the BNL release. The researchers note that the work can serve as a platform for ultrasensitive sensing of chiral molecules and their transformations in synthetic, biomedical and pharmaceutical applications.
In another development, researchers at Harvard University, the Center for Free-Electron Laser Science (CFEL), and the Max Planck Institute in Germany reported on enantiomer-specific detection of chiral molecules by microwave spectroscopy (5, 6). The approach sought to overcome limitations in circular dichroism and vibrational circular dichroism spectroscopy, which are commonly used in analysing chiral molecules, but which produce weak signals and require high sample densities (5, 6). The researchers carried out nonlinear resonant phase-sensitive microwave spectroscopy of gas-phase samples in the presence of an adiabatically switched nonresonant orthogonal electric field. They used this technique to map the enantiomer-dependent sign of an electric dipole Rabi frequency onto the phase of emitted microwave radiation (5, 6) and described how this approach can be used for determining the chirality of cold gas-phase molecules. They implemented the approach experimentally to distinguish between the S and R enantiomers of 1,2-propanediol and their racemic mixture. “We can soon measure mixtures of different compounds and determine the enantiomer ratios of each,” said Melanie Schnell, co-author of the study in a CFEL release. The researchers plan to apply the technique in a broadband spectrometer at CFEL that could measure the enantiomer ratios in mixtures of substances, and longer term, the method opens a way for separating enantiomers (6).
Ingenol mebutate, a macrocyclic diterpene ester, is a purified ingenol angelate extracted from the aerial parts of Euphorbia peplus plant. The molecule has eight chiral centers and one “nonrestricted” double bond, thus, there is a theoretical possibility of up to 512 stereoisomers (7). The ingenol mebutate is obtained from the dried, milled aerial parts of the plant by extraction followed by a series of purification steps. The final step of the process involves crystallization (7). In late 2011, the drug’s manufacturer, the Danish pharmaceutical company LEO Pharma, collaborated with TSRI to develop an efficient way to synthesize ingenol mebutate and ingenol derivatives. The scientists developed a stereocontrolled synthesis of (+)-ingenol in 14 steps from inexpensive (+)-3-carene and used a two-phase design (8). The researchers assert the results validate that two-phase terpene total synthesis is an alternative to isolation or bioengineering for preparing polyoxygenated terpenoids (8).
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