Self-Assembly of Ketals of Arjunolic Acid into Vesicles and Fibers Yielding Gel-Like Dispersions

Ten aliphatic and aromatic ketals of arjunolic acid, a renewable, nanosized triterpenic acid which is obtainable from <i>Terminalia arjuna</i>, have been synthesized upon condensation with aldehydes. Self-assembly properties of the ketals have been studied in a wide range of organic liquids. With the exception of the <i>p</i>-nitrobenzylidene derivative, low concentrations of the ketals self-assemble and form gel-like dispersions in many of the organic liquids examined. The morphologies of the assemblies, studied at different distance scales by optical, electron, and atomic-force microscopies, consisted of fibrillar networks and vesicles which were able to entrap 5(6)-carboxyfluorescein as a guest molecule. X-ray diffractograms indicate that the fibrillar objects are crystalline. A charge-transfer complex was formed from a 1:1 mixture of ketal derivatives with electron-donating and electron-accepting groups, and the 9-anthrylidene derivative in its fibrillar network dimerized upon irradiation. Results demonstrate that subtle changes in the ketal structures can lead to very different aggregation pathways

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug