Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts.

Amidation of unprotected amino acids has been investigated using a variety of 'classical" coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.

Borate esters: Simple catalysts for the sustainable synthesis of complex amides.

Chemical reactions for the formation of amide bonds are among the most commonly used transformations in organic chemistry, yet they are often highly inefficient. A novel protocol for amidation using a simple borate ester catalyst is reported. The process presents significant improvements over other catalytic amidation methods in terms of efficiency and safety, with an unprecedented substrate scope including functionalized heterocycles and even unprotected amino acids. The method was used to access a wide range of functionalized amide derivatives, including pharmaceutically relevant targets, important synthetic intermediates, a catalyst, and a natural product.

Efficient synthesis of an imidazole-substituted delta-amino acid by the integration of chiral technologies.

Two methods to produce (2S)-5-amino-2-(1-n-propyl-1H-imidazol-4-ylmethyl)-pentanoic acid were investigated. Diastereoisomeric salt resolution, using the quinidine salt, gave the desired intermediate in 98% ee and 33% yield. Asymmetric hydrogenation of various substrates gave high conversions, with up to 83% ee. Integration of these two approaches via asymmetric hydrogenation of a quinidine salt substrate followed by crystallization provided the desired intermediate in 94% ee and 76% yield.

Asymmetric hydrogenation of a 4,4-diaryl-3-butenoate; a novel approach to sertraline.

The asymmetric hydrogenation of a selectively crystallised (E)-4,4-diaryl-3-butenoate with a rhodium-PhanePhos catalyst is described, providing an intermediate to the antidepressant sertraline.