Practical Asymmetric Synthesis of Aprepitant, a Potent Human NK-1 Receptor Antagonist, via a Stereoselective Lewis Acid-Catalyzed Trans Acetalization Reaction

Abstract

A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.

Asymmetric Synthesis of Chiral 1,2-Amino Alcohols and Morpholin-2-ones from Arylglyoxals

“…Vicinal amino alcohols are found in commercial drugs that display antifungal, , antiemetic, and antidepressant properties (Figure ). One of the most prevalent applications of chiral amino alcohols is in the preparation of chiral ligands for metal-catalyzed reactions and organocatalysis .…”

An Additional Coordination Group Leads to Extremely Efficient Chiral Iridium Catalysts for Asymmetric Hydrogenation of Ketones

“…The coordination of ligands 2 to the iridium atom was verified by analysis of the single crystal structure of the complex [IrH 2 ((R)-2 c)Cl] [10] (Figure 1) obtained from the reaction of (R)-2 c with [{Ir(cod)Cl} 2 ] (cod = cyclooctadiene) in MeOH under hydrogen. In the crystal structure of [IrH 2 ((R)-2 c)Cl], ligand (R)-2 c was coordinated to the iridium atom by means of one phosphorus atom and two nitrogen atoms by a conformationally restricted eight-membered ring and a five-membered heterometal ring.…”

Thermal Healing of Copolyacrylate Elastomer Based on Catalyst‐Free Transketalization

“…The acetal/ketal can undergo reversible exchange reactions in the presence of Lewis or Brönsted acid catalyst, [ 26–28 ] and this transketalization can be applied to the synthesis of organic compounds [ 26,29 ] and natural products. [ 30 ] The acetal/ketal also can exchange with o ‐dihydroxyl compounds in absence of catalyst, [ 31 ] but their exchanges occur at slightly higher temperatures (≈90–100 °C). Similarly, the reversible ester exchange can occur between ester and alcohol, [ 32,33 ] while the ester groups are incorporated into a cross‐linked polymer network, the hydroxyl‐ester exchange can still happen at temperatures above 150 °C.…”