Synthesis of a Peroxime Proliferator Activated Receptor (PPAR) α/γ Agonist via Stereocontrolled Williamson Ether Synthesis and Stereospecific S_N2 Reaction of S-2-Chloro Propionic Acid with Phenoxides

Abstract

The stereospecific synthesis of the PPAR alpha/gamma agonist 1 was accomplished via ethylation of the optically pure trihydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperature (-30 degrees C), order of addition, and solvent (DMF). The key diastereospecific SN2 reaction of the phenol 4 with S-2-chloropropionic acid is best achieved via the sodium phenoxide of 4 derived from Na0 as the reagent of choice. The structure elucidation and key purification protocols to achieve pharmaceutical purity will also be described.

Magnesium Coordination-Directed N-Selective Stereospecific Alkylation of 2-Pyridones, Carbamates, and Amides Using α-Halocarboxylic Acids

“…Although direct S N 2 alkylations using 3 with simple alkoxide and phenoxide nucleophiles have been demonstrated, alkylation of naphthyridinone 1 in a similar fashion presented a significant challenge due to N / O chemoselectivity issues and the increased steric bulk of the nucleophile. The expected decreased reactivity of 1 presents an additional challenge since two stereodivergent reaction manifolds may be operative with electrophile 3 , namely inversion resulting from an S N 2 mechanism and retention through the intermediacy of an α-lactone .…”

Efficient One-Pot Synthesis of Highly Substituted Pyridin-2(1H)-ones via the Vilsmeier−Haack Reaction of 1-Acetyl,1-Carbamoyl Cyclopropanes

“…The results shown above demonstrated the efficiency and synthetic interest of the cyclization reaction with respect to cyclopropanes 1 bearing variable amide groups. It should be noted that the richness of the functionality, for example, halogen, halogen alkyl, and formyl groups on the pyridin-2(1 H )-ones of types 2 and 3 , may render them extremely versatile as synthons in further synthetic transformations, such as metal-mediated coupling reaction, Williamson reaction, and Henry reaction …”

Enantioselective Hydrogenation of α-Aryloxy and α-Alkoxy α,β-Unsaturated Carboxylic Acids Catalyzed by Chiral Spiro Iridium/Phosphino-Oxazoline Complexes

“…Chiral α-alkoxy carboxylic acid derivatives have received increasing attention due to their successful utility as starting materials for the asymmetric synthesis of a series of PPARs agonists . Mild and practical methods for the preparation of these compounds are still highly sought after . When we applied our Ir−SIPHOXs catalysts in the hydrogenation of α-alkoxy cinnamic acid derivatives, we found all of the catalysts ( S a , S )- 1c − 1f bearing 3,5-di- tert -butylphenyl groups on the P atom, but with different substituents on the oxazoline rings, showed essentially the same catalytic capabilities.…”