Synthesis of Enantiomerically Pure 2,5-Disubstituted 3-Oxygenated Tetrahydrofurans

Abstract

, 5 -D i s u b s t i t u t e d 3 -O x y g e n a t e d T e t r a h y d r o f u r a n sAbstract: The synthesis of enantiomerically pure 2,5-disubstituted 3-oxygenated tetrahydrofurans has been achieved from cheap and commercially available L-malic acid. This method was used to prepare an advanced intermediate toward CMI-977, a promising candidate for the treatment of chronic asthma.

Hemiacetal Esters: Synthesis, Properties, and Applications of a Versatile Functional Group

“…Indeed, their condensation with ketones such as acetone, cyclohexanone, and hexafluoroacetone blocks the two reactive OH at once and allows further synthetic elaboration. The cyclohexanone derivative is rather common in multistep synthesis, easily cleaved under acidic conditions, or conveniently converted to the hydroxyester by reaction with an alkoxide. , The product obtained from hexafluoroacetone is less common, but its higher reactivity allows a great variety of transformations once its use as a protecting group is fulfilled . Indeed, the 2,2-bis­(trifluoromethyl)-1,3-dioxolan-4-ones can be converted to the corresponding α-hydroxy acid, ester, or amide (Scheme ).…”

“…However, in the case of the reaction between an aldehyde and a β- or α-hydroxy acid, the intramolecular reaction between the acid and the hemiacetal intermediate is favored over the intermolecular second addition of an alcohol and therefore provides the corresponding cyclic HAE. This condensation is usually catalyzed by a Brønsted or Lewis acid (PTSA, H 2 SO 4 , BF 3 ·Et 2 O, ...) and requires a dehydrating reagent (P 2 O 5 , ...) or a water-removal technique. − The addition of trimethyl orthoformate to form a transient methoxy-substituted HAE appeared as an improved method to prepare a sterically hindered HAE derived from pivalaldehyde . This approach also constitutes a very popular preparation of HAE monomers for various polymerization reactions (vide infra).…”