Renewed «Isoxazoline Route» for the Synthesis of Densely Functionalized Ketones

Abstract

In this work, the «isoxazoline route» to aldols involving the [3+2]-cycloaddition of nitrile oxide to alkenes and hydrogenolysis of oxime group was revisited. To avoid regioselectivity issues, [4+1]-annulation of nitroalkenes with sulfonium ylides was used to construct the isoxazoline ring bearing an N-oxide moiety. Subsequent deoxygenative C-H functionalization using Boekelheide rearrangement and hydrogenolysis of the isoxazoline ring afforded α’-acyloxy-substituted aldols, which are difficult to access both by classical aldol reaction and the «isoxazoline route». The products are formed in good to high overall yields and as single diastereomers in most cases. The synthetic use of these aldols was showcased by their smooth transformation into diastereomerically pure triols and a 2,3-diaryl-4-hydroxy-substituted tetrahydrofurane derivative, which is structurally related to Cinncassin B.

2-((3-(4-Methoxyphenyl)-4,5-dihydroisoxazol-5-yl)methyl)benzo[d]isothiazol-3(2H)-one1,1-dioxide

“…Heterocyclic rings containing nitrogen with an oxygen atom are considered one of the best combinations in medicinal chemistry due to their diverse biological activities [1]. Isoxazoline is a five-membered heterocyclic azole ring used as a versatile structural motif and an important intermediate [2,3] to access hydroxy ketones [4,5], amino alcohols [6], and isoxazolidines [7], which are used in natural products and compounds of great importance in the synthesis of various pharmacologically active heterocycles. In addition, isoxazoline derivatives have attracted much attention due to their various pharmacological activities such as antimicrobial [8], anticancer [9], antidiabetic [10], anti-inflammatory [11][12][13], antistress [14], antibacterial [15,16], anti-Alzheimer [17], analgesic [18], insecticidal [19,20], and acaricidal activities [21].…”