Reductive transformations of 3-alkyl- and 3-aryl-5-(4-pyridyl)-2-isoxazolines

Abstract

The reactions of 3-R-(4-pyridyl)-2-isoxazolines and the products of their hydrogenolysis over Raney Ni/AICI3with s as the reducing agents were studied. New polyhydroxyprostanoids were synthesized.We have already described the synthesis of 13,15-isoxazolinylprostanoids with 15-hetaryl fragments as active pharmacophores, including the synthesis of prostanoid Ia [ 1 ]. However, an attempt to modify this compound by a method standard for similar isoxazoloprostanoids proved unsuccessful since 1,3-cycloreversion of the isoxazoline heterocycle was observed upon the action of KBH(s-Bu)3, NaCH~S(O)CH3, and BuLi, leading to destruction of the prostanoid to-chain [2]. Thus reductive transformations are probably the only suitable methods for modifying 15-pyridyl-13,15-isoxazolinylprostanoids in the preparation of prostaglandin heteroanalogs. In the present work, results are given for a study of such transformations of isoxazolinoprostanoids Ia, Ib, and model 3-veratryl-5-(4-pyridyl)-2-isoxazoline (It).The starting 2-isoxazolidines Ia-c were obtained by the 1,3-dipolar addition of nitrile oxides, generated from the corresponding nitro compounds or oximes, to 4-vinylpyridine.In accord with our isoxazoline strategy for constructing the prostanoid ~chain [3], the selective transformation of C(9)-keto-13,15-isoxazolinoprostanoids to their C(9)-t~-hydroxy derivatives in order to go from E-to F-prostanoids should be carried out prior to opening of the isoxazoline ring.* In order to avoid destruction of the isoxazoline ring, NaBI-h was used instead of K selectride for reduction of the carbonyl group in isoxazolinoprostanoids Ia-Ic. The reaction in the case of ketones Ia and Ib proceeded to give hydroxy derivatives IIa and IIb in 80% yield as a 1:2 mixture of the 9c~-and 9~-diastereomers. Under these conditions, ketone Ic is not reduced and the starting compound was recovered. In light of the lack of stereoselectivity in the reduction of the C(9)=O group described above, we tested the feasibility of selective reduction of the carbonyl group to give products of the reductive splitting of the heterocycle in isoxazolinoprostanoids lade. The hydrogenolysis of these compounds was carried out in the presence of skeleton catalyst, Raney nickel, in the AICI3--MeOH--H20 system; hydrogen in situ being the active reducing agent in this system [5]. Under these conditions, Ia-c are converted to [3-hydroxyketones IIIa-c in 54-65% yield, which corresponds to the typical scheme for splitting of 2-isoxazolines by the action of such reducing agents [5]. Ketone IVc was isolated in 20% yield in the reductive opening of isoxazoline Ic along with hydroxyketone IIIc obtained in 54% yield; ketones IVa and IVb were detected in trace amounts. The reductive splitting of 9-hydroxy-13,15-isoxazolinoprostanoids IIa and lib leads to ketodiols Va and Vb in 65-70% yield.*Prostaglandins with a C=O group in the prostane skeleton belong to the E series, while such derivatives with a C(9)--ot-OH group belong to the F series. The nomenclature for derivatives a and b has ...

Polyfunctional intermediates for the preparation of liquid-crystalline and anisotropic materials

“…Taking into account the results of our previous investigations [29,44,45] and that the β-hydroxy ketones (65) N-(CH 2 )k- …”