Reductive Recyclization of sp 3 -Enriched Functionalized Isoxazolines into α-Hydroxy Lactams

• Published in: Journal of organic chemistry Vol. 87; no. 2; pp. 1001 - 1018
• Main Authors: Chalyk, Bohdan A, Khutorianskyi, Andrii V, Vashchenko, Bohdan V, Danyleiko, Kyrylo, Grynyova, Anastasiia, Osipova, Anastasiia O, Kozytskiy, Andriy, Syniuchenko, Darya, Tsymbaliuk, Anton, Gavrilenko, Konstantin S, Biitseva, Angelina V, Volochnyuk, Dmitriy M, Komarov, Igor V, Grygorenko, Oleksandr O
• Format: Journal Article
• Language: English
• Published: United States 21-01-2022
• Subjects: Amines; Catalysis; Cycloaddition Reaction; Lactams; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.1c02301

An efficient synthesis (up to a 200 g scale) of 3-hydroxypyrrolidin-2-ones bearing alkyl substituents or functional groups at the C-5 position is described. The reaction sequence started from 1,3-dipolar cycloaddition of
generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5-carboxylates. The catalytic hydrogenolysis of the isoxazoline N-O bond was optimal upon using H
(1 atm) at rt, with the following order of the catalyst activity: Pd-C > Pd(OH)
-C > Pt-C. The reactions with Pt-C were more selective for the synthesis of pyrrolidones, while Pd-C provided the fastest conversion rates. The stirring efficiency had a positive impact on conversion rather than elevated temperatures (up to 40 °C) or pressure (up to 50 atm). The diastereoselectivity was governed mainly by steric factors, with a dr of 1:1 to 3:1 (
and
-isomers could be separated). Higher homologues (isoxazolinylacetates and -propanoates) were suitable for the synthesis of 6- or 7-substituted 4-hydroxypiperidones and 5-hydroxyazepanones, respectively. The proposed methods are tolerant to functional groups, including CF
(but not CHF
or CH
Cl), ester, and most
-Boc-protected amines. The utility of hydroxyl groups in lactams was shown by functional group transformations. Hydrogenolysis of C(5)-functionalized isoxazolines, bearing trimethylsilyl, phosphonate, or sulfone groups, was also studied to demonstrate limitations.