Reductive Recyclization of sp³-Enriched Functionalized Isoxazolines into α-Hydroxy Lactams

Abstract

An efficient synthesis (up to a 200 g scale) of 3hydroxypyrrolidin-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 in situ generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5carboxylates. The catalytic hydrogenolysis of the isoxazoline N−O bond was optimal upon using H 2 (1 atm) at rt, with the following order of the catalyst activity: Pd−C > Pd(OH) 2 −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 (cis-and trans-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 3 (but not CHF 2 or CH 2 Cl), ester, and most N-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.

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…In 2022, a group of researchers published an article regarding the formation of 3,5-disubstituted isoxazolines via the discussed method. 1,3-DP cycloaddition was an initial step in the synthetic procedure leading to the 3-hydroxypyrrolidin-2-ones, including on a large scale (up to 200 g)— Scheme 154 [ 163 ].…”

“…To sum up this short fragment of our review: undoubtedly, isoxazolines are valuable organic semiproducts, scaffolds and syntons, and numerous examples of the use of isoxazolines in organic synthesis can be found in the reviews and books [ 22 , 54 , 133 , 163 , 175 , 301 , 315 , 321 , 322 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 ].…”

“… 3,5-disubstituted 2-isoxazolines as intermediates in the synthetic route leading to the α-hydroxy lactams [ 163 ]. R 1 , R 2 = CO 2 Et, Me; Ph, Me; Et, Et; t -Bu, Me; CHF 2 , Et and others (25 examples); a (X = Cl) = NaHCO 3 , AcOEt, rt, overnight; a (X = H) = 1.…”

“… 2-Isoxazolines in organic synthesis—selected examples [ 22 , 54 , 133 , 163 , 175 , 301 , 315 , 321 , 322 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , 352 ]. …”

Synthesis of Spirocyclic and Fused Isoxazoline Building Blocks

“…Finally, we have evaluated a possibility to obtain amino acid derivatives via the hydrogenolysis of the synthesized isoxazolines. [23] Thus, the reaction of compound 3 b with H 2 in the presence of 10 mol % Pd(OH) 2 À C and Boc 2 O resulted in the formation of a ca. 1 : 3 mixture of amino ester 15 (minor product) and the corresponding lactone 16 (major product), which were isolated in 23 % and 61 % yields, respectively, after HPLC separation (Scheme 9).…”