Catalytic Reductive Recyclization of Functionalized Isoxazoline -Oxides to Pyrrolizidine-3-ones.

Pyrrolizidine is among the saturated -heterocyclic scaffolds most frequently found in natural products and pharmaceutically relevant substances. Herein, a strategy for the synthesis of polysubstituted pyrrolizidine-3-ones by catalytic reductive domino-type recyclization of properly functionalized isoxazoline -oxides was developed. The process is diastereoselective, and one diastereomer (out of four possible ones) is predominant in many of the studied cases.

[3+3]-Annulation of Cyclic Nitronates with Vinyl Diazoacetates: Diastereoselective Synthesis of Partially Saturated [1,2]Oxazino[2,3-][1,2]oxazines and Their Base-Promoted Ring Contraction to Pyrrolo[1,2-][1,2]oxazine Derivatives.

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4-1,2-oxazine -oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2-[1,2]oxazino[2,3-][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole.

Interrupted Nef Reaction of Cyclic Nitronates: Diastereoselective Access to Densely Substituted α-Chloronitroso Compounds.

The reaction of cyclic nitronic esters (isoxazoline- and 5,6-dihydro-4-1,2-oxazine--oxides) with hydrochloric acid affords geminal chloronitroso compounds bearing a distant hydroxyl group. The reaction is usually diastereoselective, and in some cases stereodivergent formation of isomers at different temperatures is observed. The discovered process represents the first example of an interrupted Nef reaction of nitronic esters.

Regio- and diastereoselective access to densely functionalized ketones the Boekelheide rearrangement of isoxazoline -oxides.

In this work, the classical "isoxazoline route" toward aldols involving the [3 + 2]-cycloaddition of nitrile oxide to alkenes and hydrogenolysis of the 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 -oxide moiety. Subsequent deoxygenative C-H functionalization using the Boekelheide rearrangement and hydrogenolysis of the isoxazoline ring afforded α'-acyloxy-substituted aldols, which are difficult to access both by the classical aldol reaction and the "isoxazoline route".

Deoxygenative Arylation of 5,6-Dihydro-4-1,2-oxazine--oxides with Arynes.

Six-membered cyclic nitronates (5,6-dihydro-4-1,2-oxazine--oxides) react with Kobayashi's aryne precursors producing 3-(2-hydroxyaryl)-substituted 1,2-oxazines via deoxygenative C-H arylation. The process involves a hitherto unknown 1,3-dipolar cycloaddition of nitronate to the aryne to give an unusual tricyclic nitroso acetal, in which the N-O bond of the isoxazoline ring is selectively cleaved upon the action of a base (CsF) or an acid (TFA). The transient cycloadducts were isolated and characterized in some cases.