Rearrangement of isoxazoline-5-spiro derivatives. Part 10. Regioselective nitrone cycloadditions to methoxycarbonylmethylenecyclopropane: Synthesis of precursors of (±)-Lupinine, (±)-Epilupinine and (±)-Elaeokanine A
“…The alkoxycarbonyl group in 1 , besides playing the role of activating the double bond toward additions, in nitrone 1,3-dipolar cycloadditions provides a high control of the regioselectivity leading to the formation of 4-alkoxycarbonyl-substituted (isoxazoline numbering) isoxazolidines …”
Section: Introductionmentioning
confidence: 99%
“…The temperature required to initiate the rearrangement of compounds of type 4 ranges from 80 to 150 °C. However, when the substrate carries a methoxycarbonyl group at the 4-position as in the isoxazolidine 7 (Scheme ) the required temperature is much higher . In such cases, FVT (flash vacuum thermolysis) conditions are preferable to avoid competing decomposition processes, either of the reagent or of the product.…”
Methyl 2-chloro-2-cyclopropylideneacetate (2) and its spiropentane analogue 3 cycloadd to dihydroisoquinoline N-oxide (9), pyrroline N-oxide (12), and C-phenyl-N-methylnitrone (16) to give 5-spirocyclopropaneisoxazolidines in good yields (58-93%). The thermal behavior of the 5-spirocyclopropaneisoxazolidines is rather differentiated, depending strongly on the constitution of the nitrone and the solvent. As nitrone 9 has the tendency to undergo cycloreversion reactions, the ketoamide rearrangement products 20 and 21 from its cycloadduct derive from the thermodynamically favored 4-spirocyclopropaneisoxazolidine regioisomers formed after the cycloreversion process. In DMSO as solvent different rearrangement processes take place, leading to benzoindolizinones in modest yields (15-21%). The cycloadducts from 12 and 16 undergo a cyclopropyl to cyclobutyl ring enlargement facilitated by the presence of a chlorine substituent on the carbon alpha to the spirocyclopropane ring. Whereas these compounds from nitrone 16 demonstrated an unusual stability, those from nitrone 12 undergo a cascade rearrangement to yield indolizinone derivatives 34, 35 cleanly (73-83% yield). This overall transformation offers a new method for the synthesis of the indolizine skeleton.
“…The alkoxycarbonyl group in 1 , besides playing the role of activating the double bond toward additions, in nitrone 1,3-dipolar cycloadditions provides a high control of the regioselectivity leading to the formation of 4-alkoxycarbonyl-substituted (isoxazoline numbering) isoxazolidines …”
Section: Introductionmentioning
confidence: 99%
“…The temperature required to initiate the rearrangement of compounds of type 4 ranges from 80 to 150 °C. However, when the substrate carries a methoxycarbonyl group at the 4-position as in the isoxazolidine 7 (Scheme ) the required temperature is much higher . In such cases, FVT (flash vacuum thermolysis) conditions are preferable to avoid competing decomposition processes, either of the reagent or of the product.…”
Methyl 2-chloro-2-cyclopropylideneacetate (2) and its spiropentane analogue 3 cycloadd to dihydroisoquinoline N-oxide (9), pyrroline N-oxide (12), and C-phenyl-N-methylnitrone (16) to give 5-spirocyclopropaneisoxazolidines in good yields (58-93%). The thermal behavior of the 5-spirocyclopropaneisoxazolidines is rather differentiated, depending strongly on the constitution of the nitrone and the solvent. As nitrone 9 has the tendency to undergo cycloreversion reactions, the ketoamide rearrangement products 20 and 21 from its cycloadduct derive from the thermodynamically favored 4-spirocyclopropaneisoxazolidine regioisomers formed after the cycloreversion process. In DMSO as solvent different rearrangement processes take place, leading to benzoindolizinones in modest yields (15-21%). The cycloadducts from 12 and 16 undergo a cyclopropyl to cyclobutyl ring enlargement facilitated by the presence of a chlorine substituent on the carbon alpha to the spirocyclopropane ring. Whereas these compounds from nitrone 16 demonstrated an unusual stability, those from nitrone 12 undergo a cascade rearrangement to yield indolizinone derivatives 34, 35 cleanly (73-83% yield). This overall transformation offers a new method for the synthesis of the indolizine skeleton.
“…The synthetic methodology based on nitrone and nitrile oxide cycloadditions to methylenecyclopropane followed by thermal rearrangement of the resulting adducts to give a functionalized pyridone (Scheme ) has already been demonstrated as a useful and versatile strategy to obtain structurally differentiated azaheterocycles, including alkaloids in racemic and nonracemic form. 1 …”
Bicyclopropylidene smoothly undergoes 1,3-dipolar cycloadditions to nitrones or nitrile oxides under different reaction conditions. The strained bisspirocyclopropanated isoxazolidines obtained from nitrones easily rearrange upon heating with selective opening of one of the two spirofused cyclopropane rings. This process produces 4-pyridone, 7-indolizinone, and 2-quinolizinone derivatives containing a spirocyclopropane moiety in the alpha-position to the carbonyl group in good yields. The same sequence of cycloaddition and rearrangement can be achieved in a "one-pot" operation with considerable benefit for the reaction yield. Bisspirocyclopropaneisoxazolines obtained from nitrile oxides are more stable than their saturated counterparts and rearrange only at higher temperature less chemoselectively. Opening of both spiro-fused cyclopropyl rings followed by aromatization produces interesting 2-substituted dihydrofuro[2,3-c]pyridine derivatives.
“…In the last decade, extensive efforts and brilliant results in the synthesis of pyrrolizidines and indolizidines by means of nitrone cycloadditions are due to Brandi and co-workers. [35][36][37][38][39][40][41][42][43][44][45][46][47][48] A peculiar feature of their strategy is the use of methylenecyclopropanes as dipolarophiles. Cycloadditions between the latter substrates and cyclic nitrones generate strained tricyclic spiroisoxazolidines, which are very prone toward further transformations such as rearrangement, ring opening, and new ring closure.…”
Due to their many forms and versatility, 1,3-dipolar cycloadditions have found copious applications in the coveted synthesis of pyrrolizidine and indolizidine alkaloids. A systematic and critical overview of these applications is the focus of the present survey.
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