Isoxazolidines, 5-spirocyclopropane

The impulse to the study of these cycloadditions came from the discovery that 5-spirocyclopropane isoxazolidines (or isoxazolines) undergo a thermal rearrangement resulting in the production of selectively substituted tetrahydro-(or dihydro) pyrid-4-ones (Scheme 42) [64], In particular, cyclic nitrones gave ultimately N-bridgehead bicyclic ketones, molecular skeleton of many alkaloid families [65]. 

Thermolysis of 3,4-m- ring-fused 5-spirocyclopropane isoxazolidines 29 in the presence of a protic acid has yielded a variety of heterocycles, including [l,6]naphthyridines, with the concomitant extmsion of ethane (Scheme 63) <2003JOC3271>. 

Scheme 93 Selective ring contraction of 5-spirocyclopropane isoxazolidines mediated by acids...

Thermolysis of 3,4-cw ring-fused 5-spirocyclopropane isoxazolidines in the presence of a protic acid, yielded 3,4-cw ring-fused azetidin-2-ones 51 with concomitant extrusion of ethylene <03JOC3271>. Bicyclic isoxazolidines have been converted into the corresponding P-lactams by sequential N-O bond cleavage, oxidation and cyclization <03JOC1207>. Intramolecular aromatic nucleophilic substitution has been established as a route for tricyclic P-lactams 52 <03T5259>. 

The thermally induced ring expansion of 5-spirocyclopropane isoxazolidines (Brandi-Guarna reaction) has been studied extensively and proved to be a general method of synthesizing variously substituted tetrahydropyridones, indolizidinones, and quinolizidinones. The process is believed to occur through diradical intermediates and was also studied by mixed restricted/unrestricted DFT (RDFT/UDFT) calculations <2001EJ04223>. Some representative... 

In an alternative two-step transformation of 5-spirocyclopropane isoxazolidines to tetrahydropyridones, for example, 7-amino cyclopropanol 214, prepared by chemoselective N-O reduction of isoxazolidine 213, was converted into 215 by treatment with Cu(OAc)2 and LiOAc in the presence of catalytic amounts of Pd(OAc)2. Interestingly, 7-amino cyclopropanols can also undergo a Pd-catalyzed domino ring-opening/cyclization/oxidation process to afford dihy-dropyridones such as 216 when the reaction is carried out in the presence of air or O2 (Scheme 49) <2005JOC5636>. 

The unexpected regiochemical outcome of the cycloaddition gave rise to a complete study of the factors influencing the regioselectivity, inasmuch as 4-spirocyclopropane isoxazolidines are unable to undergo the useful thermal rearrangement. 

Spirocyclopropane isoxazolidines 75, obtained from alkylidenecyclopropane nitrones, underwent thermally induced selective rearrangement to pyrrolo[3,4-A]pyridinones 76 <00TA897>. The same adducts 75 in the presence of a protic acid afforded exclusively p-lactams 77 (57-60% yield) accompanied by ethylene extrusion <00JA8075>. 

Treatment of bis-spirocyclopropanated isoxazolidines 551 with trifluoroacetic acid in acetonitrile furnishes 3-spiro-cyclopropanated azetidin-2-ones 552 in excellent yields (Equation 226) <2004EJ04158>. 

Under analogous reaction conditions, tricyclic isoxazolidines 85c afforded the p-homoprolines 87, probably by ring opening and A-acylation of the primary carbapenam intermediates 86c <04EJ02205>. The chemistry of spirocyclopropane isoxazolidines 85 as versatile precursors of different azaheterocycles has been reviewed <04M649>. 

Aryl or alkyl substituents on the exocyclic double bond steer the regioselec-tivity towards the formation of isoxazolidine-4-spirocyclopropanes 274-276 (Table 22, entries 1-3). A complete reversal of regioselectivity to 277-279 was observed in the reactions of methoxycarbonyl substituted methylenecyclo-... 

A new selective thermal cascade ring-enlargement process of 4-chloro-substituted spiro[cyclopropane-l,5 -isoxazolidines], leading to a new method for the synthesis of the indolizine skeleton, has been reported (see Scheme 17). Apparently, the process is made possible by the presence of a chlorine substituent on the carbon a to the spirocyclopropane ring which facilitates a cyclopropyl-to-cyclobutyl ring enlargement mediated by a polar solvent. 

Dipolar cycloadditions of nitrile oxides 216 onto 1 gave much poorer yields of cycloadducts 217 than those of nitrones 205. The cycloadditions of 216 to 1 require higher temperatures and unfavorably compete with their dimerization to furoxanes. However, stable nitrile oxides 216 with bulky substituents R that hamper dimerization, can be used. The thermal rearrangements of 5-spirocyclopropane-annelated isoxazolines 217 always required higher temperatures than the isoxazolidine counterparts. Under these conditions the second cyclopropane ring was also cleaved to give furopyridines 218 (Scheme 48) [136, 137]. 

Analogously, in 2004, it has been reported that the treatment of bis-spirocy-clopropanated isoxazolidines [202-207] with TFA in acetonitrile furnished the 3-spirocyclopropanated p-lactams in 75-96% yields [208]. 

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