Isoxazolidines rearrangement

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]. 

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. 

In the overall cycloaddition-rearrangement process [64], the C-3 - C-8a relative stereochemistry of the indolizidinone obtained by rearrangement of the isoxazolidine derives from the cycloaddition step and is not affected during the rearrangement. This allowed the control of two out of three chiral centers in a synthetic protocol for a synthesis of the amphibian alkaloid ( + )-Gephyro-toxin 223AB (Scheme 46) [65c]. 

Compound 384 derived from the reaction of two molecules of benzonitrile oxide (341) with one of BCP (3). Its formation can be explained with the cycloaddition of a second molecule of 341 to the isoxazoline Ml to give the isoxazolidine M5, which undergoes a thermal rearrangement to 384 (Scheme 54). 

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>. 

The presumed mechanism of the oxidative ring enlargement is shown for 52 (R = Ph). The first step is the oxidation of the isoxazolidine to the unstable N-oxide 58, which rearranges to the unstable dipolar 59 this yields the methylene nitrone 60 by tautomerization. 60 gives oxazine 53, through ring-chain tautomerization (79JOC1819). 

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]. 

The isoxazolidines 42e,f only gave the cyclobutane derivatives of type 46 upon thermal rearrangement (isolated in 82% yield both after heating in DMSO at 100 °C for 7 and 2 h, respectively), and 46e,f appeared to be inert to further thermal transformations. 

These authors also showed that the indolizidine skeleton can be prepared from cyclopropyl dipolarophiles (Scheme 1.16). The cycloaddition of alkyhdenecyclo-propanes 67 with various nitrones (e.g., 68) afforded the expected isoxazolidine adducts 69 and 70, commonly forming the C(5) substituted adducts 70 (97,105-108) predominantly but not exclusively (109-111). Thermally induced rearrangement of the spirocyclopropyl isoxazolidine adduct 70 afforded the piperidinones 71 (107,108). These authors propose reaction via initial N—O bond homolysis of 70 to diradical 72 followed by ring expansion through relief of the cyclopropyl ring strain forming the carbonyl of a second diradical intermediate 73, which cyclizes to afford the isolated piperidinone 71. 

The intermolecular cycloaddition route to spirocyclopropyl isoxazolidines and their subsequent rearrangement, used so widely by Brandi and co-workers (372-375) (Schemes 1.16 and 1.17, Section 1.5), has also been achieved in an intramolecular sense (Scheme 1.72). Cycloaddition of the alkenyl nitrone reagents (333a-c) afforded bicyclic isoxazolidinyl adducts 334, which rearranged under thermolysis in analogous fashion to the earlier work to give piperidinones (335) via... 

A further rearrangement route to bicyclic aminoketones has been investigated by Padwa et al. (128-134) (Scheme 1.19). Building on the allene-nitrone cycloadditions reported by Tufariello, the alkenyl isoxazolidine adducts 90 and 91 were... 

The so-called isoxazoline transposition or Angeli s rearrangement (Scheme 79) involves the conversion of methylfuroxans by treatment with alkoxides or alcoholic alkali hydroxides into the oximes of isoxazolidin-4-ones (531) (81G167). 

The isoxazolidines derived from aldehydes (17a-b) were converted to eudesmane sesquiterpenes. Thus, quatemization of isoxazolidine (18) was followed by ring expansion via a Stevens rearrangement. 

The p-lactamic ring was also formed by the acidic thermal rearrangement of spiro[cyclopropane-l,5 -isoxazolidines], [209]. The rearrangement was almost instantaneous at 90°C, as the starting material was completely converted after 2 min. 

---