Nitrones ring opening

An interesting strategy for the synthesis of pyrrolizidines and indolizidines has been developed by Brandi and co-workers. Cycloaddition between nitrones or nitrile oxides with methylenecyclopropanes generates strained tricyclic spiro compounds, which are prone toward further transformations, such as rearrangement, ring opening, and new ring closure (Scheme 10.17).116... 

Oxidative ring opening of isoxazolidines leads to nitrones. Thus, bicyclic isox-azolidines (50) and (51), treated with m-CPBA, afford nitrones (52), (53), (54), and (55) (Scheme 2.19). Conformational analysis has confirmed the key role of the nitrogen lone pair with respect to regioselectivity of the reaction and of the intramolecular kinetic deprotonation of the intermediate oxoammonium derivative (125). 

Two protected 3-amino acids, containing indolizidine and quinolizidine skeletons (607a,b), have been synthesized by using 1,3-dipolar cycloaddition of nitrones (551) and (552) to methyl ( )-5-mesyloxy-2-pentenoate. The key steps of this approach is demonstrated by novel syntheses of indolizidinone and quino-lizidinone derivatives (606a,b) and by the ring opening of the tricyclic 1,3-dipolar cycloaddition products (605a,b) (Scheme 2.268) (779). 

Enamino ester (722) does not react with DMAD under these reaction conditions, while the reaction of nitrone (167) with DMAD gives both products (722) and (723) in approximately equal amounts, irrespective of the amount of DMAD used. This implies that the two reaction pathways are independent of each other. The cycloadduct produced initially undergoes either ring opening to give enamino ester (722) or isomerizes to yield l,3-diazabicyclo[3.1.0]hex-3-ene (724). 

Evidently, the cleavage of the weak endocyclic N-0 bond is the driving force of the ring opening. The nucleophilicity of the /V-oxide oxygen atom in nitronates facilitates the backward cyclization reaction (in the case of minimization of steric hindrance). With regard to the above mentioned one cannot exclude the tautomerism between cyclic nitronates 100 and open (or chain) isomers 101. 

The retro-1,3-dipolar cycloaddition of imidazo[l,5- ][l,2,4]oxadiazoles 40, promoted by reaction with triphenylphos-phine at reflux in THF, gives the cyclic nitrones 187 (unreported yields) (Equation 15) <1997T13873>. The ring opening of compounds 40 leading to heterocycles 187 (Equation 15) can also be achieved thermally in the condensed phase under vacuum <1997TL2299>. 

The 1,2,5-oxadiazine (62) is reported to be in tautomeric equilibrium with the ring opened nitrone (63). The nitrone is the only species observed in aqueous solution (69ZOR355). The 1,3,4-thiadiazine (64), which can be regarded as a stable tetrahedral intermediate, readily ring opens to (65), which is favoured in ethanol solution (77ACH(94)391). 

In another synthetic approach for the preparation of spiro-(3-lactams, treatment of /V - m e t h v I ad am a n t a n v I nitrone 36 with methyl crotonate 37 gave rise to the spiro esters 38, which on further catalytic hydrogenation resulted in the ring opening to... 

---