Methylenecyclopropane—nitrone cycloaddition

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... 

The cycloadditions of nitrones to methylenecyclopropanes 285-287 (Table 23), 299 (Table 24, entry 3), and 311 (Table 25, entry 7) substituted on the ring occur with very high diastereofacial selectivity. Nitrone 256 gives with 1-methyl-ene-2-phenylcyclopropane (285) a mixture of four isomers in a 2 2 1 1 ratio... 

A positive feature of the reaction is that nitrile oxides are more regioselective, in cycloadditions to methylenecyclopropanes, compared to nitrones. Only traces (up to 5%) of the 4-spirocyclopropane regioisomers are generally observed with methylenecyclopropanes unsubstituted on the exocyclic double bond. The yields are only moderate, but higher with more stable nitrile oxides (Table 27, entries 5, 6, 10-12). 

Table 23. Cycloadditions of nitrones to ring-substituted methylenecyclopropanes... 

A -Pyrroline-A xides (nitrones) derived finm tartaric acids feature in several syntheses of 132 and ent- 32. The first of two routes by Brandi and co-workers commenced with a dipolar cycloaddition between the nitrone 142 (R = tert-butyldiphenylsilyl, or TBDPS) and methylenecyclopropane (143), which afforded a mixture of spirocyclopropylisoxazolidine 144 and its bridgehead epimer (10 1) (Scheme 20, top line) (5i). When heated in xylene, 144 rearranged cleanly to enaminone 145 and the indolizidinone 146, the latter undergoing ready conversion via the tosylhydrazone into the target diol, ( + )-132. A subsequent synthesis with... 

Dipolar cycloaddition of nitrone 917 to methylenecyclopropane 918 was marginally stereoselective, and gave a 1 1.2 mixture of isoxazolidine adducts 919 and 920 in 80% yield (599). Thermal rearrangement of the mixture afforded the separable ketones 921 (26%) and 922 (38%). Conversion of these into lasubines I and II, respectively, had been reported some years previously (600). The second route, also not very stereoselective, used a Wittig reaction between acetyl-methylenetriphenylphosphorane and A -protected piperidin-2-ol 923 to m e pelletierine (924), Mannich condensation of which with veratraldehyde gave a 1 2.8 ratio of the ketones 921 and 922 (60%) (601). 

Dipolar cycloadditions. The reaction of methylenecyclopropane with nitrones generates spirocyclic isoxazolidines that are prone to thermal rearrangement. Thus 4-piperidones can be prepared in a two-step process. 

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