Piperidines nitrone 1,3-dipolar cycloadditions

Oppolzer et al. (321) applied his own sultam as the auxiliary for a cychc nitrone in the synthesis of (—)-allosedamine (Scheme 12.60). The enantiomerically pure nitrone 209 was synthesized from 208 by base treatment, attack of the enolate on 1-chloro-l-nitrosocyclohexane at the nitrogen atom, and subsequent elimination of chloride. Subsequent addition of aqueous HCl gave the cyclic nitrone 209. The nitrone participated in a 1,3-dipolar cycloaddition with styrene, proceeding with complete exo-specificity. The product, 210, was obtained with a de of 93%. Two further reaction steps yield the piperidine alkaloid ( )-aUosedamine 211 in an overall yield of 21%. 

The nitrone of piperidine reacts with phenyl vinyl ether to yield a 1,3-dipolar cycloaddition product. Benzylation led to a ring-opened product which was converted to a hydroxamic acid. This is desired functionality in medicinal chemistry because it is a metal-binding ligand <03S1221>. 

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). 

Oximes of aromatic aldehydes 149 do not equilibrate under these conditions but the Lewis acid catalyst IIfCI4 both allows oxime equilibration and reverses the regioselectivity of the 1,3-dipolar cycloaddition 150 so that the final product is a piperidine 152. The regiochemical reversal is probably because the LUMO of the nitrone and the HOMO of the enone are used in 146a but, by lowering the LUMO energy of the enone, IIfCI4 switches to the HOMO of the nitrone in 150. 

Various oxidants have been used to convert pyrrolidine and piperidine into nitrones (imine oxides), of value for 1,3-dipolar cycloadditions in one method hydrogen peroxide is the oxidant in the presence of a catalyst/... 

Dipolar cycloadditions. This dipolarophile reacts with nitrones to give 4-toluenesulfinyl-5-methylisoxazolines, which on hydrogenation are transformed into /3-amino ketones. Some simple piperidine alkaloids can be synthesized by this method. 

The importance of fully or partially hydrogenated isoxazolo[2,3-a]pyridines as intermediates in the synthesis of stereochemically complex molecules, particularly alkaloids, has led to a continued high level of interest in their preparation. The route of choice remains the 1,3-dipolar cycloaddition reaction between a tetrahydropyridine A-oxide, that is a nitrone, and a dipolarophile. A number of methods for the production of the nitrone for in situ reaction have been developed. They include the oxidation of the secondary amine, piperidine, with hydrogen peroxide in the presence of... 

The hetero Diels-Alder reaction <01H1591, 01TL5693> and dipolar cycloadditions continue to constitute important approaches to piperidines. Kibayashi and co-workers used an intramolecular acylnitroso Diels-Alder reaction to synthesize (-)-lepadins A,B, and C from an acyclic precursor <01JOC3338>. An intramolecular nitrone cycloaddition was used by Machetti and co-workers to produce both enantiomers of 4-oxopipecolic acid <01T4995>. Their synthesis proceeds from a nitrone bearing an a-methylbenzylamine chiral auxiliary. Noteworthy in this report is the presence of large-scale experimental procedures the nitrone formation and cycloaddition reactions were performed on 285 mmol and 226 mmol scales, respectively. 

---