Use of Novel Nitrones in the Synthesis of Piperidine Alkaloids

Abstract

The current study focused on development of a flexible synthetic strategy for the enantioselective preparation of 2-substituted-3-hydroxypiperidines utilising chiral 3-hydroxytetrahydropyridine N-oxides. Initial studies into the regio- and stereoselectivity of the 1,3-dipolar cycloaddition reaction between O-benzyl protected 3-hydroxytetrahydropyridine N-oxide 208 and a range of alkenes, proceeded with excellent exo/endo selectivity and near perfect regioselectivity. However the anti/syn selectivity was only moderately in favour of the desired anti-compounds. Further development has led to the synthesis of a novel O-silyl protected 3-hydroxytetrahydropyridine N-oxide 198 which demonstrated enhanced reactivity towards nucleophilic attack by a wide range of Grignard and organolithium reagents. The reaction proceeded with high diastereoselectivity, affording trans-substituted hydroxylamines as the sole products except in the case of allylmagnesium bromide. Reductive cleavage of the hydroxylamines or isoxazolidine cycloadducts has generated a small library of 2-substituted- 3-hydroxypiperidines which as well as possessing functional groups that are highly amenable to elaboration. Differentially N/O-protected derivatives of many of the formed compounds have been used as key intermediates in natural product synthesis. The flexibility of the developed methodology was demonstrated by the concise synthesis of the L-rhamnosidase inhibitor (+)-swainsonine 397, which was accomplished in seven steps and 29.5% overall yield from nitrone 198. The C-2 stereocenter was installed with high diastereoselectivity, via addition of the C-lithiate of protected propargyl alcohol 491, affording trans-diastereoisomer 490 as the sole product. Extension of the developed methodology to the synthesis of quinolizidine alkaloids was realised via the substitution of protected but-3-yn-1-ol 533 as starting material with the formal synthesis of (-)-epiquinamide 529 being achieved in five steps and 20.7% overall yield from nitrone 198. Finally, through efforts to synthesise cis-2,3-substituted piperidines, methodology has been developed for synthesis of the 2,6-disubstitued-3-hydroxypiperidine motif. Oxidation of 2,3-disubstituted-N-hydroxypiperidines unexpectedly provided access to the synthetically challenging aldonitrones. Nucleophilic addition and 1,3-dipolar cycloaddition have been shown to proceed with high selectivity giving access to highly substituted stereochemically defined piperidine scaffolds.