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A short and efficient asymmetric synthesis of 5-substituted D3 pyrrolin-2-ones. A new approach to 2-pyrrolidones and pyrrolidines

Pedro MERINO*, Francisco Merchan and Tomas Tejero
Departamento de Quimica Organica, ICMA, Universidad de Zaragoza, CSIC, Zaragoza, Spain

In recent years polyhydroxylated pyrrolidines and pyrrolidones have attracted much attention, due to their ability to act as selective glycosidase inhibitors with a variety of therapeutic effects.[1] Most of the synthetic strategies directed towards the construction of those compounds involve the use of naturally occurring polyhydroxylated compounds. Whereas there have been several reports concerning this issue,[2] very scarcely has there been reported further de novo stereoselective construction of the pyrrolidine ring.[3]

In this context C-5 substituted pyrrolin-2-ones A can serve as templates for the construction of a number of highly functionalized 2-pyrrolidones and pyrrolidines by exploiting (i) functionalization of the double bond, (ii) reduction of the amide group and (iii) the latent functionality of the side chain

Earlier reports from our laboratory have established the utility of nitrones as electrophiles in highly stereoselective additions. Those studies resulted in the development of useful strategies for the asymmetric synthesis of a-amino acids,[4] a-amino nitriles,[5] a-amino aldehydes[6] and allyl amines.[7]

As shown in the Scheme we describe herein a new approach to compounds of type A starting from nitrone 1 which is readily available in high quantity from D-glyceraldehyde.[8]

The addition of lithium propiolate 2 to nitrone 1 took place with complete syn selectivity and quantitative yield to afford the prop-2-ynyl hydroxylamine 3. The relative configuration of 2 was reasonably assigned on the basis of our previous findings concerning the addition of acetylene derivatives to the nitrone 1.[7] The observed syn selectivity is in good agreement with the model previously proposed by us for the addition of other nucleophiles.[9]

The selective hydrogenation of the triple bond was achieved in 1 h at ambient temperature and atmospheric pressure using the Lindlar catalyst. The corresponding allyl hydroxylamine 4 was obtained in quantitative yield.[10] Further deoxygenation of hydroxylamine 4 was accomplished with Zn-Cu in acetic acid as a solvent. Under these conditions, the resulting allyl amine 5 could not be isolated since it cyclized spontaneously to the pyrrolin-2-one 6 which was obtained in 84% yield after purification by column chromatography.[11]

In summary, we have presented a convenient and straightforward method of preparing enantiomerically pure d3-pyrrolin-2-ones, suitable starting materials for the construction of polyfunctionalized pyrrolidines and 2-pyrrolidones. Interesting features of this synthesis include the high level of diastereoselection and the ease of the cyclization step.

Application of compounds A to the synthesis of highly functionalized pyrrolidines are currently being evaluated and will be reported in due course.


Financial support from MEC (Project PB94-0598, DGICYT, Madrid, Spain) is gratefully acknowledged.

References and Notes