Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyr­azines

Abstract

The reactions of 1-(2-haloethyl)pyrrole-2-carbaldehydes with (1S)-1-phenylglycinol or (1S)-valinol gave the corresponding fused tricyclic oxazolidines as single diastereomers from which 1,2-disubstituted 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by addition of organometallic reagents. The diastereoselectivity was dependent on the nature of both the chiral auxiliary and the organometallic reagent. The best diastereoselectivity (dr ≤ 98:2) was obtained by using Grignard reagents with the oxazolidine derived from (1S)-phenylglycinol. (+)-1-Methyl- and (+)-1-ethyl-1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by reductive removal of the N2-substituent.

Key words

asymmetric synthesis - diastereoselectivity - Grignard reagents - heterocycles - oxazolidines - tetrahydropyrrolopyrazines

References

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24

Other reaction conditions were also tested by varying the solvent (DMF), the dehydrating agent (molecular sieves), and the temperature, but less satisfactory results were obtained. Moreover, mixtures of products 12a and 13a were obtained by carrying out the reactions in the presence of a base (K₂CO₃ or Et₃N).

25

Crystallographic data for compound 14 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publications CCDC 792774; copies can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or email: [e-mail]].

26

It is noteworthy that tricyclic tetrahydrooxazolopyrazolo-pyridine structures with three carbon stereocenters have been prepared as single diastereomers from 2-pyrrole-carboxaldehyde, (S)- or (R)-α-amino acid esters, and (+)- or (-)-norephedrine. The configuration of the newly formed stereocenter in the oxazolidine ring depends only on the chirality of the norephedrine. However, the potential of such compounds as precursors of chiral iminium ions, which could serve as suitable substrates for the addition of Grignard reagents, was not considered during the work reported here.