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Synthesis 2011(6): 909-918  
DOI: 10.1055/s-0030-1258436
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Andrea Gualandi, Lucia Cerisoli, Magda Monari, Diego Savoia*
Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax: +39(051)2099456; e-Mail: diego.savoia@unibo.it;
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Publication History

Received 2 December 2010
Publication Date:
10 February 2011 (online)

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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

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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: +44 (1223)336033 or email: deposit@ccdc.cam.ac.uk].

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.