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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

    References

  • 1 Peresada VP. Medvedev OS. Likhosherstov AM. Skoldinov AP. Khim.-Farm. Zh.  1987,  21:  1054 ; Chem. Abstr. 1988, 108, 68298g
    Google Scholar
  • 2 Seredenin SB, Voronina TA, Likhosherstov AM, Peresada YP, Molodavkin GM, and Halikas JA. inventors; US  5378846.  ; Chem. Abstr. 1995, 123, 83350w
  • 3 Seredenin SB, Voronina TA, Beshimov A, Peresada VP, and Likhosherstov AM. inventors; RU  2099055.  ; Chem. Abstr. 1998, 128, 290245j
  • 4 Isomeric hydrogenated pyrrolopyridines with a free pyrrole NH group display analogous pharmacological activities. For a review, see: Varlamov AV. Borisova TN. Voskressensky LG. Synthesis  2002,  155 
    Google Scholar
  • 5 Negoro T. Murata M. Ueda S. Fujitani B. Ono Y. Kuromiya A. Komiya M. Suzuki K. Matsumoto J.-i.
    J. Med. Chem.  1998,  41:  4118 
    CrossrefPubMedGoogle Scholar
  • 6 Skoldinov AP, Likhosherstov AM, and Peresada VP. inventors; SU  798104.  ; Chem. Abstr. 1981, 95, 7337k
  • 7 Skoldinov AP, Likhosherstov AM, and Peresada VP. inventors; DE  2832488.  ; Chem. Abstr. 1980, 93, 46720h
  • 8 Skoldinov AP, Likhosherstov AM, and Peresada VP. inventors; GB  2025936.  ; Chem. Abstr. 1981, 93, 186406k
  • 9 Likhosherstov AM. Peresada VP. Vinokurov VG. Skoldinov AP. Zh. Org. Khim.  1986,  22:  2610 ; Chem. Abstr. 1987, 107, 236660u
    Google Scholar
  • 10 Flament I. Sonnay P. Ohloff G. Helv. Chim. Acta  1977,  60:  1872 
    CrossrefGoogle Scholar
  • 11 Peresada VP. Tsorin IB. Kirsanova GYu. Likhosherstov AM. Chichkanov GG. Skoldinov AP. Pharm. Chem. J.  1988,  22:  755 
    CrossrefGoogle Scholar
  • 12 Peresada VP. Medvedev OS. Likhosherstov AM. Skoldinov AP. Pharm. Chem. J.  1988,  22:  619 
    CrossrefGoogle Scholar
  • 13 Jirkovsky IL. Baudy R. Synthesis  1980,  481 
    Article in Thieme ConnectGoogle Scholar
  • 14 Jirkovsky IL. inventors; US  4188389.  ; Chem. Abstr. 1980, 92, 198428m
  • 15a Abou-Gharbia M. Moyer JA. Patel U. Webb M. Schieser G. Andree T. Haskins JT. J. Med. Chem.  1989,  32:  1024 
    Google Scholar
  • 15b Likhosherstov AM. Filippova OV. Peresada VP. Kryzhanovskii SA. Vititnova MB. Kaverina NV. Reznikov KM. Pharm. Chem. J.  2003,  37:  6 
    Google Scholar
  • 16 Katritzky AR. Jain R. Xu Y.-J. Steel PJ. J. Org. Chem.  2002,  67:  8220 
    CrossrefGoogle Scholar
  • 17 Henrik M, Weil T, Müller S, Nagel J, Kauss V, Zemribo R, and Erdmare E. inventors; WO  2009095254.  ; Chem. Abstr. 2009, 151, 245654
  • 18 Zhu B. Marinelli BA. Goldschmidt R. Foleno BD. Hilliard JJ. Bush K. Macielag M. Bioorg. Med. Chem. Lett.  2009,  19:  4933 
    CrossrefGoogle Scholar
  • 19a Alvaro G. Di Fabio R. Gualandi A. Savoia D. Eur. J. Org. Chem.  2007,  5573 
    Google Scholar
  • 19b Albano G. Gualandi A. Monari M. Savoia D. J. Org. Chem.  2008,  73:  8376 
    Google Scholar
  • 19c Savoia D. Gualandi A. Bandini M. Lett. Org. Chem.  2009,  434 
    Google Scholar
  • 19d Bandini M. Eichholzer A. Gualandi A. Quinto T. Savoia D. ChemCatChem  2010,  2:  661 
    Google Scholar
  • 20 3,4-Dihydropyrrolo[1.2-a]pyrazine and achiral iminium ions analogous to 9 have been prepared from 1-(2-aminoethyl)pyrrole; see: de Pablo MS. Gandásegui T. Vaquero JJ. García Navío JL. Alvarez-Builla J. Tetrahedron  1992,  48:  8793 
    CrossrefGoogle Scholar
  • 21 Oi R. Sharpless KB. Tetrahedron Lett.  1991,  32:  4853 
    CrossrefGoogle Scholar
  • 22 The following procedure was used to prepare methyl 1-(2-bromoethyl)-2-pyrrolecarboxylate: Blaszykowski C. Aktoudianakis E. Alberico D. Bressy C. Hulcoop DG. Jafarpour F. Joushaghani A. Laleu B. Lautens M. J. Org. Chem.  2008,  73:  1888 
    CrossrefGoogle Scholar
  • 23 Settambolo R. Mariani M. Calazzo A. J. Org. Chem.  1998,  63:  10022 
    CrossrefGoogle Scholar
  • 27a Takahashi H. Chida Y. Higashiyama K. Onishi H. Chem. Pharm. Bull.  1985,  33:  4662 
    Google Scholar
  • 27b Yamato M. Hashigaki K. Ishikawa S. Qais N. Tetrahedron Lett.  1988,  29:  6949 
    Google Scholar
  • 27c Takahashi H. Hsieh BC. Higashiyama K. Chem. Pharm. Bull.  1990,  38:  2429 
    Google Scholar
  • 27d Yamato M. Hashigaki K. Qais N. Ishikawa S. Tetrahedron  1990,  46:  5909 
    Google Scholar
  • 27e Hashigaki K. Kan K. Qais N. Takeuchi Y. Yamato M. Chem. Pharm. Bull.  1991,  39:  1126 
    Google Scholar
  • 27f Higashiyama K. Nakahata K. Takahashi H. J. Chem. Soc., Perkin Trans. 1  1994,  351 
    Google Scholar
  • 27g Higashiyama K. Nakahata K. Takahashi H. Tetrahedron  1994,  50:  1083 
    Google Scholar
  • 27h Higashiyama K. Inoue H. Takahashi H. Tetrahedron  1994,  50:  1083 
    Google Scholar
  • 27i Yamauchi T. Higashiyama K. Kubo H. Ohmiya S. Tetrahedron: Asymmetry  2000,  11:  3003 
    Google Scholar
  • 27j Amat M. Elias V. Llor N. Subrizi F. Molins E. Bosch J. Eur. J. Org. Chem.  2010,  4017 
    Google Scholar
  • 28 Demir AS. Subasi NT. Sahin E. Tetrahedron: Asymmetry  2006,  17:  2625 
    CrossrefGoogle Scholar
  • 29 SMART & SAINT, Software Reference Manuals, Version 5.051 (Windows NT Version)   Bruker Analytical X-ray Instruments Inc.; Madison: 1998. 
    Google Scholar
  • 30 Sheldrick GM. SADABS, Program for Empirical Absorption Correction   University of Göttingen; Germany: 1996. 
    Google Scholar
  • 31 Altomare A. Burla MC. Camalli M. Cascarano GL. Giacovazzo C. Guagliardi A. Moliterni AGG. Polidori G. Spagna R. J. Appl. Crystallogr.  1999,  32:  115 
    CrossrefGoogle Scholar
  • 32 Sheldrick GM. SHELXTLplus, Version 5.1 (Windows NT Version): Structure Determination Package   Bruker Analytical X-ray Instruments Inc.; Madison: 1998. 
    Google Scholar
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.