Download PDF
Synthesis 2009(12): 1999-2008  
DOI: 10.1055/s-0029-1216806
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Substituted 5-(3-Hydroxypropyl)pyrrolidin-2-ones and Pyrrolizidinones from Nitroethane via C3 Functionalized 5,6-Dihydro-4H-1,2-oxazines: A Novel Approach to Some Analogues of the Antidepressant Rolipram

Alexey Yu. Sukhorukov, Alexey V. Lesiv, Yulia A. Khomutova, Sema L. Ioffe*, Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax: +7(499)1355328; e-Mail: iof@ioc.ac.ru;
Further Information

Publication History

Received 29 January 2009
Publication Date:
12 May 2009 (online)

    Permissions and Reprints All articles of this category

Abstract

Easily accessible [(5,6-dihydro-4H-1,2-oxazin-3-yl)methyl]malonates­ 1 were converted into substituted 5-(3-hydroxypropyl)pyrrolidin-2-ones 2 and pyrrolizidinones 3, which are versatile products and intermediates for organic and bioorganic chemistry. The synthetic sequence suggested includes stereoselective two-step reduction of an oximino fragment, followed by intramolecular cyclization involving one of the CO2Me groups and decarboxylation in the last stage. The efficiency of this strategy was demonstrated by the stereoselective synthesis of pyrrolizidinone rac-4, a highly efficient analogue of antidepressant Rolipram, from nitroethane.

Key words

5,6-dihydro-4H-1,2-oxazines - reduction - pyrrolidones - pyrrolizidinones - Rolipram

    References

  • 1a Sukhorukov A. Yu. Klenov MS. Ivashkin PE. Lesiv AV. Khomutova YuA. Ioffe SL. Synthesis  2007,  97 
    Google Scholar
  • 1b Klenov MS. Lesiv AV. Khomutova YuA. Nesterov ID. Ioffe SL. Synthesis  2004,  1159 
    Google Scholar
  • 2 Sukhorukov A. Yu. Lesiv AV. Khomutova YuA. Ioffe SL. Synthesis  2009,  741 
    Article in Thieme ConnectGoogle Scholar
  • 3 Sukhorukov A. Yu. Lesiv AV. Khomutova YuA. Ioffe SL. Nelyubina YuV. Synthesis  2008,  1205 
    Article in Thieme ConnectGoogle Scholar
  • 4 Sukhorukov A. Yu. Lesiv AV. Eliseev OL. Khomutova YuA. Bondarenko TN. Lapidus AL. Ioffe SL. Mendeleev Commun.  2007,  122 
    Google Scholar
  • 5 Recently a report on the application of 5,6-dihydro-4H-1,2-oxazines in the synthesis of pyrrolizidinones 3 with another substitution pattern appeared: Zimmer R. Collas M. Czerwonka R. Hain U. Reissig H.-U. Synthesis  2008,  237 
    Article in Thieme ConnectGoogle Scholar
  • 6 Polniaszek RP. Belmont SE. J. Org. Chem.  1991,  56:  4868 
    CrossrefGoogle Scholar
  • 7 Hart DJ. Tsai Y.-M. J. Am. Chem. Soc.  1984,  106:  8209 
    CrossrefGoogle Scholar
  • 8 Fleet GWJ. Seijas JA. Vázquez-Tato MP. Tetrahedron  1991,  47:  525 
    CrossrefGoogle Scholar
  • 9 Cameron KO. Lefker BA. Chu-Moyer MY. Crawford DT. Jardine PD. DeNinno SL. Gilbert S. Grasser WA. Ke H.-Z. Lu B. Owen TA. Paralkar VM. Qi H. Scott DO. Thompson DD. Tjoa CM. Zawistoski MP. Bioorg. Med. Chem. Lett.  2006,  16:  1799 
    CrossrefGoogle Scholar
  • 10a Ponomarev AA. Noritsina MV. Krivenko AP. Chem. Heterocycl. Compd. (Engl. Transl.)  1970,  978 
    Google Scholar
  • 10b Butler DE. Leonard JD. Caprathe BW. L’Italien YJ. Pavia MR. Hershenson FM. Posche1 PH. Marriotts JG. J. Med. Chem.  1987,  30:  498 
    Google Scholar
  • 10c Coutrot P. Claudel S. Didierjean C. Grison C. Bioorg. Med. Chem. Lett.  2006,  16:  417 
    Google Scholar
  • 11 Brackeen MF. Cowan DJ. Stafford JA. Schoenen FJ. Veal JM. Domanico PL. Rose D. Strickland AB. Verghese M. Feldman PL. J. Med. Chem.  1995,  38:  4848 
    CrossrefGoogle Scholar
  • 12 See, for example: Tsoungas PG. Heterocycles  2002,  57:  915 ; and references cited therein
    CrossrefGoogle Scholar
  • 14 Sukhorukov A. Yu. Lesiv AV. Eliseev OL. Khomutova YuA. Ioffe SL. Borissova AO. Eur. J. Org. Chem.  2008,  4025 
    CrossrefGoogle Scholar
  • 16 Blanchard AN. Burnell DJ. Tetrahedron Lett.  2001,  42:  4779 
    CrossrefGoogle Scholar
  • 17 Although antidepressant Rolipram has been produced for quite a long time there is a high interest to different aspects of its synthesis and the synthesis of analogues (see ref.¹¹ or a recent report: Hunes PS. Stupple PA. Dixon DJ. Org. Lett.  2008,  10:  1389 ; and references cited therein)
    CrossrefGoogle Scholar
  • 18 Barnes DM. Ji J. Fickes MG. Fitzgerald MA. King SA. Morton HE. Plagge AM. Preskill F. Wagaw SH. Wittenberger SJ. Zhang J. J. Am. Chem. Soc.  2002,  124:  13097 
    CrossrefPubMedGoogle Scholar
  • 19a Denmark SE. Marcin RL. J. Org. Chem.  1995,  60:  3221 
    Google Scholar
  • 19b Denmark SE. Thorarensen A. Chem. Rev.  1996,  96:  137 
    Google Scholar
  • 19c Buchholz M. Reissig H.-U. Eur. J. Org. Chem.  2003,  3524 
    Google Scholar
  • 20 Gottlieb HE. Kotlyar V. Nudelman A. J. Org. Chem.  1997,  62:  7512 
    CrossrefPubMedGoogle Scholar
13

Products of this cyclization, hexahydropyrrolizidinones 6, could not be reduced to the corresponding pyrrolidones 7 at stage 2.²

15

According to our previous studies² on the hydrogenation of tetrahydrooxazine 5g, the reduction step B to C is not completely stereoselective and in addition to the 3,5-cis-isomer of C, a slight amount of the corresponding 3,5-trans-isomer is generated (both isomers can be intercepted with Boc2O). Nevertheless in the hydrogenation of 5g in the absence of Boc2O only the isomers 8g′ and 8g′′ with cis-disposition of Me and 4-MeOC6H4 groups were isolated after column chromatography. The absence of minor 3,5-trans-isomers in this mixture possibly is due to a slower cyclization step in the corresponding 3,5-trans-pyrrolidine C.