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

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 
• 1b Klenov MS. Lesiv AV. Khomutova YuA. Nesterov ID. Ioffe SL. Synthesis  2004,  1159 
• 2 Sukhorukov A. Yu. Lesiv AV. Khomutova YuA. Ioffe SL. Synthesis  2009,  741 
• 3 Sukhorukov A. Yu. Lesiv AV. Khomutova YuA. Ioffe SL. Nelyubina YuV. Synthesis  2008,  1205 
• 4 Sukhorukov A. Yu. Lesiv AV. Eliseev OL. Khomutova YuA. Bondarenko TN. Lapidus AL. Ioffe SL. Mendeleev Commun.  2007,  122 
• 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 
• 6 Polniaszek RP. Belmont SE. J. Org. Chem.  1991,  56:  4868 
• 7 Hart DJ. Tsai Y.-M. J. Am. Chem. Soc.  1984,  106:  8209 
• 8 Fleet GWJ. Seijas JA. Vázquez-Tato MP. Tetrahedron  1991,  47:  525 
• 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 
• 10a Ponomarev AA. Noritsina MV. Krivenko AP. Chem. Heterocycl. Compd. (Engl. Transl.)  1970,  978 
• 10b Butler DE. Leonard JD. Caprathe BW. L’Italien YJ. Pavia MR. Hershenson FM. Posche1 PH. Marriotts JG. J. Med. Chem.  1987,  30:  498 
• 10c Coutrot P. Claudel S. Didierjean C. Grison C. Bioorg. Med. Chem. Lett.  2006,  16:  417 
• 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 
• 12 See, for example: Tsoungas PG. Heterocycles  2002,  57:  915 ; and references cited therein
• 14 Sukhorukov A. Yu. Lesiv AV. Eliseev OL. Khomutova YuA. Ioffe SL. Borissova AO. Eur. J. Org. Chem.  2008,  4025 
• 16 Blanchard AN. Burnell DJ. Tetrahedron Lett.  2001,  42:  4779 
• 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)
• 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 
• 19a Denmark SE. Marcin RL. J. Org. Chem.  1995,  60:  3221 
• 19b Denmark SE. Thorarensen A. Chem. Rev.  1996,  96:  137 
• 19c Buchholz M. Reissig H.-U. Eur. J. Org. Chem.  2003,  3524 
• 20 Gottlieb HE. Kotlyar V. Nudelman A. J. Org. Chem.  1997,  62:  7512 

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 studies^² 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.