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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;
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Publikationsverlauf

Received 29 January 2009
Publikationsdatum:
12. Mai 2009 (online)

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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

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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.