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Reports: UR151961-UR1: Development of a Catalytic, Asymmetric Aza-Cope Rearrangement and Mannich Cyclization

Harriet A. Lindsay, Eastern Michigan University

Pyrrolidines have garnered significant interest as pharmacologically important molecules, useful scaffolds in synthesis, and as catalysts for asymmetric reactions.  Consequently, it is necessary for synthetic chemists to have multiple methods for their stereoselective synthesis at their disposal.  To this end, we have developed a Lewis-acid catalyzed aza-Cope rearrangement—Mannich cyclization for diastereoselective and in some cases enantioselective synthesis of acyl pyrrolidines.  The cationic aza-Cope rearrangement—Mannich cyclization is a tandem [3,3]-sigmatropic rearrangement of iminium cation 3 followed by cyclization of the resulting enol 4 onto the transposed iminium cation to produce acylpyrrolidine 5 (Scheme 1) [1,2].  The reaction is initiated by the formation of iminium cation 3, most frequently achieved via acid-mediated amine-aldehyde condensation (1 → 3) or oxazolidine ionization (2 → 3). In the past year, we have continued our investigation of enantioselectivity in the aza-Cope—Mannich reaction.  For this investigation, we used lessons learned from similar work examining diastereoselectivity (Scheme 2).  Previously, we found that oxazolidine 6 with 10 mole% BF3OEt2 resulted in the formation of acetyl pyrrolidine 7 in 89% yield and as one diastereomer according to 1H NMR analysis [3].  However, oxazolidine 9, lacking a methyl group at the carbinol carbon, gave only 6:1 diastereoselectivity and required heat and significantly more Lewis acid.  Likewise, we had observed lower selectivity in aza-Cope—Mannich reactions of less substituted oxazolidines where a chiral auxiliary was employed for asymmetric synthesis of acetyl and formyl pyrrolidines 14 and 17.

Scheme 2     In a complementary approach, Padron, et al. had achieved high diastereoselectivity in the synthesis of alkyl-substituted formyl pyrrolidines (Scheme 3), with the primary difference between our substrates being the amine protecting group. Padron was able to achieve essentially complete diastereoselectivity in a one-pot condensation and aza-Cope—Mannich reaction using tosyl-protected secondary amino alcohol 7 [4].  With the working hypothesis that the more electron withdrawing protecting group might improve our enantioselectivity issues (cf. Scheme 2, 16→17), we revisited our investigation of an asymmetric aza-Cope—Mannich reaction. Scheme 3 As reported last year, we synthesized enantioenriched oxazolidines 24 and 26 via microwave-assisted epoxide aminolysis of commercially available S-butadiene monoxide 7 [6].  Amino alcohol 21 was accessed in 56% yield but only 80% ee according to chiral HPLC analysis. Likewise, only 75% ee was observed for amino alcohol 25 (Scheme 4). We then treated amino alcohol 21 with paraformaldehyde and stoichiometric FeCl3 according to Padron’s conditions [3] to access formyl pyrrolidine 22.  Reduction of the aldehyde provided the stable alcohol 23, which could then be subjected to HPLC analysis.  Unfortunately, significant racemization occurred during the reaction, which resulted in only a 1.6:1 enantiomeric ratio.  Conversion of amino alcohol 21 to oxazolidine 24 followed by treatment with BF3OEt2 resulted in similarly poor selectivity.  Finally, treatment of benzhydryl protected oxazolidine 26 with BF3OEt2 also generated racemic acyl pyrrolidine 27. Scheme 4 Finally, we are investigating the synthesis of 2,2-disubstituted acyl pyrrolidines 31 [5].  To this end, we have synthesized oxazolidine 30 from amino alcohol 29 in moderate yield.  Thus far, this substrate has required elevated temperatures and superstoichiometric amounts of Lewis acid.  We are in the process of optimizing these conditions. Scheme 5     Most of the students that have participated in this project during this reporting cycle are still undergraduates at Eastern Michigan University.  Over half of these students plan to attend graduate school in chemistry or biochemistry in the next one to three years.  One additional student who received funding from ACS Project SEED to work in my lab during the summers of 2010 and 2011 returned to do research as part of her McNair Scholars program at DePaul University.  This year seven students presented posters at the spring and fall national American Chemical Society meetings.   

References

[1] Overman, L. E.; Kakimoto, M.-A.  J. Am. Chem. Soc.  1979, 101, 1310-1312. [2] For reviews of the aza-Cope rearrangement—Mannich cyclization and related reactions, see (a) The Intramolecular Mannich and Related Reactions Overman, L.; Ricca, D. in Comprehensive Organic Synthesis, Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 8, pp 1007-1046; (b) Overman, L.  Acc. Chem. Res. 1992, 25, 352-359; (c) Overman, L. E. Aldrichimica Acta 1995, 28, 107-120; (d) Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311-2352; (e) Overman, L. E. Tetrahedron 2009, 65, 6432–6446. [3] For BF3OEt2 mediated iminium cation formations in the aza-Cope-Mannich reaction, see (a) Overman, L. E.; Shim, J.  J. Org. Chem. 1991, 56, 5005; (b) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662. [4] For  FeCl3/TMSCl mediated aza-Cope—Mannich reaction, see Carballo, R. M.; Purino, M.; Ramirez, M. A.; Martin, V. S.; Padron, J. I. Org. Lett. 2010, 12, 5334.  [5] Overman, L. E.; Kakimoto, M.; Okazaki, M.; Meier, G. P. J. Am. Chem. Soc. 1983, 105, 6622.