61st Annual Report on Research 2016

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.  We found previously that oxazolidine 6 could undergo aza-Cope—Mannich reaction to form a 13:1 mixture of diastereomers [3].  However, subjecting oxazolidine 9 to similar conditions resulted in very poor diastereoselectivity (Scheme 2).  Furthermore, we were able to determine that chirality transfer in the first reaction occurred primarily via the carbinol carbon rather from the amine protecting group (not shown).  We hypothesize that incomplete chirality transfer (in either case) is a result of C-C bond rotations prior to the rate-determining aza-Cope rearrangement.  We were hopeful that increasing the rotational barrier should diastereoselectivity. 

Scheme 2

Accordingly (as reported last year), we prepared oxazolidine 13 in moderate yield and subjected it to significantly more rigorous aza-Cope—Mannich conditions, as was required for reaction of the more substituted oxazolidine (Scheme 3).  Unfortunately, the more forcing conditions may have contributed to a decrease in diastereoselectivity.  Indeed, the best case scenario provided pyrrolidine 14 in 95% conversion and 8.5:1 diastereoselectivity.  Nonetheless, to our knowledge, this is the first example of good chirality transfer in the aza-Cope Mannich reaction resulting in a 2,2-disubstituted pyrrolidine.  

Scheme 3

  Most recently, we have used lessons learned from our diastereoselectivity ACM reaction to broaden the scope of these rearrangements (Scheme 4).  In this work, we found that BF₃ catalyzed a highly diastereoselective ACM reaction of oxazolidines 16 to produce either 2-aryl- or 2-alkyl-4-acetylpyrrolidines 17 in excellent yields. 

Scheme 4

In the past year, we have synthesized oxazolidines 20 and 21 in good yields (Scheme 5).  Both readily undergo highly diastereoselective ACM reactions.  Significantly, we are able to successfully perform the reaction in the presence of a free hydroxyl, although this reaction requires longer reaction time and a full equivalent of BF₃OEt₂.  We were also pleased to find that the TMS-protected alcohol moiety of oxazolidine 21 survives the reaction conditions.  Both ACM reactions were very high yielding, producing pyrrolidines that required no further purification.  We are currently investigating chirality transfer in this reaction by beginning with a chiral α-methylbenzyl protected-amino alcohol rather than racemic benzhydryl amino alcohol 18.    

Scheme 5

As was the case in past years, students that have participated in this project during this reporting cycle are an equal mixture of undergraduate and graduate students at Eastern Michigan University.  Again this year, one ACS Project SEED student worked on a related project.  All but one of my current students plan to either enroll in PhD programs or continue on to work in chemistry in an industrial setting. 

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 s1007-1046; (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.