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42476-GB1
Development and Stereochemical Investigation of the First Microwave-Assisted Aza-Cope Rearrangement-Mannich Cyclization

Harriet A. Lindsay, Eastern Michigan University

As described in previous annual reports, we have developed the first reported microwave-assisted aza-Cope—Mannich reaction [1].  This sequence generates acylpyrrolidines in a single synthetic step while significantly reducing reaction times as compared to analogous reactions using conventional heating, which have been reported to require 10 to 72 hours [2,3].  In the simplest case, amino alcohol 48, available via epoxide aminolysis of isoprene monoxide with benzhydrylamine [4] rapidly formed 3-acylpyrrolidine 49 when subjected to microwave irradiation for 30 minutes at 70 oC or for 150 minutes at 50 oC in the presence of paraformaldehyde, camphorsulfonic acid (CSA), and MgSO4 (Scheme 1).  In an effort to determine the enantiocontrol for the aza-Cope—Mannich reaction, we again used microwave-assisted epoxide aminolysis [4] to generate amino alcohols 4 and 5 as a 1:1 mixture of diastereomers.  After chromatographic separation, we could obtain isomerically pure amino alcohol 5 in 25% yield with an additional 70% recovery of an isomeric mixture.  The absolute stereochemistry of amino alcohol 5 was determined by X-ray crystallographic analysis of the HBr salt.   Unfortunately, subjecting this amino alcohol to aza-Cope—Mannich reaction conditions as before resulted in a 1.5:1 mixture of diastereomeric acylpyrrolidines 6 (Scheme 2). 

Scheme 2

To determine whether diastereoselectivity might improve at lower temperatures, the reaction was carried out at 50 oC and at room temperature (Scheme 3, Table).  Indeed, diastereoselectivity was modestly increased from 1.8:1 to 3.2:1 by decreasing the reaction temperature from 80 to 50 oC, although a significantly longer reaction time was required for complete consumption of starting material (entries 1 and 3).  It should be noted that, because these results are preliminary, the exact reaction time required for complete conversion has yet to be determined.  Nonetheless, when the reaction was quenched after 120 minutes of irradiating at 50 oC, only 11% conversion to products was observed.  Although the identity of the major diastereomer has yet to be rigorously identified, the reaction presumable proceeds via chair 54 which would allow the sterically demanding phenyl group to be angled away from the pseudo chair [5].  Subsequent Mannich cyclization of cation 55 would lead to acylpyrrolidine 56 as the major isomer. 

Scheme 3

Table. Temperature comparison of aza-Cope—Mannich reactions of amino alcohol 5

entry

temp (oC)

time

product ratioa

(% yield)

1

80

30 min

1.8:1 (77)

2

50

120 min

3.0:1 (11.0)b

3

50

8 hrs

3.2 (75)

4c

rt (23-25)

48 hrs

3.7 (79)


aAccording to 1H NMR analysis.

bPercent of reaction mixture as determined by 1H NMR analysis (not isolated yield)

cReaction was stirred at room temperature without microwave irradiation.

We have also demonstrated that amino alcohols 1 and 11 readily undergo microwave-assisted aza-Cope rearrangement—Mannich cyclization following condensation with propionaldehyde (Scheme 4) [1].  In addition, we found that by increasing the steric demand of the amine protecting group from benzyl to benzhydryl, diastereoselectivity for anti-2-ethyl-4-acylpyrrolidines 13 and 12 could be improved from 3:1 to 8:1, respectively.          

Surprisingly, when the analogous aza-Cope—Mannich reaction was performed on the less sterically demanding S-α-methylbenzylamino alcohol 52, a 13:1 isomeric mixture favoring the anti-pyrrolidine 82 was recovered according to 1H and 1D nOe NMR analysis (results obtained by Aaron Kaufmann, BS, 2009) (Scheme 19).  It is noteworthy that, because these results are preliminary, only the relative C2-C4 stereochemistry has been determined.  While the absolute stereochemical determination is in progress, the indicated configuration is based on ample precedent [5].  In addition, due to separation issues, the stereochemistry of the minor isomer has yet to be rigorously identified.  Both of these determinations are the subject of ongoing work in our lab, as is the optimization of the stereoselectivity of the aza-Cope Mannich reaction leading to 3-acylpyrrolidine 6 (Scheme 2), and the application of diastereocontrolled aza-Cope Mannich reactions similar to that in Scheme 5 to the synthesis of natural and unnatural alkaloids.  

References

[1] Johnson, B. F.; Marrero, E. M.; Turley, W. A.; Lindsay, H. A. Synlett 2007, 893-896.

[2] Overman, L. E.; Kakimoto, M.-A.; Okazaki, M. E.; Meier, G. P. J. Am. Chem. Soc. 1983, 105, 6622-6629.

[3] Cooke, A.; Bennett, J.; McDaid, E. Tetrahedron Lett. 2002, 43, 903-905.

[4] Desai, H.; D'Souza, B. R.; Johnson, B. F.; Lindsay, H. A. Synthesis 2007, 902-910.

[5] (a) Agami, C.; Couty, F.; Lin, J.; Mikaeloff, A.; Poursoulis, M.  Tetrahedron 1993, 49, 7239-7250; (b) Agami, C.; Cases, M.; Couty, F.  J. Org. Chem. 1994, 59, 7937-7940.  (c) Agami, C.; Couty, F.; Puchot-Kadouri, C. Synlett 1998, 449-456. 

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