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Email Discussion: 30 (poster) Raymond Jones
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Pyrroloimidazoles by 1,3-Dipolar Cycloaddition: An Unexpected Epimerisation

Raymond C F Jones* and Kevin J Howard

Chemistry Department, University of Nottingham, University Park, Nottingham NG7 2RD, UK (e-mail Ray.Jones@nottingham.ac.uk)

We have recently developed a new route to homochiral pyrrolidines that involves the 1,3-dipolar cycloaddition of optically active azomethine ylides (actually imidazolinium ylides) with electron-deficient alkene dipolarophiles, followed by easy removal of the homochiral template, Scheme 1. The dipoles are prepared in situ, thus providing a one-pot tandem procedure wherein three of the five bonds of the new five-membered ring are created in one process, along with up to four new chiral centres (one of which is sacrificed in the template removal).

Scheme 1

During our development of this reaction, an unexpected result was observed.

From the cycloaddition reaction between the homochiral azomethine ylide (S)-1 and methacrylonitrile two products (ratio 8:1) were obtained. It was expected^1,2 from our model of the transition state for these cycloadditions, see below, that the two adducts would be the endo adduct 2 (major product) and exo adduct 3 (minor product), see Scheme 2.

Scheme 2

¹H N.m.r. experiments using n.O.e confirm the absolute stereochemistry of adduct 2 to be as expected; however the minor adduct was found not to be 3 but to have the absolute stereochemistry as shown in structure epi-3, i.e. epimeric at C-7a.

We assume that minor adduct 3 is formed initially (via exo approach to the anti-dipole configuration expected from our earlier work¹) and undergoes subsequent epimerisation at C-7a to epi-3 during purification, for example by a route such as shown in Scheme 3.

Scheme 3

Our rationale for this result assumes that epi-3 is more stable than primary exo adduct 3. Attempts to underpin this result using molecular modelling calculations have, however, proved unsuccessful to date.³ In all cases (we have several) where two adducts are obtained from the cycloaddition, and absolute stereochemistry has been determined, the isolated minor isomer has been found to be epimeric at C-7a to the expected exo adduct.

References

1. Jones, R. C. F.; Nichols, J. R.; Cox, M. T. Tetrahedron Lett., 1990, 31, 2333-2336.

2. Jones, R. C. F.; Howard, K. J. J. Chem. Soc., Perkin Trans. 1, 1993, 2391-2393.

3. Molecular mechanics (MM2 or MM3, via Macromodel) and semi-empirical calculations (AM1 method, via Spartan) both have epi-3 as less stable than 3, in direct opposition to our experimental findings.

(corrected 07/07/95)