Conformational analysis of the cis- and trans-adducts of the Pictet-Spengler reaction. Evidence for the structural basis for the C(1)-N(2) scission process in the cis- to trans-isomerization

The stable conformations of both the trans- and cis-1,3-disubstituted N-b-benzyl stereoisomers of the Pictet-Spengler reaction have been determined by NMR spectroscopy and X-ray crystallography in order to better understand the C(1)-N(2) cis- to trans-isomerization process. In the N-a-H series, the chair conformation was preferred for the trans-isomer 3a while the cis-isomer 3b existed predominantly in the boat form. However, in the N-a-methyl series (1a, 1b, 2a, 2b), both the cis (1b, 2b) and trans (1a, 2a) diastereomers existed in the chair conformation to relieve the A((1,2))-strain between the N-a-methyl function and the substituent at C(1). The difference in the preferred conformations of the cis-isomers in the N-a-H and N-a-methyl series (as compared to the preferred conformations in the trans-isomers) can be employed to understand the reduced rate of epimerization of cis-2b into trans-2a as compared to 3b into 3a. This provides the structural basis for the carbocation-mediated intermediate in the C(1)-N(2) scission process.