Controlling Stereoselection in Aza‐Cope‐Mannich Reactions

The synthesis of 2‐substituted cis ‐octahydroindolones from the reaction of cis ‐2‐amino‐1‐alkenylcyclopentanols with aldehydes was studied to examine whether stereoselection in the aza‐Cope–Mannich reaction could be controlled by the nature of the nitrogen substituent. 2‐Alkylamino‐1‐(1‐phenylethenyl)cyclopentanols 7 and 8 , which contain nitrogen substituents of widely differing size (Me and CHPh 2 ), were condensed with four aldehydes to give oxazolidines 9a–d and 10a‐c. Rearrangement of these intermediates at 23–60 °C, in the presence of 0.9 equiv of (±)‐10‐camphorsulfonic acid in acetonitrile, gave cis ‐octahydroindolones 11a‐d and 12a–c in yields of 77–95%. Using a combination of single‐crystal X‐ray crystallography, 1 H nOe measurements, and comparisons with known materials it was established that the N ‐methyl oxazolidines 9a–d provided exclusively cis ‐octahydroindolones having the 2‐substituent trans to the angular substituents, while N ‐benzhydryl analogs 10a–c provided exclusively the all‐cis products 12a–c. These results are interpreted to mean: (1) When the nitrogen substituent is small (Me), the stereochemistry‐determining [3,3]‐sigmatropic rearrangement occurs preferentially through a transition‐state topography having the R 2 substituent oriented quasiequatorially ( 14 → 15 → 16 ); (2) When this substituent is large (CHPh 2 ), destabilizing steric interactions between the vicinal R 1 and R 2 substituents causes the rearrangement to occur preferentially through the alternate iminium ion stereoisomer ( 17 → 18 → 19 ).