An Experimental and Theoretical Study of the Asymmetric Lithiation of 1,2,3,5,6,7-Hexahydro-3a,4a-diazacyclopenta[<i>def</i>]phenanthren-4-one

The inability of bis-N-Boc-protected octahydrophenanthroline to undergo asymmetric lithiation with (−)-sparteine is circumvented by use of a urea functionality as the directing group. Asymmetric lithiation followed by electrophile quench gives products substituted α to nitrogen in better yield (17−30%) but slightly lower enantiomeric ratio (er 84:16) than analogous lithiation of N-Boc-piperidine (er 87:13). Computational studies at the MP2/6-316(d)//B3LYP/6-316(d) level indicate that the prochiral equatorial S-hydrogen is removed preferentially over the pro-R hydrogen, with a difference in transition state activation energies of 1.26 kcal/mol, corresponding to a predicted er of 89:11. The predicted stereochemistry of the reaction was confirmed by single-crystal X-ray analysis of an aryl dibromide prepared from the enantiomerically enriched α-methyl-substituted product.