Diastereoselective Lithiation of N-Silyl-Protected (S)-Tetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-one

Abstract

An L-proline-derived imidazolone protected with an N-triethylsilyl (N-TES) group undergoes diastereoselective lithiation–electrophile quench to give C5-substituted products with syn stereochemistry. Unlike the previous N-t-Bu analogues, the N-TES derivatives may be easily N-desilylated to give secondary ureas that serve as precursors to N-phenyl chiral bicyclic guanidines. INTRODUCTION The stereoselective synthesis of variously substituted pyrrolidines by lithiation–substitution reactions continues to evolve as a valuable tool in synthetic chemistry. Based initially on (–)-sparteine-mediated deprotonation on N-Boc pyrrolidine (1, Scheme 1) reported by Beak and coworkers, recent advances in ligand design have allowed for the synthesis of enantiomeric products, or the use of sub-stoichiometric amounts of ligand under dynamic thermodynamic resolution conditions. It is also now possible to install aryl and vinyl substituents with retention of stereochemical integrity of the chiral carbanion. As part of efforts to find alternate syntheses of chiral reagents with a pyrroloimidazol(in)e framework, we reported previously the diastereoselective lithiation–substitution of t-Bu protected urea 4 to afford a series of C5-substituted products with syn stereochemistry. This approach was modeled on Beak’s observation of syn-selective lithiation–substitution in chiral cyclic carbamate 6. 9 Although lithiation of urea 4 was effective for providing diastereomerically enriched imidazolinones, it posed two challenges for development of a more general approach leading to variously N-substituted pyrroloimidazolinium salt precatalysts: First, the synthesis of 4 from L-proline-derived Cbz-proteced t-Bu amide 3 gave inconsistent yields upon scale-up. Second, removal of the N-t-Bu group from the C5-substituted products 5 required prolonged exposure to refluxing trifluoroacetic acid, which posed stability issues for substituents in certain HETEROCYCLES, Vol. 88, No. 1, 2014 347