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NIH Public AccessAuthor ManuscriptOrg Lett. Author manuscript; out there in PMC 2014 June 21.Published in final edited kind as: Org Lett. 2013 June 21; 15(12): 3134137. doi:10.1021/ol401337p.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSynthesis of Quaternary -Methyl -Amino Acids by Asymmetric Alkylation of Pseudoephenamine Alaninamide PivaldimineCedric L. Hugelshofer, Kevin T. Mellem, and Andrew G. Myers Division of Chemistry and Chemical Biology, Harvard University, Cambridge, MAAbstractThe utility of pseudoephenamine as a chiral auxiliary for the alkylative building of quaternary -methyl -amino acids is demonstrated. The process is notable for the high diastereoselectivities of your alkylation reactions, for its versatility with respect to electrophilic substrate partners, and for its mild hydrolysis circumstances, which present -amino acids without salt contaminants. Alternatively, -amino esters might be obtained by direct alcoholysis. (1S,2S)-Pseudoephenamine (R)-alaninamide pivaldimine (1) or its enantiomer serve as RANKL/RANK review substrates within a new system for the alkylative building of quaternary -methyl -amino acids. These substrates may be prepared in high yield by coupling in the suitable stereoisomers of pseudoephenamine1 and N-Boc alanine by the mixed anhydride method (pivaloyl Opioid Receptor Gene ID chloride)2 followed by N-Boc deprotection (HCl) and tert-butylimine formation (see Supporting Info). Two procedures were created to form the N-tert-butyl imine derivatives cleanly and in quantitative yield, which was crucial to achieve high yields inside the subsequent alkylation reactions. The first process involved adding pivaldehyde (two.0 equiv) to a stirring suspension of pseudoephenamine alaninamide (1 equiv) and activated 4MS in a mixed solvent of benzene and dichloromethane at 23 . Evaporation from the solvents immediately after 50 min afforded a white solid, which was held under vacuum (1 Torr) at 35 overnight to get rid of excess pivaldehyde. The solution (99 yield, est. 95 purity by 1H and 13C NMR) was utilized without having further purification. A second thriving protocol involved initial synthesis of pivaldehyde N-propyl imine as a reagent for transimination, a a lot more facile and speedy course of action than imine formation from the corresponding aldehyde.3 A mixture of pivaldehyde N-propyl imine (5.0 equiv) and pseudoephenamine alaninamide (1 equiv) was stirred in dry benzene at 23 under moderate vacuum (200 mmHg) for 30 min, during which time gas was observed to evolve in the reaction mixture (presumably Npropylamine). Concentration afforded a white solid, which was held below vacuum (1 Torr) at 35 to eliminate all traces on the transimination reagent. The item, obtained in 99 yield (est. 95 purity by 1H and 13C NMR), was used without having additional purification in subsequent alkylation reactions. These procedures have been also helpful for the preparation of (1S,2S)-pseudoephenamine (S)-alaninamide pivaldimine and its enantiomer, which [email protected]. Current address: Division of Chemistry, Ludwig-Maximilians-Universit M chen, Butenandtstrasse 5-13, 81377 M chen, Germany. Supporting Information and facts Readily available Complete experimental procedures, characterization data, and 1H and 13C NMR spectra for all synthesized compounds. This material is accessible absolutely free of charge by means of the net at http://pubs.acs.org.Hugelshofer et a.