L.Pageto be mismatched substrates in pivaldimine alkylations (vide infra). In contrast to these successful techniques

L.Pageto be mismatched substrates in pivaldimine alkylations (vide infra). In contrast to these successful techniques for imine formation, attempts to form the N-tert-butyl imine by combining the alaninamide substrate with pivaldehyde and magnesium DAPK drug sulfate, or with pivaldehyde, magnesium perchlorate, and trimethylorthorformate (catalyst and stoichiometric dehydrating agent, respectively) had been not satisfactory with respect to conversion and item purity, and efforts to purify samples with the imine only led to increased contamination with its hydrolysis product. Enolization-alkylation of substrate 1 was optimally achieved by the following protocol. A remedy of (1S,2S)-pseudoephenamine (R)-alaninamide pivaldimine (1 equiv) in dry tetrahydrofuran (THF) was transferred to a flask containing flame-dried lithium chloride (6.0 equiv), and the resulting slurry was cooled to -78 . A answer of lithium diisopropyl amide (LDA) in THF (two.2 equiv) was then added slowly down the side in the flask by cannula or syringe so as to allow the resolution of base to cool ahead of reaching the substrate option. Just after completed addition and further stirring at -78 for five minutes, the reaction flask was transferred to an ice bath for ten minutes just before cooling to -50 . An electrophile (2.five equiv) was then added towards the cold reaction option, plus the ensuing alkylation reaction was monitored by TLC (reaction instances commonly ranged from 1.5.five h). Upon completed reaction, a remedy of 1 N hydrochloric acid was added to the reaction mixture to induce hydrolysis with the tert-butyl imine function inside the alkylated product, which commonly occurred in significantly less than 3 h at 23 . Table 1 summarizes outcomes from alkylation reactions working with six different electrophiles. In all situations, diastereoselectivities equaled or exceeded 19:1, as well as the products, isolated in 83-95 yield by flash-column chromatography, had been solids. We established that the benzylation item of entry 1 had the configuration G protein-coupled Bile Acid Receptor 1 site depicted by comparison using a sample of recognized configuration, ready by an independent route (see Supporting Facts). The diastereoisomer that is definitely formed arises from replacement from the -CH bond by -C-benzyl with retention of configuration. This alkylation solution and two other folks whose stereochemistry was established unambiguously (shown in equation two of Scheme 1 and in Scheme 2 below) had been found to type a homochiral series. The goods of entries 2 of Table 1 had been presumed to possess formed analogously. Table 2 summarizes final results from three parallel alkylation reactions making use of the diastereomeric substrate (1S,2S)-pseudoephenamine (S)-alaninamide (two), otherwise carried out as described within the paragraph above. Surprisingly, in all three cases the main item was precisely the same as that formed making use of substrate 1, although the stereoselectivities and yields were reduce, making it clear that substrate 2 is mismatched.four These findings is usually rationalized by arguments that extend from our earlier studies on the enolization of ,-dialkyl pseudoephenamine and pseudoephedrine amide enolates, summarized in Figure 1.five Briefly, each matched and mismatched substrates are proposed to form exactly the same E-enolate intermediate (using the enoxy and -imino groups in trans disposition), which then undergoes alkylation predominantly or exclusively in the usual sense.six Enolization of your mismatched substrate is believed to become much less E-selective, however, because E-enolization needs approach from the base along a trajectory.