Basic, efficient, and stereoselective reactions with aldehyde substrates (linear, branched, and -tetrasubstituted aliphatic, aromatic, -oxygenated, and ,unsaturated), pseudoephenamine glycinamide (1) also serves as an exceptional substrate for aldolization with ketone substrates, supplying aldol adducts with fully substituted -centres, as illustrated by the seven examples 13-19 in Table 1. The stereochemistry of aldol adduct 16 (from methyl isopropyl ketone) was established unambiguously by X-ray evaluation of its crystalline hydrate; not surprisingly, it was identified to become completely consistent with the stereochemistry from the aldehyde aldol adducts (the methyl group acts as the “small” group). We also rigorously established the stereochemistry in the aldol adduct 18 by X-ray evaluation of a crystalline derivative (vide infra), and this also conformed to that on the other aldol merchandise. This item appears to represent a case of stereochemical matching, where the diastereofacial preferences of the enolate and the chiral ketone substrate (the latter constant having a Felkin-Ahn trajectory)[9] are reinforcing, accounting for the extraordinarily higher stereoselectivity and yield of this specific transformation. Product 19 (55 isolated yield), from methyl styryl ketone, was formed least effectively, we believe as a consequence of competitive conjugate addition (est. 15 ). As a seemingly minor point, we note that cautious analysis with the 1H NMR spectra of your majority in the purified aldol adducts from Table 1 reveals that in addition to the two rotameric forms of your anticipated syn-aldol diastereomers, trace (5 ) amounts of an “impurity” corresponding to the N O-acyl transfer solution, a amino ester, are present.Aurothiomalate Protocol [10] This reveals that the latter constitutional isomer is only slightly higher in energy than the tertiary amide form, providing a rationale for the outstanding facility in the subsequent transformations of your direct aldol products discussed under, namely their hydrolysis and reduction.Scutellarin supplier In contrast to circumstances common for hydrolysis of tertiary amides, hydrolysis from the aldol adducts of Table 1 proceeds below remarkably mild situations, far more consistent with saponification of an ester than hydrolysis of a tertiary amide (Table two). As an example, hydrolysis of aldol adduct four was complete inside four h at 23 in the presence of 1 equiv of sodium hydroxide in 1:1 THF:methanol. When hydrolysis was total, pseudoephenamine was recovered by extraction with dichloromethane in quantitative yield (95 purity), as well as the alkaline aqueous solution was lyophilized to supply the -hydroxy–amino sodium carboxylate 22 in 92 yield and 98 ee (Table 2).PMID:24578169 The inclusion of methanol was vital to prevent retroaldol fragmentation in the course of the hydrolysis, which was otherwise facile, specifically with aromatic aldol addition items. In a noteworthy instance, use in the THFmethanol-sodium hydroxide protocol with substrate 10 afforded the aromatic aldolate 25 in 94 yield and 98 ee (auxiliary recovery: 97 yield). A protected kind of the latter amino acid served as a important beginning material in the synthesis of vancomycin reported by the Nicolaou group.[11] Interestingly, the present hydrolysis circumstances are a great deal milder than these necessary for hydrolysis of pseudoephedrine[10] and pseudoephenamine[2b] amide alkylation merchandise,Angew Chem Int Ed Engl. Author manuscript; obtainable in PMC 2015 April 25.Seiple et al.Pagesuggesting that the -hydroxy group of the aldol adduct.
