Al catalysts. These -isothiocyanate methodologies afford thiocarbamate heterocycles as goods, which conveniently serve to protect the amine and alcohol functionalities on the aldol adducts, but require a 3-step process to reveal the embedded -amino acids. Strategies employing chiral glycine enolate equivalents have also been reported by the Bold,[32] Iwanowicz,[33] Caddick,[34] and Franck[35] groups. Hydroxymethylations of PKAR custom synthesis alanine equivalents to type -alkyl serine derivatives have also been reported.[36] Another notable method employs Schiff bases of glycine tert-butyl esters in aldol reactions with aldehyde substrates to provide aldol addition products which can be then treated with acid to reveal the embedded -hydroxy–amino esters. Advances within this area were reported by the Mukaiyama,[37] Belokon,[38] Miller,[39] and Corey[40] groups, and subsequently several modifications have emerged that present both syn[41] and anti[42] merchandise. Though these techniques are easy because of the facile enolization of glycine Schiff bases plus the direct conversion of the aldol items into -hydroxy–amino esters, they frequently suffer from poorAngew Chem Int Ed Engl. Author manuscript; available in PMC 2015 April 25.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSeiple et al.Pagediastereoselectivities, narrow substrate scope, and often need additional functionalization to permit separation of syn and anti aldol addition goods.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptIto, Hayashi, and Guanylate Cyclase Activator list coworkers employed -isocyano esters and amides in aldol reactions catalyzed by chiral gold(I) complexes, delivering oxazoline-4-carboxylate solutions that may be converted to -hydroxy–amino acids upon treatment with strong acid.[43] Oxazoline-4carboxylates have also been constructed by the addition of 5-alkoxyoxazoles to aldehydes catalyzed by chiral aluminum catalysts, as demonstrated by Suga and Ibata[44] and also the Evans group.[45] These systems have been located to be highly effective only with aromatic aldehyde substrates, and conversion with the oxazoline solutions to -hydroxy–amino acids demands 3 steps and harshly acidic situations. Barbas, Tanaka, and coworkers reported a system for the aldolization of phthalimidoacetaldehyde catalyzed by proline that achieved higher enantio- and diastereoselectivities, but only with -branched aldehyde substrates.[46] The Wong group has created methodology for chemoenzymatic aldolization of glycine catalyzed by threonine aldolases that, even though very stereoselective for particular aldehyde substrates, is limited in scope.[47] We believe aldolization of pseudoephenamine glycinamide presents numerous advantages. Enolization of 1 proceeds below quite mild circumstances (LiHMDS, LiCl) without having metal additives, plus the syn aldol goods are readily obtained in stereoisomerically pure form by column chromatography. A broad collection of electrophiles, such as alkyl and aryl aldehydes and ketones, undergo efficient aldolization with 1, whereas lots of other glycine equivalents react efficiently only with aryl or alkyl aldehydes, and really handful of are reported to react effectively with ketones.[48] Using the exception of chemoenzymatic approaches,[47] the aforementioned glycine equivalents all demand shielding in the -amino group, but this is not needed with our method. Hydrolysis of the aldol adducts of 1 proceeds below unusually mild conditions in comparison with other glycine equivalents, and bot.