Solvent-controlled diastereoselectivity in tryptophan-catalyzed Mannich reactions

Abstract

still yet to be developed [23][24][25][26][27][28][29][30][31][32]. In particular, none of the presently known catalysts, with the possible exception of O-(tert-butyl)-L-threonine, [28] are suitable for the stereocontrolled preparation of anti-Mannich adducts derived from hydroxyacetone (1).In the course of a research program devoted to spontaneous mirror-symmetry breaking and asymmetric organoautocatalysis, [33][34][35][36][37][38][39][40] we needed to prepare both the syn (3a) and the anti (3b) stereoisomers of the Mannich adduct from hydroxyacetone (1) and the glyoxylate-derived imine 2. Whereas 3a was easily obtained by L-proline catalysis under the reaction conditions previously described by Barbas III (Scheme 1, (a)),[11] the preparation of 3b proved more troublesome, since in our hands the L-tryptophan (L-Trp) catalysis of the reaction between 1 and 2[28] afforded (as reported) an inseparable 2:1 (anti:syn) mixture of 3b and 3a in 67% yield, after chromatographic purification (Scheme 1, (b)). Although it had been described that the use of O-(tert-butyl)-L-threonine as a catalyst in the Mannich reaction of 1 with a 4-nitrobenzaldehyde-derived imine gave improved anti:syn ratios (up to 8:1 dr, determined by NMR analysis of the crude reaction mixture), [28] both the easier availability of L-tryptophan and the instability of the Mannich adduct 3b (that precludes its careful chromatographic purification) spurred us on to optimize the anti-stereoselectivity of the L-Trp-catalyzed process. Experimental Procedure General methodsReactions were generally run in loosely-stoppered 5 mL flasks under open air with magnetic stirring. Commercially available reagents, catalysts, and solvents were purchased from Panreac, Scharlab and Aldrich and used as supplied, with the exception of dichloromethane (DCM), which was distilled from calcium hydride [41].The reaction progress was monitored by thin layer chromatography on silica gel (aluminium foils) and Abstract: Solvent effects in the L-tryptophan-catalyzed Mannich reaction between hydroxyacetone and glyoxylate imines have been examined. The use of a DMSO/1-butanol (4:1 v/v) mixture as solvent at rt provided the expected Mannich adducts in good yields, high anti-diastereoselectivity (up to 10.3:1 anti/syn ratio) and excellent enantioselectivities (up to >99.9% ee for the anti isomer)

Absolute Asymmetric Catalysis, from Concept to Experiment: A Narrative

“…We also found that when the reaction was run in the presence of preformed syn-8, the rate was independent from the initial enantiomeric purity of this compound, ruling out a mutual inhibition between the two enantiomers of the product. After developing a practical method for the highly diastereo-and enantioselective synthesis of anti-8, 47 we could demonstrate that the actual catalyst is the anti-diastereomer of the Mannich adduct, that catalyzes the formation of racemic syn-8, while the initial presence of stereoisomerically pure syn adduct does not increase the rate of the reaction. 46 It is worth noting that the nonselective (auto)catalysis by an anti-Mannich adduct had been also observed by Amedjkouh and Brandberg.…”

Enantioselective anti-Mannich reaction catalyzed by modularly designed organocatalysts

“…19–21 Cordova’s group reported the use of an acyclic β-amino acid for catalyzing the anti -Mannich reaction of ketones. On the other hand, the groups of Moyano and Lu used acyclic a-amino acid derivatives as catalysts for the anti -Mannich reactions of hydroxyacetone 20 and O -benzyl 21a or O -TBS 21b hydroxyacetones, respectively. A totally different type of amine catalysts for the anti -Mannich reaction was reported by Maruoka’s group.…”