Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline–guanidinium salt system

Abstract

COMMUNICATIONThis journal is © The Royal Society of Chemistry 2012 J. Name., 2012, 00, 1-3 | 1 are typically accessed by a base-promoted aldol reaction of an -azidoketone 2 and a non-enolizable aldehyde 3 3 (Scheme 1). Scheme 1Although these protocols render the aldol aducts 1 with optimum chemical yield, undesired mixtures of anti and syn isomers are always present. In fact, to our knowledge, there are no methodologies described in the literature that allow gaining access to -azido--hydroxy ketones 1 in a controlled diastereo-and enantioselective manner. Proline is the most popular organocatalyst. This naturally occurring amino acid is cheap, readily available in both enantiomeric forms, and can be used for a wide range of synthetic transformations. 6 Aiming to avoid the use of other synthetically elaborated organocatalysts, our group, 4 and others, 7 have demonstrated how the addition of additives can enhance the reactivity and selectivity of this off-the-bench catalyst in classical transformations such as the aldol reaction. Moreover, the addition of additives can also expand the boundaries of proline as catalyst. In this sense, we have reported the first proline-catalyzed asymmetric synthesis of chlorohydrins through the intermolecular aldol reaction between chloroacetone and aromatic aldehydes, made feasible by the participation of a guanidinium salt as an additive. Motivated by our previous results, we decided to explore the behaviour of our catalytic guanidinium salt/proline system towards a reaction like that illustrated in Scheme 1. 4-Nitrobenzaldehyde, 4a, was adopted as the model substrate for preliminary reactions. Azidoacetone (5, 1-azidopropan-2-one) was prepared in multi-gram scale, in 96% yield, from chloroacetone and sodium azide. In correspondence with our previous work, we decided to evade the use of any organic solvent, apart from ketone 5, which acts as both reagent and reaction media.8 A careful optimization of the stoichiometries involved in the reaction, time, temperature, as well as the judicious choice of the anion accompanying the guanidinium salt, revealed ideal conditions (see Supporting Information (SI) for details, Tables S1-S5). So, when a suspension of (S)-proline (10 mol%), guanidinium salt 6 (15 mol%) and 4-nitrobenzaldehyde 4a, in a moderate excess of azidoacetone 5

Cooperative Guanidinium/Proline Organocatalytic Systems

“…So far, to our knowledge, only five reports have appeared in the literature about this topic [74,88,89,101,107]. Granted the success of the TBD-derived guanidinium salts, we anticipate other species of the like will be capable of displaying similar or better properties as additives for proline or other natural amino acids.…”

“…However, there were no previous works describing the synthesis of synthon 21 in a diastereo-or enantioselective manner. Considering the efficiency of the proline/guanidinium salt organocatalytic system, it was investigated in reactions like that illustrated in Scheme 6 [107]. Azidoacetone (24, 1-azidopropan-2-one) was readily prepared from chloroacetone and sodium azide.…”

Unraveling the Role of Supramolecular Additives in a Proline‐Catalyzed Reaction

“…It demonstrates the necessity of the guanidinium salt on the reaction course, which makes possible a reaction that is not favourable with the single contribution of proline, as we have previously observed. [2][3][4] Considering that neither α,α-dichloroacetone, 1, nor aldehyde 2a possess any stereochemical information, it is intriguing the fact that the cross-aldol reaction is slow with L-proline but it works neatly with the racemic amino acid ( Table 1, entries 1 and 2). To the best of our knowledge, there aren't other catalytic systems displaying a similar behavior and it is therefore a phenomenon worth exploring.…”

“…Also, the addition of such additives broadens the scope of proline. In this sense, we have previously reported the first proline‐catalyzed asymmetric synthesis of chlorohydrins, as well as the first enantioselective preparation of α‐azido‐β‐hydroxy ketones, both made feasible by the cooperation of a proline/guanidinium salt catalytic pair.…”

Direct Catalytic Asymmetric Aldol Reaction of an α‐Azido Amide

“…[21] We reasoned that 1a would be as uitable aldol donor in the carboxylic acid oxidation state,and could be activated to catalytically generate the corresponding enolate in the context of soft Lewis acid/hard Brønsted base cooperative catalysis. [21] We reasoned that 1a would be as uitable aldol donor in the carboxylic acid oxidation state,and could be activated to catalytically generate the corresponding enolate in the context of soft Lewis acid/hard Brønsted base cooperative catalysis.…”