Metal‐Free, Enantioselective Strecker Reactions Catalyzed by Chiral BINOL and TADDOL Catalysts

Abstract

An efficient, metal-free Brønsted acidcatalyzed, enantioselective hydrocyanation of ketoimines has been developed. This BINOL phosphate-catalyzed Strecker reaction provides the corresponding amino nitriles, precursors of quaternary amino acids, in good isolated yields and enantioselectivities. Additionally, we demonstrate that chiral diols, such as TADDOL, are effective enantioselective catalysts for the hydrogen-bond activation of aldimines.Keywords: amino acids; BINOL phosphate; Brønsted acid; hydrocyanation; Strecker reaction; TADDOL The addition of hydrogen cyanide to imines, the Strecker reaction, constitutes one of the most direct and practical methods for the synthesis of a-amino acids and derivatives.[1] As a result, considerable effort has been devoted towards the development of asymmetric Strecker reactions. [2,3] In addition to various metal-catalyzed hydrocyanations, [4] promising metal-free enantioselective variants [5] have been described. Recently, we reported that chiral Brønsted acids [6,7] are efficient catalysts for highly enantioselective processes, including the hydrogenation of ketoimines, [8a,b] benzoxazines, benzthiazines, benzoxazinones [8c] and quinolines, [9] as well as direct MannichMichael reactions, [10] or the hydrocyanation of aldimines (Scheme 1). [11] In this reaction the aldimine is protonated by a chiral BINOL phosphate 1 which leads to the formation of a chiral iminium ion, a chiral ion pair. Subsequent addition of HCN results in formation of the corresponding amino nitrile and the regenerated Brønsted acid catalyst. [11] Based on our previous results and observations, we herein report the application of yet another metalfree catalyst, the chiral TADDOL, for the hydrocyanation of aldimines. Furthermore, we describe the BINOL phosphate-catalyzed asymmetric Strecker reaction of ketoimines, which is generally not only more difficult to achieve as compared to the hydrocyanation of aldimines, [4h-j,5d] but additionally leads to the formation of valuable quaternary amino acids.We initially started our investigation with the exploration of various BINOL phosphates 1a-f in the hydrocyanation of ketoimine 4 (Table 1). The best results with regard to reactivity and selectivity were obtained with catalytic amounts of 1a (5 mol %) providing amino nitrile 5 in 70 % ee (Table 1, entry 1). All other tested BINOL phosphate catalysts gave inferior results which is in agreement with our earlier developed Brønsted acid-catalyzed reactions where sterically more congested 3,3'-aryl substituents on the BINOL skeleton gave generally better results. All cyanation reactions were performed in toluene at À40 8C with 1.5 equivs. of in situ generated HCN. [12] Other cyanide sources tested, such as trimethylsilyl cyanide or acetone cyanohydrin did not lead to the desired products.Further examinations concentrated on the solvent employed, as it was previously shown to have an important impact on reactivity and selectivity in Brønst-ed acid-catalyzed transformations. In accordance with the BINOL...

Chiral Brønsted Acids for Asymmetric Organocatalysis

“…Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of N-benzylated imines derived from arylmethyl ketones generally gave comparable yields, but lower enantioselectivities.…”

Towards Tartaric‐Acid‐Derived Asymmetric Organocatalysts

“…Another interesting report relating to the potential of TADDOLs as H-bonding catalysts was published in 2007 by Rueping’s group 13. During their investigations into organocatalysed enantioselective Strecker reactions they found that BINOL-derived phosphoric acids are versatile catalysts, giving the products in good yields and with high enantioselectivities.…”

Enantioselective Synthesis of Amines by Chiral Brønsted Acid Catalysts

“…The method offers efficient access to a broad range of aromatic amino nitriles with high enantioselectivities. They also developed the enantioselective Strecker reaction of ketimines catalyzed by the same chiral phosphoric acid 1l to give products having a chiral quaternary stereogenic center with moderate to high enantioselectivities [31,32]. …”