Hydrogen-Bonding Asymmetric Metal Catalysis with α-Amino Acids: A Simple and Tunable Approach to High Enantioinduction

Abstract

While asymmetric transition-metal catalysis has become a powerful method for constructing chiral products, a challenge in this field is the identification of the correct ligand for high selectivity. We report here a simple approach to chiral catalyst formation: coupling of an available pool of Brønsted acids, namely, amino acid derivatives, with tunable ligands on copper catalysts. This system can be used to generate many different chiral environments simply by changing the amino acid or ligand employed and provides a scaffold for rapid screening and identification of the correct combination for high enantioselectivity. The latter is illustrated in the copper-catalyzed alkynylation of imines in up to 99% ee.

Chiral Brønsted Acid Directed Iron‐Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with β‐Aryl α′‐Hydroxy Enones

“…Chiral HPLC was performed using an HP series 1200 (Chiralpak AD-H column; hexane/2-propanol 85:15; 1.0 mL min À1 , 254 nm): 3,164.1,161.7,146.4 (d,J = 66 Hz),136.6,129.9 (d,J = 82 Hz),126.3,123.6 (d,J = 27 Hz),122.4,121.2,119.4 (d,J = 335 Hz),118.2,114.7 (d,J = 221 Hz),113.4 (d,J = 210 Hz),111.3,76.4,42.3,37.5,26.1,26.0 …”

“…Both transition-metal catalysis and organocatalysis have been applied to a broad range of organic transformations in synthetic organic chemistry, [2] but asymmetric catalysis by using this strategy is still in its developmental stages by comparison. [3] Proton transfer is among the most elementary of reaction steps in many chemical reactions that have played an important role in both chemistry and biology. [4] In Lewis acid catalyzed Michael-type Friedel-Crafts alkylation of indoles with a,b-unsaturated compounds, which is among the most important C À C bond-forming reactions in organic synthesis, [5,6] fast proton transfer from the indole moiety to newly generated enolate components is required, but this step is often slow and catalyst turnover is limited significantly.…”

A study on the induction of stereoselectivity in the Strecker synthesis of basic amino acid-derived α-amino nitriles

“…Next, we tried to use Boc-Pro-OH (13) as catalyst, which has been described to induce asymmetry in the addition of alkynes to imines. 23 Although 5 and 10 % of excesses in the (R)-9a epimer were obtained by using 10 and 50 mol %, respectively, of 13 as catalyst (Table 1, entries 3 and 4), this slight excess disappeared under thermodynamic control conditions required for optimizing reaction yield (entry 5). In view of the poor results on stereoselectivity obtained with the organocatalysts 12 and 13, and taking into account several reports that describe the influence of the solvent and temperature/time on the stereoselectivity of the Strecker reaction, 14,[24][25][26] we studied the influence of these factors on the synthesis of 9a and 11a.…”

Asymmetric Alkynylation of Imines by Cooperative Hydrogen Bonding and Metal Catalysis

“…Cooperative catalytic models based on chiral Brønsted acids and metal catalysis have emerged as such an alternative. Recent studies [10,11] have shown that high enatioselective alkynylations of imines can be performed according to the cooperative catalytic model shown in Scheme 1. The model comprises two well-differentiated and parallel catalytic cycles: the addition of metallic alkynylides to imines (cycle I) [12] and the use of chiral Brønsted acids as chiral imine activators (cycle II).…”

“…A more recent discovery has been recently reported by Arndtsen and co-workers, [11] in which they implement a cooperative catalytic model involving a-amino acids as chiral catalysts, copper/alkynylides as nucleophiles, and N-protected imines as substrates (Scheme 3). The catalytic manifold generates propargyl amines in good-to-excellent yields (up to 92 %) and high enantioselectivity (e.r.…”