Dual Catalysis: A Combined Enantioselective Brønsted Acid and Metal‐Catalyzed Reaction—Metal Catalysis with Chiral Counterions

Abstract

The application of chiral Brønsted acids in asymmetric organocatalysis is continuously increasing. [1][2][3] Various highly enantioselective, metal-free reactions have been developed, most of which are based on the activation of the electrophile through protonation to form a chiral ion pair. Different nucleophiles have been added to aldemines and ketoimines in an enantioselective fashion by using this approach. [2,3] We were able to demonstrate that the electrophile and nucleophile could be simultaneously activated in a combined process catalyzed by two Brønsted acids. This led to the development of the first enantioselective Mannich and Mannich-Michael reactions catalyzed directly by Brønsted acids.[2g-i] More recently, we developed the first activation of "pure" carbonyl compounds catalyzed by a chiral Brønsted acid which resulted in the first organocatalytic, enantioselective Nazarov cyclization.[2k] We now present a new dual catalysis procedure, which comprises a combined and cooperative enantioselective Brønsted acid and a metal-catalyzed alkynylation.The enantioselective addition of organometallic compounds to imines is one of the most important reactions for the preparation of chiral amines.[4] This is also valid for the alkynylations of nitrones, enamines, and aldemines, which afford the corresponding propagylamines. [5,6] Although various metal-catalyzed, enantioselective alkyne additions to imines have been reported, the enantioselective alkynylation of a-imino esters has been neglected, even though the resulting amino acids are of great biological interest.[5l] This may be due to the basic reaction conditions employed, which often lead to racemization and loss of enantioselectivity.In this context we decided to examine the alkynylation of a-imino esters catalyzed by a Brønsted acid. Based on our earlier work [2] on asymmetric ion pair catalysis we wondered whether the combination of a chiral Brønsted acid catalyst and a metal catalyst would lead to the valuable a-alkynylated amino acids. Our new concept is based on two parallel catalytic cycles I and II, in which the activation of the electrophile 2 by a chiral Brønsted acid (1) catalyst and the activation of the nucleophile 4 by a metal salt (3) proceed simultaneously (Scheme 1). This approach should lead to the formation of an intermediary chiral ion pair A and an achiral metal complex B, which after subsequent reaction give the desired amino acid 5 and the regenerated catalysts.In previous work we demonstrated that chiral binol hydrogen phosphates 1 (binol = 1,1'-bi-2-naphthyl) are excellent Brønsted acid catalysts for chiral ion-pair catalysis. Therefore, we decided to initially use these as chiral catalysts for the activation of the a-imino esters 2 (catalysis cycle I). As a metal salt (3) for the activation of the alkyne 4 (catalysis cycle II) we used silver salts, as earlier studies demonstrated that alkynyl-silver derivatives are stable in protic media and hydrolysis can only be achieved in the presence of strong acids, such as hydrochloric ac...

Copper‐Catalyzed Amine–Alkyne–Alkyne Addition Reaction: An Efficient Method For the Synthesis of γ,δ‐Alkynyl‐β‐amino Acid Derivatives

“…Toluene is the best choice for the reaction; the use of which resulted in high conversions to the desired product. The use of polar solvents, such as DMF, N-methylpyrrolidinone (NMP), and ethanol, gave lower yields of the product than the less polar 1,4-dioxane and xylene (Table 1, entries [12][13][14][15][16]. The use of pure water as a solvent also resulted in 21 % yield, whereas no product was obtained when tetrabutylammonium bromide (TBAB) was added as a phase transfer reagent (Table 1, entries 17 and 18).…”

“…Recently, Rueping and coworkers reported the addition of terminal alkynes to aamino esters by using a Brønsted acid and silver in dual catalysis. [12] Enlightened by this report, we examined various Brønsted and Lewis acids, such as HOAc, HCl, ScCl 3 , and ScA C H T U N G T R E N N U N G (OTf) 3 . However, these additives did not affect the reaction favorably.…”

Synthesis of α‐Ethynyl Glycines

“…[24] Rueping's group reported a procedure for the enantioselective addition of aryl alkynes 21b to methyl glyoxylate imine 25 by using the catalytic system that consisted of AgOAc and chiral 1,1′-bi-2-naphthol (BINOL) derived phosphoric acid 26 (Scheme 3). [27] Catalyst screenings revealed phenanthryl-substituted phosphoric acid 26 as the optimal cocatalyst to lead to the formation of (R)-27 in good yields high enantioselectivity. According to the proposed mechanism, chiral phosphoric acid 26 activates imine 25 to form chiral ion pair E. In a concurrent catalytic cycle, AgOAc activates alkyne 21 to form silver acetylide F, which then undergoes a reaction with complex E to give product 27 (Scheme 3).…”

Chiral Lewis Acids and Brønsted Acids in Asymmetric Synthesis

“…Rueping et al reported a new dual catalysis procedure, where an enantioselective activation of imines by a Br ø nsted acid is combined with a metal -catalyzed alkynylation [95] . The α -amino acids were obtained in good yields and with excellent enantioselectivities.…”