Cooperative Coexistence: Effective Interplay of Two Brønsted Acids in the Asymmetric Synthesis of Isoquinuclidines

Abstract

The application of Brønsted acids in chemical syntheses continues to rise. As well as inorganic Brønsted acids, more and more achiral and chiral organic Brønsted acids are being applied.[1] The main function of Brønsted acids is the activation of the electrophile or nucleophile. On the one hand, the transfer of a proton from the Brønsted acid to the electrophile can lead to a lowering of the energy of the LUMO, which results in activation of the electrophile and enables it to react with a nucleophile. On the other hand, the addition of Brønsted acids can lead to activation of a nucleophile, as demonstrated by the acid-catalyzed ketoenol tautomerism. In most cases only catalytic amounts of Brønsted acid are required for complete product formation. Recently, chiral Brønsted acids (*BH) enabled enantioselective transformations with aldimines and ketimines for the first time [Eq. (1)]. [2][3][4] In the first step of these reactions a proton is transferred from the Brønsted acid to the substrate to form a chiral ion pair that contains an iminium ion, which subsequently reacts with a nucleophile to form the corresponding amine and the regenerated Brønsted acid. We recently used this concept of chiral ion pair catalysis to develop highly enantioselective reactions, such as transfer hydrogenations [3] and hydrocyanations.[4]Herein we report the development of a new, double Brønsted acid catalyzed reaction in which both the electrophile and the nucleophile are activated and which provides a straightforward and effective route to isoquinuclidines in remarkably high enantioselectivities. Isoquinuclidines (5, azabicyclo[2.2.2]octanes) have N-bicyclic structures, which are the structural element of numerous naturally occurring alkaloids with interesting biological properties.[5] Furthermore, these products can be readily converted into the biologically active pipecolic acids.[6] A retrosynthetic analysis shows that these isoquinuclidines (5) can be prepared from imines (3) and cyclohexenone (4) [Eq. (2)]. [7] On the basis of our previous work we assumed that an asymmetric Brønsted acid catalyzed reaction should enable the formation of these valuable products. Our concept, based on the direct reaction between 3 and 4, provides the simultaneous, double Brønsted acid catalyzed activation of an electrophile (by a chiral Brønsted acid *BH, 1) and a nucleophile (by an achiral Brønsted acid BH, 2), whereby both activation processes behave cooperatively (Scheme 1). The fundamental requirement for a successful reaction process must be that the achiral Brønsted acid BH 2 is not able to activate the imine 3.

Highly Enantioselective Hydrogenation of Enamides Catalyzed by Chiral Phosphoric Acids

“…Rueping and coworkers successfully utilized two Brønsted acids as the catalyst for the asymmetric synthesis of isoquinuclidines. 6 Our optimized reaction conditions for the enantioselective organocatalytic hydrogenation of enamides were determined to be the following: 1 mol % of chiral phosphoric acid A4, 10 mol % AcOH, 50 □, with a ratio of enamide 1 and Hantzsch ester 2 set at 1/1.1 eq. and toluene as the solvent.…”

Asymmetric Organocatalytic Reactions of α,β-Unsaturated Cyclic Ketones

“…Some reactions are based on the Brønsted acid catalyzed activation of the imine by a chiral acid such as H8-BINOL (entry 1, Table 5) [92] or BINOL phosphate (entries 2 and 3, Table 5) [93] and of the ketone. This second activation step could also be performed by an achiral acid, if both activation processes behave cooperatively.…”

“…This second activation step could also be performed by an achiral acid, if both activation processes behave cooperatively. Generally better results are obtained with more sterically shielding aryl groups on the BINOL catalyst [93].…”

Asymmetric Brønsted Acid-catalyzed Intramolecular aza-Michael Reaction – Enantioselective Synthesis of Dihydroquinolinones

“…Enders described the synthesis of tetrahydroisoquinolines through a Brønsted acid-catalyzed reductive amination/aza-Michael domino reaction [17]. Our group and that of Gong reported independently the asymmetric synthesis of isoquinuclidines through a Brønsted acid-catalyzed Mannich/aza-Michael addition [18,19].…”