A Mechanistic Rationale for the 9-Amino(9-deoxy)epi Cinchona Alkaloids Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones

Abstract

The 9-amino(9-deoxy)epi cinchona alkaloids have expanded the synthetic potential of asymmetric aminocatalysis, enabling the highly stereoselective functionalization of a variety of sterically hindered carbonyl compounds. However, there is a lack of basic understanding of the mechanisms of cinchona-based primary aminocatalysis. Herein, we describe how a combination of experimental and theoretical mechanistic studies has revealed the origin of the stereoselectivity of the Friedel-Crafts alkylation of indoles with α,β-unsaturated ketones catalyzed by 9-amino(9-deoxy)epi quinine. An essential role for the achiral acid cocatalyst is uncovered: upon condensation of the cinchona catalyst with the enone, the resulting covalent imine intermediate and the acid interact to build-up a well-structured ion-pair supramolecular catalytic assembly, which is stabilized by multiple attractive noncovalent interactions. All the components of the assembly cooperatively participate in the stereocontrolling event, with the anion of the achiral acid being the structural element responsible for the π-facial discrimination of the iminium ion intermediate.

Highly Enantioselective, Organocatalytic, and Scalable Synthesis of a Rare cis,cis‐Tricyclic Diterpenoid

“…Although the origin of stereochemistry in the Michael addition fits the model proposed by Melchiorre and co‐workers (Figure a), which describes optimal conditions of 2:1 co‐catalyst to amine catalyst, we found that better yields were obtained in a 1:2 ratio (Table , entry 11). We, therefore, do not discount the possibility of a bifunctional effect of the catalyst on the enantioselective outcome (Figure b), as has been described for other related processes, although further study is required.…”

“… (a) Although the stereoselective outcome of our process fits the model of Melchiorre our stoichiometry and co‐catalyst are slightly different. (b) Bifunctional activation of the enone and nucleophile is also a possibility …”

Beyond static structures: Putting forth REMD as a tool to solve problems in computational organic chemistry

“…6). This class of compounds, derived from natural sources, has been identified as a promising alternative to other amino‐catalysts such as proline . ( A ) As well as its quinidine diasteteroisomer activate various carbonyl compounds with a consistently high level of stereocontrol.…”

“…According to our simulations, the rich conformational behavior of (A) is not easily rationalized in terms of four relevant (anti/syn and closed/open) conformations. [132,134] The 2D conformational map with 5, 10, 15, and 20 kcal mol 21 isocontours given in Figure 6 suggests a somewhat richer conforma-tional picture consisting of four easily accessible conformational regions (1)(2)(3)(4) and one that is less frequently visited (2 0 ). The most populated region, 1, essentially encompasses a 608 range for the C 8 AC 9 AC 0 4 AC 4a angle with no significant energy barrier.…”

“…This class of compounds, derived from natural sources, has been identified as a promising alternative to other amino-catalysts such as proline. [130][131][132][133] (A) As well as its quinidine diasteteroisomer activate various carbonyl compounds with a consistently high level of stereocontrol. Rather than addressing the origin of the stereoselectivity, which depends heavily on: concentration and nature of the acid co-catalyst, formation of hydrogen bond motifs, solvent effects, and so forth, here we revisit the gas phase conformational behavior of (A), which is one of the primary elements responsible for the control of stereochemistry.…”