Asymmetric Organocatalytic Relay Cascades: Catalyst‐Controlled Stereoisomer Selection in the Synthesis of Functionalized Cyclohexanes

Abstract

Amongst the challenges currently facing synthetic chemists is the development of efficient and elegant chemical processes that allow the rapid creation of stereochemically defined molecular complexity and diversity.[1] One of the most effective ways of achieving this goal is to implement reaction cascades; these allow multiple bond-forming events to occur in a single vessel and, as a consequence, significantly increase resource efficiency for the overall process.[1] To this end, the field of asymmetric organocatalytic cascade/domino reaction development-arguably one of the most stimulating, dynamic, and synthetically powerful areas in contemporary organic synthesis-is beginning to provide genuine solutions. [2,3] Recently, organocatalytic cascade approaches to polysubstituted chiral cyclohexanes have attracted a great deal of attention, owing to the prevalence of such motifs in pharmaceutical compounds and complex natural products. [4,5] However, despite the progress that has been achieved in this field, further advances are needed, particularly with regard to the controlled preparation of different stereoisomers by routine changes to the reaction conditions and/or catalysts employed.Recently, the combination of two organocatalysts has been elegantly employed in one-pot reactions with the controlled, sequential addition of reagents and/or catalysts throughout the course of the reaction.[6] That the vessel is not necessarily charged with all reactants and catalysts from the outset of the reaction belies incompatibilities between combinations of reactants, intermediates, or catalyst-activated species with respect to the desired product outcome. Instead of controlling the outcome of the cascade through the order or rate of addition of reactants/catalysts, our aim was to employ catalysts with orthogonal, but mutually compatible, reactant activation modes. By judicious choice of catalysts and reactants, cycle specificity can be engineered into the reaction cascade such that the product of the first catalytic cycle becomes the sole substrate which then reacts with the third "spectator" reagent.Relay catalysis has been used as an efficient strategy in non-asymmetric transformations, [7] and some examples of asymmetric metal/organocatalyst relay catalysis have also been reported.[8] Covalent-bond and bifunctional base/ Brønsted acid catalysis are two fundamental activation modes in organocatalysis. [9] We envisaged that the merging of these two fields would allow desirable levels of stereocontrol and resource efficiency in an asymmetric organocatalytic relay cascade (AORC) to polysubstituted cyclohexanes.Our proposed three-step asymmetric organocatalytic relay cascade to polysubstituted cyclohexanes is shown in Scheme 1. Initially, a bifunctional base/Brønsted acid catalyst of type 7 would preferentially activate the malonate ester 1 and the nitroalkene 2, thus promoting a chemoselective and stereoselective Michael addition.[10] The Michael adduct 5 would then be poised to participate directly in the second catalytic cyc...

Multicomponent and Multicatalytic Reactions – A Synthetic Strategy Inspired by Nature

“…Nevertheless, Dixon and co-workers reported a remarkable example in 2009. [25] Thus, the reaction of dimethyl malonate with a nitroalkene and a α, -unsaturated aldehyde in the presence of a binary organocatalytic system leads to interesting highly functionalized cyclohexane derivatives (Scheme 16). This binary organocatalytic system combines a chinchona-based thiourea and a proline-based secondary amine.…”

Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: recent advances

“…gaining further attention in the following years as catalysts for several sorts of transformations. [49][50][51] Furthermore, Cinchona-derived thiourea catalysts successfully promoted cycloaddition reactions such as [4 + 2], [3 + 2] and their formal versions, being well suited, for instance for the synthesis of 2H-pyran-2,5-diones, 52 3,3′-pyrrolidinyl spirooxindoles, 53,54 1,3-dioxolanes, 55 α-aryl isocyanoacetates and isatins, 56 as well as 2-oxazolidinones. 57…”

Evolution of asymmetric organocatalysis: multi- and retrocatalysis

“…95 The reaction was applicable for a wide range of starting materials, leading to a broad product scope. Thus, the products 219 were formed with catalyst combination I (45-87% yield, 9.3 : 1.8 : 1 d.r., up to >99% ee).…”