Organocatalyzed Cross-Nucleophile Couplings: Umpolung of Catalytic Enamines.

The concept of umpolung, or polarity reversal, introduced by Seebach and Corey nearly half a century ago, ushered a new paradigm into synthetic chemistry. Novel connections were able to be forged among functional groups that were typically inaccessible. Conceptually, an umpolung reaction is identified only upon retrosynthetic analysis. Stoichiometric examples have served as a platform to develop and refine elegant methodologies into catalytic processes. The advent of these unconventional arrangements of canonical synthons into new points of diversity has expanded the repertoire of the synthetic toolbox. Within this context, asymmetric organocatalyzed methodologies remain rare, and there are even fewer aminocatalyzed variants.Recent years have witnessed a renaissance in α-functionalizations of aldehydes, specifically in the context of oxidative umpolung strategies. Unlike previous open-shell approaches, application of a quinone-based oxidant in conjunction with an aminocatalyst leads to a discrete, substitutionally labile quinone adduct. These have proven to be valuable building blocks toward polar reactivity─auguring the advent of new avenues to construct tetrasubstituted tertiary stereocenters through the application of conventional nucleophiles to form C-C, C-N, C-O, and C-S bonds through an organocatalyzed cross-nucleophile coupling (organo-CNC) reaction. The resulting nonepimerizable stereocenter demonstrates high optical fidelity and provides a significant advancement in many applications that suffer from racemization, such as in vivo studies.This strategy harnesses a trifunctional aminocatalyst to promote an unusual SN2 reaction at a highly congested center. The selection of the quinone oxidant and nucleophile converges to a continuum of reactivity ranging from enantioselective oxidation to stereoselective substitution. A remarkable aspect of these developments is the identification of an asymmetric SN2 dynamic kinetic resolution (SN2-DKR) manifold. These organo-CNC reactions are highly modular and demonstrate complete stereocontrol from the catalyst with minimal influence from incoming chiral nucleophiles. Leveraging this facet, these technologies have been extended to peptidic bioconjugations bearing bio-orthogonoal linker molecules.This Account aims to highlight the progress, from an internal perspective, toward directing the initial result into established methodologies. Within this construct, the underlying principles of each reaction will be disseminated with specific content on inherent challenges and opportunity. Combined, these will serve as an instructive tool to stimulate applications in cross-disciplinary interfaces.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,ß-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

An Asymmetric SN2 Dynamic Kinetic Resolution.

The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

Investigation of the Organocatalytic Chlorination of 2-Phenylpropanal.

Results of an examination of the organocatalytic enantioselective α-chlorination of 2-phenylpropanal are described. Synthetic investigation including the screening of primary and secondary aminocatalysts, many different reaction conditions, and other α-branched aldehydes show that especially primary aminocatalysts can catalyze the formation of the α-chloro branched aldehydes in good yields, but only with moderate enantioselectivities. In order to try to understand the challenge in obtaining high enantioselectivity for the aminocatalytic α-chlorination of α-branched aldehydes a series of experimental investigations were performed employing 2-phenylpropanal as a model system. These investigations have been coupled with computational investigations, which provided important insight into the moderate enantioselectivity of this chlorination reaction. Analysis of the reaction showed, that the lack of control over the selectivity of formation of the (E)- and (Z)-enamine intermediate, and the clustering of reaction barriers of possible reaction pathways help to rationalize difficulties in producing high enantioselectivity.

Enantioselective α-Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy.

Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α-position. In the presence of a benzoquinone oxidant, the polarity of the α-position of racemic α-branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen-based nucleophiles and an amino acid-derived primary amine catalyst. A survey of benzoquinone oxidants identified p-fluoranil and DDQ as suitable reaction partners. p-Fluoranil enables the preparation of α-aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee, following either a one-step or a two-step, one-pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee. Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an SN 2 dynamic-kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α-position of aldehydes.

Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles.

Nucleophile-nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α-functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone-promoted oxidation to access O-bound quinol-intermediates that undergo nucleophilic substitution reactions. These quinol-intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α-thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α-branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.

Atroposelective brominations to access chiral biaryl scaffolds using high-valent Pd-catalysis.

Compounds featuring atropisomerism are ubiquitous in natural products, therapeutics, advanced materials, and asymmetric synthesis. However, stereoselective preparation of these compounds presents many synthetic challenges. This article introduces streamlined access to a versatile chiral biaryl template through C-H halogenation reactions employing high-valent Pd catalysis in combination with chiral transient directing groups. This methodology is highly scalable, insensitive to moisture and air, and proceeds, in select cases, with Pd-loadings as low as 1 mol%. Chiral mono-brominated, dibrominated, and bromochloro biaryls are prepared in high yield and excellent stereoselectivity. These serve as remarkable building blocks bearing orthogonal synthetic handles for a gamut of reactions. Empirical studies elucidated regioselective C-H activation to be predicated on the oxidation state of Pd and diverging site-halogenation to result from cooperative effects of Pd and oxidant.