The Diels-Alder reaction is probably the most powerful technology in the synthetic repertoire for single-step constructions of complex chiral molecules. The synthetic power of this fundamental pericyclic transformation has greatly increased with the emergence of asymmetric catalytic variants, and research aimed at further expanding its potential is still exciting and fascinating the chemical community. Here, we document the first asymmetric catalytic Diels-Alder reaction of in situ generated heterocyclic ortho-quinodimethanes (oQDMs), reactive diene species that have never before succumbed to a catalytic approach. Asymmetric aminocatalysis, that uses chiral amines as catalysts, is the enabling strategy to induce the transient generation of indole-, pyrrole- or furan-based oQDMs from simple starting materials, while directing the pericyclic reactions with nitroolefins and methyleneindolinones toward a highly stereoselective pathway. The approach provides straightforward access to polycyclic heteroaromatic compounds, which would be difficult to synthesize by other catalytic methods, and should open new synthetic pathways to complex chiral molecules using nontraditional disconnections.

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An organocatalytic aldehyde C-H bond arylation process for the synthesis of complex heteroaryl ketones has been developed. By exploiting the inherent electrophilicity of diaryliodonium salts, we have found that a commercial N-heterocyclic carbene catalyst promotes the union of heteroaryl aldehydes and these heteroaromatic electrophile equivalents in good yields. This straightforward catalytic protocol offers access to ketones bearing a diverse array of arene and heteroarene substituents that can subsequently be converted into molecules displaying structural motifs commonly found in medicinal agents.

The direct, catalytic, and stereoselective functionalization of carbonyl compounds at the g position represents a highly challenging and persistent problem for asymmetric synthesis. [1,2] All attempts to solve this problem must address the challenge of site selectivity as well as stereoselectivity. [3] Recently, our research group hypothesized whether dienamine catalysis could provide a general platform for designing direct vinylogous processes, [4] by exploiting the ability of chiral amine catalysts to form a nucleophilic dienamine intermediate in situ in the condensation with g-enolizable unsaturated carbonyl compounds. Dienamine catalysis was introduced in 2006 by Jørgensen and co-workers [5] to promote the direct, enantioselective g amination of a,b-unsaturated aldehydes. However, it has since found limited application. [6] A recently published perspective on the advent of organocatalysis did not number dienamine catalysis among the generic modes of activation and induction. [7] This was probably a result of the fact that g amination of enals was originally thought to follow a particular [4 + 2] cycloaddition path, [5] instead of a more general nucleophilic addition manifold.Recently, we documented that dienamine catalysis can be exploited to promote vinylogous nucleophilicity within Michael addition patterns, upon selective activation of unmodified cyclic a,b-unsaturated ketones by primary amine catalysts.[8] Herein, we report that vinylogous reactivity induced by dienamine catalysis also has synthetic potential for nucleophilic substitution reactions. Specifically, we describe the direct asymmetric g alkylation of a-substituted linear a,bunsaturated aldehydes through an S N 1 pathway. This unprecedented transformation [9] has been accomplished using an interwoven activation pathway that successfully integrates dienamine catalysis and Brønsted acid catalysis [10] simultaneously.The alkylation of carbonyl compounds is the archetypal nucleophilic substitution reaction. Recently, we and others have independently established the possibility of intercepting in situ generated stable carbocations with enamine intermediates, thereby leading to the challenging asymmetric a alkylation of aldehydes through an S N 1 pathway.[11] With the aim of applying the dienamine-induced vinylogous nucleophilicity within a substitution pattern, we focused on the S N 1-type g alkylation of unmodified unsaturated carbonyl compounds (Scheme 1).As a model reaction, we chose the direct g-alkylation of abranched aldehyde 3 with bis(4-dimethylaminophenyl)methanol 4, which can easily form a stabilized benzhydryl carbocation in situ [11b, 12] under acidic conditions (Table 1). Recently, we established the unique ability of 9-amino-9-deoxy-epi-cinchona alkaloids (chiral primary amines easily derived from natural sources) [13] to efficiently activate sterically hindered carbonyl compounds, while imparting unconventional reactivity profiles (e.g. vinylogous nucleophilicity upon condensation with cyclic enones).[8] Moreover, this class of ca...

Methods based exclusively on organocatalysts have become of major significance in synthetic chemistry.[1] The Michael addition of carbonyl compounds to nitroalkenes [2] is a challenging benchmark for such a development owing to its potential for the construction of a C À C bond with simultaneous generation of up to three adjacent stereogenic centers and because of the pivotal importance of the nitro group as a precursor to many functionalities.[3] While bifunctional thioureas [4] and chiral Brønsted bases [5] have been developed to control the stereochemistry of the process with malonate esters and related methylene-active substrates, [6] stereocontrol during the reaction involving aldehydes and ketones is most often effected from chiral cyclic secondary amines via enamine formation. [7] However, despite the recent efforts in the area, unmet challenges remain with regard to substrate generality and reaction selectivity, including both diastereoand enantioselectivity.[8] For example, proline [8a-c] and several diamine/protonic acid catalysts [8d-h] are capable of promoting the reactions with ketones, but with aldehydes poor chemical and stereochemical results are produced (syn/anti 80:20 to 90:10; 70-75 % ee). The groups of Kotsuki and Ley have described a pyrrolidine-pyridine/protonic acid system [8i] and a homoprolinetetrazole catalyst, [8j,k] which also provide excellent results for ketones. However, very poor enantioselectivities (22-37 % ee) are observed when an aldehyde is used as the substrate. Highly diastereo-and enantioselective conjugate additions involving aldehydes were reported by the groups of Hayashi and Wang using a diphenylprolinol silyl ether [8l] and a pyrrolidine-sulfonamide, [8m] respectively. Nonetheless, one drawback is the need for a large excess of the aldehyde substrate, generally 10 equivalents, which becomes a serious limitation in the case of aldehydes that are not commercially available. Most importantly, the catalysts are effective in reactions with nitrostyrenes, but with b-alkylsubstituted nitroalkenes moderate yields (50 %) [8l] or essentially no enantioselectivity (22 % ee)[8m] is produced. The need for high catalyst loading, typically 15-20 mol %, is another important inconvenience related to most of the above approaches, [8] specially when the reactions have to be scaled up. Most recently, an attractive organocatalytic Michael reaction in brine was disclosed.[8n] Again, low diastereo-and enantioselectivities (syn/anti 60:40, 38-74 % ee) are observed when aldehydes are employed. Herein we report a new catalyst design (B, Figure 1) which provides a highly efficient solution to these problems.The basis of our proposal stems from the observation that in the majority of the above catalyst systems a hydrogen-bond donor at the a-position of the pyrrolidine nitrogen atoms (A, Figure 1) is introduced to help the catalytic reaction to proceed.[9] This observation can be correlated to the aminecatalyzed aldol additions wherein a hydrogen-bond motif arising from the same position i...