Paolo Melchiorre

Targeting structural and stereochemical complexity by organocascade catalysis: construction of spirocyclic oxindoles having multiple stereocenters.

The structural complexity and well-defined three-dimensional architecture of natural molecules are generally correlated with specificity of action and potentially useful biological properties. This complexity has inspired generations of synthetic chemists to design novel enantioselective strategies for assembling challenging target structures and reproducing the rich structural diversity inherent in natural molecules. This symbiotic correlation between natural compounds synthesis and the discovery of effective asymmetric—generally catalytic—technologies lies at the heart of the synthetic chemistry innovation. Despite the substantial advances made thus far, the construction of highly strained polycyclic structures (particularly those that contain spiro-stereocenters) and the generation of all-carbon quaternary stereocenters still remain daunting targets for synthesis. The spirocyclic oxindole core is featured in a number of natural products as well as medicinally relevant compounds (Figure 1), but its stereocontrolled synthesis, particularly installing the challenging spiro-quaternary stereocenter, poses a great synthetic problem. Only a few venerable asymmetric transformations, such as cycloaddition processes or the intramolecular Heck reaction, have proven suitable for achieving this challenging goal. Herein we show that asymmetric organocascade catalysis, which exploits the ability of chiral amines to efficiently combine two modes of catalyst activation of carbonyl compounds (iminium and enamine catalysis) into one mechanism, allows the direct, one-step synthesis of complex spirooxindolic cyclohexane derivatives; these products have three or four stereogenic carbon atoms and are obtained with extraordinary levels of stereocontrol starting from simple precursors. Specifically, we developed complementary organocatalytic multicomponent domino reactions based on two distinct organocatalysts, A and B, which efficiently activate carbonyl compounds such as ketones and aldehydes, respectively, toward multiple asymmetric transformations in a welldefined cascade sequence. Both strategies provide straightforward access to natural product inspired compound collections, which would be difficult to synthesize by other enantioselective methods.

Cinchona‐based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds

Asymmetric aminocatalysis exploits the potential of chiral primary and secondary amines to catalyze asymmetric reactions. It has greatly simplified the functionalization of carbonyl compounds while ensuring high enantioselectivity. Recent advances in cinchona-based primary amine catalysis have provided new synthetic opportunities and conceptual perspectives for successfully attacking major challenges in carbonyl compound chemistry, which traditional approaches have not been able to address. This Review outlines the historical context for the development of this catalyst class while charting the landmark discoveries and applications that have further expanded the synthetic potential of aminocatalysis.

Asymmetric Catalysis of Diels–Alder Reactions with in Situ Generated Heterocyclic ortho-Quinodimethanes

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.

Photochemical activity of a key donor–acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes

Asymmetric catalytic variants of sunlight-driven photochemical processes hold extraordinary potential for the sustainable preparation of chiral molecules. However, the involvement of short-lived electronically excited states inherent to any photochemical reaction makes it challenging for a chiral catalyst to dictate the stereochemistry of the products. Here, we report that readily available chiral organic catalysts, with well-known utility in thermal asymmetric processes, can also confer a high level of stereocontrol in synthetically relevant intermolecular carbon–carbon bond-forming reactions driven by visible light. A unique mechanism of catalysis is proposed, wherein the catalyst is involved actively in both the photochemical activation of the substrates (by inducing the transient formation of chiral electron donor–acceptor complexes) and the stereoselectivity-defining event. We use this approach to enable transformations that are extremely difficult under thermal conditions, such as the asymmetric α-alkylation of aldehydes with alkyl halides, the formation of all-carbon quaternary stereocentres and the control of remote stereochemistry. The combination of organocatalytic and photoredox cycles has attracted much attention for its ability to solve long-standing problems in asymmetric catalysis. Here, it is shown that easily available chiral organic catalysts can guide both the stereoselectivity-defining events and, through the transient formation of photon-absorbing chiral electron donor–acceptor complexes, the photoactivation of the substrates.

Organocascade Reactions of Enones Catalyzed by a Chiral Primary Amine

Enantioselective catalysis is one of the most efficient chemical approaches to the challenging issues associated with structural and stereochemical complexity. This approach is attractive as it is the only rational means of producing useful chiral compounds with high optical purity in an economical, energy-saving, and environmentally benign way. Recently, the potential of asymmetric catalysis has been expanded by the introduction of simple chiral small organic molecules as highly efficient catalysts for many transformations. One of the most powerful organocatalytic strategies is organocascade catalysis. This process exploits the ability of chiral amines to efficiently combine two modes of catalytic activation of carbonyl compounds (iminium and enamine catalysis) into one mechanism, thereby allowing the rapid conversion of simple achiral starting materials into stereochemically complex products with multiple stereocenters and very high optical purity. This one-step strategy requires neither protection/deprotection steps, which can be time-consuming and costly, nor isolation of intermediates. The recent advances in the field of chiral secondary amine catalysis have set the scene for the development of many highly efficient organocascade reactions based on the selective activation of aldehydes. However, little progress has been achieved in the corresponding transformations of ketones, mainly because of the inherent difficulties in generating congested covalent intermediates from secondary amines and ketones. Herein, we show that chiral primary amine catalysis offers a powerful alternative in the design of novel and synthetically useful organocascade reactions, thus providing a practical solution to the issue of activating a,b-unsaturated ketones toward a well-defined enamine–iminium tandem sequence. Specifically, we have developed a series of organocascade approaches that affords straightforward access to a range of formal Diels–Alder adducts 4a–i, which have three or four stereogenic centers, with very high optical purity (Figure 1). Importantly, we found that catalyst 1, a chiral primary amine directly derived from natural cinchona alkaloids, efficiently activates acyclic enones while selectively directing the reaction manifold toward a stepwise double-Michael addition sequence instead of a pericyclic path. The resulting unique stereochemical outcome renders the presented methodology, which complements the venerable [4+2] cycloaddition transformations, a novel synthetic route to valuable cyclohexane derivatives. Recently, chiral secondary amine catalysis has proved efficient in promoting the stereoselective Diels–Alder reactions that use cyclic enones as dienes and involve in situ dienamine activation. On the other hand, the corresponding transformations with linear a,b-unsaturated ketones proceeded with essentially no enantioselectivity. We then investigated whether the versatility of 9-amino(9-deoxy)epi-hydroquinine 1, which we and other research groups have independently established as an effective catalyst for ketone activation, may be exploited to combine enamine–iminium activations of acyclic enones, as this cascade sequence would lead to a formal Diels–Alder adduct (Figure 1). This idea was mainly driven by our recent application of 1 to catalyze an intramolecular tandem reaction of linear enones, based on an iminium–enamine pathway. Initially, we focused on the identification of a suitable compound 3, which was able to initially act as a Michael Figure 1. Organocascade with enones promoted by chiral primary amine 1: enamine–iminium activation for a double-Michael sequence. EWG = electron-withdrawing group.

Diastereodivergent asymmetric sulfa-Michael additions of α-branched enones using a single chiral organic catalyst.

A significant limitation of modern asymmetric catalysis is that, when applied to processes that generate chiral molecules with multiple stereogenic centers in a single step, researchers cannot selectively access the full matrix of all possible stereoisomeric products. Mirror image products can be discretely provided by the enantiomeric pair of a chiral catalyst. But modulating the enforced sense of diastereoselectivity using a single catalyst is a largely unmet challenge. We document here the possibility of switching the catalytic functions of a chiral organic small molecule (a quinuclidine derivative with a pendant primary amine) by applying an external chemical stimulus, in order to induce diastereodivergent pathways. The strategy can fully control the stereochemistry of the asymmetric conjugate addition of alkyl thiols to α-substituted α,β-unsaturated ketones, a class of carbonyls that has never before succumbed to a catalytic approach. The judicious choice of acidic additives and reaction media switches the sense of the catalysts diastereoselection, thereby affording either the syn or anti product with high enantioselectivity.

Proline-Catalyzed Asymmetric Formal α-Alkylation of Aldehydes via Vinylogous Iminium Ion Intermediates Generated from Arylsulfonyl Indoles

Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for modern synthetic chemistry. The impressive level of scientific competition and high quality research generated in this area have opened up new synthetic opportunities that were considered inaccessible only a few years ago. Even reactions that had been considered impossible became a reality through aminocatalysis. One of the best validations of this approach is the development of the catalytic, asymmetric direct a-alkylation of aldehydes. This highly challenging and valuable C C bond-forming strategy was completely unknown before the advent of asymmetric aminocatalysis. In 2004, Vignola and List presented the first catalytic asymmetric intramolecular a-alkylation of haloaldehydes under enamine catalysis. They demonstrated the ability of proline-derived catalysts to overcome the classical drawbacks associated with the stoichiometric alkylation of preformed aldehyde enolates, such as the tendency toward aldol condensation and the Canizzaro or Tischenko reactions. However, extension of their aminocatalytic strategy to an intermolecular version failed because of deactivation of the amine catalyst by N-alkylation with the alkyl halide. Thus, chemists started to search for different aminocatalytic strategies to accomplish the challenging goal of an intermolecular formal aldehyde a-alkylation. In 2006, Ibrahem and C2rdova reported a non-asymmetric catalytic intermolecular a-allylic alkylation of aldehydes by combination of transition-metal and enamine catalysis. More recently, MacMillan and co-workers exploited a new aminocatalytic activation concept, based on radical intermediates, to solve the synthetic problems of the catalytic asymmetric aallylation, arylation, enolation, and vinylation of unmodified aldehydes. Herein, we report a new challenging strategy for the asymmetric intermolecular enamine-catalyzed formal a-alkylation of aldehydes. The novel approach is founded upon the use of a reagent 1 (Scheme 1), which, because of the presence

Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their α and β positions, little progress has been achieved in the enantioselective carbon–carbon bond formation γ to a carbonyl group. Here, we show that primary amine catalysis provides an efficient way to address this synthetic issue, promoting vinylogous nucleophilicity upon selective activation of unmodified cyclic α,β-unsaturated ketones. Specifically, we document the development of the unprecedented direct and vinylogous Michael addition of β-substituted cyclohexenone derivatives to nitroalkenes proceeding under dienamine catalysis. Besides enforcing high levels of diastereo- and enantioselectivity, chiral primary amine catalysts derived from natural cinchona alkaloids ensure complete γ-site selectivity: The resulting, highly functionalized vinylogous Michael adducts, having two stereocenters at the γ and δ positions, are synthesized with very high fidelity. Finally, we describe the extension of the dienamine catalysis-induced vinylogous nucleophilicity to the asymmetric γ-amination of cyclohexene carbaldehyde.

Light in Aminocatalysis: The Asymmetric Intermolecular α-Alkylation of Aldehydes†

Following the light: Photoredox catalysis along with aminocatalysis have proved to be the right combination for one of the most challenging asymmetric transformation in organic synthesis: the direct intermolecular alpha-alkylation of aldehydes.

Asymmetric organocatalytic cascade reactions with alpha-substituted alpha,beta-unsaturated aldehydes.

In the past decade, asymmetric aminocatalysis has become a fundamental synthetic strategy for the stereoselective construction of chiral molecules. The extraordinary pace of innovation and progress in aminocatalysis has been dictated mainly by the discovery of distinct catalytic activation modes which have enabled previously inaccessible transformations. To the same extent, the design of novel structural classes of organic catalysts has also ignited the field, enabling the activation of challenging types of carbonyl substrates. Whereas chiral secondary amines have proven invaluable for the asymmetric functionalization of aldehydes, primary amine catalysis has offered the unique possibility of participating in processes between sterically demanding partners. Therefore it overcomes the inherent difficulties of chiral secondary amines in generating congested covalent intermediates. Chiral primary amine based catalysts have been successfully used for the enamine activation of challenging substrates, such as a,a-disubstituted aldehydes and ketones. In 2005, Ishihara and Nakano additionally extended the potential of chiral primary amines to include the iminium ion activation of a-acyloxy-acroleins toward a stereoselective Diels–Alder process. However, the use of a,b-disubstituted unsaturated aldehydes still represents an elusive and fundamental target for asymmetric aminocatalysis. This is particularly true when considering that an alternative asymmetric metal-catalyzed strategy for the functionalization of this compound class is also lacking. Herein we show that the chiral primary amine catalyst 1 provides an efficient solution to this longstanding and sought after issue, activating a,b-disubstituted enals toward a welldefined iminium/enamine tandem sequence (Scheme 1). Specifically, we developed organocascade reactions which combine two intermolecular and stereoselective steps involving a Michael addition/amination pathway. The described olefin aryl-amination and thio-amination processes afford straightforward access to valuable precursors of a-amino acids which have two adjacent stereogenic centers, one of which is quaternary, with very high optical purity. Recently we and others, independently, 5] established chiral primary amine 1—directly derived from natural cinchona alkaloids—as an effective catalyst for ketone activation. We additionally demonstrated the versatility of 1, which can combine orthogonal catalysis modes (iminium and enamine activations) into one mechanism, thus promoting an intramolecular tandem reaction with a,b-unsaturated ketones. On this basis, we hypothesized whether the unique ability of catalyst 1 to engage in iminium ion formation with encumbered enones while enforcing high geometric control and facial discrimination, might be extended to the challenging class of a,b-disubstituted enals. Preliminary investigations revealed that the TFA salt of 1 was able to promote the Friedel–Crafts alkylation of 2-methyl-1H-indole with (E)-2methylpent-2-enal with high enantioselectivity, indicating that a selective p-facial shielding of the iminium intermediate is effective [Eq. (1)]. The poor diastereocontrol, however, clearly demonstrates that the enamine-based protonation step escapes catalyst control. Nevertheless, the ability of 1 to impart high stereocontrol in the iminium activation of a-branched enals prompted us toward a more intriguing target: the creation of multifunctional compounds, having two contiguous stereocenters, in a one-step process. In addition to the benefit of generating Scheme 1. Targeting a,b-disubstituted unsaturated aldehydes.