Kim L. Jensen

The Diarylprolinol Silyl Ether System: A General Organocatalyst

The past few decades have witnessed some of the most important and revolutionizing advances in the field of asymmetric catalysis. Chemists no longer rely solely on natural sources as the starting point of their synthetic strategy, as in chiral pool or auxiliary-based synthesis. Instead, naturally occurring chiral motifs are selected and, either unchanged or after modification, used in substoichiometric amounts as chiral catalysts or ligands. In this way, they effectively transfer their chirality to prochiral substrates, thereby rapidly amplifying and diversifying the arsenal of useful chiral building blocks available to the synthetic community. A long-standing goal in the pursuit of new catalytic systems is the discovery of general catalysts. Ideally, such catalytic systems should be capable of promoting a large number of enantioselective reactions, via multiple modes of activation, with good substrate tolerance and high stereoselectivity. In this Account, we describe the synthetic usefulness, efficiency, selectivity, and robustness of the diarylprolinol silyl ether system as the catalyst in various reactions of aldehydes. Based on the diarylprolinol silyl ether system, several studies on enamine-mediated transformations of saturated aldehydes have resulted in the introduction of different functionalities into the α-position of aldehydes in a highly stereoselective manner. This HOMO-activation concept was later extended to include α,β-unsaturated aldehydes, which after condensation with the aminocatalyst generate a dienamine species capable of undergoing stereoselective Diels-Alder-type reactions. As a result, the effective functionalization of the γ-position of the aldehyde is achieved. Recently, the activation principle was further developed to include 2,4-dienals, which form trienamine intermediates upon condensation with the aminocatalyst. The trienamines effectively react with carbon-centered dienophiles, forming aldehyde products having up to four contiguous stereocenters. Because of the concerted nature of the reaction and the efficient catalyst shielding of the β-position, the stereoinduction is achieved at the remote ε-position of the original aldehyde. Complementary to the enamine-mediated activations, α,β-unsaturated aldehydes can also be efficiently functionalized by applying the diarylprolinol silyl ether system via conjugate addition through iminium-ion-mediated processes, that is, LUMO-activation. In such reactions, the aminocatalyst not only effectively shields one of the enantiotopic faces of the enal, it also ensures excellent chemoselectivity, affording 1,4-adducts as the only products. Several different carbon and heteroatom nucleophiles can be added in a highly stereoselective fashion. The ability of the catalysts to participate in various enamine- and iminium-ion-mediated processes also makes them ideal for the sequential addition of nucleophiles and electrophiles in a cascade manner. These cascade reactions thereby afford access to products having at least two stereocenters. In the years to come, the diarylprolinol silyl ether catalysts will probably maintain their prominent position as general catalysts in the field of aminocatalysis. Moreover, recent efforts devoted to mechanistic studies might soon engender further advances with this versatile catalytic system, particularly in the areas of activation modes, catalyst loadings, and industrial applications.

Achieving Molecular Complexity by Organocatalytic One‐Pot Strategies—A Fast Entry for Synthesis of Sphingoids, Amino Sugars, and Polyhydroxylated α‐Amino Acids

A major driving force for the intriguing developments in the field of total synthesis over the past century is the proficiency with which biological systems transform simple starting materials into complex molecular frameworks. Although necessary issues such as selectivity and synthetic efficiency to construct intricate biological structures can be addressed nowadays to a high degree, new aspects such as diversity and operational efficiency are becoming more important, because of the demand for making complex molecular architectures by effective and simple methodologies. In this respect, catalytic cascade reactions involving two or more selective transformations in one pot are emerging as an attractive tool to overcome the operational limitations associated with traditional “Stop-and-Go” synthesis. Organocatalysis has been shown to be a powerful tool for forming multiple stereocenters in a one-pot protocol by employing either a single catalyst or a combination of catalysts. We became interested in the 4,5-disubstituted isoxazoline-N-oxide motif, since it has the potential to serve as an important building block for diversity orientated total synthesis. Several approaches to isoxazoline-N-oxides are present in the literature either in a racemic fashion, starting from enantiomerically pure compounds, or by employing stoichiometric amounts of a chiral reagent. We envisioned that 4,5-disubstituted isoxazoline-N-oxides having up to three stereocenters could be obtained through a highly stereoselective one-pot procedure using simple and commercially available starting materials in combination with one or two organocatalysts (Scheme 1). Herein, we report a new enantioand diastereoselective one-pot protocol to access 4,5-disubstituted isoxazoline-Noxides, as well as demonstrate the use of this protocol for the de novo synthesis of b,g-dihydroxylated and b,g,d-trihydroxylated a-amino acid derivatives, phytosphingosines, and amino sugars. Recently, our group reported an efficient and highly enantioselective procedure for the formation of optically active a-bromo aldehydes. Encouraged by the size and leaving group ability of the bromine, we evaluated the possibility of an in situ entrapment, thereby, generating a new class of chiral 1,2-dielectrophiles to participate in multiple-bond-forming cascade sequences. To our delight, the chirality stored within this a-carbonyl sp-carbon center, formed by the direct a-bromination of aldehydes 1 by the electrophilic bromination reagent 2 catalyzed by the TMSprotected diaryl-prolinol 3, is fully exploited by a basepromoted face-selective Henry addition of nitroacetates and subsequent stereospecific O-alkylation, furnishing the enantioand diastereoselective synthesis of 4,5-disubstituted isoxazoline-N-oxides 4 in one pot (Table 1). The generality of this one-pot, three-step sequence was explored and the results are outlined in Table 1. It appears that b-branched aldehydes 1a–c provided the 4,5-disubstituted isoxazoline-Noxides 4a–c as single diastereomers in high yield (68–85%) and excellent enantioselectivity (94–96% ee ; Table 1, entries 1–3). Nonconjugated unsaturated systems 1d and linear unbranched substrates 1e–f were also well-tolerated, giving the isoxazoline-N-oxide products 4d–f in yields of 50– 90%, d.r. values ranging from 73:27 to greater than 20:1, and ee values of 92–94% (Table 1, entries 4–8). To expand the product diversity, the described three-step, one-pot protocol was extended to the formation of the corresponding Schiff base of the a-bromoaldehyde, which subsequent to an aza-Henry/alkylation cascade provided the Scheme 1. Synthesis of 4,5-disubstituted isoxazoline-N-oxides by using organocatalysis. TMS= trimethylsilyl.

Asymmetric One‐Pot Sequential Organo‐ and Gold Catalysis for the Enantioselective Synthesis of Dihydropyrrole Derivatives

A direct asymmetric one-pot synthesis of optically active 2,3-dihydropyrroles from propargylated malononitrile and N-Boc-protected (Boc = tert-butoxycarbonyl) imines is presented. The approach is based on a bifunctional organocatalytic Mannich-type reaction and a subsequent gold-catalyzed alkyne hydroamination and isomerization. The compatibility of both catalytic systems is presented and the overall transformation results in good yields (up to 70 %) with high selectivities (endo/exo > 10:1) and enantioselectivities (up to 88 % ee). The absolute configuration of the final products is unambiguously established by X-ray analysis. To highlight the synthetic potential of the accessed heterocyclic compounds, their transformation into 1-pyrrolines, which represent direct precursors of pyrrolidines, is presented.

Target-directed organocatalysis: a direct asymmetric catalytic approach to chiral propargylic and allylic fluorides.

A simple, direct one-pot organocatalytic approach to the formation of optically active propargylic fluorides is presented. The approach is based on organocatalytic alpha-fluorination of aldehydes and trapping and homologation of the intermediate providing optically active propargylic fluorides in good yields and enantioselectivities up to 99% ee. The procedure takes place by addition of NFSI, in the presence of 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (as low as 0.25 mol %) as the catalyst, to aldehydes in combination with dimethyl 2-oxopropylphosphonate and 4-acetamidobenzenesulfonyl azide. The scope of the reaction is demonstrated by the formation of a number of optically active propargylic fluorides. It is also shown that optically active fluoro-containing triazoles can be obtained in one-pot procedures from aldehydes using click-chemistry. Furthermore, important coupling and multicomponent reactions of the optically active propargylic fluorides can be performed without affecting the enantiomeric excess. The direct one-pot formation of optically active allylic fluorides from aldehydes is also demonstrated. Finally, the mechanisms for both the formation of the propargylic and allylic fluorides are outlined.

Synthesis of 1,2,4-triazolines: base-catalyzed hydrazination/cyclization cascade of α-isocyano esters and amides.

A convenient, efficient synthesis of 1,2,4-triazolines from α-isocyano esters/amides and azodicarboxylates is presented. The developed reaction cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing the triazolines in good to excellent yields (75-99%). Phosphine-catalyzed and preliminary asymmetric phase-transfer catalysis approaches have also been investigated.

Enantioselective One-Pot Synthesis of α-Amino Esters by a Phosphine-Catalyzed [3+2]-Cycloaddition Reaction

Phosphine-catalyzed [3+2]-cycloaddition reactions of electron-deficient allenes and alkynes with α,β-unsaturated carbonyl compounds can give access to important highly functionalized cyclopentenes.1 The seminal example of such a transformation was first reported by Lu et al. in 1995,2 and its asymmetric version in 1997 by the group of Zhang.3 However, it took another ten years before the potential of this annulation strategy using chiral phosphine catalysts was studied more intensively.4 The last decade has witnessed considerable progress in the development of suitable new chiral phosphine catalysts and their application in asymmetric [3+2]-cycloaddition reactions.5

Organocatalytic iminium ion/carbene reaction cascade for the formation of optically active 2,4-disubstituted cyclopentenones.

An organocatalytic iminium ion/N-heterocyclic carbene (NHC) cascade reaction between β-keto phenyltetrazolesulfones and α,β-unsaturated aldehydes, providing direct access to optically active 2,4-disubstituted cyclopent-2-enones, has been developed. The products are isolated in good yields with high enantioselectivities.

An Asymmetric Organocatalytic One‐Pot Strategy to Octahydroacridines

A major focus of organocatalysis has been the development of domino, cascade, and one-pot reactions. These classes of reactions enable the construction of molecules with great structural complexity with a minimum of manual operations, thereby saving time, effort, and production cost. Moreover, given the current focus on the development of more environmental-friendly procedures, these reactions, with their fewer purification steps, are useful alternatives to the classical stepwise approaches. Recently, the aza-Diels–Alder reaction between an N-aryl imine and an olefin moiety (the Povarov reaction) has attracted considerable attention, 5] as this reaction provides a simple route to a variety of nitrogen-containing polycyclic structures. In general, N heterocycles are of broad interest due to their vast abundance in natural and pharmaceutical compounds, and for instance tetrahydroquinolines have shown biological activity in numerous examples. However, though they possess a tetrahydroquinoline core structure, suggesting potentially interesting biological properties, the class of octahydroacridines remains virtually unexplored due to their limited availability. This type of compounds may be accessed through an intramolecular Povarov reaction, in which an e,z-unsaturated aldehyde upon condensation with an aryl amine, subsequently undergoes a formal cycloaddition and re-aromatization, affording the final product. However, access to optically active octahydroacridines has so far exclusively been based on a chiral pool approach and, furthermore, limited diastereomeric control is often observed. To the best of our knowledge, no catalytic asymmetric approaches to these interesting N-heterocyclic structures have been described to date. We imagined a route (Scheme 1), in which the addition of malononitrile derivatives to an a,b-unsaturated aldehyde employing aminocatalysis would furnish a suitable intermediate, which could be trapped in a following condensation/ cyclization cascade by an aniline derivative. Optimally, the stereocenter of the initial addition step would direct the subsequent cycloaddition, hereby controlling the formation of the optically active octahydroacridines with high diastereoselectivity. Herein, we describe a protocol for the preparation of a series of octahydroacridines having four stereocenters with excellent enantioand diastereomeric control. A rationale for the stereochemical outcome of the reaction is proposed, and further derivatizations of the products are demonstrated, such as the selective hydrolysis of one of the nitrile functionalities, leading to octahydroacridines with five stereocenters. In order to reach an efficient one-pot protocol, the initial organocatalytic addition step was first investigated. At the outset, slightly modified conditions to those previously reported were applied. Accordingly, with malononitrile 2a, 2 equiv of hex-2-enal (1a), and 10 mol% of (S)-2-[bis(3,5bistrifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (3) as the catalyst in CH2Cl2, full and clean conversion to the desired Michael addition intermediate was observed. Consequently, the anticipated condensation/Povarov cascade was attempted, and, gratifyingly, the addition of 1.5 equiv of 4-nitroaniline (4a) and 2 equiv of trifluoroacetic acid (TFA) to the diluted reaction mixture at 30 8C gave clean conversion to the proposed product with excellent diastereomeric control. With these conditions in hand, the scope of the reaction was examined by varying the a,b-unsaturated aldehyde 1, malononitrile 2, and aniline 4 (Table 1). The developed reaction concept showed great tolerance towards a variety of aliphatic a,b-unsaturated aldehydes 1. Saturated and unsaturated side chains of different length were successfully applied (Table 1, entries 1–5, 18) and, furthermore, benzyl ether and homobenzyl functionalities were tolerated (entries 6 and 7). Generally, high yields (59 to 93 %), taking into account the multiple reaction steps being involved, were observed with excellent stereocontrol (89 to 99% ee and > 20:1 d.r. in all examples). Interestingly, no Scheme 1. Synthetic outline for the formation of octahydroacridines. TMS= trimethylsilyl.

Asymmetric synthesis of γ-nitroesters by an organocatalytic one-pot strategy.

An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of α,β-unsaturated aldehydes is presented. The procedure is based on merging the enantioselective organocatalytic nitroalkane addition with an N-bromosuccinimide-based oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.

On the Mechanism of the Organocatalytic Asymmetric Epoxidation of α,β‐Unsaturated Aldehydes

Mechanistic studies on the organocatalytic epoxidation of α,β-unsaturated aldehydes explore the autoinductive behavior of the reaction and establish that the hydrate/peroxyhydrate of the product is acting as a phase-transfer catalyst. Based on these studies, an improved methodology that provides high selectivities and decreased catalyst loading, through the addition of chloral hydrate, is developed.