Dieter Enders

Control of four stereocentres in a triple cascade organocatalytic reaction

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centres continue to be important in both academic and industrial laboratories. In particular, catalytic asymmetric multi-component ‘domino’ reactions, used during total syntheses of natural products and synthetic building blocks, are highly desirable. These reactions avoid time-consuming and costly processes, including the purification of intermediates and steps involving the protection and deprotection of functional groups, and they are environmentally friendly and often proceed with excellent stereoselectivities. Therefore, the design of new catalytic and stereoselective cascade reactions is a continuing challenge at the forefront of synthetic chemistry. In addition, catalytic cascade reactions can be described as biomimetic, as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products. Here we report the development of an asymmetric organocatalytic triple cascade reaction for the synthesis of tetra-substituted cyclohexene carbaldehydes. This three-component domino reaction proceeds by way of a catalysed Michael/Michael/aldol condensation sequence affording the products with good to moderate yields (25–58 per cent). During this sequence, four stereogenic centres are formed with high diastereoselectivity and complete enantioselectivity. In addition, variation of the starting materials can be used to obtain diverse polyfunctional cyclohexene derivatives, which can be used as building blocks in organic synthesis.

Asymmetric Michael Additions to Nitroalkenes

The asymmetric conjugate addition of various carbon and heteroatom nucleophiles to nitroalkenes as a tool for the construction of highly functionalized synthetic building blocks is presented. Diastereoselective, substrate-controlled 1,4-additions are also included. Besides auxiliary controlled asymmetric Michael additions, external asymmetric versions employing enantiopure additives, addition-elimination processes with enantiopure leaving groups, and catalytic asymmetric syntheses are described. The use of the highly reactive nitroalkenes as Michael acceptors opens the way to synthetically very useful C−C and C−X bond-forming reactions and subsequent transformations as is demonstrated by various applications. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Organocatalytic Asymmetric Aza‐Michael Additions

The catalytic aza-Michael addition is an important reaction within synthetic organic chemistry, given the significance of the biologically and synthetically interesting products, such as beta-amino acids and beta-lactams. In the last decade organocatalysis emerged as a powerful tool in asymmetric synthesis and had a large impact on the development of asymmetric and catalytic conjugate additions of nitrogen nucleophiles to Michael acceptors. In this review a first summary of the recent rapid progress of asymmetric organocatalyzed aza-Michael reactions is presented.

Organocatalytic Asymmetric Domino Reactions: A Cascade Consisting of a Michael Addition and an Aldehyde α-Alkylation†

The development of asymmetric reactions using small organic molecules as catalysts, which are often nontoxic, environmentally friendly, and stable under aerobic and aqueous reaction conditions, has attracted much attention in recent years. Domino reactions provide an efficient means to construct complex molecules in a single process, while minimizing the number of manual operations and the generation of chemical waste and easing purification. Organocatalytic domino reactions can combine these advantages, and many interesting reactions have been developed during the past few years. The asymmetric secondary-amine-catalyzed Michael addition of aldehydes and ketones to nitroalkenes is a direct entry to g-nitroaldehydes and -ketones, which has been applied by our group in organocatalytic triple-cascade reactions. In 2004, List and Vignola reported the first catalytic asymmetric intramolecular a-alkylation of aldehydes. Asymmetric organocatalytic domino reactions consisting of a Michael addition and an alkylation have been recently developed to form enantioenriched and highly functionalized cyclopropane and cyclopentane derivatives. These reactions involve iminium–enamine activation and utilize a,b-unsaturated aldehydes and bromomalonates or bromo-b-ketoesters. We envisaged aldehydes A and the wiodonitroalkene B as potential substrates for a domino reaction made up of Michael addition and intramolecular alkylation, leading to either the cyclopentanecarbaldehydesC or the classical Michael-initiated ring-closure (MIRC) products D (Scheme 1). While the MIRC compounds D are not observed, the cyclic g-nitro-substituted aldehydes C are synthetically useful compounds, which may be converted into cyclic g-amino acids containing an all-carbon-substituted quaternary stereogenic center considered as a challenging task. g-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system of mammals, and many of its derivatives show biological activity. For example, Gabapentin, Pregabalin, and Vigabatrin have been commercialized as drugs to treat neurological disorders. Thus, the efficient stereoselective synthesis of gamino acids is of great interest, and many asymmeric auxiliary-based and metal-catalyzed methods have been developed. Recently, organocatalytic asymmetric syntheses of acyclic g-amino acids have been reported. Herein we report an organocatalytic domino Michael addition/alkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene (B) involving enamine–enamine activation. The process is highly stereoselective and leads to the g-nitroaldehydes C, which contain an all-carbonsubstituted quaternary stereogenic center. Furthermore, a novel cyclic g-amino acid was easily synthesized from the domino product in two steps. Diphenylprolinol silyl ether 1 shows good catalytic activity and gives excellent levels of asymmetric induction in the Michael addition of aldehydes to nitroalkenes. Therefore, we initially investigated its use as a catalyst in the reaction between propanal (4a) and nitroolefins bearing different leaving groups in the w position (OMs, Br, I; Ms= mesyl). In the case of the bromo and mesylate derivatives, the initial Michael addition occurred in good yield (70–80%); however, the desired cyclopentane product 6a was not formed. Using the w-iodonitroalkene 5 the domino reaction occurred and cyclopentane 6a was obtained in a low yield of 20% (entry 1, Table 1). Although the diastereoselectivity was only moderate (d.r. 70:30), the enantiomeric excess was excellent (trans : 94% ee, cis : 95% ee). Encouraged by this initial result, we undertook a detailed optimization study. Scheme 1. Secondary-amine-catalyzed domino reaction consisting of a Michael addition and an intramolecular alkylation proceeding by tandem enamine–enamine activation.

N-heterocyclic carbene catalyzed activation of esters: a new option for asymmetric domino reactions.

Esters-what else! A new strategy in NHC organocatalysis allows the α-, β- and γ-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities.

Exploiting the Electrophilic Properties of Indole Intermediates: New Options in Designing Asymmetric Reactions

Indole has been one of the most intensively investigated aromatic heterocycles. With the exponential growth of literature reports, especially in the two areas of organocatalysis and transition-metal catalysis, it might be challenging for organic chemists to adopt a holistic approach in designing reactions based on a substrate reactivity strategy, as compared to a functional-group activation approach. Moreover, while the nucleophilic Friedel–Crafts type reactivity of indoles has been extensively reviewed, the electrophilic iminium type reactivity of the corresponding intermediates of indoles is rarely discussed (Scheme 1). Herein we critically examine this untapped potential of the indole heterocycle, restricting it mainly to enantioselective annulations of 1Hindoles and new frontier developments in this field. In classical organic chemistry indole is classified as a pexcessive heterocycle which undergoes electrophilic substitutions, such as halogenations, Mannich and Michael reactions. This nucleophilic property is attributed to the imbedded enamine in the indole framework which provides a nucleophilic character at the C3 position (Scheme 1). This characteristic enamine type reactivity, or broadly termed in the literature as a Friedel–Crafts type reaction, has been intensively exploited recently, especially in organocatalysis and gold catalysis by designing novel diastereoand enantioselective reactions. In addition, there is an increasing tendency to explore the reactivity of the indole nitrogen atom in enantioselective cyclization reactions. All these reactions require the synthesis to be planned around the nucleophilic properties of indoles. While the above mentioned enamine type reactivity allowed for nucleophilicity on C3, an enamine attack produces an iminium intermediate which confers a momentary electrophilic site on C2. If this incipient C2 electrophile is trapped by an inbuilt nucleophile, indolines with new stereogenic centers are formed by dearomatization (Scheme 1). This strategy was first adopted in the synthesis of tricyclic frameworks, such as pyrroloindolines, by MacMillan et al. By employing organocatalysis with an imidazolidinone, an enantioselective Friedel–Crafts type reaction of a tryptamine derivative with an a,b-unsaturated aldehyde was achieved. Subsequently, an amino group on the 3-substituent acts as a nucleophile to trap the incipient iminium electrophile with excellent diastereoand enantioselectivies [Scheme 2, Eq. (1)]. Subsequently, Trost et al. reported an enantioselective palladium-catalyzed C3-allylation strategy to effect the in-situ trapping of the iminium cation through a prefunctionalized amino or hydroxy group on the C3 substituent with very good to excellent enantioselectivities [Scheme 2, Eq. (2)]. Barluenga et al. developed an enantioselective variant using tungsten Fischer carbenes containing a 8phenylmenthol chiral auxiliary to achieve cyclopenta annulation through a C C bond formation at the indole C2 [Scheme 2, Eq. (3)]. Davies et al. also reported a rhodiumcatalyzed enantioselective version of such a [3+2] indole annulation reaction [Scheme 2, Eq. (4)]. Reisman et al. have recently published a (R)-BINOLSnCl4 catalyzed indole annulation variant. Very recently, Gouverneur et al. demonstrated an enantioselective approach to such tricyclic indolines by using fluorine electrophiles to quarternarize indole C3 and trapping the C2 iminium species by a C3tethered nucleophile [Scheme 2, Eq. (5)]. Scheme 1. Enamine versus iminium type reactivity of indole.

Synthesis of diastereo- and enantiomerically pure α-amino-γ-oxo acid esters by reaction of acyliminoacetates with enamines derived from 6-membered ketones

Abstract A new efficient diastereo- and enantioselective synthesis of α-amino-γ-oxo acid esters by reaction of acyliminoacetates with enamines is described. By employing the concept of double stereodifferentiation, complete asymmetric induction (de ≧99.9%) for the C-C bond formation is obtained. Desulphurization of a sulphur containing product leads to the corresponding acyclic amino acid derivatives. The virtually complete anti -diastereo- and enantioselectivities are interpreted by a Diels-Alder like transition state.

Merging Organocatalysis and Gold Catalysis: Enantioselective Synthesis of Tetracyclic Indole Derivatives through a Sequential Double Friedel–Crafts Type Reaction

Annulated indoles, fused at the C2and C3-position, are chemically and biologically interesting as key structural motifs in many natural products and as pharmaceutically active substances. Furthermore, annulated, tetracyclic indoles containing a seven-membered ring, such as in 1 (Scheme 1), have shown anticancer activities on leukemia and colon cell lines, as well as antiproliferative activities through DNA intercalation. However, accessing such seven-membered-ring-containing polycycles is synthetically challenging owing to the preferential six-membered-ring formation in the cyclisation step. The reactivities of the indole C3and C2-position, as well as the indole nitrogen, provide many opportunities to access enantiopure, annulated indole derivatives. This can be achieved, for example, with an intramolecular Friedel–Crafts type reaction or an aza-Michael addition of the indolic nitrogen on a suitable acceptor. While reports on the enantioselective synthesis of polycyclic indoles using various catalytic activation modes, especially in the fields of organocatalysis and gold catalysis, are numerous, most of such synthetic strategies required substrates containing a prefunctionalised indole, either on the C3or the C2-position (Scheme 1). In view of limited precedence for the synthesis of annulated indoles from C3,C2-unsubstituted indoles 2, we hypothesised that chiral, polycyclic indoles could be accessed enantioselectively through a single-pot tandem operation. To the best of our knowledge, an enantioselective variant of such a transformation is not yet known. Moreover, we envisioned that the recent surge in utilising one-pot, multicatalytic, tandem reactions combining distinct organocatalytic and transition-metal cycles could be used as a viable strategy to obtain enantiopure, annulated indoles. This emerging area has also spurred some efforts in utilising indole as a key substrate in enantioselective, sequential reactions. In our synthetic planning, we were interested in combining both organocatalysis and gold catalysis, especially the latter to access nonconventional molecular frameworks through domino and rearrangement reactions. It is worth noting that the pioneering studies on gold catalysis by Echavarren et al. and Zhang et al., as well as very recent reports, allowed complex functionalisations of indole substrates containing an intramolecular tethered alkyne. We now wish to report an efficient and highly enantioselective one-pot, multicatalytic, C2/C3-annulation of indoles, giving rise to tetracyclic, seven-membered-ring-containing derivatives 1. The new protocol utilises the bifunctional ortho-alkyne-substituted nitrostyrenes 3 as substrates, allowing two sequential Friedel–Crafts type reactions. The nitroalkene moiety is activated through hydrogen-bonding organocatalysis, to incorporate the stereochemical information in the first Friedel–Crafts reaction,and the alkyne functionality provides access to gold catalysis and its alkynophilicity, to effect the second Friedel–Crafts/ring expansion cascade. [a] C. C. J. Loh, J. Badorrek, Prof. Dr. G. Raabe, Prof. Dr. D. Enders Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) Fax: (+49) 241-809-2127 E-mail : enders@rwth-aachen.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201102793. Scheme 1. Strategy comparison between current work and known methods.

Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenylmethyl)-indoles via a quadruple domino Friedel–Crafts-type/Michael/Michael/aldol condensation reaction

A new organocatalytic quadruple domino Friedel-Crafts-type/Michael/Michael/aldol condensation reaction has been developed. In this one-pot multi-component process acrolein, various indoles and nitroalkenes are used as starting materials. The diphenylprolinol TMS-ether catalysis provides a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivities (dr = 91 : 9 to >95 : 5, ee = 94 to >99%).

Asymmetric syntheses via metalated chiral hydrazones : Overall enantioselective α-alkylation of acyclic ketones

Abstract A general method is described, which allows the overall enantioselective α-alkylation of acyclic ketones in good overall yields (44–86%,, 4 steps) and enantioselectivities ranging routinely from > 94% ee up to virtually complete asymmetric induction (99.5% ee). The acyclic ketones are transformed to their corresponding “SAMP -hydrazones” ( S )- 2 by reaction with the enantiomerically pure hydrazine ( S )-l-amino-2-methoxymethyl-pyrrolidine [ SAMP , ( S )- 1 ], readily available from ( S )-proline. Metalation to form chiral azaenolates ( S )- 3 of E cc Z cn -configuration and then alkylation to product hydrazones 4 followed by hydrazone cleavage via acidic hydrolysis of methiodides 9 in a two phase system or ozonolysis, leads to α-substituted, enantiomerically enriched, acyclic ketones 5 . In special cases, where a phenyl group is directly attached to the newly generated center of chirality ( 5n , o , p ), only low enantiomeric excesses are observed. 17 Examples, including first applications in natural product synthesis (cf 5abe and h ) are summarized