Achieving Molecular Complexity via Stereoselective Multiple Domino

Article Cite This: Acc. Chem. Res. 2017, 50, 2809-2821

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Achieving Molecular Complexity via Stereoselective Multiple Domino Reactions Promoted by a Secondary Amine Organocatalyst Pankaj Chauhan, Suruchi Mahajan, and Dieter Enders* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany CONSPECTUS: In the last two decades, organocatalysis has emerged as an intensively investigated and rapidly growing area of research facilitating many known and many new transformations to provide efficient novel entries to complex molecules of high stereochemical purity. The organocatalysts have not only shown their efficiency for catalyzing the reactions in which one bond is formed, but they have also been effectively exploited in various versions of one-pot reactions. Domino reactions are one of the most important classes of one-pot reactions, where the target structure can be obtained in one pot without changing any reaction conditions while each reaction occurs as a consequence of the intermediates generated in previous steps. Owing to the synthetic importance and operational advantages associated with the use of organocatalysts and the development of domino reactions, various asymmetric transformations leading to a complex structure of choice have been explored. The early era of organocatalysis exhibits a limited growth in the development of asymmetric domino reactions with special emphasis on two reactions occurring one after the other. In 2006, our group made a step forward to develop more complex domino reactions catalyzed by a secondary amine organocatalyst, wherein three reactions take place in one pot to provide cyclohexene carbaldehydes bearing four stereogenic centers with excellent stereocontrol. This triggered our interest to develop new organocatalytic domino sequences, especially for multiple domino reactions. After our seminal contribution, domino reactions catalyzed by secondary amine organocatalysts not only became more popular, but they also could be catalyzed by other classes of organocatalysts, such as bifunctional hydrogen bonding catalysts, chiral Brønsted acids, and N-heterocyclic carbenes. The mode of activation in this triple domino reaction relied on the sequential generation of enamine and iminium intermediates using a proline-based chiral secondary amine organocatalyst. By employing this strategy, we have developed several triple domino reactions leading to the formation of carbo- and heterocyclic structures bearing multiple stereogenic centers with excellent levels of stereoselectivities. The applications of the secondary amine organocatalysts have been further extended to more complex quadruple domino sequences. Moreover, these multiple domino sequences have been combined successfully with other transformations in one pot to create densely functionalized polycyclic compounds. This Account gives an overview of our research in the area of organocatalytic asymmetric multiple domino reactions with special emphasis on the secondary amine catalyzed triple and quadruple domino reactions via a sequential generation of enamine and iminium intermediates. The multiple cascade reactions assisted by di- and tri-iminium and -enamine species as well as other types of organocatalysts have been excluded from the scope of this Account.

1. INTRODUCTION Enzyme catalyzed transformations have always motivated chemists to develop chemo-, regio-, and stereoselective syntheses of complex molecules by mimicking nature’s enzyme machinery under mild conditions. One of these types of enzyme mimics are small organic molecule catalysts, that is, organocatalysts.1 A major realm of organocatalysts consists of amino acids, alkaloids, and their derivatives, and even enantiopure synthetic organic molecules have also been identified as efficient organocatalysts. The use of small organic molecules as catalysts has a long history of about two centuries;2 however, organocatalysis as a field came into existence at the turn of the millennium. Since then, the field of organocatalysis has reached an extraordinary level with the development of new catalysts with novel activation modes. Several classes of small organic molecules have been identified © 2017 American Chemical Society

and developed to facilitate the new transformations ranging from simple carbon−carbon and carbon−heteroatom bond formations to more complex one-pot transformations3 including domino sequences,4 sequential and synergistic catalysis with other types of catalysts such as transition metals5 and photoredox catalysts.6 At the same time, the development of sustainable chemical transformations has become one of the major goals of synthesis chemists working in academia and industry. As a result, chemists started channeling their efforts to innovate chemical processes by developing new catalysts with high efficiency and recyclability, applying efficient energy sources, and by avoiding purification steps in multiple step synthesis. The major problem Received: August 18, 2017 Published: November 10, 2017 2809

DOI: 10.1021/acs.accounts.7b00406 Acc. Chem. Res. 2017, 50, 2809−2821

Article

Accounts of Chemical Research Scheme 1. Concept of Iminium−Enamine Activation and Origin of Stereoselectivity

Scheme 2. Secondary Amine-Catalyzed Asymmetric Robinson Annulation and Related Domino Michael/Aldol Condensation

associated with the traditional stop and go synthesis includes the cumbersome, time-consuming, and expensive isolation of intermediates. Increasing environmental concern led to the enforcement of new criteria of atom-, redox-, step-, and poteconomy, as well as protecting group free synthesis. Many variants of one-pot reactions including domino and cascade reactions and multicomponent consecutive reaction sequences can fulfill these criteria. One of the most interesting and efficient types of one-pot transformations is the domino reaction. The best definition of a domino reaction is given by Tietze, “a domino reaction is a process involving two or more consecutive reactions in which subsequent reactions result as a consequence of the functionality formed by bond formation or fragmentation in the previous step.”7 The greatest advantage of domino reactions over classical synthesis and other one-pot variants is that two or more reactions are carried out in a single operation under the same reaction conditions. The field of organocatalysis has laid a strong foundation for the development of new asymmetric domino sequences. These domino sequences provide complex structures by controlling the formation of several stereogenic centers and lead to the

formation of key intermediates for natural product synthesis by reducing the reaction time, effort, production costs, and energy.

2. BACKGROUND The year 2000 witnessed the renaissance of organocatalysis, when the groups of List8 and MacMillan9 independently and simultaneously used the concept of HOMO raising via enamines 3 of aldehydes and LUMO lowering via iminium ions 2 of enals 1 in chiral secondary amine-catalyzed organic transformations, respectively (Scheme 1). Undoubtedly, aminocatalysis via enamine and iminium intermediates has led the field of organocatalysis in the construction of new and interesting enantiopure scaffolds. The development of new domino reactions by combining iminium−enamine approaches remains at the forefront of asymmetric organocatalysis. The capacity of the amino catalysts to generate iminium ion and enamine intermediates makes them ideal for catalyzing asymmetric domino reactions to afford α,β-disubstituted carbonyl compounds 4. Excellent levels of enantio- and diastereoselectivity in the domino reactions catalyzed by a secondary amine bearing a bulky group are attributed to the steric hindrance provided by the side-chain of the catalyst to the 2810


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Accounts of Chemical Research incoming nucleophile and electrophile in the case of iminium and enamine intermediates, respectively. The very first example of such an organocatalytic domino reaction where the combination of iminium and enamine species is involved came from Barbas’s group in the year 2000.10b The authors described an L-proline-catalyzed asymmetric Michael addition/aldol condensation reaction, that is, a Robinson annulation reaction between the diketone 5 and methyl vinyl ketone (6) to provide the Wieland−Miescher ketone (7) in 49% yield and 76% ee (Scheme 2). This domino sequence is started by iminium ion formation from L-proline C1 and methyl vinyl ketone, which undergoes first a Michael addition followed by an intramolecular aldol reaction assisted by the corresponding enamine intermediate. A related domino Michael/aldol reaction of the β-ketoesters 8 with the α,βunsaturated ketones 9 catalyzed by imidazolidine catalyst C-2 was developed by Jørgensen et al. in 2004.11 This approach leads to the construction of cyclohexanones 10 bearing up to four stereocenters. A year later, three independent reports were published simultaneously from the research groups of List,12 MacMillan13 and Jørgensen14 on organocatalytic domino reactions involving iminium−enamine activation modes to generate two vicinal stereocenters. There have also been some other reports where the domino sequence was initiated by the enamine intermediate. In this regard, the first example came from the Barbas group, which reported the self-aldolization of acetaldehyde to (+)-5-hydroxy(2E)-hexenal in 2002.15 Soon after that, the same group reported the proline-catalyzed trimerization of simple aldehydes 11 via two consecutive aldol reactions mediated by enamine intermediates to afford tetrahydropyran structures (Scheme 3).16

Scheme 4. Triple Domino Michael/Michael/Aldol Condensation Reaction

component Michael/Michael/aldol condensation sequence between aliphatic aldehydes 11, nitroalkenes 13, and α,βunsaturated aldehydes 1. Of special note is the atom economy of the triple cascade and that water is the only side product. The enantiomers of the carbaldehydes 14 could be obtained by employing the enantiomer of the catalyst ent-C-3. This method is quite general in terms of substrate scope of the aliphatic aldehyde 11. The best results were obtained with the more reactive aryl substituted nitroalkenes 13 and enals 1, whereas alkyl substituted substrates provided lower yields. Furthermore, acrolein (R3 = H) was tolerated in the triple domino sequence to give the trisubstituted cyclohexene carbaldehydes. The synthetic application of the cyclohexene carbaldehyde products generated through the triple domino reaction has been demonstrated by transforming them to the corresponding alcohols, carbocyclic acids and amino alcohols. By the judicious choice of aldehyde precursors for the triple domino reaction, various bicyclic and tricyclic carbaldehydes could be easily synthesized, which constitute the structural motifs of several biologically active natural products such as the hainanolides, and amphilectanes. Regarding the mechanism, it is postulated that in the first step the catalyst C-3 activates the aliphatic aldehyde by enamine formation, which then selectively adds conjugatively to the nitroalkene (Scheme 5). Subsequent hydrolysis releases Michael adduct 15 and the catalyst, which then forms the

Scheme 3. L-Proline-Catalyzed Asymmetric Synthesis of Tetrahydropyrans

Scheme 5. Proposed Mechanism of Triple Domino Michael/ Michael/Aldol Condensation Reaction

3. TRIPLE DOMINO REACTIONS 3.1. Triple Domino Reactions Initiated by an Enamine Intermediate

In the first few years, the flourishing field of organocatalysis showed limited growth in the development of asymmetric domino reactions. Only domino transformations involving two bond formation reactions were reported. In 2006, our group came up with the idea of multiple domino reactions and developed the first asymmetric organocatalytic triple domino reaction to construct four consecutive stereogenic centers (Scheme 4).17 This asymmetric organocatalytic triple cascade reaction employed a highly effective secondary amine organocatalyst C-3, which was originally introduced to organocatalysis in 2005 by Jørgensen’s18 and Hayashi’s19 groups independently. The domino process leads to the formation of cyclohexene carbaldehydes 14 bearing four vicinal stereocenters in an exceptional level of asymmetric induction via the three2811


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Accounts of Chemical Research Scheme 6. One-Pot Triple Domino/Diels−Alder Sequence

iminium ion species with α,β-unsaturated aldehyde 1 to facilitate a nitro-Michael addition of the initially formed nitroalkane product 15 to furnish enamine intermediate 16. In the last step, an intramolecular aldol condensation occurs via iminium ion 17, which upon hydrolysis leads to the desired cyclohexene product 14 and returns the catalyst for further cycles. This mechanism was supported by ESI-MS measurements and DFT calculations.20 In continuation of our efforts to construct complex structures, a one-pot triple domino/Diels−Alder sequence was developed (Scheme 6).21 The initial triple domino Michael/Michael/aldol condensation reaction between aldehydes 18, nitroalkenes 13, and enals 1 was catalyzed by C-3 to afford the cyclohexane carbaldehydes 19 followed by the Lewis acid mediated Diels−Alder reaction to directly access the highly diastereomerically enriched and enantiopure polyfunctionalized tricyclic frameworks via five new C−C bond formations with control of eight stereocenters. This organocatalytic triple cascade/Diels−Alder sequence leads to the formation of decahydroacenaphthylenes 20 and decahydrophenalenes 21, depending on the length of the enal fragment, which are characteristic structural units of diterpenoid natural products. The diastereo-divergence between the decahydroacenaphthylene 20 and the decahydrophenalene 21 products could be explained by drawing different possible transition states (Figure 1). When n = 0, the diene moiety approaches suitably from below the enal face in an “endo” fashion (TS-1) to avoid the possible steric interaction with the phenyl group. Whereas in

the case of a longer side chain when n = 1, the approach of the diene from both beneath and above the enal face is possible (TS-3 to TS-6). However, NOE analysis of the products revealed that the diene approached the dienophile from the top. Out of the two “top face” approaches of the diene, the transfused endo-configuration (TS-5) is preferred as it minimizes steric interactions with the phenyl substituents and the nitro group. Employing the organocatalytic triple domino strategy in combination with a base mediated intramolecular sulfa-Michael addition, highly substituted cis-configured thiadecalins 24 and the corresponding hexahydro-benzothiophene core (n = 0) could also be prepared in two steps (Scheme 7).22 This efficient one-pot asymmetric synthesis requires diphenylprolinol TMSether C-3 as a catalyst, thioester containing aldehyde 22, nitroalkenes 13, and enals 1 as substrates for the initial construction of the cyclohexene carbaldehydes 23, and then potassium carbonate to furnish the intramolecular sulfa-Michel addition to generate six consecutive stereocenters with virtually complete enantioselectivity. Due to their significant biological activities and structural complexity, the synthesis of highly functionalized tricyclic chromanes bearing multiple stereogenic centers is of great importance in organic synthesis and medicinal chemistry. Based on our interest in asymmetric synthesis to develop novel organocatalytic triple domino sequences, we have recently disclosed a stereoselective synthesis of highly functionalized tricyclic chromane scaffolds (Scheme 8).23 The protocol utilized the secondary amine catalyst C-3 to promote the domino Michael/Michael/aldol condensation reaction between aliphatic aldehydes 11, nitrochromenes 25 and α,β-unsaturated aldehydes 1. The salient features of this transformation include the efficient synthesis of tricyclic chromanes 26 bearing four contiguous stereogenic centers including a tetrasubstituted carbon for a wide substrate scope, with excellent stereoselectivities, and a successful scale-up reaction. 3.2. Triple Domino Reactions Initiated by an Iminium Ion Intermediate

Our group has also demonstrated that the generation of an iminium species could initiate a triple domino sequence. In this regard, an organocatalytic three component triple domino reaction between various 3-vinylindoles 27 and two molecules of α,β-unsaturated aromatic aldehydes 1 has been developed to provide efficient entry to fused tetracyclic pyridocarbazole derivatives 28 (Scheme 9).24 This secondary amine (C-3) catalyzed domino transformation involves a Diels−Alder/azaMichael/aldol condensation sequence to generate six stereo-

Figure 1. Possible transition states for the intramolecular Diels−Alder reaction. 2812


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Accounts of Chemical Research Scheme 7. Two Step Triple Domino/Sulfa-Michael Addition

Scheme 8. Stereoselective Synthesis of Highly Functionalized Tricyclic Chromanes via a Triple Domino Reaction

Scheme 10. Proposed Mechanism for Diels−Alder/AzaMichael/Aldol Condensation Reaction

Scheme 9. Triple Domino Diels−Alder/Aza-Michael/Aldol Condensation Reaction

iminium species 31, which in turn provides the fused tetracyclic pyrido-carbazole products 28 upon hydrolysis. 3.3. Triple Domino Reactions Initiated by Enolate Formation

A triple domino reaction has been developed, in which the secondary amine catalyst is not only involved in the generation of an iminium or enamine species but also acts as a base to generate an enolate intermediate. Employing the organocatalyst C-3, a highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes, 34, bearing a quaternary oxindole moiety via a triple domino Michael reaction followed by a Wittig olefination in one pot has been reported (Scheme 11).25 Starting from equimolar amounts of simple substrates, viz., oxindoles 32, conjugated dienes 33, and α,β-unsaturated aldehydes 1, high molecular complexity could be achieved via the formation of three new C−C bonds and six stereocenters, including a quaternary one. The exact mechanism of this domino sequence is not known; however it was proposed that catalyst C-3 not only enables the formation of enamine and iminium intermediate but also facilitates the initial Michael addition of oxindole 32 to (E,E)-5nitro-2,4-pentadienoic acid ethyl ester (33) by acting as a Brønsted base to generate enolate 35 as a tight ion pair with the protonated C-3 (Scheme 12). The initially generated Michael adduct 36 could also be observed by mass spectrometry. It was then assumed that the intermediate Michael adduct 36

genic centers via the formation of three C−C bonds, one CC bond, and one C−N bond with an excellent level of diastereoand enantioselectivities. Most of the α,β-unsaturated aromatic aldehydes resulted in good domino product yields; however a heteroaryl (i.e., 2-furanyl) substituted α,β-unsaturated aldehyde gave only a low yield of 14%. The triple domino reaction is proposed to start with the asymmetric Diels−Alder reaction of the electron-rich 3vinylindole dienes 27 and the dienophile enal 1, where the latter is activated via the formation of an iminium ion with the catalyst (Scheme 10). This stereoselective cycloaddition results in the formation of a tetrahydrocarbazole intermediate 29, which then undergoes an aza-Michael addition to another molecule of α,β-unsaturated aldehyde activated through the generation of a second iminium species. The aza-Michael addition delivers the enamine intermediate 30, which is well suited for an intramolecular aldol condensation to furnish an 2813


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Accounts of Chemical Research Scheme 11. Triple Domino Michael Reaction

>96% diastereomeric excess after purification of the products through column chromatography.

Scheme 12. Proposed Mechanism of the Triple Michael Domino Reaction

Scheme 13. Domino Michael/Henry Condensation/ Michael/Aldol Condensation Reaction

The proposed catalytic cycle for this quadruple domino sequence was supported by detection of various intermediates (41−44) through ESI-MS measurements and control experiments that demonstrate the involvement of C-3 in all domino steps (Scheme 14). It was proposed that the reaction is initiated through the enamine formation from acetaldehyde (39) and the amine catalyst C-3. The enamine intermediate undergoes a Michael addition to nitroalkene 13 to afford nitroalkane 45. The latter reacts with another molecule of acetaldehyde activated through the formation of an iminium species, to furnish nitroalkene 46 via a Henry reaction followed by dehydration. Nitroalkene 46 then undergoes a Michael addition of an enamine, generated from a third acetaldehyde molecule and the catalyst, to afford dialdehyde 47, which upon intramolecular aldol condensation through an enamine intermediate and subsequent hydrolysis affords the desired cyclohexene products 40 with the liberation of the catalyst for the next cycle. A two component organocatalytic branched quadruple domino sequence involving a Michael acceptor and two equivalents of an aldehyde led to the formation of polyfunctionalized cyclohexene derivatives bearing four contiguous stereogenic centers (Scheme 15). This branched domino sequence involves a Michael addition with a parallel oxidation, a second Michael addition, and a final aldol condensation.29 With enantiomers of the diphenylprolinol TMS-ether catalyst C-3 and ent-C-3 and IBX as an oxidant, the reaction of dihydrocinnamaldehyde (48) with the various βnitroalkenes 13 afforded both enantiomers of the cyclohexene products 49 in excellent stereoselectivities. The research group of Rueping was also able to achieve the synthesis of a similar series of cyclohexene carbaldehydes 49 via a quadruple cascade reaction consisting of a hydrogenation/Michael/Michael/aldol condensation cascade sequence between enals and β-nitroalkenes in the presence of Hantzsch’s ester as a reducing agent.30

undergoes a second Michael addition immediately with enal 1, which in turn is activated through the formation of an iminium ion to provide an enamine intermediate 37. The latter then cyclizes by a third Michael reaction to form the polysubstituted cyclopentane, 38.

4. QUADRUPLE DOMINO REACTIONS 4.1. Quadruple Domino Reactions Initiated by an Enamine Intermediate

In 2010, in parallel with the groups of Hong26 and Gong,27 our group moved a step forward toward developing asymmetric organocatalytic quadruple domino reactions through the sequential generation of enamine and iminium intermediates.28 In a microwave (MW) assisted quadruple domino Michael/ Henry condensation/Michael/aldol condensation reaction employing acetaldehyde (39) and β-nitroalkenes 13 as substrates and secondary amine C-3 as organocatalyst, the trisubstituted cyclohexene carbaldehydes 40 could be efficiently synthesized in good domino yields, high enantioselectivities and low to moderate diastereoselectivities (Scheme 13). All products were obtained with an exceptionally high level of 2814


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Accounts of Chemical Research Scheme 14. Proposed Mechanism for Domino Michael/Henry Condensation/Michael/Aldol Condensation Reaction

Scheme 15. Branched Domino Michael/Oxidation/Michael/Aldol Condensation Sequence

cyclohexene product 49 with release of the catalyst for the next cycles.

Furthermore, the dihydrocinnamaldehyde could be successfully replaced with (E)-5-phenylpent-4-enal (50) to afford virtually diastereo- and enantiopure product 51. The scope of the branched cascade sequence was further extended for the stereoselective synthesis of spirooxindoles 53 by using α,βunsaturated oxindoles 52 as an acceptor instead of the βnitroalkenes. It was proposed that in the catalytic cycle, aldehyde 48 initially forms an enamine intermediate 54 with the catalyst, which then undergoes a Michael addition to nitroalkene 13 to form γ-nitro aldehyde 55 (Scheme 16). Concurrently, an iminium ion species 56 is generated by oxidation of the enamine 54. This iminium ion reacts with the Michael adduct 55 to generate another iminium intermediate 58 through the intramolecular aldol condensation of Michael adduct 57. Subsequent hydrolysis of iminium ion 58 provides the

4.2. Quadruple Domino Reactions Initiated by an Iminium Intermediate

In 2009, Gong and co-workers described a new organocatalytic four-component domino oxa-Michael/Michael/Michael/aldol condensation reaction between alcohols 59, two molecules of acrolein 60, and nitroalkenes 13 (Scheme 17).27 The domino sequence was proposed to occur through an iminium− enamine−iminium−enamine sequence to enable the consecutive formation of four new bonds with three adjacent stereocenters on highly functionalized trisubstituted cyclohexene carbaldehyde derivatives 61 with excellent stereoselectivities. 2815


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Accounts of Chemical Research

carbaldehydes 70 could be synthesized in good domino yields, and excellent diastereo- and enantioselectivities. An extension of the secondary amine catalyzed quadruple domino reactions has recently been reported using enol ethers 71 as one of the reaction partners to produce a new series of highly functionalized complex tricyclic ethers 73 (Scheme 22).34 The combination of the secondary amine ent-C-3 catalyzed oxa-Michael/Michael/Michael/aldol condensation reaction with the lanthanide complex catalyzed hetero-Diels− Alder reaction in one pot led to the formation of tricyclic polyethers 73 bearing six contiguous stereogenic centers via the formation of six new bonds. A series of tricyclic products could be obtained in acceptable yields with excellent stereoselectivities. The major limitations of this protocol include a higher catalyst loading of the metal complex and a slow reaction rate. In 2009, Hong and co-workers reported the first example of the asymmetric organocatalytic quadruple domino reaction of ((E)-2-nitrovinyl)phenol (74) with two different α,β-unsaturated aldehydes 1 using a secondary amine-acetic acid salt as an organocatalyst, C-3·AcOH (Scheme 23).26 The reaction involves the sequential generation of two iminium and two enamine intermediates to facilitate an oxa-Michael/Michael/ Michael/aldol condensation sequence to provide an efficient entry to tricyclic chromanes 75 with excellent stereoselectivities. Later on the groups of Li35 and Wang36 followed a similar organocatalytic quadruple strategy to afford tricyclic chromanes by using 2-hydroxy α,β-unsaturated ketones or 2hydroxyaryl-2-oxobut-3-enoates instead of nitrovinylphenol 74. Working with a similar strategy, a secondary amine catalyzed organocatalytic quadruple domino aza-Michael/Michael/Michael/aldol reaction sequence of indol-2-methylene malononitriles 76 with two molecules of aromatic enals 1 has been developed (Scheme 24).37 Due to the problem of tautomerization in the corresponding adduct 77 to the corresponding enol form 78, the aldehyde was trapped through a Wittig reaction in the same pot to afford the tetracyclic annulated indole derivatives 79 bearing six stereogenic centers in high diastereoand enantioselectivities with four newly formed C−C bonds and one C−N bond in one pot. The proposed reaction mechanism for this organocatalytic quadruple cascade synthesis of tetracyclic aldehydes includes initiation by an enantioselective aza-Michael addition of indole2-methylene malononitriles 76 to α,β-unsaturated aldehyde 1 under iminium activation, to afford Michael adduct 80 (Scheme 25). The corresponding enamine generated from 80 undergoes an intramolecular Michael addition to provide tricyclic malononitrile derivative 81, which can in turn act as nucleophile for a Michael addition to another molecule of

Scheme 16. Proposed Mechanism of the Branched Domino Michael/Oxidation/Michael/Aldol Condensation Sequence

Applying a similar approach, a new method for the asymmetric synthesis of cyclohexene carbaldehyde derivatives has been developed, where the quadruple domino sequence is initiated by a Michael-type-Friedel−Crafts reaction.31−34 The domino Michael-type-Friedel−Crafts/Michael/Michael/aldol condensation reaction between indoles 62, two molecules of acrolein (60), and β-nitroalkenes 13 catalyzed by diphenylprolinol TMS-ether C-3 led to the formation of 3-(cyclohexenylmethyl)-indoles 63 bearing three stereogenic centers in moderate to excellent yields and excellent stereoselectivities (Scheme 18).31 A drawback in the substrate scope was that an aliphatic nitroalkene did not provide the desired product. A closely related quadruple cascade sequence employing the aniline derivatives 64 instead of indoles as substrates also worked very well to afford the corresponding stereopure products 65 with virtually complete asymmetric induction (Scheme 19).32 The quadruple cascade employing benzylidenemalonodinitrile (66) instead of nitroalkene as an acceptor is also feasible, affording the adducts 67 with excellent stereoselectivities. When one molecule of cinnamaldehyde (1a) was used instead of a second equivalent of acrolein (60), the cyclohexene carbaldehydes 68 bearing four stereogenic centers could be synthesized with high chemo- and stereocontrol (Scheme 20). In a follow-up work, a quadruple domino sequence initiated by a vinylogous Friedel−Crafts reaction of 1,1-bis(aryl)alkenes 69 with acrolein (60) has been disclosed (Scheme 21).33 Under similar optimized conditions, a series of cyclohexene

Scheme 17. Domino Oxa-Michael/Michael/Michael/Aldol Condensation Reaction

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Scheme 18. Quadruple Domino Michael-type-Friedel−Crafts/Michael/Michael/Aldol Condensation Reaction of Indoles

Scheme 19. Quadruple Domino Michael-type-Friedel−Crafts/Michael/Michael/Aldol Condensation Reaction of Aniline Derivatives

Scheme 20. Quadruple Domino Michael-type-Friedel−Crafts/Michael/Michael/Aldol Condensation Reaction between Anilines, Nitroalkene, Acrolein, and Cinnamaldehyde

Scheme 21. Quadruple Domino Vinylogous Friedel−Crafts/Michael/Michael/Aldol Condensation Reaction

enal activated through iminium ion formation. The resulting intermediate 82 undergoes an intramolecular aldol reaction through the corresponding enamine intermediate to give tetracyclic aldehyde 77. The latter reacts in situ with the Wittig reagent to yield the final product 79. In the context of the development of more complex structures, a new asymmetric organocatalytic quadruple domino reaction using α-ketoamides 83 with two equivalents of α,βunsaturated aldehydes 1 has been developed.38 The process is catalyzed by the (S)-diphenylprolinol TMS-ether C-3 to furnish a series of tetra-aryl-substituted 2-azabicyclo[3.3.0]octadienone

derivatives 84 with excellent diastereoselectivities and very good enantioselectivities via an aza-Michael/aldol condensation/vinylogous Michael/aldol condensation sequence (Scheme 26). Interestingly, when α,β-unsaturated aryl aldehydes bearing strong electron-donating substituents such as the 2-methoxy, 3,4,5-tris(benzyloxy), and heteroaryl 3-[1(tert-butoxycarbonyl)-1H-indol-2-yl] groups were employed, the isomeric 3-azabicyclo[3.3.0]octadienone products 85 were obtained as single diastereomers, albeit with low to moderate enantioselectivities. We found that the biggest limitation in this domino sequence in terms of the substrate scope is that aryl 2817


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Scheme 22. One-Pot Quadruple Domino Oxa-Michael/Michael/Michael/Aldol Condensation/Hetero-Diels−Alder Reaction

Scheme 23. Domino Oxa-Michael/Michael/Michael/Aldol Condensation Sequence

Scheme 24. Quadruple Domino Aza-Michael/Michael/Michael/Aldol Reaction

substituted ketoamides and enals are required to provide good results. The quadruple domino sequence is initiated by the asymmetric aza-Michael addition of α-ketoamides 83 to the iminium ion generated from α,β-unsaturated aldehydes 1 and the catalyst (Scheme 27). The resulting aza-Michael adduct 86 then undergoes an intramolecular aldol condensation through an enamine intermediate to give lactam 87, which tautomerizes to 2-hydroxypyrroles 88. The latter reacts from the C5-position with a second molecule of enal 1 through iminium ion formation to achieve the vinylogous 1,4-addition. The corresponding intermediate 89 undergoes a subsequent intramolecular aldol condensation through an enamine intermediate to provide bicyclic products 84 with regeneration of the catalyst through hydrolysis. The formation of the isomeric products could be rationalized by the reactivity of the 2-hydroxypyrroles 88 at the C3-position rather than the C5position. The addition of 2-hydroxypyrrole 88 to the iminiumactivated α,β-unsaturated aldehyde provides intermediate 90,

Scheme 25. Proposed Catalytic Cycle for the Quadruple Domino Aza-Michael/Michael/Michael/Aldol Reaction

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Accounts of Chemical Research Scheme 26. Quadruple Domino Aza-Michael/Aldol Condensation/Vinylogous Michael/Aldol Condensation Reaction

that the development of asymmetric multiple domino sequences directed toward specific targets, such as natural products and pharmaceuticals, will make these one-pot processes even more valuable and practical. General rules of thumb for efficient secondary amine-catalyzed domino reactions are given in Scheme 28.

Scheme 27. Proposed Catalytic Cycle for the Quadruple Domino Aza-Michael/Aldol Condensation/Vinylogous Michael/Aldol Condensation Reactions

Scheme 28. Some Thumb Rules for Efficient Secondary Amine-Catalyzed Domino Reactions

which in turn undergoes an intramolecular aldol condensation via enamine formation to afford bicyclic compounds 85.

■

5. CONCLUSION This Account summarizes the recent research work from our group on the design, development, and applications of organocatalytic multiple domino reactions toward the construction of highly functionalized complex structures. A range of triple and quadruple domino reactions catalyzed by a secondary amine organocatalyst have been developed, which provide direct and efficient entry to carbocyclic and heterocyclic scaffolds bearing multiple stereogenic centers with an excellent level of stereocontrol. The salient features of these domino sequences include the use of easily available commercial catalysts and substrates and simple one-pot protocols providing very good domino yields and excellent stereoselectivities under mild reaction conditions. These organocatalytic domino reactions are even combined with other reactions in one-pot reactions to further attain some more diverse scaffolds with increasing molecular complexity. In spite of these exciting results there is still more room for further development of new multiple domino protocols for the asymmetric synthesis of biologically relevant molecular structures. The major limitations found in the development of multiple domino sequences include the limited number of substrate classes activated through the secondary amine catalysts, the lack of generality in the substrate scope, and the high catalyst loading. In future, efforts to design and develop more complex domino reactions leading to the selective products will be the major focus of our group. We envisage

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Dieter Enders: 0000-0001-6956-7222 Notes

The authors declare no competing financial interest. Biographies Pankaj Chauhan completed his Ph.D. under the supervision of Prof. Swapandeep Singh Chimni from Guru Nanak Dev University, India, in 2012. In April 2013, he started his postdoctoral research in the group of Prof. Dieter Enders at RWTH Aachen University, Germany. Currently, he is working as a subgroup leader in the same research group. His research interests include asymmetric synthesis, organocatalysis, photoredox catalysis, and domino reactions. Suruchi Mahajan completed her Ph.D. under the supervision of Prof. Rakesh Kumar Mahajan from the same university in 2013. Then she moved to Aachen and started her postdoctoral research in the research group of Prof. Dieter Enders at RWTH Aachen University, Germany. Her research interests include organocatalysis and asymmetric synthesis as well as the synthesis of new surfactants and their interactional studies with drugs. Dieter Enders studied chemistry at the Justus Liebig University Giessen and completed his doctoral degree under the supervision of 2819


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W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual Catalysis Strategies in Photochemical Synthesis. Chem. Rev. 2016, 116, 10035− 10074. (7) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131−163. (8) List, B.; Lerner, R. A.; Barbas, C. F., III Proline-Catalyzed Direct Asymmetric Aldol Reactions. J. Am. Chem. Soc. 2000, 122, 2395−2396. (9) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New Strategies for Organic Catalysis: The First Highly Enantioselective Organocatalytic Diels−Alder Reaction. J. Am. Chem. Soc. 2000, 122, 4243− 4244. (10) For seminal work, see: (a) Eder, U.; Sauer, G.; Wiechert, R. New Type of Asymmetric Cyclization to Optically Active Steroid CD Partial Structures. Angew. Chem., Int. Ed. Engl. 1971, 10, 496−497. (b) Bui, T.; Barbas, C. F., III A Proline-Catalyzed Asymmetric Robinson Annulation Reaction. Tetrahedron Lett. 2000, 41, 6951− 6954. (11) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Highly Enantio- and Diastereoselective Organocatalytic Asymmetric Domino Michael-Aldol Reaction of β-Ketoesters and α,β-Unsaturated Ketones. Angew. Chem., Int. Ed. 2004, 43, 1272−1277. (12) Yang, J. W.; Hechavarria Fonsecca, M. T.; List, B. Catalytic Asymmetric Reductive Michael Cyclization. J. Am. Chem. Soc. 2005, 127, 15036−15037. (13) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. Enantioselective Organo-Cascade Catalysis. J. Am. Chem. Soc. 2005, 127, 15051−15053. (14) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. Asymmetric Multicomponent Domino Reactions and Highly Enantioselective Conjugated Addition of Thiols to α,β-Unsaturated Aldehydes. J. Am. Chem. Soc. 2005, 127, 15710−15711. (15) Córdova, A.; Notz, W.; Barbas, C. F., III Proline-Catalyzed OneStep Asymmetric Synthesis of 5-Hydroxy-(2E)-hexenal from Acetaldehyde. J. Org. Chem. 2002, 67, 301−303. (16) Chowdari, N. S.; Ramachary, D. B.; Córdova, A.; Barbas, C. F., III Proline-Catalyzed Asymmetric Assembly Reactions: Enzyme-Like Assembly of Carbohydrates and Polyketides from three Aldehyde Substrates. Tetrahedron Lett. 2002, 43, 9591−9595. (17) (a) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Control of Four Stereocentres in a Triple Cascade Organocatalytic Reaction. Nature 2006, 441, 861−863. (b) Enders, D.; Hüttl, M. R. M.; Raabe, G.; Bats, J. W. Asymmetric Synthesis of Polyfunctionalized Mono-, Bi-, and Tricyclic Carbon Frameworks via Organocatalytic Domino Reactions. Adv. Synth. Catal. 2008, 350, 267−279. (18) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Enantioselective Organocatalyzed a Sulfenylation of Aldehydes. Angew. Chem., Int. Ed. 2005, 44, 794−797. (19) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael Reaction of Aldehydes and Nitroalkenes. Angew. Chem., Int. Ed. 2005, 44, 4212−4215. (20) (a) Alachraf, M. W.; Handayani, P. P.; Hüttl, M. R. M.; Grondal, C.; Enders, D.; Schrader, W. Electrospray Mass Spectrometry for Detailed Mechanistic Studies of a Complex Organocatalyzed Triple Cascade Reaction. Org. Biomol. Chem. 2011, 9, 1047−1053. (b) Shinisha, C. B.; Sunoj, R. B. Unraveling High Precision Stereocontrol in a Triple Cascade Organocatalytic Reaction. Org. Biomol. Chem. 2008, 6, 3921−3929. (21) Enders, D.; Hüttl, M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Organocatalytic One Pot Asymmetric Synthesis of Functionalized Tricyclic Carbon Frameworks from Triple Cascade/Diels-Alder Sequence. Angew. Chem., Int. Ed. 2007, 46, 467−469. (22) Enders, D.; Schmid, B.; Erdmann, N.; Raabe, G. Asymmetric Synthesis of Thiadecalines via an Organocatalytic Triple Cascade/ Sulfa-Michael Sequence. Synthesis 2010, 2010, 2271−2277. (23) Kumar, M.; Chauhan, P.; Valkonen, A.; Rissanen, K.; Enders, D. Asymmetric Synthesis of Functionalized Tricyclic Chromanes via an

Professor Dieter Seebach in 1974. After his postdoctoral research at Harvard University with Professor E. J. Corey, he returned to Giessen and obtained his habilitation in 1979. In 1980, he moved to the University of Bonn as an Associate Professor, and in 1985 he accepted a position as Professor of Organic Chemistry at the RWTH Aachen University, where he is a Senior Professor since 2014. His research interests are asymmetric synthesis, the synthesis of biologically active compounds, and organocatalysis.

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REFERENCES

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Accounts of Chemical Research Organocatalytic Triple Domino Reaction. Org. Lett. 2017, 19, 3025− 3028. (24) Enders, D.; Joie, C.; Deckers, K. Organocatalytic Asymmetric Synthesis of Tetracyclic Pyridocarbazole Derivatives by Using a DielsAlder/aza-Michael/Aldol Condensation Domino Reaction. Chem. Eur. J. 2013, 19, 10818−10821. (25) Zou, L.-H.; Philipps, A. R.; Raabe, G.; Enders, D. Asymmetric Synthesis of Fully Substituted Cyclopentane-Oxindoles via an Organocatalytic Triple Michael Domino Reaction. Chem. - Eur. J. 2015, 21, 1004−1008. (26) Kotame, P.; Hong, B.-C.; Liao, J.-H. Enantioselective Synthesis of the Tetrahydro-6H benzo[c]chromenes via Domino Michael−Aldol Condensation: Control of Five Stereocenters in a Quadruple-Cascade Organocatalytic Multi-Component Reaction. Tetrahedron Lett. 2009, 50, 704−707. (27) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-F.; Wei, M. H.; Yang, X.-L. Asymmetric Organocatalytic Four-Component Quadruple Domino Reaction Initiated by Oxa-Michael Addition of Alcohols to Acrolein. Chem. - Eur. J. 2009, 15, 6815−6818. (28) Enders, D.; Krü ll, R.; Bettray, W. Microwave-Assisted Organocatalytic Quadruple Domino Reactions of Acetaldehyde and Nitroalkenes. Synthesis 2010, 2010, 567−572. (29) Zeng, X.; Ni, Q.; Raabe, G.; Enders, D. A Branched Domino Reaction: Two Component Quadruple Organocatalytic Asymmetric Synthesis of Polyfunctionalized Cyclohexene Derivatives. Angew. Chem., Int. Ed. 2013, 52, 2977−2980. (30) Rueping, M.; Haack, K. L.; Ieawsuwan, W.; Sunden, H.; Blanco, M.; Schoepke, F. R. Nature-inspired Cascade Catalysis: Reaction Control through Substrate Concentration-double vs. Quadruple Domino Reactions. Chem. Commun. 2011, 47, 3828−3830. (31) Enders, D.; Wang, C.; Mukanova, M.; Greb, A. Organocatalytic Asymmetric Synthesis of Polyfunctionalized 3-(Cyclohexenylmethyl)indoles via a Quadruple Domino Friedel-Crafts-type/Michael/ Michael/Aldol Condensation Reaction. Chem. Commun. 2010, 46, 2447−2449. (32) Erdmann, N.; Philipps, A. R.; Atodiresei, I.; Enders, D. An Asymmetric Organocatalytic Quadruple Cascade Initiated by a FriedelCrafts-Type Reaction with Electron-Rich Arenes. Adv. Synth. Catal. 2013, 355, 847−852. (33) Philipps, A. R.; Fritze, L.; Erdmann, N.; Enders, D. An Asymmetric Organocatalytic Quadruple Domino Reaction Employing a Vinylogous Friedel-Crafts/Michael/Michael/Aldol Condensation Sequence. Synthesis 2015, 47, 2377−2384. (34) Dochain, S.; Vetica, F.; Puttreddy, R.; Rissanen, K.; Enders, D. Combining Organocatalysis and Lanthanide Catalysis: A Sequential One-Pot Quadruple Domino/Diels-Alder Asymmetric Synthesis of Functionalized Tricycles. Angew. Chem., Int. Ed. 2016, 55, 16153− 16155. (35) Liu, L.; Zhu, Y.; Huang, K.; Wang, B.; Chang, W.; Li, J. Asymmetric Organocatalytic Quadruple Cascade Reaction of 2Hydroxychalcone with Cinnamaldehyde for the Construction of Tetrahydro-6H-benzo[c]chromene Containing Five Stereocenters. Eur. J. Org. Chem. 2014, 2014, 4342−4350. (36) Geng, Z.-C.; Zhang, S.-Y.; Li, N.-K.; Chen, J.; Li, H.-Y.; Wang, X.-W.; Li, N. Organocatalytic Diversity-Oriented Asymmetric Synthesis of Tricyclic Chroman Derivatives. J. Org. Chem. 2014, 79, 10772−10785. (37) Enders, D.; Greb, A.; Deckers, K.; Selig, P.; Merkens, C. Quadruple Domino Organocatalysis: An Asymmetric Aza-Michael/ Michael/Michael/Aldol Reaction Sequence Leading to Tetracyclic Indole Structures with Six Stereocenters. Chem. - Eur. J. 2012, 18, 10226−10229. (38) Joie, C.; Deckers, K.; Raabe, G.; Enders, D. An Asymmetric Organocatalytic Quadruple Cascade to Tetraaryl-Substituted 2Azabicyclo[3.3.0]octadienones. Synthesis 2014, 46, 1539−1546.

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Achieving Molecular Complexity via Stereoselective Multiple Domino

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