Interplay between Organocatalysis and Multicomponent Reactions in

Chapter 4

Downloaded by DUKE UNIV on November 5, 2017 | http://pubs.acs.org Publication Date (Web): November 2, 2017 | doi: 10.1021/bk-2017-1258.ch004

Interplay between Organocatalysis and Multicomponent Reactions in Stereoselective Synthesis Daniel G. Rivera1,* and Márcio W. Paixão2 1Center

for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana, Cuba 2Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, 13565-905, Brazil *E-mail: [email protected]

Multicomponent reactions (MCRs) serve as powerful approaches for the synthesis of bioactive heterocyclic compounds and natural products. Owing to their high chemical efficiency, atom economy and diversity-generating character, these processes have been intensively exploited in drug discovery and chemical biology programs. As chiral ketones and aldehydes are key components in stereocontrolled MCRs, methods for the asymmetric functionalization of carbonyl compounds are relevant for the development of novel stereoselective multicomponent approaches. In the last decade, organocatalysis has been successful in the α-, β-, γand even ε-asymmetric functionalization of carbonyls, thus showing promise for its combination with MCRs in the pursuit of highly stereoselective cascade sequences. This chapter highlights a recent international endeavor that combines the diversity and complexity-generating character of MCRs with the high stereoselection of organocatalysis for the synthesis of enantiomerically pure compounds. The reaction sequences comprise the asymmetric aminocatalytic functionalization of α,β-unsaturated aldehydes followed by isocyanide-MCRs with such oxo-components as chiral inputs. Methods described herein provide a convergent and stereoselective

© 2017 American Chemical Society Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

way of producing natural product-like compounds such as hydroquinolines, chromenes, epoxy- and depsi-peptides.


Introduction Enantiomerically pure or enriched small organic molecules are key starting materials in organic synthesis. Chiral building blocks are in high demand in the total synthesis of complex natural products and in drug discovery and development, as well as in the production of pesticides, fragrances and advanced materials (1). Asymmetric organocatalysis is considered a cutting-edge tool for the synthesis of bioactive molecules and chiral building blocks, in most cases achieving similar success as metal-based asymmetric catalysis (2–6) Similarly, multicomponent reactions (MCRs) (7) serve as powerful approaches for the synthesis of bioactive heterocyclic compounds (8–10) and natural products (11). MCRs are procedures wherein more than two building blocks react in one pot to afford a structure including moieties from all reactants (7, 12). Among the MCRs, those employing isocyanides are generally considered as type II MCRs (13), as they involve a sequence of reversible mono- and bimolecular events that proceed sequentially until an irreversible step traps the final product, i.e., the exothermic oxidation of the CII of isocyanides to CIV. The divalent carbon atom of isocyanides shows a particular reactivity toward nucleophiles and electrophiles, a feature – that along with carbenes – renders isocyanides as exceptional chemical species. In general, MCRs are considered a subclass of domino reactions, as all transformations are performed in one pot under similar reaction conditions and in a time-resolved manner (14). Accordingly, several chemical bonds are formed with high chemical efficiency, thus allowing the generation of high levels of structural diversity and complexity. Such intrinsic characteristics of MCRs may be further improved by combination with pre- and post-MCR modifications, although most examples have been described for the latter approach (15, 16). In the past few years, various research groups have recognized the potential of combining the capacity of organocatalysis for generating enantiomerically enriched compounds with the synthetic power of MCRs in the diversification of such chiral pools (17–21). This strategy is conceptually different from both organocatalytic asymmetric MCRs (22–24) and organocatalytic multicomponent domino reactions (25, 26). In these latter approaches, the chiral small molecule directly catalyses the multicomponent process, while the first approache relies on the organocatalytic asymmetric functionalization of carbonyl compounds that are subsequently used in diastereoselective MCRs, either in one-pot protocols or not. As organocatalysis has proven great efficiency in the α-, β- (27–30), γ- and ε-asymmetric (31, 32) functionalization of ketones and aldehydes, its combination with the available repertoire of MCRs – incorporating such carbonyl components as chiral inputs – provides a manifold of synthetic possibilities. A recent review by Banfi et. al. (33) covered the literature reports up to 2014 on MCRs including enantioenriched components arising from both organocatalytic and biocatalytic approaches. This chapter highlights reports 50 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


from our own laboratories dealing with the design of approaches comprising the asymmetric aminocatalytic functionalization of α,β-unsaturated aldehydes followed by isocyanide-MCRs. We illustrate how this combined strategy enables the stereoselective synthesis of complex scaffolds, including natural product-like compounds such as epoxy-peptidomimetics, hydroquinolines, piperidines, chromenes and cyclic depsipeptides. As part of an international endeavor to honour the contribution of Prof. Ernest Eliel to Organic Chemistry, we hope not only to encourage further progress in the fields of MCRs and organocatalysis, but especially to advocate their combination as a powerful tool in the stereoselective synthesis of complex enantioenriched molecular scaffolds.

Results and Discussion Aminocatalytic Epoxidation of α,β-Unsaturated Aldehydes Followed by Passerini Three-Component Reaction Among the several organocatalytic approaches known for the asymmetric functionalization of carbonyl compounds, our initial effort focused on the development of an eco-friendly, one-pot aminocatalytic epoxidation α,β-unsaturated aldehydes followed by a Passerini three-component reaction (3CR) to furnish epoxy-peptidomimetics (34). For this, we implemented a modification of a protocol developed by Jørgensen’s group (35) for the synthesis of enantioenriched epoxy-aldehydes using a diarylprolinol silyl ether catalyst. As depicted in scheme 1, after a series of parallel experiments with varied organocatalysts, it was found that aryl-modified diarylprolinol silyl ether 2 is an effective catalyst for the epoxidation of a variety of α,β-unsaturated aldehydes in aqueous conditions. The Passerini-3CR is the condensation of an aldehyde or ketone, a carboxylic acid and an isocyanide to produce an α-acyloxy carboxamide skeleton (36). This type of scaffold is of frequent occurrence in natural products such as the depsipeptides, and in this case is combined with an epoxide functionality at the vicinal position. Importantly, the procedure could be implemented in one-pot by carrying out the initial organocatalytic step in the solvent mixture EtOH/H2O 3:1 (v/v) followed by addition of the carboxylic acid and the isocyanide. Scheme 1 illustrates just a selection of the epoxy-peptidomimetics obtained by this protocol, in which the substrate scope includes the use of aliphatic and aromatic conjugated aldehydes, as well as N-protected amino acids, aromatic and aliphatic carboxylic acids. In all cases, final compounds were obtained in good to excellent yields in a diastereoselectivity of about 3:1. However, the poor diastereoselection is due to the multicomponent step, as it was initially proven that the organocatalytic step rendered the epoxy-aldehydes in excellent enantio and diastereoselectivity. On the other hand, the Passerini-3CR turned out to be poorly diastereoselective, despite the fact that it was undertaken with a chiral aldehyde functionalized at α and β positions. Overall, this work comprised the first report of a one-pot organocatalytic multicomponent reaction sequence based on an asymmetric epoxidation reaction and a Passerini-3CR. 51 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 1. One-pot synthesis of epoxy-peptidomimetics by an eco-friendly aminocatalytic epoxidation of α,β-unsaturated aldehydes followed by the Passerini-3CR.

Aminocatalytic Conjugate Addition of 1,3-Cycloalkanediones to α,β-Unsaturated Aldehydes Followed by a Novel Isocyanide-MCR This second section describes the development of a highly stereoselective one-pot approach for the synthesis of complex molecular hybrids incorporating moieties such as hydroquinolines, chromenes, piperidines, peptides, lipids and glycosides. The strategy involved the implementation of an asymmetric organocatalytic conjugate addition of dicarbonyl compounds to α,β-unsaturated aldehydes, followed by an intramolecular isocyanide-based MCR including a chiral bifunctional intermediate, an amine and an isocyanide component. Owing to low diastereoselectivity of intermolecular isocyanide-based MCRs, we aimed at utilizing an intramolecular MCR, as these typically provide better stereocontrol as compared to their intermolecular versions (24, 33). Similarly, the chosen organocatalytic process should provide an enantiomerically enriched chiral intermediate bearing a pair of reactive functionalities suitable to exert stereocontrol during the intramolecular MCR. As shown in Scheme 2, we implemented an organocatalytic procedure developed independently by the groups of Rueping (37, 38) and Jørgensen (39) followed by a novel isocyanide-MCR including a chiral bifunctional substrate (40). The initial cascade process comprises the asymmetric conjugate addition of dimedone (5) to 2-pentenal (6) catalyzed by diarylprolinol silyl ether 7, followed by acetalization to cyclic hemiacetal 8. This intermediate fulfills the requisite of being a biologically relevant chiral substrate as well as having two functionalities suitable for the MCRs, i.e. an aldehyde and a conjugated enol (41). 52 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Scheme 2. One-pot organocatalytic conjugate addition/isocyanide-MCR sequence to 2-amido-hydroquinolin-6-ones. Since the multicomponent step did not work well in CH2Cl2, we sought to implement the whole sequence in one pot by addition of trifluoroethanol (TFE) after formation of organocatalytic product 8. In this way, the second step is carry out in the solvent mixture CH2Cl2/TFE (1:1, v/v) leading to the 2-amido-hydroquinolin-6-ones 10a-j. It must be noticed that the presence of 10 mol% of organocatalyst 7 (a secondary amine) did not interfere in the isocyanide-MCR, as no product including this fragment was detected. A key feature of this approach is the different stereochemical outcome derived from variation of primary amine. As shown in Scheme 2, the use of benzyl amine led to almost no diastereoselectivity in the multicomponent step, while the chiral (S)-α-methylbenzyl amine provided the product 10b in enantiopure form with an excellent diastereoselectivity (>99:1). The relative configuration of hydroquinolin-6-ones 10a,b was determined by NMR analysis, proving the cis configuration of the two substituents. After the scope of this reaction was addressed, the focus was posed on the variation of the four different components to produce structurally diverse tetrahydroquinoline scaffolds 10c-j (scheme 2). Thus, the 1,3-dicarbonyl and aldehyde was varied during the initial organocatalytic step while the amine and isocyanide stayed the same in the isocyanide-MCR. As before, the one-pot processes were performed without isolation of intermediate 8, but the subsequent MCR was simply carried out by addition of TFE, the amine and isocyanide components immediately after completion of the organocatalytic step. The stereoselectivity of the multicomponent sequence leading to hydroquinolinones 10c-j proved once more to be excellent using chiral amines (α-MeBn and amino acids), while unbranched n-butyl and benzyl amines provided poor stereocontrol. The use of either S or R-α-methylbenzyl amine as well as either D- or L-amino acid methyl esters provided the same stereo-differentiation to the cis isomers. Intriguingly, an experiment with bulky achiral amines such as cyclohexyl and t-butyl amines resulted in moderate diastereoselectivity for 10h but excellent one for 10i, proving also achiral amines with bulky substituents at 53 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


α-position can induce stereoselection in the MCR. To expand the scope of this diversity-oriented approach, we sought to implement the one-pot protocol for the synthesis of piperidinocoumarine hybrids substituted at positions 1, 2 and 4. Scheme 3 illustrates the one-pot approach leading to piperidinocoumarine hybrids 14 utilizing enantiomerically enriched chromenone 11 and piranocoumarine 12. As before, enantiomerically pure hybrids were produced in an excellent diastereomeric ratio, with the cis isomers as major products as proven by NMR. Finally, we were able to generate even higher structural complexity in a one-pot organocatalytic/MCR protocol with the incorporation of natural product fragments of peptidic, lipidic and saccharidic nature into piperidine-based hybrid architectures. Scheme 4 depicts the implementation of the multicomponent step with very complex substrates such as di and tripeptidic isocyanide and glucosyl amine. These substrates proved to react readily with the chiral cyclic hemiacetals arising from the organocatalytic step, showing that the combination of the two processes encompasses useful complexity-generation characteristics.

Scheme 3. One-pot organocatalytic conjugate addition/isocyanide-MCR sequence to piperidinocoumarine hybrids.

Scheme 4. One-pot synthesis of hydroquinolin-6-one and piperidinocoumarine hybrids by an organocatalytic conjugate addition/isocyanide-MCR sequence. 54 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Aminocatalytic Conjugate Addition of Nitroethanol to α,β-Unsaturated Aldehydes Followed by the Ugi Multicomponent Reaction The Ugi four-component reaction (42) – i.e., the condensation of a primary amine, a carboxylic acid, an aldehyde/ketone and an isocyanide – is a powerful synthetic tool to produce N-substituted peptides and peptidomimetics (13, 43–45). An important variation of the Ugi reaction is the so-called Ugi five-center four-component reaction (Ugi-5C-4CR) developed in 1996 (46). The Ugi’s concept behind this remarkable process was the utilization of α-amino acids as bifunctional scaffolds, which lead to a six-membered ring α-adducts that evade the classic Mumm rearrangement enabling the attack of the solvent methanol. A diastereoselective version of this reaction employing Lewis acid catalysts has been also reported (47). A modification of this reaction was developed by Ugi himself using trifunctional scaffolds like the amino acid lysine, thus leading to cyclic scaffold (48). In this new variant, named Ugi five-center three-component reaction (Ugi-5C-3CR), the α-adduct evolves through an intramolecular acylation of the side chain amino group leading to an α-amino-ε-lactam derivative. α-Homoserine has also been used as trifunctional building block for this reaction by Kim and coworkers during the synthesis of α-aminobutyrolactones (49). In this report, the intramolecular acylation of the α-homoserine primary alcohol is the key step in this new variant of the Ugi-5C-3CR. Interestingly, an external amine can be used as external nucleophile instead of a nuclephilic alcohol (50). Recently, unprotected carbohydrates and α-amino acids were employed as chiral bifunctional substrates of this type of isocyanide-MCR to enable the diastereoselective formation of novel cyclic glycopeptidomimetics (51). This third section describes a novel approach consisting of the preparation of chiral 4,5-disubstituted 2-hydroxytetrahydropyrans and their utilization as inputs for the Ugi-multicomponent synthesis of cyclic depsipeptide mimics. The overall strategy involves an initial asymmetric organocatalytic conjugate addition of nitroethanol to α,β-unsaturated aldehydes, followed by an Ugi-5C-3CR including the chiral cyclic hemiacetal and a variety of amino acids and isocyanides. The rationale of using the 2-hydroxytetrahydropyran scaffold lies at its bifunctional character, as the aldehyde group may react with the other Ugi components to form the α-adduct, while the appendage primary hydroxyl group undertakes the intramolecular acylation leading to a new type of depsipeptide mimic (Scheme 5). An efficient approach previously developed by Hayashi and co-workers (52) was chosen as initial organocatalytic step towards cyclic hemiacetals. The process comprised the asymmetric conjugate addition of nitroethanol to α,β-unsaturated aldehydes catalyzed by a diphenylprolinol silyl ether 7, which after cyclization rendered the enantioenriched 4,5-disubstituted 2-hydroxy-tetrahydropyrans 20. After having access to a pool of enantioenriched 4,5-disubstituted 2-hydroxy-tetrahydropyrans (20), we turned to the synthesis of the cyclic depsipeptide mimics 21 by the Ugi-5C-3CR with such chiral hemiacetals. Isocyanide-MCRs have been used to produce macrocyclic lactams resembling naturally occurring depsipeptide (53), but in most cases the MCR is not responsible for the ring closure step and it has never been used to produce 55 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


medium-size lactone rings. As depicted in scheme 5, hemiacetal 20 effectively reacted with a variety of amino acids (Val, Leu, Phe, PhGly, Met, His and Trp) and isocyanides (including peptidic, lipidic and glycosidic ones) at room temperature to afford nine-membered ring depsipeptides 21a-q. These compounds were produced with low diastereoselectivity, meaning that the stereogenic centers at the hemiacetal exert no stereocontrol over the multicomponent reaction. As we aimed at improving the diastereoselectivity of this reaction, parallel experiments using various Lewis acid catalysts were carried out, as a previous report had shown that such catalysts enhance the diastereoselection of the classic Ugi-5C-3CR between amino acids, isocyanides and aromatic aldehydes (47). However, after several attempts and screening of conditions, there was no improvement in the diastereoselectivity of this system.

Scheme 5. Multicomponent synthesis of cyclic depsipeptides by an organocatalytic conjugate addition/Ugi-5C-3CR sequence.

Conclusions Herein we have covered examples from our laboratories showing the development of stereoselective – eventually one-pot – sequences leading to complex hybrid molecules. These approaches enable the incorporation of different molecular fragments into a single skeleton, and with very low synthetic cost. Overall, the reports confirm that the asymmetric aminocatalytic functionalization of carbonyl compounds is an effective pre-MCR process capable of providing enantiomerically enriched building blocks for subsequent multicomponent diversification. Three isocyanides-MCRs were successfully employed after organocatalytic funcionalization of aldehydes: a) the classic Passerini-3CR, b) 56 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

a new three-component reaction of cyclic hemiacetals (derived from conjugated enols) with amines and isocyanides and c) a variant of the Ugi-5C-3CR of cyclic hemiacetals with unprotected amino acids and isocyanides. The versatility of this diversity-oriented strategy relies on the vast number of organocatalytic steps capable of producing chiral carbonyl compounds to be next reacted with other components for generating high levels of molecular complexity. We envisage that other iminium, enamine and related organocatalytic processes may be combined with varied MCRs, hence expanding the repertoire of stereoselective synthesis.


Acknowledgments We are grateful to CNPq, FAPESP (14/50249-8 and 15/17141-1) and CAPES (CAPES-MES/Cuba Program) for financial support to the projects herein reviewed.

References Carreira, E. M.; Kvaerno. L. Classics in Stereoselective Synthesis; WileyVCH: Weinheim, 2009. 2. List, B. The ying and yang of asymmetric aminocatalysis. Chem. Commun. 2006, 819–824. 3. Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Enantioselective Organocatalysis Using SOMO Activation. Science 2007, 316, 582–585. 4. Dalko, P. I.; Moisan, L. In the Golden Age of Organocatalysis. Angew. Chem., Int. Ed. 2004, 43, 5138–5175. 5. Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; Jørgensen, K. A. The Diarylprolinol Silyl Ether System: A General Organocatalyst. Acc. Chem. Res. 2012, 45, 248–264. 6. Narayanaperumal, S.; Rivera, D. G.; Silva, R. C.; Paixão, M. W. Terpene-Derived Bifunctional Thioureas in Asymmetric Organocatalysis. ChemCatChem 2013, 5, 2756–2773. 7. Multicomponent Reactions; Zhu, J., Bienyamé, H., Eds.; Wiley-VCH: Weinheim, 2005. 8. Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Small Heterocycles in Multicomponent Reactions. Chem. Rev. 2014, 114, 8323–8359. 9. Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity. Angew. Chem., Int. Ed. 2011, 50, 6234–6246. 10. Wessjohann, L. A.; Rhoden, C. R. B.; Rivera, D. G.; Vercillo, O. E. Cyclic Peptidomimetics and Pseudopeptides from Multicomponent Reactions. Top. Heterocycl. Chem. 2010, 23, 199–226. 11. Touré, B. B.; Hall, D. G. Natural Product Synthesis Using Multicomponent Reaction Strategies. Chem. Rev. 2009, 109, 4439–4486. 12. Brauch, S.; van Berkel, S. S.; Westermann, B. Higher-order multicomponent reactions: beyond four reactants. Chem. Soc. Rev. 2013, 42, 4948–4963. 1.

57 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


13. Dömling, A.; Ugi, I. Multicomponent Reactions with Isocyanides. Angew. Chem., Int. Ed. 2000, 39, 3168–3210. 14. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. 15. Kumar, A.; Vachhani, D. D.; Modha, S. G.; Sharma, S. K.; Parmar, V. S.; Van der Eycken, E. V. Post-Ugi gold-catalyzed diastereoselective domino cyclization for the synthesis of diversely substituted spiroindolines. Beilstein J. Org. Chem. 2013, 9, 2097–2102. 16. Marcaccini, S.; Torroba, T. In Multicomponent Reactions; Zhu, J., Bienyamé, H., Eds.; Wiley-VCH: Weinheim, 2005; pp 33−75. 17. Moni, L.; Banfi, L.; Basso, A.; Galatini, A.; Spallarossa, M.; Riva, R. Enantio- and diastereoselective synthesis of highly substituted benzazepines by a multicomponent strategy coupled with organocatalytic and enzymatic procedures. J. Org. Chem. 2014, 79, 339–351. 18. Morana, F.; Basso, A.; Riva, R.; Rocca, V.; Banfi, L. The homo-PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α-Oxo- or α-Hydroxy-γ-acylaminoamides and Chromanes. Chem. Eur. J. 2013, 19, 4563–4569. 19. Albrecht, L.; Jiang, H.; Jørgensen, K. A. A Simple Recipe for Sophisticated Cocktails: Organocatalytic One-Pot Reactions—Concept, Nomenclature, and Future Perspectives. Angew. Chem., Int. Ed. 2011, 50, 8492–8509. 20. Riguet, E. Enantioselective Organocatalytic Friedel-Crafts Alkylation Reaction of Indoles with 5-Hydroxyfuran-2(5H)-one: Access to Chiral γ-Lactones and γ-Lactams via a Ugi 4-Center 3-Component Reaction. J. Org. Chem. 2011, 76, 8143–8150. 21. Umbreen, S.; Brockhaus, M.; Ehrenberg, H.; Schmidt, B. Norstatines from Aldehydes by Sequential Organocatalytic α-Amination and Passerini Reaction. Eur. J. Org. Chem. 2006, 4585–4595. 22. van Berkel, S. S.; Bögels, B. G. M.; Wijdeven, M. A.; Westermann, B.; Rutjes, F. P. J. T. Recent Advances in Asymmetric Isocyanide-Based Multicomponent Reactions. Eur. J. Org. Chem. 2012, 3543–3559. 23. de Graaff, C.; Ruijter, E.; Orru, R. V. A. Recent developments in asymmetric multicomponent reactions. Chem. Soc. Rev. 2012, 41, 3969–4010. 24. Ramón, D. J.; Yus, M. Asymmetric Multicomponent Reactions (AMCRs): The New Frontier. Angew. Chem., Int. Ed. 2005, 44, 1602. 25. Enders, D.; Grondal, C.; Hüttl, M. R. M. Asymmetric Organocatalytic Domino Reactions. Angew. Chem., Int. Ed. 2007, 46, 1570–1581. 26. Pellissier, H. Stereocontrolled Domino Reactions. Chem. Rev. 2013, 113, 442–524. 27. Melchiore, P.; Marigo, M.; Carlone, A.; Bartole, G. Asymmetric Aminocatalysis – Gold Rush in Organic Chemistry. Angew. Chem., Int. Ed. 2008, 47, 6138–6171. 28. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471–5569. 29. Erkkilä, A.; Majander, I.; Pihko, P. M. Iminium Catalysis. Chem. Rev. 2007, 107, 5416–5470. 58 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


30. Trost, B. M.; Brindle, C. S. The direct catalytic asymmetric aldol reaction. Chem. Soc. Rev. 2010, 39, 1600–1632. 31. Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Mechanisms in aminocatalysis. Chem. Commun. 2011, 47, 632–649. 32. Melchiorre, P. Cinchona-based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds. Angew. Chem., Int. Ed. 2012, 51, 9748–9770. 33. Banfi, L.; Basso, A.; Moni, L.; Riva, R. The Alternative Route to Enantiopure Multicomponent Reaction Products: Biocatalytic or Organocatalytic Enantioselective Production of Inputs for Multicomponent Reactions. Eur. J. Org. Chem. 2014, 2005–2015. 34. Deobald, A. M.; Correa, A. G.; Rivera, D. G.; Paixão, M. W. Organocatalytic asymmetric epoxidation and tandem epoxidation/Passerini reaction under eco-friendly reaction conditions. Org. Biomol. Chem. 2012, 10, 7681–7684. 35. Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. Asymmetric Organocatalytic Epoxidation of α,β-Unsaturated Aldehydes with Hydrogen Peroxide. J. Am. Chem. Soc. 2005, 127, 6964–6289. 36. Banfi, L.; Riva, R. The Passerini Reaction. Org. React. 2005, 65, 1–140. 37. Rueping, M.; Sugiono, E.; Merino, E. Asymmetric Iminium Ion Catalysis: An Efficient Enantioselective Synthesis of Pyranonaphthoquinones and βLapachones. Angew. Chem., Int. Ed. 2008, 47, 3046–3049. 38. Rueping, M.; Sugiono, E.; Merino, E. Asymmetric Organocatalysis: An Efficient Enantioselective Access to Benzopyranes and Chromenes. Chem. Eur. J. 2008, 14, 6329–6332. 39. Franke, P. T.; Richter, B.; Jørgensen, K. A. Organocatalytic Asymmetric Synthesis of Functionalized 3,4-Dihydropyran Derivatives. Chem. Eur. J. 2008, 14, 6317–6321. 40. Echemendía, R.; de la Torre, A. F.; Monteiro, J. L.; Pila, M.; Corrêa, A. G.; Westermann, B.; Rivera, D. G.; Paixão, M. W. Highly Stereoselective Synthesis of Natural Product-like Hybrids by an Organocatalytic/ Multicomponent Reaction Sequence. Angew. Chem., Int. Ed. 2015, 54, 7621–7625. 41. This type of isocyanide-MCR has been previously reported in an intermolecular manner, see: Castellano, T. G.; Neo, A. G.; Marcaccini, S.; Marcos, C. F. Enols as Feasible Acid Components in the Ugi Condensation. Org. Lett. 2012, 14, 6218–6221. 42. Marcaccini, S.; Torroba, T. The use of the Ugi four-component condensation. Nat. Protocols 2007, 2, 632–639. 43. Dömling, A. Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem. Rev. 2006, 106, 17–89. 44. Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Multiple Multicomponent Macrocyclizations (MiBs): A Strategic Development Towards Macrocycle Diversity. Chem. Rev. 2009, 109, 796–814. 45. Dömling, A.; Wang, W.; Wang, K. Chemistry and Biology Of Multicomponent Reactions. Chem. Rev. 2012, 112, 3083–3136. 59 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


46. Demharter, A.; Hörl, W.; Herdtweck, E.; Ugi, I. Synthesis of Chiral 1,l′-Iminodicarboxylic Acid Derivatives from a-Amino Acids, Aldehydes, Isocyanides, and Alcohols by the Diastereoselective Five-CenterFour-Component Reaction. Angew. Chem., Int. Ed. Engl. 1996, 35, 173–175. 47. Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini, M. A. Titanium catalysis in the Ugi reaction of α-amino acids with aromatic aldehydes. Org. Lett. 2004, 6, 3281–3284. 48. Ugi, I.; Demharter, A.; Hörl, W.; Schmidt, T. Ugi Reactions with Trifunctional α-Amino Acids, Aldehydes, Isocyanides and Alcohols. Tetrahedron 1996, 52, 11657–11664. 49. Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.; Lee, D. H. A Facile Synthesis N-Carbamoylmethyl-α-aminobutyrolactones by the Ugi Multicomponent Condensation Reaction. Tetrahedron Lett. 1998, 39, 7109–7110. 50. Khoury, K.; Sinha, M. K.; Nagashima, T.; Herdtweck, E.; Dömling, A. Efficient Assembly of Iminodicarboxamides by a “Truly” Four-Component Reaction. Angew. Chem., Int. Ed. 2012, 51, 10280–10283. 51. Voigt, V.; Mahrwald, R. Multicomponent Cascade Reactions of Unprotected Carbohydrates and Amino Acids. Org. Lett. 2015, 17, 2606–2609. 52. Gotoh, H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Diphenylprolinol Silyl Ether as a Catalyst in an Asymmetric, Catalytic, and Direct Michael Reaction of Nitroethanol with α,β-Unsaturated Aldehydes. Org. Lett. 2009, 11, 4056–4059. 53. León, F.; Rivera, D. G.; Wessjohann, L. A. Multiple Multicomponent Macrocyclizations Including Bifunctional Building Blocks (MiBs) Based on Staudinger and Passerini Three-Component Reactions. J. Org. Chem. 2008, 73, 1762–1767.

60 Cheng et al.; Stereochemistry and Global Connectivity: The Legacy of Ernest L. Eliel Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

Interplay between Organocatalysis and Multicomponent Reactions in

Recommend Documents