Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• organocatalysts with a bulky substituent at C2 were synthesized from chiral imines derived from (R)-glyceraldehyde acetonide by diastereoselective allylation followed by a sequential hydrozirconation/iodination reaction. The new compounds were found to be effective organocatalysts for the Michael addition of

• aldehydes to nitroolefins and enantioselectivities up to 85% ee were achieved. Keywords: enantioselective synthesis; Michael addition; organocatalysis; pyrrolidines; synthetic methods; Introduction In the first decades of the 21st century, the enantioselective organocatalysis has witnessed a tremendous

• chiral pool, we have now focused on the synthesis of new chiral pyrrolidines capable of creating a sterically demanding environment due to the presence of a bulky 2,2-disubstituted-1,3-dioxolan-4-yl moiety at C2 from chiral imines derived from (R)-glyceraldehyde. The Michael addition of aldehydes to

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• synthesis and application of a recyclable immobilized analogue of benzotetramisole (BMT) used in a catalytic enantioselective Michael addition/cyclization reactions under continuous-flow conditions (Scheme 11) [60]. Resin-bound catalyst 10 was swollen with dichloromethane in a medium-pressure chromatography

Construction of bis-, tris- and tetrahydrazones by addition of azoalkenes to amines and ammonia

• Artem N. Semakin,
• Aleksandr O. Kokuev,
• Yulia V. Nelyubina,
• Alexey Yu. Sukhorukov,
• Petr A. Zhmurov,
• Sema L. Ioffe and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2016, 12, 2471–2477, doi:10.3762/bjoc.12.241

• -tetraazaadamantane derivative was demonstrated. Keywords: azoalkenes; α-halogen hydrazones; heterocage compounds; hydrazone ligands; Michael addition; Introduction Hydrazones are extensively used as key structural units in the design of various functional molecular and supramolecular architectures [1][2][3][4][5

Methylenelactide: vinyl polymerization and spatial reactivity effects

• Judita Britner and
• Helmut Ritter

Beilstein J. Org. Chem. 2016, 12, 2378–2389, doi:10.3762/bjoc.12.232

• attack of the thiol takes place. This can be clearly seen in the 1H NMR spectra (Figures S18 and S19, Supporting Information File 1). Thioacetic acid was used as a potential chain-transfer agent due to its lower nucleophilicity. However, a complete thiol-Michael addition can be seen in Figure 8 (not full

• conversion of MLA due to the impurities of thioacetic acid like disulfide and acetic acid). In this context, the iodine catalyzed thiol-Michael addition was investigated [11]. Controlled radical polymerization of MLA via RAFT Since MLA acts as a vinyl monomer, it was also interesting to evaluate the

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• + 2] annulation between 5H-thiazol-4-ones and nitroalkenes [10]. In this stepwise process, the use of 3,5-dichlorophenyl as the substituent group of the urea in catalyst V would remarkably increase the free energy difference between R- and S-selection in the first Michael addition step, and also

Unusual reactions of diazocarbonyl compounds with α,β-unsaturated δ-amino esters: Rh(II)-catalyzed Wolff rearrangement and oxidative cleavage of N–H-insertion products

• Valerij A. Nikolaev,
• Jury J. Medvedev,
• Olesia S. Galkina,
• Ksenia V. Azarova and
• Christoph Schneider

Beilstein J. Org. Chem. 2016, 12, 1904–1910, doi:10.3762/bjoc.12.180

• provides a good way for the synthesis of multi-functionalized N-arylpyrrolidines by the same “metal–carbene” methodology with yields of up to 82% [15]. The reactions occur as a domino process involving an initial formation of N-ylides A followed by the intramolecular Michael addition with the conjugated

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• in the field of molecular recognition, however, without being tested as catalysts [5][6][7][8][9][10]. A first example of enantioselective Michael addition has been reported for guanidine 3, albeit with low selectivity [11]. Compounds 4 and 5, inspired by the structure of ptilomycalin A and related

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• intermediate 7. Synthesis of THQ 10, by initial aza-Michael addition, followed by formation of the tertiary alcohol 9, which was then cyclised with H2SO4. Synthesis of THQ 14 by initial acylation, cyclisation with H2SO4 and reduction with borane·dimethyl sulphide complex. N-Alkylation of 13 and 14. Facile

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

• Atul A. Dhavan,
• Rahul D. Kaduskar,
• Loana Musso,
• Leonardo Scaglioni,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2016, 12, 1624–1628, doi:10.3762/bjoc.12.159

• A straightforward route to the intriguing 2,3-pyrrolidinedione system appeared to be the Michael addition of a suitable amine to ethyl acrylate, followed by a Dieckmann cyclization with diethyl oxalate [10][11]. We chose the p-methoxybenzyl (PMB) protecting group for the amine, because of its facile

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• precursor and thus particular ring systems [9][10][11]. Most heterocycles in polyketides are formed by specialised PKS domains and tailoring enzymes. These can be active during assembly of the nascent PKS precursor (as for example in the case of pyran/furan formation via oxa-Michael addition, see chapters

• thioester to a hydroxy group (d in Scheme 2). A Michael addition–lactonisation cascade leads to pyranones with a substituent in the 4-position 16 (e in Scheme 2). 3-Acylfuran-2-ones (19, 3-acyltetronates) are formed by acylation–Dieckmann condensation between 2-hydroxythioesters 18 and β-ketothioesters 17

• (f in Scheme 2). The oxidative cyclisation after C–H activation of alkyl carbons is known for the formation of furan rings 21 (g in Scheme 2). 1.1 Pyrans 1.1.1 oxa-Michael addition: The oxa-Michael addition on an α,β-unsaturated thioester intermediate leads to oxygen heterocycles along with the

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• (R2 = H, Ph 71.5:28.5 to 90.5:9.5 er). In 2010, the Kobayashi group reported the calcium-catalyzed Michael addition of dibenzylmalonate (86) to N-acryloyloxazolidinones 87 followed by enantioselective protonation of a chiral calcium enolate to access 1,5-dicarbonyl compounds 90 (Scheme 21) [44]. The

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• Pavol Jakubec Alistair J. M. Farley Darren J. Dixon Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom 10.3762/bjoc.12.104 Abstract The enantio- and diastereoselective Michael addition of a δ-valerolactone-derived

• amine, following our well-established protocol [6][7][8][9][10][11][12]. The key quaternary stereocentre of keramaphidin B, we envisaged, would be installed through an enantio- and diastereoselective organocatalytic Michael addition [13][14][15] between pronucleophile 8 and the known substituted furanyl

• nitroolefin 9 under the control of a cinchona-derived bifunctional Brønsted base/H-bond donor organocatalyst developed in our group and others [16][17][18][19]. Bifunctional organocatalysed Michael addition studies In our previous total syntheses of nakadomarin A [5][7][20] and manzamine A [10] the

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• nucleophiles attacking the vinyliminium intermediates generated in situ from the indol-3-ylmethanols (the Michael addition) to form the intermediates. This is followed by the CPA-promoted cyclization, affording the final products bearing three continuous chiral centers. Besides, they also reported the CPA

• diastereoselectivities (all >95:5 dr) and enantioselectivities (up to >99% ee, Scheme 58) [75]. Mechanistic studies showed that this cascade reaction proceeded via a vinylogous Michael addition/Friedel–Crafts process involving a dual H-bonding activation of substrates. In 2015, Wang and co-workers reported Lewis acid

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• )-ones 1 as pronucleophiles in organocatalyzed Michael addition reactions 2-Thio-1H-imidazol-4(5H)-ones 1 (R = SBn) have been reported to be effective equivalents of N-subtituted (alkyl, aryl, allyl) α-amino acids in conjugate addition reactions to both, nitroalkenes and α-silyloxy enones as Michael

• acceptors in reactions promoted by bifunctional Brønsted bases. 1.2.1 Nitroalkenes as acceptors. Investigation of the base-catalyzed Michael addition reaction of 2-thio-1H-imidazol-4(5H)-ones 4 to nitroalkenes 5 [55] revealed that cinchona alkaloids such as quinine, (DHQ)2Pyr or even thiourea tertiary amine

• demonstrated to be either less reactive and/or less stereoselective in their addition reaction to nitrostyrene thus affording the corresponding Michael adducts with no diastereoselectivity and/or poor enantioselectivity (Scheme 3). Useful applications of the Michael adducts coming from the Michael addition of

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• this producing organism, L-arginine is diastereoselectively hydroxylated to afford (3S)-3-hydroxy-L-arginine. The ring-closure reaction then occurs with formal inversion of the β-stereocenter (but quite likely through an aza-Michael addition to the α,β-unsaturated intermediate) [119][120][121]. The

• studies [123][124]. It should also be noted that a biomimetic domino guanidinylation–aza-Michael-addition reaction for the synthesis of the capreomycidine scaffold has been developed, which only furnished the target structures as stereoisomeric mixtures though [125]. The epicapreomycidine-derived

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• a variety of reactions such as aza-Morita–Baylis–Hillman reactions [19][20][21], Rauhut–Currier reactions [22][23][24][25][26][27], Michael addition reactions [28][29][30][31][32][33][34][35], and various cycloadditions [36][37][38][39]. In recent years, our group has focused on the development of

Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions

• José M. Andrés,
• Miriam Ceballos,
• Alicia Maestro,
• Isabel Sanz and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2016, 12, 628–635, doi:10.3762/bjoc.12.61

• bifunctional thioureas on sulfonylpolystyrene resins has been studied in the nitro-Michael addition of different nucleophiles to trans-β-nitrostyrene derivatives. The activity of the catalysts depends on the length of the tether linking the chiral thiourea to the polymer. The best results were obtained with

• nitro-Michael addition; supported catalysts; thioureas; Introduction The use of chiral bifunctional thioureas that allow the simultaneous activation of a electrophile, by hydrogen bonding, and a nucleophile, by deprotonation, plays a major role in the stereoselective formation of C–C bonds in different

• from the reaction mixtures by filtration, thoroughly washed with methanol, dried and reused in the next cycle. General procedure for the Michael addition of 2-nitrocyclohexanone to β-nitrostyrene using immobilized catalyst VI Method A, in organic solvent: The reactions were carried out as previously

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel–Crafts alkylation, Michael addition, Diels–Alder and aza-Henry reactions. However, the 1,2-aminoindanol core

• through an organocatalyzed asymmetric domino-Michael addition/Henry reaction (Scheme 8) [36]. These heterocyclic products are important chiral building blocks for the synthesis of organocatalytic frameworks and ligands for chiral metal complexes, both with the potential ability to induce chirality. They

• by the catalyst ent-6 through hydrogen-bonding interactions in a bifunctional manner. Thus, the ternary complex formed in the transition state TS5 leads to an enantioselective Friedel–Crafts-type Michael addition by the attack of indole 2 to the electrophilic prochiral center on the nitroalkene 20 in

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• the thiourea group interact with one or two carbonyl groups of phenylbutenoate 2 (Scheme 5). Another catalytic reaction catalyzed by a primary amine-thiourea that leads to multiple chiral centers is the asymmetric desymmetrization of 4,4-disubstituted cyclohexadienones 5, using the Michael addition of

• prochiral ketones 35 or 36, catalyzed by a primary amine-thiourea 37 developed by Jacobsen. The proposed pathway is based on desymmetrization of 35 or 36 by an intramolecular Michael addition of the corresponding enamines to an α,β-unsaturated ester, to yield bicyclic or spiro-bicyclic products 38 and 39

• excellent enantioselectivities (83–96% ee) [31]. In 2009, Cobb and co-workers disclosed the asymmetric intramolecular Michael addition of nitronates 62 onto conjugated esters utilizing the cinchona-derived thiourea 63 (Scheme 22) [32]. The reaction proceeded with excellent selectivity and afforded products

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• for the asymmetric synthesis of functionalised cyclopentanones was disclosed in 2009 by Rovis. The chiral secondary amine 60 catalyzes the initial asymmetric Michael addition of an 1,3-diketone and an enal to afford a δ-ketoaldehyde 61. Subsequently, a cross-benzoin reaction of the latter promoted by

• the NHC precatalyst 22, installs the cyclopentenone system (Scheme 37). It may be noted that the absolute stereochemistry of the process is controlled by the prolinol catalyst 60 and the NHC precatalyst 22 is achiral. Control experiments revealed that the Michael addition is reversible but the NHC

Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

• Laura A. Bryant,
• Rossana Fanelli and
• Alexander J. A. Cobb

Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

• recently inspired to use the (de-Me-DHQ)2PHAL catalyst HCPD-44 in the addition of α-substituted nitro acetates 43 also into nitroolefins 41 (Scheme 11b) [43][44][45][46]. In a fascinating report, Melchiorre and co-workers use the 9-amino-CPD system CPD-48 to control the Michael addition of thiols 46 into α

• vinylogous Michael addition reaction [48]. In this process, cyclic enones 52 are added to nitroalkenes 41 using dienamine catalysis (Scheme 13). Although no model is suggested with respect to how the 6’-OH is involved, it is clearly of importance as the analogous 6’-OMe derived cupreine catalyst gives

• hydroxydiketopiperizine system 56 with very high diasterecontrol. Once again, the authors invoke a critical role for the 6’-OH group in the co-ordination and activation of the electrophile in these processes. Cyclopropanations Not unrelated to the Michael addition in a mechanistic sense, is the asymmetric

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors

• Ming-Liang Zhang,
• Deng-Feng Yue,
• Zhen-Hua Wang,
• Yuan Luo,
• Xiao-Ying Xu,
• Xiao-Mei Zhang and
• Wei-Cheng Yuan

Beilstein J. Org. Chem. 2016, 12, 295–300, doi:10.3762/bjoc.12.31

• successfully used as chiral organocatalysts for the asymmetric Michael addition and Mannich reactions [12][13][14]. Meanwhile, the Henry reaction is one of the most important carbon–carbon bond-forming reactions that provides straightforward access to β-nitroalcohols, which can be further transformed into

A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates

• Hong-Bo Zhang,
• Yong-Chun Luo,
• Xiu-Qin Hu,
• Yong-Min Liang and
• Peng-Fei Xu

Beilstein J. Org. Chem. 2016, 12, 253–259, doi:10.3762/bjoc.12.27

• trifluoroacetic anhydride in DCM (Scheme 2). Finally, we propose a mechanism for the reaction. Initially, substrate 1 is activated by catalyst (I), which reacts with substrate 2 via two Michael addition reactions to sequentially produce II and III. Then, IV is generated from III by an aldol reaction. Finally, the

Facile synthesis of 4H-chromene derivatives via base-mediated annulation of ortho-hydroxychalcones and 2-bromoallyl sulfones

• Srinivas Thadkapally,
• Athira C. Kunjachan and
• Rajeev S. Menon

Beilstein J. Org. Chem. 2016, 12, 16–21, doi:10.3762/bjoc.12.3

• , deprotonation of 7a by Cs2CO3 generates the phenoxide anion 9. A hetero-Michael addition of 5 and 9 results in the formation of a stabilized carbanion which may be represented as the resonance structures 10 or 11. The α-sulfonyl carbanion 11 then undergoes an intramolecular Michael addition to the β-carbon of

• forming event (conversion of 11 to 12) here is completely regioselective as the Michael addition of the stabilized carbanion 11 occurs selectively at the α-sulfonyl position (not at the less hindered terminal of the allylic carbanion 11). Conclusion In conclusion, a base-mediated, facile synthesis of 3

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

• Jose I. Martínez,
• Uxue Uria,
• Maria Muñiz,
• Efraím Reyes,
• Luisa Carrillo and
• Jose L. Vicario

Beilstein J. Org. Chem. 2015, 11, 2577–2583, doi:10.3762/bjoc.11.277

• all cases. Keywords: asymmetric diastereodivergent; enantioselective; Michael addition; nitroalkenes; nitroesters; organocatalysis; squaramides; Introduction The absolute stereochemistry of a molecule has a paramount influence on the properties that this compound will have when interacting with

• advantage of the Michael addition of nitroalkenes and using two different bifunctional catalysts derived from cinchona alkaloids (catalyst 4) or cyclohexadiamine (catalyst 6). These catalysts, both with the same absolute backbone chirality, allow us to control the syn or anti selectivity obtaining the final