A permutation approach to the assignment of the configuration to diastereomeric tetrads by comparison of experimental and ab initio calculated differences in NMR data

• Przemysław J. Boratyński

Beilstein J. Org. Chem. 2017, 13, 2478–2485, doi:10.3762/bjoc.13.245

• four diastereomers can help to assign their relative configurations. This method was exercised on a set of diastereomeric Cinchona alkaloid derivatives, where 13C NMR data always identified the proper configuration. The presented approach is also an attempt to quantify the assignment by exclusion

• Cinchona alkaloids 1–4 obtained in our laboratory were analyzed (Figure 1, for references, see Supporting Information File 1). The configurations of these derivatives were established based on previous X-ray studies for compounds 2a and 3d, NOESY experiments combined with molecular modeling for compounds

• 1 and 2 were obtained by epimerization at C9. Mixtures of the isomers of 1 were formed in TBAF desilylation of Cinchona 4-TMS-triazole derivatives. Partial isomerisation of 2a into 2b was performed by transient deprotonation using in situ generated sodium methylsulfinylmethylide (Scheme 1). Both

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• ][16][17][18][19][20]. Following the pioneering reports of Wynberg et al. [25] and Merck scientists [26] who employed cinchona alkaloid-derived quaternary ammonium salts for asymmetric epoxidations [25] and the α-methylation of a phenylindanone derivative [26] in the late 1970s, early 1980s already

• , cinchona alkaloids remained the preferred chiral backbones for novel phase-transfer catalysts and applications thereof until the beginning of the 21st century. Pioneering contributions with these powerful catalysts were reported by the groups of O’Donnell [27], Lygo [28], and Corey [29]. The turn of the

• nucleophiles dates back to 2002, when Kim and Park described the first use of cinchona alkaloid-based quaternary ammonium salts A (i.e., derivative A1) for the enantioselective α-fluorination of β-ketoesters 1 by using N-fluorobenzenesulfonimide (NFSI, 2) as the fluoride-transfer reagent [73] (Scheme 2). By

Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides

• Ryota Miyaji,
• Yuuki Wada,
• Akira Matsumoto,
• Keisuke Asano and
• Seijiro Matsubara

Beilstein J. Org. Chem. 2017, 13, 1518–1523, doi:10.3762/bjoc.13.151

• solvent (Table 1, entries 4–7). Other brominating reagents (Figure 1) were also investigated; however, NBA (4a) still afforded the best enantioselective results (Table 1, entries 8–10). In addition, other bifunctional organocatalysts derived from easily available cinchona alkaloids exhibited similarly

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• strategies with chiral transition metals [27][28][29][30][31][32][33], organocatalysts such as secondary amines [34][35][36], nucleophilic phosphines [26][37][38][39][40][41][42][43][44], tertiary amines [45], N-heterocyclic carbenes (NHCs) [46][47][48], and cinchona alkaloid derivatives [25][28][49][50

• variety of organocatalysts (a–f) were investigated in CH2Cl2 at −20 °C for 12 h to evaluate their ability to promote the transformation (Table 1, entries 1–6). When cinchona alkaloid-derived catalyst a and quinine-derived amine catalyst b were tested, however, poor yields or ee values were obtained

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

• Matthew A. Horwitz,
• Elisabetta Massolo and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2017, 13, 762–767, doi:10.3762/bjoc.13.75

• ] nucleophiles using bifunctional cinchona alkaloid catalysts. The Sasai and Enders groups used a phosphinothiourea to enable a Rauhut–Currier reaction to form bicyclic enones [16]. The Tian and Lin group used alkyne-tethered cyclohexadienones in an arylrhodation/conjugate addition sequence that

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

• Runjun Devi and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2017, 13, 571–578, doi:10.3762/bjoc.13.56

• number of cinchona alkaloid-derived ligands which allow the dihydroxylation of alkenes of almost all substitution patterns with high enantioselectivity. Noteworthy is that the SAD is not limited to only E-allylic alcohols in its choice of substrates as is the SAE process. Moreover, the SAD is much more

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

• chiral counterions in less polar solvents. Up to 61% ee could be obtained using cinchona alkaloids as catalysts [26]. The subsequent work of Tan and co-workers with guanidine catalyst 8 achieved enantioselectivities as high as 99% ee [19]. In recent years functionalized chiral amines have been

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• this method, the one-pot reaction of isatin derivatives 301, iminophosphorane 302, and diphenyl phosphonate in the presence of Cinchona-derived thiourea as the catalyst afforded α-aminophosphonates 303 in 70–81% yields and with 70–84% ee (Scheme 62) [100]. The trans-1,5-benzodiazepines 307 bearing both

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

• 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

• subsequently subjected to a Swern oxidation to yield the aldehyde 21 in 88% yield. Finally, treatment of the aldehyde with Petasis reagent afforded the target bisalkene RCM precursor 5 in a satisfactory 42% yield. Conclusion In conclusion we have utilized a bifunctional cinchona-derived thiourea organocatalyst

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

• , unprotected isatins failed to gave the desired products under the same conditions. As shown in the binding model, the catalyst activated the carbonyl groups through hydrogen bonds, while the allyltributyltin reagent attacked the 3-carbonyl group from the Si face, forming (R)-isomers. Cinchona alkaloid

• catalysts Cinchona alkaloids and their derivatives have been widely used as chiral catalysts in many reactions [44] and also show synthetic utilities in the synthesis of enantiomerically pure 3-substituted 3-hydroxyoxindoles. In 2013, Wu and co-workers reported the cinchona alkaloid (cat. 14)-catalyzed

• -diols was deprived by the amino group of the catalyst, and then the anion attacked isatin from the Re face, followed by release of one mol equivalent trifluoroacetate. The enol anion retrieved the proton from the catalyst to give the (S)-products. In 2013, Chimni and co-workers designed the cinchona

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

• 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

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

• [12]. Cinchona-derived thioureas have been also prepared by co-polymerization of polyfunctionalized thiols with olefins [23]. Our interest in the search for novel bifunctional thioureas as organocatalysts [24][25][26][27] lead us to consider the preparation of different polymeric materials decorated

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

• origin of the asymmetric induction was proposed. In the plausible transition state TS12, acidic hydrogen atoms from both hydroxy and thiourea moieties would activate and fix the nitroalkene. Simultaneously, the tertiary amine of the cinchona framework would deprotonate the acidic proton of acetylacetone

• in the chiral induction of the process. The authors proposed the transition state TS14, where the NH groups and the OH group of the squaramide would coordinate to the nitroalkene 3 through hydrogen-bonding interactions with the nitro group. Simultaneously, the amine in the cinchona alkaloid would

(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

• 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

• stereochemistry of the carbon bearing the R2 group. Very recently, Wang and co-workers used a cinchona alkaloid-based bifunctional thiourea 103 as the catalyst of choice to an organocatalytic domino process. This domino reaction involded a Michael cyclization–tautomerization reaction sequence between isatylidene

• -unsaturated aldehydes 108, affording the desired products 110 in moderate to good yields and good to excellent stereoselectivities (Scheme 35). Recently, Wang and co-workers disclosed an asymmetric synthesis of dihydrocoumarins 113 containing adjacent stereogenic centers, utilizing the cinchona-derived

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

• Laura A. Bryant Rossana Fanelli Alexander J. A. Cobb School of Chemistry, Food and Pharmacy (SCFP), University of Reading, Whiteknights, Reading, Berks RG6 6AD, United Kingdom 10.3762/bjoc.12.46 Abstract Cinchona alkaloids with a free 6'-OH functionality are being increasingly used within

• . Keywords: bifunctional; cupreidine; cinchona; cupreine; organocatalysis; Introduction The cinchona alkaloids, comprising quinine (QN), quinidine (QD), cinchonidine (CD), cinchonine (CN, Figure 1), and their derivatives have revolutionized asymmetric catalysis owing to their privileged structures. The

• optimize their stereoselective behaviour has seen their utility burgeon dramatically over the last decade. Of particular note is the use of these cinchona systems within bifunctional thiourea catalysis [3][4][5][6][7][8][9][10][11][12]. Cupreine (CPN) and cupreidine (CPD), the non-natural demethylated

Bifunctional phase-transfer catalysis in the asymmetric synthesis of biologically active isoindolinones

• Antonia Di Mola,
• Maximilian Tiffner,
• Francesco Scorzelli,
• Laura Palombi,
• Rosanna Filosa,
• Paolo De Caprariis,
• Mario Waser and
• Antonio Massa

Beilstein J. Org. Chem. 2015, 11, 2591–2599, doi:10.3762/bjoc.11.279

• elaborations en route to the targets of medicinal interest (Figure 1). A high yield (usually >95%) and a maximum level of enantioselectivity of 74% ee were obtained but only in the presence of large amounts of cinchona alkaloid-based thiourea-containing organocatalysts (15 mol %) and after an unacceptably long

• reaction time (72 h) [21][22]. Readily available chiral ammonium salts (e.g., cinchona alkaloid-based or commercially available Maruoka catalysts) were also investigated, but the enantioselectivity was lower, reaching a maximum of 46% ee [23]. Gratifyingly, a very efficient heterochiral crystallization

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

• 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

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• used to carry out an asymmetric alkylation reaction (Scheme 4). The monoalkylation of phosphine–borane complex 15 was performed in the presence of the Cinchona alkaloid ammonium salt 16 [50]. However, the enantioselectivity of the reaction was low. Imamoto et al. prepared a new tetraphosphine ligand 19

• diphenylphosphine to a range of nitroalkenes 56 has been described using a bifuntional Cinchona alkoid/thiourea catalyst 58 [132]. The catalyst 58 is able to simultaneously activate both the electrophilic and nucleophilic reagents. On one hand the thiourea presumably binds the nitro group while on the other hand

Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives

• Akshay Kumar and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2014, 10, 929–935, doi:10.3762/bjoc.10.91

• been found to catalyze a variety of carbon–carbon bond-forming reactions [25][26][27][28][29][30]. Small peptides derived from acyclic amino acids, primary-secondary diamines, Cinchona-based primary amines, and thioureas with a primary amine functionality etc., have found many successful applications

• 86% yield and 88% ee (Table 5, entry 9). A recently reported similar reaction catalyzed by Cinchona alkaloid-based primary amine catalyst requires high catalyst loading and is only suitable for N-unprotected isatylidenemalononitrile derivatives [5]. In contrast, our methodology is suitable for both N

Addition of H-phosphonates to quinine-derived carbonyl compounds. An unexpected C9 phosphonate–phosphate rearrangement and tandem intramolecular piperidine elimination

• Łukasz Górecki,
• Artur Mucha and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 883–889, doi:10.3762/bjoc.10.85

• ; Introduction Medicinal, organocatalytic and stereoselective properties of quinine make it the most prominent representative of Cinchona alkaloids [1], a group of natural compounds of a unique three-dimensional structure. The structure involves a particular arrangement of two rigid heterocyclic fragments

• novel contribution to the reactivity of quinine although similar eliminations of piperidine in Cinchona alkaloids have been reported in the literature. Accordingly, heating of quinine or derivatives in acids provided either quino-/cinchotoxine ketones or their tautomeric enol esters, depending on the

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• derivatives bearing a pendant nitrogen nucleophile, and the source of chirality was a substoichiometric quantity of the cinchona alkaloid derivative (DHQ)2PHAL (70). This method was shown to work very well with several different pendant nucleophiles, but the N-acetamido nucleophile was found to be optimal

Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

• Lin Yan,
• Zhiqiang Han,
• Bo Zhu,
• Caiyun Yang,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2013, 9, 1853–1857, doi:10.3762/bjoc.9.216

• and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371 10.3762/bjoc.9.216 Abstract In the presence of a commercially available Cinchona alkaloid as catalyst, the asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates, with α-fluoro-β-keto esters as

• compounds with chiral quaternary carbon centres containing a fluorine atom. Results and Discussion In the preliminary experiments, we investigated the reaction of α-fluoro-β-ketoester 1a with MBH carbonate 2a as the model substrate, in the presence of several commercially available Cinchona alkaloids as

•  1, entry 2). Next, we screened a series of C2-symmetric bis-Cinchona alkaloids as catalysts under the same conditions (Table 1, entries 3–7). (DHQD)2PHAL showed moderate catalytic activity; 3aa was obtained in 67% yield with 71% ee and 60:40 dr (entry 3). The effects of solvent were then

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• including cinchona alkaloid derivatives, chiral phosphoric acids, chiral amino alcohols, chiral thioureas, chiral guanidines, and chiral 1,2,3-triazolium chlorides. In this review, the research work of enantioselective desymmetrization of meso-aziridines is organized into sections according to the employed

• organocatalysts. Cinchona alkaloid derivatives The first organocatalytic enantioselective desymmetrization of meso-aziridines was discovered by Hou and co-workers in 2007 [40] with various arylthiols as nucleophiles in CCl4 at 0 °C in the presence of cinchonine-derived phase-transfer catalysts (PTCs, Figure 2, OC

• -1 to OC-6). The substituent on the bridgehead nitrogen of cinchona alkaloids has a great impact on the enantioselectivity of the reactions. The catalyst OC-2 with 9-anthracenylmethyl on the bridgehead nitrogen is more efficient than other cinchona alkaloid-derived catalysts for the desymmetrization