Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• (entry 6, Figure 9), it was less than that obtained (74% ee) by N-fluorosultam (R)-27-6 with the same substrate (see the previous section 1-27). 1-29. N-Fluorinated cinchona alkaloid derivatives by combination with Selectfluor In 2000, Shibata and Takeuchi reported a far more practical enantioselective

• fluorination method. They discovered that the fluorination of carbanions with Selectfluor occurred in a highly enantioselective manner when carried out in the presence of cinchona alkaloid derivatives [95]. This method consisted of two simple steps. Firstly, the cinchona alkaloid is reacted with Selectfluor in

• reported by Banks when quinuclidine was N-fluorinated with Selectfluor [62] (Scheme 67). Subsequently, in 2001, Shibata et al. presented full details of their studies including the definitive identification of N-fluorinated cinchona alkaloids by X-ray crystallography analysis and further applications [96

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• Deniz Tozendemir Cihangir Tanyeli Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey 10.3762/bjoc.17.43 Abstract Cinchona alkaloid-derived organocatalysts are widely employed in various asymmetric transformations, yielding products with high enantiopurity. In this

• %) catalyst loading. Selected enantiomerically enriched sulfa-Michael addition products were subjected to oxidation to obtain the corresponding sulfones. Keywords: asymmetric synthesis; bifunctional catalysis; cinchona alkaloids; organocatalysis; sulfa-Michael reaction; Introduction Derivatives of the

• naturally occurring cinchona alkaloids have shown remarkable performance as organocatalysts for stereoselective synthesis in the past decade [1][2][3][4][5][6]. Among them, quinine-derived organocatalysts make a noteworthy appearance in the formation of new stereogenic centres, which can serve as valuable

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• center. This in turn led to their increased nucleophilicity as compared to the standard Ugi adducts. As such, the stereocenter at the peptidyl position could be installed and stereodefined through the reaction with a suitable electrophile. Towards this end, we were able to deploy an asymmetric cinchona

• alkaloid-promoted electrophilic fluorination producing enantioenriched post-Ugi adducts fluorinated at the peptidyl position. Keywords: cinchona alkaloids; electrophilic fluorination; enantioselective synthesis; 2-oxo-aldehydes; Ugi reaction; Introduction Multicomponent reactions (MCRs) [1][2][3][4][5][6

• carbonyl compounds promoted by cinchona alkaloid derivatives developed independently by Shibata, Takeuchi and co-workers [65][66] and by the group of Cahard [67][68][69][70]. The method proved to be applicable to a broad range of substrates under a variety of conditions [71][72][73][74][75][76][77][78] and

NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides

• Alyn T. Davies,
• Mark D. Greenhalgh,
• Alexandra M. Z. Slawin and
• Andrew D. Smith

Beilstein J. Org. Chem. 2020, 16, 1572–1578, doi:10.3762/bjoc.16.129

• stereogenic trifluoromethyl centers is through enantioselective addition of enolates or their equivalents to prochiral trifluoromethyl ketones (Figure 1A). Within this area, a common catalytic approach has utilized aliphatic ketones as enolate equivalents using prolinamide, cinchona, or hybrid catalysts that

New α- and β-cyclodextrin derivatives with cinchona alkaloids used in asymmetric organocatalytic reactions

• Iveta Chena Tichá,
• Simona Hybelbauerová and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2019, 15, 830–839, doi:10.3762/bjoc.15.80

• recycle catalysts. However, only a limited number of organocatalytic moieties and functional groups have been attached to CD scaffolds so far. Cinchona alkaloids are commonly used to catalyze a wide range of enantioselective reactions. Thus, in this study, we report the preparation of new α- and β-CD

• derivatives monosubstituted with cinchona alkaloids (cinchonine, cinchonidine, quinine and quinidine) on the primary rim through a CuAAC click reaction. Subsequently, permethylated analogs of these cinchona alkaloid–CD derivatives also were synthesized and the catalytic activity of all derivatives was

• ) the cinchona alkaloid moiety can be successfully attached to CD scaffolds through a CuAAC reaction, (ii) the permethylated cinchona alkaloid–CD catalysts showed better results than the non-methylated CDs analogues in the AAA reaction, (iii) promising enantiomeric excesses are achieved, and (iv) the

A novel and practical asymmetric synthesis of eptazocine hydrobromide

• Ruipeng Li,
• Zhenren Liu,
• Liang Chen,
• Jing Pan,
• Kuaile Lin and
• Weicheng Zhou

Beilstein J. Org. Chem. 2018, 14, 2340–2347, doi:10.3762/bjoc.14.209

• and methallyl iodide [10]. However, these methods were undermined by expensive reagents, poor yields, harsh reaction conditions, or complex synthetic procedures. Phase-transfer asymmetric catalysis using cinchona alkaloid-derived quaternary ammonium salts is a practical method in organic synthesis [11

• ][12][13]. In our prior publication [14], this method was selected as the technology for the development of a process to prepare (R)-(+)-1-(5’-bromopentyl)-1-methyl-7-methoxy-2-tetralone, a key intermediate of dezocine, and N-(p-trifluoromethylbenzyl)cinchonidinium bromide (3) among 17 cinchona

Enantioselective phase-transfer catalyzed alkylation of 1-methyl-7-methoxy-2-tetralone: an effective route to dezocine

• Ruipeng Li,
• Zhenren Liu,
• Liang Chen,
• Jing Pan and
• Weicheng Zhou

Beilstein J. Org. Chem. 2018, 14, 1421–1427, doi:10.3762/bjoc.14.119

• 10.3762/bjoc.14.119 Abstract In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2-tetralone (3a), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1-methyl-7-methoxy-2-tetralone with 1,5

• separated by two times of resolution with L-tartaric acid and D-tartaric acid (Scheme 1). Phase-transfer asymmetric catalysis with cinchona alkaloid-derived quaternary ammonium compounds has become one of the topics in stereoselective synthesis in both industry and academia [6][7][8][9]. It was reported [10

• . (Some reports on the non-stereoselective alkylation of 2 were given in references [11][12]). In this paper, several cinchona-derived phase-transfer catalysts were screened for this reaction, and the structure–activity relationship for the catalysis was studied. In addition, optimizations had been made

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• catalytic amounts of chiral phase-transfer agents [32][33][34]. Although the literature contains examples of calixarene derivatives used as phase-transfer catalysts (PTCs) [35], the first asymmetric quaternary ammonium salts derived from cinchona alkaloids based on the calixarene skeleton were prepared by

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• ]. An extensively used two-component variant of this reaction consists in using a preformed imine. Among chiral metal complexes, a wide variety of organocatalysts [26][27][28][29][30][31][32][33][34] has been used to promote asymmetric Mannich reactions. Among them, cinchona alkaloid 1 was employed in

• -dicarbonyl compounds 5 performed in the presence of chiral cinchona alkaloid-derived squaramide 6 [36]. A range of chiral 3-amino-2-oxindoles 7 was obtained under mild reaction conditions in high to quantitative yields (78–99%) and uniformly excellent enantioselectivities (90–99% ee) as shown in Scheme 2. In

• diastereoselectivity of 90% de was achieved in the reaction of 1-benzoylacetone (R2 = Me, R3 = Ph) which afforded the corresponding single diastereoisomeric product in 96% yield and 95% ee. In 2018, Tanyeli et al. reinvestigated this type of reactions in the presence of related cinchona alkaloid-derived squaramide

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• catalyzed by a phase-transfer catalyst [74]. Their previous findings on the same reaction using a Cinchona-based phase-transfer catalyst [75] was further improved by using Maruoka’s binaphthyl-derived ammonium salt 110. The formation of intermediate 112 (chiral catalyst still attached to the substrate) from

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• afford diastereoisomeric catalysts (Sa,R,R)-C8, and (Sa,S,S)-C8, respectively. In the Michael addition of dimethyl malonate to the racemic nitroalkene 6, the cinchona-based catalysts C1–C3 performed poorly and provided the desired Michael adduct 7 in less than 10% yields (Table 1, entries 1–3). The lower

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

• Lingjun Xu,
• Shuwen Han,
• Linjie Yan,
• Haifeng Wang,
• Haihui Peng and
• Fener Chen

Beilstein J. Org. Chem. 2018, 14, 309–317, doi:10.3762/bjoc.14.19

• stereocontrol in alcoholytic catalytic asymmetric desymmetrizations of meso-cyclic anhydrides is of special interest [1][2][3][4][5][6][7]. Major families originating from natural products include cinchona alkaloids [8][9][10][11][12][13][14][15][16][17] and proteinogenic α-amino acids such as proline [18][19

• -derived bifunctional derivatives catalyzed asymmetric alcoholysis of anhydride, the exploration of new effective and easily accessible fully synthetic organocatalysts through further modification of this privilege motif are always needed. Our present design is inspired by cinchona-derived sulfonamides

Nucleophilic fluoroalkylation/cyclization route to fluorinated phthalides

• Masanori Inaba,
• Tatsuya Sakai,
• Shun Shinada,
• Tsuyuka Sugiishi,
• Yuta Nishina,
• Norio Shibata and
• Hideki Amii

Beilstein J. Org. Chem. 2018, 14, 182–186, doi:10.3762/bjoc.14.12

• ). Previously, Shibata et al. reported a cinchona alkaloid/Me4NF-catalyzed nucleophilic enantioselective trifluoromethylation of carbonyl compounds [33][34][35]. Initially, we tried to conduct the reaction of 2-cyanobenzaldehyde (2) with CF3–SiMe3 in the presence of cinchona alkaloids 9/TMAF combination (Table

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