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

• easy to make from the corresponding cinchona alkaloids, making them attractive compounds for methodologists to have within their catalyst arsenal. They seem particularly suited to catalysis with systems that have an aromatic ring next to a five-membered ring – e.g., indoles, indenones, isatin etc

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

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

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

• 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

• -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

• enantioselective desymmetrization of a phospholene meso-epoxide by cinchona alkaloids to P,C-chirogenic 3-hydroxy-2-phospholene derivatives 93 and 94. Among the four main components of cinchona alkaloids, quinidine (OC-57) proved to be the most effective base in the enantioselective rearrangement of epoxide, and

• -aziridines are plentiful and can be found in a diverse set of privileged structures, including cinchona alkaloids-based PTCs, L-proline-derived amino alcohols, chiral phosphorous acids, chiral thioureas, chiral guanidines, and chiral 1,2,3-triazolium chlorides. But for the desymmetrization of meso-epoxides

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• under different protocols in which the stereoselectivity of the reaction can be introduced through the use of a chiral catalyst [9][10] (Lewis acid, Brønsted acids, L-proline, Cinchona alkaloids derivatives, thioureas, etc.), or by the addition of chiral amines to α,β-unsaturated esters [11][12] or the

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• stereoselective meso-anhydride ring opening represents an important approach for providing multiple stereogenic centres in the target molecule [55][56][57]. In this feat the Cinchona alkaloids have emerged as powerful organocatalysts. A ball-milling-assisted highly efficient asymmetric ring opening of meso

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• thiochromenes; and (3) Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquinolines, using chiral proline and its derivatives (Figure 2), chiral bifunctional thioureas, cinchona alkaloids and other organocatalysts (Figure 3). For each reaction, the initial screening result of various

• , thiochromene or 1,2-dihydroquinolin structural motifs. Screened chiral proline and its derivatives as organocatalysts. Rb = rubidium. Screened chiral bifunctional thiourea, its derivatives, cinchona alkaloids and other organocatalysts. Diarylprolinolether-catalyzed tandem oxa-Michael–aldol reaction reported by

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

• Sergei Žari,
• Tiiu Kailas,
• Marina Kudrjashova,
• Mario Öeren,
• Ivar Järving,
• Toomas Tamm,
• Margus Lopp and
• Tõnis Kanger

Beilstein J. Org. Chem. 2012, 8, 1452–1457, doi:10.3762/bjoc.8.165

• unsaturated 1,4-diketones catalyzed by thiourea and squaramide derivatives with Cinchona alkaloids afforded the formation of a new C–C bond in high yields (up to 98%) and enantiomeric purities (up to 93%). The absolute configuration of the product was suggested from comparison of the experimental and

• investigated the organocatalytic approach to the asymmetric desymmetrization of the title compounds with malonates. Three types of organocatalysts providing noncovalent interactions were used for this purpose: Cinchona alkaloids (I–V), thiourea derivatives (VI, VII) and squaramide derivatives (VIII, IX

• high. Cinchona alkaloids (Table 1, entries 1–4) catalyzed the reaction with low stereoselectivity. There was a remarkable difference in their reaction rates. Quinine (II) and quinidine (IV, Table 1, entries 2 and 4) were more efficient than cinchonine (I) and cinchonidine (III, Table 1, entries 1 and 3

Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

• Jin-Sheng Yu,
• Feng Zhou,
• Yun-Lin Liu and
• Jian Zhou

Beilstein J. Org. Chem. 2012, 8, 1360–1365, doi:10.3762/bjoc.8.157

• to report our initial results about the catalytic asymmetric Michael addition of unprotected 3-prochiral oxindoles to 1,4-naphthoquinone. Results and Discussion We began the reaction development by the evaluation of different chiral catalysts derived from cinchona alkaloids in the reaction of 3

Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

• Wen-Bin Yi,
• Xin Huang,
• Zijuan Zhang,
• Dian-Rong Zhu,
• Chun Cai and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 1233–1240, doi:10.3762/bjoc.8.138

• , Boston, MA 02125, USA 10.3762/bjoc.8.138 Abstract A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of β-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from

• electrophilic reaction with Selectfluor (F-TEDA-BF4, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)), as developed by Bank [7][8][9]. The Cahard [10][11][12] and Shibata [13][14] groups combined cinchona alkaloids and Selectfluor for asymmetric fluorination of substrates such as

• imido-protected phenylglycines (up to 94% ee), indanones and tetralones (up to 91% ee), ethyl α-cyanotolyl acetates (up to 87% ee), and cyclic β-ketoesters (up to 80% ee) [15]. A catalytic approach for the cinchona alkaloids and Selectfluor combinations has also been developed [16]. The Togni group

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• (tetrafluoroborate); TEDA = triethylenediamine) [27][28][29] marked some important discoveries: First, a new generation of highly enantioselective chiral fluorinating reagents, derived by fluorine transfer [30] from F–TEDA to the quinuclidine portion of cinchona-alkaloids, was introduced by the groups of Cahard [31

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• % yield [17]. In 2008–2009, we found that chiral nonracemic cinchona alkaloids and guanidines act as Brønsted bases to generate ammonium or guanidinium enolates for the enantioselective electrophilic trifluoromethylation of β-keto esters with Umemoto reagents with good enantioselectivities in the range 60

C₂-symmetric bisamidines: Chiral Brønsted bases catalysing the Diels- Alder reaction of anthrones

• Deniz Akalay,
• Gerd Dürner,
• Jan W. Bats and
• Michael W. Göbel

Beilstein J. Org. Chem. 2008, 4, No. 28, doi:10.3762/bjoc.4.28

• exerted by chiral Brønsted bases. Moderate to excellent stereoselectivities of products 3 have been reported using pyrrolidines 4 [1][2], cyclic guanidine 5 [3], or cinchona alkaloids 6 [4] as catalysts. Recently, we could promote this type of cycloaddition by metal-free bisoxazolines 7 in up to 70% ee

Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me₃SiCF₂SO₂Ph and PhSO₂CF₂H reagents catalyzed by chiral quaternary ammonium salts

• Chuanfa Ni,
• Fang Wang and
• Jinbo Hu

Beilstein J. Org. Chem. 2008, 4, No. 21, doi:10.3762/bjoc.4.21

• catalysts for asymmetric synthesis, cinchona alkaloids and their derivatives can catalyze an amazing array of synthetically important reactions, providing access to chiral products of high enantiopurity [32][33]. Several examples have been reported on the enantioselective incorporation of trifluoromethyl

• difluoromethylation reaction with catalyst 6a or 8a, and the results are shown in Table 3. Although the two types of cinchona alkaloids 6a and 8a are almost equally effective when benzaldehyde was tested, 6a was chosen due to its generality towards other aldehydes such as 4-chlorobenzaldehyde 1b. In general, the