Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• asymmetric addition reaction of racemic naphthylindole 42 with azodicarboxylate 43 under chiral phosphoric acid catalysis. In the presence of CPA 2, 42 and 43 reacted and underwent dynamic kinetic resolution to afford naphthylindoles 44 with axial chirality in moderate to good yields (50–98%) and high

• also achieved the first catalytic asymmetric construction of axially chiral 3,3’-bisindole scaffolds 49 bearing both axial and central chirality by employing the CPA-14-catalyzed asymmetric addition reaction of 2-substituted 3,3’-bisindoles 47 to isatin-derived 3-indolylmethanols 48. The isatin-derived

• carbazole derivatives 57 via asymmetric addition and chirality transfer. In the presence of CPA 9, axially chiral N-arylcarbazoles were obtained in moderate to good yields (51–97%) with good to excellent enatioselectivity (87–96% ee, Scheme 20a) [73]. More importantly, the same group reported the synthesis

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• necessary for this transformation. Recently, copper hydride (CuH) catalysis has been a wonderful procedure for olefin hydrofunctionalization via the formation of nucleophilic alkylcopper intermediate. In 2016, Buchwald and co-workers described a CuH-catalyzed asymmetric addition of olefin to ketones [65

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• . Enantioselective tail-to-head cyclization of neryl chloride derivatives. Cation–π interactions in anion binding-catalyzed asymmetric addition reactions: a) addition of indoles to pyrones and b) allylation of α-chloro glycinates. Bisthiourea catalyzed oxa-Pictet–Spengler reaction of indole-based alcohols and

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• described by Herrera et al. for the first time using primary aromatic diamines 31 as organocatalysts. The application of this class of catalysts for the Michael asymmetric addition of 4-hydroxycoumarins 1 to enones 2 is interesting from the point of view of organocatalysis, since the presence of two primary

• -withdrawing and electron-donating substituents were well tolerated in either coumarin or imine portion, and electron-withdrawing substituents at ortho-position of the imine phenyl ring afforded the corresponding products with excellent yields and moderated to good ee. The asymmetric addition of malonic acid

• recently, the strategy via introducing secondary interactions for the design of the bifunctional catalysts achieved wide application in asymmetric reactions [74]. Wu et al. described a Mannich asymmetric addition of cyanocoumarins 39 to isatin imines 112 catalyzed by an amide-phosphonium salt 114. This

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• [46]. Catalytic systems based on pyridine-oxazolines ligands Currently, the most studied ligand class is focused on pyridine-oxazolines (PyOx). The first report for the use of this type of ligand for the asymmetric addition of arylboronic acids to cyclic enones was published by the Stoltz group in

• ) [6]. In 2019, another expansion of the substrate scope for the synthesis of substituted flavanones was done by Liu et al. (Table 24). The prepared flavanones were further tested for their cancerostatic activity [7]. In 2019, Timmerman et al. applied the asymmetric addition of phenylboronic acid to a

• the solvent (86% yield, 71% ee, Scheme 19) [54]. Significant successes of the Stanley group were achieved in the subsequent study of the as yet unexplored asymmetric addition of arylboronic acids to 3-aryl-2-cyclohexenones, where double benzyl quaternary stereogenic centres were formed [55]. The

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• assumed by analogy. Dehydration of compound 13b in the presence of p-toluenesulfonic acid gives dihydropyran 14 as a single stereoisomer (Scheme 4). Conclusion In summary, a convenient protocol for the synthesis of phosphoryl-substituted pyrrolidines with three contiguous stereocenters via asymmetric

• addition of β-keto phosphonates to nitroolefins and subsequent reductive cyclization of enantioenriched, diastereomerically pure Michael adducts was developed. The present study also demonstrates that the diastereoselective cascade Henry/acetalyzation reaction with keto nitro phosphonates and aldehydes

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• silyl ether-protected 2-hydroxypropanals 15a and 15b via literature procedures [10], followed by the application of the Still–Gennari Z-selective Horner–Wadsworth–Emmons olefination [11]. Koide’s group [12][13] reported that the asymmetric addition of the enyne 16 to acetaldehyde in the presence of zinc

• the (R,R)-ProPhenol ligand [16] to accomplish a catalytic asymmetric addition of methyl propynoate to acetaldehyde to give 18 in high enantiopurity (98% ee). Jacobsen’s group [17][18] utilized the Noyori Ru-catalyzed transfer hydrogenation [19] of the 3-butyne-2-one 19, which gave 20 with 97% ee. The

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

• bearing fluorine and nitrogen atoms involves the asymmetric addition of α-fluoro-β-ketoesters or α-fluoro-α-nitro esters to appropriate electrophiles [84][85][86][87][88][89]. Results and Discussion Initially, we prepared a series of Ugi adducts 8 by varying acid, 2-oxo-aldehyde, amine, and isocyanide

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• chiral natural products and bioactive molecules. Hence, this review focuses on the progress made over the past 20 years for heterocyclic acceptors. Keywords: conjugate addition; copper catalysis; heterocyclic Michael acceptor; organometallics; Introduction The copper-catalysed asymmetric addition of

• strategies that target the synthesis of chiral heterocyclic motives [12][13][14]. Among these, methodologies based on the copper-catalysed asymmetric addition of organometallics are especially valuable because of i) the compatibility between copper catalysts and heteroatoms present in the starting materials

• ACA of alkenylalanes to N-substituted-2,3-dehydro-4-piperidones. Copper-catalysed asymmetric addition of dialkylzinc reagents to N-acyl-4-methoxypyridinium salts formed in situ. Copper-catalysed ACA of organozirconium reagents to N-substituted 2,3-dehydro-4-piperidones and lactams. Copper-catalysed

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• -divergent borylative coupling of styrenes 395 with N-phosphinoyl and N-thiophosphinoyl imines 394 to afford α,β-disubstituted γ-borylated nonracemic amines 396–399. A combination of CuMes with either (R,R)-Ph-BPE or (R)-(Sp)-Josiphos afforded the targeted products in high ees (Scheme 63). The asymmetric

• addition of benzylic–Cu intermediates to imines proceeds through a flexible linear transition state which is sensitive to the steric environment surrounding the copper catalyst. This observation provided the opportunity to achieve either diastereomer depending on the choice of the ligand L45 or L46. Based

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• the formal synthesis of triptolide (Figure 2, route N) [43]. This synthesis highlighted the palladium-catalyzed asymmetric addition of arylboronic acid 37 to 3-methylcyclohex-2-en-1-one (38) to form the C-10 quaternary chiral center, and a subsequent Claisen rearrangement and an aldol reaction to

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• -ligands [23]. The asymmetric addition of various nucleophiles to unsaturated sulfones is also considered as an effective route to chiral sulfones. The conjugated addition of arylboronic acids to unsaturated sulfones under catalysis of Rh complexes was reported [24][25][26]. It was shown that arylboronic

• acceptors and aldehydes [27][28][29][30][31][32], ketones [33], α-cyano esters [34][35], β-keto esters [35], β-keto acids [36], thiomalonates [37], nitroalkanes [38], oxindoles [39] and thiols [40] as Michael donors. There are only few examples of the use of sulfones as Michael donors in asymmetric addition

• reactions. Thus, ketonitrosulfones were obtained with good enantiomeric excesses via asymmetric addition of α-nitrosulfones to enones in the presence of organocatalysts [41]. Asymmetric addition of β-ketosulfones to nitroalkenes was implemented using various organocatalysts [42]. The reaction of

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

• derivative which undergoes a Henry-type reaction with nitromethane in the first flow step (Flow I). The resulting nitroalkene undergoes an asymmetric addition catalyzed by a supported PS–(S)-pybox–calcium chloride catalyst at 0 °C using two columns (Flow II). This is the enantio-determining step of the

Chromium(II)-catalyzed enantioselective arylation of ketones

• Gang Wang,
• Shutao Sun,
• Ying Mao,
• Zhiyu Xie and
• Lei Liu

Beilstein J. Org. Chem. 2016, 12, 2771–2775, doi:10.3762/bjoc.12.275

• asymmetric addition to ketones remains a big challenge probably due to the decreased reactivity and selectivity [36][37]. A breakthrough was made by the Sigman group who reported the catalytic enantioselective addition of allylic bromides and propargyl halides to arylaliphatic ketones using oxazoline ligands

Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji–Trost coupling

• Sebastian Bretzke,
• Stephan Scheeff,
• Felicitas Vollmeyer,
• Friederike Eberhagen,
• Frank Rominger and
• Dirk Menche

Beilstein J. Org. Chem. 2016, 12, 1111–1121, doi:10.3762/bjoc.12.107

• alkaloids of marine origin. Additional features of this route include the stereoselective generation of the central amine core with an appending quaternary center by an asymmetric addition of a Grignard reagent to a chiral tert-butanesulfinyl ketimine following an optimized Ellman protocol and a cross

• the chiral amine core of these alkaloids. For the synthesis of the nitrogen appending the quaternary center we tested a method developed by the Ellman group [46][47], which relies on an asymmetric addition of organometallic reagents to enantiopure tert-butanesulfinyl ketimines of type 29 and 30

• further studies for modular heterocycle synthesis. Experimental Preparation of 31 by asymmetric addition of allylmagnesium bromide to 29 In a flame-dried flask (SS)-N-(1-((tert-butyldimethylsilyl)oxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (29, 1.37 g, 4.70 mmol, 1.0 equiv) was dissolved in 12 mL

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

• alkoxide species C. Reductive elimination of species C gave the product and regenerated the active iridium catalyst. Recently, Qiu and co-workers developed a novel chiral ligand L5 based on a chiral-bridged biphenyl backbone and successfully achieved the asymmetric addition of arylboronic acids to N

• proline and its derivatives [31]. Recently, Hoveyda and co-workers designed a novel amino acid amide catalyst (cat. 4) for the asymmetric addition of unsaturated organoboranes to carbonyls and imines, producing the corresponding enantiomerically pure alcohols and amines in excellent yields [32]. As shown

• same group reported the organocatalytic asymmetric addition reactions of isatins with electron-rich aromatics sesamols using the cinchona alkaloid-derived thiourea catalyst (cat. 17) under mild conditions. In the presence of 10% catalyst, sesamols reacted with isatins smoothly in tert-butyl ether at

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

• of incorporating this scaffold into diverse organocatalysts. In 2008, Seidel’s group published a new example of an asymmetric addition of indoles to nitroalkenes, employing a novel catalyst design [24]. The authors envisioned that a protonated 2-pyridyl substituent could increase the acidity of the

• the compounds 32a–d, being S. Later, He and co-workers reported the use of several chiral multiple hydrogen-bond donating tertiary amine-based organocatalysts in the asymmetric addition of acetylacetone (36a) to the β-nitroalkenes 3. They found the thiourea 37 as a highly suitable catalytic structure

• external Brønsted acid. Proposed transition state TS7 for the Friedel–Crafts reaction of indole and α,β-unsaturated acyl phosphonates catalyzed by ent-4. Possible transition states TS8 and TS9 in the asymmetric addition of indoles 2 to the β,γ-unsaturated α-ketoesters 26 catalyzed by ent-4. Transition

(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

• -vinylindoles 51 [29]. Desymmetrization of meso-anhydrides by Chin, Song and co-workers [30]. Desymmetrization of meso-anhydrides by Connon and co-workers [31]. Asymmetric intramolecular Michael reaction [32]. Asymmetric addition of malonate to 3-nitro-2H-chromenes 67 [33]. Intramolecular desymmetrization

Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation

• Jochen Kraft,
• Martin Golkowski and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 166–171, doi:10.3762/bjoc.12.18

• benchmark test for selectivity, the palladium-catalyzed asymmetric addition of dimethyl malonate to 1,3-diphenylallyl acetate was often used in the literature for testing the scope of carbohydrate derived ligands for this purpose [9][10][11][12][13]. For instance, Kunz and Gläser have demonstrated the

Chiral Cu(II)-catalyzed enantioselective β-borylation of α,β-unsaturated nitriles in water

• Lei Zhu,
• Taku Kitanosono,
• Pengyu Xu and
• Shū Kobayashi

Beilstein J. Org. Chem. 2015, 11, 2007–2011, doi:10.3762/bjoc.11.217

• desired β-borylated product was isolated as the β-hydroxynitrile after subsequent oxidation, with complete retention of the expected stereochemistry. β-Hydroxynitriles, which are conventionally synthesized by asymmetric addition of acetonitrile to aldehydes [6][20] or by lipase- or nitrilase-catalyzed

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

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• is achieved via an asymmetric addition of phenylethylzinc to the imine N-oxide 2.66 yielding the corresponding 3,4-dihydroisoquinoline-N-hydroxide 2.68. Further reductive cleavage of the hydroxylamine moiety followed by activation with 4-nitrophenyl chloroformate [79] yields the intermediate 2.69. In

Metal-mediated aminocatalysis provides mild conditions: Enantioselective Michael addition mediated by primary amino catalysts and alkali-metal ions

• Matthias Leven,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2013, 9, 155–165, doi:10.3762/bjoc.9.18

• direct aldol reaction, which is mediated by copper ions and amino acid derivatives [14] or enamine nucleophilic addition to palladium π-allyl electrophiles [15][16][17]. We report the development of new catalysts based on chiral 1,2-diamines and present their application in the asymmetric addition of 4

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

• bicyclic guanidines [7][9][12]. Xiao et al. reported the addition of nitroalkanes to 4-oxo-enoates, using chiral urea derivatives [7]. Miura et al. achieved an asymmetric addition of α,α-disubstituted aldehydes to maleimides catalyzed by primary amine thiourea organocatalyst [13]. Wang et al. reported the

• addition of dialkylmalonates and nitromethane to 4-oxo-4-arylbutenoates catalyzed by N,N´-dioxide-Sc(OTf)3 complexes [8]. Despite these and other successful experimental results, the asymmetric addition of malonates to symmetric aromatic unsaturated 1,4-diketones has not been systematically studied