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

• -pyrrol-2(3H)-ones bearing quaternary stereocenters were obtained in acceptable yield (up to 75%) and enantioselectivity (up to 73% ee). Keywords: asymmetric catalysis; bifunctional catalysts; Henry reaction; organocatalysis; 1H-pyrrole-2,3-diones; Introduction Asymmetric organocatalysis has been

• bifunctional, thiourea-tertiary amine catalyst 3b, derived from quinine and L-valine, furnished a similar result to catalyst 3a (Table 1, entry 2). Next, the reaction was attempted with catalyst 3c derived from L-phenylalanine and catalyst 3d derived from L-phenylglycine, and improvements in enantioselectivity

• were observed (Table 1, entries 3 and 4). Changing L-phenylalanine to D-phenylalanine furnished catalyst 3e, and the enantioselectivity was improved to 61% ee (Table 1, entry 5). Having identified 3e as the best catalyst, we undertook a solvent screening for this transformation with 20 mol % 3e at 30

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

• Minami Odagi,
• Yoshiharu Yamamoto and
• Kazuo Nagasawa

Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22

• 3 in high yield with high enantioselectivity. A computational study of the transition state of this reaction revealed that inter- and intramolecular hydrogen-bonding networks between catalyst and substrate are critical for obtaining high enantioselectivity [22]. Based upon these insights, we

• ) [23]. Initially, the R3 substituent on the chiral spacer of the catalyst 1 was optimized (Table 1, entries 1–4). The catalyst with a benzyl group at R3 (1a) afforded 5a in excellent yield with moderate enantioselectivity for R configuration (Table 1, entry 1) [24][25]. When R3 was changed to a phenyl

• group, the enantioselectivity was slightly increased to 59% ee (Table 1, entry 2). In the case of a methyl group, 5a was obtained in 98% yield with 50% ee (Table 1, entry 3). An isopropyl group as R3 group was most effective, affording 5a with 66% ee (Table 1, entry 4). Next, we optimized R1 and R2 on

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

• explains our observation, that the D-psico-configurated ligand 10a requires higher temperatures for formation of the endo complex 17n and thus, results in a slower reaction rate and in a lower enantioselectivity compared to ligand 9a. Conclusion In summary, we have synthesized four spiro-fused carbohydrate

Enantioselective additions of copper acetylides to cyclic iminium and oxocarbenium ions

• Jixin Liu,
• Srimoyee Dasgupta and
• Mary P. Watson

Beilstein J. Org. Chem. 2015, 11, 2696–2706, doi:10.3762/bjoc.11.290

• ; enantioselectivity; iminium ion; oxocarbenium ion; Introduction Nitrogen and oxygen heterocycles with α-stereogenic centers represent important classes of biologicially active compounds [1][2][3][4][5][6][7]. Enantioselective addition of chiral nucleophiles to imines, iminium ions, carbonyls, or oxocarbenium ions

• reaction time could be reduced. Addition of alkynes with aryl, alkyl and trimethylsilyl substituents were successful, with the highest enantioselectivity observed when (trimethylsilyl)acetylene was used (94% ee). Just before Li’s report of the alkynlation of N-arylisoquinolinium ions, Taylor and Schreiber

• solvent also affect the enantioselectivity, with iPr2N(n-Pr) and CH2Cl2 proving best. Notably, only 1,2-addition was observed. With respect to the alkyne, activated terminal acetylenes, such as ynones and propriolates, are best for this reaction. Unactivated alkynes give products in reasonable yields (63

Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• expected, both the chemical yield and enantioselectivity were improved, and the adduct 5 was obtained in 92% yield with 80% ee. In our preliminary DFT calculation, the HB-donor moiety would recognize an oxyanion generated from phenolic OH of substrates with tertiary amine moiety of the catalyst. It was

• as (2R) by reference from the previous work [32][33]. Encouraged by this result, we next designed the new catalyst E with a stronger electron-withdrawing CF3 group on the aromatic ring, and applied it to the present AIOM reaction of 7 (Table 1, entry 7). To our delight, the enantioselectivity was

• improved to 85% ee while maintaining the high reactivity. Employing catalyst E we further investigated the reaction conditions and found that a scale-up synthesis can be performed using only 1 mol % of E with no loss of enantioselectivity, although gentle heating was required to ensure a high chemical

A novel and practical asymmetric synthesis of dapoxetine hydrochloride

• Yijun Zhu,
• Zhenren Liu,
• Hongyan Li,
• Deyong Ye and
• Weicheng Zhou

Beilstein J. Org. Chem. 2015, 11, 2641–2645, doi:10.3762/bjoc.11.283

• acetate aldol reaction [10]. However, these methods are undermined by poor yield, low enantioselectivity, and complex synthetic procedure. Chiral tert-butanesulfinamide, developed by García Ruano and Ellman, has been proven to be a broadly useful reagent for the preparation of chiral amines via the chiral

Recent advances in copper-catalyzed asymmetric coupling reactions

• Fengtao Zhou and
• Qian Cai

Beilstein J. Org. Chem. 2015, 11, 2600–2615, doi:10.3762/bjoc.11.280

• enantioselectivity and efficiency. In 2012, Cai et al. [45] developed the first copper-catalyzed asymmetric intramolecular Ullmann C–N coupling reaction through a desymmetrization strategy. The reaction lead to the enantioselective formation of indolines and tetrahydroquinolines in high yields and up to >99% ee

• additives such as 4-(N,N-dimethylamino)pyridine caused an unexpected inversion of enantioselectivity in the Cu-catalyzed asymmetric desymmetrization of α,α-bis(2-iodobenzyl)glycines when (2S,3aS,7aS)-octahydro-1H­indole-2-carboxylic acid was used as chiral ligand [47] (Scheme 18). In 2015, Cai et al

• )butanoates with CuI/BINOL-derived ligands in 2013, affording the chiral coupling products and recovered starting material with high enantioselectivity (Scheme 21). Recently, the aforementioned kinetic resolution strategy was applied to another type of substrates [51], leading to the formation of cyano

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

• already discussed [21][22][23], the bifunctional nature of organocatalysts plays an important role in this reaction to attain satisfactory levels of enantioselectivity. The presence of additional hydrogen donors such as urea groups positively affected the enantioselectivity both in the presence of chiral

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

• product syn-3n in good yield and high diastereo- and enantioselectivity (Table 1, entry 14). Disappointingly, when we tested β-alkyl-substituted nitroalkenes (R2 = iPr or n-Pr) we could not identify the formation of the desired addition product, and a complex mixture of products was obtained as a

• also heteroaryl moieties were well tolerated in the reaction (Table 2, entries 12 and 13). In the same line, functionalized nitroalkene 2n could also be successfully used in the reaction leading to adduct anti-3n in good yield, diastereo- and enantioselectivity (Table 2, entry 14). The use of bulkier

• products in good to excellent yields and with high enantioselectivity. ORTEP diagrams for anti-3a and syn-3o respectively. Diastereodivergent cascade Michael/Michael reaction using catalysts with the same absolute chirality reported in our group. Diastereodivergent enantioselective Michael reaction using

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• proceed via the chair-like transition state 104, afforded key intermediate 105 with high diastereo- and enantioselectivity. Preparation of the δ-lactone 106 of the A ring of xeniolide F was then realized by treatment of Claisen product 105 with the methylene Wittig reagent, followed by desilylation and

Copper-catalysed asymmetric allylic alkylation of alkylzirconocenes to racemic 3,6-dihydro-2H-pyrans

• Emeline Rideau and
• Stephen P. Fletcher

Beilstein J. Org. Chem. 2015, 11, 2435–2443, doi:10.3762/bjoc.11.264

• concentration, temperature and catalyst loading were also investigated (not shown) with no improvement on the enantioselectivity. After extensive optimization, the highest enantiomeric excess obtained was only 83% ee and so we decided to examine other leaving groups (Table 2). Like allyl chloride 2a, allyl

• , allyl phosphate 2d was found to provide 5 with good selectivity (77% ee, Table 2, entry 5). 3,6-Dihydro-2H-pyran-3-yl diethyl phosphate (2d) was also the only substrate to react using our previously reported AAA conditions (CuI, ligand A, CHCl3) [26], albeit with poor enantioselectivity (29% ee, Table 2

• giving low ee). The combination of CuOTf in CH2Cl2 gave the best enantioselectivity (up to 83% ee, Table S1 entry 3, Supporting Information File 1) with ligand G. Unlike with 2a, CuClO4 did not give high ee with 2d; the highest value obtained was 43% ee (Table S1, entry 14). Interestingly Et2O gave mixed

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• control of the regio- and enantioselectivity of the addition. The aim of this review is to report recent breakthroughs achieved in this challenging field. Keywords: conjugate additions; electron-deficient alkenes; enantioselective catalysis; extended Michael acceptors; organometallic nucleophiles

• [1]. Notably, the design and study of novel families of chiral enantiopure ligands has enabled a fine control of the regio- and enantioselectivity of the reaction, using a variety of nucleophilic and electrophilic substrate associations, with remarkable applications in total syntheses [2]. Polyenic

• total synthesis demonstrated that the nucleophilic copper compound could be generated in situ [14][15]. The design of efficient catalytic protocols could therefore be envisioned, enabling fine-tuning of the regio- and the enantioselectivity of the reaction. In order to tackle this challenge, many

Synthesis of α,β-unsaturated esters via a chemo-enzymatic chain elongation approach by combining carboxylic acid reduction and Wittig reaction

• Yitao Duan,
• Peiyuan Yao,
• Yuncheng Du,
• Jinhui Feng,
• Qiaqing Wu and
• Dunming Zhu

Beilstein J. Org. Chem. 2015, 11, 2245–2251, doi:10.3762/bjoc.11.243

• or low enantioselectivity toward these compounds. The Mycobacterium CAR-catalysed carboxylic acid reduction was combined with Wittig reaction to establish a new chemo-enzymatic approach to the synthesis of α,β-unsaturated esters. As described in the Experimental section, the holo-CAR enzyme mixture

C–H bond halogenation catalyzed or mediated by copper: an overview

• Wenyan Hao and
• Yunyun Liu

Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230

• source (Scheme 25). On the other hand, Du and Jia [72] developed a route for the asymmetric chlorination of similar carbonyl substrates 80 via copper-catalyzed asymmetrical α-chlorination in the presence of a chiral ligand. The yield of all products 81 was excellent, and the enantioselectivity, however

Ru complexes of Hoveyda–Grubbs type immobilized on lamellar zeolites: activity in olefin metathesis reactions

• Hynek Balcar,
• Naděžda Žilková,
• Martin Kubů,
• Michal Mazur,
• Zdeněk Bastl and
• Jiří Čejka

Beilstein J. Org. Chem. 2015, 11, 2087–2096, doi:10.3762/bjoc.11.225

• found as reaction products by GC–MS. Enantioselectivity was not established. Similar dependence of catalytic activity on the type of support was found for RCM of DAF (Figure 3). The initial TOFs (calculated from conversion at 5 min) decreased in the order: HGIIN+Cl−/MCM-22 (1770 h−1) > HGIIN+Cl−/MCM-56

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

• chiral 2,2′-bipyridine ligand L for 1 h. After successive addition of cinnamonitrile (1a) and bis(pinacolato)diboron, the resulting mixture was stirred at room temperature for 12 h. Subsequent oxidation by treatment with NaBO3 was conducted to determine the enantioselectivity. The desired β

• enantioselectivity in water. The conjugated system tends to undergo Lewis acid assisted isomerization in water [18]. With three mixtures of 1b with different E/Z ratios in hand, their activity toward boron conjugate addition and the sense of stereoselection were examined under the optimal conditions (Table 1). After

• stirring the reaction mixture for 12 h and subsequent oxidation, β-hydroxynitrile 2b was obtained in the same yield and with the same enantioselectivity, irrespective of substrate geometry. Notably, the E/Z geometry of α,β-unsaturated nitrile 1b did not have an influence on the initial reaction rate, nor

Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions

• Paul P. Kelly,
• Anja Eichler,
• Susanne Herter,
• David C. Kranz,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2015, 11, 1713–1720, doi:10.3762/bjoc.11.186

• configuration of the newly generated chiral centre was highly dependent on substitution and subtle changes in substrate structure resulting in significant changes in both conversion and enantioselectivity. The active site library of 93 P450cam variants promises to be a useful tool for the discovery of new P450

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

• Ivan Bassanini,
• Karl Hult and
• Sergio Riva

Beilstein J. Org. Chem. 2015, 11, 1583–1595, doi:10.3762/bjoc.11.174

• for example Zang et al. [49], Kobayashi and Makino [50], Gross et al. [51]). Nowadays lipases are not only used to achieve simple polycondensation reactions, but are exploited due to their chemo-, stereo- and enantioselectivity. In addition, they are seen as environmentally friendly alternative to

The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine

• Piotr Roszkowski,
• Jan. K. Maurin and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2015, 11, 1509–1513, doi:10.3762/bjoc.11.164

• desired amine was obtained in only 11% yield and with an enantioselectivity of 60% ee (Table 1). The low chemical yield probably results from the limited solubility of the imine in acetonitrile. When dichloromethane was used as a solvent, the chemical yield increased to 65% and the stereoselectivity

Regioselective synthesis of chiral dimethyl-bis(ethylenedithio)tetrathiafulvalene sulfones

• Flavia Pop and
• Narcis Avarvari

Beilstein J. Org. Chem. 2015, 11, 1105–1111, doi:10.3762/bjoc.11.124

• possibilities hardly addressed so far in TTF chemistry is the oxidation of the sulfur atoms into sulfoxides or sulfones. Indeed, only two reports deal with the oxidation of BEDT-TTF into BEDT-TTF monosulfoxides (Scheme 1), along with enantioselectivity issues [27][28]. We describe herein the synthesis

Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel–Crafts alkylations

• Tommaso Pecchioli,
• Manoj Kumar Muthyala,
• Rainer Haag and
• Mathias Christmann

Beilstein J. Org. Chem. 2015, 11, 730–738, doi:10.3762/bjoc.11.83

• dilution experiments (Table 4). The best yield and enantioselectivity of 13 was obtained using PG-57 (4b) and lowering the concentration from 0.63 to 0.30 M (Table 4, entry 4). Contrarily, PG-95 (4a) did not lead to any appreciable improvement (Table 4, entry 3). By reducing the concentration to 0.10 M, 4b

• enantioselectivity (Table 6, entries 2, 3 and 4). Catalyst 4a showed turnover rates comparable with the traditional imidizolidin-4-one 16 (Table 6, entries 1 and 4). In conclusion, high- (PG-95, 4a) or low- (PG-30, 4c) loaded support were less active when compared to an intermediate degree of functionalization (PG

• and 4b enabled homogeneous reactions without loss of efficiency due to immobilization. The activity of multivalent catalyst 4a was comparable with that exhibited by the traditional MacMillan’s catalyst, while 4b was shown to be superior. Nevertheless, erosion in enantioselectivity was observed

Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity

• Sergey Tin,
• Tamara Fanjul and
• Matthew L. Clarke

Beilstein J. Org. Chem. 2015, 11, 622–627, doi:10.3762/bjoc.11.70

• appeared for enamines that are activated by a chelating group, or can potentially isomerise to an NH imine during catalysis [4][5]. A few papers have appeared with good enantioselectivity for some quite specific enamines, but despite the importance of these contributions, catalyst loadings around 1 mol

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

• , enantioselective tandem conjugate addition–aldol reaction of cyclic enones [19]. While tandem conjugate addition–α-functionalization reactions were well known prior to Feringa’s publication [20] (Scheme 1), this work was unique because of the high enantioselectivity that was observed through the use of a chiral

• enantioselectivities by using a phosphoramide ligand [85]. Table 1 highlights the different substrates and alkyl metal nucleophiles that were studied in this work. Though the use of the Cbz group in the ECA reaction provided the product in good yield and enantioselectivity (Table 1, entry 1), entries 2 and 3 show that

• the best enantioselectivities were observed with the N-carboxyphenyl protecting group. The authors were also able to employ the more reactive alkylaluminium reagents in this reaction, although there was a decrease in the enantioselectivity (Table 1, entries 5 and 6). When the ECA of a 5-membered

Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

• Hongnan Sun,
• Binbin Huang,
• Run Lin,
• Chao Yang and
• Wujiong Xia

Beilstein J. Org. Chem. 2015, 11, 524–529, doi:10.3762/bjoc.11.59

• intriguing strategy for the synthesis of substituted morpholines through Cu(OTf)2-catalyzed ring-opening/closing reactions of aziridines and halogenated alcohols in high yield and enantioselectivity (Scheme 1a) [21]. However, this method suffered from the need for transition metal catalysts and low

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• were intercepted with cyanide [71]. The enantioselectivity induced in this step was as a result of using a chiral auxiliary, 8-phenylmenthyl attached to the carbamate (Scheme 19). Other natural product syntheses have used the anodic oxidation approach, often as the first step in a synthesis campaign to