A versatile and efficient approach for the synthesis of chiral 1,3-nitroamines and 1,3-diamines via conjugate addition to new (S,E)-γ-aminated nitroalkenes derived from L-α-amino acids

• Vera Lúcia Patrocinio Pereira,
• André Luiz da Silva Moura,
• Daniel Pais Pires Vieira,
• Leandro Lara de Carvalho,
• Eliz Regina Bueno Torres and
• Jeronimo da Silva Costa

Beilstein J. Org. Chem. 2013, 9, 832–837, doi:10.3762/bjoc.9.95

• the same route employed for (−)-2b and utilized as standard (Figure 1). The racemic nitroalkene (+/−)-2b showed a very good separation factor in the chromatograph chiral column used. Figure 1 shows that (−)-2b prepared from L-phenylalanine was enantiomerically pure (enantiomeric excess > 99%). HPLC

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks

• Sushil K. Maurya,
• Mark Dow,
• Stuart Warriner and
• Adam Nelson

Beilstein J. Org. Chem. 2013, 9, 775–785, doi:10.3762/bjoc.9.88

• , and the terminating building block 12b, were prepared by using established methods [14]. The enantiomeric excess (68% ee) of the hydroxy alcohol 11 was determined by conversion into the corresponding diastereomeric O-methyl mandelate esters. The terminating building blocks 12a and 13 were prepared by

Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives

• Martina Bonsignore,
• Maurizio Benaglia,
• Laura Raimondi,
• Manuel Orlandi and
• Giuseppe Celentano

Beilstein J. Org. Chem. 2013, 9, 633–640, doi:10.3762/bjoc.9.71

• modest to good yields. The N-formyl-L-proline (2) led to a racemic product in 21% yield, suggesting the importance of having a bulky group on the nitrogen atom. In order to validate our hypothesis, we also tested the N-Boc-L-proline methyl ester (3): the enantiomeric excess was 19% and the yield was 49

• , afforded the product with 36% yield and 70% enantiomeric excess. The presence of a hydroxy group on the scaffold of the catalyst (cat. 16, Table 2, entry 14) led to a racemic product, while the silyl ether derivative (17, Table 2, entry 15) promoted the reaction with good enantioselectivity, showing that

• comparison with literature data. N-(Phenyl)-1-phenylethanamine. This product was purified by flash column chromatography on silica gel with a 98:2 hexane/ethyl acetate mixture as eluent. 1H NMR (300 MHz, CDCl3) δ 7.23 (m, 7H), 6.61 (m, 3H), 4.48 (q, 1H), 1.53 (d, 3H). The enantiomeric excess was determined

Chemoenzymatic synthesis and biological evaluation of enantiomerically enriched 1-(β-hydroxypropyl)imidazolium- and triazolium-based ionic liquids

• Paweł Borowiecki,
• Małgorzata Milner-Krawczyk and
• Jan Plenkiewicz

Beilstein J. Org. Chem. 2013, 9, 516–525, doi:10.3762/bjoc.9.56

• after 30 h giving product (+)-6b in 90% ee (Table 2, entry 4), and after 49 h the stereochemical course reached 54% conversion yielding the slower reacting enantiomer (+)-5b with high enantiomeric excess (Table 2, entry 5, 98% ee). The highest optical purity for (+)-6b (90% ee) and the shortest reaction

• of enantiomers of 1-(1H-1,2,4-triazol-1-yl)propan-2-ol (±)-3b with various tested lipases was less efficient than that of (±)-3a. Resolution of (±)-3b proceeded with good yield, but the enantiomeric excess of the slower reacting enantiomer (alcohol (+)-5b) was less than 98%. The faster reacting ester

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

• ester moiety to a Weinreb amide [18] followed by changing the nitrogen protecting group to a carbamate furnished the key intermediate 6, which could be further alkylated with Grignard reagents to give β’-amino protected α,β-enone 1 in good overall yield and high enantiomeric excess. As Grignard reagents

Inter- and intramolecular enantioselective carbolithiation reactions

• Asier Gómez-SanJuan,
• Nuria Sotomayor and
• Esther Lete

Beilstein J. Org. Chem. 2013, 9, 313–322, doi:10.3762/bjoc.9.36

• secondary alkyllithiums to (E)- and (Z)-cinnamyl alcohols and amines 4 in the presence of stoichiometric or substoichiometric amounts of (−)-sparteine (L1) led to the corresponding alkylated products 5 in high enantiomeric excess (Scheme 2a). The chiral benzylic organolithium intermediates, which are

• stabilized by coordination with a Lewis-basic substituent, react with different electrophiles in a highly diastereoselective manner. On the other hand, when acetals derived from cinnamyl alcohols are used as substrates, cyclopropanes 6 can be obtained in high enantiomeric excess by warming the reaction

• closure and dehydration generates the substituted indoles 13 with high enantioselectivities (enantiomeric excess up to 86%) (Scheme 4). Different functional groups can be introduced at the C-2 position of the indoles by varying the electrophile [13][14]. The procedure has also been extended to the

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• known to limit racemization in peptide coupling reactions [16]. The enantiomeric excesses of the starting materials were ca. 95%. No erosion of stereochemistry in the products 12 was observed as determined by chiral HPLC. Recrystallization of 12 from ethanol did not increase the enantiomeric excess of

• enantiomeric excess. Isolating the potassium salt proved necessary, as attempts at preforming the potassium salt in dry DMF, followed by addition to the chiral α-bromoamide, led to ee’s of ca. 60%. Although both chiral acids are readily available from commercial sources, their enantiomeric excesses seem to be

• limited to ca. 95%. For these studies, ee’s >90% were sufficient; if material with higher enantiopurity is needed, we note that one recrystallization of (S)-1 from ethyl ether increases the enantiomeric excess from 94% to 97.4%. In an alternative approach that provides material with high enantiomeric

Asymmetric Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene

• Magnus Rueping and
• Sadiya Raja

Beilstein J. Org. Chem. 2012, 8, 1819–1824, doi:10.3762/bjoc.8.208

• and N-triflylphosphoramides 4–6 (Table 1) [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] as the catalysts. We were delighted to see that the reaction proceeded smoothly at different temperatures and that the product could be obtained with an enantiomeric excess of 8% ee

• -Diels–Alder reaction. From the different catalysts tested, phosphoric acid diester 4b, with the 2,4,6-triisopropylphenyl substituent in the 3,3’-position of the BINOL backbone, proved to be the best catalyst, and the product was obtained with an encouraging enantiomeric excess of 74% (Table 1, entry 3

• , when the reaction was carried out in a 2:1 mixture of hexane/toluene the product exhibited excellent enantioselectivity (Table 1, entry 13). Further improvement of selectivity was obtained by increasing the hexane/toluene ratio to 3:1, which delivered the product with an excellent enantiomeric excess

Imidazolinium and amidinium salts as Lewis acid organocatalysts

• Oksana Sereda,
• Nicole Clemens,
• Tatjana Heckel and
• René Wilhelm

Beilstein J. Org. Chem. 2012, 8, 1798–1803, doi:10.3762/bjoc.8.205

• transformed directly by anion metathesis to the salt 21. Conclusion It was possible to prepare new metal-free Lewis acids containing bis-imidazolinium cations and investigate the salts as organocatalysts. Although with enantiopure chiral salts no enantiomeric excess was observed, it was shown for the first

Enantioselective total synthesis of (R)-(−)-complanine

• Krystal A. D. Kamanos and
• Jonathan M. Withey

Beilstein J. Org. Chem. 2012, 8, 1695–1699, doi:10.3762/bjoc.8.192

• ), 71.8 (C2), 127.1, 129.1 and 132.0 (C5H, C6H, C8H and C9H); HRMS–ESI [M + H]+ calcd for C11H21O2, 185.1542; found, 185.1539. Enantiomeric excess was determined by HPLC analysis (Chiralcel OD-H, hexane/2-propanol 95:5, 1.0 mL min−1): tR 14.7 min (minor), 15.4 (major). Structure of (R)-(−)-complanine

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

• organocatalysts with their percentage of conversion (% yield) and enantiomeric excess (ee) is presented in tabular form, and the best catalyst is used for the given individual scheme. Review 1 Organocatalytic oxa-Michael additions to access functionalized chromenes 1.1. Reactions of 2-hydroxybenzaldehydes with

• aromatic substituents at the C-2 position in up to 70% yield and 60% enantioselectivity in dichloromethane at room temperature, while C-2 aliphatic analogues were obtained in 90% enantiomeric excess, but with only 20% yield, under identical conditions. Taking the advantages of the above methodology

• and high enantiomeric excess of 4H-chromenes 6 with a wide range of substrates (Scheme 6). The potential of less well-explored alkynals as Michael acceptors was further explored, when Alemán et al. [48] in 2010 reported the synthesis of chiral 4-amino-4H-chromene 8 by reaction of salicyl-N-tosylimine

Synthesis and evaluation of new guanidine-thiourea organocatalyst for the nitro-Michael reaction: Theoretical studies on mechanism and enantioselectivity

• Tatyana E. Shubina,
• Matthias Freund,
• Sebastian Schenker,
• Timothy Clark and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2012, 8, 1485–1498, doi:10.3762/bjoc.8.168

• particle size: 0.035–0.070 mm). NMR spectra were recorded on a Bruker Avance 300. FAB mass spectra were measured with a Micromass: ZabSpec. The enantiomeric excess of products was determined by chiral HPLC analysis in comparison with authentic racemic material. HPLC measurements were performed using

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

• Marcus Frings,
• Isabelle Thomé and
• Carsten Bolm

Beilstein J. Org. Chem. 2012, 8, 1443–1451, doi:10.3762/bjoc.8.164

• essentially no effect on both yield and enantioselectivity (Table 1, entries 8 and 9). In previous studies it was found that the enantioselectivity in some thiourea-catalyzed reactions was dependent on the concentration of the substrates and that in several cases the enantiomeric excess could significantly be

• (urea) concentration from 0.25 mol/L to 0.025 mol/L caused a distinct improvement of the enantiomeric excess and the enantiomer ratio of the product 20 raised from 58:42 to 72:28 (Table 1, entry 6 vs entry 10). In addition, product 20 was isolated in a slightly better yield (92%). The attempt to reduce

Highly enantioselective access to cannabinoid-type tricyles by organocatalytic Diels–Alder reactions

• Stefan Bräse,
• Nicole Volz,
• Franziska Gläser and
• Martin Nieger

Beilstein J. Org. Chem. 2012, 8, 1385–1392, doi:10.3762/bjoc.8.160

• organocatalytic Diels–Alder reactions to build up a tricyclic system. Herein, an asymmetric induction up to 96% enantiomeric excess was obtained by the use of imidazolidinone catalysts. This approach can be utilized to construct the tricyclic system in numerous natural products, in particular the scaffold of

• (model system II) 19 (Scheme 4, Table 4). Hydrochloric acid has been proven to be the best co-catalyst (Table 4, entry 1), providing cis-19 in good yield and with an enantiomeric excess of 96%. Even perchloric acid and trifluoroacetic acid gave high enantiomeric excesses but in much poorer yields (Table

•  4, entries 2 and 3). Using para-toluenesulfonic acid also afforded cis-19 in good yield, but its enantiomeric excess could not be determined (Table 4, entry 4). Trifluoromethanesulfonic acid as co-catalyst only led to decomposition (Table 4, entry 5). Under these optimized reaction conditions, we

Cyclodextrin nanosponge-sensitized enantiodifferentiating photoisomerization of cyclooctene and 1,3-cyclooctadiene

• Wenting Liang,
• Cheng Yang,
• Masaki Nishijima,
• Gaku Fukuhara,
• Tadashi Mori,
• Andrea Mele,
• Franca Castiglione,
• Fabrizio Caldera,
• Francesco Trotta and
• Yoshihisa Inoue

Beilstein J. Org. Chem. 2012, 8, 1305–1311, doi:10.3762/bjoc.8.149

• enantioselectivities. Interestingly, the enantiomeric excess (ee) was a critical function of the solution pH. For instance, 3 gave (+)-1E in 4.4% ee at pH 1.9 but a doubled 9.0% ee at pH 10. The largest pH-induced ee change was observed for 5, which afforded (−)-1E in 4.8% ee at pH 6.5 but antipodal (+)-1E in 9.8% at

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

• solvent, the residue was purified by flash column chromatography (8:1 hexane/EtOAc) to give (S)-ethyl 2-methyl-2-fluoro-3-oxo-3-phenylpropanoate (2a) as a colorless oil. (S)-Ethyl 2-methyl-2-fluoro-3-oxo-3-phenylpropanoate (2a) 51% yield, 70% ee. The enantiomeric excess was determined by HPLC on (R,R

• )-Ethyl 2-benzyl-2-fluoro-3-oxo-3-phenylpropanoate (2b) 59% yield, 60% ee. The enantiomeric excess was determined by HPLC on Regis Chiral 5 Micron with hexane/iPrOH (90:10) as the eluent. Flow rate: 0.8 mL/min, λ = 254 nm; tminor = 8.732 min, tmajor = 10.352 min; 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, J = 7.2

• Hz, 3H), 3.48 (d, J = 14.1 Hz, 1H), 3.67 (d, J = 14.1 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 7.14–7.23 (m, 5H), 7.26 (m, 2H), 7.36 (m, 1H), 7.91 (d, 2H); APCIMS m/z: 301.1 (M+ + 1). (R)-Ethyl 2-chloro-2-fluoro-3-oxo-3-phenylpropanoate (2c) 71% yield, 66% ee. The enantiomeric excess was determined by HPLC

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition

• Kim A. Fredriksen,
• Tor E. Kristensen and
• Tore Hansen

Beilstein J. Org. Chem. 2012, 8, 1126–1133, doi:10.3762/bjoc.8.125

• software), with EtOAc/hexanes of technical quality. Enantiomeric excess was determined by HPLC analysis using analytical columns (Chiralpak AS-H or AD-H from Daicel Chemical Industries). The Cinchona organocatalysts 2 and 3 were prepared from quinine (1) as described in the literature [15]. Dithiol 5 was

• phase was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to give the product as a colorless oil. This is a known compound [17]. Enantiomeric excess was determined by HPLC analysis (Chiralpak AS-H, 50% iPrOH in isohexane, 0.3 mL/min

• then 25% EtOAc in hexanes) to give the product as a colorless solid. This is a known compound [18]. Enantiomeric excess was determined by HPLC analysis (Chiralpak AD-H, 20% iPrOH in isohexane, 1.0 mL/min): tR = 7.3 min and 14.7 min. General procedure for asymmetric Michael addition of thiophenol to

Regio- and stereoselective oxidation of unactivated C–H bonds with Rhodococcus rhodochrous

• Elaine O’Reilly,
• Suzanne J. Aitken,
• Gideon Grogan,
• Paul P. Kelly,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2012, 8, 496–500, doi:10.3762/bjoc.8.56

• , respectively, were prepared in good yield under the same conditions as those employed for alcohol 10d. The 19F NMR of Mosher’s ester 14d showed a single peak suggesting an enantiomeric excess of greater than 95%. It should be noted, however, that authentic samples of the enantiomers are not available and it is

• hydroxylation. The MTPA (Mosher) ester 12d was prepared on reaction of alcohol 10d with (R)-methoxytrifluorophenylacetic acid in the presence of DCC and pyridine. Only one diastereomer was clear in the 1H NMR, but examination of the 19F NMR clearly showed two fluorine resonances from which an enantiomeric

• excess of 93% was calculated. The S-camphanic ester 11d was prepared in a 76% yield resulting from the reaction of the alcohol 10d with S-camphanic acid chloride in the presence of pyridine. 1H NMR analysis revealed that the resulting ester was a single diastereomer, and the absolute stereochemistry of

Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis

• Magnus Rueping,
• Teerawut Bootwicha and
• Erli Sugiono

Beilstein J. Org. Chem. 2012, 8, 300–307, doi:10.3762/bjoc.8.32

• increasing the residence time to 60 min (Table 3, entry 3 versus entry 2). The catalyst loading can be decreased to 0.5 mol % without loss of reactivity and selectivity; the desired tetrahydroquinoline was isolated in 96% yield with 94% enantiomeric excess (Table 3, entry 5). A further decrease of catalyst

The interplay of configuration and conformation in helical perylenequinones: Insights from chirality induction in liquid crystals and calculations

• Elisa Frezza,
• Silvia Pieraccini,
• Stefania Mazzini,
• Alberta Ferrarini and
• Gian Piero Spada

Beilstein J. Org. Chem. 2012, 8, 155–163, doi:10.3762/bjoc.8.16

• as where p is the helical pitch (in μm) of the cholesteric phase, and c and r are the concentration (molar fraction) and the enantiomeric excess of the dopant, respectively. The sign of HTP is taken as positive or negative if the induced cholesteric is right- or left-handed, respectively. The HTP of

Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope

• Aélig Robin,
• Valentin Köhler,
• Alison Jones,
• Afruja Ali,
• Paul P. Kelly,
• Elaine O'Reilly,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2011, 7, 1494–1498, doi:10.3762/bjoc.7.173

• turned out to be the most efficient for the epoxidation of the tetrahydropyridine ring, with substrate 7b epoxidised to 8b in 73% conversion. Racemic epoxide 8b was synthesised to confirm the structure of the biotransformation product and to determine the enantiomeric excess. This was found to be 18% for

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

• Xacobe C. Cambeiro,
• Rafael Martín-Rapún,
• Pedro O. Miranda,
• Sonia Sayalero,
• Esther Alza,
• Patricia Llanes and
• Miquel A. Pericàs

Beilstein J. Org. Chem. 2011, 7, 1486–1493, doi:10.3762/bjoc.7.172

• the determination of the enantiomeric excess of the products. Acknowledgements This work was funded by MICINN (Grant CTQ2008-00947/BQU and Consolider Ingenio 2010 Grant CSD2006-0003), DIUE (Grant 2009SGR623), and ICIQ Foundation. P.O.M. and R. M.-R. thank MICINN for Juan de la Cierva fellowships.

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• lipase in the presence of the acidic chemocatalysts and for reduction of zeolite-catalyzed side reactions [30][31]. The substrates and supercritical CO2 were fed continuously, thus omitting the use of organic solvents for product extraction. An enantiomeric excess of 97% was achieved for the product (R

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

• up to 91% enantiomeric excess, with either F–TEDA (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) in acetonitrile solution or NFSI (N-fluorobenzenesulfonimide) in dichloromethane solution as fluorinating reagents. The effects of various reaction parameters and of the

• prepared in situ from Me2AlCl and several chiral diols, were not catalytically active. However, the well-established Lewis acid [(R,R-TADDOLato)TiCl2] [82] (Scheme 1) displayed good catalytic activity (5 mol %, 1→1-F in 4 h) and gave (S)-1-F with an enantiomeric excess of 28% (for a complex incorporating

• fluorination by choosing NFSI (N-fluorobenzenesulfonimide) as the reagent with better solubility. Reaction with NFSI in dichloroethane gave 1-F with 24% ee (5 mol % K1, 40 °C, 3 d, 66% conversion), which is close to the enantiomeric excess observed with F–TEDA in acetonitrile at the same temperature (Table 2

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• conversion nor enantiomeric excess were observed to degrade over time, under steady-state conditions. Furthermore, with the initial ligand tested (Skewphos) the enantioselectivity achieved was similar to that obtained in conventional solvents (66% ee). Nevertheless, a further screening of a battery of