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

• mmol) and ee 78%. The enantiomers were separated by HPCL using the following conditions: Chiralcel AD-H, n-hexane/iPrOH 70:30, 1.0 mL/min, 10 °C, 12.3 min (minor; R-enantiomer), 25.5 min (major; S-enantiomer). The product was dissolved in a mixture of dichloromethane (6 mL) and heptanes (4 mL) and

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

• arises as a key methodology for chemical production of enantiomerically enriched chiral compounds in terms of atom economy and reduced waste generation [2][3][4][5][6]. Nowadays, many very effective methodologies exist that allow the formation of a chiral compound as a single enantiomer. However, and

• achieved by selecting the correct enantiomer of the catalyst, the relative configuration is typically governed by intrinsic factors associated to the mechanistic profile of the reaction and very often the formation of the major diastereoisomer is determined from the very beginning of the reaction and

• syn-3a in excellent yield, an acceptable 88:12 dr and 98% ee. As expected, the use of the pseudoenantiomeric catalyst 5 provided the corresponding enantiomer ent-syn-3a with similar results. Moving to cyclohexanediamine-based catalyst 6 resulted in the same behaviour as observed in our previous report

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

• enantiomerically pure and configurationally stable nine-membered E,Z-dienone 80. The synthesis of the enantiomer of dienone 80, ent-80, was accomplished by a route parallel to that presented in Scheme 8a, starting from ent-77. The highly efficient construction of these versatile intermediates provides a basis to

• synthesize a variety of natural products containing this macrocyclic structural motif. Based on chiral enone 80 and its enantiomer, ent-80, coraxeniolide A (10) and β-caryophyllene (22) were synthesized in five and four further steps, respectively. The synthesis of 10 continued with a trityl perchlorate

• antheliolide A (18) by Corey. a) Synthesis of enantiomer 80, b) total syntheses of coraxeniolide A (10) and c) β-caryophyllene (22) by Corey. Total synthesis of blumiolide C (11) by Altmann. Synthesis of a xeniolide F precursor by Hiersemann. Synthesis of the xenibellol (15) and the umbellacetal (114) core by

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

• alkylation (AAA) reactions [5][6][7] can be used in dynamic kinetic asymmetric transformations (DYKAT) [8][9][10][11][12][13][14][15] to provide single enantiomer products from racemic starting materials. Mechanistically some of these have been shown to occur by direct enantio-convergent transformations [16

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

• Josiphos enantiomer used, in both cases with good enantioselectivities (85–92% ee). Subsequent chain elongation followed by a 1,4-ACA reaction was described and enabled the enantioselective insertion of an additional methyl group. With trialkylaluminium reagents Only a few systems are known to perform

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

• same article the authors showed that only the (L)-enantiomer of dimethyl malate afforded polymers. A racemate of malate esters gave only short polymers; showing nicely that efficient polymerization of diacids can only be achieved with carboxylic groups of similar reactivity. The poly(hexanediol-2

Synthesis of racemic and chiral BEDT-TTF derivatives possessing hydroxy groups and their achiral and chiral charge transfer complexes

• Sara J. Krivickas,
• Chiho Hashimoto,
• Junya Yoshida,
• Akira Ueda,
• Kazuyuki Takahashi,
• John D. Wallis and
• Hatsumi Mori

Beilstein J. Org. Chem. 2015, 11, 1561–1569, doi:10.3762/bjoc.11.172

• ,S)-2. The other enantiomer (R,R)-2 was synthesized in the same manner. The cyclic voltammetry measurement on racemic-1 indicated the first and second oxidation potentials (E11/2, E21/2) and their difference ΔE (= E21/2 − E11/2) to be 0.52, 0.83, and 0.31 V by utilizing glassy carbon as working

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

• : chiral diamines; enantioselective reduction; epinastine; mianserin; ruthenium complexes; Introduction Mianserin (1) is a tetracyclic compound widely used as a drug in the treatment of depression. Despite the fact that the (S)-(+)-enantiomer of mianserin is more potent than the (R)-antipode in

• pharmacological tests for antidepresant activity [1][2][3], it is still administered as a racemate probably due to the fact that no serious adverse effects have been recorded for the (R)-enantiomer. Interestingly, no enantioselective synthesis of mianserin has been developed so far. The synthesis of racemic

• another important active substance, epinastine, in enantiomerically pure form (Figure 1). Epinastine (2) is a histamine H1 receptor antagonist and is used as racemic mixture in eye drops to relieve the symptoms of allergic conjunctivitis. Analogously as in the case of mianserin, the (S)-enantiomer is the

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

• Ana Čikoš,
• Irena Ćaleta,
• Dinko Žiher,
• Mark B. Vine,
• Ivaylo J. Elenkov,
• Marko Dukši,
• Dubravka Gembarovski,
• Marina Ilijaš,
• Snježana Dragojević,
• Ivica Malnar and
• Sulejman Alihodžić

Beilstein J. Org. Chem. 2015, 11, 1447–1457, doi:10.3762/bjoc.11.157

• ]. Only one enantiomer at 8-C was isolated, showing retention of stereochemistry. This would support the hypothesis that the difference in energies of the 6-membered ring anomers relative to a 5-membered ring is sufficient to drive the conversion of 3 to 4. Conclusion In this paper we have presented the

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

• time in the middle of 80s by Dunitz and Wallis through the synthesis of the (S,S,S,S)-enantiomer of tetramethyl-bis(ethylenedithio)tetrathiafulvalene (TM-BEDT-TTF) (Scheme 1) [1], thus opening opportunities towards the preparation of chiral molecular conductors [2]. Since then a large number of chiral

• for C16H16N2S8: C, 38.99; H, 3.27; N, 5.68; S, 52.05; found: C, 38.65; H, 3.05; N, 5.34; S, 52.43 (%). (R,R)-3: The same synthetic procedure was followed as for the (S,S) enantiomer starting from (R,R)-5. Yield 55%. Anal. calcd for C16H16N2S8: C, 38.99; H, 3.27; N, 5.68; S, 52.05; found: C, 38.71; H

• , 116.56, 112.02, 111.44, 50.10, 44.04, 30.38, 27.39, 21.36 ppm; MALDI–TOF MS (m/z): 444 [M]+ (Mcalcd = 443.86); Anal. calcd for C12H12O2S8: C, 32.41; H, 2.72; O, 7.19; S, 57.68; found: C, 32.72; H, 2.55; O, 6.95; S, 57.93 (%). (R,R)-1: The same synthetic procedure was followed as for the (S,S)-enantiomer

Chiroptical properties of 1,3-diphenylallene-anchored tetrathiafulvalene and its polymer synthesis

• Masashi Hasegawa,
• Junta Endo,
• Seiya Iwata,
• Toshiaki Shimasaki and
• Yasuhiro Mazaki

Beilstein J. Org. Chem. 2015, 11, 972–979, doi:10.3762/bjoc.11.109

• −341 (c 0.83 in CH2Cl2), respectively. Figure 2 depicted the electronic circular dichroism (ECD) spectra of the enantiomers of (+)/(−)-3 and (+)/(−)-9, and their UV–vis absorption spectra. The ECD spectrum of the (−)-9 enantiomer exhibited a clear bisignate CD curve with a negative peak at 274 nm and a

• 1,3-bis(4-iodophenyl)-1,3-diisopropylallene (9) and organozinc species derived from 4,5-bis(methylthio)TTF. Optical resolution of the enantiomer 3 and its precursor 9 was achieved by a recyclable HPLC on a chiral stationary phase. The ECD spectra were measured, and the obtained spectra allowed for the

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

• enantioselectivities when 30 mol % of the catalyst was used. Interestingly, when the Lewis acid is switched to the lanthanide triflate, Yb(OTf)3 or Y(OTf)2, the opposite configuration of the product was obtained (the S enantiomer was obtained vs. the R enantiomer that is obtained when MgBr2 is used). In 2001, the

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• starting point [47][70]. A potential obstacle to the application of organocatalytic systems based on naturally occurring trans-4-hydroxy-L-proline as the catalytic moiety is how to access both series of enantiomeric products, since the enantiomer of the naturally occurring hydroxyproline is not easily

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

• Paweł Borowiecki,
• Daniel Paprocki and
• Maciej Dranka

Beilstein J. Org. Chem. 2014, 10, 3038–3055, doi:10.3762/bjoc.10.322

• -6 production [48]. Moreover, Boland and McDonought [49][50] found that preferably the (+)-enantiomer of promethazine is particularly effective in inhibiting the formation of bone resorbing cells (osteoclasts) thus providing a new class of agents useful for preventing or even treating bone loss

• was superior to other enzymes in both the reaction rate and the obtained enantiomeric excess values of the slower reacting enantiomer (S)-(+)-5. In this case, racemic alcohol (±)-3 has been successfully resolved affording the unreacted substrate (S)-(+)-5 in enantiopure form (>99% ee), whereas the

• active ester (R)-(−)-6a of high enantiomeric excess (95% ee) and leaving thereby slower reacting enantiomer (S)-(+)-5 of very high enantiomeric purity (98% ee). On the other hand, from the view point of remaining the enatiopurity of alcohol (S)-(+)-5, ethereal solvents (Et2O and MTBE) which yielded (S

Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space

• Simon A. Herbert,
• Laura J. van Laeren,
• Dominic C. Castell and
• Gareth E. Arnott

Beilstein J. Org. Chem. 2014, 10, 2751–2755, doi:10.3762/bjoc.10.291

• removal of the oxazoline. This avoids the need to resort to the more expensive oxazoline enantiomer derived from D-tert-leucine. Probing the impact of inherently chiral calix[4]arenes To date we have focused on developing the synthetic methods for meta-functionalised inherently chiral calix[4]arenes, our

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

• László Tóth,
• Yan Fu,
• Hai Yan Zhang,
• Attila Mándi,
• Katalin E. Kövér,
• Tünde-Zita Illyés,
• Attila Kiss-Szikszai,
• Balázs Balogh,
• Tibor Kurtán,
• Sándor Antus and
• Péter Mátyus

Beilstein J. Org. Chem. 2014, 10, 2594–2602, doi:10.3762/bjoc.10.272

• ,b were separated on a Chiralpak IA column using hexane/dichloromethane as eluent and online HPLC-ECD spectra of the separated enantiomers were recorded. Due to their similar chromophoric system, the HPLC-ECD spectra of 7a and 7b were quite similar. The first-eluting enantiomer of 7a had an intense

• broad positive Cotton effect (CE) at 378 nm, negative ones at 314, 305, 272 nm and positive ones at 284, 279 and 224 nm (Figure 4a). The HPLC-ECD spectrum of the first-eluting enantiomer of 7b showed similar ECD pattern with somewhat different shape and intensities in the 290–240 nm range (Figure 4b

• , 1335, 1488, 2227, 2923 cm−1; HRMS–ESI (m/z): [M+Na]+ calcd for C25H18N4O3Na, 445.1277; found, 445.1271; Anal. calcd for C28H18N4O3 (422.14): C, 71.08; H, 4.29; N, 13.26; found: C, 71.05; H, 4.30; N, 13.25. First eluting enantiomer of 7c: retention time (tR) 21.41 min (Chiralpak IA, hexane

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• enantioenriched piperidinone 47, and thus a single enantiomer of rhazinilam may be prepared. The formal synthesis of (+)-rhazinilam commenced with palladium-catalyzed decarboxylative allylic alkylation of known carboxy-lactam 49 to afford benzoyl-protected piperidinone 50 in 97% yield and 99% ee (Scheme 11) [84

• to the compound’s natural antipode. Our lab’s novel approach to (−)-quinic acid (21) allowed access to either enantiomer of this important substance. We have also intercepted a key intermediate in Danishefsky’s synthesis of (±)-dysidiolide (29), rendering the former racemic route enantioselective

Phosphinocyclodextrins as confining units for catalytic metal centres. Applications to carbon–carbon bond forming reactions

• Matthieu Jouffroy,
• Rafael Gramage-Doria,
• David Sémeril,
• Dominique Armspach,
• Dominique Matt,
• Werner Oberhauser and
• Loïc Toupet

Beilstein J. Org. Chem. 2014, 10, 2388–2405, doi:10.3762/bjoc.10.249

• ) complexes formed (Table 1, entries 4 and 5), although for HUGPHOS ligands bis(phosphine) complexes have never been isolated so far. Raising the temperature to 120 °C caused the catalyst activity to drop significantly and led predominantly to the (S)-enantiomer, suggesting a profound transformation of the

Oligomerization of optically active N-(4-hydroxyphenyl)mandelamide in the presence of β-cyclodextrin and the minor role of chirality

• Helmut Ritter,
• Antonia Stöhr and
• Philippe Favresse

Beilstein J. Org. Chem. 2014, 10, 2361–2366, doi:10.3762/bjoc.10.246

• enzymatic catalyzed asymmetric enantiomer-differentiating oligomerizations was investigated. In addition, the poor influence of cyclodextrin on the enantioselectivity of enzymatic catalyzed asymmetric enantiomer-differentiating oligomerizations was studied. Keywords: cyclodextrin; enantioselectivity

• reaction of chiral phenol derivatives, respectively. Thus, the enantioselectivity of enzymatic asymmetric enantiomer-differentiating oligomerizations of a chiral mandeloamide-phenol derivative as model compound and the influence of cyclodextrin is a main subject of the present study. Results and Discussion

• peroxidase the (S)-enantiomer 1 slightly enriches the reaction solution. Additionally to that, it was of some interest to verify, whether the complexation of the enantiomers with RAMEB-CD affects the conversion of the enantiomers. Therefore, the relatively slow oligomerizations in the presence of laccase

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• stereoselectivity; steric hindrance between the tert-butyl group of the allenoate and the 9-phenanthryl group of the alkene suppressed the formation of the γ-isomer, affording α-adducts as the major regioselective products, with steric shielding of the si-face facilitating production of the major enantiomer (Scheme

• proposed that the major enantiomer formed through re-face attack of the ylide onto the Michael acceptor, rather than attack from the sterically hindered si-face. 2.16 Michael additions Asymmetric Michael addition is one of the most studied enantioselective processes in organic synthesis, with many

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• chiral auxiliary and oxidized to diacid 99. Converison into its potassium salt yielded squalene synthase inhibitor (S)-19. In a similar sequence, the minor diastereomer from the sulfuration, 1-epi 98, was converted into the opposite enantiomer (R)-19 (Scheme 12A). Reversing the steps for the introduction

• )-19. Both enantiomers of 19 were tested in in vitro assays for their ability to inhibit squalene synthase. Enantiomer (S)-19 was found to be 16-fold more potent than the (R)-enantiomer, with IC50 values of 68 and 1120 nM, respectively [36]. Fumonisin B2 (1997) Fumonisin B2 (20) belongs to the family

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• presence sodium acetate in dioxane at 100 °C. The compound was prepared on the 10 mg scale in 67% yield. In contrast to its (3R,4R)-enantiomer (not shown), compound (3S,4S)-23 showed inhibitory activity toward human purine nucleoside phosphorylase (PNP) with a slow-onset binding constant Ki* = 0.032 nM. In

Rational design of cyclopropane-based chiral PHOX ligands for intermolecular asymmetric Heck reaction

• Marina Rubina,
• William M. Sherrill,
• Alexey Yu. Barkov and
• Michael Rubin

Beilstein J. Org. Chem. 2014, 10, 1536–1548, doi:10.3762/bjoc.10.158

• , produces species 9 and 12, respectively. It was proposed that the diastereomeric complex 12 has a higher propensity toward further hydropalladation than 9. Accordingly, the latter species releases the (S)-enantiomer of 2,5-dihydrofuran 3 (path I), while the former undergoes a series of reversible

• hydropalladations and β-hydride eliminations, resulting in the formation of a thermodynamically more favoured η2-complex 14, which ultimately produces the (R)-enantiomer of the isomeric product 4. Later, a number of research groups pursued the design of alternative diphosphine ligands to achieve better regio- and

• . Results and Discussion Our approach to the PHOX ligands with a chiral cyclopropyl backbone is presented in Scheme 3. The synthesis began from optically active 1-methyl-2,2-dibromocyclopropanecarboxylic acid (15) [65] readily available in both enantiomeric forms. The S-enantiomer of acid 15 was converted

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

• precursor such as 13a (Table 1) [49]. A nucleophilic phosphide reagent was prepared by deprotonation of 13a in the presence of (−)-sparteine. The subsequent alkylation of the lithium phosphide with an electrophile proceeded with good enantiocontrol via dynamic resolution. One enantiomer is thermodynamically

• excesses were reported. As expected, a mechanistic study suggested that the major enantiomer of product was formed from the major diastereomer of the platinum–phosphido intermediate [63]. Glueck and co-workers also developed an analogous method for the tandem alkylation/arylation of primary phosphines on

• following years, the scope and mechanism were elaborated [202][203][204]. In accordance with the mechanism given in Scheme 10, it was concluded that the major enantiomer of the product 108 was derived from the major diastereomer of the Pd-phosphido intermediate. Korff and Helmchen have prepared several

Molecular recognition of isomeric protonated amino acid esters monitored by ESI-mass spectrometry

• Andrea Liesenfeld and
• Arne Lützen

Beilstein J. Org. Chem. 2014, 10, 825–831, doi:10.3762/bjoc.10.78

• use of isotopically labelled substrates in the sense of an isomer labelled guest method (ILGM) (Figure 3) which is closely related to the enantiomer labelled guest method (ELGM) introduced by Sawada [22]. Here, a competitive recognition experiment using a non-labelled substrate and a mass-labelled