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

• became clear that when using alkylzirconocene nucleophiles and Cu catalysis, derivatised 3,6-dihydro-2H-pyrans are difficult to obtain in high enantiomeric excess. Moreover, both optimised systems gave poor yield; 25% yield with 100% conversion from allyl chloride 2a and 17% yield with 31% conversion

• quite robust so that we could also determine its enantiomeric excess during the course of the reaction. Initially 2a is racemic but it becomes scalemic to slowly reach 34% ee when the reaction is complete (~12 hours). From these observations and our experimental demonstration that 2a is much more stable

Olefin metathesis in air

• Lorenzo Piola,
• Fady Nahra and
• Steven P. Nolan

Beilstein J. Org. Chem. 2015, 11, 2038–2056, doi:10.3762/bjoc.11.221

• solvents, and yielded products with high enantiomeric excess (ee). The results where comparable to previously reported results for molybdenum-catalyzed systems [57], although the latter was used under inert conditions. In 2003, Blechert et al. reported the first systematic example of olefin metathesis in

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

• highest enantiomeric excess 95%, but with only 26% chemical yield (Table 1, entry 6). Subsequently other catalysts were tested in order to improve the efficiency of the reduction. The catalyst 12, which is based on N-tosyl-(1S,2S)-1,2-diphenylethane-1,2-diamine (TsDPEN), gave amine 7 with 72–73% ee

• amine developed by us [16] was tested. This catalyst possesses similar activity to catalyst 12 and gave the product with 75% enantiomeric excess and 52% yield. Applying dimethylformamide as a solvent led to lower asymmetric induction and to significant reduction of the yield to 21%. The

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• reagent feed time) in order to evaluate this hydrogenation process. The process proved robust allowing reproducible and safe generation of the desired product in both high yield and enantiomeric excess. Additionally, semi-continuous liquid–liquid extraction, in-line distillation and product

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

• mixture. As reported in the literature, immobilization of chiral imidazolidin-4-ones on polymeric support might affect the formation of the desired products and lead to decreased enantioselectivities [58]. Indeed, in all the experiments reported in Table 1 the enantiomeric excess of 13 was lower compared

• ). Nevertheless, the observed enantiomeric excess of the product 13 is still low when compared with those (93% ee, at −30 °C) originally reported in the case of the traditional (S)-phenylalanine-based imidazolidin-4-one [53]. Using the optimized solvent system (Table 1), we then turned our attention to study the

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• iodoarenes in the presence of peroxides. Chiral iodoarenes, such as 197, served as the catalysts in the asymmetric C–O coupling of sulfonic acids with ketones. The enantiomeric excess of the product was not higher than 58% due, in particular, to instability of the configuration of the products, α-sulfonyloxy

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

• bromo derivative, which conducted in toluene gives mainly the product of single inversion, whereas carried out in methanol it provides exclusively the product of net retention. Enantiomeric excess of optically active promethazine and ethopropazine were established by HPLC measurements with chiral

• analytical HPLC separation studies of the corresponding pairs of enantiomers and for the measurement of the enantiomeric excess values of the compounds prepared in the biocatalyzed reactions, the afore-prepared alcohol (±)-3 was reacted with the appropriate acyl chloride in dry dichloromethane in the

• obtained with excellent enantiomeric excess (>99% ee), while the remaining alcohol (S)-(+)-5 was recovered only with 96% ee due to the fact that the reaction definitely stopped at 49% conversion being reached after two weeks. The specificity of this lipase for the (R)-alcohol was evident since even after

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

• a Varian 3900 gas chromatograph equipped with a WCOT fused-silica column (25 m × 0.25 mm). This allowed to determine the b:l ratio. In order to determine the enantiomeric excess, a sample of the reaction mixture (toluene) was treated with LiAlH4 for 0.5 h. After filtration, the toluene solution

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

• monomeric residual of each oligomerization was measured twice. The obtained enantiomeric excess (ee) values of the monomeric residual are given in Table 1. Because of the rapid conversion of the monomer 1 during the oligomerization with highly active peroxidase–H2O2 system at room temperature, the reaction

• of the oligomers synthesized with laccase from the racemate 1. Oligomerization of N-(4-hydroxyphenyl)mandelamide (1). Enantiomeric excess values (ee) of the monomeric residual of the enzymatic oligomerization of 1.

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• cyclic dipeptide [5]. In these reactions, N-substituted imines react with HCN to yield (S)-α-aminonitriles with remarkably high enantiomeric excess (ee). One example is shown in Scheme 3. However, when benzaldehyde and NH3 instead of the N-substituted imine were employed as the substrates, the reaction

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• determination of the enantiomeric excess of a chiral amine based on the use of phosphorinanes derivatives. Two synthetic pathways i) the AT reaction and ii) the direct use of chlorophosphate were evaluated for the derivatization of chiral amine (or alcohol) as reported in Scheme 6. For the AT reaction (i) [23

• reduction of a prochiral ketone. The phosphoramidate (Scheme 32-iii) was the most efficient catalyst for these two reactions (ee: 95–98%, conversion 87–98%). In relation with asymmetric synthesis, the determination of the enantiomeric excess (ee) is usually achieved by different methodologies including

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

• preparative HPLC or recrystallization. Nucleophilic substitution of pure diastereomer (RP)-2a with methyllithium afforded the phosphine–borane (S)-4 with 94% enantiomeric excess. The substitution resulted in inversion of the configuration at the phosphorus center. Deboranation of the air stable borane adduct

• favored by the spartein auxiliary. The enantioselectivity was found to be time and temperature dependent. Simple stirring of the intermediate (−)-sparteine–lithium complex of 13a for 1 h at 25 °C prior to alkylation resulted in an increase in enantiomeric excess of 14a. The organocatalyst 16 has also been

• alkenylphosphine 81c was formed. The highest enantiomeric excess measured by chiral HPLC was 56%. No reaction was observed without the palladium catalyst [165]. Gillaizeau and co-workers have demonstrated the use of α-amido enol phosphates 88 as vinylic coupling partners in the palladium-catalyzed C–P cross

Asymmetric total synthesis of a putative sex pheromone component from the parasitoid wasp Trichogramma turkestanica

• Danny Geerdink,
• Jeffrey Buter,
• Teris A. van Beek and
• Adriaan J. Minnaard

Beilstein J. Org. Chem. 2014, 10, 761–766, doi:10.3762/bjoc.10.71

• substituents have been constructed [20]. Starting from 3, the first conjugate addition using (R,SFe)-L1 afforded 4, as expected in high yield and excellent enantiomeric excess (Scheme 1). Reduction with DIBALH, followed by Horner–Wadsworth–Emmons olefination and again asymmetric conjugate addition gave 6 in 77

• from 6. Both the enantiomeric excess and the diastereomeric excess of 8 were excellent which is important as the response of insects to their pheromones can be highly sensitive to the stereoisomeric composition. A number of procedures exist to reduce ketones to their corresponding methylene groups

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• show any racemisation at all, not even after a longer time of storage. For the latter three the enantiomeric excess was not determined on this step: Further conversion as depicted in Scheme 4 and Table 2 delivered piperidinols 11a, 11b and 11d in ≥99% ee. As no intermediate in the conversion of 7 to 11

• File 1). Indeed, under optimized conditions (1.2 equiv I2, P(OEt)3, Et3N (5–6 equiv)/CH2Cl2 1:2; −78 °C then warming to rt) the piperidinols 11a–d were isolated after saponification (during work up) of triethylphosphate and chromatographic purification in 68–82% yield and high enantiomeric excess (90

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

• Kazutaka Shibatomi,
• Takuya Okimi,
• Yoshiyuki Abe,
• Akira Narayama,
• Nami Nakamura and
• Seiji Iwasa

Beilstein J. Org. Chem. 2014, 10, 323–331, doi:10.3762/bjoc.10.30

• equiv of rac-12 based on NFSI afforded the corresponding product 13 in higher enantioselectivity than that obtained in the reaction with 2 equiv of NFSI, along with 27% ee of 14; however the enantiomeric excess of 13 was not sufficiently high (47% ee). These results suggested that the reaction proceeded

New hydrogen-bonding organocatalysts: Chiral cyclophosphazanes and phosphorus amides as catalysts for asymmetric Michael additions

• Helge Klare,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2014, 10, 224–236, doi:10.3762/bjoc.10.18

• quinine, gives modest yields (60%) albeit with low enantiomeric excess (13% ee). Lowering the reaction temperature with catalyst 4 results in a slightly higher enantiomeric excess (27% ee, Table 2), however the yield drops to only 30%. We anticipated an increase in enantioselectivity for the epimer 5 as

• motifs. Indeed cis-catalyst 14a exhibited an excellent efficacy with 98% isolated yield and a good enantioselectivity of up to 75% ee (Table 4). It is noteworthy, that the enantiomeric excess can easily be increased to >99% by recrystallization. While enantioselectivities with 14a are slightly higher in

• -hydroxynaphthoquinone to β-nitrostyrene. The open-chain triamide catalyst 7a performs with nearly quantitative yields (98%) and moderate enantiomeric excess of 51%, even at 2% catalyst loading (Table 2). Cyclodiphosphazane cis-14a shows the same efficiency with 98% isolated yields and an even improved enantiomeric

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• kinetic resolution [156], albeit with unsatisfactory enantiomeric excess. The undesired enantiomer was then selectively cleaved using another enzyme with reversed selectivity to give enantiopure pyranone 181. Cyclopropanation was achieved using a Michael addition initiated ring closure yielding diester

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• -allyl-3-methyl-5-pentyl-1,2-dioxolane (136) in 47% yield (Scheme 31) [261]. The asymmetric peroxidation of methyl vinyl ketones 137a–e with 9-amino-9-deoxyepiquinine 138 and CCl3COOH afforded hydroxydioxolanes 139a–e with high enantiomeric excess (ee 94–95%) (Scheme 32) [262]. The Kobayashi synthesis of

A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

• Erli Sugiono and
• Magnus Rueping

Beilstein J. Org. Chem. 2013, 9, 2457–2462, doi:10.3762/bjoc.9.284

• isolated in 59% yield and 93% enantiomeric excess (Table 1, entry 1 vs entry 2). Improvement of the reaction yield shows the superior performance of the microflow reactor since the light penetration through the microchannels was significantly increased. A slight improvement of yield was achieved when the

• reaction was carried out at 55 °C (Table 1, entry 3). Noticeable improvement on the chemical yield was observed when the reaction was conducted at a lower concentration providing the product in 74% isolated yield and 94% enantiomeric excess (Table 1, entry 4 vs entry 3). Further decrease of the

Synthesis of the spiroketal core of integramycin

• Evgeny. V. Prusov

Beilstein J. Org. Chem. 2013, 9, 2446–2450, doi:10.3762/bjoc.9.282

• ). Subsequent Leighton crotylation [7] using commercially available (R,R)-E-Crotyl-Mix was employed to introduce the two stereocenters at C25/C26 with anti-relationship in excellent yield and enatioselectivity. The enantiomeric excess of the crotylation product was estimated by esterification with (R)-α

A protecting group-free synthesis of the Colorado potato beetle pheromone

• Zhongtao Wu,
• Manuel Jäger,
• Jeffrey Buter and
• Adriaan J. Minnaard

Beilstein J. Org. Chem. 2013, 9, 2374–2377, doi:10.3762/bjoc.9.273

• ]. According to Sharpless et al. [18], 5 mol % of Ti(OiPr)4 and 7.5 mol % of DIPT were used, so at least 20% excess of tartrate ester in order to obtain the maximum enantiomeric excess. The use of freshly distilled DIPT and Ti(OiPr)4 was important to obtain consistently 88% ee. With epoxide (2R,3R)-4 at hand

• (2S,3R)-4, triol (2S,3S)-3 was obtained in high yield but a 6% loss in enantiomeric excess was observed (see Supporting Information File 1). Considering these disappointing results using nerol as the starting material, oxidation to (S)-1 was not performed. Conclusion In summary, we have developed an

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• which is related to the very short residence time distribution. In all cases 20% diastereomeric excess (de) and 99% enantiomeric excess (ee) were observed. A continuous run of the reactant solution was carried out for 10 hours in order to check enzyme stability at higher temperature. Stable operation

• mL of sample was collected and the reaction was terminated by adding a 30% trichloroacetic acid solution. Then, all samples were extracted with 2 mL of internal standard solution (1,3-dimethoxybenzene in ethyl acetate). The enantiomeric excess (ee) and the diasteriomeric excess (de) of phenylserine

• rate of 25 °C/min. The injector temperature was fixed at 250 °C and the detector temperature at 250 °C. Determination of enantiomeric excess (ee) and diastereomeric excess (de) Determination of the enantiomeric excess (ee) and the diastereomeric excess (de) was achieved by HPLC using a chiral column

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• -temperature was improved significantly from 25 to 68% ee. The highest enantiomeric excess of chlorohydrin (92% ee) was obtained by simple decreasing the reaction temperature to −78 °C. A series of substituted cis-stilbene oxides were desymmetrized in very good yield and high stereoselection, and the

• PINDOX OC-98 for the enantioselective ring-opening of cyclic meso-epoxides with SiCl4 to produce chlorohydrins in moderate to good enantiomeric excess (Scheme 21). The stereoselectivities are very sensitive to the ring size of the cyclic oxides. For example, when cyclohexene oxide was used as a substrate

Preparation of optically active bicyclodihydrosiloles by a radical cascade reaction

• Koichiro Miyazaki,
• Yu Yamane,
• Ryuichiro Yo,
• Hidemitsu Uno and
• Akio Kamimura

Beilstein J. Org. Chem. 2013, 9, 1326–1332, doi:10.3762/bjoc.9.149

• enhanced the yield of 2a to 58% (Table 1, entry 3). The enantiomeric excess of trans-2a was estimated to be 95% by HPLC analysis, which was the same ee level of precursor 1a. Thus, no epimerization at the C3 chiral center occurred during the reaction. The stereoselectivity was improved to 8:2. The

• analyses using ChiralPak ID and IC (Table 2, entries 1, 2, and 4), the enantiomeric excesses of most of products 2 were high, and their original values were maintained (Table 2, entries 3, 5, 6, 8, and 9). Interestingly, significant epimerization occurred during the reaction of 1h; the enantiomeric excess

Synthesis of the tetracyclic core of Illicium sesquiterpenes using an organocatalyzed asymmetric Robinson annulation

• Lynnie Trzoss,
• Jing Xu,
• Michelle H. Lacoske and
• Emmanuel A. Theodorakis

Beilstein J. Org. Chem. 2013, 9, 1135–1140, doi:10.3762/bjoc.9.126

• enantioselectivity and short reaction time, we decided to pursue this conversion at 40 °C where we obtained an enantiomeric excess of 90% (70% yield after 14 days). The enantiomerically enriched Hajos–Wiechert-like diketone 8 (ee > 90%) was then subjected to a selective protection of the C-6 enone motif to yield