Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• then furnished rac-4b, the substrate for enzymatic resolution. Using an immobilized lipase enzyme as the catalyst (and under slightly different conditions from those described in Scheme 1), one enantiomer of the racemic β-lactam 4b was completely transformed into the ester 5b, while the other

• enantiomer of β-lactam 4b remained intact. The net result was that a fluorinated stereocentre was rapidly constructed, with defined absolute configuration, within a nitrogen heterocycle. Conclusion When the concept of selective fluorination is applied in the context of N-heterocycles, the resulting molecules

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• using the improved Sharpless conditions with the newer AQN based ligands, producing excellent ee’s for both enantiomers of the diol, 95% for the enantiomer derived from AD-mix α, and 97% for the enantiomer from AD-mix β (Table 1). The corresponding isolated yields under these conditions were 54% and 56

• obtained from integration of the signals for each enantiomer matched the chiral HPLC analysis of the derivatised dibenzoates closely; for example the ee’s for 28b and 28a, from the 1 mol % osmium, 5 mol % PHAL conditions, were 82% and 91% by NMR respectively and 83% and 91% by HPLC for the corresponding

• standard acquisition parameters revealing the partial enantiomer overlap. Partial 19F{1H} NMR (400 MHz, L-(+)-DIPT/CDCl3, 300 K) spectra of 28b and 28a using optimised conditions: SW 40; AQ = 0.8; O1P −230; d1 = 5; 32 or 64 scans. Key steps from the synthesis of 6-fluoro-D-olivose (6) from D-glucose (1

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• . As an example, (R)-limonene smells of oranges, whereas the (S)-enantiomer has a turpentine-like (with a lemon note) odor. The difference in physiological effects of enantiomers is of utmost importance especially for the pharmaceutical industry, but increasingly also in agrochemicals [2][3] and even

• in materials sciences, as evidenced by the introduction of chiral organic light emitting diodes [4][5]. In certain cases, one enantiomer may be harmful. This was the case, for example, with the drug thalidomide (Figure 1), the (R)-enantiomer of which was sold to pregnant women as a sedative and

• antiemetic in the 1960s. The (S)-enantiomer turned out to be teratogenic. The crucial role of chirality presents a great challenge for synthetic chemists. Asymmetric synthetic methods have emerged and after the development of ample analytical methods over the last few decades, asymmetric synthesis has seen

Stereodivergent synthesis of jaspine B and its isomers using a carbohydrate-derived alkoxyallene as C₃-building block

• Volker M. Schmiedel,
• Stefano Stefani and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2013, 9, 2564–2569, doi:10.3762/bjoc.9.291

• therefore leads to a stereodivergent approach to the natural product and its enantiomer. The gold-catalyzed 5-endo-cyclization affords the corresponding dihydrofurans, which after separation, azidation of the enol ether moiety and two subsequent reduction steps give the natural product and its stereoisomers

• natural product (Scheme 2). A subsequent 5-endo-cyclization of the resulting allenyl alcohols leads to a mixture of diastereomeric dihydrofurans, which can be separated by HPLC (only the (S)-enantiomer is depicted). This allows the synthesis of the natural product and its enantiomer by functionalization

• of both diastereomers. The cis-configured amino alcohol moiety at C-3 and C-4 is installed by azidation and subsequent reduction steps leading to the final products. The presented strategy allows the preparation of jaspine B, its enantiomer and two diastereomers, all of which are known for their

Bidirectional cross metathesis and ring-closing metathesis/ring opening of a C₂-symmetric building block: a strategy for the synthesis of decanolide natural products

• Bernd Schmidt and
• Oliver Kunz

Beilstein J. Org. Chem. 2013, 9, 2544–2555, doi:10.3762/bjoc.9.289

• ][4][5][6] and its enantiomer ent-1 [7] have emerged as highly valuable starting points for target molecule syntheses which rely on dual olefin metathesis reactions. The two metathesis transformations may either be two identical CM [8][9] or RCM steps [10], yielding C2-symmetric products in which the

Biosynthesis of rare hexoses using microorganisms and related enzymes

• Zijie Li,
• Yahui Gao,
• Hideki Nakanishi,
• Xiaodong Gao and
• Li Cai

Beilstein J. Org. Chem. 2013, 9, 2434–2445, doi:10.3762/bjoc.9.281

• and D-glyceraldehyde (Scheme 5) [48]. Fortunately, the resulting diastereomers were easily separated with cation exchange resin (Ca2+ form) under elevated temperature to realize the preparative-scale production of both sugars [48][49][50][51]. L-Tagatose Unlike its enantiomer D-tagatose which is a

Synthetic scope and DFT analysis of the chiral binap–gold(I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

• María Martín-Rodríguez,
• Luis M. Castelló,
• Carmen Nájera,
• José M. Sansano,
• Olatz Larrañaga,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2013, 9, 2422–2433, doi:10.3762/bjoc.9.280

• is TS11exo (Figure 7), is in good agreement with the experimental results in which a high ee of the corresponding stereoisomer was observed. The formation of the enantiomer (TS11ent) was found to have an activation barrier of 4.5 kcal mol−1 higher in energy. That difference can be a consequence of

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

• continues even today with clevidipine (2.3, Cleviprex) which obtained FDA approval in 2008. In contrast to the previous compounds clevidipine is a very short acting calcium channel blocker and is used as a single enantiomer being administered intravenously rather than orally. Due to its labile

• demonstrated allowing biological evaluation of either enantiomer and comparison of the obtained results. Through these studies it was found that the S-(−)-enantiomer of amlodipine is the biologically active one although there appears to be no significant difference in the pharmacokinetic behaviour between the

• ). The required (R)-enantiomer of ethyl nipecotate can in turn be obtained by a number of different methods including the resolution of the racemate using L-(+)-tartaric acid obtained from full saturation of ethyl nicotinate. More modern methods involve a two-step process wherein ethyl nicotinate (2.52

Elucidation of the regio- and chemoselectivity of enzymatic allylic oxidations with Pleurotus sapidus – conversion of selected spirocyclic terpenoids and computational analysis

• Verena Weidmann,
• Mathias Schaffrath,
• Holger Zorn,
• Julia Rehbein and
• Wolfgang Maison

Beilstein J. Org. Chem. 2013, 9, 2233–2241, doi:10.3762/bjoc.9.262

• in 11-R3 by the adjacent oxygen and hyperconjugation lead to a rather low BDH of 74.9 kcal/mol (B3LYP/6-31+G**). Biocatalytic allylic oxidation of theaspirane (1) with lyophilisates of PSA. Only one enantiomer of racemic compounds is shown. Intramolecular silyl modified Sakurai reaction to

• (1). Only one enantiomer of racemic compounds is shown. Oxidation of vitispirane (23) with PSA gave enone 24 and two diastereomeric allyl alcohols 26a and 26b. A putative intermediate is epoxide 25, which upon hydrolysis would give allyl alcohols 26a and 26b. Oxidation of the latter might provide

• enone 24. Only one enantiomer of racemic compounds is shown. Model substrates 11A and 11B that allowed a determination of accurate BDH298 values with the CBS-QB3 method. Optimized geometries and BDH298 values of radicals derived from 11 and 12 for gas phase and PCM calculations. Supporting Information

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• enantiomer. With eleven synthetic operations and a longest linear sequence of only seven steps, this route is highly convergent and employs a novel Rh-carbenoid-mediated formation of 30 as its key step. The synthesis of the natural enantiomer of (+)-K252a [(+)-27] was carried out in an analogous fashion

A concise enantioselective synthesis of the guaiane sesquiterpene (−)-oxyphyllol

• Martin Zahel and
• Peter Metz

Beilstein J. Org. Chem. 2013, 9, 2028–2032, doi:10.3762/bjoc.9.239

• synthesis of the unnatural enantiomer of 1 enabled a structural revision of this compound and established its relative and absolute configuration as depicted in Figure 1 [4]. During the total synthesis of (−)-9-deoxyenglerin A, compound 1 had already been prepared enantiomerically pure in 14 steps starting

Bioinspired total synthesis of katsumadain A by organocatalytic enantioselective 1,4-conjugate addition

• Yongguang Wang,
• Ruiyang Bao,
• Shengdian Huang and
• Yefeng Tang

Beilstein J. Org. Chem. 2013, 9, 1601–1606, doi:10.3762/bjoc.9.182

• that the two enantiomers of katsumadain A might show different behaviors in the biological studies from each other as well as from the racemic compounds, we also synthesized (+)-katsumadain A in a similar way by simply replacing the catatalyst B with its enantiomer in the organocatalytic 1,4-conjugate

Synthesis of the calcilytic ligand NPS 2143

• Henrik Johansson,
• Thomas Cailly,
• Alex Rojas Bie Thomsen,
• Hans Bräuner-Osborne and
• Daniel Sejer Pedersen

Beilstein J. Org. Chem. 2013, 9, 1383–1387, doi:10.3762/bjoc.9.154

• R-enantiomer of (R)-3 and related aminoalcohols display both significantly higher potency and target selectivity than their S-enantiomers, we believe that this is a critical shortcoming in the previously reported syntheses [13][14]. Herein, we wish to report a detailed, reproducible and scalable

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

• Jiayang Li,
• Yi Kuang,
• Junfeng Shi,
• Yuan Gao,
• Jie Zhou and
• Bing Xu

Beilstein J. Org. Chem. 2013, 9, 908–917, doi:10.3762/bjoc.9.104

• -enantiomer 2 or racemic 3) conjugates with L- or D-diphenylalanine to afford compounds (R)-Fbp-FF (2a), (R)-Fbp-ff (2b), and (RS)-Fbp-FF (3a) (Fbp = flurbiprofen). The attachment of racemic ibuprofen to L-diphenylalanine yields compound (RS)-Ibp-FF (4a) (Ibp = ibuprofen). Since the direct use of

Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis

• Stephan Klopries,
• Uschi Sundermann and
• Frank Schulz

Beilstein J. Org. Chem. 2013, 9, 664–674, doi:10.3762/bjoc.9.75

• erythromycin and rapamycin is D3-labelled to a varying extent in the presence of 10 mM rac-4, corresponding to 5 mM of the naturally accepted (S)-enantiomer. Significant incorporation of SNAC-activated methylmalonate 4 into the biosynthesis of erythromycin and rapamycin requires no significantly different

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

• the S-enantiomer to be more stable by 4.4 kcal/mol, which is in qualitative agreement with the experimental data. Conclusion In conclusion, a series of enantiomerically pure Lewis bases directly derived from commercially available enantiopure (S)-proline or its derivatives was synthesized and tested

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

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

• the lithium atom leads to lower yields and the opposite enantiomer (S)-3-methylindoline (S)-46 with low enantiomeric excess (22% ee) when (−)-sparteine (L1) is used (Scheme 16b). However, in this case, the (1R,2R)-N,N,N’,N’-tetramethylcyclohexane-1,2-diamine (L4) proves to be a more efficient ligand

A new synthetic protocol for coumarin amino acid

• Xinyi Xu,
• Xiaosong Hu and
• Jiangyun Wang

Beilstein J. Org. Chem. 2013, 9, 254–259, doi:10.3762/bjoc.9.30

• can be prepared, which greatly expands the usage of this synthetic protocol. Coumarin non-natural amino acids with a substituent at the 5- or 8-position can also be prepared and a respective study is ongoing in our laboratory. The L-enantiomer was proved to be able to be incorporated into a protein

• length protein (12.9 kDa) was only expressed in the presence of 1a; even the final product was racemic. Since thioredoxin has no intrinsic fluorescence, the fluorescent band corresponding to mutant thioredoxin in the right panel of Figure 2 must come from incorporated 1a. The L-enantiomer is assumed to

• be accepted exclusively from the racemic mixture since there is not any report indicating that D-amino acids exist in proteins. A related report proved that in the incorporation of a non-natural amino acid into a protein, the L-enantiomer is accepted exclusively from the racemic mixture [19

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

• the influence of the stereochemistry at the chiral center. In the current work, we examine the replacement of the p-methoxyphenyl ring with basic moieties that may increase aqueous solubility while maintaining activity, and we also developed synthetic routes to produce each enantiomer of these

• crystallization from ethyl ether allowed us to unambiguously assign the absolute configuration of each enantiomer. Shown in Figure 2 are the (S)-enantiomer (left, magenta) and (R)-enantiomer (right, cyan) of 1. It is interesting to note that the hydrogen-bond formed between the amide N–H and the unsubstituted

• compounds were measured by using laser nephelometry at pH 3.0, 5.0, and 7.4 (Table 2). Analysis of the data reveals several trends. First, with the exception of a single case in which enantiomer potencies are similar (14c, ΔEC50 < 3-fold), six other comparisons reveal the (S)-enantiomer to be more active

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

• )-enantiomer of 17 should be generated in majority. The experimentally favored enantiomer is indeed (R)-configured with 83% ee (Table 2, entry 7). This value is in good agreement with an energetic differentiation of the enantio-determining transition states of 2.3 kcal/mol although no solvent dependent effects

• (minor, (S)-enantiomer) and 13.3 min (major, (R)-enantiomer [23]. 4-Hydroxy-3-(3-oxocycloheptyl)coumarin. 1H and 13C NMR data were found to be in agreement with the literature data [23]. Chiral HPLC: The measurements were performed with an eluent consisting of 90% hexanes and 10% isopropanol on a Diacel

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• ) predicted to interact with the tryptophan ring of (R)-5 (Figure 2A). This same hydrophobic site in TcCYP51 binds the fluoroaryl rings of fluconazole and posaconazole in co-crystal structures [14]. The predicted binding mode of the enantiomer (S)-5 was described previously [16] and is distinct from that

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• quantities and derivatives of viridic acid (1), required the development of a more efficient and milder approach. In this endeavor we envisioned two routes. The first one uses improved peptide-coupling protocols, leading to the natural enantiomer (Scheme 1) [11]. The blueprint of the synthesis was planned as

Determination of the relative configuration of tropinone and granatanone aldols by using TBDMS ethers

• Ryszard Lazny,
• Aneta Nodzewska,
• Katarzyna Sidorowicz and
• Przemyslaw Kalicki

Beilstein J. Org. Chem. 2012, 8, 1877–1883, doi:10.3762/bjoc.8.216

• isomerization; granatanone; stereoselective reaction; tropinone; Introduction Enantiomerically pure, and racemic, diastereomerically pure aldols of tropinone have been used as key intermediates in stereoselective syntheses of natural tropane alkaloids and their analogues [1], including the unnatural enantiomer

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• , the γ-lactam 6{1,1,1} was obtained in 66% yield (with 80% es; % es = % major enantiomer, corresponding to 60% ee). Overall, the above-mentioned one-pot sequence, in which both workups and purifications are minimized, proved serviceable in the desired parallel-synthesis sequence. Parallel library