Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

• Markus Menke,
• Pardha Saradhi Peram,
• Iris Starnberger,
• Walter Hödl,
• Gregory F.M. Jongsma,
• David C. Blackburn,
• Mark-Oliver Rödel,
• Miguel Vences and
• Stefan Schulz

Beilstein J. Org. Chem. 2016, 12, 2731–2738, doi:10.3762/bjoc.12.269

• mass spectra (Figure 3) and gas chromatographic retention times of pure (Z)-1, the (E/Z)-mixture obtained by the Hoyveda–Grubbs II catalyst, and 2 with those of the natural compound proved the frog compound to be (Z)-tetradec-5-en-13-olide (1). For the determination of the absolute configuration of the

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• Dracocephalum rupestre, have been synthesized in a one-pot reaction. The separation of 2a–d and 3a–d was achieved by preparative HPLC. The four stereoisomers of each natural product were separated by analytical chiral HPLC and their absolute configuration was studied by the combination of HPLC–ECD measurements

• and TDDFT–ECD calculations. The synthesized flavonoid alkaloids were further characterized by physicochemical and in vitro pharmacological studies. Keywords: absolute configuration; Dracocephalum rupestre; dracocephins A–B; ECD calculation; flavonoid alkaloids; HPLC–ECD; Introduction Flavonoid

• racemates (2a, 2c/2b, 2d; 3a, 3c/3b, 3d) by HPLC–ECD analysis (Figure 1). The planar structure and absolute configuration of the first-eluted stereoisomer of dracocephins A (±)-2a–d was determined by single-crystal X-ray diffraction analysis as (2R,5”S)-2a [2]. The biosynthesis of these flavonoid

A detailed view on 1,8-cineol biosynthesis by Streptomyces clavuligerus

• Jan Rinkel,
• Patrick Rabe,
• Laura zur Horst and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 2317–2324, doi:10.3762/bjoc.12.225

• labelling experiments that gave insights into the cyclisation mechanism of the bacterial 1,8-cineol synthase. Results The absolute configuration of the intermediate terpinyl cation While the two possible cyclisation pathways via (R)- and (S)-6 to 1 cannot be distinguished with unlabelled GPP, its two

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• enantioselectivities. The absolute configurations of annulation adducts 3 were assigned based on X-ray crystallographic analysis of a single crystal of 3r [20]. Through an analysis of the absolute configuration of adduct 3, it is proposed that a plausible reaction mechanism should be similar to the DP-TAA-catalyzed [4

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

• Wiesława Perlikowska,
• Remigiusz Żurawiński and
• Marian Mikołajczyk

Beilstein J. Org. Chem. 2016, 12, 2234–2239, doi:10.3762/bjoc.12.215

• stereostructure–bioactivity relationship in biologically active compounds [18][19], including selected prostanoids [20][21][22], we decided to synthesize all four rosaprostol stereoisomers 1a–d in enantiomerically pure form (Figure 2). The two rosaprostol stereoisomers 1c and 1d have an absolute configuration at

• in the ketoacid (−)-7 by L-Selectride produced the second stereoisomer of rosaprostol (+)-1c, [α]D20 = +60.1 (CHCl3). The overall yield of the four-step conversion of (−)-3 into (+)-1c was 54.5%. With regard to the assignment of the absolute configuration to (+)-3, it is important to notice that

• (−)-1a obtained herein has the absolute configuration R at the C-2 stereogenic center. As the chirality at this carbon atom remains unchanged in the four-step conversion of (+)-3 into (−)-1a, the same chirality has to be assigned to the corresponding carbon atom (now C-3) in (+)-3. Taking into account a

Determination of the absolute stereostructure of a cyclic azobenzene from the crystal structure of the precursor containing a heavy element

• Reji Thomas and
• Nobuyuki Tamaoki

Beilstein J. Org. Chem. 2016, 12, 2211–2215, doi:10.3762/bjoc.12.212

• date there have been several spectroscopic, diffraction methods developed to determine the absolute stereostructure of chiral molecules [26][27][28][29][30][31][32][33][34][35]. The non-empirical methods employed to determine the absolute configuration of a molecule include circular dichroism, exciton

• [45]. In this study, we employ this enantiomer as a precursor for the determination of the absolute configuration of its reduced product, which is expected as one of the enantiomers of (E)-2. In order to characterize the reduced product we have carried out the 1H NMR spectroscopy of the compound and

• enantiomer of (E)-2. According to the Cahn–Ingold–Prelog (CIP) priority rules [51], the absolute configuration of the reduced product should be ‘R’. The priorities of the functional groups on the reduced product reverse on removal of the bromine atom from the parent structure. Comparing the HPLC and CD data

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• tropical fruit tree Annona muricata in 1998 [72]. The relative stereochemistry within the THF diol core was assigned as threo-cis-threo, whereas the absolute configuration present in cis-solamin was not established at the time of isolation. Then in 2006, the groups of Figadère and Brown were able to show

Chiral ammonium betaine-catalyzed asymmetric Mannich-type reaction of oxindoles

• Masahiro Torii,
• Kohsuke Kato,
• Daisuke Uraguchi and
• Takashi Ooi

Beilstein J. Org. Chem. 2016, 12, 2099–2103, doi:10.3762/bjoc.12.199

• efficiently converted into 4ga and 4ha with rigorous relative and absolute stereocontrol (Table 2, entries 15 and 16). The absolute configuration of 4ca was unequivocally determined by X-ray crystallographic analysis (Figure 2), and the stereochemistry of the remaining examples was assumed to be analogous

New furoisocoumarins and isocoumarins from the mangrove endophytic fungus Aspergillus sp. 085242

• Ze’en Xiao,
• Senhua Chen,
• Runlin Cai,
• Shao’e Lin,
• Kui Hong and
• Zhigang She

Beilstein J. Org. Chem. 2016, 12, 2077–2085, doi:10.3762/bjoc.12.196

• ) [16][17], which allowed the assignment of the absolute configuration of 2 as (2R,3R,7R) (Figure 3). Moreover, the predicted ECD curves of 2 and its relevant enantiomer were computed at the [B3LYP/6-31 G(2d,p)] level, and the experimental ECD curve of 2 agreed well with the predicted one (Figure 4), in

• the optical rotation of 3 with data reported for dihydrocoumarins [18], it was possible to assign the absolute configuration of C-7 as R. So, the structure of compound 3 was identified as (R)-2-isopropyl-7-methyl-6,7-dihydro-9H-furo[3,2-h]isochromen-9-one. Asperisocoumarin D (4) was isolated as a

• spectrum (Figure 5), allowed the definition of the absolute configuration at C-7 (R) of compound 4 [18]. Thus, the structure of compound 4 was identified as (R)-2-isopropyl-7-methyl-6,7-dihydro-9H-furo[3,2-h]isochromen-9-one. Asperisocoumarin E (5) was obtained as a pale yellow powder and the molecular

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• 32 of each of these kinetic resolutions had the same absolute configuration. Combining these two complementary catalysts leads to a highly efficient parallel process wherein each catalyst enantioselectively hydrolyzes one enantiomer of the epoxide, ultimately forming diol (R)-32 in 92% yield with 89

Varioloid A, a new indolyl-6,10b-dihydro-5aH-[1]benzofuro[2,3-b]indole derivative from the marine alga-derived endophytic fungus Paecilomyces variotii EN-291

• Peng Zhang,
• Xiao-Ming Li,
• Xin-Xin Mao,
• Attila Mándi,
• Tibor Kurtán and
• Bin-Gui Wang

Beilstein J. Org. Chem. 2016, 12, 2012–2018, doi:10.3762/bjoc.12.188

• indolyl-6,10b-dihydro-5aH-[1]benzofuro[2,3-b]indole derivative, varioloid A (1), was isolated from the marine alga-derived endophytic fungus Paecilomyces variotii EN-291. Its structure was elucidated on the basis of extensive analysis of 1D and 2D NMR data and the absolute configuration was determined by

• cyclized bisindolyl benzenoid derivatives (compounds 1 and 2) (Figure 1). The rare planar structure of compound 2 was previously reported but the full NMR data were not disclosed and the relative and absolute configuration had not been determined [13]. Herein we describe the isolation, structural

• elucidation including the assignment of the absolute configuration, and the cytotoxicity studies of these compounds. Results and Discussion Varioloid A (1), obtained as a light brown solid, has the molecular formula C26H24N2O5 as established from a prominent pseudomolecular ion peak at m/z 445.1766 [M + H

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• -diene (120) with the acylnitroso dienophile 119 (Scheme 24) [10]. The reaction proceeded in 81% overall yield with a major cycloadduct 121 and minor diastereomer 122, with 98% de. The absolute configuration of the major cycloadduct was confirmed by an independent synthesis from the known bicyclic (1R,4S

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• base the retro-aldol reaction of some cycloadducts with kinetic resolution of the enantiomers. In three cases, the retro-aldol products (48–83% ee) could be recrystallized to high enantiopurity (≥95% ee). The absolute configuration of several compounds is supported by anomalous X-ray diffraction and by

• chemical correlation. Keywords: absolute configuration; anthrone; cycloaddition; kinetic resolution; lipase; Introduction In guanidinium ions charge delocalization is an important factor to stabilize the protonated form. As a result, guanidines are exceptionally strong nitrogen bases. As part of the

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• containing water or deuterium oxide allowed for detailed insights into the cyclisation mechanisms of the bacterial terpene cyclases. Keywords: absolute configuration; biosynthesis; enzyme mechanisms; structure elucidation; terpenes; Introduction Terpenes are structurally fascinating natural products with

• established the structure of T-muurolol (2). The absolute configuration was determined as (1R,6S,7R,10R)-(+)-T-muurolol (2) from its optical rotary power ([α]D23 = +99.4 (c 1.10, CH2Cl2)). This is the same compound as was reported from a terpene cyclase from Streptomyces clavuligerus (accession number

• face. These data established the structure of 4-epi-cubebol (3). Its optical rotary power was determined as [α]D24 = +7.1 (c 0.29, CH2Cl2). This points to the same enantiomer as reported from the heartwood of Cryptomeria japonica [44], but the absolute configuration of 3 remains unknown. The (+)-4-epi

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

• an azide nucleophile. The synthesis of allyl alcohol C from D-glucose was reported by us earlier. Our synthesis started with the homoallyl alcohol 3 (with defined ‘R’ absolute configuration at the C3-quaternary center) that is obtained from D-glucose as reported earlier by us in 37% overall yield [15

• the ratio of 18:82 in 83% yield. With the understanding of SAE mnemonic, we assigned the absolute configuration in epoxide 8 as 7S,8S and in epoxide 9 as 7R,8R. Subsequently, major isomers of epoxy alcohols 8 and 9 were individually subjected to regioselective epoxide ring opening using trimethyl

• orientation indicating 5’S absolute configuration as anticipated from the SAE mnemonic in compound 8. As the C5’ and C6’ stereocenters in 14 are derived from the regioselective SN2 opening of epoxide 8 by NaN3, the configuration at the C6’ (carrying azido group) was therefore assigned as 6’R. In the 1H NMR

Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

• Hee Seung Jang,
• Yubin Kim and
• Dae Young Kim

Beilstein J. Org. Chem. 2016, 12, 1551–1556, doi:10.3762/bjoc.12.149

• yield and enantioselectivity (Table 2, entry 13). The absolute configuration of adducts 3 was determined to be R by comparison of the specific rotations and HPLC properties with literature values [36.37]. The stereochemical outcome in the above addition reaction was rationalized by a proposed

Selective bromochlorination of a homoallylic alcohol for the total synthesis of (−)-anverene

• Frederick J. Seidl and
• Noah Z. Burns

Beilstein J. Org. Chem. 2016, 12, 1361–1365, doi:10.3762/bjoc.12.129

• isomer 6 in 46% yield and 84% ee (Table 1, entry 1). Constitutional isomer 7 was also observed (4:1 ratio of 6:7), as well as dibromide 8 and other racemic brominated byproducts (see Supporting Information File 1). The absolute configuration of 6 was assigned through its subsequent conversion into

• (−)-anverene (1, see below), the absolute configuration of which was determined by the isolation chemists on natural material by X-ray crystallography [10]. Interestingly, using the same enantiomer of ligand, the bromochlorides derived from prenol and homoprenol (5) have the same absolute configuration. This

Synergistic chiral iminium and palladium catalysis: Highly regio- and enantioselective [3 + 2] annulation reaction of 2-vinylcyclopropanes with enals

• Haipan Zhu,
• Peile Du,
• Jianjun Li,
• Ziyang Liao,
• Guohua Liu,
• Hao Li and
• Wei Wang

Beilstein J. Org. Chem. 2016, 12, 1340–1347, doi:10.3762/bjoc.12.127

• not shown). The absolute configuration of cyclopentanes 3’ and 3’’ were determined based on the derivatives 7h’ and 7h’’ of 3h (Scheme 2) [95]. We proposed two possible transition states (TS) 8a’ and 8a” to rationalize the observed configurations (Scheme 3). The trans-C=C double bond in iminium ion 4

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• nucleophiles for the conjugate addition–enantioselective protonation of α-aminoacrylates (vide infra). In 2010, Mikami and co-workers reported a hydrogen atom transfer strategy for the synthesis of β-perfluorobutyl-α-amino ester 13 in low yield and modest enantioselectivity, and the absolute configuration of

• , Frost reported that using the same catalyst system, phenyltrimethoxysilane (49a) could be added to dimethyl itaconate (50) with modest enantioselectivity and without defining the absolute configuration of the major stereoisomer (Scheme 11b) [32]. Darses and Genet reported the highly enantioselective Rh

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

• Barry M. Trost,
• Michael C. Ryan and
• Meera Rao

Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110

• , sulfinate ester 11 was synthesized and subjected to alkylation with (5-trimethylsilyl)-4-pentynylmagnesium iodide. Because the order of addition was reversed, it is important to note that 12 has the opposite absolute configuration. In this way, sulfoxides containing m-xylyl, o-methoxyphenyl, and cyclohexyl

• unsatisfactory (Table 3, entry 5). m-Xylyl 19 was similarly disappointing (Table 3, entry 6). However, o-anisyl 20 was interesting in that it was able to maintain high enantiomeric ratios of 14 in both THF and acetone and with the same absolute configuration (Table 3, entry 7). This could possibly be due to a

• lithium aluminum hydride in excellent yield. The absolute configuration of the [3.1.0] pyrrolidines was assigned by analogy to 76, which was determined to be (R,R) by single crystal X-ray crystallography. Mechanistic studies After having successfully developed this synthetic methodology, a few questions

Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji–Trost coupling

• Sebastian Bretzke,
• Stephan Scheeff,
• Felicitas Vollmeyer,
• Friederike Eberhagen,
• Frank Rominger and
• Dirk Menche

Beilstein J. Org. Chem. 2016, 12, 1111–1121, doi:10.3762/bjoc.12.107

• , this approach enables a more versatile elaboration of different configurations as present in the manzacidins and/or originally postulated for this class of marine natural products. Notably, the absolute configuration of manzacidin C was initially proposed as shown in Figure 1 [2] and subsequently

• dimer in the crystal lattice, which is stabilized by two hydrogen bonds between the urea oxygen atoms and the tosyl-protected nitrogens. This also unambiguously confirms the absolute configuration of 39 and corroborates our prediction of the asymmetric adduct 31. We then attempted the installation of

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• )-selectivity (up to >20/1 Z/E ratio, Scheme 52) [70]. Besides, the absolute configuration of the products can be controlled by the chiral CPA, selectively affording the (R)- or (S)-enantiomer based on the catalyst used. 3-Indolylmethanols have been recongnized as reactive precursors in organic synthesis for

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• correlations for the cis- and trans-configuration. However, the absolute configuration of the chiral centers could not be resolved yet. Moreover, the origin of the different isomers is not clear. Due to their alleged instability upon exposure to air and light, one could speculate that isomerization occurs

• . Structure elucidation was achieved via extensive NMR measurements. The absolute configuration of the chiral centers could be resolved through comparison of the experimental CD spectrum with calculated data. This metabolite showed inhibitory activity towards the bacterium Arthrobacter crystallopoietes with

• miuraenamide A (31) the absolute configuration was determined. Marfey´s method was employed to show that L-alanine and N-methyl-D-tyrosine are present. Furthermore, after acid hydrolysis, methylation and application of modified Mosher´s method the absolute configuration at the oxygen bearing C-9 was deduced as

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• a single recrystallization step (Scheme 2). The product could be deprotected to provide the known compound 5 with no deterioration in enantioselectivity. The absolute configuration of 3a was deduced to be S by comparison the specific optical rotation data of 5 with literature data [10][12], and the

Three new trixane glycosides obtained from the leaves of Jungia sellowii Less. using centrifugal partition chromatography

• Luíse Azevedo,
• Larissa Faqueti,
• Marina Kritsanida,
• Antonia Efstathiou,
• Despina Smirlis,
• Gilberto C. Franchi Jr,
• Grégory Genta-Jouve,
• Sylvie Michel,
• Louis P. Sandjo,
• Raphaël Grougnet and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2016, 12, 674–683, doi:10.3762/bjoc.12.68

• . Similarly, H-13 unveiled the same interactions with H-1 and H-9 while H-14 correlated with H-8 (Figure 4). In order to determine the absolute configuration of the compounds 1–3, ECD spectra prediction was used [36][37]. The absolute configuration of 1 was assigned as 2R, 6S, 7R, 10R, and 11S by ECD analysis

• similar interactions with H-1 (δ 1.72) and H-9 (δ 1.56, 1.67). The absolute configuration of 2 was determined to be 2R, 3S, 6S, 7R, and 10S by ECD analysis. As compound 1, two Cotton Effects (CE) from the n→π* transition of the α,β-unsaturated lactone were revealed at 225 and 275 nm with alternative signs

• aglycone [39]. The absolute configuration of 3 was assigned as 1R, 6R, 7S, and 10S. Three CE's were observed on the experimental ECD spectrum at 240, 305 and 350 nm due to the n→π* transition of the α,β-unsaturated ketone. The foregoing data led to identify 3 as 6-hydroxyguaiane congener (Figure 2) and the