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

• prepared in excellent yield and ee by alkylation of carboxy-lactam 49 (see Scheme 11) [84]. Oxidative cleavage of the terminal double bond and subsequent reduction with LiAlH4 afforded N-benzylpiperidine-alcohol 56 [84]. Hydrogenolysis of the N-benzyl group and re-protection with di-tert-butyl dicarbonate

N–O Cleavage reactions of heterobicycloalkene-fused 2-isoxazolines

• Jaipal R. Nagireddy,
• Geoffrey K. Tranmer,
• Emily Carlson and
• William Tam

Beilstein J. Org. Chem. 2014, 10, 2200–2205, doi:10.3762/bjoc.10.227

• isoxazoline-cleavage methodology to the preparation of biologically active natural products, including novel antibacterial, antifungal and anticancer treatments [8][9][10][11]. Some common methods of reductive N–O bond cleavage in isoxazolines include hydrogenolysis using Raney nickel, reduction by LiAlH4

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

• tricarballylic acid intermediate. Conversion of the free carboxylic acid moieties into their benzyl esters followed by cleavage of the tert-butyl ester gave 108. This fragment was then coupled with diol 109 to afford the fully protected fumonisin B2 precursor 110. Final hydrogenation and hydrogenolysis of all

• tricyclic intermediate 121. Cleavage of the TBS ethers and hydrogenolysis of the benzyl ester in presence of amidine 122 yielded trinem 23a as its amidinium salt 123. Trinem 123 exhibited antibacterial activity against a variety of strains, with MIC’s of 1.0 μg/mL against Staphylococcus aureus 853E and 0.1

• work-up provided alcohol 141. Coupling under Mitsunobu conditions with an appropriate alcohol, e.g., 3-hydroxypyridine, reduction of the tert-butyl ester with DIBAL-H, and treatment with TBS triflate gave silyl ether 142. Hydrogenolysis of 142 using Pd/BaSO4 produced the free aziridine, which was then

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• -couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers. Keywords: carbohydrate

• mimetics; hydrogenolysis; multivalent glycosystems; 1,2-oxazines; samarium diiodide; Suzuki cross-coupling; Introduction Carbohydrates are the class of biomolecules with the highest structural diversity [1][2]. Specific carbohydrates are responsible for cell-type specific interactions [3] and they are

• provided compound 16 in 83% yield. This protecting group should allow its removal together with the benzyl group during hydrogenolysis. Surprisingly, a benzyl protection under the same conditions was not possible. Before approaching divalent compounds such as 1 we wanted to convert our building blocks into

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

• precursors to a variety of compounds. The transformations leading to thymidine or its derivatives 3 involved: (a) the metal-catalyzed hydrogenolysis of products 2 [51][52][54][55] (or their 5-(4-tolylthio)methyl derivatives [57]), or (b) the reduction of methylammonium iodides derived from compounds 2 with

• total yield of 45%. The cyclohexylidene protecting group was then removed in refluxing aq AcOH. The resulting diastereoisomers 39 were separated by reversed phase HPLC to yield two pure isomers and the remaining two as an inseparable 1:1 mixture. These were further deprotected by hydrogenolysis under

Unusual polymorphism in new bent-shaped liquid crystals based on biphenyl as a central molecular core

• Anna Kovářová,
• Svatopluk Světlík,
• Václav Kozmík,
• Jiří Svoboda,
• Vladimíra Novotná,
• Damian Pociecha,
• Ewa Gorecka and
• Natalia Podoliak

Beilstein J. Org. Chem. 2014, 10, 794–807, doi:10.3762/bjoc.10.75

• –c to yield the phenyl esters 17a–c. In the next step, the hydroxylic group was released by the palladium-catalysed hydrogenolysis of the benzyl group and the formed phenols 18a–c were acylated with acids 8–10 to produce the series of compounds IV–VI. For clarity, chemical formulae of the studied

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• by 1H NMR as separate signals for the CHF2 group. The adducts 18b–d were hydrolyzed to acids 19b–d in quantitative yields and did not form hydrochlorides similar to the CF3 aminophosphinic acids 13a–b and 17a–d. Hydrogenolysis of the 17a–d and 19a–d efficiently gave free acids 14 and 20, but required

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

• Rajendra S. Rohokale and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2014, 10, 667–671, doi:10.3762/bjoc.10.59

• , hydrogenolysis of the benzyl group and reduction of the azido group by using 10% Pd/C, in one pot, gave 2b in 30.1% overall yield from 3b. The spectral and analytical data was found to be in good agreement with reported data ([α]D30 −5.1(c 0.51, 1 M HCl). [α]D30 −6.2 (c 0.4, 1 M HCl)) [21]. Conclusion In

From porphyrin benzylphosphoramidate conjugates to the catalytic hydrogenation of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin

• Marcos C. de Souza,
• Leandro F. Pedrosa,
• Géssica S. Cazagrande,
• Vitor F. Ferreira,
• Maria G. P. M. S. Neves and
• José A. S. Cavaleiro

Beilstein J. Org. Chem. 2014, 10, 628–633, doi:10.3762/bjoc.10.54

• substitution was promoted by microwave irradiation in N-methyl-2-pyrrolidinone. Attempts to remove the benzyl groups of the phosphoramidate moiety by hydrogenolysis with 10% Pd/C led to the cleavage of the P–N bond and the reduction of the macrocycle to hydroporphyrin-type derivatives. The extent of the effect

• [5][6]. This undesired result pointed to the synthesis of a phosphoramidate derivative different from the diisopropyl one. Here, we describe the synthesis of the analogue porphyrin dibenzylphosphoramidates 1a–c. Attempts to remove the benzyl groups by mild hydrogenolysis over 10% Pd/C led to the

• porphyrin dibenzylphosphoramidates 1a and 1b by hydrogenolysis were carried out with H2 and 10% Pd/C in the presence of triethylamine in order to establish a mild environment for the catalyst [10]. However, when the porphyrin dibenzylphosphoramidates were subjected to these conditions the spectroscopic

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

• we choose a Cbz protecting group for the amino acids 1a–c due to the mild cleavage conditions (hydrogenolysis), we decided to introduce a Boc group at the N-terminus of methionine 1d to avoid desulfuration (–EtSMe → –Et) in the later deprotection. In order to suppress the formation of the only

• 5e (along with 30% of reisolated starting material), illustrating the tendency of reagent 6 to attack the side chain ester moiety. Synthesis of syn-amino alcohols C Already the NaBH4 reduction (in MeOH at −40/0 °C) of ketones 7a and 7b and subsequent hydrogenolysis of the Cbz-group in one-pot

• [74] (or N-Selectride) and subsequent hydrogenolysis of the Cbz-group in one-pot delivered the benzyl amines syn-9a and 9b in accordance with the Felkin–Anh model in excellent yields and as pure diastereomers as indicated by 400 MHz 1H NMR (Scheme 4). Unfortunately, L-Selectride proved to be too

Convergent synthesis of a tetrasaccharide repeating unit of the O-specific polysaccharide from the cell wall lipopolysaccharide of Azospirillum brasilense strain Sp7

• Pintu Kumar Mandal,
• Debashis Dhara and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2014, 10, 293–299, doi:10.3762/bjoc.10.26

• transformed to the target compound 1 in an overall 69% yield following a sequence of reactions consisting of (a) the conversion of the N-phthaloyl group to an acetamido group [41], (b) the hydrogenolysis with hydrogen over Pearlman’s catalyst [42], and (c) the saponification with sodium methoxide. A NMR

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• proved to give the best yields, probably due to the higher reactivity of the corresponding hydrazones. Furthermore, the double bond of 29 was selectively hydrogenated under palladium on charcoal, while hydrogenolysis of the hydrazine moiety occurred in the presence of Raney nickel (Scheme 22). Following

• catalytic enantioselective HDA/allylboration sequence. Total synthesis of a thiomarinol derivative. Synthesis of an advanced intermediate 27 for the east fragment of palmerolide A. Bicyclic piperidines from tandem aza-[4 + 2]-cycloaddition/allylboration. Hydrogenolysis reactions of hydrazinopiperidines

Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

• Léa Bouché,
• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 213–223, doi:10.3762/bjoc.10.17

• crucial final palladium-catalyzed hydrogenolysis of the 1,2-oxazine moiety was optimized resulting in a reasonably efficient approach to a series of new seven-membered carbohydrate mimetics. Keywords: aminooxepanes; carbohydrate mimetics; hydrogenolyses; Lewis acid-induced; lithiated allenes; nitrones

• reduction of 19 with sodium borohydride the intermediate alcohol was heated with triethylamine (to avoid the deprotection of the TBS-group) and compound 20 was obtained in 75% yield (over three steps). The previously isolated unprotected triols 14, 15 and 20 were subjected to standard hydrogenolysis

• may be unfavorable. In order to avoid this side-reaction we performed hydrogenolysis experiments in alternative solvents, e.g. with ethanol or isopropanol, but small amounts of the corresponding side products were also observed in these experiments. Unpolar solvents were not suitable for the

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• chromatography at the level of 9. With these optimized conditions in hand, we performed a series of Ugi reactions using azides 2a–d, glycolic acid, various aldehydes and isocyanides (Scheme 2). After a fast purification through a short silica gel column, the Ugi adducts 9a–n were submitted to hydrogenolysis and

Novel supramolecular affinity materials based on (−)-isosteviol as molecular templates

• Christina Lohoelter,
• Malte Brutschy,
• Daniel Lubczyk and
• Siegfried R. Waldvogel

Beilstein J. Org. Chem. 2013, 9, 2821–2833, doi:10.3762/bjoc.9.317

• all-syn-15 was subsequently cleaved by hydrogenolysis using standard conditions (Scheme 6) [69]. The tricarboxylic acid all-syn-16 was isolated in almost quantitative yield. In this protocol the heterogeneous catalyst did not affect the quinoxaline moieties by over-reduction. With this versatile

• 1. Condensation of the nitrobenzyl esters 10 and 11 with hexaammoniumtriptycene hexachloride 4. Hydrogenolysis to tricarboxylic acid all-syn-16. Alkylation of all-syn-16 renders terminal alkene all-syn-17. Alkylation of (−)-isosteviol diketone 9 with 5-bromo-1-pentene. Direct synthesis of alkylated

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• catalyst 10 (Scheme 3; lower) was prepared in a short synthesis starting from the primary bromide 23 [22]. Hydrogenolysis (24, 67%) [41] and subsequent conversion to the triazolium salt completed the short synthesis (52% over 3 steps). X-Ray structural analysis of 5, 6 and 7 The X-ray crystal structures of

3-Pyridinols and 5-pyrimidinols: Tailor-made for use in synergistic radical-trapping co-antioxidant systems

• Luca Valgimigli,
• Daniele Bartolomei,
• Riccardo Amorati,
• Evan Haidasz,
• Jason J. Hanthorn,
• Susheel J. Nara,
• Johan Brinkhorst and
• Derek A. Pratt

Beilstein J. Org. Chem. 2013, 9, 2781–2792, doi:10.3762/bjoc.9.313

• antioxidants (10–12). Results and Discussion Synthesis. The preparation of compounds 4a, 4b and 5–8 involved installation of the aryl alcohol moiety as the final step via a Cu-catalyzed benzyloxylation/hydrogenolysis sequence on the corresponding pyri(mi)dyl halides, whereas the preparation of 4c, 4d and 9

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

• reduction of carbonyl compounds bearing an electronegative group in α-position [37]. After palladium-catalyzed hydrogenolysis of α-azidotetrahydrofuranols rac-9 and rac-10 an inseparable mixture of racemic jaspine B (rac-1) and its C-2-epimer rac-2 was obtained. Hence the natural product and its

• indicates that a (partial) epimerization at C-4 occurs under the reaction conditions employed. The diastereoselective reduction of the carbonyl group with L-selectride afforded the α-azidotetrahydrofuranones 9 and 10 in 66% yield over three steps. Subsequent hydrogenolysis of 9 and 10 afforded a mixture of

• to an enhanced difference of dipole moments and hence Rf values of the two isomers (Scheme 7). Final hydrogenolysis of the separated diastereomers 16 and 17 led to deprotection of the hydroxy group and simultaneous reduction of the azido group. Jaspine B (1) and its (2S,3R,4R)-diastereomer 2 were

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

• presence of sodium ethoxide delivers epoxide 1.87. The material is next subjected to hydrogenolysis using Pd/C in methanol with a 1 bar hydrogen pressure to reductively ring open the epoxide. Finally, the transformation of the alcohol to the mesylate 1.88 occurs under standard conditions. In order to

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

• -step sequence yielded azetidine 107. After oxidation with hydrogen peroxide, the resulting N-oxide cleanly underwent a [1,2]-Meisenheimer rearrangement upon heating in tetrahydrofuran. The so-formed azocine 108 was converted to amine 109 by hydrogenolysis of the N–O bond. Amide formation with acid

Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

• Matthew B. Plutschack,
• D. Tyler McQuade,
• Giulio Valenti and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 2022–2027, doi:10.3762/bjoc.9.238

• hydroxylamine hydrochloride (4 equiv) in methanol resulted in full conversion to compound 2. At a total flow rate of 5 mL/min at 60 °C using a 20 mL reactor (4 minutes residence time), we achieved a throughput of 177 mg/min (24-fold improvement relative to batch). The hydrogenolysis of the oxime illustrates a

• available from Thales). With a flow rate of 1 mL/min at 100 bar and 70 °C using a 10% Pd/C CatCart, a throughput of 8 mg/min was achieved. The crude reaction solution was pure by NMR and was used without further purification. As shown in Table 1, the hydrogenolysis represents a bottleneck in the synthesis

Synthesis of mucin-type O-glycan probes as aminopropyl glycosides

• David Benito-Alifonso,
• Rachel A. Jones,
• Anh-Tuan Tran,
• Hannah Woodward,
• Nichola Smith and
• M. Carmen Galan

Beilstein J. Org. Chem. 2013, 9, 1867–1872, doi:10.3762/bjoc.9.218

• the α-sialyl linkage in 6 was also unambiguously confirmed by the NMR data (H-3eq’ δ = 2.25 ppm, Δδ [H-9’a–H-9’b] = 0.36 ppm) [24]. Then, carbohydrate antigen 1 was obtained also by catalytic hydrogenolysis with Pd/C in methanolic HCl of 18 to yield the amine-containing derivative in 98% yield. To

• followed by reduction of the azide group in the linker by catalytic hydrogenolysis using hydrogen and Pd/C to give trisaccharide 7 in 52% yield, after the 5 step unmasking sequence. Conclusion A highly convergent and stereoselective strategy has been used to access mucin-type glycan targets 1–7. The

The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow

• Kimberley A. Roper,
• Malcolm B. Berry and
• Steven V. Ley

Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207

• reaction [42], and more recently stereospecific hydrogenolysis, Stille and Suzuki reactions have been used to further elaborate these useful products [43][44][45]. The triphenylphosphine oxide byproduct can often be difficult to remove from the reaction mixture, requiring extensive, time-consuming

Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues

• Xu-Wen Li,
• Jennifer Herrmann,
• Yi Zang,
• Philippe Grellier,
• Soizic Prado,
• Rolf Müller and
• Bastien Nay

Beilstein J. Org. Chem. 2013, 9, 1551–1558, doi:10.3762/bjoc.9.176

• nonselectively oxidized products. The crude product 21a was then submitted to benzyl group hydrogenolysis. As expected upon completion of the reaction, the 4,5-dihydrofuro[3,2-c]quinoline N-oxide ring system 22 was obtained as a racemic pair of diastereoisomers in a 1:1 ratio, supposedly formed through the

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• synthesis of this compound began with benzyl protection of 2-chloroquinolin-8-ol followed by installation of the [18F]-label and Pd-catalyzed hydrogenolysis to give the target compound. Compound 149 potently bound to Aβ-Zn aggregates (Kd = 1.5 nM) and showed rapid uptake and washout in normal mice (10% ID/g