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

Diastereoselective synthesis of nitroso acetals from (S,E)-γ-aminated nitroalkenes via multicomponent [4 + 2]/[3 + 2] cycloadditions promoted by LiCl or LiClO₄

• Leandro Lara de Carvalho,
• Robert Alan Burrow and
• Vera Lúcia Patrocinio Pereira

Beilstein J. Org. Chem. 2013, 9, 838–845, doi:10.3762/bjoc.9.96

• the 1,3-dipolarophile occurred by the Re face on the opposite side to the bulky lateral chain at HC(4). In order to prove the applicability of the aminated nitroso acetals, the N–O bonds contained in 9c were easily cleaved under hydrogenolysis conditions to give the corresponding pyrrolizidin-3-one

• nitroalkenes and/or their respective nitronates in cycloaddition reactions. Synthetic route toward the chiral (S,E)-γ-aminated nitroalkenes 5a–c and their 1,3-diamine derivatives. Transition-state models to stereoselective approaches in the multicomponent cycloadditions of 5a–c. Hydrogenolysis of 9c to

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• ) oxidative cleavage of the double bond with OsO4/NaIO4, and (3) hydrogenolysis of the benzyl ester [36][48]. Although the Seebach methodology provides a highly stereoselective way to α-alkylated prolines, there are several shortcomings to the originally developed protocols [47]. In the oxazolidinone

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• . Alkylation of L-alanine benzyl ester with ethyl bromoacetate afforded amine 3 [46], on which N-Fmoc protection and subsequent carefully conducted hydrogenolysis of the benzyl ester were performed [47], to give acid 4 in acceptable overall yield. Condensation of acid 4 with secondary amine 2 proved to be

• hydrogen atmosphere at room temperature. The reaction was accurately monitored by TLC in order to prevent hydrogenolysis of the Fmoc group. The suspension was filtered on a layer of celite, the solution was evaporated under reduced pressure, and the crude was dissolved in AcOEt and then extracted three

Glycosylation efficiencies on different solid supports using a hydrogenolysis-labile linker

• Mayeul Collot,
• Steffen Eller,
• Markus Weishaupt and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 97–105, doi:10.3762/bjoc.9.13

• /bjoc.9.13 Abstract Automated oligosaccharide assembly requires suitable linkers to connect the first monosaccharide to a solid support. A new hydrogenolysis-labile linker that is stable under both acidic and basic conditions was designed, synthesized and coupled to different resins. Glycosylation and

• cleavage efficiencies on these functionalized solid supports were investigated, and restrictions for the choice of solid support for oligosaccharide synthesis were found. Keywords: glycosylation; hydrogenolysis; linkers; oligosaccharides; resins; solid-phase synthesis; Findings Since Bruce Merrifield

• issues. Cleavage of the linker by hydrogenolysis results in a free amine functionality for the immobilization of oligosaccharides on glycan arrays or for the synthesis of glycoconjugates. Hydrogenolysis on a solid support has been used previously in peptide chemistry [37]. In the early 1980s, catalytic

An improved synthesis of a fluorophosphonate–polyethylene glycol–biotin probe and its use against competitive substrates

• Hao Xu,
• Hairat Sabit,
• Gordon L. Amidon and
• H. D. Hollis Showalter

Beilstein J. Org. Chem. 2013, 9, 89–96, doi:10.3762/bjoc.9.12

• conditions of catalytic hydrogenolysis provided, in 96% yield, the known phosphonate polyether alcohol 6, the synthesis of which had been accomplished previously by a different route [17]. Activation of the alcohol moiety of 6 to the succinimidyl carbonate 7 was carried out under standard conditions in 87

Removal of benzylidene acetal and benzyl ether in carbohydrate derivatives using triethylsilane and Pd/C

• Abhishek Santra,
• Tamashree Ghosh and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2013, 9, 74–78, doi:10.3762/bjoc.9.9

• -diol derivatives [10][11]. It can be removed under acidic hydrolysis as well as under neutral conditions (e.g., hydrogenolysis). The benzylidene acetal can also be regioselectively opened under reductive conditions to produce partially benzylated derivatives [12][13][14]. A number of methods have been

• reported for the removal of benzylidene acetals by using strong protic and Lewis acids [10][11][15] as well as some heterogeneous acidic catalysts [16][17]. Removal of benzylidene acetal under nonacidic conditions includes hydrogenolysis using hydrogen gas over Pd/C [18], or treatment with hydrazine [19

Synthesis of a derivative of α-D-Glcp(1->2)-D-Galf suitable for further glycosylation and of α-D-Glcp(1->2)-D-Gal, a disaccharide fragment obtained from varianose

• Carla Marino,
• Carlos Lima,
• Karina Mariño and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2012, 8, 2142–2148, doi:10.3762/bjoc.8.241

• 100.4 and 99.3 for C-1 of the β and α-anomers, respectively. Derivative 8 is ready to be activated by the trichloroacetimidate method, for the synthesis of larger oligosaccharides. Conventional de-O-benzoylation and subsequent hydrogenolysis of 8 afforded disaccharide 1 in good yield (Scheme 1). The NMR

Automated synthesis of sialylated oligosaccharides

• Davide Esposito,
• Mattan Hurevich,
• Bastien Castagner,
• Cheng-Chung Wang and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2012, 8, 1601–1609, doi:10.3762/bjoc.8.183

• hydrogenolysis affording good yields of the trisaccharide 16, equipped with an amino spacer for conjugation. The synthesis of GM3 trisaccharide 16 proved that compound 4 is efficient for installing the capping sialyl α-(2→3) galactose unit into synthetic oligosaccharides. Furthermore, conditions applied to the

• temperature (0 °C) and longer time (2 h) proved sufficient to drive the reaction to higher conversion and trisaccharide 19 was isolated in 33% overall yield with respect to resin loading. Hydrogenolysis under standard conditions afforded the fully deprotected trisaccharide 20 in 78% yield. These conditions

• yield before hydrogenolysis gave the final trisaccharide 16 in 91% yield. The efficiency of the solid-phase and the solution-phase syntheses was compared. The solution-phase synthesis of trisaccharide 16 was completed with an overall yield of 42% (taking into account the preparation of compound 14, 69

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• , in which one of the guanidino Boc protecting groups was also removed. Hydrogenolysis of the Cbz protecting groups of 7 and 8 gave the corresponding amines 16 and 17, respectively (Scheme 4). These were coupled with the previously synthesised side chains 18, 19 [10] and 12, by using HATU as the

Studies on the substrate specificity of a GDP-mannose pyrophosphorylase from Salmonella enterica

• Lu Zou,
• Ruixiang Blake Zheng and
• Todd L. Lowary

Beilstein J. Org. Chem. 2012, 8, 1219–1226, doi:10.3762/bjoc.8.136

• ]. In the other phosphorylation reactions reported in this paper, the anomeric stereochemistry was determined in an analogous manner. Compound 18 was then deprotected in two steps, namely catalytic hydrogenolysis and then, without further purification, treatment with a mixture of CH3OH–H2O–Et3N 5:2:1 to

• phosphate with 22, which afforded the desired compound, 23, in 75% yield. Hydrogenolysis of the benzyl groups and deacylation led to the formation, in 67% yield, of Manp-1P derivative 10. Synthesis of 4-methoxy derivative 11 As illustrated in Scheme 3, the synthesis of the 4-methoxy Manp-1P analogue 11

• formed in 70% yield by phosphorylation as described for the synthesis of 9–11. Catalytic hydrogenolysis in the presence of NaHCO3 was used to cleave all the benzyl groups, which gave the 6-methoxy Manp-1P derivative 12 in 91% yield. The second route to 12 began with methyl 2,3,4-tri-O-benzoyl-α-D

Multistep organic synthesis of modular photosystems

• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2012, 8, 897–904, doi:10.3762/bjoc.8.102

• with tert-butyl carbazate under mild conditions. The protected hydrazide 27 was obtained in 59% yield over two steps. The Cbz protecting groups were removed chemoselectively by hydrogenolysis over Pd–C in the presence of acetic acid, and the obtained diamine was reacted with the activated asparagusic

An easy α-glycosylation methodology for the synthesis and stereochemistry of mycoplasma α-glycolipid antigens

• Yoshihiro Nishida,
• Yuko Shingu,
• Yuan Mengfei,
• Kazuo Fukuda,
• Hirofumi Dohi,
• Sachie Matsuda and
• Kazuhiro Matsuda

Beilstein J. Org. Chem. 2012, 8, 629–639, doi:10.3762/bjoc.8.70

• O-benzyl group by catalytic hydrogenolysis, the GGPL-I homologue I-a was obtained. In the same way, the GGPL-I sn-isomer I-b was derived from a mixture of 4b and 5b available from the reaction between 1 and (R)-glycidol (Scheme 1 and Scheme 2b). 1H NMR characterization of I-a, I-b and the related

Branching out at C-2 of septanosides. Synthesis of 2-deoxy-2-C-alkyl/aryl septanosides from a bromo-oxepine

• Supriya Dey and
• Narayanaswamy Jayaraman

Beilstein J. Org. Chem. 2012, 8, 522–527, doi:10.3762/bjoc.8.59

• , leading to a 2-deoxy-2-C-alkyl septanoside containing free hydroxyl groups. Towards this effort, 4 was subjected first to a hydrogenolysis (Pd/C, H2), which afforded D-manno-sept-3-uloside 13 as single diastereomer in good yield (Scheme 4). The configuration of C-2 in 13 was confirmed through HMQC and

• moieties in 13, resulting from the concomitant reduction of the exocyclic double bond in 4, was also observed. The presence of the ketone functionality in 13 was inferred from the resonance at 208.4 ppm in the 13C NMR spectrum. Subsequent to hydrogenolysis, the treatment of 13 with NaBH4 facilitated the

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• derivatives (piperidines and pyrrolidines). However, during the final deprotection step by hydrogenolysis, the reaction resulted in the formation of the disubstituted urea 10 or, unexpectedly, monosubstituted ureas 12, 16 and 19 (Figure 3), depending on the starting material. Pyrrolidine derivatives were

• isocyanate in dimethoxyethane at 85 °C afforded urea 23 (15% yield over two steps). Reaction of compound 24 directly with benzyl isocyanate in dimethoxyethane at 85 °C afforded urea 25 in 72% yield (Scheme 1B). The hydrogenolysis of benzyl ureas 23 and 25 unexpectedly proceeded in a different manner

• amounts of the benzyl urea that could not be fully hydrolysed, even after prolonged reaction times. In order to figure out whether the benzyl urea moiety might have any effect on the activity and specificity against trehalases, derivative 13 was also synthesized by direct hydrogenolysis of starting

Dependency of the regio- and stereoselectivity of intramolecular, ring-closing glycosylations upon the ring size

• Patrick Claude,
• Christian Lehmann and
• Thomas Ziegler

Beilstein J. Org. Chem. 2011, 7, 1609–1619, doi:10.3762/bjoc.7.189

• task because the benzylidene group must remain unaffected. After careful optimization, hydrogenation of 3a with Lindlar catalyst (Pd on BaCO3) in ethanol at room temperature gave 4a in 91% yield, which was sufficiently pure to be used in the next step without further purification. No hydrogenolysis of

• prepared by hydrogenolysis of the known Z-protected glucosides 3c [33] and 3d [36]. Finally, compounds 4a–d were condensed with pentafluorophenyl ester 2 (ethyl acetate, 25 °C, 16 h) to afford the prearranged glycosides 5a–d in 78–89% yield (Figure 2). As the condensation of ester 2 and amines 4 progressed

Evaluation of a commercial packed bed flow hydrogenator for reaction screening, optimization, and synthesis

• Marian C. Bryan,
• David Wernick,
• Christopher D. Hein,
• James V. Petersen,
• John W. Eschelbach and
• Elizabeth M. Doherty

Beilstein J. Org. Chem. 2011, 7, 1141–1149, doi:10.3762/bjoc.7.132

• ® systems have been used successfully for a variety of reductions; some of the more notable applications including O-debenzylation, CBz-hydrogenolysis, aromatic ring saturation, imine reduction, and enantioselective carbonyl reductions [8][10][11][12][13]. In our hands, the ThalesNano H-Cube® and the H-Cube

Multicomponent synthesis of artificial nucleases and their RNase and DNase activity

• Anton V. Gulevich,
• Lyudmila S. Koroleva,
• Olga V. Morozova,
• Valentina N. Bakhvalova,
• Vladimir N. Silnikov and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2011, 7, 1135–1140, doi:10.3762/bjoc.7.131

• diamides. The benzyl groups can be easily removed from compounds 4 by the standard hydrogenolysis procedure. For example, using Pd/C as catalyst we obtained the target peptidomimetics 5 in up to 90% yield. Thus, we synthesized a number of racemic peptidomimetics 4 and 5, containing aliphatic or aromatic

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• addition of D2O to the reaction on work up. The major and minor diastereoisomers of 5a were separated by careful chromatography on silica gel into single stereoisomers. Completion of the syntheses required hydrogenolysis of the (S)-N-methylbenzyl moiety of 5a. A range of conditions and catalysts were

• explored for the hydrogenolysis of 5a, however cleavage of the C–N bond proved very difficult and a satisfactory method could not be found. Therefore, (S)-α-(p-methoxyphenyl)ethylamine (3b) was explored as an alternative amine for the aza-Michael reaction, as removal of this amine using ceric ammonium

Synthesis, reactivity and biological activity of 5-alkoxymethyluracil analogues

• Lucie Brulikova and
• Jan Hlavac

Beilstein J. Org. Chem. 2011, 7, 678–698, doi:10.3762/bjoc.7.80

• ) which was obtained in 38–40% yield, however, the authors were unable to account for its formation. An attempt at hydrogenolysis of the methoxy group of derivative 1 using H2 and Pd/C afforded 5-(3,3,3-trifluoro-1-methoxyprop-1-yl)-5,6-dihydro-2'-deoxyuridine (8) indicating that ring reduction occurred

• instead of hydrogenolysis (Scheme 2). The synthesis of a large range of alkoxyhalogenalkyl 2'-deoxyuridine nucleosides was successfully performed by Kumar and co-workers over the years 1989–1994 [9][10][11][12][13]. Almost all of these compounds were synthesized in order to evaluate their biological

Tribenzotriquinacenes bearing three peripheral or bridgehead urea groups stretched into the 3-D space

• Jörg Tellenbröker and
• Dietmar Kuck

Beilstein J. Org. Chem. 2011, 7, 329–337, doi:10.3762/bjoc.7.43

• ) chloride and charcoal in refluxing methanol (Scheme 1) [23], and afforded a mixture of the triamino-TBTQs 10 and 11 in good yield (81%). However, catalytic hydrogenolysis of compounds 8 and 9 at ambient temperature under medium pressure [20][24][25] proved to be even more efficient and gave the TBTQ