Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• chemical synthesis. In principle, they can function as inexpensive, chiral and densely functionalized starting materials. On the other hand, the use of amino acid starting materials routinely necessitates protective group chemistry, and in reality, large-scale preparations of even the simplest side-chain

• structure-adapted database searches will uncover such protected amino acid derivatives in abundance, with little effort involved. Part of the reason for the impulsive willingness to adopt protective group chemistry is most surely connected to the fact that only minor quantities of end material are required

• liberating the acylated derivative from its copper salt using 8-hydroxyquinoline as an organic chelating precipitant [8]. While both useful and creative, the copper chelation procedure carries with it many of the same shortcomings as other types of protective group chemistry. However, by a change of the

Synthesis and characterization of pH responsive D-glucosamine based molecular gelators

• Navneet Goyal,
• Hari P. R. Mangunuru,
• Bargav Parikh,
• Sonu Shrestha and
• Guijun Wang

Beilstein J. Org. Chem. 2014, 10, 3111–3121, doi:10.3762/bjoc.10.328

• better understand the scope of D-glucosamine derivatives as gelators, we synthesized and screened a novel class of N-acetylglucosamine derivatives with a p-methoxybenzylidene acetal protective group. This modification did not exert a negative influence on the gelation. On the contrary, it actually

• of the headgroup of this class of LMWGs lays the basis for the design of organo/hydrogelators with desired functionalities. The p-methoxybenzylidene acetal is more pH responsive in comparison to the benzylidene acetal protective group. The p-methoxybenzylidene acetal can be cleaved in the presence of

• ]. Previously we mostly focused on the modification of the C-2 position of the benzylidene acetal protected headgroups 1 and 2 (Figure 1). We obtained the general structural requirements for acyl derivatives at the 2-position. In this study, we explore the substituent effect at the benzylidene acetal protective

Exploration of C–H and N–H-bond functionalization towards 1-(1,2-diarylindol-3-yl)tetrahydroisoquinolines

• Michael Ghobrial,
• Marko D. Mihovilovic and
• Michael Schnürch

Beilstein J. Org. Chem. 2014, 10, 2186–2199, doi:10.3762/bjoc.10.226

• and 6). A carbonyl protective group on the nitrogen of THIQ proved to be crucial, as only traces of the correct m/z for desired product 6i were observed (GC–MS) in case of unprotected THIQ 4d (Table 2, entry 8) and also benzyl-protected 4c showed no reaction (6h, Table 2, entry 7). Pathways to

• desired product 1 (see Table 9, note a). Still, only a moderate yield of 37% was achieved in case of 2-tolyl- (1j, Table 9, entry 7) and 30% with the 1-naphthyl-substituted product 1i (Table 9, entry 6). As proof of concept, the Boc-protective group could be removed via our previously established protocol

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

• methanol/THF. In summary, by optimizing the protective group strategy and the reductive cleavage methods we were able to prepare the desired rigid p-terphenyl-linked carbohydrate mimetic 30 in twelve steps starting from D-isoascorbic acid, but in only six steps with respect to crucial intermediate 4. The

Improving the reactivity of phenylacetylene macrocycles toward topochemical polymerization by side chains modification

• Simon Rondeau-Gagné,
• Jules Roméo Néabo,
• Maxime Daigle,
• Katy Cantin and
• Jean-François Morin

Beilstein J. Org. Chem. 2014, 10, 1613–1619, doi:10.3762/bjoc.10.167

• alkyne protective group, the half-macrocycle 5 was obtained by Castro–Stephens–Sonogashira coupling with previously reported 3,5-diiodooctylbenzene [39] in good yields despite of the possible polymerization side reaction (54% yield). TMS-protected alkynes were, then, installed on the half-macrocycle to

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• attached to the anomeric center of the glucosamine moiety using oxazoline 6 [37][38][39]. Deacetylation and subsequent installation of the benzylidene protective group then gave alcohol 9. Coupling of 9 with (S)-2-chloropropanoic acid in the presence of sodium hydride resulted in the formation of protected

• with the reduction of the azide in compound 14 with PMe3 and subsequently the primary amine and Fmoc protected glutamic acid allyl ester were condensed under influence of HATU and DiPEA to give the orthogonally protected compound 15 in 57% yield. To make 15 suitable for SPPS, the allyl protective group

• first replaced by electron-withdrawing acetyl groups. This protective group pattern provides higher acid stability of the glycosidic linkage and permits removal of the Boc group using more stringent conditions. Thus, treatment of 14 with 60% aqueous acetic acid in the presence of two equivalents of

Solid-phase-supported synthesis of morpholinoglycine oligonucleotide mimics

• Tatyana V. Abramova,
• Sergey S. Belov,
• Yulia V. Tarasenko and
• Vladimir N. Silnikov

Beilstein J. Org. Chem. 2014, 10, 1151–1158, doi:10.3762/bjoc.10.115

• confirmed by TLC, RPC and mass spectrometry before and after removal of the Boc protective group (see Supporting Information File 1 for details). It is interesting to note that the mobility of the homooligomers in TLC decreased with increasing of their length (Table S1, Supporting Information File 1). This

• fact helped us to estimate the comparative length and purity of homooligomers. The yield in each cycle was 96–98%. After completion of the pentamer synthesis and cleavage of the oligomer from the support, the Boc protective group was removed by trifluoroacetic acid (TFA). Target homopentamers 7a,d,e

• , 1H, H5), 2.75–2.64 (m, 2H, NH2CH2), 1.81 (d, J = 0.8 Hz, 3H, CH3), 1.39 (dd, J = 11.1, 10.0 Hz, 1H, H3), 1.35–1.30 (dd, J = 11.6, 10.6 Hz, 1H, H5); MALDI–TOFMS (m/z): [M – Tr + 2H]+ (the Tr protective group was removed during the sample preparation) calcd for C10H17N4O3 241.13; found, 241.45

Synthesis of zearalenone-16-β,D-glucoside and zearalenone-16-sulfate: A tale of protecting resorcylic acid lactones for regiocontrolled conjugation

• Hannes Mikula,
• Julia Weber,
• Dennis Svatunek,
• Philipp Skrinjar,
• Gerhard Adam,
• Rudolf Krska,
• Christian Hametner and
• Johannes Fröhlich

Beilstein J. Org. Chem. 2014, 10, 1129–1134, doi:10.3762/bjoc.10.112

• /bjoc.10.112 Abstract The development of a reliable procedure for the synthesis of the 16-glucoside and 16-sulfate of the resorcylic acid lactone (RAL) type compound zearalenone is presented. Different protective group strategies were considered and applied to enable the preparation of glucosides and

• protection of the more nucleophilic 4’-phenol and subsequent glucosylation or sulfation should lead to the desired products. For the development of a reliable protective group strategy and subsequent reaction optimization, 2,4-dihydroxybenzoic acid isopropyl ester (9) [29] was used as a RAL mimic. For

• behavior of ZEN (1) and the ZEN mimic 9. After this second setback the protective group strategy was changed again within a third approach. Considering steric hindrance and methods for selective deprotection under relatively mild conditions led us to the use of triisopropylsilyl (TIPS) protection for

Visible-light-induced, Ir-catalyzed reactions of N-methyl-N-((trimethylsilyl)methyl)aniline with cyclic α,β-unsaturated carbonyl compounds

• Dominik Lenhart and
• Thorsten Bach

Beilstein J. Org. Chem. 2014, 10, 890–896, doi:10.3762/bjoc.10.86

• protective group, the reaction was complete within six hours and delivered exclusively the tricyclic products 19. The Boc-protected product 19a was obtained in only 30% yield, however; the result indicates that the Boc protecting group is not ideal for reactions in MeOH as the solvent (vide infra). A higher

Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis

• Frank Hahn,
• Nadine Kandziora,
• Steffen Friedrich and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2014, 10, 634–640, doi:10.3762/bjoc.10.55

• aldehyde 11 The synthesis of the common precursor aldehyde 11 was accomplished from di(menth-1-yl)succinate (14) through a known route described by Omura et al. (Scheme 2) [15][16][17]. The final oxidation state at C10 in 12 was installed after protective group removal to primary alcohol 15 followed by

Synthesis of nucleotide–amino acid conjugates designed for photo-CIDNP experiments by a phosphotriester approach

• Tatyana V. Abramova,
• Olga B. Morozova,
• Vladimir N. Silnikov and
• Alexandra V. Yurkovskaya

Beilstein J. Org. Chem. 2013, 9, 2898–2909, doi:10.3762/bjoc.9.326

• selective cleavage of the aromatic phosphotriester bond by the F− anion, the oxoethyl fragment is quite stable to β-elimination. We succeeded in the mild deprotection of derivative 20 containing the Boc protective group with formic acid but, to our surprise, we failed in this way when the L-tryptophan

• moiety was linked to the 5’-OH group of 2’-dG (conjugate 6). In this case, the deprotection was accompanied by the cleavage of the guanine base at pH 1–5 in aqueous solutions and under the action of a TFA/CH2Cl2 mixture. So, we replaced Boc by the trifluoroacetyl protective group and synthesized the

• additional building block 15 to obtain conjugate 6 (Scheme 4). Keeping in mind the possibility of a further modification of fully protected derivative 31, we chose the acid labile MMTr protective group for the linker to obtain conjugate 7 because such protection is orthogonal to the protective groups of

Gold-catalyzed oxycyclization of allenic carbamates: expeditious synthesis of 1,3-oxazin-2-ones

• Benito Alcaide,
• Pedro Almendros,
• M. Teresa Quirós and
• Israel Fernández

Beilstein J. Org. Chem. 2013, 9, 818–826, doi:10.3762/bjoc.9.93

• ][37][38][39][40][41]. The Boc protective group has been widely used in allene chemistry, being an inert and recommended partner in gold- and palladium-catalyzed aminocyclizations of allenes [42]. On the other hand, reports of gold-catalyzed cyclizations leading to heterocycles that contain more than

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

• modular approach to our synthesis with an intrinsic transferability to variously substituted malonates. After optimization, mono-t-Bu-protected malonate provided the best starting point for the synthesis (Scheme 1) [34]. The sterically demanding protective group prevented decarboxylation during the

Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

• Marcin Jasiński,
• Dieter Lentz and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2012, 8, 662–674, doi:10.3762/bjoc.8.74

• -protected derivative 9, selective removal of the N-protective group could be achieved under the applied conditions. After prolonged reaction times (16 h) there was no significant change in the tested sample. A complete deprotection of 9 leading to dihydroxylated compound 15 was possible in high overall

• at low temperatures [49] also provided the expected compound 14 (Table 2, entry 7); however, the analytically pure sample of this compound could only be isolated in 18% yield. Therefore, the protocol applying a TMS-ethyl substituent as a more easily removable O-protective group turned out to be much

• monitoring. However, the attempted isolation and purification of this compound by column chromatography provided amino alcohol 17 as the only product in high yield (92%). The limited stability of the TMS protective group is evident from the results presented in Scheme 7. Treatment of freshly prepared

Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes

• Nora L. Löw,
• Egor V. Dzyuba,
• Boris Brusilowskij,
• Lena Kaufmann,
• Elisa Franzmann,
• Wolfgang Maison,
• Emily Brandt,
• Daniel Aicher,
• Arno Wiehe and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2012, 8, 234–245, doi:10.3762/bjoc.8.24

• multivalent host and guest molecules becomes available with this synthetic strategy. In the future, the pseudorotaxanes designed here should be easily converted into rotaxanes after cleavage of the Boc protective group at the axle ends and attachment of stopper groups to the terminal amines. Results and

• complexation-induced signal shifts are even stronger than similar shifts observed for other rotaxanes with a diamide moiety [101]. The fact that proton “3” also shifts significantly indicates that binding may also involve the carbonyl group of the Boc protective group. A reversible shuttling between both the

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

• , containing two amide bonds and variable substituents, can be synthesized by the Ugi reaction with subsequent removal of diamine residue (Scheme 1). Original substrates for the synthesis could be aliphatic diisocyanides 3, amines (with an easily removable protective group) and aldehydes. We used an

A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

• Christian Eidamshaus,
• Roopender Kumar,
• Mrinal K. Bera and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2011, 7, 962–975, doi:10.3762/bjoc.7.108

• attempts to incorporate proline-derived moieties failed. N-Benzylproline (41) turned out to be almost insoluble in ethereal solvents, which might explain why the desired β-ketoenamide was not formed [43]. To increase the solubility of the proline component, we changed the protective group from benzyl to

Homoallylic amines by reductive inter- and intramolecular coupling of allenes and nitriles

• Peter Wipf and
• Marija D. Manojlovic

Beilstein J. Org. Chem. 2011, 7, 824–830, doi:10.3762/bjoc.7.94

• functional group compatibility in this methodology, we sought to develop a new approach for the protective group-free synthesis of homoallylic amines. The ease of synthesis of N-metalloimines by hydrometalation of nitriles could potentially provide suitable intermediates for this synthetic strategy. In this

Gold-catalyzed heterocyclizations in alkynyl- and allenyl-β-lactams

• Benito Alcaide and
• Pedro Almendros

Beilstein J. Org. Chem. 2011, 7, 622–630, doi:10.3762/bjoc.7.73

• the presence of a protective group at the hydroxy moiety. These gold-catalyzed oxycyclizations were successfully extended to trishomopropargylic alcohol 29, which afforded the oxycyclization/hydroxylation adduct 30a with concomitant MOM cleavage (Scheme 14). In contrast, the presence of a phenyl

Enantioselective synthesis of tricyclic amino acid derivatives based on a rigid 4-azatricyclo[5.2.1.0^2,6]decane skeleton

• Matthias Breuning,
• Tobias Häuser,
• Christian Mehler,
• Christian Däschlein,
• Carsten Strohmann,
• Andreas Oechsner and
• Holger Braunschweig

Beilstein J. Org. Chem. 2009, 5, No. 81, doi:10.3762/bjoc.5.81

• MeOCH=PPh3 (Scheme 4). The selective hydrolysis of the enol ether moiety in 18 in the presence of the N-Boc-protective group was achieved by using trichloroacetic acid. The desired endo-configured aldehyde 15 was thus available in only two steps in good 64% overall yield from 9. After oxidation of 15 to

Synthesis of mesogenic phthalocyanine-C₆₀ donor–acceptor dyads designed for molecular heterojunction photovoltaic devices

• Yves Henri Geerts,
• Olivier Debever,
• Claire Amato and
• Sergey Sergeyev

Beilstein J. Org. Chem. 2009, 5, No. 49, doi:10.3762/bjoc.5.49

• (MEMCl) in the presence of i-Pr2EtN as a base. The general choice of acetal as a protective group was dictated by its excellent stability in the presence of the strong bases, required for the cyclotetramerization of phthalonitriles. Among various popular acetal protective groups, the relatively polar MEM

• modest yields of 10a–d actually correspond to those reported earlier for other A3B-type phthalocyanines: yields higher than 20% are rare in such reactions [45][49][50][51]. The MEM protective group in 10a–d was then quantitatively removed to give 4a–d upon treatment with pyridinium tosylate (PPTS) in t

2-Phenyl- tetrahydropyrimidine- 4(1H)-ones – cyclic benzaldehyde aminals as precursors for functionalised β²-amino acids

• Markus Nahrwold,
• Arvydas Stončius,
• Anna Penner,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2009, 5, No. 43, doi:10.3762/bjoc.5.43

• N1-Cbz-protective group of 4 can be chemoselectively cleaved by carefully monitored hydrogenolysis on 10% Pd/C in dry THF solution. The pure fully deprotected tetrahydropyrimidinone rac-7 was obtained after recrystallisation from ethyl acetate. Although 7 proved to be stable under inert gas

• of the three protons at C5 and C6 parallel those of the syn-configured compound cis-12, but not those of the anti-configured compound trans-12 [36]. The high value of the 3JAX-coupling constant of around 10 Hz does not significantly change after removing the N3-Boc-protective group, as exemplified by

Sordarin, an antifungal agent with a unique mode of action

• Huan Liang

Beilstein J. Org. Chem. 2008, 4, No. 31, doi:10.3762/bjoc.4.31

• and electronic constraints (Scheme 11). Selective Lemieux-Johnson cleavage of the vinyl groups using OsO4 and NaIO4 in the presence of PhB(OH)2 [33] afforded the dialdehyde 54. Racemic sordaricin (2) was completed after a few standard redox and protective group manipulations. The synthesis of