Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• starting from azide 1 by first protecting the 3-OH group with an allyloxycarbonyl (Alloc) protecting group followed by regioselective reductive opening of the 4,6-O-benzylidene acetal using NaCNBH3 and HCl in diethyl ether, and successive phosphitylation of the liberated 4’-OH functionality with N,N

• DBU to provide a free amino group, the 2’-NH2 and 3-OH groups could be differentiated in the next acylation step by using DCC as activating agent for the N-acylation, and Steglich reaction conditions (DCC and DMAP) for the O-acylation. Following removal of the Alloc protecting group was readily

• separation of the anomeric α/β mixture furnished the anomerically pure trisaccharide 15. Next, three acyl residues were introduced at positions 2’, 3’ and 3 by successive deprotection–acylation sequence. The N-Fmoc protecting group was removed using DBU and the resulting free amino group was acylated with (R

The synthesis of the 2,3-difluorobutan-1,4-diol diastereomers

• Robert Szpera,
• Nadia Kovalenko,
• Kalaiselvi Natarajan,
• Nina Paillard and
• Bruno Linclau

Beilstein J. Org. Chem. 2017, 13, 2883–2887, doi:10.3762/bjoc.13.280

• protecting group resulted in a significant increase in mass, and therefore, chromatographic purification of the protected intermediates upon scale-up was inconvenient. As previously reported [17], epoxide opening of cis-2 with Olah’s reagent (HF·py) led to an 80% yield of the fluorohydrin after just three

• procedure is deemed to have low risk. Nonetheless, care must be taken and the reaction was run with the protection of a blast shield. In order to reduce the relative contribution of the protecting group to the overall weight of the intermediates, the use of an acetonide was explored. Given the starting

• increase). An investigation to use the much smaller acetonide protecting group, which can be used for the cis-1,4-butenediol starting material, was carried out. It was found that the use of Et3N·3HF for the epoxide opening step also lead to acetal rearrangement, leading to a more stable 1,3-dioxolane ring

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• support by means of an Fmoc/tert-butyl protecting group strategy on a preloaded Fmoc-Lys(Boc)Wang resin (0.57 mmol/g loading) using 10 mL polypropylene reactors. HfLeu containing peptides were synthesized with an Activo-P11 automated peptide synthesizer (Activotec, Cambridge, United Kingdom). Couplings of

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• the resulting amine 18, cleavage of the alcohol protecting group, Jones oxidation and formation of the methyl ester afforded the corresponding dipeptide isostere Boc-Ser(PMB)-ψ[(Z)-CF=CH]-Gly-OMe (19). In the same way, Boc-Val-ψ[(Z)-CF=CH]-Gly-OMe, Boc-Leu-ψ[(Z)-CF=CH]-Gly-OMe and Boc-Ala-ψ[(Z)-CF=CH

• = 75:25). Further modifications (removal of the sulfinyl group and the silyl protecting group in acidic conditions, transformation of the amine in methyl carbamate and oxidation of the primary alcohol into the corresponding carboxylic acid) gave the final isostere 93. In 2013, Pannecoucke and co

• -workers proposed a new strategy based on a chemoenzymatic reduction of ethyl 2-oxocyclopentanecarboxylate (94) using Baker’s yeast to afford the corresponding chiral alcohol 95 (Scheme 19) [53]. Then, reduction of the ester into the primary alcohol, its selective protection by a silyl protecting group

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• chose hydrazine tetrazole 10j to continue the synthesis, as it was obtained in excellent yield, it shows distinct NMR spectra and offers the possibility of further functionalization after removal of the Boc protecting group. Therefore, compound 10j was subjected to hydrazinolysis with hydrazine

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• propargylamines 7 in high yields and satisfactory diastereomeric ratios by cleaving off the TMS protecting group with TBAF. In previous investigations, the choice of solvent and Lewis acid were controversially discussed [13][14][45][46][47][48][49][50][52][53][54][55]. Nonpolar solvents (DCM < THF < Et2O

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• behavior in fluorination in view of selectivity and to explore substrate dependency and chemodifferentiation. Based on the different stereochemical structures of the selected model diols as well as the nature of the N-protecting group used, we expected differences in their chemical behavior under

• -membered diol stereoisomers (±)-1 and (±)-4 proved to be highly substrate dependent and on the basis of our earlier findings on substrate determinant fluorinations [37], we next investigated the effect of the nature of the N-protecting group on this reaction. The treatment of N-Cbz-protected dihydroxylated

• amide intermediate T17 which undergoes an intramolecular cyclization to give (±)-17 (Scheme 8). A similar aziridinium opening reaction with fluoride can be found in [38][39]. Interestingly, when changing the N-protecting group from benzoyl in (±)-14 to Cbz ((±)-18), the fluorination with Deoxofluor

Synthesis of ergostane-type brassinosteroids with modifications in ring A

• Vladimir N. Zhabinskii,
• Darya A. Osiyuk,
• Yuri V. Ermolovich,
• Natalia M. Chaschina,
• Tatsiana S. Dalidovich,
• Miroslav Strnad and
• Vladimir A. Khripach

Beilstein J. Org. Chem. 2017, 13, 2326–2331, doi:10.3762/bjoc.13.229

• selective benzylation of its equatorial hydroxy group [14] followed by chlorochromate oxidation gave, after removal of the benzyl protecting group in 26, the diketone 27. Its reduction proceeded regio- and stereoselectively to afford the 2α,3β-diol 28. Finally, treatment of this compound with KOH in MeOH

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• the electrophilic fluorination reagent NFSI (compared with nucleophilic fluorination reagents such as DeoxoFluor). Accordingly, two aldehyde substrates (7a and 7b) were prepared [21][22], containing either a phthalimide or a Boc protecting group. Electrophilic fluorination was attempted according to

• 7a (containing the phthalimide protecting group) suggested that the undesired difluorinated compound 12 was formed as the major product. An additional complication was that the phthalimide protecting group of 12 seemed to be at least partially sensitive to sodium borohydride [23]. In contrast, the

• substrate 7b (containing the Boc protecting group) was successfully converted into the desired fluorohydrin 11, albeit in poor yield. The optical purity of 11 was established through Mosher ester analysis (see Supporting Information File 1). With the fluorohydrin 11 in hand (Scheme 1), the next task was to

Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly

• Weizhun Yang,
• Bo Yang,
• Sherif Ramadan and
• Xuefei Huang

Beilstein J. Org. Chem. 2017, 13, 2094–2114, doi:10.3762/bjoc.13.207

• ]. A significant drawback of the reactivity-based chemoselective glycosylation method is the requirement that the glycosyl donor must bear higher anomeric reactivities than the acceptor for preferential donor activation. As a result, extensive protecting group manipulations have to be carried out to

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• the phthaloyl clamping groups to present the oligosaccharide chain in a favorable conformation for cyclization. After hydrolyzing the anomeric protecting group, several conditions were tried to close the ring and glycosylation with the trichloroacetimidoyl leaving group in 23 activated with

• size of the macrocycle formed during the glycosylation (Scheme 12) [80][81]. Thioglycoside donor 45 containing a 2-O-propargyl group and acceptor 46 with an azide-containing protecting group were connected using a click reaction to afford the tethered intermediate 47. Upon treatment with NIS/TfOH

• by Ito and Ogawa who implemented DDQ-mediated oxidative transformation of the p-methoxybenzyl (PMB) protecting group at the C-2 position of the donor into a tethering mixed acetal with a hydroxy group of the acceptor [94]. The early studies have successfully applied this PMB-based IAD method to the

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• –Gilbert homologation [128][129] under Bestmann–Ohira conditions [130][131], a Schwartz hydrozirconation/iodination sequence [132], and appropriate protecting group manipulations. Vinyl iodide 21, which comprises the C8–C13 segment was prepared from TBDPS-protected (R)-hydroxy-2-methylbut-3-ene 20 that was

• protected C1–C13 fragment 24; the latter was then transformed into alkyl iodide 25 via several functional group interconversions and protecting group manipulations. Negishi cross-coupling of 25 with vinyl iodide 19 then furnished the full length intermediate 26 in moderate yield. Simultaneous removal of the

• strategies to access and assemble the chiral fragments. Moreover, they sought to employ a fully silyl-based protecting group strategy (including protection of the diol motif in the C12–C20 core extension) that would enable global deprotection after attachment of the polyunsaturated side chain. The major

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

• Raja Ben Othman,
• Mickaël J. Fer,
• Laurent Le Corre,
• Sandrine Calvet-Vitale and
• Christine Gravier-Pelletier

Beilstein J. Org. Chem. 2017, 13, 1533–1541, doi:10.3762/bjoc.13.153

• modest diastereoselectivities (65:35) in favor of the 5’R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5’S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported. Keywords: diastereoselective alkynylation

• temperature [52] but, even at 0 °C, the components in the reaction mixture were largely degraded. The protection of uracil nitrogen at N-3 position by an allyl group did not significantly modify the 5’R/5’S ratio (Table 2, entry 3). Increasing the bulkiness of the ketal protecting group by introducing an

• that, contrary to that which was observed with ketal groups, the major diastereomer 4a obtained using tert-butyldimethylsilyl ether displayed the 5’S configuration. As was noted for isopropylidene as a protecting group, decreasing the temperature (Table 2, entry 7) or protecting the N-3 nitrogen of

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• . When the coupling is carried out at P(V) level, 3´-arylphosphate diesters (3 in Scheme 1) are normally used as building blocks and activated with arylsulfonyl chloride or azolide in the presence of an auxiliary nucleophilic catalyst [14], or a catalytically active phosphate protecting group, such as

• oligonucleotide. Since the phosphate protecting groups are normally base-labile and the repeatedly removable 5´-O protecting group is acid-labile, the 2´-O-protection should preferably be removable under orthogonal conditions. For this purpose, numerous protecting groups have been proposed [18][19], the fluoride

• obtain oligonucleotide–PEG–peptide conjugates [55][56]. The Fmoc protecting group was first removed and the peptide was assembled on the exposed amino function. Since the peptide moiety did not contain acid labile side chain protections, the oligonucleotide sequence could then be assembled by the

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• diastereoselectivity (3:97 dr). To further extend the reaction scope, we attempted to exchange the N-Boc group of the 3-substituted oxindoles with other protecting groups, such as Bn, CH3 or an acetyl group. The results demonstrated that only an acetyl protecting group proved to be well tolerated, providing for the

Total synthesis of elansolids B1 and B2

• Liang-Liang Wang and
• Andreas Kirschning

Beilstein J. Org. Chem. 2017, 13, 1280–1287, doi:10.3762/bjoc.13.124

• iodide 17 after O-acylation, iodination of the terminal alkyne and finally diimide-mediated syn-reduction [11]. Next, DDQ-mediated removal of the PMB protecting group yielded vinyl iodide 18. The synthesis of both fragments 13 and 18 set the stage for the Suzuki–Miyaura coupling which delivered the

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• moieties. Nonetheless, by taking advantage of the differential reactivity of the anomeric center, a selective activation at this position is possible. As a result, protecting group-free strategies to effect glycosylations are available thanks to the tremendous efforts of many research groups. In this

• linchpin for protecting-group-free glycosylation is an exploitation of the differential reactivity of the anomeric center. Two key features of the anomeric center provide this possibility. Firstly, the anomeric position of all unprotected monosaccharides is a reducing end (i.e., in equilibrium as an

• selective deprotonation of this hydroxy group over the others. This selective creation of a better nucleophile in the presence of the other protonated hydroxy groups can be regarded as an umpolung process. Despite this seeming difficulty, some protecting-group-free strategies to synthesize glycosides and

Synthesis of alkynyl-substituted camphor derivatives and their use in the preparation of paclitaxel-related compounds

• M. Fernanda N. N. Carvalho,
• Rudolf Herrmann and
• Gabriele Wagner

Beilstein J. Org. Chem. 2017, 13, 1230–1238, doi:10.3762/bjoc.13.122

• for the synthesis of 12 and 13 introduced the alkyne into the 2-position of the camphor skeleton, to provide the sultams 17. The removal of the acetal-protecting group occurred under comparatively mild conditions by stirring a mixture of 17 with acetone and conc. HCl. Acetone as solvent was best as it

• shift in compound 15, where the alkynyl substituent is nearby. As an alternative to the introduction of an acetal, an imine was tested for its suitability as a protecting group for the carbonyl moiety, as shown in Scheme 6. 3-Oxocamphorsulfonylimine 3 was converted into the imine 19 by reaction with 2

• higher ppm values (approx. 190 ppm) would have been expected. The removal of the imine-protecting group turned out to be somewhat difficult and could be performed only under relatively harsh acidic conditions using aqueous HCl under reflux to provide 12 in moderate yield. Overall, the protection of the

Aqueous semisynthesis of C-glycoside glycamines from agarose

• Juliana C. Cunico Dallagnol,
• Alexandre Orsato,
• Diogo R. B. Ducatti,
• Miguel D. Noseda,
• Maria Eugênia R. Duarte and
• Alan G. Gonçalves

Beilstein J. Org. Chem. 2017, 13, 1222–1229, doi:10.3762/bjoc.13.121

• reductive amination to accomplish such a synthesis through a short protecting-group-free route and (c) the compatibility of the starting material and all reaction conditions to the aqueous media, here we present the aqueous semisynthesis of mono- and disaccharide glycamines obtained by hydrolysis and

• obtain C-glycofuranose-containing glycamines through a short, protecting-group-free and aqueous-based semisynthesis. Our present study also addressed the obstacles frequently faced in reductive amination of carbohydrates (such as byproduct accumulation and purification issues) and contributed to provide

• -anhydro-α-L-galactopyranose unit (naturally present in the agarose structure) to all glycamines synthesized, constituting an amino-substituted C-threofuranoside moiety, which is closely related to (+)-muscarine. Keywords: amino sugar; 3,6-anhydro-α-L-galactopyranose; polysaccharide (agar); protecting

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

• Tue Heesgaard Jepsen,
• Emil Glibstrup,
• François Crestey,
• Anders A. Jensen and
• Jesper Langgaard Kristensen

Beilstein J. Org. Chem. 2017, 13, 988–994, doi:10.3762/bjoc.13.98

• 91% yield to furnish carboxylic acid 6. The subsequent 6π-electrocyclization performed in refluxing toluene in the presence of a catalytic amount of 2,6-di-tert-butyl-4-methylphenol (BHT) led to lactone 7 in 83% yield. The removal of the Ts-protecting group was initially attempted with SmI2 but

• pharmacological evaluations. However, since our aim was to develop a strategy for the late stage N-functionalization applicable for a medicinal chemistry SAR approach, the route described above was unsatisfactory. Therefore we turned our attention to an alternative protecting group, namely the Cbz group (see

• similar system [22], the final hydrogenolysis of the Cbz protecting group with H2 and either Pd/C or Pd(OH)2 (up to 50 mol % catalyst loading) in EtOAc, MeOH or AcOH was attempted, but no trace of the desired lactone 9 was observed. A control experiment with the addition of tosyl chloride after the

First total synthesis of kipukasin A

• Chuang Li,
• Haixin Ding,
• Zhizhong Ruan,
• Yirong Zhou and
• Qiang Xiao

Beilstein J. Org. Chem. 2017, 13, 855–862, doi:10.3762/bjoc.13.86

• presented with 22% overall yield by using tetra-O-acetyl-β-D-ribose as starting material. An improved iodine-promoted acetonide-forming reaction was developed to access 1,2-O-isopropylidene-α-D-ribofuranose. For the first time, ortho-alkynylbenzoate was used as protecting group for the 5-hydoxy group. After

• subsequent Vorbrüggen glycosylation, the protecting group could be removed smoothly in the presence of 5 mol % Ph3PAuOTf in dichloromethane to provide kipukasin A in high yield and regioselectivity. Keywords: gold catalysis; kipukasin A; marine nucleoside; total synthesis; Vorbrüggen glycosylation

• ). Kipukasin A could be constructed by Vorbrüggen glycosylation [22][23] of a properly protected glycosyl donor 3 with uracil (4). Neighboring group participation of the 2’-O-acetyl group stereoselectively facilitate the β-glycosidic bond formation. Thus, the choice of a suitable protecting group at 5-OH

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

• Runjun Devi and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2017, 13, 571–578, doi:10.3762/bjoc.13.56

• would be the non-requirement of any protecting group to construct the chroman ring. To test this seemingly straightforward approach, we initially attempted to synthesize (±)-2 utilizing the cyclization of (±)-triol 14 (Scheme 2) as the key step. Thus, commercially available 2,5-difluorobenzaldehyde (10

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• organic synthesis, very recent examples have been selected and will be discussed here. In the context of green chemistry [11], protecting-group free organic synthesis has received particular attention in the last years, because of atom economy [12][13][14][15] and reduction of synthetic steps [16]. It has

• been demonstrated by Yoshida that protecting-group-free synthesis could be feasible using flash chemistry and microreactor technology [17][18]. Recently, Yoshida and co-workers developed flash methods for the generation of highly unstable carbamoyl anions, such as carbamoyllithium, using a flow

• Yoshida reported another remarkable finding on the use of protecting-group-free organolithium chemistry. In particular, the flash chemistry approach was exploited for generating benzyllithiums bearing aldehyde or ketone carbonyl groups [20]. This reaction could be problematic for two reasons: a) the

Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

• Ramana Sreenivasa Rao and
• Chinnasamy Ramaraj Ramanathan

Beilstein J. Org. Chem. 2017, 13, 428–440, doi:10.3762/bjoc.13.46

• reflux conditions, the piperazine-2,6-dione 7a from 4-benzenesulfonyliminodiacetic acid was obtained only in 50% yield along with the formation of benzenesulfonic acid (Table 1, entry 1). The formation of benzenesulfonic acid may be due to the labile nature of the benzenesulfonyl protecting group

Total synthesis of a Streptococcus pneumoniae serotype 12F CPS repeating unit hexasaccharide

• Peter H. Seeberger,
• Claney L. Pereira and
• Subramanian Govindan

Beilstein J. Org. Chem. 2017, 13, 164–173, doi:10.3762/bjoc.13.19

• C2-participating levulinyl ester protecting group ensured selective formation of the trans-glycoside upon activation of 11 by NIS/TfOH in the presence of the C5 linker to produce glucoside 12 in 70% yield [24]. Cleavage of the C2 levulinyl ester of 12 by treatment with hydrazine acetate furnished 13

• obtain 35, required several protecting group manipulation steps: cleavage of the two acetate esters of 31 to produce diol 32 was followed by the reaction with trimethyl orthoacetate to provide the ortho-ester 33, which was regioselectively opened under acidic conditions to afford disaccharide acceptor 34

• containing a C3 hydroxy group [28]. Glycosylation of disaccharide 34 using galactose building block 9, activated by NIS/triflic acid, produced trisaccharide 35 with high α-selectivity by virtue of the C4-participating benzoyl ester protecting group of 9 [36]. Trisaccharide 35 was transformed into a