The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• control) gave the desired racemic N-ethoxycarbonyl-1-benzyltetrahydroisoquinolines 5a–h with intact ethoxycarbonyl protection of the phenolic groups (Table 2). Simultaneous phenol deprotection and reduction of the carbamate group (route A) to an N-methyl group was accomplished by lithium alanate reduction

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• into a primary alcohol with sodium borohydride affords compound 23. The protection of the hydroxy group of compound 23 was carried out by TBDPSCl in the presence of imidazole and N,N-dimethylformamide (DMF) as solvent, and deprotection of the benzoyl group by ammonolysis provides silylated compound 24

• oxathiolane derivative 4 with silylated cytosine, which afforded 79 as a mixture of the cis- and trans-nucleosides. The process used N-protected cytosine and further chromatographic separation. The deprotection with a methanolic ammonia solution provided racemic (±)-BCH-189 (1c). In vitro studies of (±)-BCH

• ) catalyst to obtain nucleoside derivative 79a, followed by deprotection using methanolic ammonia (Scheme 27). Cousins et al. [49] carried out the coupling of enantiomerically enriched oxathiolane propionate 44 with silylated cytosine in the presence of the Lewis acid trimethylsilyl iodide (TMSI), which gave

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• of biaryl aldehyde intermediates 8, reduction [60] in the case of nitriles 14, or Boc deprotection [61] for 14k, m, o according to standard protocols (Schemes 4–7; for details, see Supporting Information File 1). Although it may seem counterintuitive to first convert aldehydes 8 and nitriles 14 into

• obtained via TBHP-mediated cyclization of 23 and subsequent TBS-deprotection of intermediate 24 with pyridine and HF·pyridine complex [66] in a total yield of 26% over the two steps. The longest linear sequence was 7 steps, with an overall yield of 5%. Finally, the reaction mechanism of the oxidative

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• NaHCO3 solution and water. After drying and evaporation of the solvent in vacuo, crude products were obtained and were purified by column chromatography. General procedure for deprotection In a round-bottom flask, the protected bile acid tetrazole (0.20 mmol) was dissolved in an ethanolic KOH solution

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• esterification step. In the retrosynthesis, compound 107 is conceived as the branching intermediate to access both brevipolides M and N (Scheme 13). The 5,6-dihydro-α-pyrone moiety can be derived from alkyne 108 via the sequential deprotection, Lindlar reduction, and oxidation. The propargylic alcohol moiety is

Chemical syntheses and salient features of azulene-containing homo- and copolymers

• Vijayendra S. Shetti

Beilstein J. Org. Chem. 2021, 17, 2164–2185, doi:10.3762/bjoc.17.139

• by using [Pd(allyl)Cl]2 and JackiePhos as a ligand to obtain the polymer 30 in 52% yield. The deprotection of the N-Boc functionality led to the formation of poly[2,6-aminoazulene] 31 in excellent yields (Scheme 7C). The N-Boc-protected polymer 30 possessed good solubility in organic solvents and its

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• methodology, they synthesized 2,3,6,7-anthracenetetracarbonitrile (90) in a good yield (84%) by double intermolecular Wittig reaction of the protected benzenetetracarbaldehyde 87 with reagent 88, followed by deprotection and double ring-closing reaction of intermediate 89; they used a mixture of triflic acid

• -anthracenetetracarbonitrile (90) by double Wittig reaction followed by deprotection and intramolecular double ring-closing reaction. Homo-elongation protocol for the synthesis of substituted acene diesters/dinitriles. Synthesis of two new parental BN anthracenes via borylative cyclization. Synthesis of substituted

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• be quite challenging to prepare. Moreover, problems can occur during the removal of the PGs, since partially deprotected compounds can generate insoluble aggregates [24]. Incomplete deprotection and residual PGs can largely affect the properties of the obtained polymer. Chemical synthesis provides

• synthetic steps. In general, BBs are equipped with a reactive anomeric LG to allow for glycosylation and suitable PGs to ensure regio- and stereocontrol [25]. Even though, in most cases, BB preparation follows straightforward protection/deprotection strategies, the low selectivity and yield of certain

• a solid support following a linear approach (Figure 1D). Cycles of glycosylation and selective deprotection are iteratively performed to access the desired polysaccharide with full control over the length and the monosaccharide sequence [32]. Upon completion of the assembly, the desired product is

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• highly site-selective and wide functional-group tolerant reaction. To test this protocol versatility over biologically relevant scaffolds, a COCF3-leelamine analogue 48 with two sterically differentiated benzylic sites was selectively aminated at the secondary benzylic site. After Tces deprotection, the

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• synthesis and coupling efficiency on the synthesizer, significant loss of the hydrocarbon-linked group was observed during the alkaline deprotection conditions [115]. After insertion into a 19-mer DNA-ON, modification 79 did not show any significant increase in Tm. This trend was changed when the

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• . Deprotection followed by fluorination with FClO3 gave (R)- and (S)-28-3 in good yields. X-ray crystallography was used to determine the structure and confirm the absolute stereochemistry of (S)-28-3. The optically active reagents (R)- and (S)-28-3 were effective in the enantioselective fluorination of cyclic

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• afforded N1-Bn and N2-Bn tetrazoles 13 and 14 in low yield (31%) and again with little regiodiscrimination (N1-Bn/N2-Bn = 1:1.2). The synthesis of appropriately protected C6-tetrazole donors 11–14 was accomplished to allow for regioselective deprotection and unveil C4-acceptor capability within a broader

• -phosphate 21. Deprotection utilised 0.6 equiv of Pd/C (0.1 equiv per benzyl group) and 0.6 equiv of Pd(OH)2/C to afford 21 in 72% yield after 24 h. NMR analysis of 21 confirmed the presence of a C6-tetrazole (δC = 160.8 ppm), alongside an anomeric phosphate (δP = −2.15 ppm), and 1H coupling constant data (δ

Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

• Ivan P. Mosiagin,
• Olesya A. Tomashenko,
• Dar’ya V. Spiridonova,
• Mikhail S. Novikov,
• Sergey P. Tunik and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2021, 17, 1490–1498, doi:10.3762/bjoc.17.105

• methodology for the preparation of pyrido[2,1-a]pyrrolo[3,2-c]isoquinoline derivatives A (Scheme 1). The previously developed Pd-catalyzed protocol for the preparation of these compounds could be used only for arylation of pyrrole N-benzyl protected starting materials C [17]. The deprotection of the product

• ]isoquinoline backbone from N-unprotected pyrrolylpyridinium salts and, unlike the Pd-catalyzed version cyclization, avoids the deprotection step that is accompanied by isomerization. Molecular structure of compound 3a, displacement parameters are drawn at 50%. Molecular structure of compound 13, displacement

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• functional groups as they were unveiled. The functionalized C5 fragments were coupled via reductive amination revealing the C10 carbon backbone. Deprotection of the alcohol and amine functional groups successfully provided ent-pavettamine as a TFA salt. Keywords: chiral sulfoxide; ent-pavettamine

• addition of the chiral auxiliary. Our attention then turned to the stereoselective reduction of 8. Chelation-controlled reduction of 8 using ZnCl2 and DIBALH allowed for the successful formation of 16 as a single diastereomer (Scheme 4), as evidenced by 1H NMR spectroscopy [18]. TBS deprotection furnished

• the 1,3-diol motif [19]. The group is also associated with ease of deprotection, which is well documented in carbohydrate and sugar chemistry [20]. Comparison of our new route involving trityl and TBS protections with our previously published acetonide protection route for the synthesis of 4, showed

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• deprotection with TBAF and aqueous methanolic ammonia resulted in the formation of 2′-deoxy-2′-(thymine-1-yl)ethyluridine (11) in 37% yield. When the same procedure was repeated with N3-benzoyluridine (10) the double-headed nucleoside 11 was obtained in 67% yield (Scheme 3) [35]. The double-headed nucleoside

• . Global deprotection of 32 using palladium-catalyzed hydrogenation conditions resulted in the formation of the targeted double-headed nucleoside 33 (Scheme 8) [33]. The double-headed nucleoside 33 was dimethoxytritylated, phosphitylated, and incorporated into duplex and its ability to recognize

• (Scheme 17) [54]. The tert-butyldimethylsilyl-protected (TBDMS) nucleoside 76 was first hydrolyzed using NaOH, which was followed by TBDMS deprotection using tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran (THF) to afford the double-headed nucleoside 77. The TBDMS-protected nucleoside 73 was

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• organometallic compounds to the iminic carbon [1][2][3]. The ready availability of both enantiomers of tert-butanesulfinamide in large-scale processes, the easy deprotection of the amine under mild acidic conditions, and a practical procedure for recycling the chiral auxiliary [4][5] have contributed to the

• reaction intermediate that was not isolated. Treatment of 115 with potassium hexamethyldisilazide (KHMDS) led to the sulfinyl piperidine derivative 116, and final deprotection under acidic conditions produced enantioenriched 2-allylpiperidine (117) as its hydrochloride (Scheme 32) [121]. Compound 117 has

• co-workers described the diastereoselective synthesis of 1-substituted isoquinolones using one-pot addition–cyclization–deprotection of the imine with Grignard reagents [130]. In this work, the addition to chiral imines 146, 148 and 150 was performed using 2,2’-dipyridyl- or 4-methylmorpholine (NMM

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• a robust protecting group and to conduct final deprotection under neutral conditions. After initial experimentation with benzyl glycosides (Scheme 1, PG = OBn), phenyl thioglycosides (Scheme 1, PG = SPh), readily available from 1,6-anhydropyranoses [39] as we described earlier [40] were found to

• -catalyzed hydrogenolysis in ethanol/acetic anhydride appeared to be a logical deprotection step [26], the desired fluoro sugars were contaminated with varying quantities of unidentified byproducts. However, clean debenzylation was achieved by first converting the azide to an acetamide on reaction with

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• kinetics and higher solubility in organic solvents, useful for automated synthesis, such as the Beaucage reagent [86]. Conveniently, during deprotection of the support-bound oligonucleotide, aminolysis removes the β-thiobenzoylethyl group from the backbone to generate the free PS2-modified oligonucleotide

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• deprotection was achieved via 20% piperidine in DMF (1 × 2 min and 1 × 18 min) to prepare the resin for the next coupling step. The resin was washed three times with each solvent in the given order DMF, DCM, and DMF after every reaction step. Peptide sequences T7: H-HAIYPRH-NH2 Modified T7: dipalmitoyl-Dap

• . Coupling of Fmoc-Dap(Fmoc)-OH and Fmoc deprotection were carried out as described above. To ensure the complete lipidation of the two free amines of Dap, 8 equiv of palmitic acid, 8 equiv of HATU, and 12 equiv of DIPEA in DMF were used. Cleavage of the peptide–lipid conjugates from the solid support and

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• deprotection was achieved by using trifluoroacetic acid (TFA) before the preparative HPLC. The synthesis of compounds A22 and A23 was accomplished by an alternative route elaborated in Scheme 5. Coupling of compound 5 and intermediate 2 was achieved by using HATU and DIPEA in a DMF/CH2Cl2 mixture to form the

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• cyclized radicals 22 couple subsequently with TEMPO providing lactams 12a–k after deprotection of the TMS groups. The cyclized tertiary alkoxyamines (R3 = Me) are known to be thermally labile [89][90][91][92] and consequently 4-isopropenylpyrrolidones 12g,k are isolated as the exclusive products. The

• α-(aminoxy)amides 9. Thermal radical cyclization of compounds 9 and further deprotection (general procedure) The α-(aminoxy)amide 9 (0.65 mmol) was heated in t-BuOH (6 mL) in a microwave reactor at 150 °C for 1 h. The reaction mixture was diluted with diethyl ether (5 mL), transferred into a round

Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

• Naohiro Horie,
• Takao Yamaguchi,
• Shinji Kumagai and
• Satoshi Obika

Beilstein J. Org. Chem. 2021, 17, 622–629, doi:10.3762/bjoc.17.54

• attention to the reactivity of each nucleobase. Finally, the acetyl group was successfully removed by extending the deprotection time to 10 h. The yield range of the designed oligonucleotides ON1–ON3 was 12–25%, as shown in Table 1. Duplex-forming ability of oligonucleotides modified with GuNA[Me]-A, -G, or

• treated with a 1:1 mixture of 7 N ammonia solution in methanol and 40% aq. methylamine at room temperature for 10 h to remove the solid support, and then the mixture was heated at 60 °C for 10 h (mC) or 15 h (A and G). After deprotection, the oligonucleotides were rapidly purified using a Sep-Pac® Plus

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

• Kenji Morokuma,
• Shuntaro Tsukamoto,
• Kyosuke Mori,
• Kei Miyako,
• Ryuichi Sakai,
• Raku Irie and
• Masato Oikawa

Beilstein J. Org. Chem. 2021, 17, 540–550, doi:10.3762/bjoc.17.48

• and Figure 2, were unambiguously determined later from crystallographic and spectroscopic studies of the 2R-derivative 9 (see below). Scheme 3 shows the synthesis of the (2R)-enantiomer of MC-27, 4. The deprotection of the PMB group of 9 (tR 11.5 min in Figure 2) by CAN proceeded smoothly at rt to

• only a monocarboxylic acid product, and the menthyl ester remained unaffected (structure not shown). Fortunately, the complete deprotection of the two esters was cleanly possible under acidic conditions (6 M aq HCl, 1,4-dioxane, 75 °C, 4 days) to furnish (2R)-MC-27 (4) in 48% yield (Scheme 3), the

• ], which gratifyingly furnished (2S)-TKM-38 (3*) in a good yield (77%) after ion-exchange chromatography (Dowex® 50W x8-200, H+ form). LiOH, which was used for the final deprotection in the synthesis of the MC-27 enantiomers 4 and 4* (see Scheme 3 and Scheme 4), was not capable of facilitating the removal

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• derivative. Such nitrogen protection/deprotection (e.g., acetylation/deacetylation) is often used in the other synthetic strategies described in Scheme 1. Therefore, the starting isatin was acetylated first with acetic anhydride [47] in 95% yield and then reduced with various complex borohydrides (e.g

• with inversed configuration of the double bond. Several synthetic strategies starting from isocyanate [22][23] or oxindole [4][12] precursors work well only with protected nitrogen(s) in the starting compounds whose preparation and protection/deprotection also lengthens the total synthesis and