1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• rapid build-up of target molecules (see Scheme 1a) [7]. Once the important skeletal carbon–carbon bonds have been formed around the thioketal carbon, the sulfur-heterocycle can perform its primary function as a temporary protecting group and be chemoselectively hydrolyzed to afford a carbonyl functional

• , control of the reactivity of Raney nickel (which always has to be employed in excess and in a heterogenous system), can be quite time consuming. Finally, the 1,4-dithiane or -dithiin ring system need not necessarily be considered as a temporary tethering of protecting group, but can also become an

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• of atom economy and protecting-group-free synthesis dominating the field of total synthesis. In this new era, total synthesis is moving towards natural efficacy by utilizing both the biosynthetic knowledge of divergent synthesis and the latest developments in radical chemistry. This contemporary

• protecting-group-free synthesis [13], are gradually drawing more and more the interest of organic chemists as a sustainable way to deliver structurally diverse chemical libraries for biological screening. The current review is focusing on selected examples utilizing a radical-based divergent total synthesis

• products kadsulignan E (235) and heteroclitin J (236) depending on the appropriate substitution of DBCODs. Selection of radical termination at the 3- and 1-positions, respectively, can be engineered by the strategic incorporation of a TES protecting group at the 1-position (see 243) for heteroclitin J (236

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• had previously reported a similar rearrangement for the synthesis of a grayanane-type skeleton [21]. Further methylation and protecting group interconversions lead to an advanced tricyclic structure 5, which could be further elaborated into relay intermediate 1. Although Matsumoto’s approach does not

• substituted cyclohexanone 9, corresponding to the future C ring [24]. After deprotonation, the C3 position was stereoselectively alkylated using propargyl bromide, and the benzyl protecting group was cleaved with FeCl3, leading to spontaneous lactone closure. A Luche reduction stereoselectively converted

• the PMB protecting group, Dess–Martin oxidation, and SmI2-induced cyclization. This last step was highly selective, giving solely the intermediate 17. The synthesis was then pursued by the hydroboration–oxidation of the monosubstituted alkene, followed by stereoselective epoxidation of the 1,1

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

• Raphael Bereiter,
• Marco Oberlechner and
• Ronald Micura

Beilstein J. Org. Chem. 2022, 18, 1617–1624, doi:10.3762/bjoc.18.172

• alcohol. We build on a commercially available imidazopyridine derivative and conceived a protecting group strategy to enhance solubility and selectivity to orchestrate the installation of the exocyclic amino and hydroxy groups. Results and Discussion 1-Deazaguanine Previously described syntheses for 1

• tetrahydropyranyl protecting group. The final step was then accomplished by hydrogenation of benzyl ether 31 to obtain 1-deazahypoxanthine (30) in 44% overall yield. Conclusion We have developed convenient synthetic routes for 1-deazaguanine (11) and 1-deazahypoxanthine (30). Starting from readily accessible 6-iodo

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A

• Takumi Matsumoto,
• Takefumi Kuranaga,
• Yuto Taniguchi,
• Weicheng Wang and
• Hideaki Kakeya

Beilstein J. Org. Chem. 2022, 18, 1560–1566, doi:10.3762/bjoc.18.166

• )-protected ᴅ-serine 12 (Scheme 2). Treatment of the olefin 15 with trifluoroacetic acid (TFA) cleaved the Boc protecting group and the acetonide to deliver unsaturated amino alcohol 16. The amino group in 16 was protected by the fluorenylmethyloxycarbonyl (Fmoc) protecting group for solid-phase peptide

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• phosphates can be hydrolysed under basic, acidic or reductive conditions [26]. Although acidic conditions could not be used due to the lability of the nitrogen Boc-protecting group, we found that the TIPS-protected cycloadduct 10b could be cleanly transformed into the ketone 11b with excess Red-Al [28

• ], together with a small amount of the over reduced alcohol 12b, which could be reoxidized to 11b (Scheme 4). Other substrates failed to deliver appreciable yields of the ketone under the same conditions. These studies validate the role of TIPS ether as protecting group for the primary alcohol. At this stage

• we wondered whether it was possible to perform the whole synthetic sequence with this protecting group. Accordingly, the enol phosphate 13 was synthesized in five steps (26% overall yield) from 1,4-butanediol (Scheme 5). Since cycloaddition with the Wightman reagent 6 releases hydrogen chloride in

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

• Maxime Pypec,
• Laurent Jouffret,
• Claude Taillefumier and
• Olivier Roy

Beilstein J. Org. Chem. 2022, 18, 845–854, doi:10.3762/bjoc.18.85

• -methylhydrazine as a submonomer was adopted in this work (Figure 2). Benzyl bromoacetate, rather than tert-butyl bromoacetate, successfully used in the past for the synthesis of peptoids in solution [22], was chosen as the starting substrate to ensure orthogonality of the C-terminal protecting group with respect

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability. Keywords: drug substance; indole synthesis; key intermediate; protecting group; telescoping

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• ), the corresponding products 8b–g were obtained in only moderate yields with decreased selectivity. Replacing the Boc-protecting group on the imine site by a Cbz group led to a largely decreased selectivity (8h). For a series of substrates with various substituents on the 5, 6, or 7-position, including

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• was possible. However, the high conversion rates of the reagents to the desired products were not reflected in the isolated product yields, which was attributed to the workup and purification processes. It was also possible to demonstrate a moderate influence of the N-protecting group on the reaction

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• could be regarded as a protective group by shielding the internal alkenyl site. In 2016, the Rebek group achieved the site-selective reduction of an α,ω-diazide compound by trimethylphosphine (PMe3) in aqueous solution with a cavitand host as the protecting group for one of the azide sites (Figure 5

• , and factors like steric and electronic effects of the nucleophile and substrate and the polarity of the solvent would influence the product ratio [75]. Here, as illustrated above, the authors introduced the cage host J as the noncovalent protecting group of the internal reactive sites, which directed

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• conformer. Aiming to generalize the discovered transformation, a brief scope of the reaction with respect to the N-tert-butanesulfinyl imine substrate was next performed (Figure 2). The protecting group R1 on the oxindole nitrogen atom was found to have a moderate effect on the reactivity, with R1 = Bn

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• cyclization is observed. Moreover, the use of the electron-withdrawing protecting group on the indole N atom could favor the formation of 4,5-fused indoles by decreasing the nucleophilicity at the indole C3 position. However, detailed studies of the effect of the electronic nature of the indole NH protecting

• group on the regioselectivity are yet to be reported for SEAr-based intramolecular cyclization and annulation reactions of 3,5-unsubstituted, 4-substituted indoles. Such studies in this area will certainly aid in elucidating the regioselectivity more precisely. SEAr-based, CAr–C bond-forming cyclization

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• suitable protected linear precursor A (Scheme 2, PG: protecting group), the resulting carboxylic acid obtained can directly be activated and subjected to cyclization. If the glycine allyl ester is incorporated as the last building block into the C-terminus of the peptide, this concept should provide a high

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• because of the longer time needed. Next, we screened different protecting groups for the oxindole. Previously, Boc-protected oxindole 2a gave us the product in 75% yield, in dr 2.6:1 and in ee 90%/94% (Scheme 1, 3a). With a Cbz-protecting group the enantioselectivity decreased to 82%/88% (Scheme 1, 3b

• ). The use of a sterically more demanding Fmoc-protecting group decreased the ee values even more for the minor diastereoisomer (Scheme 1, 3c). Surprisingly, with benzyl-protected oxindole, the reaction did not proceed (Scheme 1, 3d), which implies that the carbonyl group of the carbamate moiety in the N

• -protecting group and electron-withdrawing properties of the protection groups are essential for coordination with the catalyst and for the reactivity of the Michael acceptor. Using a tosyl-protected oxindole the reaction was sluggish, the yield was low and the enantioselectivity could not be determined

Synthesis and bioactivity of pyrrole-conjugated phosphopeptides

• Qiuxin Zhang,
• Weiyi Tan and
• Bing Xu

Beilstein J. Org. Chem. 2022, 18, 159–166, doi:10.3762/bjoc.18.17

• in the backbone of 2a leads to 7, which bears an additional positive charge compared to 2a. A ᴅ-tetraleucine (l4) replaces ᴅ-diphenylalanine (ff) in 2d and 2e to form 8a and 8b, respectively. Adding a Boc protecting group at the N-terminus of 2a produces 9. Attaching a guanidinoacetic acid motif to

• , we introduced the N-methylpyrrole (Py) units into the peptides obtained via solution-phase amide bond formation to produce 2a–h, 3a,b, 4a,b, 5a,b, 6a–c, 7, 8a,b, 11a,b, 12a–c, 13, 14, and 15a–c. We conjugated two Py units successively to the peptide ffpy and kept the Boc protecting group of the

• cytotoxicity, respectively. Capping the N-terminus with a Boc-protecting group (9) or a guanidinoacetic acid motif (10a and 10b) renders the molecules with higher cytotoxicity (resulting in cell viabilities of about 70%) than those of 2f and 2g. Compounds without phosphorylation (11a, 11b and 12a–c) show

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• groups in one step produced 16 in 86% yield. However, attempts to perform the ring-closure reaction of the Boc-protected amide 16 by an intramolecular Heck reaction failed and led to degradation of the starting material. Most likely, the electron-withdrawing tert-butyloxycarbonyl protecting group

• hampered this transformation [24]. Therefore, the same synthetic way was repeated with ethoxymethyl ether as the protecting group to give 17. The ESI mass spectrum provided evidence that cyclization occurred with formation of 18. However, protection with chloromethyl ethyl ether was achieved only in 18

• % yield. This is most likely due to the strongly basic conditions (NaH) needed for the attachment of the ethoxymethyl protecting group, which might lead to deprotonation at the CH2 group (C7) followed by the formation of undesired side products. Being disappointed by the inefficiency of this route with at

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

• Sandeep Kumar,
• Jyotirmoy Maity,
• Banty Kumar,
• Sumit Kumar and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2022, 18, 95–101, doi:10.3762/bjoc.18.10

• unusual removal of TBDPS was observed when nucleosides 22a,b were treated with 2 M NaOH in dioxane and water (1:1). A literature search showed that the TBDPS protecting group could be removed under basic conditions [35][36]. However, removal of the TBDPS group from the primary hydroxy group of a

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• -diaminobutyric acid (Dab), ornithine (Orn), or lysine (Lys). Utilising the Alloc protecting group allowed the coupling of 4-carboxyphenylboronic acid once the linear sequence had been synthesised (Scheme 2C). The intramolecular SMC between 6- or 7-bromotryptophan and the boronic acid afforded the stapled

Stepwise PEG synthesis featuring deprotection and coupling in one pot

• Logan Mikesell,
• Dhananjani N. A. M. Eriyagama,
• Yipeng Yin,
• Bao-Yuan Lu and
• Shiyue Fang

Beilstein J. Org. Chem. 2021, 17, 2976–2982, doi:10.3762/bjoc.17.207

• synthesis of monodisperse polyethylene glycols (PEGs) and their derivatives usually involves using an acid-labile protecting group such as DMTr and coupling the two PEG moieties together under basic Williamson ether formation conditions. Using this approach, each elongation of PEG is achieved in three steps

• – deprotection, deprotonation and coupling – in two pots. Here, we report a more convenient approach for PEG synthesis featuring the use of a base-labile protecting group such as the phenethyl group. Using this approach, each elongation of PEG can be achieved in two steps – deprotection and coupling – in only

• method is expected to significantly lower PEG synthesis cost. Keywords: base-labile; monodisperse; PEG; polyethylene glycol; protecting group; Introduction Polyethylene glycols and derivatives (PEGs) have found wide applications in many areas [1][2][3][4][5][6]. For some applications, polydisperse PEGs

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• washed with MeOH (3 × 20 mL) and DCM (3 × 20 mL). Tripeptide 8 was recovered (1.6 mmol). The unreacted resin was capped with MeOH in a mixture of MeOH/DIPEA/DCM (1:2:7, 10 mL) for 5 h. The Fmoc protecting group was removed following the general procedure and the remaining amino acids were successively

Total synthesis of the O-antigen repeating unit of Providencia stuartii O49 serotype through linear and one-pot assemblies

• Tanmoy Halder and
• Somnath Yadav

Beilstein J. Org. Chem. 2021, 17, 2915–2921, doi:10.3762/bjoc.17.199

• step synthesis, though the former involved two extra steps for the synthesis of the first glycosidic donor and one chromatographic separation. The synthesis of the desired product was achieved through manipulations of the appropriate protecting group on the monosaccharides and subsequent realization of

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• mixture of two rotamers in a ≈2:1 ratio at 25 °C, probably caused by the Cbz-protecting group (see Supporting Information File 1, page S26). It is worth mentioning that the attempts to prepare polyhydroxylated pyrrolidine 2 directly from epoxide 5 by the one pot Cbz-removal/aminocyclization under

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

• ) the solvent, iv) presence of a participating or chiral auxiliary protecting group, v) the presence of a conformationally locked protecting group, vi) the presence of a glycosyl acceptor tethering group, and/or vii) the presence of an exogenous nucleophilic additive. The distinction between α- and β

• ammonolysis in methanol affords compound 1c. The silylation of 1c with TBDPSCl was carried out, and then coupling reaction with tert-Boc-Met-Leu-Phe-OH in the presence of DCC and HOBt provided compound 98. The tert-Boc protecting group was further removed in formic acid, and the resulting nucleoside peptide

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• concomitant formation of the urea or thiourea moiety, respectively. The corresponding N-Boc-protected precursors of the desired catalysts, 5a and 5b, were obtained in low to good yields. The removal of the Boc-protecting group with trifluoroacetic acid afforded the desired N-sulfinylthioureas (S,R)- and (S,S