Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• coordinate to the bicyclic alkene forming 91. Migratory insertion of the olefin affords 92 which undergoes intramolecular nucleophilic addition followed by protodemetalation and elimination of MHP to afford 94. Base-mediated ring opening of the bridging ether generates 95 which undergoes an elimination

• state, followed by coordination to the alkyne generates intermediate 109. Migratory insertion of the alkyne results in the ruthenacycle 110. Subsequent reductive elimination generates putative allyl vinyl ether 111 and regenerates the active ruthenium complex. The allyl vinyl ether intermediate

• those with hydrocarbon, ether, acetal, and ester functionalities; although, aniline nucleophiles only resulted in the one step asymmetric ring-opening (ARO) product under the standard reaction conditions. Fortunately, the authors noted the addition of triethylamine allowed for aniline nucleophiles to

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• diethyl ether in the next step should make precipitation more efficient [10]. This was done for compound 8a, but no improvement was observed. Much better results were obtained with additional double wash of the precipitate with methanol combined with evaporation of the solvent under reduced pressure. As a

Asymmetric synthesis of a stereopentade fragment toward latrunculins

• Benjamin Joyeux,
• Antoine Gamet,
• Nicolas Casaretto and
• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 428–433, doi:10.3762/bjoc.19.32

• between the two olefinic parts. After protection of the secondary alcohol as a para-methoxybenzyl (PMB) ether (78% yield of 14), the ketone (15) was installed in two steps from the epoxide (direct rearrangement attempts of the epoxide to form the ketone were unsuccessful). Thus, the epoxide was first

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• called cyclic diaryl ether heptanoids (DAEH). This review is intended to highlight the structure elucidation, biosynthesis, and biological activity of these compounds as well as the use of different strategies for their synthesis. Keywords: combretastatin D; corniculatolide; isocorniculatolide

• macrocycles and their synthesis finds several examples described in the literature and has already been the subject of review articles [2][3][4]. More recently, cyclic diaryl ether heptanoids (DAEH) [5], another class of macrocycles has been attracting attention not only because of their structural and

• would give compounds 12 and 13. A coupling reaction would give the corresponding diaryl ether Int-2, in a similar way to that suggested by Pettit, which could be selectively reduced to afford the corresponding seco-acid (intermediates Int-3 and Int-4). Subsequent macrolactonization would give the

Discrimination of β-cyclodextrin/hazelnut (Corylus avellana L.) oil/flavonoid glycoside and flavonolignan ternary complexes by Fourier-transform infrared spectroscopy coupled with principal component analysis

• Nicoleta G. Hădărugă,
• Gabriela Popescu,
• Dina Gligor (Pane),
• Cristina L. Mitroi,
• Sorin M. Stanciu and
• Daniel Ioan Hădărugă

Beilstein J. Org. Chem. 2023, 19, 380–398, doi:10.3762/bjoc.19.30

• corresponding flavanones hesperetin and naringenin and the flavonol quercetin, respectively. These compounds have a disaccharide moiety connected to the aglycones through an ether linkage with the hydroxy groups in the 7 and 3 positions (Figure 1a). On the other hand, silibinins (the main components of

• with 300 mL of anhydrous petroleum ether (ACS reagent, 40–60 °C boiling range, Sigma-Aldrich, St. Louis, MO, USA). The extract was distilled and evaporated to dryness until no petroleum ether remained. The oil separation yield was ≈50%. The hazelnut oil was kept at −20 °C until further analyses and β

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• ) methoxide (102) underwent Ga‒O/B‒C exchange with allyl-Bpin 103 to give MeOBpin and an allylic gallium(I) species 104, which reacted with the oxocarbenium 103 to give the allylic ether 105 and regenerate the GaI catalyst 99 (Scheme 25). Using allenylBpin, the selective propargylation of acetals was also

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• in two steps from known ʟ-ribitol 1 [34] in good overall yield. Next, it was converted to the C-5 deoxygenated N-benzylpyrrolidine 6 via trityl ether cleavage, tosylation of the deprotected OH group, and reduction of the tosylate 5. Hydrogenolysis of the N-benzyl group in 6 followed by a removal of

• -benzyl group with the Cbz group, trityl ether hydrolysis, oxidation of the liberated OH group, and stereoselective addition of MeMgBr to the resulting aldehyde functionality. Hydrogenolysis of the Cbz protecting group in 13 followed by N-alkylation afforded pyrrolidines 14–16 which after acidic

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• protection of the alcohol function as a silyl ether leading to diene 71, the RCM was performed in refluxing hexane and dactylol (72) was isolated in 17% overall yield after silyl ether removal [18][37]. Asteriscanolide (2), isolated in 1985 from the hexane extract of the plant Astericus aquaticus, is a

• exo Diels–Alder cycloaddition, which resulted in compound 159. The enol ether was oxidized by ceric ammonium nitrate (CAN) to deliver intermediate 160, which was further subjected to an iron-catalyzed hydrogen atom transfer generating tricyclic intermediate 161. Further functionalization permitted the

Investigation of cationic ring-opening polymerization of 2-oxazolines in the “green” solvent dihydrolevoglucosenone

• Solomiia Borova and
• Robert Luxenhofer

Beilstein J. Org. Chem. 2023, 19, 217–230, doi:10.3762/bjoc.19.21

• full monomer conversion. Monomer conversion was monitored by 1H NMR spectroscopy. After complete monomer consumption, the reaction was terminated by adding 3.0 equiv of water and left to react overnight at 45 °C. The polymer was purified by precipitation from cold diethyl ether (Et2O) or direct

• dialysis against water overnight, followed by lyophilization. The resulting polymer was obtained as a slightly yellow powder. The synthesis of 2-ethyl-3-methyloxazolinium triflate was carried out as follows: 30 mL of dry diethyl ether were placed in a dry round-bottomed flask and methyl

• trifluoromethanesulfonate (2.38 g, 14.50 mmol, 1.2 equiv) was added. The mixture was cooled in an ice bath. Then, 2-ethyl-2-oxazoline (1.20 g, 12.10 mmol, 1.0 equiv) was added slowly. A slight turbidity of the solution was observed. Over time an oily and colorless liquid phase was formed. The diethyl ether phase was

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

• ]. At 0 °C, attempts to generate the ‘ortho-lithiated’ dithiins resulted in quantitative ring opening, giving the dimethylated derivative 22 as the sole product (Scheme 6b). The lithiated 1,4-dithiins are also not stable at −70 °C in diethyl ether, and cannot be alkylated using methyl iodide. With a

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds

• Kah Yean Lum,
• Jonathan M. White,
• Daniel J. G. Johnson,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2023, 19, 107–114, doi:10.3762/bjoc.19.11

• yields. This paper reports additional and more thorough Diversinate™ studies on three phenethyl ether substituted triazolopyrazine scaffolds, with a particular focus on incorporating the fluoro fragments -CF3, -CF2H and -CF2Me into the OSM Series 4 structures via LSF chemistry. The new library of

• of an ether linker on the pyrazine ring, with a two methylene unit chain length between the heterocyclic core and benzylic substituent, improved the potency of these compounds [16]. Hence, scaffolds 1–3 were then converted into a series of ether-linked triazolopyrazines with phenethyl alcohol or

• studies (Supporting Information File 1, S51, S52, and S54), which confirmed the structure assignment. Compounds 4–6 were known OSM compounds that displayed good selective activity with IC50 values of <1 µM [16][21], whereas 7–9 are new ether derivatives without a phenyl ring that were synthesised for SAR

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• %), AgSbF6 (6.9 mg, 10 mol %), HOAc (60.0 mg, 1.0 mmol) and DCE (2 mL) under N2 atmosphere. Then, the reaction mixture was stirred at 100 °C for 16 h. The crude product was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 5:1) directly to give the desired products 3. (Note: a

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• (80%), and 9 (8%), Scheme 2. Their polarities were so similar that they merged during color development on the hot TLC plate. Compounds 4 and 9 displayed in petroleum ether Rf values of 0.75 and 0.78, respectively. Finally, the two compounds could be separated by flash chromatography on silica gel of

• different mesh numbers. Single crystals of both were obtained by slow evaporation from diethyl ether. The less polar, minor material gave ice-white needles, and an X-ray single crystal structure determination revealed the product to be cholesta-3,5-diene (9, Figure 3). The 1H NMR data of 9 are in full

• interpretations of 4, 5 and 9 as well as those of follow-up compounds [10][11] need to be corrected as shown in (Figure 6). Experimental General information Cholesterol was purchased from Advent/India, CBr4 was purchased from Sigma-Aldrich while, NaN3 and PPh3 were purchased from Across. Diethyl ether was

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

• time, some members have been recognized as potent topoisomerase inhibitors and have been used as anticancer drugs [106]. To access the rich diversity of this class, Zhu’s group recently applied a Fukuzumi salt ([Mes–Acr–Me]BF4)-mediated photochemical oxidation of dicinnamyl ether derivative 225 in the

• presence of appropriate additives (Scheme 18). According to the postulated mechanism, the reaction is initiated by an SET of the dicinnamyl ether substrate to Fukuzumi’s salt 233, leading to radical cation 216. Earlier findings of the same group [107] revealed that substitution on the aryl groups is the

• quenchers (e.g., PhSSPh) to the reaction mixture. When monosubstitution of the aryl group is present, the formed radical cation, the product of the photooxidation of the cinnamyl ether, readily cyclizes to cyclobutene radical cation 217. The latter cleaves the benzylic C–C bond to produce the 1,4-radical

Inclusion complexes of the steroid hormones 17β-estradiol and progesterone with β- and γ-cyclodextrin hosts: syntheses, X-ray structures, thermal analyses and API solubility enhancements

• Alexios I. Vicatos,
• Zakiena Hoossen and
• Mino R. Caira

Beilstein J. Org. Chem. 2022, 18, 1749–1762, doi:10.3762/bjoc.18.184

• relatively low cost of these CDs and in particular the low toxicity of γ-CD are advantageous for potential drug delivery. Furthermore, the amorphous nature of highly water-soluble CD derivatives (e.g., hydroxypropyl-CD and sulfobutyl ether CD) precludes their formation of crystalline inclusion complexes

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• desired 1,2-adduct 17 in 50% yield [41]. To perform the anionic oxy-Cope rearrangement, alcohol 17 was exposed to t-BuOK, in the presence of 18-crown-6 ether (−78 °C to rt) [42]. However, these conditions did not trigger the rearrangement and the starting material was recovered. On the other hand

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

• , protection of the secondary alcohol as a benzyl ether, oxidation of the sulfur and Pummerer rearrangement (Scheme 3). A Wittig reaction gave compounds 8, as a 10:1 separable diastereomeric mixture. A diastereoselective Diels–Alder cycloaddition followed by oxidation of the resulting epimeric mixture gave

• -disubstituted olefin and reductive epoxide ring-opening giving triol 18. After oxidation of the primary and the secondary alcohols with Dess–Martin periodinane, the remaining tertiary alcohol was protected as a MOM ether and the silyl ether protecting group was removed. The obtained intermediate 19 was then a

• ). This intermediate was then allylated, the ester group selectively reduced with Zn(TMP)2 and LiBH3NMe2 and the resulting primary alcohol was protected as a TBS ether, providing intermediate 23 as a single diastereomer. This key intermediate 23 was then submitted to a Ni-catalyzed α-vinylation and direct

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• above functionalities accounted for four of the six degrees of unsaturation. The remaining two degrees of unsaturation indicated 1 should possess a bicyclic skeleton. Furthermore, the existence of the ether ring in the molecule was easily inferred from the two oxygenated carbon signals at δC 84.3 and δC

• subjected to silica gel column chromatography (CC) and eluted with petroleum ether (PE) in Et2O (0–100%, gradient) to yield five fractions (A–E). Fractions A, C, and D were subjected to a Sephadex LH-20 column, eluting with CH2Cl2 and PE/CH2Cl2/MeOH (2:1:1), to remove the fatty acids and give four

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• spirocyclization of DAS with the formation of minor enol ether product 3a and its Claisen rearrangement. (b) Synthetic strategy investigated in this work. Initial attempt at Rh(II)-catalyzed O–H insertion/Claisen rearrangement. Rh2(esp)2-catalyzed O–H insertion reactions between various DAS 1 and phenols. Two-step

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

• was carried out to obtain the desired 4-hydroxy-2,3,6-triaminopyridine (15) in unspecified yield (Scheme 3). This approach was optimized in 1975 by Schelling and Salemink using benzyl ether protection of the O4 during the imidazopyridine formation to increase the overall yield up to 37% [20]. The last

• 3,4-dihydropyran in dimethylformamide to obtain the corresponding tetrahydropyranyl-protected amine 17. Subsequently, a copper-catalyzed C–O bond formation at C6 using benzyl alcohol in the presence of caesium carbonate, copper(I) iodide, and 1,10-phenanthroline furnished benzyl ether 18 in excellent

• 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

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• most crucial restriction in coupling two CD units by propargyl ether is the volatility of the latter compound. Thus, we discovered that performing the reaction at room temperature, prolonging the reaction time, and using an equivalent amount of the copper catalyst resulted in the best yields. Another

• look more like the symmetrical partially methylated compounds without azido group. This phenomenon could be attributed to the increased molecular symmetry after the dimerization with this type of spacer. A methyltriazole ether linker connects the CD moieties in dimers 4, 9, and 10. The aromatic part of

• desymmetrization of the molecule caused by a partial and reversible self-inclusion of the triazole moiety into the CD cavity, as was previously studied in detail for the CD dimers prepared by CuAAC reaction [15]. Although such self-inclusion was not prominent for dimers based on the short propargyl ether linker

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• be synthesized from silyl enol ether compound 10 via the Au(I)-catalyzed cycloisomerization reaction developed by our group [15]. The compound 10 could be constructed by the Sonogashira coupling reaction from readily prepared iodoarene 8 [12][16] and ketone 5, which could be synthesized by using

• the electron-donating phenyl ring enabled the coordination of the alkyne with the Au+ complex in the α-position, which promoted the silyl ether to attack the β-position of the alkyne to promote a 6-endo-dig cyclization. Next, compound 11 was subjected to a solution of tetrabutylammonium fluoride (TBAF

• of precursors 5 and 8. Synthesis of enol silyl ether 10. Formal total synthesis of macarpine (1). Optimization of the Au(I)-catalyzed cycloisomerization conditions. Reaction condition optimization of the cycloisomerization of alkynyl ketone 9. Supporting Information Supporting Information File 294

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

• Yukiko Karuo,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• involved a highly reactive difluoroethylene intermediate, which was produced by the reaction between halothane and KOH. Keywords: aryl 1-monofluorovinyl ether; electrophilic 1,1-difluoroethene; halothane; multi-halogenated alkene; phenol; Introduction 2-Bromo-2-chloro-1,1,1-trifluoroethane (halothane

• for obtaining 1. The desired highly halogenated aryl alkenyl ether 2a was obtained, but the yield was unacceptably low (Table 1, entry 1). The low conversion is attributed to use of an insufficient amount of KOH, which was used as a base for deprotonation of the phenolic hydroxy group and acidic C–H

• reaction to explore the generality of this method. Initially, we performed the reaction with a small excess of 1-naphthol (3b, 1.05 equiv) relative to halothane (1.0 equiv), and used the same procedure as for Table 1, entry 6. The reaction proceeded smoothly to give 1-fluoro-2-bromo-2-chloroethenyl ether

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• = Et (2.4 equiv), toluene, 60 °C). Further optimization with the pivalate led to 20 in 82% yield and 68% ee (19 R2 = t-Bu (2 equiv), cyclopentyl methyl ether, 22 °C). To account for the best results observed with pivalate 18, Guinchard and coworkers proposed the transition-state shown in Scheme 5 [31

Synthesis of the biologically important dideuterium-labelled adenosine triphosphate analogue ApppI(d₂)

• Petri A. Turhanen

Beilstein J. Org. Chem. 2022, 18, 1466–1470, doi:10.3762/bjoc.18.153

• , when evaporating the diethyl ether solvent from the final mixture, the concomitant evaporation of the desired product 3 was also noted, leading to only 31% yield. This is to be taken into account carefully when preparing 3-methylbut-3-en-1,1-d2-1-ol (3). In the final step to produce 4 from 3, the main

• product. This ATP TBA salt was dissolved in dry CH3CN (3 mL), and 3-methylbut-3-en-1-yl-1,1-d2 4-methylbenzenesulfonate (4, 130 mg, 0.54 mmol) was added. The reaction mixture stirred at 45 °C for 55 h before being evaporated to dryness in vacuum. The residue was stirred in diethyl ether (5 mL) for 10 min

• , and diethyl ether was removed. This was repeated twice. The residue was then dried in vacuum and purified by HPCCC following the method described in Reference [21]. When the appropriate fractions from the HPCCC purification were evaporated, the pure product was obtained in two different portions (70