Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• succeeded by the usual hydrogenolysis to furnish the carboxylic acid anti,syn-8a in 79% isolated yield and the lactone anti,syn-7b was recovered in 13% yield (Scheme 4) which was considered to be the reflection of the original composition of anti,syn-7a and -7b. The relative stereochemistry of anti,syn-8a

Efficient one-step synthesis of diarylacetic acids by electrochemical direct carboxylation of diarylmethanol compounds in DMSO

• Hisanori Senboku and
• Mizuki Hayama

Beilstein J. Org. Chem. 2024, 20, 2392–2400, doi:10.3762/bjoc.20.203

• acid 2c and defluorinated carboxylic acid 2a. Fluorine-containing starting material 1c and defluorinated diphenylmethanol (1a) were detected by 1H NMR analysis. At the same time, it is presently unclear whether 2a was produced in a carboxylation–defluorination or defluorination–carboxylation sequence

• xanthenol (1k) provided xanthene-9-carboxylic acid (2k) in an excellent yield of 90%. Phenyl(thiophen-2-yl)acetic acid (2l) could also be synthesized in an excellent yield of 92% yield by electrochemical carboxylation of phenyl(thiophen-2-yl)methanol (1l). Although a wide range of substrates was shown to be

• triphenylmethanol (1n) was subjected to the electrochemical carboxylation, a small amount of carboxylic acid was obtained as a complex mixture. However, in the 1H NMR spectrum of the organic component after extraction with aqueous base, we observed a singlet at δ 5.55 ppm, which could be assigned to the methine

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines

• Michał Błauciak,
• Dominika Andrzejczyk,
• Błażej Dziuk and
• Rafał Kowalczyk

Beilstein J. Org. Chem. 2024, 20, 2313–2322, doi:10.3762/bjoc.20.198

• enhancing the reactivity of a relatively inert acceptor does not necessarily lead to increased reaction rates, involves the use of more reactive nucleophiles. In this context, varying the stabilization energy of carboxylic acid derivatives by switching from oxoesters to thioesters is the significant

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• scope of reactivity and determination of deuterium retention using a combination of deuterated aldehydes, [D1]-, and/or [D2]-isocyanides. We began with the venerable Ugi 4-component reaction (Ugi-4CR), first reported by Ivar Ugi in 1959 [28]. The Ugi-4CR utilizes an amine, carbonyl, carboxylic acid, and

• converted to a carboxylic acid via typical saponification conditions without loss of deuterium (See Supporting Information File 1 for conditions). Biginelli reaction products, no deuterium scrambling was observed. Six site-specific deuterated Biginelli products are revealed in good yield with no deuterium

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

• lack the carboxylic acid are included (Figure 13). Altenusin (47) is biosynthetically obtained through reductive cleavage of 4-hydroxyalternariol (19) and it was already mentioned in one of the first reports on Alternaria metabolites when it was isolated from Alternaria tenuis (synonymous to A

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• are able to recognise carboxylic acid and sulphate groups along glycosaminoglycan chains using clusters of positively charged amino acids [33], also mediate a wide variety of cell–cell and cell–pathogen communication, controlling immune cell functions, and overseeing cellular trafficking [34]. Another

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• -dicarbonyl compounds and their one-pot transformation pave the way for MCR syntheses of pyrazoles. 1,3-Dicarbonyl compounds can, for example, be generated in situ from enolates and carboxylic acid chlorides. They can be converted to the corresponding pyrazoles 1 in a consecutive multicomponent reaction with

Allostreptopyrroles A–E, β-alkylpyrrole derivatives from an actinomycete Allostreptomyces sp. RD068384

• Marwa Elsbaey,
• Naoya Oku,
• Mohamed S. A. Abdel-Mottaleb and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2024, 20, 1981–1987, doi:10.3762/bjoc.20.174

• : Allostreptomyces; β-alkylpyrrole; conformer; cytotoxic; DFT; 4-formylpyrrole-2-carboxylic acid; Introduction β-Alkylpyrroles are key structural motifs in biomolecules and functional organic materials [1]. For instance, β-alkylpyrroles are the main building blocks for the life-essential tetrapyrrole pigments

• many marine natural products [6][7], pyrroles substituted with long hydrocarbon chains (pyrrole lipids) are seldomly isolated, and their presence is limited to certain marine organisms [8]. A series of 3-alkylpyrrole-2-carbaldehydes/carboxylic acid/methylcarboxylate was reported from the marine sponge

• a fermentation extract of Allostreptomyces sp. RD068384, a strain belonging to an almost unstudied actinomycetes genus within the family Streptomycetaceae. Compounds 1–5 are characterized by a pyrrole-2-carboxylic acid core decorated with a formyl group and an alkyl side chain. Secondary metabolites

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• first attached to carboxylic acid functionalized DNA headpiece 7a (first reverse amidation). Next, the ester was hydrolyzed to obtain acid 9, and finally, a second reverse amidation with aniline afforded 10. Both the reverse amidation and the ester hydrolysis were performed following literature

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• 191036, Russian Federation 10.3762/bjoc.20.164 Abstract In this work, we report an efficient approach to 2-oxoazetidine-3-carboxylic acid derivatives based on a thermally promoted Wolff rearrangement of diazotetramic acids in the presence of nucleophiles. The method allows easy variation of the

• well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters. Keywords: β-lactams; diazotetramic acids; nucleophiles; spirocycles; thermolysis; Wolff rearrangement; Introduction The importance of the β-lactam

• ketenes 2 generated by a thermally promoted Wolff rearrangement [3]. The interaction of such ketenes with nucleophiles of different nature could serve as a source of libraries of structurally diverse 2-oxoazetidine-3-carboxylic acid derivatives 3 (Scheme 1). The 2-oxoazetidine-3-carboxylic acid

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• -ring bioisostere, but as carboxylic acid one, Schwarz et al. [79] developed tetrazole-based pregabalin bioisosteres 113–118 (Scheme 18). The target protein α2-δ is involved in neurotransmitters release reduction, as a model of anxiety and neuropathic pain. In general, submicromolar affinities were

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• -aminoimidazole scaffold prevented the GBB reaction to occur [52]. As it has already been described, DNA encoded GBB adducts can be effectively used in DEL screening techniques. Hwang et al. incorporated 2-amino-6-chloropyrimidine-4-carboxylic acid into a DNA sequence, reacted the resulting conjugate 51 through a

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• which the Z-configuration of the chlorovinyl fragment was detected. Post-Ugi transformations As previously mentioned [32], the introduction of the convertible 2‑bromo-6-isocyanopyridine into the Ugi bisamide structure allows the conversion of the newly formed amide into a carboxylic acid fragment after

• acid hydrolysis. Similar results were obtained by Dömling and co-workers [27], who used 2-nitrobenzyl isocyanide as a universal convertible isocyanide, and the amide group was also converted into a carboxylic acid under the conditions of acid hydrolysis (Scheme 2). Therefore, taking into account the

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• acid, indole-2-carboxylic acid, pyrrole-2-carboxylic acid or N-phenylglycine has allowed the use of these compounds in the Ugi reaction without triggering competitive reactions. The additional functional group present in the resulting Ugi adduct can be leveraged in different post-condensation

• choice [23]. Synthesis of piperazinones On the basis of these results, we planned to synthesise piperazinone derivatives following a similar strategy. Thus, we chose different deactivated 2-amino-substituted carboxylic acid derivatives such as the indole-2-carboxylic acid, recently used in a similar

• strategy with aromatic amines [24], pyrrole-2-carboxylic acid and N-phenylglycine, and carried out their reactions with arylglyoxals, alkylamines and isocyanides (Scheme 5). As we expected, the cyclization product 9 was observed, although the complete cyclization of the Ugi adduct, found as the enol

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• of 10% Pd/C and 5% Pd/CaCO3 yielded reduced compound 19. Cleavage of the THP group with Amberlist-15® resin and a final Jones oxidation of the primary alcohol to the carboxylic acid, led to cyclization with the 17β-OH group affording the lactone 20 in a moderate overall yield (Scheme 6). Biological

• of a set of azomethine ylides and the 16-arylidene steroids 48a,b. Ylides were generated in situ by the nitrogen attack of the thiazolidine ring from 1,3-thiazolidine-4-carboxylic acid to a carbonyl group of acenaphthenequinone. The resulting reaction produced an iminium group, which promoted the

• on normal human peripheral blood mononuclear cells (PBMC). In 2003, a direct transformation of tetraoxanes to amides via carboxylic acid was also reported by the same research group [68]. Some amides were synthesized using methyl glycinate, di-n-propylamine, and piperidine with significant

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• condensation of 73 and 74, followed by highly-diastereoselective vinylogous Mukaiyama aldol reaction and subsequent protecting group manipulations [81][82][83]. The separately synthesized left and right segments, 72 and 75, were then assembled via Horner–Wadsworth–Emmons (HWE) olefination to give carboxylic

• acid 76 in a 4:1 diastereomeric ratio. Thioesterification and removal of the TBS group furnished the desired thioester 77 as a mimic of biosynthetic intermediate 64. With synthetic substrate 77 for enzymatic conversions in hand, Sherman and co-workers attempted to overexpress TylGIV and TylGV, however

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• formation of a) an alkoxy-NHI which is causing a significant downfield shift of the protons in alpha-position (orange) compared to the free alcohol 2 (blue) and b) oxidation of p-tolylmethanol (3a, blue) to the aldehyde 4a (green) and carboxylic acid 4a’ (red). Reaction conditions: An equimolar mixture of

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• a carboxylic acid. SAM is used as a donor of the methyl group [67][68][69]. The linear cyanobactin aeruginosamide B, produced by Microcystis aeruginosa PCC 9432, was the first RiPP reported to be O-methylated at its C-terminus [70]. LahSB is a SAM-dependent MT encoded in the lah BGC of

• . BmbA/BotOMT is the only O-MT involved in the biosynthesis of bottromycin [81]. It O-methylates the aspartate by transforming its carboxylic acid group to a methyl ester in the ultimate step in biosynthesis [79]. The remaining methylations are catalysed by C-MTs, which will be addressed in a following

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• design of the reported DAs, we designed and synthesized a series of DAs featuring a second-generation DASA switching motif and different chain lengths of the alkyl linker (i.e., DAn) that connects the DASA indoline motif with the hydrophilic part (i.e., the carboxylic acid motif, Scheme 1). The alkyl

• cellular compatibility was good. These DAn biocompatibility results are the first example showing the intrinsic cytocompatibility of macroscopic soft DA scaffolds. Conclusion Amphiphilic DASAs with alkyl linkers of different length connecting to a carboxylic acid were prepared. Photochemical properties of

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• produce a carboxylic acid (R1CO2H) and a primary alcohol (R1CH2OH). When a mixture of formaldehyde (HCHO) and a non-enolizable aldehyde (R1CHO) is treated with a strong base, the latter is preferentially reduced to the alcohol (R1CH2OH) while formaldehyde is oxidized to formic acid (HCO2H). Herein excess

• other is oxidized to a carboxylic acid. The mechanistic pathway of the intramolecular, intermolecular, and crossed-Cannizzaro reactions is well-known and is depicted in Figure 1 [7][8][9][10][11]. As per contemporary mechanistic understanding of this disproportionation reaction, it involves the transfer

• -transfer catalyst in the presence of KOH as the base. Canipelle et al. [28] put forward an improved Cannizzaro disproportionation of 4-biphenylcarboxaldehyde into the corresponding alcohol and carboxylic acid products employing cyclodextrins as the phase-transfer agent. A Cannizzaro desymmetrization

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• reaction between aminofuranes and maleic anhydride can be carried out successfully in vegetable oils and waxes. The reaction was successfully carried out in sunflower seed oil, olive oil, oleic acid and lauryl myristate under mild reaction conditions. A series of epoxyisoindole-7-carboxylic acid and

• conventional Diels–Alder reactions [95][118][119][120][121][122][123][124]. On the other hand, the initially exo carboxylic acid substituent in the oxanorbornene ring is converted to its endo isomer by epimerization upon heating the cycloadduct in a mixture of pyridine–glacial acetic acid (1:1). In the process

• and in good yields. The ring stereochemistry (exo- or endo-geometry) of the product, epoxyisoindole-7-carboxylic acid, is easily determined by 1H NMR by evaluating the coupling constants of the protons Ha, Hb and Hc (Figure 2) [119][127][128]. The values of the coupling constants shown in Figure 2 are

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• alkene 2j carboxylic acids were used successfully in this MCR, demonstrating a great reaction scope (Scheme 2 and Figure 2). Remarkably, the best yields were obtained when heterocyclic carboxylic acid components like 1H-pyrrole-3-carboxylic acid (2n), 2-furoic acid (2o) and 5-nitrofuran-2-carboxylic acid

• (2e) were used. The corresponding products 5nb, 5ob and 5ec were achieved in 63, 51 and 49% yields, respectively. 1-Boc-azetidine-3-carboxylic acid (2i) also gave the corresponding product 5ib in 54% yield. Considering the carbonyl component, 1-chloropropan-2-one (3a) was used to access the

• efficient Ugi4CR approach. Easy access to isatin from the 3-protected oxindole scaffold was demonstrated using mild reaction conditions. Flexibility of the carboxylic acid component and also the carbonyl one (ketone/aldehyde) was exhibited in the library of Ugi adducts obtained in moderate to good yields

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• –elimination pathway will dominate over hydrolysis. This preference was crucial to prevent the formation of undesired carboxylic acid products [28][30][31]. These results also align with the observations previously reported by Takeda and co-workers [24]. The reaction was carried out using a large excess (10

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• smoothly under the set conditions to form the corresponding phenyl(TMP)iodonium(III) carboxylates 7aa–ad in high yield. Additionally, a range of aliphatic carboxylic acids such as acetic acid (6e), pivalic acid (6f), cyclohexanecarboxylic acid (6g), and aliphatic carboxylic acid with acidic α-proton (6h

• ) was also tolerated under these conditions to produce the corresponding phenyl(TMP)iodonium(III) carboxylates (3ae, 7af–ah) in 63–81% yield without any signs of side reactions. The adenosine receptor antagonist acefylline (6i) was also used as a carboxylic acid to give the corresponding phenyl(TMP

• )iodonium(III) carboxylate 7ai in 86% yield, opening up new avenues for structural modifications of drug candidates to improve their properties and consequently, bioactivities [38][39][40]. The umbelliferone-3-carboxylic acid derivative 6j was also employed to produce the phenyl(TMP)iodonium(III

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• been five natural MMFs isolated and characterized, with all of the MMFs being isolated from Streptomyces coelicolor W75 (Figure 1B). These compounds are 2,3,4-trisubstituted furans, and all five contain a carboxylic acid at the three position and a hydroxymethyl group at the four position. They differ

• the carboxylic acid in the three position, the phenyl group is most likely too electron-donating, as well as potentially being too sterically bulky. Finally, pyrrole 21 was tested and ultimately resulted in an inconclusive amount of conversion. Compound 21 does not ionize well on our LC–MS and thus we