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

• enantiospecific synthesis of two artificial glutamate analogs designed based on IKM-159, an antagonist selective to the AMPA-type ionotropic glutamate receptor. The synthesis features the chiral resolution of the carboxylic acid intermediate by the esterification with ʟ-menthol, followed by a configurational

• independently be synthesized from the racemic carboxylic acid intermediate (rac)-7 [6]. For such a chiral resolution, we recently discovered that ʟ-(−)-menthol (8) is of use as a chiral auxiliary in the enantiospecific synthesis of the other analogs 2 and 5 (see Figure 1) [4], and the strategy was found to also

• (rac)-16 (87% yield), followed by alkaline methanolysis (74% yield) [17] and Pinnick oxidation (43% yield) [18][19][20], delivered carboxylic acid (rac)-19. Unfortunately, an attempt to improve the oxidation yield was not fruitful; the oxidation of aldehyde (rac)-18 with TEMPO [21] resulted in a lower

Synthesis of N-perfluoroalkyl-3,4-disubstituted pyrroles by rhodium-catalyzed transannulation of N-fluoroalkyl-1,2,3-triazoles with terminal alkynes

• Olga Bakhanovich,
• Viktor Khutorianskyi,
• Vladimir Motornov and
• Petr Beier

Beilstein J. Org. Chem. 2021, 17, 504–510, doi:10.3762/bjoc.17.44

• an electrophile, the crude product 2a was treated with butyllithium, followed by the reaction with carbon dioxide to afford pyrrole carboxylic acid 6 in a good overall yield (Scheme 5). The trifluoromethyl group on the nitrogen was not affected by these highly basic reaction conditions. The mechanism

• transannulation/carboxylation process was demonstrated for the construction of the functionalized pyrrole 2-carboxylic acid with an N-trifluoromethyl functionality. Thus, this work improves the synthetic access to N-perfluoroalkyl-3,4-disubstituted pyrroles. Selected pyrrole-containing natural products, drugs

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• and cis isomers of 2-hydroxy-2-oxo-3-[(phenoxyacetyl)amino]-1,2-oxaphosphorinane-6-carboxylic acid (16, Figure 3) were prepared and evaluated as inhibitors of the zinc-containing β-lactamase II from B. cereus. However, neither stereoisomer had any significant activity [6]. The phosphonodepsidipeptide

• . Structure of 2-hydroxy-2-oxo-3-[(phenoxyacetyl)amino]-1,2-oxaphosphorinane-6-carboxylic acid (16). Synthesis of α-phosphonodepsidipeptides as inhibitors of leucine aminopeptidase. Synthesis of α-phosphonodepsidipeptide 17 as coupling partner for cyclen-containing phosphonodepsipeptides as inhibitors of

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• this effect is not fully clear. It might be linked to the electrophilicity of the carboxylic acid moiety that experiences an electron-withdrawing effects from the fluorine atom (see the comparison of the acidity in Table 2) [58]. In another study, tRNAPro was preloaded with proline analogues, and a

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• Roche and Genentech researchers have described the first route to this scaffold for their FAK and EGFR mutant programs, respectively [1][2]. Both processes started from the versatile 4-iodo-2-methoxynicotinaldehyde (3). Oxidation to the carboxylic acid followed by chlorodehydration afforded the key

Supramolecular polymers with reversed viscosity/temperature profile for application in motor oils

• Jan-Erik Ostwaldt,
• Christoph Hirschhäuser,
• Stefan K. Maier,
• Carsten Schmuck and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2021, 17, 105–114, doi:10.3762/bjoc.17.11

• acid (GCP) or the aminopyridine carbonyl pyrrole carboxylic acid (ACP). At low temperatures, small cyclic structures are formed. However, at elevated temperatures, a ring–chain transformation leads to the formation of a supramolecular polymer. We demonstrate that this effect is dependent on the

• in polar solvents such as DMSO (Ka > 1010 M−1) and water (Ka > 102 M−1) [26], but it also limits its solubility in nonpolar solvents. Therefore, another BU was also employed in this study, namely the less polar aminopyridine carbonyl pyrrole carboxylic acid (ACP). The ACP motif (Figure 2a) can be

• , 64293 Darmstadt, Germany 10.3762/bjoc.17.11 Abstract We report novel supramolecular polymers, which possess a reversed viscosity/temperature profile. To this end, we developed a series of ditopic monomers featuring two self-complementary binding sites, either the guanidiniocarbonyl pyrrole carboxylic

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• ). These results are in agreement with our previous investigations related to pH-switchable and ionic strength-responsive dendritic amphiphiles appended with dendritic carboxylic acid functionalities [40][41]. The physiological ionic strength thus efficiently screens the repulsive contribution of the

Circularly polarized luminescent systems fabricated by Tröger's base derivatives through two different strategies

• Cheng Qian,
• Yuan Chen,
• Qian Zhao,
• Ming Cheng,
• Chen Lin,
• Juli Jiang and
• Leyong Wang

Beilstein J. Org. Chem. 2021, 17, 52–57, doi:10.3762/bjoc.17.6

• carboxylic acid groups and one amide, which could be assemblied into the stable spiral structure by hydrogen-bond and other noncovlant interactions. DGG was synthesised by introducing an octadecyl moiety into the glutamic skeleton in 78.6% yield according to the reported route (Supporting Information File 1

Control over size, shape, and photonics of self-assembled organic nanocrystals

• Chen Shahar,
• Yaron Tidhar,
• Yunmin Jung,
• Haim Weissman,
• Sidney R. Cohen,
• Ronit Bitton,
• Iddo Pinkas,
• Gilad Haran and
• Boris Rybtchinski

Beilstein J. Org. Chem. 2021, 17, 42–51, doi:10.3762/bjoc.17.5

• ][37][38]. Additionally, the aqueous self-assembly incorporating carboxylic acid groups in the covalent unit design has been shown to result in complex and tunable self-assembly modes [39][40][41][42]. Crystalline self-assembly We have found that the nonclassical crystallization of 1 in neutral aqueous

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• accomplished, followed by the reductive workup of the resulting selenoxide and an increase in its temperature, eliminating selenoxide to generate carboxylic acid (−)-83 in 90% yield. This acid was subjected to Curtius rearrangement [55] in the presence of DPPA as a source of azide, providing isocyanate (−)-84

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• cycloaddition adduct E, which is converted to the corresponding carboxylic acid (not shown) upon reaction work-up. This elegant reaction was applied in the synthesis of marcfortine B (8), reported by Trost and co-workers in 2007 [38] and 2013 [39]. The synthesis of marcfortine B (8) began with palladium

Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides

• Vladimir Ilkin,
• Vera Berseneva,
• Tetyana Beryozkina,
• Tatiana Glukhareva,
• Lidia Dianova,
• Wim Dehaen,
• Eugenia Seliverstova and
• Vasiliy Bakulev

Beilstein J. Org. Chem. 2020, 16, 2937–2947, doi:10.3762/bjoc.16.243

• appear at 154.1‒159.7 ppm which is close to 156 ppm which is the value found for N-sulfonyl amidines of 1,2,3-thiadiazole-4-carboxylic acid prepared by another method [22] and was clearly different from the thioamide carbon signal at 185‒187 ppm in the 13C NMR spectra of starting materials 1. A final

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• . A reported method for accessing these similar scaffolds suffers from a low product yield and harsh reaction conditions (32%, 130 °C) [45][46]. One of the obtained N-aryl-4,5-unsubstituted pyrroles, 4l, could undergo hydrolysis to form the (pyrrol-3-yl)carboxylic acid 4w. The latter can react readily

UV resonance Raman spectroscopy of the supramolecular ligand guanidiniocarbonyl indole (GCI) with 244 nm laser excitation

• Tim Holtum,
• Vikas Kumar,
• Daniel Sebena,
• Jens Voskuhl and
• Sebastian Schlücker

Beilstein J. Org. Chem. 2020, 16, 2911–2919, doi:10.3762/bjoc.16.240

• ], followed by further functionalization with ethylamine at the carboxylic acid in two steps to obtain the GCP ethyl amide, which has been synthesized before, by a different method [9]. The novel building block for GCI was synthesized in a 4-step synthesis adapted from a previous work [28] and then

• functionalized accordingly, yielding the GCI ethyl amide (for detailed synthesis routes, see Scheme S1 and Scheme S2 in Supporting Information File 1). The functionalization of the binding motifs GCP and GCI were performed since in the presence of the free guanidinium moiety the free carboxylic acid leads to a

Easy access to a carbohydrate-based template for stimuli-responsive surfactants

• Thomas Holmstrøm,
• Daniel Raydan and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2020, 16, 2788–2794, doi:10.3762/bjoc.16.229

• commercially available levoglucosan. It was shown that the building block could undergo alkylations under strongly basic conditions. The building block with azido groups could furthermore take part in CuAAC reactions, generating derivatives with ester or carboxylic acid functionalities. In addition, the

• refluxing the compounds in an aqueous solution of NaOH giving access to the carboxylic acid derivatives 16 and 17 (Scheme 3) demonstrating the versatility of the azido groups to be handles for introducing other metal-chelating groups. The simplicity of the synthetic steps and the versatility of the products

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• 13, which only needed to be oxidised to the carboxylic acid 14 then coupled to piperidine in order to deliver the target compound, 2. However, the oxidation of 13 proved to be unexpectedly troublesome. Mild oxidising agents caused incomplete consumption of 13, while vigorous conditions led to the

Synthesis of 4-substituted azopyridine-functionalized Ni(II)-porphyrins as molecular spin switches

• Jannis Ludwig,
• Tobias Moje,
• Fynn Röhricht and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2589–2597, doi:10.3762/bjoc.16.210

• shown that the spin switching efficiency is strongly dependent on the solvent and on the substituent at the 4-position of the pyridine unit. We now introduced thiol, disulfide, thioethers, nitrile and carboxylic acid groups and investigated their spin switching efficiency. Keywords: azopyridines; Ni(II

• that methoxy substitution (σ = −0.27) improved the spin switching efficiency in organic solvents to >98% in both directions [13]. However, the switching efficiency drops in protic solvents, particularly in water [3][14]. We now synthesized sulfur and carboxylic acid substituted record players aiming at

• or strain might be the reasons for the deviations. We cannot exclude that these groups coordinate directly to the Ni ion. Whereas the thiol (1h) and thiolate (1h−) exhibit disappointingly low switching efficiencies (Δ = 28% and 34%), the carboxylic acid (1j) and the corresponding carboxylate anion

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• between carboxylic acid/alcohol 76 and enal 77 (Scheme 10a) [46]. Analogously to the mechanism outlined in Scheme 9, it was proposed that formation of excited state iminium ion 66* is used to oxidise 76 to give radical cation 76•+ and alkyl radical 66•. Nucleophilic addition from the carboxylic acid or

• carboxylic acids 155 with alkenes 156. A low yielding benzylation reaction was required for determination of enantioselectivities and a large excess of alkene was required for the reaction. The reaction is proposed to proceed via hydrogen-bonded complex 157, that lowers the triplet energy of the carboxylic

• acid so that a Dexter energy transfer process is possible from the photocatalyst to the substrate to promote 155 into its triplet state, which can then cyclise with 156 to give enantioenriched cycloaddition products 158. The selectivity of this reaction is generally low (6 examples, up to 93:7 er, 67

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• to the functional group transformation (molecular-surgery-type functionalization) by treating them with NaOH in EtOH/H2O (10:1) under reflux conditions to first convert esters functionality into the corresponding carboxylic acid derivatives. As displayed in Scheme 47, these acid derivatives were then

Naphthalene diimide bis-guanidinio-carbonyl-pyrrole as a pH-switchable threading DNA intercalator

• Poulami Jana,
• Filip Šupljika,
• Carsten Schmuck and
• Ivo Piantanida

Beilstein J. Org. Chem. 2020, 16, 2201–2211, doi:10.3762/bjoc.16.185

• –7.81 (m, 4H, ArH), 7.64–7.58 (m, 4H, ArH), 7.42–7.20 (m, 10H, ArH), 6.90 (br. s, 2H, NH), 4.13–4.03 (m, 10H, CH2), 3.75–3.53 (m, 5H, CH2), 2.84–2.67 (m, 5H, CH2), 1.35 (s, 18H, Boc ), 1.28–1.21 (m, 6H, aliphatic proton). Synthesis of 4: To a solution of pyrrole carboxylic acid (A, 2 equiv), HCTU (2

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• the respective products. Employing the optimum reaction conditions, Lectka and co-workers fluorinated phenylalanine-containing di- and tripeptides to give the products 70a–f in modest to excellent yield (34–84%, Scheme 29). The carboxylic acid function could be free or protected as an ester without

Synthesis of 6,13-difluoropentacene

• Matthias W. Tripp and
• Ulrich Koert

Beilstein J. Org. Chem. 2020, 16, 2136–2140, doi:10.3762/bjoc.16.181

• subsequent reduction of the anthraquinone gave 1,4-difluoroanthracene. After ortho-lithiation and reaction with phthalic anhydride a carboxylic acid was obtained whose Friedel–Crafts acylation and subsequent reductive removal of the oxygen-functionalities resulted in the formation of the target compound. The

• phthalic anhydride in THF precooled to –100 °C [16]. Using these conditions, the carboxylic acid 12 was isolated in 82% yield. The subsequent Friedel–Crafts acylation proofed to be challenging. Using reagents like PCl5 resulted in a quantitative substitution of the fluorine substituents in the

• two fluorine substituents was investigated. The retrosynthetic analysis for this strategy is shown in Scheme 1. The formation of the C5,5a-bond colored in red could be accomplished by an intramolecular Friedel–Crafts type acylation with the acylium-cation intermediate 6. The corresponding carboxylic

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• . The removal of the silyl protecting group and hydrolysis of the methyl ester afforded the carboxylic acid 108. A subsequently attempted Suzuki–Miyaura coupling of 108 with vinyl boronates was described as “capricious”, and thus the acid was esterified with the tert-butyl donor reagent 109 to afford

• -butyl esters with formic acid gave the carboxylic acid 9, 7, or 5. Additionally, the treatment of the thailanstatin A tert-butyl ester with lithium chloride generated the thailanstatin B tert-butyl ester. Ghosh used a similar cross-metathesis/Suzuki–Miyaura coupling sequence for the preparation of

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• associated with controlling their stereochemical outcome [33][34][35] severely restrict their applicability in medicinal chemistry [36]. The typical Passerini three-component reaction (P-3CR) of a carboxylic acid 1, an aldehyde 2, and an isocyanide 3 being conducted in a polar-aprotic solvent such as THF or

• -component reaction (U-4CR) a carboxylic acid 1, an aldehyde 2, and an isocyanide 3 are complemented by a primary amine 5 that altogether undergo a condensation into a peptide-like adduct 6. These reactions are typically conducted in polar protic solvents such as methanol or water. Several examples of