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

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• hydroxamic acid 6 µM; sodium butyrate 6 µM). Extraction The mycelium was separated from the fermentation broth using a centrifuge and subsequently extracted with ethanol in a 1:1 ratio using ultrasound, three times for 20 minutes each. The combined organic solvents were dried with a rotary evaporator to

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• (HDACs) play an essential role in the transcriptional regulation of cells through the deacetylation of nuclear histone and non-histone proteins and are promising therapeutic targets for the treatment of various diseases. Here, the synthesis of new compounds in which a hydroxamic acid residue is attached

• both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively. Keywords: alkylation; aminolysis; HDAC inhibitors; hydroxamic acid; pyrimidine; Introduction Histone deacetylases (HDACs) are a family of intracellular proteins responsible for removing acetyl groups in histones

• ) cap [1][2][5]. One of the most commonly used zinc chelating groups in HDACs inhibitors is a hydroxamic acid moiety (–CONHOH) [6][7][8][9][10][11][12][13][14][15]. The ability of hydroxamic acids to form chelates with various metal cations, including the Zn2+ ion found in the catalytic center of most

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

• HDACs [14]. Trichostatin contains a hydroxamic acid as zinc-binding motif, inspiring the design of a wide range of synthetic HDAC inhibitors. The essential Zn2+-binding group is attached to a non-polar linker, delivering it inside the cavity through a narrow channel. The cap region is responsible for

Tenacibactins K–M, cytotoxic siderophores from a coral-associated gliding bacterium of the genus Tenacibaculum

• Yasuhiro Igarashi,
• Yiwei Ge,
• Tao Zhou,
• Amit Raj Sharma,
• Enjuro Harunari,
• Naoya Oku and
• Agus Trianto

Beilstein J. Org. Chem. 2022, 18, 110–119, doi:10.3762/bjoc.18.12

• repeated cadaverine–succinic acid motifs terminated by a hydroxamic acid functionality, were elucidated by NMR and negative MS/MS experiments. Compounds 1–3 were inactive against bacteria and a yeast but displayed cytotoxicity against 3Y1 rat embryonic fibroblasts and P388 murine leukemia cells at GI50 in

• -hydroxyamide group (C16: δC 46.7; C27: δC 47.2) were obviously larger than the methylenes adjacent to the amide group (C20: δC 38.52; C31: δC 38.52), consistent with the reported data for avaroferrin [22], bisucaberins [18], and nocardamines [23]. However, this trend is inversed in the hydroxamic acid terminus

• . The methylene carbon C35 adjacent to the hydroxamic acid group showed a smaller chemical shift (δC 28.0). The positional assignment of C34 and C35 was made by a ROESY correlation observed between H34 and 32-NH (Figure 2). To verify the structure deduced from the NMR analysis, an MS/MS analysis was

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

• 5.41 ppm [dd, J = 7.9, 1.7 Hz, H1]) supported an α-linked manno 1-phosphate derivative. This material complimented our recently reported C6-hydroxamic acid derivative as a bioisostere for mannuronic acid 1-phosphate [20], and will be enabling for evaluating non-native glycosyl 1-phosphates in

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• [3]. Among these drugs, panobinostat (Farydak, Novartis) an FDA approved drug, has been recognized as a pan-deacetylase inhibitor [9][10]. As a hydroxamic acid pan-HDACi, it is zinc-dependent, capable of binding in a bidentate fashion to the zinc-containing catalytic domain of the HDACs, and

• 1H NMR and 13C NMR as shown in Supporting Information File 1. Finally, the ethyl ester 11 was converted to the hydroxamic acid derivative, TOI1 using the bidentate nucleophile hydroxylamine either under neutral or basic conditions [36][37]. We first explored neutral conditions where aqueous

• final two steps, the reductive amination reaction and the hydroxamic acid preparation. Using the same reaction conditions developed for TOI1, we proceeded with precursors 22 and 23, which were obtained in 61% and 68% yield, respectively. The desired hydroxamic acid TOI2 and TOI3-rev were obtained in 49

α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

• Shital K. Chattopadhyay,
• Subhankar Ghosh,
• Sarita Sarkar and
• Kakali Bhadra

Beilstein J. Org. Chem. 2019, 15, 2524–2533, doi:10.3762/bjoc.15.245

• the important anticancer drug suberoylanilide hydroxamic acid (SAHA) from its α,ß-didehydro derivative is described. The didehydro derivative is obtained through a cross metathesis reaction between a suitable terminal alkene and N-benzyloxyacrylamide. Some of the didehydro derivatives of SAHA were

• species (ROS) as some apoptotic features. Keywords: anticancer drug; cross metathesis; HDAC inhibition; hydroxamates; reactive oxygen species; Introduction Suberoylanilide hydroxamic acid (SAHA, 1, Figure 1, vorinostat [1][2], has now emerged as a FDA approved drug for the treatment of relapsed and

• hydroxamic acid derivative belinostat (2) is also approved for the treatment of peripheral T-cell lymphoma (PTCL) [9]. On the other hand, trichostatin A (3), containing an α,ß-unsaturated hydroxamic acid unit is the best known HDAC inhibitor which shows antifungal activities [10][11]. Because of the

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• eigenvalue in the Hessian second order matrix) [28][38][39][40][41]. Structures of some bioactive 4-oxoquinoline-3-carboxamide derivatives 1–4 with different bioactive profiles. Ki = binding affinity; AHA = acetohydroxamic acid (standard urease inhibitor); SAHA = suberoylanilide hydroxamic acid (an FDA

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• ] and the didehydrohydroxamate TSA (2) [24], display useful anticancer properties through inhibition of histone deacetylase enzymes (HDAc) and are used as FDA-approved drugs. Similarly, the cyclic peptide Chap-31 (3) [25] with a terminal hydroxamic acid residue has shown promising anticancer activity

• , participated in the reaction nearly equally well to give the corresponding CM products 6h–j. Hydrogenation of each of these compounds separately led to the corresponding saturated hydroxamic acid derivatives 7h–j with concommittant cleavage of the terminal benzyl ester functionality. In an extension to the

• ], separately. Fortunately, both the reactions proceeded well and the desired amino acid derivatives 7k and 7l were obtained in good yields after hydrogenation. Conclusion In conclusion, we have developed a direct access to functionalized hydroxamic acid derivatives using a cross-metathesis reaction between N

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• has been reported. Fragment-based design In 2012 Klein et al. obtained the benzamides 46 and 47, as well as the hydroxamic acid 48 as hits within an SPR screening, which were further evaluated in ITC experiments in order to have a clearer view on the thermodynamic parameters (Figure 21). The

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• prolonged survival in a C. elegans infection model [62]. Hydroxamic acid-containing molecules addressing the same enzyme were developed by the Hartmann group; these compounds showed a moderate reduction of biofilm formation resulting from a lowered release of the structural biofilm component extracellular

Oxidative cycloaddition of hydroxamic acids with dienes or guaiacols mediated by iodine(III) reagents

• Hisato Shimizu,
• Akira Yoshimura,
• Keiichi Noguchi,
• Victor N. Nemykin,
• Viktor V. Zhdankin and
• Akio Saito

Beilstein J. Org. Chem. 2018, 14, 531–536, doi:10.3762/bjoc.14.39

• of guaiacols. Results and Discussion Our initial studies commenced with the screening of solvents and I(III) reagents for the oxidative cycloaddition reaction of hydroxamic acid 1a with 1,3-cyclohexadiene (2a, Table 1). In the presence of BTI (1.5 equiv), in polar solvents such as methanol

• -alkylammonium periodates. To our delight, the sole use of DIB in a mixed solvent of DCM and methanol gave the endo-cycloadduct 6aa as a single regioisomer in 84% yield starting from hydroxamic acid 1a and guaiacol (5a, Scheme 2). The structure of 6aa was determined by single crystal X-ray analysis [24]. It

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• ). Recent research of the Whiting group revealed a wide spectrum of results on the reactions of hydroxamic acid analogues 35 with various dienes 37 using the copper/oxazoline/air catalytic system (Scheme 10) [69]. Conclusions of an experimental as well as a computational approach to understanding the

• group. Further, the yields of products varied from high to moderate, depending upon the reaction time due to the competitive decomposition of the nitroso species, reducing the yield. The chemoselectivity of this system also depends on the reactivity of the hydroxamic acid: the higher the reactivity, the

Recent advances in N-heterocyclic carbene (NHC)-catalysed benzoin reactions

• Rajeev S. Menon,
• Akkattu T. Biju and
• Vijay Nair

Beilstein J. Org. Chem. 2016, 12, 444–461, doi:10.3762/bjoc.12.47

• the formation of hydroxamic acid derivatives are also discussed in this section for convenience. Acylimines function as electrophiles in NHC-catalysed aza-benzoin reaction with aldehydes. The reactive acylimine is generated in situ by the action of base on the sulfonylamide derivative 30 [34

Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds

• Sophie Letort,
• Sébastien Balieu,
• William Erb,
• Géraldine Gouhier and
• François Estour

Beilstein J. Org. Chem. 2016, 12, 204–228, doi:10.3762/bjoc.12.23

• , the macrocycle has no influence on the degradation of the nerve agent. This might be rationalized by the inclusion of the triazole ring into the CD’s cavity by a tumbling phenomenon as shown by Monflier et al. [81]. This process would therefore prevent any interaction of the hydroxamic acid group with

• partially-protected 2,6-dimethyl-β-CD (Scheme 7) [88]. Finally, CDs bearing an oxime (36 and 39a) or a hydroxamic acid (39b) group in position 3 were prepared as previously described via an azide–alkyne cycloaddition (Scheme 7) [76][80]. Synthesis of difunctionalized β-CD derivatives: As the hydrolytic

Copper-mediated synthesis of N-alkenyl-α,β-unsaturated nitrones and their conversion to tri- and tetrasubstituted pyridines

• Dimitra Kontokosta,
• Daniel S. Mueller,
• Dong-Liang Mo,
• Wiktoria H. Pace,
• Rachel A. Simpson and
• Laura L. Anderson

Beilstein J. Org. Chem. 2015, 11, 2097–2104, doi:10.3762/bjoc.11.226

• hydroxylamines, as well as N-alkenyl and N-arylnitrones [1][2][3][4][5]. We have discovered that when this transformation is performed with oxime and hydroxamic acid substrates, these reactive intermediates can be accessed and subsequently rearrange to a variety of challenging organic fragments and heterocyclic

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• hydroxamic acid (5, SAHA, Figure 1) [43]. Another early application of microreactor technology was reported in 2005 detailing the assembly and subsequent decoration of the fluoroquinolinone scaffold 6 resulting in the synthesis of a library of analogues including the well-known antibiotic ciprofloxacin (6

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

• system; different β-keto esters and hydroxamic acid derivatives can be used [203]. The acetoxylation at the α’-position of α,β-unsaturated ketones with Mn(OAc)3 was studied in detail. It is suggested that manganese(III) acetate causes the generation of C-radicals from ketones followed by the

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• oxidation. Hydroxamic acid 17 was then obtained by coupling with O-benzylhydroxylamine followed by hydrogenolysis. The cis-aziridine hydroxamic acid 17 showed good inhibitory activity against several matrix metalloproteinases, in particular MMP-3 and MMP-9, with IC50’s of 164 nM and 83 nM, respectively [63

Metal-free aerobic oxidations mediated by N-hydroxyphthalimide. A concise review

• Lucio Melone and
• Carlo Punta

Beilstein J. Org. Chem. 2013, 9, 1296–1310, doi:10.3762/bjoc.9.146

• hydroxamic acid and O2. NHPI-catalyzed reaction of adamantane under NO atmosphere. Nitration of alkanes and alkyl side-chains of aromatics. Radical mechanism for the nitration of alkanes catalyzed by NHPI. Benzyl alcohols from alkylbenzenes. Catalytic cycle of laccase-NHDs mediator oxidizing system. DADCAQ

Cascade radical reaction of substrates with a carbon–carbon triple bond as a radical acceptor

• Hideto Miyabe,
• Ryuta Asada and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2013, 9, 1148–1155, doi:10.3762/bjoc.9.128

• 2002 that hydroxamic acid derivatives are useful achiral templates in enantioselective Diels–Alder reactions [69][70]. To study the effect of hydroxamate ester as an achiral template in the intermolecular radical reaction, our experiments began with the investigation of cascade radical addition

Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors

• Matthias G. J. Baud,
• Thomas Leiser,
• Vanessa Petrucci,
• Mekala Gunaratnam,
• Stephen Neidle,
• Franz-Josef Meyer-Almes and
• Matthew J. Fuchter

Beilstein J. Org. Chem. 2013, 9, 81–88, doi:10.3762/bjoc.9.11

• class IV. Despite their name, several HDACs are able to deacetylate a number of nonhistone protein substrates [10][11]. Sirtuins are structurally and mechanistically distinct enzymes. To date, only two compounds that inhibit HDACs have been FDA approved: suberoylanilide hydroxamic acid (SAHA, 1, trade