High-pressure activation for the solvent- and catalyst-free syntheses of heterocycles, pharmaceuticals and esters

• Kelsey Plasse,
• Valerie Wright,
• Guoshu Xie,
• R. Bernadett Vlocskó,
• Alexander Lazarev and
• Béla Török

Beilstein J. Org. Chem. 2025, 21, 1374–1387, doi:10.3762/bjoc.21.102

• protocol was even applied in the elegant syntheses of platencin [30], and steroid derivatives [31]. Despite these encouraging applications, there is a broad area to be developed for the advancement of green synthesis efforts. Continuing our program on developing environmentally benign synthetic methods [32

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• tetracyclic steroid scaffolds such as 17β-estradiol [18], where the diazocine core mimics the framework of the bioactive compound (Figure 1a). The other option is to attach the diazocine photoswitch as a substituent (appendix) to the biologically active molecule (Figure 1b) [6][10][19][20][21]. The art of

• switching properties even in an aqueous environment and are therefore promising switches in photopharmacological applications. a) Structural similarity of N-acetyl diazocine 1 with known 17βHSD3-inhibitor tetrahydrodibenzazocine (THB) [17] and parent diazocine with steroid scaffolds [18]. b) Parent

Discovery of ianthelliformisamines D–G from the sponge Suberea ianthelliformis and the total synthesis of ianthelliformisamine D

• Sasha Hayes,
• Yaoying Lu,
• Bernd H. A. Rehm and
• Rohan A. Davis

Beilstein J. Org. Chem. 2024, 20, 3205–3214, doi:10.3762/bjoc.20.266

• aeruginosa biofilm inhibitors and antibiotic enhancers. Large-scale extraction and isolation studies resulted in the discovery of four new and minor natural products, ianthelliformisamines D–G (4–7) and the known steroid, aplysterol (8). Compounds 4–7 were fully characterised following 1D/2D NMR, MS and UV

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

• biological activity was determined for these compounds. Pestauvicomorpholine A (34) is an exceptional hybrid metabolite with fusion of a polyketide-derived resorcylic lactone and the steroid dihydroergosterol, which was isolated from the fungus Pestalotiopsis uvicola [174]. Its structure was determined by

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

• is compelling evidence that incorporating a heterocyclic moiety into a steroid can alter its pharmacological and pharmacokinetic properties, driving intense interest in the synthesis of such hybrids among research groups. In this review, we present an overview of recent synthetic methodologies

• heterocyclic moieties containing three or more (hetero)cycles. Moreover, many compounds are accompanied by data on their biological activities, such as antiproliferative, antimalarial, antimicrobial, antifungal, steroid antagonist, and enzyme inhibition, among others, aimed at furnishing pertinent insights for

• the future design of more potent and selective drugs. Keywords: biological activity; drug development; heterocycle; spiro steroid; synthetic transformations; Introduction Small-ring heterocycles constitute valuable scaffolds in medicinal chemistry for generating biologically active derivatives

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• ketone led to the linear α-alkylated product, followed by the alkylation of the methylene ketone with the second benzyl alcohol then afforded the dialkylated product. Remarkably, the drug donepezil, a steroid derivative and a fatty acid derivative were synthesized using this procedure (Scheme 29B). In

Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• et al. applied a fluorescence-based DNA cleavage assay coupled with HiTES to Streptomyces clavuligerus and identified the steroid 11α-hydroxyprogesterone (14) as an effective elicitor and characterized 10 cryptic enediyne-derived natural products, designated clavulynes A (15) and B–J with unusual

• skeleton in which a substructure of desferrioxamine (DFO, 38), a well-known secondary metabolite [78], is condensed at the end of the steroid skeleton. It is thought that DFO is produced as a result of the activation of a silent gene, whereas the steroid skeleton may be a component of the culture medium

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• resulting cation intermediate at C-4' to induce an acyl shift, forming the steroid-like structure of 7 with a 6-6-6-5 ring (Figure 2). Swapping terpenoid cyclases in heterologous expression systems A search of the genome database for Trt1-homolog CYCs revealed the enzyme AusL (41% identity with Trt1) in

Anion–π catalysis on carbon allotropes

• M. Ángeles Gutiérrez López,
• Mei-Ling Tan,
• Giacomo Renno,
• Augustina Jozeliūnaitė,
• J. Jonathan Nué-Martinez,
• Javier Lopez-Andarias,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2023, 19, 1881–1894, doi:10.3762/bjoc.19.140

• intermediate XIV [24][25]. Thus, this reaction can be considered as the anion–π catalysis counterpart of the steroid cyclizations catalyzed in nature with the charge inverted, conventional cation–π interactions [15]. Anion–π catalysis on fullerene dimers The strength of anion–π interactions increases with face

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• reported. Systems with secondary carbocations on rings bearing prenyl side chains are commonly observed in steroid biosynthesis. These type of cyclization reactions have been vigorously studied by Hess [31][32][33][34][35][36] and Wu [37][38]. In these systems, the secondary carbocation and the double bond

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• intramolecular transesterification. The method was also applied in the derivatization of a steroid derivative 95, affording the corresponding product 96 (Scheme 19) [42]. The reactions are [6 + 1] and [7 + 1] annulations for cyclohex-2-enone and cyclohept-2-enone, respectively. The treatment of (M)-2'-methyl

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

• –517. Keywords: Appel reaction; azidolysis; cholesterol; crystal structure; Walden inversion; Introduction 3β-Hydroxycholest-5-ene (cholesterol) is a structural and physiologic amphipathic steroid in human and animals as well. Cholesterol is an essential component of the plasma membrane, where it

• at C3 [12]. In this way, substitutions at the stereogenic homoallylic carbon atom can proceed with retention of configuration. Concurrently, a so-called i-steroid rearrangement leads, for instance, to 6β-azido-3α,5-cyclo-5α-cholestane by 6β-face attack of the steroidal substrate by the nucleophile

• ·OEt2 [12]. All of those results confirmed the involvement of regio- and stereospecific i-steroid and retro-i-steroid rearrangements. Later, tetrabutylammonium halides were used as cost effective and stable alternatives of TMS-based reagents [15]. Treatment of compound 4 (Scheme 1) with NaN3 in

Preparation of β-cyclodextrin/polysaccharide foams using saponin

• Max Petitjean and
• José Ramón Isasi

Beilstein J. Org. Chem. 2023, 19, 78–88, doi:10.3762/bjoc.19.7

• ]. The aglycone part is composed of steroid and triterpene molecules [3]. Not only present in plants [4][5], saponins have also been discovered in marine animals, such as sea cucumbers [6] or starfish [7]. Chemical structures of this family are varied [1], so they will show different properties [8

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

• ingredients (APIs) is necessary to render them bioavailable. This study addresses the poor solubility of two potent steroid hormones, 17β-estradiol (BES) and progesterone (PRO), via their complexation with two water-soluble native cyclodextrins (CDs) namely β-CD and γ-CD. The hydrated inclusion complexes β

• the hormones BES and PRO, while the complex γ-CD·BES was readily shown to be isostructural with γ-CD·PRO by PXRD. Severe disorder of the encapsulated steroid molecules in the respective channels of the CD molecular assemblies was evident, however, preventing their modelling, but combination of the

• (BES) and progesterone (PRO), the steroid hormone associated with female fertility and pregnancy. Both compounds have very low aqueous solubility values (3.6 × 10−3 mg·cm−3 at 27 °C, and 8.81 × 10−3 mg·cm−3 at 25 °C, respectively) [6][7][8]. This drawback hinders their use as medications in hormone

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• - and steroid-modifying CYPs across the plant CYPome, present a structure-based summary of their reactions, and highlight recent examples of particular interest to the field. Our review therefore provides a comprehensive up-to-date picture of CYPs involved in the biosynthesis of triterpenoids and

• steroids in plants as a starting point for future research. Keywords: biosynthesis; CYPs; cytochrome P450 monooxygenases; plants; steroid; sterol; triterpene; triterpenoid; Introduction Triterpenoids are a large class of natural products derived from precursors containing 30 carbon atoms and composed of

• [7]. Hence, there is considerable interest in CYPs involved in triterpenoid and steroid metabolism in plants not only for improving our understanding of plant specialised metabolism, but also for synthetic biology and chemoenzymatic synthesis. In this review, we will provide an extensive overview of

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

• cyclodextrin as the anchoring template. For example, cyclodextrin would fix the steroid substrate with a certain set of orientation, which exposes one certain C–H bond to the metalloporphyrin catalytic moiety and produces site-selective oxidized product. As shown in Figure 8, in this methodology, the steroid

• the end. Once the two parts were mixed in the reaction system, the two p-tert-butylphenyl groups of the substrate 27 were recognized by the β-cyclodextrin and anchored through the host–guest binding. At this stage, the steroid core exposed the 6-position C–H bond to the metalloporphyrin unit catalytic

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• and metabolic stability of the molecule [16]. Steroid molecules with nitrogen-containing heterocyclic rings are promising candidates for the treatment of many types of cancer or hormonal disorders [17]. There are several examples of steroidal tetrazoles showing anticancer potential (Figure 1) [18][19

• , derivatives of bile acid, androstene, and cholestane were prepared, with the tetrazole ring not being fused to the steroid core [30][31][32][33]. Some fused steroidal tetrazole derivatives were obtained by intramolecular 1,3-dipolar cycloaddition [34][35]. It should be noted that the Schmidt reaction

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• a biosynthetic pathway for the novel steroid asperflotone (72), it was suggested that its source was asperfloroid (73), a similar steroid isolated from the same source fungus, Aspergillus flocculosus [23]. First, reduction of the C8–C9 double bond and oxidation at C15 would provide α-ketol 74

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• product (98% yield) (Scheme 20C). More complex structures like dipeptides and substrates containing multiple Lewis-basic functionalities also presented good yields and chemoselectivities with this protocol. The robust allylation reaction was tested in even more complex structures, including steroid

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• , active methylene compounds, and a conjugated enol acetate of a steroid were all fluorinated in moderate to high yields. The fluorination of anisole required high temperature and neat conditions suggesting that the fluorination power of 20-2 is not so high. 1-21. Perfluoro[N-fluoro-N-(4-pyridyl)acetamide

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• process facilitated the fluorination of sclareolide (1) and complex steroid 3. Sclareolide (1) is a naturally available terpenoid with antifungal and anticancer activities [23]. Under the optimized reaction conditions, sclareolide (1) is fluorinated at the C2 and C3 positions in 42% (see 2a) and 16% yield

• [24]. This manganese porphyrin catalytic system was also effective in the direct site-selective fluorination of complex steroid scaffold 3, containing 28 unactivated C–H bonds. Based on the authors’ analysis of steric and electronic factors, it was suggested that the methylene units at C2 and C3 of

• -economical approach to several tryptophan-containing peptides with significant potential for drug discovery and medicinal chemistry. Positional selectivity was observed at the C2 position due to the presence of the pyrimidine directing group. Interestingly, alkynylative conjugation of tryptophan to a steroid

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• methodology was extended to the synthesis of potentially bioactive derivatives, such as heterofused coumarins 162a and 162b, azepinone-like 162c, and steroid-based triazolo-fused isoindoline 162d [65]. Ru-catalyzed synthesis of fully decorated triazoles A series of 1,4,5-trisubstituted triazoles 172 was

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• stereoselectivity, and olefin 84h containing a biologically relevant steroid moiety was successfully hydroalkylated under these conditions. This confirmed the potential of this strategy to forge challenging carbon sp3–sp3 bonds. The proposed mechanism starts with a Ni(I) species (A), which acts as a radical

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols

• Marek Kõllo,
• Marje Kasari,
• Villu Kasari,
• Tõnis Pehk,
• Ivar Järving,
• Margus Lopp,
• Arvi Jõers and
• Tõnis Kanger

Beilstein J. Org. Chem. 2021, 17, 581–588, doi:10.3762/bjoc.17.52

• chemistry and synthetic biology. Stereo- and regioselective hydroxylation at C9 (steroid numbering) is carried out using whole-cell biocatalysis, followed by the chemical cleavage of the C–C bond of the vicinal diol. The two-step method features mild reaction conditions and completely excludes the use of

• Discussion Synthesis of starting compounds for enzymatic hydroxylation In order to estimate the possible diversity of the substrates as starting materials for the biocatalytic transformation, cortisol (1) was converted to a hydroxylated steroid derivative 2 by reduction of the C20 carbonyl group with NaBH4

• was approximately 1:10 (estimated by HRMS analysis). The steroid compounds were extracted from the supernatant and purified by column chromatography on silica gel as the stationary phase. The outcome of the enzymatic hydroxylation in position C9 using KSH-based biocatalysis is given in Table 1. With

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