Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• C14 β-OH group. The revised synthetic route is described in Scheme 2. At first, 4 was subjected to a Pd/C-catalyzed hydrogenation to afford the desired A/B-cis fused intermediate 7 along with its C5 epimer as a 2:1 separable mixture in a quantitative yield. By treating 7 with the Bestmann ylide

• -catalyzed anaerobic conditions [30], 11 was transformed into the C14 hydroxylated intermediate 12 as epimeric mixture in 42% yield and dr = 1:5, among which the undesired 14α-hydroxy epimer was the major component. Interestingly, the use of Co(acac)2 or Mn(acac)2 as the catalyst [31][32] instead of Fe(acac

• key C14 β-hydroxylated intermediate 16 in 53% yield, accompanied by the separable C14 α-OH epimer in 27% yield. Later on, we assumed to achieve the deprotection of the sugar motif and the reduction of the C11 carbonyl of 16 simultaneously under Li–NH3(l) conditions, which would directly afford the

Total syntheses of highly oxidative Ryania diterpenoids facilitated by innovations in synthetic strategies

• Zhi-Qi Cao,
• Jin-Bao Qiao and
• Yu-Ming Zhao

Beilstein J. Org. Chem. 2025, 21, 2553–2570, doi:10.3762/bjoc.21.198

• present substantial challenges in developing a unified synthetic strategy capable of accessing diverse members of this family. The Zhao group recently achieved the first total synthesis of the Ryania diterpenoid garajonone (8) and its epimer 3-epi-garajonone. Unlike the representative ryanodine

A chiral LC–MS strategy for stereochemical assignment of natural products sharing a 3-methylpent-4-en-2-ol moiety in their terminal structures

• Rei Suo,
• Raku Irie,
• Hinako Nakayama,
• Yuta Ishimaru,
• Yuya Akama,
• Masato Oikawa and
• Shiro Itoi

Beilstein J. Org. Chem. 2025, 21, 2243–2249, doi:10.3762/bjoc.21.171

• . Alternatively, PNB ester (2S,3R)-9, the C3-epimer of 8, was synthesized from (2S,3S)-13 via a Mitsunobu reaction using p-nitrobenzoic acid (PNBOH) and DEAD in 39% yield for two steps [28]. The stereoisomers (2R,3R)-10, and (2R,3S)-11 were prepared in the same manner starting from commercially available (3R)-14

• incompatible with LC–MS detection, necessitating a relatively larger amount of sample for analysis. In contrast, a key advantage of our method is the use of a PNB group as the acyl moiety, which enables direct conversion to a C3-epimer via a Mitsunobu reaction, thereby streamlining the synthesis of the four

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• , we treated it to Zn powder in AcOH to facilitate the N-walking transformation, and generated keto-ibogamine product 33 as a mixture of diastereomers (Scheme 4c). Then, reduction of ketone to methylene under Wolff–Kishner–Huang conditions provided ibogamine and its epimer in a 1:1.3 ratio. This result

• 26b just following the same route for synthesis of tatertinggine, and the yield of each step was basically comparable (Scheme 4b). Starting from 12-OMe-tabertinggine, Zn-promoted N-walking and ketone reduction provided ibogaine in 1:3 ratio with the major epimer. Indole oxidation with DMDO provided 34

• gymnothespirolignan A in excellent yield and good diastereoselectivity [38] (Scheme 6c). The minor epimer is gymnothespirolignan C, another natural product of this family. This cascade reaction supports the proposed biogenetic pathway of the newly isolated novel siprocyclic gymnothelignans. The bioinspired double

Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• important [145][146][147]. For example, the diastereoisomeric monofluorophosphonates 83 and 84 were compared in their ability to bind to a phosphosugar-processing enzyme. Epimer 84 was found to bind with 100-fold higher affinity than epimer 83, and this was attributed to a lower-energy binding conformation

Organocatalytic kinetic resolution of 1,5-dicarbonyl compounds through a retro-Michael reaction

• James Guevara-Pulido,
• Fernando González-Pérez,
• José M. Andrés and
• Rafael Pedrosa

Beilstein J. Org. Chem. 2025, 21, 473–482, doi:10.3762/bjoc.21.34

• mixture with its epimer. An epimerization process was observed when a 0.014 M solution of racemic anti-1 in toluene was stirred at room temperature in the presence of the prolinol derivative A (20 mol %). This process led to a mixture of syn/anti epimers that changed over time and reached a ratio of 1:7

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

• . Epimer at the 2 position of anti,syn-7a (syn,syn-7a): 1H NMR (300.40 MHz, CDCl3) δ 1.30 (t, J = 7.2 Hz, 3H), 4.00 (d, J = 8.4 Hz, 1H), 4.08 (dd, J = 6.3, 8.1 Hz, 1H), 4.26–4.34 (m, 2H), 5.00 (quint, J = 5.7 Hz, 1H), 5.22 (d, J = 12.0 Hz, 1H), 5.27 (d, J = 12.3 Hz, 1H), 7.31–7.41 (m, 5H); 13C NMR (75.45

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

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

• ]. Isoaltenuene (55), the 4a-epimer of altenuene, was first isolated from Alternaria alternata [260]. Its proposed structure including its relative configuration was determined by NMR spectroscopy and unambiguously confirmed by total synthesis of the (+)-enantiomer [249]. Whenever the chirality was determined, it

• including the absolute configurations were determined by NMR spectroscopy and by comparison of measured and calculated ECD spectra. They showed an insignificant inhibition of α-glucosidase with IC50 values of 726 and 451 μM, respectively [206]. A further epimer 60 was isolated from Penicillium sp. but

Elucidating the glycan-binding specificity and structure of Cucumis melo agglutinin, a new R-type lectin

• Jon Lundstrøm,
• Emilie Gillon,
• Valérie Chazalet,
• Nicole Kerekes,
• Antonio Di Maio,
• Ten Feizi,
• Yan Liu,
• Annabelle Varrot and
• Daniel Bojar

Beilstein J. Org. Chem. 2024, 20, 306–320, doi:10.3762/bjoc.20.31

• steric clashes or density effects). Another supporting finding can be seen in the fact that CSB (exhibiting iduronic acid in α-configuration, rather than its epimer, glucuronic acid, in β-configuration) showed virtually no binding to CMA1, further arguing for contacts of the GAG chain with the binding

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• group was introduced following the same method to produce PAF 4.15. By using the same methodology, the epimer of PAF 4.15 was synthesized. The group of Bittman reported in 1995 the synthesis of PAF with a four-step sequence starting from S-glycidol 5.1 in which the acylation of the sn-2 position was

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

• refluxing toluene was reported to proceed with retention of configuration to afford the β-epimer 6 [16]. Another nice application of this chemistry was recently reported by Oestreich and co-workers, who converted 3β-hydroxypregn-5-en-20-one into the corresponding 3-bromo derivative, which also occurred with

• inversion. For note, the 1H NMR spectrum of 5 revealed the presence of ca. 15% of the β-epimer 6, which could result from an incomplete stereospecificity of the substitution opening an alternative reaction path. Also in this case, the NMR data are then in agreement with the reported ones [18]. In light of

• signal is attributed to the H-3 of (15%) byproduct 3β-azidocholest-5-ene; **denotes to two protons of the 3β-azidocholest-5-ene epimer [12]. Chemical structure of three isomeric cholesterols. Selected previously described cholesterol derivatives with interesting antibacterial and cytotoxic activities [9

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

• alcohol on the A ring in 75% yield. The C3 epimer was also obtained in 4% yield and confirmed by X-ray diffraction. Hydrogenation of the sterically hindered C1–C2 alkene was accomplished using a combination of Mn(dpm)3 and Ph(iPrO)SiH2, providing grayanotoxin III in 51% yield. The authors also achieved

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• multigram scale, affording (−)-7-amino-7,8-dihydrobisabolene (4) and its C7-epimer as an 83:17 mixture of diastereomers in 87% overall yield. Unfortunately, these diastereomers were not separable by conventional column chromatography. Although this diastereomeric mixture could be converted into a variety of

• , we decided to prepare solid derivatives of 4 (and its C7-epimer) that could be purified by recrystallization. Although the α-bromoacetamide [10] and p-bromobenzamide derivatives of these amines are solids, no change in dr was observed upon recrystallization from a variety of solvents. Fortunately, we

• ultimately found success with the benzamide derivative 5, which could be prepared from the mixture of 4 and its C7-epimer in 93% yield upon treatment with benzoyl chloride. Recrystallization of the resulting mixture of diastereomeric amides from cyclohexane improved the dr from 83:17 to 95:5 (as determined

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• minor diastereoisomeric epimer in the phosphorus atom was also isolated in less than 8% yield (Scheme 23) [48]. The authors further performed detailed mechanistic investigations experimentally and theoretically [49][50]. Dinaphth-1-yl-N-alkyl-N-benzylphosphinamides 134 were also applied to the tandem

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• , respectively. In turn, the Gibbs energies of activation corresponding to the endo approaches indicate that cycloadduct 4 (ΔG‡1+2j->4-endo = 19.3 kcal/mol) is more kinetically favorable than its epimer 4' (ΔG‡1+2j->4'-endo = 20.3 kcal/mol). The small free energy difference (1.0 kcal/mol) between the two

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban

• Martin Vrbický,
• Karel Macek,
• Jaroslav Pochobradský,
• Jan Svoboda,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2022, 18, 438–445, doi:10.3762/bjoc.18.46

• de were observed and the presence of the major S-enantiomer in the products 1 and 2 was confirmed by chiral HPLC analysis. Moreover, an enhancement of the abundance of the major epimer in the nitroaldols 22, 24, and 26 as well as the amides 27 and 28 was examined. Generally, epimers represent pairs

• ) values (83–90%) than in the previously published study (up to 72% ee) [13]. The introduction of a chiral moiety into the structure of aldehydes 16, 18 and 20 led to the formation of nitroaldols 22, 24, and 26 as pairs of epimers. Unfortunately, the attempts of separating the minor epimer were

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

• the mixture of 38 and 39 induced a second α-ketol rearrangement to 40 as a tautomeric mixture. The same research group later utilized the same [3 + 2] cycloaddition and α-ketol rearrangement approach to prepare the 2′′′-epimer of 35, which bears an inverted methyl acetal in the dioxane ring, but this

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• depending on the type of underlying duplex, and these 4'-substituents were able to modulate the binding affinities for the parent 2'-modifed oligonucleotides [209]. siRNA containing inserts of the C4’ α-epimer of 2'-F,4'-OMe-rU, in either the sense or antisense strands, triggered gene silencing with

Fluorine effect in nucleophilic fluorination at C4 of 1,6-anhydro-2,3-dideoxy-2,3-difluoro-β-D-hexopyranose

• Danny Lainé,
• Vincent Denavit,
• Olivier Lessard,
• Laurie Carrier,
• Charles-Émile Fecteau,
• Paul A. Johnson and
• Denis Giguère

Beilstein J. Org. Chem. 2020, 16, 2880–2887, doi:10.3762/bjoc.16.237

• reactions were monitored using 19F NMR spectroscopy with 2-fluoro-4-nitrotoluene as internal standard. Fluorodeoxygenation of glucopyranose 2 gave galactose 10 (inversion of configuration), as the only diastereoisomer (Table 1, entry 1). Interestingly, the epimer at C4 (compound 3) provided galactose 10

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

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

• in a high yield and enantioselectivity (Scheme 5) [17][18]. The Rubottom oxidation [28] of 43 gave a separable mixture of the desired 44 and its C-14 epimer (≈7:1 ratio). The reductive deoxygenation of 44 proceeded via the tosylhydrazone to afford 45, which upon desilylation and alkyne isomerization

• 12c gave a separable mixture of the desired 49 (52%) along with the C-14 epimer (8%). More recently, the Ghosh group provided an alternative synthesis from the triacetyl ᴅ-glucal 60 (Scheme 8) [31]. The exhaustive hydrolysis and selective protection as the 4,6-O-di-tert-butylsilylene derivative 61 [32

Indium-mediated C-allylation of melibiose

• Christian Denner,
• Manuel Gintner,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2019, 15, 2458–2464, doi:10.3762/bjoc.15.238

• main product was crystallized and the configuration was determined by X-ray analysis proving the expected syn-configuration (compound 2-syn) [CCDC 1922520] (Figure 1). Epimer 2-syn was applied to Zemplén conditions prior to the ozonolysis. Conventional work-up, neutralization with acidic ion exchange

• further work up. This reaction mixture was cooled to −78 °C, purged with ozone for two minutes followed by reductive work-up employing triphenylphosphine which gave the corresponding glycosylated elongated aldoses 4-syn in full conversion as determined by TLC. Epimer 2-anti was reacted accordingly, after

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• difficulty in extraction of 40 and 41 from the large quantity of alumina. Dehydration of the mixture of 40 and 41 in benzene quantitatively afforded a 1:2 mixture of 42 and its C-3 epimer 41. Reduction of the epimers with sodium borohydride and subsequent treatment with hydrochloric acid (2 N) gave single

• isomer 43. Treatment of 43 with methoxide ions in methanol at room temperature for 15 min gave the desired C-5 trans-butenolide 8 (40%) along with its C-5 cis-epimer 44 (60%), which is the sole product from the base-catalyzed isomerization of 43. Epoxidation of 43 gave a C-4,5-epoxide intermediate, which

• troublesome work (60% yield) due to the formation of the thermodynamic more stable C-5 cis-epimer 44 [66]. Thus, it may not be possible to obtain the desired triptophenolide methyl ether (8) in a satisfactory yield for a target-oriented synthesis. As the key structure element of various di- and triterpenes

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• stereochemistry, they were synthesized from the aziridine ketone (2S,1'R)-36 readily available from Weinreb amide (2S,1'R)-18 which already contained the required configuration at C2 (Scheme 11) [47]. Introduction of the 3R configuration in xestoaminol C and 3S in its epimer was achieved by stereoselective

• syntheses of this compound the general approach which employs the aziridine ester (2R,1'R)-5b as a starting material allows to also obtain its 5'-epimer and norfuranomycin (2S,2'R)-133 [87]. To construct the 2,5-dihydrofurane ring the aziridine alcohol (2R,1'R,1''R)-134 (Scheme 35) [88] was converted to the

• )-135 instead of the allyl residue opened the way to synthesis of ʟ-(+)-furanomycin and its 5'-epimer. MeBmt (2S,3R,4R,6E)-139 is a nonproteinogenic amino acid found as a constituent of the naturally occurring cyclic peptide cyclosporine currently in medical use as immunosuppressant [89]. Syntheses of