Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• total synthesis of the halichondrin family of natural products (Scheme 11) [37][38]. Ketone 57, an intermediate in the synthesis of halichondrins, bears a β-alkoxy substituent, which raises concerns about potential epimerization via a retro-oxa-Michael/oxa-Michael pathway (Scheme 11A). To address this

• issue, the authors first examined a model system. When β-alkoxythioesters (S)-52 were coupled with chiral alkyl iodides (S)-53 and (R)-53 under the developed conditions, the desired β-alkoxy ketones 54 were obtained in good yields without epimerization, affording optically pure products. These results

• % yield. No epimerization at the β-position was observed, and 57 was obtained as a single product. Subsequent removal of the silyl protecting group under PivOH buffer/TBAF conditions, followed by PPTS treatment, enabled spiroketal formation. Finally, epimerization at C38 with TMSOTf completed the total

Total synthesis of asperdinones B, C, D, E and terezine D

• Ravi Devarajappa and
• Stephen Hanessian

Beilstein J. Org. Chem. 2025, 21, 2730–2738, doi:10.3762/bjoc.21.210

• tryptophan were explored. Different approaches were adopted for the functionalization of C4–C7 prenylindoles at C-3 using Negishi cross-coupling methods. The asperdinones are among the rare tryptophan-derived indole alkaloids which appear to have undergone epimerization due to genetic alteration of specific

• Bock in 1987 [16]. It is of interest that although the biosynthesis of 3-indolylbenzoquinone-2,5-dione ent-5 is initiated with ʟ-tryptophan and anthranilic acid [17], the resulting natural products 1–4 possess a (3R) configuration. This is because of an epimerization mediated by the non-ribosomal

• ), members of a new class of prenylated 3-indolyl-2,5-benzodiazepine-1,4-diones and diketopiperazine alkaloids, respectively, through Negishi cross-coupling and related C–H functionalization strategies. Importantly, no epimerization was observed during the Negishi coupling or throughout the subsequent steps

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• transpositions [31]. Starting from (S)-carvone (67), reaction with allyl bromide introduced an allyl group to give 68, which was then converted to the bicyclic compound 69 via a ring-closing metathesis (RCM) reaction followed by one-pot epimerization at the α-position of the carbonyl group (Scheme 7

Rapid access to the core of malayamycin A by intramolecular dipolar cycloaddition

• Yilin Liu,
• Yuchen Yang,
• Chen Yang,
• Sha-Hua Huang,
• Jian Jin and
• Ran Hong

Beilstein J. Org. Chem. 2025, 21, 2542–2547, doi:10.3762/bjoc.21.196

• undesired stereochemistry at C3 due to a possible chair-like transition state like 10a (Scheme 2B). This phenomenon is consistent with the observations from previous syntheses [31][35][36]. We anticipated that late-stage epimerization might invert the configuration once the acyl group is revealed at the C2

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• (C6F5)3B triggered a Meinwald rearrangement, generating aldehyde 66. Nucleophilic addition, oxidation of the resulting alcohol, and base-promoted epimerization at C6 of 67' delivered 67. Subsequent dihydroxylation of the alkene in 67 and protection of the resulting 1,2-diol as a cyclic carbonate

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• enamine 9b, which was completely consumed in 6 hours at room temperature. Following acidic hydrolysis of the enamine, a mixture of α-trifluoromethylated ketone diastereomers was obtained, and subsequent epimerization with K2CO3 afforded 19 as a single stereoisomer in 48% yield. The equatorial position of

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• for the construction of carbon–carbon and carbon–heteroatom bonds. Unlike many ionic reactions, radical reactions are often functional group tolerant and carried out under mild, neutral conditions, avoiding harsh acidic or basic conditions that can promote epimerization or decomposition of the product

Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

• Jin-Fang Lü,
• Jiang-Feng Wu,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2025, 21, 2072–2081, doi:10.3762/bjoc.21.162

• synthesis of (–)-isochaetominine A was increased from 25.4% to 30.8% over five steps. Secondly, a new protocol featuring the use of an aged solution of K2CO3/MeOH to quench the DMDO epoxidation-triggered cascade reaction was developed, which allowed the in situ selective mono- or double epimerization at C11

• /C14 as shown by the diastereodivergent synthesis of a pair of diastereomers of versiquinazoline H from its tripeptide precursor. This double epimerization at the last-step allowed the enantiodivergent synthesis of two enantiomers in either racemate form or two pure enantiomers from the same precursor

• aspera chaetominine B. Keywords: epoxidation; selective epimerization; stereodivergent synthesis; structural revision; tandem reaction; Introduction In contemporary organic chemistry, due to the widespread application of modern separation and analytical techniques, the structural elucidation and

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• with the desired C6 chiral center was constructed via intermediate 229, where the sulfinyl group induced K+–oxygen chelation to form a six-membered transition state prior to protonation from the less hindered face. Acid-mediated epimerization at C9 of 230 yielded compound 231, which was transformed

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• undesired anomeric epimerization, leading to the production of two stereoisomers in a ratio of α/β = 1:1.6 [28][29]. To increase the yield and minimize anomeric epimerization, we employed the more reactive reagent, methyl 2,2-dimethoxypropanoate, which contains a hemiketal moiety. As expected, the reaction

• In conclusion, we could successfully synthesize the pure R-isomer of pyruvated galactose, simultaneously avoiding anomeric epimerization. The crystal structure of pyruvylated galactose, potentially stabilized by hydrogen bonding, provided direct evidence confirming the diastereochemistry of the

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• as a PMB ether. Compound 84 could be obtained from the all-syn isomer 85 through an epimerization process. In route B, compound 86 was proposed to be synthesized from methyl ester 87. The transformation involved reduction of 87 to a primary alcohol, conversion of the alcohol into the corresponding

• iodide, and subsequent nucleophilic substitution with deprotonated (R,R)-91. The introduction of the OPMB functionality in compound 88 could then be achieved by following the steps employed in the transformation of 84 to 83. The synthesis via route A began with efforts to optimize the epimerization of

A convergent synthetic approach to the tetracyclic core framework of khayanolide-type limonoids

• Zhiyang Zhang,
• Jialei Hu,
• Hanfeng Ding,
• Li Zhang and
• Peirong Rao

Beilstein J. Org. Chem. 2025, 21, 926–934, doi:10.3762/bjoc.21.75

• .) of 24 led only to epimerization at C10 or slow decomposition of the starting material (see Supporting Information File 1, Table S1). Pleasingly, treating 24 with HMDS and TMSI regioselectively generated the expected TMS enol ether [46], which underwent a Li/Si exchange in the presence of MeLi

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• reduction with LiAlH₄, which led to a further decrease in the degree of unsaturation of the pyrazolodiazepine core, while the more sterically hindered exocyclic amide moiety remained intact. However, both reactions were accompanied by partial epimerization, and careful kinetic control was therefore required

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

• resulted in a slight decrease in enantioselectivity compared to the result obtained when starting from a 1:2 mixture of syn/anti-1. Scheme 6 presents a possible explanation for the epimerization of the pure rac-anti-1 adduct. The reaction of the more reactive enantiomer anti-(3R,4S)-1 with catalyst A leads

• to enamine E, which epimerizes at C-4 and, after hydrolysis, provides the adduct syn-(3R,4R)-1 with an initial er of 4:96. This diastereoselective epimerization phenomenon promoted by an organocatalyst has not been previously described. The study emphasizes the reversibility of some organocatalyzed

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• -glycosides had to be employed in order to obtain anomerically pure indirubin-N-glycosides. As expected, no epimerization was observed during the base-mediated condensation as no aqueous acid was employed. All products were isolated as the pure Z-configured isomers (determination by NMR, the other isomer was

The scent gland composition of the Mangshan pit viper, Protobothrops mangshanensis

• Jonas Holste,
• Paul Weldon,
• Donald Boyer and
• Stefan Schulz

Beilstein J. Org. Chem. 2024, 20, 2644–2654, doi:10.3762/bjoc.20.222

• occurring DKPs usually consist only of the ʟ,ʟ-diastereomer, here both syn- and anti-diastereomers were observed. This may be due to slow epimerization due to enolization within the gland or during sample preparation and storage, as the ᴅ,ʟ-diastereomers of proline DKPs are more stable than the ʟ,ʟ

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• epimerization of α-substituted intermediates. The lack of the conserved GM (11) motif preceding the αFG helix, which is highly conserved in other types of reductase-competent KRs, was also observed in A2-type KRs. The absence of this region in the electron density map of the A2-type AmpKR11 [30] may indicate a

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

• numerous modified techniques, which established the greener side of the reaction. The use of Lewis acid catalysis in this regard [34][35][36][37][38][39] played a significant role, which also suppressed the epimerization in the case of chiral molecules. Among the various Lewis acid catalysts such as

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

• 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

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• amount of the C-9 epimerization product 11 might be explained by a competing radical oxidation of the organoborane intermediate IM-16 by oxygen when the oxidation step is opened to air [32][33]. On the other hand, an alternative mechanism for the formation of 11 involving the oxidation of the 9-epi-IM-16

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• the other hand, the chemoenzymatic process using purified Sgd TE from its biosynthesis and a linear peptide SNAC substrate gave the macrocycle in an acceptable yield without epimerization (Scheme 3). Although NAC-containing thioesters were widely employed, as described above, it had several

• limitations, such as possible Cα epimerization [45] during SNAC coupling and essential HPLC purification, which was generally difficult and time-consuming. Developing other different methods, exceptionally more straightforward approaches to access activated substrates, would solve this inevitable bottleneck

• at the biomimetic position (17a), which not only alleviated the epimerization in the macrolactamization process compared to other positions, but also enabled investigation of its biosynthetic pathway [60]. They also identified a stand-alone enzyme known as SurE, which is classified as a penicillin

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• : epimerization domain, TE: thioesterase domain, KS: ketosynthase domain, AT: acyl transferase domain, KR: ketoreductase domain, TauD: taurine dioxygenase domain. Substrate specificity of A and KS domains is presented at the top of each module (FA: fatty acyl, Arg: arginine, MM: methyl malonyl, Asp: aspartic acid

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• -specific A-domain; A2, ʟ-Pro-specific A-domain; A3, ʟ-Val-specific A-domain; A4, ʟ-Orn-specific A-domain; A5, ʟ-Leu-specific A-domain; E, epimerization domain; C, condensation domain; TE, thioesterase domain. (A) Adenylation reaction in a nonribosomal peptide synthetase. (B) Structures of aminoacyl-AMS

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• bond formation. Additional common domains include epimerization (E) domains for converting naturally occurring ʟ-amino acids to ᴅ-amino acids, methyltransferase (MT) domains that typically methylate specific N atoms, and terminal condensation (CT) domains which cyclize the growing peptide chain and