Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• . Hydrolytic kinetic resolution of 209 afforded enantioenriched epoxide (S)-209, which was opened regioselectively with lithium acetylide. The allylation and [3 + 2]-cycloaddition with tosyl azide led to 212. Treatment with Rh2(OAc)4 induced a [2,3]-Wittig rearrangement and subsequent hydrolysis afforded 213

Synthesis and stereochemical analysis of dynamic planar chiral oxa[7]orthocyclophene

• Yukiho Hashimoto,
• Yuuya Kawasaki,
• Kazunobu Igawa and
• Katsuhiko Tomooka

Beilstein J. Org. Chem. 2026, 22, 436–442, doi:10.3762/bjoc.22.30

• alkyne 6. Subsequent preparation of the lithium acetylide using n-BuLi, followed by treatment with formaldehyde, afforded propargyl alcohol 3a in 70% yield over three steps. The reaction of 3a with Red-Al generated a vinyl aluminum species, which was then treated with iodine to provide the iodinated Z

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• commercially available lithium bis(trimethylsilyl)amide (LiHMDS), but the latter was found inconvenient for routine syntheses due to high moisture sensitivity which prevented reproducibility of the reaction conditions. To overcome this difficulty, the LiHMDS solution was instead prepared in situ by reacting

Recent advances in the cleavage of non-activated amides

• Eun-Sol Choi and
• Hyo-Jun Lee

Beilstein J. Org. Chem. 2026, 22, 352–369, doi:10.3762/bjoc.22.23

• of 2 equivalents of TCCA as a chlorinating reagent and 2.5 equivalents of lithium benzoate (LiOBz) as a base, primary amides are converted into the corresponding N,N-dichloroamide intermediates 46, which then undergo smooth nucleophilic acyl substitution with alcohols to afford esters. The substrate

• unactivated tertiary amides under transition-metal-free conditions [73]. Lithium hexamethyldisilazide (LiHMDS) was used to activate the amide, enabling smooth cleavage of the C–N bond even in sterically hindered substrates (Scheme 22a). Using p-methylaniline as a nucleophile in the presence of three

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• , constructing the [2.2.2]-bridged ring within the (+)-nominine followed by protection of the primary alcohol as mesylate. Using lithium bromide as the bromine source, an SN2 reaction was performed, and the allylic position was oxidized with tert-butyl peroxide and selenium dioxide to generate the enone 104

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• reported an alternative strategy for alkenyl chloride synthesis employing lithium chloromethylenecarbenoids generated in situ from chloroiodomethane

One-pot synthesis of ethylmaltol from maltol

• Immanuel Plangger,
• Marcel Jenny,
• Gregor Plangger and
• Thomas Magauer

Beilstein J. Org. Chem. 2025, 21, 2755–2760, doi:10.3762/bjoc.21.212

• opted for deprotonation with lithium reagents. Attempted double deprotonation with methyl lithium afforded a complex reaction mixture, from which ethylmaltol (1) was isolated in 11% together with an inseparable impurity tentatively assigned as 6 based on NMR analysis (Table 1, entry 2). Switching to the

• less nucleophilic and sterically more hindered base lithium diisopropylamide (LDA), the yield of ethylmaltol (1) increased to 25% and maltol (2) was recovered in 17% (Table 1, entry 3). Notably, treatment of maltol (2) with LDA resulted in a deep purple solution with no apparent solubility issues. We

• nucleophilicity of the intermediate lithium alkoxides and to the softer nucleophilic character at C vs O for lithium dienolates. While the dianion strategy was able to convert maltol (2) to ethylmaltol (1) in yields of up to 57%, the reactions suffered from an unsatisfactory purity profile. First, interconversion

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

• alkylation was diasteroselective. In the next steps, addition of isopropenyllithium to the lactone moiety led to a hemiketal, which was then opened and a protecting group on the hydroxy group was installed, furnishing fragment 42. Key convergent coupling of this total synthesis was performed by lithium

• butenolide moiety, selective α-methylation, formation of a lactam, reduction of the former to an amine, and installation of two different protecting groups. Aryl bromide 53 (fragment B) was then ready for coupling. Lithium–halogen exchange in fragment B 53 and subsequent 1,2-addition to fragment A 47

• coupling was carried out via lithium–halogen exchange, 1,2-addition, and subsequent oxidation to give ketone 48. Photoinduced excited-state Nazarov cyclization installed the cyclopentenone C-ring with correct stereoconfiguration at C9 and C10 in excellent yield. Ketone reduction and global deprotection

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

• -carbonyl reduction by dissolved lithium metal in liquid NH3 solution, and the C11 α-hydroxylated intermediate 13 was obtained as a single diastereoisomer in 54% yield. Lastly, as expected, a Co(acac)2-catalyzed Mukaiyama hydration of 13 afforded the desired natural product sarmentogenin (2) in 69% yield

Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• -3-yl lithium derivative, followed by electrophilic trapping of the thiolate and base-induced cyclization to afford the 3-hydroxy-TT [25]. Route II is represented by the single example of a one-pot reaction of 2-methylquinoline and 3-bromothiophene-2-carbaldehyde in the presence of elemental S and

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• in four steps. Subsequent conjugate addition of the lithium anion of TMS-acetonitrile to 15, followed by careful one-pot protonation of the resulting enolate with ethyl salicylate and TMS removal with CsF, gave 16 bearing three properly arranged substituents. Grignard 1,2-addition to ketone 16

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

• ; and subsequent conversion of the ketone in 20 to the vinyl iodide in 21 – via hydrazone formation, lithium–halogen exchange, and final nucleophilic substitution – secured the Norrish–Yang cyclization precursor 22. Following systematic optimization of reaction conditions, irradiation of 22 with 100 W

Stereoselective electrochemical intramolecular imino-pinacol reaction: a straightforward entry to enantiopure piperazines

• Margherita Gazzotti,
• Fabrizio Medici,
• Valerio Chiroli,
• Laura Raimondi,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2025, 21, 1897–1908, doi:10.3762/bjoc.21.147

• represent the most established approach to imino-pinacol coupling (Scheme 1), with zero-valent metals traditionally employed as reductants and various strategies extensively explored [2]. The use of alkali metals [3][4][5], as lithium and sodium, and alkaline earth metals [6], as magnesium, are

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

• (37) followed by reduction with Zn/Ba(OH)2 and partial re-oxidation (Scheme 12A) [52]. They can also be obtained from o-halogenated benzyl bromides 40 by lithium–halogen exchange followed by nucleophilic substitution and a second lithium–halogen exchange with iodine (Scheme 12B) or by nickel-catalysed

Convenient alternative synthesis of the Malassezia-derived virulence factor malassezione and related compounds

• Karu Ramesh and
• Stephen L. Bearne

Beilstein J. Org. Chem. 2025, 21, 1730–1736, doi:10.3762/bjoc.21.135

• (100 MHz, CDCl3) δ 171.5, 149.6, 135.5, 130.1, 124.6, 124.5, 122.7, 119.0, 115.3, 113.1, 83.6, 52.1, 30.9, 28.2 ppm. These spectroscopic data agreed with those in the literature [28]. 2-(1-(tert-Butoxycarbonyl)-1H-indol-3-yl)acetic acid (22). A solution of lithium hydroxide (LiOH·H2O, 2.1 g, 51.8 mmol

Influence of the cation in hypophosphite-mediated catalyst-free reductive amination

• Natalia Lebedeva,
• Fedor Kliuev,
• Olesya Zvereva,
• Klim Biriukov,
• Evgeniya Podyacheva,
• Maria Godovikova,
• Oleg I. Afanasyev and
• Denis Chusov

Beilstein J. Org. Chem. 2025, 21, 1661–1670, doi:10.3762/bjoc.21.130

• system is more efficient than the earlier described usage of the pure NaH2PO2: higher solubility of the potassium, rubidium and cesium salts compared to the sodium and lithium and a proper pH of the reaction medium. Acidic catalysis strongly accelerates the rate of hemiaminal and iminium ion formation

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

• traced back to 3-oxetanone. In 2018, Bull and co-workers disclosed the first lithium-catalysed thiol alkylation using electron-rich 3-aryloxetan-3-ols 142 (Scheme 35) [84]. This protocol is completely chemoselective as no ring-opening was observed and the resulting oxetane sulphides 143 were obtained in

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

• results, with reactant decomposition observed. Similarly, when the lithium derivative was reacted with CuSPh to form the corresponding heterocuprate species prior to reacting with the epoxide, the same decomposition occurred, despite this strategy being successful in a related case. Finally, replacing the

• reacting it with Eschenmoser’s salt, followed by hydrolysis with lithium hydroxide. The resulting unsaturated acid 54, isolated in 92% yield, underwent asymmetric hydrogenation using both (Ra)-50 and (Sa)-50 catalysts. This step provided the respective compounds 55 and 56 in excellent high yield and

• in 96% yield. Hydrolysis of the acetate group in 69 with potassium carbonate followed by treatment with TBDMSCl and imidazole converted it into silyl ether 70. The ester group in 70 was then hydrolyzed using lithium hydroxide, and the resulting acid was coupled with Evans’ chiral oxazolidinone in the

Supramolecular assembly of hypervalent iodine macrocycles and alkali metals

• Krishna Pandey,
• Lucas X. Orton,
• Grayson Venus,
• Waseem A. Hussain,
• Toby Woods,
• Lichang Wang and
• Kyle N. Plunkett

Beilstein J. Org. Chem. 2025, 21, 1095–1103, doi:10.3762/bjoc.21.87

• at Urbana-Champaign, Urbana, IL, 61801, United States 10.3762/bjoc.21.87 Abstract This study explores the solution- and solid-state assembly of phenylalanine-based hypervalent iodine macrocycles (HIMs) with lithium and sodium cations. The metal cation binding of HIMs was evaluated by addition of

• lithium tetrakis(pentafluorophenyl)borate ethyl etherate LiBArF20 and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate NaBArF24. The electron-rich, outwardly projected carbonyl oxygens of the HIM co-crystalize with the cations into bent supramolecular architectures. Both crystal structures show a

• pattern of assembly between HIM and metal cation in 2:1 ratio. While association with sodium leads to a polymer-like network, the lithium crystal structure was limited to dimeric assemblies of HIM. In the lithium-coordinating complex, the oxygen–lithium–oxygen bond angle is approximately 98.83

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• reaction with nucleophilic lithium amide from n-propylamine, the reduction of phosphine oxide 9 by trichlorosilane/triethylamine, and the N-acylation of 10 with cinnamoyl chloride in three steps (Scheme 1). We also analyzed amide compound 7 by HPLC analysis using a chiral stationary phase column with a CD

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

• followed by interception of the lithium enolate with PhNTf2 to give enol triflate 25 in 59% overall yield. The following palladium-catalyzed methoxycarbonylation produced methyl ester 26 in a satisfactory yield of 84%. TIPS-protected allylic alcohol 28 was selected as the appropriate precursor for the α,β

Cu–Bpin-mediated dimerization of 4,4-dichloro-2-butenoic acid derivatives enables the synthesis of densely functionalized cyclopropanes

• Patricia Gómez-Roibás,
• Andrea Chaves-Pouso and
• Martín Fañanás-Mastral

Beilstein J. Org. Chem. 2025, 21, 877–883, doi:10.3762/bjoc.21.71

• species A which is in equilibrium with the Cu–O enolate B [11]. In the presence of excess of LiOt-Bu, a salt metathesis reaction between this base and intermediate B generates lithium enolate C and LCuOt-Bu to close the copper catalytic cycle. The formation of a lithium enolate is consistent with the

• different diastereoselectivity observed when other bases featuring different metal cations were used (Table 1, entry 2 vs entry 5), and the absence of any significant stereochemical influence from the copper complex (Table 1, entries 9–14). Lithium enolate C would then undergo a diastereoselective conjugate

• summary, we have discovered an unanticipated Cu–Bpin-promoted diastereoselective dimerization of 4,4-dichloro-2-butenoic acid derivatives. The reaction occurs via initial Cu–Bpin insertion followed by keto–enol isomerization and salt metathesis to generate a lithium enolate which is then trapped by a

Regioselective formal hydrocyanation of allenes: synthesis of β,γ-unsaturated nitriles with α-all-carbon quaternary centers

• Seeun Lim,
• Teresa Kim and
• Yunmi Lee

Beilstein J. Org. Chem. 2025, 21, 800–806, doi:10.3762/bjoc.21.63

• % yield under basic conditions using sodium hydroxide and tert-butanol. The reduction of nitrile 3q with lithium aluminum hydride generated amine 7 in an 85% yield, whereas the selective hydrogenation of the alkene moiety of 3q using a Pd/C catalyst in a H2 gas environment smoothly produced product 8 in a

Recent advances in the electrochemical synthesis of organophosphorus compounds

• Babak Kaboudin,
• Milad Behroozi,
• Sepideh Sadighi and
• Fatemeh Asgharzadeh

Beilstein J. Org. Chem. 2025, 21, 770–797, doi:10.3762/bjoc.21.61

• generates an electric current. Some of its applications include batteries (e.g., lithium-ion batteries) and fuel cells. These cells are usually in a divided state. Electrolytic cell These cells require an external voltage to drive chemical reactions. They use electrical energy to carry out a non-spontaneous

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• interactions and enhanced electronic stabilization through lithium coordination. This explains the critical role of lithium in achieving a high enantioselectivity. Isotope-labeling experiments using 10B-enriched 1,1-diborylalkanes (S)-49 further supported this mechanism, showing a stereoinvertive

• addition mechanism. In this pathway, the chiral α-borylalkylcopper intermediate approaches from the face opposite to the leaving group, consistent with the observed stereochemical outcome. To explore the stereochemical origins and examine the mechanistic influence of the lithium benzoate additive

• energy compared to (S,S)-TS9. Both transition states demonstrated a lithium center's coordination involving bromide, benzoate, and ligand oxygen atoms. The (S,R)-TS8 transition state exhibited a significantly shorter Li–Br interaction distance (2.81 Å compared to 3.74 Å in (S,S)-TS9), offering