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

• encumbered tricyclic lactone 84 via an intramolecular [6 + 2] cycloaddition (Scheme 8). Attempts to achieve an asymmetric version of the cycloaddition were unsuccessful. Treatment of the lactone with MeMgBr, followed by mesylation and elimination of the resulting hemiacetal, afforded enol ether 85. Reaction

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

• core, successfully completing the first asymmetric total synthesis of ryanodol (4) in 41 steps. To elucidate the role of the C15 hemiacetal hydroxy group in ryanodine (1)-type diterpenoid natural products in binding to ryanodine receptors, the authors initially proposed reducing the lactone moiety in

• anhydroryanodine (not shown) to the corresponding hemiacetal. However, common reducing agents proved ineffective for lactone reduction. Leveraging previous findings, the authors implemented an alternative strategy involving two sequential intramolecular reductive cyclizations to invert the configuration of the C3

• conditions induces the first intramolecular reductive cyclization, affording hemiacetal 27. This intermediate is then transformed via a one-pot sequence involving epoxidation, fragmentation, and re-epoxidation to give epoxide 29. A second intramolecular reductive cyclization of 29 under Li/NH3 forms the

Ex-situ generation of gaseous nitriles in two-chamber glassware for facile haloacetimidate synthesis

• Nikolai B. Akselvoll,
• Jonas T. Larsen and
• Christian M. Pedersen

Beilstein J. Org. Chem. 2025, 21, 2465–2469, doi:10.3762/bjoc.21.188

• used building blocks in glycosylations. For the synthesis chamber (A) was loaded with trifluoroacetamide (6 equiv) in pyridine. In the other chamber (B), the hemiacetal (ca. 500 mg, 1 equiv) was dissolved in CH2Cl2 together with a catalytic amount of DBU. Upon addition of trifluoroacetic anhydride

• turned out to be unsuccessful as the reaction seemed to achieve an equilibrium, with some amount of hemiacetal left. Generally, it was observed that the trifluoroacetimidates were somewhat more sensitive to flash column chromatography, suggesting a higher reactivity compared to the trichloroacetimidates

• transformation of the peracetylated glucose hemiacetal 2 in the other chamber (B), giving 73% isolated yield of the corresponding acetimidate 6 (Figure 2). Similarly, the chlorodifluoroacetimidate 7 was synthesized in 79% yield. From these reactions it is clear that the less reactive (disarmed) peracetylated

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

• Friedel–Crafts reaction. Next, the cyclohexadienone moiety could be activated by an acid to undergo a rearrangement reaction to provide eupomatilone. The exocyclic THF ring might exist as diverse forms such as hemiacetal, acetal, lactone or acetal-linked dimer. The (hemi)acetal moiety could generate an

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• 153 and 154 to give the corresponding esters 44 and 152 driven by MeOH attack (Scheme 47) [87]. Hu and co-workers (2021) developed an N-doped carbon black-supported PdBi bimetallic catalyst (Pd5Bi5/NCB) for the oxidative esterification of cinnamyl alcohols via hemiacetal 156 oxidation (Scheme 48A) [88

• ]. A similar reaction, reported by Zheng and co-workers (2020) utilized a graphene-supported Au/Pd catalyst to achieve the aerobic oxidative esterification of cinnamyl alcohol 157 via oxidation of the hemiacetal embedded in the catalyst surface 158 to obtain the corresponding ester 44 in quantitative

• yield (Scheme 48B) [89]. Furthermore, Doris and co-workers (2019) also utilized a Au catalyst for oxidative esterification reactions. Herein, Au nanoparticles supported on carbon nanotubes (AuCNT) catalyzed the conversion of cinnamyl alcohol 157 to the corresponding ester 44 via hemiacetal-anchored on

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• aldehydes and phenols. The mechanism involves the reaction of the azide with the hemiacetal XLII generated in situ from the aldehydes and alcohols, followed by coupling with the alkynes to form the triazole ring. Both, copper triflate and copper metal are essential for the success of the reaction. On the

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• order to lead to the expected fluorinated tetrahydropyridazines (Figure 4). Results and Discussion First, the difluoro- and trifluoromethylated hydrazones 3a–f were synthesized by condensing the corresponding hydrazide with the fluorinated aldehyde hemiacetal 2a or 2b (Scheme 2). Benzyl and tert-butyl

• Supporting Information File 30: Experimental procedures, product characterization, X-ray analysis and copies of NMR spectra. Acknowledgements The authors gratefully acknowledge Central Glass Co. for the gift of trifluoro- and difluoroacetaldehyde hemiacetal.

Synthesis of tricarbonylated propargylamine and conversion to 2,5-disubstituted oxazole-4-carboxylates

• Kento Iwai,
• Akari Hikasa,
• Kotaro Yoshioka,
• Shinki Tani,
• Kazuto Umezu and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2024, 20, 2827–2833, doi:10.3762/bjoc.20.238

• anhydride, the intermediately formed hemiacetal underwent acetylation, leading to N,O-acetals 1. In this method, an acid amide can be used as an amine masked with an acyl group. Subsequent elimination of acetic acid occurred to afford 2 in situ upon treatment with a base, enabling nucleophilic addition with

• molecule on this cation, followed by tautomerism (path a). The intramolecular attack of an amide carbonyl on this cationic site in intermediate 10, leading to the formation of oxonium ion 11, is also possible (path b). After the addition of water, the formed hemiacetal 12 was hydrolyzed to give the

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• keto function of the hydrazone moiety and the open-chain hemiacetal or aldehyde hydrate in Brønsted acid medium to access 1H-imidazo[5,1-c][1,4]oxazine derivatives (Scheme 1) [21]. Considering that the hydrazone function at C-4 of 4a–r may exist in a tautomeric equilibrium with the corresponding ene

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

• transformation of the aryl glyoxals is outlined below (Scheme 4), which depicts the coordination of the hemiacetal B with the metal catalyst to give C, followed by hydride transfer to form the metal-coordinated Cannizzaro product D. Another intramolecular asymmetric Cannizzaro reaction was reported by Wu et al

• nickel(II) complex 96 to the same basic conditions resulted in the formation of the Cannizzaro adduct hemiacetal Ni(II) complex 97 in 56–65% yield predominantly with the byproduct 98 in less than 5% yield (Scheme 26) [93]. Schmalz and coworkers transformed 2-formylarylketones 99 into 3-substituted

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• formation of a hemiacetal intermediate in gilvocarcin biosynthesis [9][38][39] and the AlpH-catalyzed ʟ-glutamylhydrazine adduct formation [14]. Notably, this C12 hydroxy group is absent in the quinone intermediate 3 of the cofactor-dependent pathway. Collectively, these observations suggest that the

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• during chromatography, and so an alternate method was developed to generate a single product by promoting the formation of the hemiacetal series 12a–f. Following the rearrangement reaction, chromatography of the chlorides using silica with 2% water added led to the isolation of 12a,c–f in good yield

• open chain aldehydes present in solution (≈5%) with a doublet at δ 9.6 ppm, with the configuration of the hemiacetal centre confirmed in the solid state by X-ray crystallography on 12a and 12d. The 1H and 13C NMR spectra for 13b,d,e were similar to the starting materials, except that the resonances

• small amounts of the C2 epimers. Oxidation of the hemiacetal 12a gave a moderate and unoptimised yield of 40% for lactone 24. The probable mechanism for the transformation with SOCl2 and under Appel conditions is shown in Figure 2. The reaction of alcohol 10 with the electrophiles gives the

Isolation and structure determination of a new analog of polycavernosides from marine Okeania sp. cyanobacterium

• Kairi Umeda,
• Naoaki Kurisawa,
• Ghulam Jeelani,
• Tomoyoshi Nozaki,
• Kiyotake Suenaga and
• Arihiro Iwasaki

Beilstein J. Org. Chem. 2024, 20, 645–652, doi:10.3762/bjoc.20.57

• )/δC 206.9 (C-9) connected C-11 and C-8 through a ketone carbonyl carbon at C-9 and hemiacetal carbon at C-10, revealing the 16-membered macrolide structure of 1. The HMBC, δH 4.27 (H-1’)/δC 85.3 (C-5), revealed that the disaccharide moiety was connected to C-5. Finally, considering the molecular

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• equivalents to react with various nucleophilic reagents [90]. In 2014, Heimgartner et al. first developed the condensation reaction of a commercially available fluoral hemiacetal with acylhydrazides to yield trifluoromethylated acylhydrazones, and these fluorinated compounds underwent heterocyclization

Visible-light-induced nickel-catalyzed α-hydroxytrifluoroethylation of alkyl carboxylic acids: Access to trifluoromethyl alkyl acyloins

• Feng Chen,
• Xiu-Hua Xu,
• Zeng-Hao Chen,
• Yue Chen and
• Feng-Ling Qing

Beilstein J. Org. Chem. 2023, 19, 1372–1378, doi:10.3762/bjoc.19.98

• acyloins (Scheme 1a). Anand’s group [25] demonstrated that a NHC-catalyzed selective acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal afforded the analogous products (Scheme 1b). In comparison, the synthesis of trifluoromethyl aliphatic acyloins is still

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• allylic alcohol isomerization in 137 resulting in the aldehyde 138. This aldehyde, in close proximity to the tertiary alcohol, leads to the production of the hemiacetal 139 which can finally undergo an oxidation producing the final bicyclo[2.2.2]lactone product 136. In 2011, the Radhakrishnan laboratory

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• . Alongside this, H-B-9-BBN underwent reduction of the ester or lactone 57, to give a hemiacetal intermediate 58, which underwent B‒O/B‒H transborylation with HBpin to give an O-Bpin hemiacetal 59. Borane-mediated collapse of the O-Bpin hemiacetal gave an aldehyde 60 which reacted with the O-Bpin enolate 52

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• acetone and water to a hemiacetal that can decompose to 11 (Scheme 4B) [43]. Furthermore, 1 shows an interesting photochemistry (Scheme 4C). A [2 + 2] cycloaddition of the endocyclic double bonds yields 12 whose formation is understandable from conformers 1c and 1d. The all-cis stereoisomer 14 requires a

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• , as measured by the disappearance of olefinic signals, was immediate upon addition of base and a compound assigned as 9a appeared. The major intermediate was assigned as the hemiacetal 9a rather than ketone 9, due to the 0.31 ppm upfield shift for H5 (δ 4.83 ppm, CD3OD) relative to known ketone 9 (δ

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• the cyclic hemiacetal 9 in modest yield (Scheme 2). Therefore, compound 8 was protected as silyl or benzyl ether using standard techniques. Unfortunately, no hydrolysis under several basic conditions provides the target ketone, no conversion and/or decomposition being observed (Scheme 3). Enol

• diastereomers. Therefore, we decided to oxidize the acetal in 23 to the corresponding lactone (Scheme 9). The acetal was first hydrolyzed to the hemiacetal 24 in quantitative yield. Oxidation of 24 proved delicate due to the lability of the tertiary allylic alcohol, and the presence of acid-sensitive protecting

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

• manner. MaCYP71CD2 is a bifunctional CYP that hydroxylates C23 and additionally introduces a C24–C25 epoxide on the side chain of tirucalla-7,24-dien-3β-ol (19), yielding dihydroniloticin (20). MaCYP71BQ5 then oxidises the methyl group C21 to a formyl group, leading to spontaneous hemiacetal ring

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• oligosaccharides having multiple α-glycosidic linkages by AGA [171]. Additional strategies include the dehydrative glycosylation of glucosyl hemiacetal [172] or the halide-catalyzed in situ anomerization of glucosyl iodide donors that yielded α(1–6)-hexaglucans [173]. The halide-catalyzed in situ anomerization

• donors to synthesize fully deacetylated COS up to 12mer. After each glycosylation step, the 4-methoxyphenyl group at the anomeric position was oxidatively removed and the resulting hemiacetal was transformed into the trichloroacetimidate glycosyl donor for the next glycosylation step [252]. An orthogonal

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

• /hemiacetal avoiding undesirable elimination to the enamine, or attack at other electrophilic sites in complex substrates. The presence of a fluorine source like diethylaminosulfur trifluoride (DAST) or the Lewis acid boron trifluoride diethyl etherate (BF3·OEt2) result in the formation of reactive iminium or

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• mixture of E/Z isomers. Further, double bond cleavage of nucleoside 120 followed by benzoylation produced the benzoic acid ester of the hemiacetal analogue 121 which was finally converted into double-headed nucleoside 122 via Vorbrüggen coupling reaction followed by deprotection using methanolic ammonia

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• . These observations are consistent with the recently reported instability of O-acylated GlcNAc under basic conditions due to elimination reactions of transient hemiacetal intermediates [38]. This instability of amino sugar hemiacetals underscores the requirement to both protect the anomeric position with

• thioacetic acid [54][55]. Hence, the hemiacetals were reacted with thioacetic acid in pyridine to give acetamides 49–58 (Scheme 5) and the target trifluoro analogs 59 and 60. Reversing the order of hemiacetal and acetamide formation was not an option because NBS-promoted hydrolysis of 2-acetamido