Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• -carboxamide-1,4-benzodiazepin-5-ones when enantiopure (S)-(−)-α-methylbenzylamine and arylglyoxals were used. Thus, a reversal of diastereoselectivity was observed depending on the cyclization methodology employed, the reduction of a nitro group or the Staudinger/aza-Wittig on azide derivatives. This

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• cyclisation of alkenyl N-tosylamides using BF3-activated aryl iodane(III) carboxylates to create 3-fluoropiperidines [35]. The challenges faced relate to selectivity due to competing carboxyaminations (18, 18’), rather than fluoroamination (17, 17’), and difficulties in controlling the diastereoselectivity

• aminofluorination using BF3·Et2O with a chiral aryliodide 16 catalyst (Scheme 20) [44]. The study successfully obtained various chiral fluorinated oxazine products 38 with high enantioselectivity (up to >99% ee) and diastereoselectivity (up to >20:1 dr). Control experiments showed that using Py·9HF or Et3N·3HF as

• HVI reagent has also shown to dictate the regioselectivity of the reaction. Future research efforts should focus on further developing access to new heterocycles, as well as designing better systems to incorporate high levels of diastereoselectivity and enantioselectivity into chiral halogenated

Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• to be the determining step for the enantioselectivity, while the diastereoselectivity is mainly induced by the chiral alkylated naphthol intermediate in the second annulation step (Scheme 46). Xu et al. [80] realized asymmetric [4 + 1] cyclization of yne-allylic esters with pyrazolones. This

A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• oxidation strategy to obtain α-chlorosulfoxides from sulfides using hydrochloric acid as a bifunctional reagent [22]. This strategy accommodates a broad range of substrates and offers high diastereoselectivity and regioselectivity. Several LSF modifications of amino acids and pharmaceutical derivatives

• . Additionally, pyrrolidine, anazepane, and morpholine scaffolds successfully underwent the reaction. Another notable feature of this method is its high diastereoselectivity. All products were ultimately obtained as p-toluenesulfonic acid salts (Scheme 27). In 2021, Zhang et al. developed an electrochemical

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• 8d exhibited an enhancement in reaction diastereoselectivity, resulting in the isolation of product 11d with a dr of 6.7:1 in favor of the trans-diastereoisomer. Remarkably, the formation of a fully substituted quaternary center was possible, as observed for the product 11g, where the trans

• the diastereoselectivity of the nucleophilic attack of the β-lactam on the radical cationic intermediate was influenced by stereoelectronic factors. Compounds unsubstituted at position C-3 of the β-lactam ring, 11d–h, showed modest stereoselectivity with a higher dr (6.7:1) for compound 11d, which has

• an electron-donating methoxy group on the phenyl substituent. Derivatives with a 3-OTBS side chain, 12c–e, displayed moderate diastereoselectivity, except for the higher diastereoselectivity achieved for 12f (dr 20:1), probably due to steric effects, albeit at the expense of a reduced isolated yield

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

• indicated DMSO as the best for the attainment of high yields and diastereoselectivity (entries 1–5 vs 6 in Table 4), we further examined bases in this solvent to find out that t-BuOK behaved nicely, and the reaction of 2b with 2.0 equiv of diethyl malonate for 0.5 h at room temperature furnished 93% yield

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• were achieved exclusively (dr > 20:1) in good yields (83% and 89%) and enantioselectivity (96% and 90%). On the other hand, the reactions with (Z)-crotyldioxaborinane 30 resulted in lower yields (33% for 32 and 61% for 34). However, the diastereoselectivity towards the syn products remained notably

• high (9:1 and >20:1), along with impressive enantioselectivity levels (92% and 98% ee). A slight loss of diastereoselectivity in the reaction of the PMP-imine with (Z)-crotyldioxaborinane 30 was attributed to the spontaneous isomerisation of the imine to the cis-isomer. The crotylboronates were

• (DHQ)2PHAL catalyst 138 has been identified as the most efficient that afforded high yield and enantioselectivity with a 10 mol % loading. The diastereoselectivity was 20:1 or better in most cases and was found to be independent of the reaction conditions. The optimised protocol involved stirring 1

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• of interest is the selectivity (either enantio- or diastereoselectivity), which is predicted as the difference in energies between the selectivity-governing transition states ∆∆G‡ (Figure 3). Whereas the application of the above described representations and models to such problems is rather modern

Electrochemical allylations in a deep eutectic solvent

• Sophia Taylor and
• Scott T. Handy

Beilstein J. Org. Chem. 2024, 20, 2217–2224, doi:10.3762/bjoc.20.189

• more substituted end (gamma addition) was the major product in both cases, although alpha addition was also observed. In the case of crotyl bromide, no diastereoselectivity was noted for the gamma product. Non-allylic halides such as benzyl bromide, propargyl bromide, and ethyl bromoacetate (Table 3

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• from curcumins and arylidenemalonates is reported. This strategy works in the presence of aqueous KOH using TBAB as a suitable phase transfer catalyst at room temperature. The functionalized cyclohexanones are formed as major products in moderate to excellent yields with complete diastereoselectivity

• in most cases. A triple Michael adduct, tetrahydrochromen-4-one, is also formed as a side product in a few cases with excellent diastereoselectivity. Keywords: arylidenemalonates; curcumins; cyclohexanones; diastereoselective synthesis; Michael reaction; tetrahydrochromenones; Introduction There is

• –acceptor with nitroalkenes, resulting in multi-substituted cyclohexanones through a cascade inter–intramolecular double Michael addition process with high diastereoselectivity [26][27]. Subsequently, the enantioselective versions of the above reaction and a similar diastereoselective cascade Michael

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• considering the diastereoselectivity observed when enantiopure (S)-α-methylbenzylamine was used as chiral component in the two-step syntheses from amine surrogates [22], we assayed our new strategy to achieve a one-pot diastereoselective synthesis of benzodiazepinones 6 (Scheme 2, Table 2). Interestingly, the

• single diastereomer (Scheme 5, Table 3), while N-phenylglycine afforded the enamine derivative 10 (Scheme 6, Table 4). Both structures were confirmed by single-crystal X-ray diffraction of compounds 9a and 10a (Figure 2). The diastereoselectivity observed in the hemiaminals and their stability can be

• , without purification, was treated with caesium carbonate (1 equiv) and heated to reflux for an hour. Gratefully, the dipyrrolopiperazinone derivatives 12 were obtained with high yields and complete diastereoselectivity in an efficient and simple way (Scheme 11, Table 6). The structure of these systems was

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

• phosphine-based ligand (L). This methodology was applied to the alkynol moiety of ethinylestradiol (8) (86% yield), and alkynols derived from ethisterone, levonorgestrel, lynestrenol, and epiandrosterone (epi-ADT), obtaining excellent yields (85–93%) and high diastereoselectivity (dr > 20:1) in all cases. α

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• the total synthesis of saframycin A (5) and jorunnamycin A (103), the application of a non-standard NRPS module to the synthetic substrate analogs realized the rapid construction of an appropriately functionalized complex scaffold in one pot, with precise control of regio- and diastereoselectivity

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• the 54% and 63% yield, respectively (Table 1, entries 3 and 4). We observed an increase in Norrish II fragmentation in these cases. The observed diastereoselectivity was poor, supporting the radical character of the ring-closing event. A similar trend was observed when studying the methanesulfonyl (Ms

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• -3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity. The reaction was finished by in situ generation of activated 5-(alkylimino)cyclopenta-1,3-dienes from addition of alkyl isocyanide to two molecules of but-2-ynedioates and sequential formal [3 + 2] cycloaddition

• -aza-1,3-butadienes [40][41][42][43][44]. Recently, we have found that the three-component reaction of isoquinolines, dialkyl but-2-ynediaotes and 5,6-unsubstituted 1,4-dihydropyridines afforded functionalized isoquinolino[1,2-f][1,6]naphthyridines in good yields and with high diastereoselectivity via

• diastereoselectivity of the reaction, the concerted addition process is much more likely. However, it is difficult to distinguish between these two reaction processes at present. Conclusion In summary, we investigated the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• , epiandrosterone, hecogenin, rockogenin, and tigogenin. All of them were successfully converted into boronic esters with high diastereoselectivity. In 2021, Cook and co-workers [45] unveiled the photomediated trifluoromethylation of alcohols by converting alcohols into thiocarbonates (Scheme 8). This copper

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• benzophenones 22a,b in moderate yields (Scheme 8) [38]. Again, no trend was observed depending on the structure of the chromones. 1,3-Bis(silyloxy)-1,3-butadienes The reaction of 11a–c with 1,3-bis(silyloxy)-1,3-butadienes 6a–h, catalyzed by Me3SiOTf, afforded products 23a–j with excellent diastereoselectivity

• -(trifluoroacetyl)chromone (14a) with 1,3-bis(silyloxy)-1,3-butadienes proved not to be successful in our hands. However, reaction of 3-(trifluoroacetyl)thiochromone (31) with 1,3-bis(silyloxy)-1,3-butadienes 6a,b, in the presence of Me3SiOTf, afforded products 32a,b with excellent diastereoselectivity (Scheme 16

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• spiropyridazine-benzosultam 3aa with 10% yield and high diastereoselectivity (Table 1, entry 2). Encouraged by this result, we tested several solvents to determine their effect on the [4 + 2] annulation reaction. Acetonitrile showed the best result, providing the highest yield (Table 1, entries 3–7). We also

• was tested, resulting in the expected spiropyridazine-benzosultams 3ab–al in good to excellent yields with high diastereoselectivity. For N-benzoyl hydrazones 2b–g, the electronic effect of R3 group on the [4 + 2] annulation reaction was significant. Electron-withdrawing groups gave relatively higher

Construction of diazepine-containing spiroindolines via annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates

• Xing Liu,
• Wenjing Shi,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1923–1932, doi:10.3762/bjoc.19.143

• satisfactory yields and with good diastereoselectivity (reaction 3, Scheme 1) [57]. Very recently, we found that the base-catalyzed [4 + 3] cycloaddition reaction of isatin-derived MBH carbonates with various α,β-unsaturated N-arylaldimines affords spiro[indoline-3,5'-pyrrolo[3,4-b]azepine] derivatives

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

• diastereoselectivity ratio with exo/endo21/20 = 1.9 nearly doubled. The same was true for the enantioselectivity, which increased from 23% ee for control 20 to 55% ee for anion–π catalyst 21. These results were in support that stabilization of the intrinsically disfavored exo transition state VII on the polarizable

• ) to 2-chloroacrylonitrile (29) was selected (Figure 5) [68]. In the presence of 5 mol % of the best fullerene catalyst 21, conversion into dicyanide 30 reached 72% within 5 days at ambient temperature [67]. While enantioselectivity was negligible, dr 5.3:1 was the best diastereoselectivity among all

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• diastereoselectivity is caused by the different R2/R2’ and R3/R3’groups which no longer have the same stereochemistry as that shown in Scheme 8. Double cycloadditions for bis[spirooxindole-pyrrolizidine] compounds After completing the pseudo-five-component double cycloaddition reactions leading to polycyclic

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• only they demonstrate that the oxygen-promoted 1,4-addition of α-(aminomethyl)acrylates with free N–H bonds is a productive process, but also that the tert-butanesulfinyl moiety is well tolerated and that 1,4-stereoinduction can be achieved. Hence, in order to improve the levels of diastereoselectivity

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• diastereoselectivity (dr > 99:1) was observed in the reaction of chiral ketones. Hoveyda and co-workers [82] employed two types of NHC–Cu(I) complexes to catalyze the protoboration of terminal allenes to obtain vinylboranes (Scheme 60). A set of alkyl- and aryl-substituted allenes was used as substrates. The

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• terminal alkynes at room temperature (Scheme 15a) [67]. The ability to tune the reactivity of the trityl ion rationally improves the approach with excellent regio- and diastereoselectivity for the unsymmetric ethers. In 2018, Ye et al. reported a CDC reaction to form C(sp)–C(sp3) coupling products from

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• last step involves the enamine intermediate which drives an intramolecular aldol condensation to form the final product 5. In this elegant cascade process, catalyst 1 promotes three consecutive carbon–carbon bond forming steps generating four stereogenic centers with high diastereoselectivity and