Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• due to the energetically favorable dissociation of Mo(CO)n into Mo(CO)n−1 which was proven to be a highly exothermic reaction in the presence of metal catalysts especially after the dissociation of the first CO group [23]. It should be noted that the best overall yield for the synthesis of 4a using

Synthesis of the 3’-O-sulfated TF antigen with a TEG-N₃ linker for glycodendrimersomes preparation to study lectin binding

• Mark Reihill,
• Hanyue Ma,
• Dennis Bengtsson and
• Stefan Oscarson

Beilstein J. Org. Chem. 2024, 20, 173–180, doi:10.3762/bjoc.20.17

• TEG-N3 spacer attached is described. The synthesis of the TF antigen comprises seven steps, from a known N-Troc-protected galactosamine donor, with an overall yield of 31%. Both the spacer (85%) and the galactose moiety (79%) were introduced using thioglycoside donors in NIS/AgOTf-promoted

• following acetylation without purification of the intermediate, why the synthesis is high-yielding (20% overall yield) and easily scalable (9 g of protected disaccharide 7 and 1 gram of target 2 were synthesized). Experimental General methods All reactions containing air- and moisture-sensitive reagents

N-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N–H insertion reaction

• Grigory Kantin,
• Pavel Golubev,
• Alexander Sapegin,
• Alexander Bunev and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 1841–1848, doi:10.3762/bjoc.19.136

• the Rh2(esp)2 in both electronic and steric factors (see Supporting Information File 1). When Rh2(OAc)4 (1 mol %) was used, a 1.7:1 ratio of 6a/9a insertion products was observed, which is not much different from the result obtained with Rh2(esp)2. However, the overall yield of insertion products

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• yield to 25%. Reducing the amount of hydrazine hydrate to 3 equivalents (EtOH, reflux, 2 h) had a similar effect and gave an 85:15 mixture of 5 and 6 in an overall yield of 22%. In refluxing MeOH (3 equiv of N2H4∙H2O, 2 h), a mixture of 5 and 6 in a ratio of 89:11 was obtained in 31% overall yield. In

Radical chemistry in polymer science: an overview and recent advances

• Zixiao Wang,
• Feichen Cui,
• Yang Sui and
• Jiajun Yan

Beilstein J. Org. Chem. 2023, 19, 1580–1603, doi:10.3762/bjoc.19.116

• polymerization. The use of a solvent can lower the viscosity of the polymerization system, leading to better mass and heat transfer. Good heat transfer can reduce the Trommsdorff–Norrish effect [22]. Meanwhile, the inhibited termination reactions cause a significant increase in the overall yield

Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

• Tzu-Yu Huang,
• Mario Djugovski,
• Sweta Adhikari,
• Destinee L. Manning and
• Sudeshna Roy

Beilstein J. Org. Chem. 2023, 19, 1545–1554, doi:10.3762/bjoc.19.111

• -difluoroalkenes and the co-elution of the aniline byproducts during column chromatography with the desired products affected the overall yield of the reaction. For a complete optimization list with all conditions that were screened, see Supporting Information File 1. With the optimized conditions in hand, we

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• concentration. HMF was then directly used in the Knoevenagel condensation with rhodanine in Pro/Gly yielding product 3j in 72% yield. The overall yield for this two-step process was 36%. As some of the products have already been described in the literature, we compared our results with the reported conditions

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

Linker, loading, and reaction scale influence automated glycan assembly

• Marlene C. S. Dal Colle,
• Manuel G. Ricardo,
• Nives Hribernik,
• José Danglad-Flores,
• Peter H. Seeberger and
• Martina Delbianco

Beilstein J. Org. Chem. 2023, 19, 1015–1020, doi:10.3762/bjoc.19.77

• scale [19], and linkers [20][21] affect the overall yield of solid phase peptide synthesis (SPPS). In the past decades, several supports and linkers have been developed and commercialized for SPPS, enabling a wide range of applications. Solid supports are available with different linker loadings, with

• to the glycan structure, with minimal variations such as presence or absence of a linker playing an important role in the post-AGA process. In some cases, performing post-AGA manipulations on resin dramatically improved the overall yield of the process. Future efforts need to focus on the development

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• explain why at lower onium salt amount and shorter reaction times the diastereoselectivities are higher but at the expense of the overall yield. With the optimized reaction conditions in our hands, we next explored the scope of the domino reaction. Structurally diverse onium compounds 2 were tested to

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• -catalyzed conjugate addition and subsequent trapping of the zinc enolate by acylation or aldol reaction with an overall yield of 71–78% and good stereoselectivity (Scheme 57) [105][106][107]. Recently, Poock and Kalesse demonstrated the first total synthesis of halioxepine, a meridoterpene isolated from the

• contains six contiguous stereogenic centers out of which four are all-carbon quaternary stereocenters. The authors have achieved the stereoselective synthesis of waihoensene for the first time with a 3.8% overall yield (15 steps) (Scheme 59). The construction of the triquinane core included a Cu-catalyzed

• by the trapping of the metal enolate with Vilsmeier–Haack reagent. This way, the β-chloroaldehyde 143 was isolated in 69% yield and 92% ee. Further transformation of this compound resulted in the taxol core in only 4 steps with 11% overall yield while retaining the correct stereochemistry introduced

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups

• Ita Hajdin,
• Romana Pajkert,
• Mira Keßler,
• Jianlin Han,
• Haibo Mei and
• Gerd-Volker Röschenthaler

Beilstein J. Org. Chem. 2023, 19, 541–549, doi:10.3762/bjoc.19.39

• (5). This compound was synthesized smoothly within three steps in 16.6% overall yield. The synthetic route commenced from the preparation of N-protected amine 3, followed by the deprotection of benzylamine 3 to furnish 4 and ended with the diazotization of 4 using tert-butyl nitrite. As a result, the

Mechanochemical solid state synthesis of copper(I)/NHC complexes with K₃PO₄

• Ina Remy-Speckmann,
• Birte M. Zimmermann,
• Mahadeb Gorai,
• Martin Lerch and
• Johannes F. Teichert

Beilstein J. Org. Chem. 2023, 19, 440–447, doi:10.3762/bjoc.19.34

• ]. First, the silver(I)/NHC complex 4 had to be synthesized and isolated prior to transmetallation with copper(I) chloride [48][49]. The required formation of silver(I) complex 4 diminishes the overall yield of copper complex 5. As an additional disadvantage, the silver(I) byproducts have to be carefully

Asymmetric synthesis of a stereopentade fragment toward latrunculins

• Benjamin Joyeux,
• Antoine Gamet,
• Nicolas Casaretto and
• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 428–433, doi:10.3762/bjoc.19.32

• reduced on its primary carbon in presence of LiAlH4, and the resulting secondary alcohol was oxidized in presence of Dess–Martin periodinane (DMP), giving ketone 15 in 78% yield over the two steps. This six-step sequence to 15 was performed in a 35% overall yield from starting material 10. The aldehyde

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• compound 2 in an overall yield of 25% after 5 steps, bypassing the macrolactonization problem evidenced in the previously envisaged route. Intrigued by the problem encountered by Boger, Deshpande decided to investigate different reaction conditions for the formation of the macrocycle using the Mitsunobu

• , and the formal synthesis of 2 was achieved after 8 steps with an overall yield of 4.5%. Rychnovsky and Hwang hypothesized that the low yields from the Mitsunobu reaction in the previous synthesis of compound 2 were linked to the instability of the allylic oxyphosphonium ion formed with intermediates

• acetic anhydride followed by epoxidation using m-CPBA gave protected epoxide 50. Subsequent removal of the acetate group using ammonia led to racemic compound 1 (Scheme 8). Rychnovsky and Hwang succeeded in the total syntheses of combretastatin D-2 (2) in a 36% overall yield after 13 steps and

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• reaction and was subjected to deprotection of the triisopropylsilyl group with tetra-n-butylammonium fluoride (Bu4NF). Similarly triad 121 was prepared by the click reaction between dyads 119 and azido-ferrocene 120 in a 40% overall yield. The photophysical investigation revealed that dyad 119 exhibited

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• in two steps from known ʟ-ribitol 1 [34] in good overall yield. Next, it was converted to the C-5 deoxygenated N-benzylpyrrolidine 6 via trityl ether cleavage, tosylation of the deprotected OH group, and reduction of the tosylate 5. Hydrogenolysis of the N-benzyl group in 6 followed by a removal of

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• note, this compound entails the oxabicyclo[4.2.1]nonane core present in schindilactone A (68). The synthesis of schindilactone A (68) was achieved in 29 steps (0.11% overall yield). 1.1.2.2 Late-stage introduction of cyclooctene: The marine sesquiterpene dactylol (72), isolated from both sea hare

• protection of the alcohol function as a silyl ether leading to diene 71, the RCM was performed in refluxing hexane and dactylol (72) was isolated in 17% overall yield after silyl ether removal [18][37]. Asteriscanolide (2), isolated in 1985 from the hexane extract of the plant Astericus aquaticus, is a

• , the total synthesis included 24 steps, with an overall yield of 5% and 4% for albolic acid (178) and ceroplastol II (179), respectively. To synthesize these 3 complex natural products, they used the same method to access the [5-8-5] tricyclic advanced intermediate 184. After that, different strategies

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• analogues, whereas the variation of the acyl chlorides did not affect the reaction significantly. The synthetic application is demonstrated by formation of non-natural and natural dienone-containing terpenes such as β-ionone which was available in 4 steps and 6% overall yield. Keywords: cross coupling

• the alkyne terminus significantly decreased the yield. Finally, non-natural and natural dienone-containing terpenes were synthesized such as β-ionone (3), which was available in 4 steps (6% overall yield). Thereby, the synthetic utility was demonstrated by a late-stage introduction of the dienone unit

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• at room temperature to form the expected Diels–Alder adduct 32, while non-cyclic vinyl disulfones require heating to 80 °C for 20–48 h. Deoxygenation of the epoxide and desulfonylation with sodium amalgam affords barrelene (33) in an excellent overall yield from oxepin. The chlorinated 1,4-dithiin

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• effect (Table 3, entry 3). We then investigated longer reaction times (4 × 50 min, 4 × 0.500 mmol), but without additional electrolyte the overall yield of 38% was significantly lower. It was possible to compensate for this to some degree by using TBABF4 as shown in Table 3, entry 2. This adjustment

• improved the overall yield to 43%. Finally, we investigated a variety of substituted benzyl acetates 3 (Figure 1). Substitutions para to the iodine led with F- and Cl-derivatives 1b and 1c to strongly diminished yields of 15% and 26%, respectively, due to expected lower yields in the Friedel–Crafts step

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• the latter, which is proven in the number of steps and the overall yield, hence establishing it as highly appealing for further development (Scheme 1). In order to identify the new pharmaceutical leads of tomorrow, drug discovery relies on the available chemical space rising from existing chemical

• chiral aldehyde 127 and Boc-protected amine 128, followed by zinc reduction of the nitro group and subsequent protection of the amine by a tosyl group in 27% overall yield. Irradiating 129 with blue light at 30 W in the presence of 1 mol % of [Ir(dtbbpy)(ppy)2]PF6 and 5 equiv of KHCO3 in THF resulted in

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

• required. Luo's team used Davis’ oxaziridine followed by treatment with K2CO3 to equilibrate the hydroxyketone, delivering an inseparable epimeric mixture (1:3) of 63 in 31% overall yield. An additional TBS protection allowed separation of the epimers. After acidic treatment, pure rhodomollein XX and 3-epi

• -membered triflate 71 was synthesized from diketone 26 in 5 steps and 37% overall yield. Both fragments were assembled by a Sonogashira cross-coupling, affording 72 in 72% yield. In a first attempt, TBS protection was considered on the bicylo[3.2.1]octane. However, later in the strategy, the deprotection

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

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

• Raphael Bereiter,
• Marco Oberlechner and
• Ronald Micura

Beilstein J. Org. Chem. 2022, 18, 1617–1624, doi:10.3762/bjoc.18.172

• desired triamine 9. After cyclization of the resulting 4-ethoxy-2,3,6-triaminopyridine (9) with formic acid leading to ethyl-protected compound 10 and liberation of the O6 with hydrogen bromide, 1-deazaguanine (11) was formed in 2 to 4% overall yield (Scheme 2) [18]. The approach by Gorton and Shive

• was carried out to obtain the desired 4-hydroxy-2,3,6-triaminopyridine (15) in unspecified yield (Scheme 3). This approach was optimized in 1975 by Schelling and Salemink using benzyl ether protection of the O4 during the imidazopyridine formation to increase the overall yield up to 37% [20]. The last

• attempt to refine the synthesis of Gorton and Shive, was described by Temple and co-workers in 1976 by their preparation of 1-deaza-6-thioguanine analogues with 28% overall yield [21]. Synthesis of 1-deazaguanine Our route to 1-deazaguanine 11 started from 6-iodo-1-deazapurine (16) (Scheme 4), which can