Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• -alkenyl β-ketoamides 16, in yields ranging from 74% to 94%, in excellent enantiomeric excess (up to 98% ee), and in modest to poor diastereoisomeric ratios (dr up to 70:30). The authors observed that the nature of the activator had a substantial influence on the reaction enantio- and diastereoselectivity

• cascade aza-Michael addition/olefin hydroalkylation reaction between N-tosylallylamines and α,β-unsaturated ketones using a catalytic system of a gold(I) complex and a silver salt [45]. The spiro compound 25, which was obtained in moderate yield and with poor diastereoselectivity after a 20 h reaction

• diastereoselectivity in the synthesis of bicyclic compounds (dr > 20:1, Scheme 19, 37d, 37e, and 37g). Substrates containing Lewis base moieties (Scheme 19, 36k) were tolerated in the reported reaction conditions, thereby representing a synthetic gain over other olefin isomerization methodologies. An important feature

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• diastereoselectivity (cis/trans ratio = 1:99). The preferential formation of the trans-configured products for furan nucleophiles may be due to the fact that the addition of furan is reversible leading to equilibration to the more stable trans product. To test this hypothesis, we monitored the reaction by HPLC (Table

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• Re-face of the imine (Scheme 4) [1][36]. The nucleophilic addition reactions to N-tert-butanesulfinyl imines were also described by Ellman and co-workers who reported the addition of allylmagnesium bromide to ketimines. The employment of Grignard reagents showed greater diastereoselectivity than

• reactions using organolithium and organocerium compounds. In some examples, the use of organolithium is feasible through the use of aluminum-derived additives [15]. In this study, the influence of solvents on diastereoselectivity was also observed. They found that the reactions performed in noncoordinating

• solvents, such as toluene and dichloromethane, took place with high diastereoselectivity. However, solvents such as ether and THF had a negative impact on stereoselectivity [15]. On the other hand, recent studies developed by Sirvent and Foubelo demonstrated the influence of the solvents in both the yield

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• diastereoselectivity. The carbamate substituent adopted the axial disposition in the proposed transition state 145, as shown in Scheme 34 [69]. In another report by Rychnovsky and Gisinsky, two of the tetrahydropyran rings of the potent molluscicide cyanolide A were synthesized via a silyl-Prins cyclization and

• mixture of cis- and trans-220 (dr = 4.1:1.0). It was explained that the diastereoselectivity of the product depends on the size of the substituent. For example, when the substituent is sterically small, it occupies the pseudoaxial position in the reactive conformation 218 (Scheme 52). Li et al. utilized

• allylic geminal bissilyl alcohol 221 for the construction of THP ring A of (−)-exiguolide via Prins cyclization with an aldehyde in the presence of Lewis acid as a promoter [95]. High yield and excellent diastereoselectivity were obtained under standard silyl-Prins cyclization conditions using TMSOTf as

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• for all dioxygenated amides 9 the stereocenter at the alkoxyamine unit will be destroyed in the subsequent radical reaction, the low diastereoselectivity at that center is not of concern. In contrast, in the reactions of silylamides 8e–g bearing enantiomerically pure 1-arylethyl substituents with

• enantiomerically pure (S)-propylene oxide ((S)-7b) the dioxygenated amides (2R,4S)-9i–k were predominately formed with 3:1 anti/syn diastereoselectivity in the radical coupling with TEMPO irrespective of the aryl substituent (Table 2, entries 9, 11, and 12), whereas the sequence of amide 8e with (R)-propylene

• oxide ((R)-7b) provided the product (2S,4R)-9i in a much better 8:1 anti/syn coupling diastereoselectivity (Table 2, entry 10). The configuration of the major anti-diastereomer of alkoxyamine 9j was determined by X-ray crystallography after desilylation and hydrochloride formation (see Supporting

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• -dioxaphospholane-4,5-dicarboxylate (168) gave the corresponding phosphonodepsipeptides 169 in 65–86% yields under mild conditions. Although the diisopropyl ester was applied instead of diethyl ʟ-tartrate, a low diastereoselectivity (ratios varied from 55:45 to 67:33) was observed as well. Acetophenone (170

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• levels of diastereoselectivity (Scheme 48). Further development by Brigaud et al. allowed the synthesis of CF3-substituted pseudoprolines structurally related to oxazolidines 194 and 195 [124]. Viehe et al. also contributed by developing the chloroalkylamino reagent 199, bearing a geminal CF3 group

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• majority of the substituents on the aryl group of the nitrostyrenes 1. However, a higher diastereoselectivity towards the endo-isomer was observed when strong electron-withdrawing groups (EWGs) were present in the dienophile. For example, in the case of the 4-cyano and the 3-nitro-substituted derivative

Au(III) complexes with tetradentate-cyclam-based ligands

• Ann Christin Reiersølmoen,
• Thomas N. Solvi and
• Anne Fiksdahl

Beilstein J. Org. Chem. 2021, 17, 186–192, doi:10.3762/bjoc.17.18

• ) catalysis of the cyclopropanation reaction, where complex 5a-Au(III) and 6a-Au(III) gave full conversion in 1 hour and 12 hours, respectively (Table 1, entries 4 and 5). The cyclopropyl product 11 was obtained in >90% yield and high cis diastereoselectivity (up to 74% de), similar to our previous studies

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• standard Ugi–azide reaction conditions [35][36][37][38][39] in a one-pot, tandem process. Subjecting glucose-derived lactam 1 to such a procedure gave the desired product in good yield, but with virtually no diastereoselectivity, as shown in Scheme 2. Optimization and scope An initial optimization study

• highest yield and diastereoselectivity, thus were chosen as optimal (Table 1, entry 9.). We also tried to isolate the imine after the reduction step and carry out the second step in a solvent commonly used for the Ugi–azide reaction alone. For this, we observed a significant decrease in overall yield and

Selective and reversible 1,3-dipolar cycloaddition of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones under microwave irradiation

• Alexander P. Molchanov,
• Mariia M. Efremova,
• Mariya A. Kryukova and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2020, 16, 2679–2686, doi:10.3762/bjoc.16.218

• investigated using only convection heating. The aim of the current work is to investigate the regio- and diastereoselectivity of the microwave-assisted (3 + 2) cycloaddition of 6-aryldiazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones. Results and Discussion Herein, we report the 1,3-dipolar

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

• Ziyi Li,
• Li Wang,
• Yunqi Huang,
• Haibo Mei,
• Hiroyuki Konno,
• Hiroki Moriwaki,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2020, 16, 2671–2678, doi:10.3762/bjoc.16.217

• )-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine. The reactions were conducted under operationally convenient conditions affording the corresponding Mannich adducts with up to 87% yield and 70:30 diastereoselectivity. The isomeric products can be separated using regular column chromatography to

• diastereoselectivity. First, a series of pilot experiments in dichloromethane were performed to scan the base in the reaction. When using LDA and LiHMDS instead of n-BuLi, the yields were noticeably increased to 83% and 87%, respectively (Table 1, entries 2 and 3). In particular, the use of LiHMDS resulted in improved

• diastereoselectivity (69:31 dr, Table 1, entry 3). On the other hand, the solvent was found to show a significant effect on this transformation (Table 1, entries 4–6) and the results indicated dichloromethane was the best choice. Variation of the loading amount of 1-ethynyl-4-methoxybenzene (2a) did not provide any

Hierarchically assembled helicates as reaction platform – from stoichiometric Diels–Alder reactions to enamine catalysis

• David Van Craen,
• Jenny Begall,
• Johannes Großkurth,
• Leonard Himmel,
• Oliver Linnenberg,
• Elisabeth Isaak and
• Markus Albrecht

Beilstein J. Org. Chem. 2020, 16, 2338–2345, doi:10.3762/bjoc.16.195

• measurement of the yield and the diastereoselectivity was possible by NMR spectroscopy. The nitro-Michael reaction of 3 equivalents propanal (14) and β-nitrostyrene (15) with 25 mol % of 13a-H2 after 2 days at room temperature resulted in 45% yield of product 16 and a nearly 1:1 diastereomeric ratio (Table 2

• [(13b)1(5)5Ti2], but did not lead to a control of enantioselectivity. A reasonable diastereoselectivity of 60% de was observed for both catalysts. The limited solubility of these complexes caused a significant reduction of the yield at room temperature and due to this the reaction was not performed at

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• conjugated nitroolefins in the presence of a chiral Ni(II) complex to give nitro keto phosphonates with two stereocenters with excellent enantioselectivity and moderate to high diastereoselectivity. These products were used for a reductive cyclization leading to pyrrolidin-3-ylphosphonic acid and for

• to the possibility of creating enantiomerically pure compounds with several stereocenters through the directed regulation of diastereoselectivity in subsequent transformations, which can be realized as stepwise or cascade processes. Due to this reason, the Michael reaction was successfully used over

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• yield and high enantioselectivity (Scheme 7) [15][16]. The Achmatowicz oxidation and ionic reduction generated the enone 58, which is regioisomeric with 53. The 1,4-addition of lithium dimethylcopper gave the desired cis-55 with high a diastereoselectivity (25:1). The cross-metathesis of 55 with 3

• with a 6:1 diastereoselectivity. The Red-Al reduction of 94, protection of the 2° alcohol, and reduction of the enoate to an allylic alcohol were prerequisites for the stereoselective 2,3-sigmatropic selenoxide rearrangement to generate 95. Further protecting group manipulation and Johnson–Lemieux

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• equiv of NMO, yielding bicyclic derivatives 19 in moderate yields and high diastereoselectivity (de > 95%). The observed diastereoselectivity was rationalized considering two transition states of the PKR, and assuming the CF3 group occupies an axial position due to the steric and electrostatic

• )8 followed by the addition of NMO), and starting from the pure anti diastereoisomer of 1,7-enyne 20, the expected bicyclic enone was obtained in good yield and high diastereoselectivity (de > 95%). An attempt to extend the PKR to the formation of a fused tricyclic structure, starting from 1,7-enyne

• -propargyl-N-[2-(trifluoromethyl)allyl]amides 24 were treated with dicobalt octacarbonyl to afford the cobalt alkyne complex, which was then heated in CH3CN. Under these conditions, trifluoromethylated cyclopentenone 25a was obtained in high yield (81%) and diastereoselectivity (anti/syn = 94:6) (Scheme 11

NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides

• Alyn T. Davies,
• Mark D. Greenhalgh,
• Alexandra M. Z. Slawin and
• Andrew D. Smith

Beilstein J. Org. Chem. 2020, 16, 1572–1578, doi:10.3762/bjoc.16.129

• tolerated, giving a consistent diastereoselectivity of ≈75:25 dr (Scheme 2). Following chromatographic purification, the desired products 12–14, respectively, were isolated in 59–71% yield as single diastereoisomers with excellent enantioselectivity (95:5 to >99:1 er). The relative and absolute

One-step route to tricyclic fused 1,2,3,4-tetrahydroisoquinoline systems via the Castagnoli–Cushman protocol

• Aleksandar Pashev,
• Nikola Burdzhiev and
• Elena Stanoeva

Beilstein J. Org. Chem. 2020, 16, 1456–1464, doi:10.3762/bjoc.16.121

• -one [28] and benzo[a]quinolizin-4-one [27], respectively, in moderate yields. Attempts by Krasavin et al. showed that isoquinoline itself demonstrated modest reactivity and diastereoselectivity in reactions with thiodiacetic anhydride (8) [12]. It can be concluded that due to their stability the

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• both (R) and (S)-isomers, and 1,1-diphenylethene (216c) under UV irradiation. As the products spirothietane-pyrrolidinones 320 were obtained in 65–89% yield. The diastereoselectivity was controlled by the steric effect of the ortho-substituents on the phenyl ring [88] (Scheme 59). The intermolecular

• photochemical [2 + 2] cycloaddition reaction was performed both in benzene solution and in the solid state, affording 78% yield with a ratio of syn/trans 8.7:1 and 61% de for syn-isomers at 15 °C in crystals, while no diastereoselectivity could be observed in benzene solution [16] (Scheme 72). In 2001, they

Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

• Carlos H. Escalante,
• Eder I. Martínez-Mora,
• Carlos Espinoza-Hicks,
• Alejandro A. Camacho-Dávila,
• Fernando R. Ramos-Morales,
• Francisco Delgado and
• Joaquín Tamariz

Beilstein J. Org. Chem. 2020, 16, 1320–1334, doi:10.3762/bjoc.16.113

• materials, which were accompanied by a decomposition residue. In contrast, maleimides 7b and 7c reacted efficiently to furnish the respective endo/exo adducts 9a–d/10a–d in good to high endo diastereoselectivity and yields (Table 2, entries 1–4). The cycloaddition with 7c led to the best selectivity (vide

• diffraction crystallography of both endo 9m and exo 10m adducts (Figure 2) [43]. In addition, the thermal cycloadditions of 2-vinylpyrroles 8a–j and maleimides 7b,c took place satisfactorily to deliver the expected adducts 9e–p/10e–p, also with high endo diastereoselectivity and good yields (Table 2, entries

• . Accordingly, the R2 substituent in the diene would play an important role in directing the endo/exo orientation of the approach to the maleimide at the transition state (TS). Therefore, the endo diastereoselectivity is apparently not controlled by the presence or the absence of the substituent bonded to the

Synthesis of 3-substituted isoxazolidin-4-ols using hydroboration–oxidation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles

• Lívia Dikošová,
• Júlia Laceková,
• Ondrej Záborský and
• Róbert Fischer

Beilstein J. Org. Chem. 2020, 16, 1313–1319, doi:10.3762/bjoc.16.112

• -hydroxypyrrolidines certainly makes the 4-hydroxyisoxazolidines important and valuable structural fragments in drug discovery. Keywords: 2,3-dihydroisoxazoles; diastereoselectivity; heterocycles; hydroboration–oxidation; isoxazolidin-4-ols; Introduction 2,3-Dihydroisoxazoles (often referred to as 4-isoxazolines

Ferrocenyl-substituted tetrahydrothiophenes via formal [3 + 2]-cycloaddition reactions of ferrocenyl thioketones with donor–acceptor cyclopropanes

• Grzegorz Mlostoń,
• Mateusz Kowalczyk,
• André U. Augustin,
• Peter G. Jones and
• Daniel B. Werz

Beilstein J. Org. Chem. 2020, 16, 1288–1295, doi:10.3762/bjoc.16.109

• were formed with complete diastereoselectivity, leading to a single isomer. In order to establish the structure of the isomers, a single crystal obtained for compound 9c was studied by X-ray diffraction analysis which showed, that the Ph(C-2) group and Fc(C-5) substituent were mutually cis-oriented

• (Figure 1). Tentatively, the same configuration was also attributed to all tetrahydrothiophenes 9a,f–l that were formed as single isomers (Table 1). However, the diastereoselectivity changed in reactions that were conducted with alkyl ferrocenyl thioketones 8d–e with 5a. Thus, the reaction with 8d led to

• these observations it was difficult to explain the complete diastereoselectivity of tetrahydrothiophene formation observed in the reactions of aryl ferrocenyl-substituted thioketones 8a,c,f with cyclopropanes 5a–f bearing aryl groups. Tentatively, a repulsive interaction of aryl groups rather than

Diversity-oriented synthesis of 17-spirosteroids

• Benjamin Laroche,
• Thomas Bouvarel,
• Martin Louis-Sylvestre and
• Bastien Nay

Beilstein J. Org. Chem. 2020, 16, 880–887, doi:10.3762/bjoc.16.79

• structures due to the poor diastereoselectivity of the Diels–Alder reaction in this case. Finally, we expect to apply this strategy to complementary reactions like the Pauson–Khand reaction that may be useful to cyclize enyne substrates like 5–7 and expand the spirosteroid diversity. All compounds will be

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• , and could even be extended to functionalized sulfonyl cyanides, though providing lower yields. In every case, the diastereoselectivity was high (dr > 19:1:1) and in favor of the all-trans-product. Conclusion In this review, we summarized the photophysical properties of aromatic aldehydes and the

Efficient synthesis of dipeptide analogues of α-fluorinated β-aminophosphonates

• Marcin Kaźmierczak and
• Henryk Koroniak

Beilstein J. Org. Chem. 2020, 16, 756–762, doi:10.3762/bjoc.16.69

• studies, the Pudovik reaction worked with satisfactory yield and diastereoselectivity [30]. Unfortunately, we were not able to isolate the pure anti-isomer in every case. The latest research shows that this reaction can successfully be carried out under milder conditions, without any solvent and in the

• presence of a weak base [33]. After testing many modifications, it turned out that the use of triethylamine (1 equiv) as a base, and without a solvent, gave the best results with aldehydes 4 (1 equiv) and diethyl phosphite (1 equiv). These conditions not only increased the diastereoselectivity of the