Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

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

• catalysts, this group found that the intramolecular oxa-Michael addition using 20 mol % of the diarylprolinol organocatalyst 37 in the presence of benzoic acid gave 38. The use of the enantiomer of 37 gave the dihydropyran with the opposite configuration at C-11. The catalytic hydrogenation of 38 proceeded

• iodine-catalyzed Mukiyama–Michael addition of the ketene silyl acetal 104 to 103 afforded the trans-1,5-disubstituted tetrahydropyranone 105. After the generation of the C-3-exocyclic olefin and functional group manipulation, the Takai olefination [40] of the aldehyde 106 gave the trans-vinyl iodide 107

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

• nucleophilic addition, the authors suggested the tentative mechanism depicted in Scheme 34. As shown, γ-fluoride loss from enolate I, formed after the conjugate Michael addition, would lead to the formation of difluoroenone II. This could in turn undergo a nucleophilic addition of water, followed by a retro

Recent synthesis of thietanes

• Jiaxi Xu

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

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• the C=C double bond of maleimides was reported [96]. The iminoxyl radicals were detected by EPR spectroscopy, but the non-radical mechanism (copper-catalyzed Michael addition) can not be excluded completely. Application of the oxime radicals in organic synthesis: intramolecular reactions There are two

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• precursors affords both enantiomers Δ-10 (from CuClO4) and Λ-10 from (Cu(CH3CN)4PF6). UV–vis and circular dichroism spectroscopic studies evidence that the helical chirality exhibited by these two catalysts could be reversed by redox stimuli. These complexes could perform enantioselective Michael addition

• trifluoromethylation of heteroaromatics with redox-active iminosemiquinone ligands. Reversal of helical chirality upon redox stimuli and enantioselective Michael addition with a redox-reconfigurable copper catalyst. Interaction of guanidine-copper catalyst with oxygen and representative coupling products. a4 mol

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• dienyne precursors in three steps, from (S)- and (R)-citronellal, through a diastereoselective Michael addition, chemoselective dibromoolefination, and a one-pot Wittig olefination/alkyne-bond formation. The enantiopure dienynes were then converted into the enantiomeric hydroazulenes in 53% and 55% yield

• enantiopure trienyne or diene–diyne metathesis precursors were readily obtained from (S)-citronellal by a highly diastereoselective organocatalytic Michael addition. Erogorgiaene An exceptionally stereoselective synthesis of erogorgiaene (12) (95% E-selectivity) was reported by Hoveyda et al. [80]. They

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• hydroxylamine was added to compound 11 in methanol, and a predominant polar spot was observed by TLC. However, the isolated product was not the expected TOI1, as 1H NMR revealed two new peaks at δ 4.53 and 2.66 ppm (Supporting Information File 1, Figure S36) presumably indicating that a favorable Michael

• addition followed by intramolecular cyclization or vice versa provided compound 12, which was validated by 13C and DEPT NMR studies (Supporting Information File 1 Figures S37and S38). Marred with these observations, compound 11 was treated with aqueous hydroxylamine in the presence of strong base (i.e., 10

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• -anchored indole-5-carboxylic acid was successful during the homogeneous two-phase alkenylation reaction. Subsequently, during its removal from the support under alkaline conditions, N-alkylation occurred through a Michael addition to the acrylate 2a, followed by the formation of the methyl ester of the 5

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• results with α-bromocarboxylic acid derivatives 167 substituted with Oppolzer’s camphor sultam, which provided carboxylated products 168 in good yield (80%) and excellent diastereomeric ratio (98:2) (Scheme 53). The same group reported an electrocatalytic Michael addition of chiral acetoacetic derivatives

• diastereoselective Michael addition reactions [103][104]. The glycine–nickel complex 184 was deprotonated using a radical anion generated from the electrochemical reduction of azobenzene. The anionic Ni complex 185 acted as a good C-nucleophile towards Michael acceptors 186 resulting in diastereoisomeric mixtures of

• 187 and 187'. Moreover, the modified Ni-complexes obtained after Michael addition could be easily decomposed using HCl in MeOH, releasing functionalized amino acid 189 along with the quantitative recovery of the chiral auxiliary (S)-BPB 188 (Scheme 59). Recently, Kise’s group reported an efficient

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

• conjugated to a cystein residue of serum albumin via a Michael addition reaction. At the same time, it is well known that 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin and its chlorin derivatives generate singlet oxygen by the light irradiation under atmospheric oxygen [31]. These tetrapyrrole macrocycles

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• Strukturchemie, Universitätsstraße 1, D-40225 Düsseldorf, Germany 10.3762/bjoc.15.262 Abstract Starting from substituted alkynones, α-pyrones and/or 1H-pyridines were generated in a Michael addition–cyclocondensation with ethyl cyanoacetate. The peculiar product formation depends on the reaction conditions as

• alkynylation–Michael addition–cyclocondensation (AMAC) multicomponent syntheses of α-pyrones [23]. While most α-pyrones neither fluoresce in solution nor in the solid state specific substitution patterns have been identified for fluorophore design for this heterocyclic family. Tominaga and co-workers

• effects of base and temperature on Michael addition–cyclocondensation sequences in the formation of α-pyrones and/or 1H-pyridines starting from diversely substituted alkynones and cyanoethylacetate. This bifurcating domino process furnishes small chromophore libraries which were characterized by

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• their isolation and structural characterization are still less common. A very convenient access to such betaines is provided by the nucleophilic addition of tertiary phosphanes to electron-deficient alkenes, alkynes and allenes (phospha-Michael addition), which generates the betaines as reactive

• -catalyzed reactions of acetylenic ketones and esters with pinacolborane have been discussed [7][8]. The Michael addition of PPh3 at acetylenic carbonyl compounds generates phosphonium/vinyl anion intermediates which have been trapped with CH-, NH-, OH- and SH-acids [5]. In this manner, the 1:1:1 reaction of

• (Scheme 2). They turned out to be excellent substrates for transamidation reactions (reaction 1) [18], whereas tertiary phosphanes Ph2P–X (X = SiMe3, Cl) underwent Michael addition leading to silylphosphanylation (reaction 2) or hydrophosphorylation (reaction 3) of the C–C-triple bond, respectively [19

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• ]. Oxidation, iodocarboxylation and elimination yielded the lactone 43. A series of functional group manipulations provided enone 44, which underwent a cuprate-mediated Michael addition and liberation of the aldehyde 46 upon ozonolysis. After intramolecular aldol condensation the resulting enone 47 was

Targeted photoswitchable imaging of intracellular glutathione by a photochromic glycosheet sensor

• Xianzhi Chai,
• Hai-Hao Han,
• Yi Zang,
• Jia Li,
• Xiao-Peng He,
• Junji Zhang and
• He Tian

Beilstein J. Org. Chem. 2019, 15, 2380–2389, doi:10.3762/bjoc.15.230

• high intracellular concentration of GSH is another feature for HepG2 cells. Therefore, amounts of work on HepG2 cell imaging have targeted GSH as the characteristic biomarker [40][41]. Strategies like reduction of disulfide [42][43][44] and Michael addition [45][46][47] have been utilized to design

Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular 1,3-dipolar cycloaddition

• Yulia V. Khoroshunova,
• Denis A. Morozov,
• Andrey I. Taratayko,
• Polina D. Gladkikh,
• Yuri I. Glazachev and
• Igor A. Kirilyuk

Beilstein J. Org. Chem. 2019, 15, 2036–2042, doi:10.3762/bjoc.15.200

• and 3-nitropentane (Scheme 1). In brief, the reaction of nitrocyclohexane and acrolein in a CH3ONa/CH3OH solution afforded the corresponding nitroaldehyde 3b with a 70% yield. Of note, the Michael addition of 3-nitropentane to acrolein was accompanied by remarkable tarring and gave a much lower yield

Fluorinated azobenzenes as supramolecular halogen-bonding building blocks

• Esther Nieland,
• Oliver Weingart and
• Bernd M. Schmidt

Beilstein J. Org. Chem. 2019, 15, 2013–2019, doi:10.3762/bjoc.15.197

• ][22][23][24]. Huber and co-workers demonstrated the activation of a carbonyl group by halogen bonding, and successfully applied this concept to catalysts for Michael addition reactions [25] and also employed neutral [26], and hypervalent iodolium derivatives as activators in a halide abstraction

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• ]pyrrolidin-1-yl group [64]. The synthesis of the corresponding pyrrolidine (3S,3'R)-68 began from the aziridine (E)-acrylate (2R,1'S)-69a (Scheme 18) readily prepared from the aldehyde (2S,1'S)-6 [31]. Michael addition of nitromethane to the acrylate (2R,1'S)-69a gave an inseparable mixture (70:30) of

• -Boc-3,4-diaminopentanoic acid ((3R,4S)-155) was synthesized from the Z-acrylate (2R,1'R)-156a prepared in a highly (88:12) stereoselective olefination of the aziridine aldehyde (2S,1'R)-6 (Scheme 40) [60]. Michael addition of (S)-1-phenylethylamine to 156a gave almost pure (>99:1) β-amino ester 157

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• -benzenedicarboxylate), Puthiaraj and co-workers have unprecedently discovered the catalytic activity of this metal-organic framework (MOF) for the synthesis of imidazo[1,2-a]pyridines [100]. The three-component, one-pot reaction between 1, 3 and nitromethane (10, Scheme 5) involved an intermolecular aza-Michael

• addition with a subsequent intramolecular cyclization catalyzed by Cu(BDC)MOF. Further, the LC–MS study of the reaction mixture has shown the imine formation to be the major pathway rather than β-nitrostyrene. The reaction involved a two-step reaction mechanism in which aza-Michael adduct 13 was formed in

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• covalent inhibitor of 4-amino-4-deoxychorismate (ADC) synthase, which is the enzyme that catalyzes the conversion of chorismate and glutamine into ADC and glutamate, the first step in the biosynthesis of p-aminobenzoic acid (PABA) in bacteria [6]. Specifically, AbC binds via a Michael addition between a

• , which suggests a suitable level of structural truncation of compound 2. Further docking studies, using covalent docking, also showed that both atrop-O-benzyl-desmethyl-abyssomicin C and 2 can bind to the active site cysteine via a Michael addition to the α,β-unsaturated ketone, still maintaining the

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• diphenylbut-3-yne-1,2-dione (3a) increased from 63 to 76%. The terminal cyclization step, consisting of a Michael addition of benzoyl hydrazide (4b) to diphenylbut-3-yne-1,2-dione (3a) followed by a cyclizing addition of the central hydrazide nitrogen atom to the carbonyl group, was monitored by GC–MS and

• consecutive three-component process clearly is superior. With four bond-forming steps (activation, alkynylation, Michael addition, and cyclization) the average yield per bond-forming step accounts to 94%. With the optimized conditions of the consecutive three-component synthesis in hand (hetero)arylglyoxylic

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• University, Leninskie Gory, 1, 119991, Mosсow, Russian Federation 10.3762/bjoc.15.127 Abstract Functionally substituted sulfones with stereogenic centers are valuable reagents in organic synthesis and key motifs in some bioactive compounds. The asymmetric Michael addition of β-ketosulfones to conjugated

• ; Michael addition; nickel complexes; nitroalkenes; Introduction Sulfones are widely used in organic synthesis, particularly, in various reactions of C–C and C=C-bond formation [1][2][3][4]. The use of sulfones in Julia–Kocienski [1] and Ramberg–Bäcklund reactions [2] made this class of compounds

• acids are attached to 1,2-disubstituted α,β-unsaturated sulfones in the presence of the Rh/(S,S)-chiraphos catalytic system. Modern methods for the synthesis of functionalized sulfones, with stereocenters in the side chain, by Michael addition are based, mainly, on the use of vinyl sulfones as Michael

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• asymmetric Michael addition of n-butanal to β-nitrostyrene that was used as a model reaction. This work supports the potential of multicomponent reactions towards the assembly of catalysts and their simultaneous functionalization for immobilization. Keywords: flow chemistry; heterogeneous catalysis

• solvents and conditions. As PFA-supported catalyst 3 proved more effective than 4, a comprehensive screening of solvents was carried out for the asymmetric Michael addition catalyzed by 3. This study showed that the yield can be increased up to 90% using isopropanol (Table 1, entry 9), while the

• material by β-nitrostyrene (50 times as residence time calculated) limits the formation of the Michael product and, consequently, lowers the chemical efficiency. Despite the good level of diastereocontrol in Michael addition (dr 95:5 syn/anti), a little drop in the enantioselectivity was observed (i.e., 74

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• ) [21][22]. While these methods give access to highly substituted products, the requirement for a strong base could jeopardize their application in the context of synthesis of complex molecules. Furthermore, an electron-withdrawing group must be present on 18 to enable the Michael addition with thiol 14

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• electrophilic oligodeoxynucleotides (ODNs) was achieved using dimethyl-Dmoc (dM-Dmoc) as amino protecting group. Due to the high steric hindrance of the 2-(propan-2-ylidene)-1,3-dithiane side product from deprotection, the use of excess nucleophilic scavengers such as aniline to prevent Michael addition of the

• that contain electrophilic groups. However, at the current state of art one drawback of the technology is that large excess aniline has to be used as a scavenger to prevent the deprotection side product 1 from reacting with the deprotected ODNs via Michael addition. Aniline is a weak nucleophile, but

• aniline is needed to induce the β-elimination (see Scheme 1) and to prevent the side product 1 from reacting with the deprotected ODN via Michael addition [40]. Aniline is a weak base and only mildly nucleophilic. Electrophiles that are compatible with ODNs but reactive toward it are rare. However, using

Switchable selectivity in Pd-catalyzed [3 + 2] annulations of γ-oxy-2-cycloalkenones with 3-oxoglutarates: C–C/C–C vs C–C/O–C bond formation

• Yang Liu,
• Julie Oble and
• Giovanni Poli

Beilstein J. Org. Chem. 2019, 15, 1107–1115, doi:10.3762/bjoc.15.107

• hour) generated annulated product 4a arising from C-allylation (C–C bond forming)/intramolecular O-Michael addition (O–C bond forming) sequence. The purification of the crude reaction was easier using the Pd(OAc)2 and dppb system (Table 1, entry 2), which was thus chosen to continue the optimization