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

• projected by Lei’s group as the common scaffold for the divergent synthesis of this class. Finally, the closely related congener 90 [43] was envisaged to originate by a radical rearrangement of the common scaffold 88. Initially, Lei’s group unfolded the synthesis of 83 on a decagram scale, utilizing an

• properties, such as potent inhibition of 11-β-hydroxysteroid dehydrogenase type I and inhibition of Candida albicans [48]. Although earlier syntheses have been reported recently for magninoids [50][51], Lou’s group envisioned a divergent plan based on a late-stage bioinspired semipinacol rearrangement

• a semipinacol rearrangement leading to 95, followed by subsequent cyclization to natural products guignardone A (96) and C (97). This process involved 1,2-allyl migration and C–O bond formation through a semipinacol rearrangement and a cyclodehydration cascade reaction (Scheme 8). Following the same

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• oxidative anionic oxy-Cope rearrangement of the tertiary alcohol arising from the 1,2-addition of a 1,3-dimethylallyl reagent to 2,5-cyclohexadienone connected to the α’-methoxy-γ-pyrone motif. Keywords: α’-methoxy-γ-pyrone; 2,5-cyclohexadienone; oxy-Cope; quaternary carbon; Robinson-type annulation

• -dimethylallyl motif to 5 giving 17, followed by the anionic oxy-Cope rearrangement of the dienol into cyclohexenone 18. After desaturation, the resulting 2,5-cyclohexadienone 19 would provide a modular platform to construct the side chain of the target and analogues. Note that this updated route required the

• desired 1,2-adduct 17 in 50% yield [41]. To perform the anionic oxy-Cope rearrangement, alcohol 17 was exposed to t-BuOK, in the presence of 18-crown-6 ether (−78 °C to rt) [42]. However, these conditions did not trigger the rearrangement and the starting material was recovered. On the other hand

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• group where an immobilized lipase (e.g., CALB) facilitated the derivatization of high-boiling benzyl alcohol in scaled Curtius rearrangement reactions. Ultimately, this approach negated the use of column chromatography in favor of a simple trituration process to isolate pure carbamate products [106

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

• , olefin, ketone or epoxide functionalities. From a biosynthetic point of view, grayananes arise from an oxidative rearrangement of the ent-kaurane skeleton (Scheme 1). The diversity is generated by cytochromes P450 (CYP) enzymatic oxidation of the grayanane skeleton [17]. The biological activities and low

• converted to 3 through a 6-step sequence involving reduction of the aromatic ring and oxidation of the enone to a dienone. The resulting dienone 3 underwent a key photoinduced santonin-like rearrangement in the presence of acetic acid, furnishing 4 in high yield. It should be noted that the group of Hiraoka

• had previously reported a similar rearrangement for the synthesis of a grayanane-type skeleton [21]. Further methylation and protecting group interconversions lead to an advanced tricyclic structure 5, which could be further elaborated into relay intermediate 1. Although Matsumoto’s approach does not

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• insertion of carbenes derived from diazo arylidene succinimides (DAS) into the O–H bond of phenols is described. The initial adducts underwent a thermally promoted Claisen rearrangement followed by DABCO-catalyzed intramolecular 5-exo-trig oxa-Michael addition. Keywords: Claisen rearrangement; diazo

• 50 °C for 12 h, underwent the Claisen rearrangement to give diastereomerically pure maleimide 4a in 4% yield [15]. While for our study at the time the formation of 3 and 4 were viewed as a minor side-reaction, later be started pondering the possibility of giving the observed transformation a stronger

• impetus from the synthetic point of view. Specifically, we wanted to see if Rh(II)-catalyzed insertion of DAS-derived carbenes could be performed into the O–H bond of phenols and if the resulting phenoxy-substituted succinimides 5 could also undergo a Claisen rearrangement. The products of the latter (6

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

• through different formations of the 1-deazapurine heterocycle. The syntheses of the diethyl 2,6-pyridinedicarbamate precursors via Curtius rearrangement, however, involved explosive chelidamyl diazide intermediates 3 (Scheme 1) [18][19]. Markees and Kidder used an ethyl protection for the O6 and described

• (H-C(8)), 149.08 (H-C(4)), 160.86 (H-C(6)); ESIMS (m/z): [M − H]− calcd for 134.04; found, 134.03. Syntheses of C4-substituted diethyl 2,6-pyridinedicarbamates 4, passing hazardous and explosive diacylazide intermediates 3 that are required for Curtius rearrangement in the final step [19]. Synthesis

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• , the breaking of the C–C bond of intermediate 7 led to the generation of the expected final product 4a through retro-one reaction. It was also shown that the side product, 1-benzyl-4,5-dimethyl-1,3-dihydro-2H-imidazol-2-one (8) was formed from 1a through simply thermal rearrangement. Nucleophilic

An alternative C–P cross-coupling route for the synthesis of novel V-shaped aryldiphosphonic acids

• Stephen J. I. Shearan,
• Enrico Andreoli and
• Marco Taddei

Beilstein J. Org. Chem. 2022, 18, 1518–1523, doi:10.3762/bjoc.18.160

• commercially available and can often be difficult to prepare. Most often, the challenge is, in fact, not the synthesis of the phosphonic acid itself, but that of the phosphonic ester precursor [21]. Perhaps the most well-known C–P coupling procedure is the Michaelis–Arbuzov rearrangement involving a reaction

Synthesis of meso-pyrrole-substituted corroles by condensation of 1,9-diformyldipyrromethanes with pyrrole

• Baris Temelli and
• Pinar Kapci

Beilstein J. Org. Chem. 2022, 18, 1403–1409, doi:10.3762/bjoc.18.145

• , which is an acid-catalyzed rearrangement of the substituent in intermediates of the condensation reaction. The structures of the meso-pyrrole substituted corroles were identified by using 1H NMR, 1H,1H-COSY NMR and HRMS techniques (see Supporting Information File 1). The 1H NMR spectrum of 2a is shown

Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme

• Jia-Hua Huang,
• Jian-Ming Lv,
• Liang-Yan Xiao,
• Qian Xu,
• Fu-Long Lin,
• Gao-Qian Wang,
• Guo-Dong Chen,
• Sheng-Ying Qin,
• Dan Hu and
• Hao Gao

Beilstein J. Org. Chem. 2022, 18, 1396–1402, doi:10.3762/bjoc.18.144

• stereogenic centers at C2, C6, C10, and C14 introduced during the two cyclization steps, FC-type diterpene synthases (DTSs) could be divided into 16 subtypes [20]. Furthermore, considering the modes of potential carbocation rearrangement and final carbocation quenching, there might be more FC-type DTSs in

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• presence of another ligand (like C-Raf) leads to rearrangement of binding of AIE-molecules around a target protein (like 14-3-3ζ), and thus to differences in fluorescence, we have a mechanism that can possibly be exploited in analytical applications. Experimental Energy grids To compute a map of affinities

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• Achmatowicz rearrangement [18]. Addition reactions of nucleophiles to the C–O double bond of furfurals represent an obvious synthetic approach to 2-furyl carbinols. We reasoned that for carbinols derived from C3-triorganosilyl-substituted furfurals, the OH unit could be exploited to assist C–Si bond

• alkoxides We first contemplated the possibility to promote C3–Si bond functionalization through intramolecular activation by alkoxides [15]. It was reported that lithium alkoxides A undergo 1,4-silyl migration (Brook rearrangement) to generate C2-lithiated furans C, which in turn can react in the presence

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• . Oxidation of the latter compound to the α-keto-β-hydroxy ester IV using DMDO and subsequent heating in PhCF3 triggered an α-ketol rearrangement which led to ketol V. Diastereoselective reduction gave α,β-dihydroxyester 35 which was converted to (−)-jiadifenoxolane A (36) in five further steps. Palau’amine

• of an α-ketoester through Riley oxidation and its use in an α-ketol rearrangement in the synthesis of (−)-jiadifenoxolane A (36) [15]. Azomethine imine cycloaddition towards the synthesis of the proposed structure of palau’amine (44) [19]. Intramolecular diastereoselective carbonyl-ene reaction of an

Lewis acid-catalyzed Pudovik reaction–phospha-Brook rearrangement sequence to access phosphoric esters

• Jin Yang,
• Dang-Wei Qian and
• Shang-Dong Yang

Beilstein J. Org. Chem. 2022, 18, 1188–1194, doi:10.3762/bjoc.18.123

• Herein, we report a Lewis acid-catalyzed Pudovik reaction–phospha-Brook rearrangement sequence between diarylphosphonates or -phosphinates and α-pyridinealdehydes to access valuable phosphoric ester compounds. This transformation provides an extended substrate scope that is complementary to similar

• previously reported base-catalyzed transformations. Keywords: Lewis acid; phospha-Brook rearrangement; phosphoric esters; Pudovik reaction; Introduction Phosphoric esters are widely used in agrochemistry, biological sciences, clinical treatments, as well as in general organic transformations [1][2][3][4][5

• with highly air-sensitive and hazardous phosphorus halides, with the assistance of a suitable base [19][20][21][22][23][24]. As an alternative pathway, the phospha-Brook rearrangement [25][26][27][28][29][30] represents a green approach to phosphoric esters since it uses α-hydroxyphosphonates, which

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• homophthalimides 8 [10][11][12]. We reasoned that a similar strategy could be adopted for the preparation of 1,2,4-trisubstituted 1,4-DHIQs 9 if access to their diazo precursors 10 was gained. N-Sulfonyl analogs of compounds 10 have recently been synthesized via an innovative Dimroth rearrangement of 4

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH₄/I₂ system

• Lin Chen,
• Xuan Zhou,
• Zhiyong Chen,
• Changxu Wang,
• Shunjie Wang and
• Hanbing Teng

Beilstein J. Org. Chem. 2022, 18, 1032–1039, doi:10.3762/bjoc.18.104

• for carboxylic acids, the carbon source is the carboxyl group. When carboxylic acids were used, the carboxyl moiety was first converted to an isocyanate via Curtius rearrangement [82][83][84][85], then reacted with imidazole to form the carbonylimidazole, and eventually reduced to the methyl moiety

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• enzyme VlmA [18]. This intermediate is hypothesized to be transformed into the azoxy bond-containing intermediate via an intramolecular rearrangement accompanied by a concomitant oxidation [18]. Although the exact mechanisms of azoxy bond formation remain unclear, VlmH and VlmA cooperate to biosynthesize

• the case of azodyrecin biosynthesis. The mechanism for the subsequent rearrangement of the ester intermediate for azoxy bond formation remains unclear; however, the conservation of the two hypothetical proteins Ady6/Ady8 among the biosynthetic gene clusters of valanimycin, KA57-A, and azodyrecins may

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• ) probably undergoes rearrangement, decarboxylation, methylation reaction, and further modification to generate compounds 1 and 2. Conclusion S. sp. KIB-H1544 was isolated from the rhizosphere soil of Datura stramonium L. Two novel diarylcyclopentenones daturamycins A and B and one new p-terphenyl

Molecular diversity of the base-promoted reaction of phenacylmalononitriles with dialkyl but-2-ynedioates

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 991–998, doi:10.3762/bjoc.18.99

• -carboxamides with unprecedented rearrangement of the alkyl group [34] (reaction 4 in Scheme 1). Inspired by these novel reactions and in continuation of our aim to develop domino reactions of electron-deficient alkynes [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], we have investigated the

Electroreductive coupling of 2-acylbenzoates with α,β-unsaturated carbonyl compounds: density functional theory study on product selectivity

• Naoki Kise and
• Toshihiko Sakurai

Beilstein J. Org. Chem. 2022, 18, 956–962, doi:10.3762/bjoc.18.95

• 2 and subsequent rearrangement to 3 are also discussed. In particular, the latter mechanism was studied using density functional theory (DFT) calculations and it was suggested that the ΔG for the cyclization step of an intermediate enolate anion determines the product selectivity. Results and

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• method to synthesize 1,2-azaphospholidine 2-oxide derivatives 13. Arylphosphinyl azides generate arylphosphinyl nitrenes under photoirradiation. The phosphinyl nitrenes underwent an intramolecular insertion into the ortho C–H bond of the aryl group accompanied with the Curtius-like rearrangement as well

Efficient production of clerodane and ent-kaurane diterpenes through truncated artificial pathways in Escherichia coli

• Fang-Ru Li,
• Xiaoxu Lin,
• Qian Yang,
• Ning-Hua Tan and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2022, 18, 881–888, doi:10.3762/bjoc.18.89

• cyclase) act on geranylgeranyl diphosphate (GGDP) to perform regio- and stereoselective cyclizations or skeleton rearrangement reactions via carbocation chemistry to form diverse and versatile carbon skeletons; and ii) multiple post-modification enzymes, most often cytochrome P450s, decorate the carbon

• ]. In the biosynthesis of terpentetriene, GGDP was first cyclized by a class II DTS (Cyc1) that contains a conserved DxDD motif to form terpentedienyl diphosphate (TDP) via a syn-labda-13-en-8-yl+ diphosphate intermediate (Figure 2), which, prior to deprotonation, can be followed by rearrangement to

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• achieved within milliseconds initializing bromine–lithium exchange of bromochloromethane to generate (chloromethyl)lithium. This carbenoid species readily reacts with terpenyl pinacol boronates 17, resulting in the formation of intermediate 18, which undergoes 1,2-anionotropic rearrangement to the

• homologated pinacol boronate 19. As the rearrangement is a much slower process, the reaction mixture is passed through a second reactor at elevated temperature with a residence time of 9 s to allow full conversion to the homologated pinacol boronate 19. This species can then be directly pumped to a second

• rearrangement resulting in the formation of thymol (41) along with its regioisomers 42 and 43. However, using an excess of isopropanol and a relatively low concentration of the organic substrates in scCO2 (5% w/w), thymol (41) is produced in a good yield (72%) and selectivity (92.2%) as shown by GC

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

• Timur O. Zanakhov,
• Ekaterina E. Galenko,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2022, 18, 738–745, doi:10.3762/bjoc.18.74

• derivatives of 4-oxo-1,4-dihydropyridine-3-carboxylic acid 2 via Mo(CO)6-mediated rearrangement of methyl 2-(isoxazol-5-yl)-3-oxopropanoates 1 (Scheme 1). Results and Discussion Based on our experience of using isoxazoles in the synthesis of heterocyclic compounds [14][15][16][17][18], we hypothesized that

• rearrangement of methyl 2-(isoxazol-5-yl)-3-oxopropanoates 1. High yield transformations of compound 2 provide easy access to 2,4,6-triaryl-substituted and 1,2,5,6-tetrasubstituted nicotinates. Approaches to the synthesis of alkyl 4-oxo-1,4-dihydropyridine-3-carboxylates. Synthesis of 4-oxo-1,4-dihydropyridine

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• technologies microwave and flow were combined are the Dimroth rearrangement exemplified for the conversion of 1,3-thiazine 3 to the corresponding 3-substituted hydropyrimidine 4 (Scheme 7, reaction 1) [48]. A noteworthy example was recently published by Organ and co-workers [49]. A three-component reaction of

• temperature of the nanostructured particles (Figure 4B). The Claisen rearrangement of the electron-deficient aryl allyl ether 9 was chosen to compare the versatility and performance of inductive heating with conventional and microwave heating (Scheme 8A) [50]. The effectiveness of inductive heating is clearly

• at 110–160 bar to form the O-allyl phenol which was heated in a second reactor to 265 °C where the Claisen rearrangement under near-critical conditions occurred to yield 2-allyl-4,6-difluorophenol (12) in 64% yield. In this example, the two reactors made of steel were heated directly by the external