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

• their anti-inflammatory activity (see Section 3). Reaction of compounds 166 and 167 gave the corresponding diaryl ether 168, which was converted to phenol 169 using a Baeyer–Villiger oxidation reaction followed by hydrolysis. Subsequent phenol allylation reaction followed by Claisen rearrangement led to

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• allene 14, giving a boryl diene 16. A Cope rearrangement of the boryl diene 16 followed by transborylation gave the dienyl boronic ester 18 and regenerated the catalyst (Scheme 5). Chang reported the alkoxide-promoted hydroboration of N-heteroarenes with HBpin, the first explicit example of a B‒N/B‒H

• ‒N/B‒H transborylation with HBpin to regenerate BH3 and give the N-Bpin-indoline product 27; 2) two molecules of H2B-N-indoline underwent rearrangement to regenerate BH3 and gave a bisindolinylborane 28. The bis-N-indolinylborane then underwent B‒N/B‒H transborylation with HBpin to regenerate H2B-N

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

• construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki–Hiyama–Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson–Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis

• iterative addition of geranyl (C10) or farnesyl (C15) building blocks derived from isoprene as starting unit and further structure rearrangement and functionalization [1]. This ubiquitous distribution highlights their pivotal role in living systems such as cell wall structural agent or ecological mediator

• precursor. The proposed strategies include metathesis, Nozaki–Hiyama–Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization (including SmI2), Pauson–Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition, and biocatalysis. In particular, the purpose will focus on the

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• rearrangement [57]. Although, these protocols are useful and have exhibited wide applications in organic synthesis (Figure 2), the scope of these reported methods may suffer from drawbacks such as harsh reaction conditions, use of expensive reagents, prolonged reaction times, low product yields, and cumbersome

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• conformers [26][38][39][40][41], pointing to a higher energy barrier between their conformers in comparison to the barriers between the conformers of 1. Like observed for germacrene A [40] and hedycaryol [41][42], 1 readily undergoes a Cope rearrangement to γ-elemene (5) above 120 °C (Scheme 3C), while the

• structure was subsequently secured by preparation from 1 through Cope rearrangement [20] and through dehydration of elemol (7) with POCl3 in pyridine yielding 5 and β-elemene (8) (Scheme 3D) [45]. Compound 5 has also frequently been reported from natural sources especially after heat treatment of the sample

• dehydration of (−)-1(10)-valencen-7β-ol (35) (Scheme 10C) [92], but has not been isolated from natural sources. Compound 22 could be formed from I1a by Wagner–Meerwein rearrangement to I1c and deprotonation (Scheme 7). This hydrocarbon ([α]D22 = +26, c 0.06) has been obtained as a dehydration product of

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

• condensation of enals 6 with aldehydes 7a or ketones 7b [6][7][8][9][10][11], isomerization of alkynones 8 [12][13][14][15], Horner–Wadsworth–Emmons reaction of unsaturated phosphonates 9 and aldehydes 10 [16][17], and dehydrogenation of enones 11 [18]. Further, Claisen rearrangement of vinyl propargylic

Identification and determination of the absolute configuration of amorph-4-en-10β-ol, a cadinol-type sesquiterpene from the scent glands of the African reed frog Hyperolius cinnamomeoventris

• Angelique Ladwig,
• Markus Kroll and
• Stefan Schulz

Beilstein J. Org. Chem. 2023, 19, 167–175, doi:10.3762/bjoc.19.16

• amorph-4-en-10β-ol (14) from a natural source. Alcohol 14 has been isolated before [17][18] or obtained by rearrangement from (+)-α-ylangene [25]. In the latter case the (4S)-stereoisomer of 14 was formed, as the isopropyl group is not affected by the rearrangement (see Figure S3 in the Supporting

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

• of this heterocycle is quite challenging due to the ease of the β-fragmentation pathway of lithiated derivatives (Scheme 2). Chlorination or oxygenation of the ring sulfur atom(s) in 1, followed by Pummerer-type rearrangement and elimination, affords a straightforward access to the more useful

• access to building block 2. The benzannelated series of 1,4-dithiane heterocycles 5–7 can in principle be obtained using Parham’s α-halocarbonyl condensation and rearrangement approach, starting from benzene-1,2-dithiol. More conveniently, however, ethanedithiol and cyclohexanone can be condensed, and

• synthesis starts from a carbonyl compound, wherein an aldehyde can undergo ‘umpolung’ into a cis-vinyl anion equivalent via a 1,3-dithiolane-to-1,4-dithiane rearrangement (Scheme 10b). The potential of the method is demonstrated by the synthesis of (Z)-9-tricosene or muscalure (59), which is the natural sex

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• at C3 [12]. In this way, substitutions at the stereogenic homoallylic carbon atom can proceed with retention of configuration. Concurrently, a so-called i-steroid rearrangement leads, for instance, to 6β-azido-3α,5-cyclo-5α-cholestane by 6β-face attack of the steroidal substrate by the nucleophile

Organophosphorus chemistry: from model to application

• György Keglevich

Beilstein J. Org. Chem. 2023, 19, 89–90, doi:10.3762/bjoc.19.8

• . elaborated a Lewis acid-catalyzed one-pot synthesis of phosphinates and phosphonates staring from pyridinecarboxaldehydes and diarylphosphine oxides [2]. This protocol is the analogy of the Pudovik reaction, followed by the phospha-Brook rearrangement applied mainly for the synthesis of phosphoric ester

Improving the accuracy of ³¹P NMR chemical shift calculations by use of scaling methods

• William H. Hersh and
• Tsz-Yeung Chan

Beilstein J. Org. Chem. 2023, 19, 36–56, doi:10.3762/bjoc.19.4

• rearrangement of Equation 1 and Equation 2 to give Equation 4, where the intercept b1 in Equation 4 simply incorporates the calculated shielding and chemical shift of the reference as shown. Calculation of the absolute shielding of the reference is therefore irrelevant if one is using a scaling method, and

• chemical shift of −181 ppm. Compound 32 underwent a stereospecific thermal [1,5]-sigmatropic rearrangement to bicyclic 33 exhibiting a 31P NMR chemical shift of −79 ppm. Pyrolysis of 33 at 480 °C gave isomeric 34 having a 31P NMR chemical shift of −14 ppm, while H2O2 oxidation of compounds 33 and 34 gave

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