(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• with subsequent reduction of the olefin motif respectively. In contrast to the approach of Mykhailiuk, this route yields the exo-1,5-BCHs as the major diastereomer. 1,5-BCH (±)-64 and 1,5-BCH (±)-71 were prepared as bioisosteres of the fungicides fluxapyroxad and boscalid, respectively [45]. Comparison

• planarity. Brown and co-workers prepared the [2]-ladderanes via a multistep sequence from diene 147 including an intramolecular [2 + 2] cycloaddition (to (±)-148) and a Wolff rearrangement (to (±)-150) (Scheme 16A) [63]. This approach yielded predominantly the endo diastereomer of trans-[2]-ladderanes 150

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• separated by 0.21 ppm. In the 13C NMR spectrum of 11a–f, a ≈10 ppm upfield shift for the chloroacetal was seen to δ ≈92 ppm from the C5 acetal present in the starting materials. Only a single diastereomer was formed for all 3,3-disubstituted rearrangement products due to the hindrance on the endo-face, with

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• IIIa,b led to a lower reaction rate compared to their pyridine counterparts. However, the cis diastereomer (IIIb) showed significantly enhanced enantioselectivity compared to its equivalent pyridine-based ligand with the same configuration (see Supporting Information File 1, part S5). This change from

α-(Aminomethyl)acrylates as acceptors in radical–polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping

• Angel Palillero-Cisneros,
• Paola G. Gordillo-Guerra,
• Fernando García-Alvarez,
• Olivier Jackowski,
• Franck Ferreira,
• Fabrice Chemla,
• Joel L. Terán and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2023, 19, 1443–1451, doi:10.3762/bjoc.19.103

• ZnMe2 (entries 9 and 10). This difference can be ascribed to a less favorable homolytic substitution reaction of ZnMe2 in relation to its higher analogues and is in line with previous literature observations [11]. The configuration of the major diastereomer was determined by chemical correlation (Scheme

• concomitant deprotection of the nitrogen and the ester groups. The sample was found to have a negative optical rotation, thereby indicating that the major enantiomer present had S configuration [26]. This allowed to establish that the configuration of the major diastereomer present in (RS)-14b was (RS,S), and

• configuration of the major diastereomer of (RS)-14b. Air-promoted tandem 1,4-addition–aldol condensation reactions of Et2Zn with α-(aminomethyl)acrylates. Diagnostic experiments for a radical mechanism and for enolate formation. Diagnostic experiments with N-benzyl enoate 10. Reactivity manifolds for the air

The unique reactivity of 5,6-unsubstituted 1,4-dihydropyridine in the Huisgen 1,4-diploar cycloaddition and formal [2 + 2] cycloaddition

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

Beilstein J. Org. Chem. 2023, 19, 982–990, doi:10.3762/bjoc.19.73

• crystal structure of compound 4k (Figure 1, CCDC 2059918). Though there are four chiral centers in the product structure of the isoquinolino[1,2-f][1,6]naphthyridine, the 1H NMR spectra of the products all showed that only one diastereomer was produced in the reaction, which showed that this reaction has

• ]naphthyridines 4. Because all reactions in this process are retro-equilibrium reactions, the most thermodynamically stable diastereomer is preferentially produced in the reaction. In the absence of isoquinoline, the 5,6-unsubstituted 1,4-dihydropyridine acts as an active enamine, which adds to dimethyl

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

• time led to the formation of only one diastereomer, but in a low yield of 11%. Neither the addition of LiCl helped to increase the diastereoselectivity of the reaction (Table 1, entry 8). See Supporting Information File 1, for complete optimization of the reaction conditions. Achieving

Construction of hexabenzocoronene-based chiral nanographenes

• Ranran Li,
• Di Wang,
• Shengtao Li and
• Peng An

Beilstein J. Org. Chem. 2023, 19, 736–751, doi:10.3762/bjoc.19.54

• diastereomers, C3-symmetric (P,P,P/M,M,M)-117 and C1-asymmetric (P,P,M/M,M,P)-117 were separated and each racemic diastereomer was resolved into the enantiomers by chiral HPLC. The CPL spectra of both enantiomers show a maximum centered at 643 nm, a glum value estimated as 3 × 10−4 for (P,P,P/M,M,M)-117. The

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• intramolecular esterification gave the cyclized products 74 and 75 in 82% yield with a 5:1 ratio of anti/cis diastereomers accompanied by a dimeric byproduct 76 in 2.5% yield. The anti-diastereomer with cis-PhO and Me groups as major product 74 is attributed to the stereoelectronic effect between the n-orbital

• of the etheric oxygen atom and the antibonding orbital of the P=O bond (the stereoelectronic effect), leading to the more stable anti-diastereomer 74 (Scheme 16) [38]. In the phostone 74 was installed a linker 2-(5-aminopentoxy) group via transesterification with benzyl N-(5-hydroxypentyl)carbamate

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

• TMSOTf) promoted trapping gave the aldol adducts 4 in good to excellent diastereoselectivity (up to a single diastereomer), but the yields were relatively low (25–44%). To overcome this limitation, the authors used TMSOTf to prepare and isolate the corresponding silyl enol ethers, which were later

• high diastereoselectivity and good to excellent yields. In most cases, the authors detected only a single diastereomer in the crude reaction mixture (NMR). Using the enantiomeric form of the ligand or the chiral sulfoximine reagent, four diastereomeric β-aminoketones can be produced in excellent

• (Scheme 51B) [94]. Giving only a single diastereomer with good enantioselectivity using a Rh/bicyclo[2.2.2]octane-2,5-diene (bod) complex, a broad variety of spiro compounds were isolated in good to excellent yields. The authors have also shown that this skeleton provides a great opportunity to prepare

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• -stereocenter [32]; a significant downfield shift of this signal (up to 0.5 ppm) could be expected for the diastereomer with the ᴅ-α-stereocenter with respect to the ʟ-isomer. To prove the recyclability of the t-Bu-containing (S)-N-benzylproline-derived ligand L7, the ʟ-(pMeCysNi)L7 complex was decomposed by

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• investigated the Cu-catalyzed borylacylation of bicyclic alkenes 1 (Scheme 11) [45]. Like the previous borylative difunctionalization reactions, it was found the reaction generated a single exo,exo diastereomer. A brief investigation into an enantioselective variant of the borylacylation was investigated

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

• diastereomeric mixture (α-position of the lactone, OTES) (Scheme 11) [36]. Interestingly, in this transformation the G-II-mediated ring formation was performed in the presence of MgBr2, which acted as an epimerization agent at the lactol position yielding compound 67 as a single diastereomer in 65% yield. Of

• in α-position to the keto function. This terminal double bond prefigures the late RCM cyclization. trans-Hydrindanone 87 was isolated as a single diastereomer and possesses 5 out of the 10 stereogenic centers of nitidasin (93). In parallel, (−)-citronellene (88) was converted into derivative 89

• presence of a terminal methyl ketone function did not influence the reaction outcome as compound 133 produced cycloadduct 134 in the same low-moderate yield. Interestingly, the reaction was highly selective and only one single diastereomer was formed (Scheme 26). However, replacement of the allylic alcohol

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

• conformation of the transition state. A chair transition state is less preferred because of inherent non-bonding interactions of some hydrogens. This has been discussed in detail in the original publication by Taber and Gunn, favoring 9 as the main diastereomer [13]. Our results confirm these data. To increase

• ) (for mass spectra see Supporting Information File 1). A minor diastereomer 14 was obtained in 9% yield after isolation by RP-HPLC using a LiChroPrep RP-18 phase because conventional column chromatography did not allow for good separation from the major products. Only one face of the carbonyl groups

• underwent nucleophilic attack, leading the formation of the three desired compounds. The diastereomer 14 showed the same linear retention index I = 1596 and the same mass spectrum as A. After detailed NMR analysis, the relative configuration of the natural product could be determined. The most stable

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

• chemoselective and stereospecific mild hydrodesulfurization with Raney nickel in acetic acid affords the target compound 59 as a single Z-diastereomer. Interestingly, glacial acetic acid proved to be the only solvent that could avoid both undesired overreduction and cis–trans isomerization of the alkene bond. It

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• acyl chloride 6a proceeds well at 23 °C in CH2Cl2 with the use of a stoichiometric amount (1.3 equiv) of AgOTf providing the aza-Nazarov product 7a in 57% yield and as single diastereomer, whereas no cyclization was observed in the absence of AgOTf (Table 1, entries 1 and 2). When the same reaction was

• chloride at 60 °C in 95% yield (2.6 g) and with a dr (E:Z) of 3:1 (Scheme 2a). When imine 5b was reacted with 6b on an 8.0 mmol scale with the use of AgOTf (20 mol %) in acetonitrile at 80 °C, the aza-Nazarov product 7c was isolated in 61% yield (1.42 g) as a single diastereomer. This result clearly

• 19b–d in good yields (54–69%). We were pleased to see that the CF3-substituted aza-Nazarov product 19e was isolated as single diastereomer in 76% yield along with only 8% of the minor diastereomer. Surprisingly, aza-Nazarov products 19f with a 4-Cl substituent on the phenyl ring as well as 19g and 19h

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

• ). This intermediate was then allylated, the ester group selectively reduced with Zn(TMP)2 and LiBH3NMe2 and the resulting primary alcohol was protected as a TBS ether, providing intermediate 23 as a single diastereomer. This key intermediate 23 was then submitted to a Ni-catalyzed α-vinylation and direct

• a TBS ether, α,β-desaturation, dithiane addition, MOM protection and dithiane deprotection. The fragment 25 was lithiated with t-BuLi and the fragment 29 was then added, forming the coupling product as a 5:5:1:1 separable mixture of diastereomers (Scheme 5). The desired diastereomer 30 was isolated

• single diastereomer. The stereochemistry and absolute configuration of the obtained tetracyclic structure 32 was confirmed by NOESY NMR and X-ray crystallography. Some additional modifications were required on the structure to synthesize principinol D: oxidation of the secondary alcohol to the

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

• Michael-type spirocyclization as detailed in Scheme 4. In two cases (7a and 7c), the major (syn) and minor (anti) diastereomers were separated chromatographically and characterized. In one case (7a), the structure of the major (syn) diastereomer was unequivocally confirmed by single-crystal X-ray

• crystallography. In all other cases, only the pure syn diastereomer was isolated and characterized. The yields of spirocyclic products were generally modest to good over two steps. An electron-accepting group in the benzylidene portion (5j) or an N-benzyl substitution in the starting material (5g) lowered the

• the formation of complex product mixtures at the Claisen rearrangement step. 3,5-Dimethylphenoxy-substituted substrate 5h gave the best diastereomeric ratio in the series. The preference for the formation of the syn diastereomer in each case (and for 5a→7a in particular) can, in principle, be

Rhodium-catalyzed intramolecular reductive aldol-type cyclization: Application for the synthesis of a chiral necic acid lactone

• Motoyuki Isoda,
• Kazuyuki Sato,
• Kenta Kameda,
• Kana Wakabayashi,
• Ryota Sato,
• Hideki Minami,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1642–1648, doi:10.3762/bjoc.18.176

• ) moieties (Table 1, entry 7). Interestingly, using the higher coordinating solvents, DMF or DMPU, preferentially gave the opposite diastereomer, i.e., the major product being the anti-form with regard to CH3 (Cα) and OH (Cβ) moieties (anti-2a, Table 1, entries 10 and 11). For stereochemistry assignment, the

• . In addition, we demonstrated a new approach to a necic acid lactone 2j that is a diastereomer of monocrotalic acid, a key intermediate of monocrotalin. Bioactive natural products bearing a 3-hydroxy-2-methyllactone scaffold. Monocrotaline and its structural components. Molecular structure of necic

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

• by 1H NMR based on integration of the C7-methyl signals). A second recrystallization from cyclohexane afforded 5 as a single stereoisomer (>99:1 dr) with 42% overall recovery of material (corresponding to 51% recovery of the major diastereomer 5). Having finally separated the C7-diastereomers, we

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• crystal X-ray analysis (CCDC 2201614). As evinced by the NMR data, only one diastereomer of product 3aa was obtained. Contrary to the isoxazole-annulated products of a [3 + 2] cycloaddition of nitrones to FPDs [35], product 3aa appears to be stable on storage in solution, which was confirmed by the fact

• the same diastereomer 3ia with a good 54% yield. Conclusion To conclude, we have developed a facile synthetic approach to spirofuranoxindoles 3 via the highly diastereoselective formal [4 + 1] cycloaddition reaction of FPDs 1 with diazooxindoles 2. The obtained compounds 3 were found to be stable

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

• 27. Subsequent oxidation gave α-ketoester 28 which was used in an intramolecular, Lewis acid-mediated aldol reaction, presumably via tridentate complex transition state III, to give diol 29 as a single diastereomer. Inversion of the secondary alcohol and deprotection gave preussochromone D (30

• diastereomer not shown) via transition state VII where pseudo-1,3-strain is minimized. Nineteen further steps were necessary to give the naturally occurring jatrophen 51. (−)-Hopeanol In the synthesis of the polyphenolic natural product (−)-hopeanol (59), Nicolaou et al. used an α-ketoester moiety as a

• alcohol 56, which was dehydroxylated to the diastereomeric cations VIII and IX. Friedel–Crafts reaction gave diastereomeric lactones 57 and 58. The major diastereomer 58 could be converted to the complex polyphenol (−)-hopeanol (59) in seven further steps. (+)-Camptothecin In the formal synthesis of the

Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

• Oleg A. Levitskiy,
• Olga I. Aglamazova,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2022, 18, 1166–1176, doi:10.3762/bjoc.18.121

• ). Complex 4 was easily separated from the minor diastereomer by column chromatography. The structure and purity of (S)-4 was confirmed by NMR data, including HMBC, HSQC and COSY 2D techniques. The assignment of the α-stereocenter as (S) was based on the NOESY data (see Supporting Information File 1 and

• , the (R,S):(R,R) diastereomeric ratio was changed from 1:1 to 13:1 in favor of the thermodynamically more stable (R,S) diastereomer. The experiment with thiophenol performed under the same reaction conditions (a two-fold excess of thiol and the Et3N additive) gave the cysteine derivatives in 88% yield

• and with 12:1 diastereoselectivity; again, the (R,S) diastereomer was the dominant (entry 4, Table 2), in line with the previous results with tolylthiol. In case of an aliphatic thiol (benzylthiol), the results were qualitatively similar. The diastereomeric ratio is inverted in favor of the

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• [17] gave (Z)-4 as a single diastereomer through anti elimination. Overall, TDD was obtained from ʟ-tryptophan in a high yield of 37% over eight linear steps. HPLC analysis on a chiral stationary phase showed that 4 obtained through this second route was enantiomerically enriched (80% ee by peak

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

• diastereoselectivity and the principal diastereomer was rightly deemed to be trans-configured (vide infra). The order of mixing the reagents was found to be crucial for the successful arylation of compound 10a. Specifically, the arylation was conducted on adding a DCM solution of substrate 10a to a vigorously stirred

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• diastereoselectively with TPC (2a), resulting in the formation of bis-spirocyclic meso compound 3a in which the three phenyl substituents attached to the cyclopropane ring are oriented in the same direction (Scheme 2). This suggests that the diastereomer 3a resulting from the approach of the 1,3-dipole 1 from the less

• cyclopropene 2e led to the formation of the diastereomer with all three substituents (at the cyclopropane ring) oriented in the same direction. A notable substituent effect on the reactivity of cyclopropene dipolarophiles 2 was observed for the reactions between PRP (1) and derivatives of 2,3-diphenylcycloprop

• observed signals were at the limit of detection and whether they actually correspond to a minor diastereomer could not be ascertained unambiguously. The major product 4 was purified by recrystallization of the crude mixture from MeOH and obtained in 62% yield. The structure and relative configuration of