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

• reprotonation at C-1 of 1, leading to four different stereoisomers of cation I, i.e., I1 with a trans-decalin skeleton, its enantiomer I2, I3 representing the cis-decalin skeleton, and its enantiomer I4 (Scheme 6A). In principle, the eudesmane skeleton can also be formed through cyclisations induced by

• ], Acritopappus prunifolius [79], Aniba riparia [80], Juniperus oxycedrus [81], and Laggera alata [82] has not been determined. The (−)-enantiomer of 11 with the structure as shown in Scheme 9C was reported from Cabralea cangerana ([α]D20 = –1.3, c 1.3, CDCl3) [83], Zanthoxylum naranjillo (no value specified) [84

• ], and Chiloscyphus polyanthos ([α]D = −3.0, c 2.41, CHCl3) [85]. The (+)-enantiomer of 11 is known from Cinnamomum camphora ([α]D25 = +1.79), representing the first isolated enantiomerically enriched material [86]. The low value of the optical rotation of 11 makes configurational assignments based on

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

• Information File 1). The same enantiomer was isolated from the wood oil of Cryptomeria japonica [17]. Therefore, the enantiomer R-14 from the frogs is different to the plant compound. This finding may point to a biosynthesis of 14 by the frogs themselves or by associated microorganisms, although uptake from

• synthesis and characterization showed that this compound is the opposite enantiomer of 14 known from plants. This may indicate biosynthesis in the frog, but more work has to be performed to establish this. Furthermore, a short diversity-oriented synthesis based on the work of Taber and Gunn [13] enabled

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

• used dihydrodithiin-scaffolding is tentatively indicated on the target structures 70–81 [62][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]. D’Alonzo, Palumbo, Guaranga and co-workers also developed a de novo synthesis of the unnatural enantiomer of the iminosugar drug miglustat

• [81]. Miglustat is a biologically active analog of the natural product deoxynojirimycin, and its enantiomer also shows a promising profile in early biological activity studies. In future applications of 1,4-dithiane or -dithiin building blocks, the recently described zincation protocol by Knochel and

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

• were only reported for the natural compound (nat-cholesterol, 1) and its enantiomer (ent-cholesterol, ent-1) (Figure 1) [3]. While 1 and ent-1 are characterized by hydroxy groups in β-position at C3, epicholesterol (epi-1) has an α-OH at C3. Diets of animal sources like red meat, liver, milk, and

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

• , requiring only two purification steps [77]. FGI of 146 led to (−)-enantiomer 147, which serves as the radical point od divergence of this plan. HAT-initiated transannular free-radical cyclization of (−)-enantiomer 147 according to Baran’s protocols [78] provided the benzyl-protected (−)-pseudocopsinine 148

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• irradiation. The resulting iodoaryl cation radical abstracts the hydrogen atom from the benzylic position to form a benzyl radical, whose bromination gives the racemic benzyl bromide. The second step takes place without the participation of light and leads to only one enantiomer due to the assistance of the

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

• anticipated that the amide 5 could be hydrolyzed to give a single enantiomer of amine 4. However, we found that amide 5 was remarkably resistant to hydrolysis, even under forcing conditions. For example, no amide hydrolysis was observed in concentrated aqueous NaOH solution at reflux (with or without an

• silica gel resulted in extensive decomposition. Therefore, the crude imine was immediately hydrolyzed using aqueous citric acid [14], affording (−)-7-amino-7,8-dihydrobisabolene (4) as a single stereoisomer in 90% yield over the two steps. The enantiomer of 4 is itself a natural product with cytotoxic

• hydrolyzed under basic conditions (Scheme 2) to form the enantiomer of halichonic acid B ((−)-2). It is interesting to note that halichonic acid B exists exclusively as an open-chain 4-hydroxycarboxylic acid even though the corresponding γ-lactones typically form spontaneously. Indeed, no lactone formation

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• -syntheses that are required [1][2][3][4]. Additionally, whereas either enantiomer of BINOL is relatively inexpensive (109 $/mol), it is not the case with SPINOL (17,000 $/mol), and VAPOL is not commercially available. Although one could synthesize these precursors as well, this multistep synthesis is time

• time. Consequently, the availability of each CPA enantiomer requires significant synthetic efforts from the diphenol precursor. In order to address these issues, we became interested in exploring C1-symmetrical CPAs, in which the chirality resides exclusively at the phosphorus atom. For this

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

• diminished yield for 15 (70%), lowering the overall yield of TDD to 33% over eight steps. The major enantiomer of 4 obtained from this second route was identical to natural TDD (Figure 1D) which is thus S-configured, i.e., derived from ʟ-tryptophan. Moreover, the olefinic double bond in 4 is Z-configured as

• enantiomer can only lead to a chiral dimer that, if formed at all, may crystallise less efficiently. Bioactivity testing Previous reports have mentioned that TDD (4) exhibits no antibacterial activity, without providing information about the test organisms used [9]. For this reason, and because of the above

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• (+)-ximaocavernosin P [(+)-1]. Further, these isothiocyano-containing enantiomers were usually isolated as scalable mixture (where one enantiomer predominates) with an enantiomeric excess of ca. 80% [11]. In contrast, the two neutral cadinane-type enantiomers (4 and 5) were produced as racemic mixture (1:1 ratio

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• the native substrate 2-Me-GPP, seems to imply that the isomerization through suprafacial allylic transposition of diphosphate should result in the intermediate (S)-2-Me-LPP (Figure 1B), which would be the opposite enantiomer as suggested by Cane [23]. This prompted us to investigate whether (R)- or (S

• %) (structures are shown in Figure 2). Reproducibility of these results was demonstrated in triplicates. While these data showed that enantiomerically enriched (R)-2-Me-LPP is more efficiently converted into 1 than the enriched S enantiomer, the enantiomeric purity of the substrates was not sufficiently high to

• decide, if only one enantiomer of LPP serves as the precursor to 1. Purification of the enantiomers of 2-Me-LPP In order to obtain the enantiomers of 2-Me-LPP with high purity, the synthetically obtained enantiomerically enriched compounds 6a and 6b were purified by HPLC using a chiral stationary phase

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• resolution of the latter and the conversion of the suitable enantiomer to the drug lumateperone is disclosed in our patent application. Structure of lumateperone. First synthetic route leading to lumateperone (1). Alternate synthesis of lumateperone. Alternate synthetic approaches leading to racemic

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• )-38, featuring the BINOL unit on the axle, does not allow for higher stereoselectivities (19% ee), but interestingly gives the other product enantiomer as the main product (see Figure 9). In 2016, Takata and co-workers reported a pyridine-based rotaxane catalyst for the O-acylative asymmetric

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban

• Martin Vrbický,
• Karel Macek,
• Jaroslav Pochobradský,
• Jan Svoboda,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2022, 18, 438–445, doi:10.3762/bjoc.18.46

• oral anticoagulants). All these human drugs can be considered as modern medicaments, which were developed and approved during the past three decades [8]. The chirality of the mentioned oxazolidine-2-ones is a crucial factor for their therapeutic effect, because only a single enantiomer affords the

• desired biological activity. Hence, only the S-enantiomer of rivaroxaban (2) (sold under trade name Xarelto®) exhibits a strong inhibitory activity against coagulant factor Xa, whereas the R-enantiomer is almost inactive (IC50 = 0.7 nM for S vs 2300 nM for R) [7]. Similarly, in the case of the oxazolidine

• enantioselectivity was achieved with the copper(II) complexes of ligands Ia, IIa, IIIa, and IV. Fortunately, these catalysts provided the R-enantiomer of nitroaldol 21 as the major product, which can be subsequently transformed to S-linezolid (1) (the active stereoisomer). On the other hand, the catalysts derived

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• on the screening of various bifunctional H-bonding catalysts, and in this regard, the reaction catalyzed by quinine-derived thiourea catalyst 3b furnished the product 4a in 55% yield and 71% ee (Table 1, entry 5). The other enantiomer was obtained when the reaction was carried out using the

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• approach, 1 was mono-O-allylated to 2 under similar conditions reported previously for monobenzylation (Scheme 3) [50]. Iodination (3) and subsequent elimination of the iodide with zinc dust gave allylic alcohol 4 as a single enantiomer, which was esterified with Boc-protected glycine to allyl ester 5

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

• Shun Saito,
• Kanji Indo,
• Naoya Oku,
• Hisayuki Komaki,
• Masashi Kawasaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2939–2949, doi:10.3762/bjoc.17.203

• -octadienoic acid (5), and one prenylated tryptophan derivative, 6-(3,3-dimethylallyl)-N-acetyl-ʟ-tryptophan (6). The enantiomer ratio of 4 was determined to be approximately S/R = 56:44 by a recursive application of Trost’s chiral anisotropy analysis and chiral HPLC analysis of its methyl ester. Compounds 1–5

• between the diastereomer pairs. The enantiomer ratio of 4 was estimated to be S/R = 56:44 or near by chiral phase HPLC analysis of 4' on a cellulose tribenzoate-coated silica gel column (Figure 4). Thus, 4 was concluded to be an enantiomeric mixture of (2E,4E)-7-hydroxy-2,4-dimethyl-2,4-octadienoic acid

• with an approximate enantiomer ratio of S/R = 56:44. The 1H and 13C NMR spectra of 5 were quite similar to those of 4 (Table 1 and Table 2), except for the lack of the oxymethine proton resonance and replacement of the doublet methyl resonance by a singlet signal with a six-proton intensity. These

Biological properties and conformational studies of amphiphilic Pd(II) and Ni(II) complexes bearing functionalized aroylaminocarbo-N-thioylpyrrolinate units

• Samet Poyraz,
• Samet Belveren,
• Sabriye Aydınoğlu,
• Mahmut Ulger,
• Abel de Cózar,
• Maria de Gracia Retamosa,
• Jose M. Sansano and
• H. Ali Döndaş

Beilstein J. Org. Chem. 2021, 17, 2812–2821, doi:10.3762/bjoc.17.192

• ligand rotamers were considered during the optimization process. Only one enantiomer was selected for running the calculations for simplicity. The obtained results are gathered in Figure 1 and Figure 2. These calculations show that for ligands L1 and L3, conformer A and conformer B, resulting from a free

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• were inactive towards the examined α-glucosidases. The enantiomer of 2 was the only one that still exhibited inhibitory activity against yeast α-glucosidase [2]. To our knowledge, the sole total synthesis of (−)-codonopsinol B and similar hydroxylated pyrrolidines to date was reported in the above

• )-enantiomer [18]. We have used ᴅʟ-proline for three reasons: first, it provides the target compounds 1 and 2 in their racemic form, second, it is able to catalyze the conjugate addition between N-EWG-protected hydroxylamines and enals effectively, and third, based on our experience, the products obtained by

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• found that out of four stereoisomers, the β-configured ʟ-(−)-enantiomer 1 (EC50 = 0.02 µM) is more potent in primary human lymphocytes than the β-configured ᴅ-(+)-enantiomer 1a (EC50 = 0.2 µM) in CEM cells [14]. Similarly, the 5-fluoro-substituted analogue of cytidine, i.e., β-configured ʟ

• -(−)-enantiomer 2, exhibits potential antiviral activity against HIV-1 (EC50 = 0.009 µM) in CEM cells. However, the corresponding ᴅ-(+)-enantiomer is less active against HIV-1 (EC50 = 0.84 µM) [15]. The fusion of an appropriate sugar element, carbacycle, or heterocyclic equivalent with an activated base results

• higher antiviral activity and lower toxicity of the unnatural ʟ-(−)-enantiomer over the ᴅ-(−)-enantiomer. The enantiomers of natural nucleosides are known to have a greater biological activity since they possess structural and configurational similarity to naturally occurring counterparts. In turn, for

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• /mismatched combination of chirality, we employed both enantiomers of tert-butyl sulfinamide with the (S)-enantiomer of the pyrrolidine building block. The introduction of green chemistry principles into chemical transformations is an important goal toward sustainable production and manufacturing. Asymmetric

• and enantiomeric purities (Table 1, entries 12 and 13). In terms of the stereochemical outcome, both sulfinylthioureas C1 and urea C2 afforded the same enantiomer as the main product. Furthermore, both diastereomers of both catalysts also directed the Michael addition toward the same enantiomer. These

• of adduct 8a dropped to 51%, when the excess of butanal (6a) was reduced from 3 to 1.5 equivalents. The diastereoselectivity increased to 93:7 and the enantioselectivity for the major enantiomer was 19:81 and 16:84 for the minor enantiomer, respectively (Table 3, entry 2). A base exchange had no

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• -substituents. For example, only the S enantiomer from a racemic mixture of 19 was capable of being rearranged; (R)-19 was recovered from the reaction mixture with 84% ee, whereas (S)-19 had been stereospecifically converted to 20 in 49% yield and 86% ee (Figure 5). The final example of asymmetric α-ketol

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• following details: two reports present the unsuccessful syntheses of brevipolide H [13][14] and four reports cover the successful syntheses of brevipolide H [15] and its enantiomer [16], brevipolide M [17], and brevipolide N [17][18], respectively. To the best of our knowledge, this work presents the first

• synthesize brevipolide H (8), but unexpectedly ended up with the isolation of its enantiomer (ent-8) [16]. Common to the most of the reported retrosynthetic analyses of brevipolide, compound 8 is disconnected at the cinnamate ester bond giving β-hydroxy cyclopropyl intermediate 44 and (E)-p-methoxycinnamic

• compound 82. This molecule is expected to be available from cross metathesis of olefins 83 and 84. These two intermediates can then be readily prepared from optically active oxirane 85 and its enantiomer which can be derived through the Sharpless epoxidation of penta-1,4-dien-3-ol (86). In the synthesis

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• of biological interest, as evidenced by the facile preparation of the (S)-enantiomer of a potent CRTH2 receptor antagonist. The importance of the 3,3-spirooxindole core and its access through enantioselective enolate alkylation. Substrate scope. aIsolated yield. bDetermined by CSP-HPLC. cValue in

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• the seleniranium ring. Through favorable cation–π interactions with the catalyst, the (S,S)-intermediate reacts faster than its opposing enantiomer, allowing for excellent yields up to 95% and high enantioselectivities up to 91% ee. In contrast to the previous example, in which the chloride anion was

• between the catalyst and the substrate, which exclusively stabilize the transition state that forms the major enantiomer. Furthermore, Gouverneur and co-workers established an enantioselective nucleophilic fluorination protocol using a chiral bis-urea catalyst 41 and CsF as an inorganic fluoride source