Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• . Examples of prominent natural products: N-butyrylhomoserine lactone (1), pyoverdin (2), malleicyprol (3), bongkrekic acid (4), vancomycin (5), and amphotericin B (6). Biosynthetic principles of (A) assembly line-like pathways and (B) discrete multi-enzymatic assemblies. Assembly line-like pathways use

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

• described to give β-hydroxylactones with high diastereoselectivities. The stereoselectivity of this cyclization is highly solvent dependent and can give syn- or anti-β-hydroxylactones with high diastereoselectivity. This methodology was also applied to the synthesis of a chiral necic acid lactone which is a

• structural component of the pyrrolizidine alkaloid monocrotaline. Keywords: β-hydroxylactone; intramolecular reductive aldol cyclization; necic acid lactone; rhodium catalyst; Introduction Carbon–carbon bond-forming reactions are among the most important reactions in the synthetic chemistry toolbox and the

• formation systems, we herein report a rhodium-catalyzed intramolecular reductive aldol-type cyclization and its application for the synthesis of a chiral necic acid lactone. Results and Discussion Rh-catalyzed intramolecular cyclization When applying our previously reported conditions [43], 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

• based on nuclear Overhauser effect (NOE) correlations (see the Supporting Information File 1 for additional details). This analysis showed that the minor product 9 corresponded to the lactone of (−)-halichonic acid B. At this point, all that remained to complete the syntheses of the halichonic acids was

• chromatography. Similarly, hydrolysis of lactone 9 under analogous conditions afforded halichonic acid B ((−)-2) in 76% yield. 1H and 13C NMR data for the synthetic compounds (−)-1 and (−)-2 were identical to those reported for the halichonic acids, confirming the proposed structures of these natural products

• confirmed [4][5]. For the sake of comparison, the diastereomeric lactone 10 was also hydrolyzed under the same conditions to form the “unnatural” product 11 in 70% yield, which we have designated (−)-isohalichonic acid B. Although the NMR spectra of (−)-2 and 11 are quite similar, we did note a significant

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• , including two all-carbon quaternary centers, together with the non-enolizable cyclic α-diketone moiety collectively render aberrarone as an attractive but challenging synthetic target. Its congener elisabanolide (2) with a lactone in the D ring shows their potential biosynthetic relationship [2]. These

Oxa-Michael-initiated cascade reactions of levoglucosenone

• Julian Klepp,
• Thomas Bousfield,
• Hugh Cummins,
• Sarah V. A.-M. Legendre,
• Jason E. Camp and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2022, 18, 1457–1462, doi:10.3762/bjoc.18.151

• oxymethylene bridge [8][9][10]. Many selective nucleophilic additions are known, and the reaction has been applied to the synthesis of disaccharides [11], the pheromone eldanolide [12], and flavoring compounds such as whiskey lactone [13]. The use of heteronucleophiles can also be used to initiate cascade

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• on the synthesis and the coupling of three main fragments. The central fragment was synthesized via a regio-and stereoselective nitroso Diels–Alder reaction with an enol phosphate, followed by reductive cleavage of the phosphate to the ketone 11b. Coupling studies of this fragment with the lactone

• . Common structural motifs include a polyunsaturated acyclic chain with an unsaturated lactone ring and an amine-containing side chain (Figure 1). These natural products have attracted much attention due to their original structure and to their activity as inhibitors of the serine/threonine phosphatase

• preparation and the coupling of three main fragments (Figure 2): the lactone fragment 3, the central fragment 4 and the cyclohexane fragment 5. We have previously described the enantioselective synthesis of the lactone fragment 3 [18]; we now disclose the synthesis of the oxazinone 4 and attempts for coupling

Enantioselective total synthesis of putative dihydrorosefuran, a monoterpene with an unique 2,5-dihydrofuran structure

• Irene Torres-García,
• Josefa L. López-Martínez,
• Rocío López-Domene,
• Manuel Muñoz-Dorado,
• Ignacio Rodríguez-García and
• Miriam Álvarez-Corral

Beilstein J. Org. Chem. 2022, 18, 1264–1269, doi:10.3762/bjoc.18.132

• some contamination of the product with lactone 5 can arise at low pH values, which goes in detriment of the yield. The 2,5-dihydrofuran ring in target compound 1 was obtained through a Ag(I)-mediated intramolecular addition of the hydroxy to the allene group, a process that transformed allene 3 into

• alcohol 6 with amberlyst-15® leading to the monoterpene 1. Other systems tested for the elimination of the hydroxy group in 6 were pyridinium p-toluenesulfonate (PPTS) and camphorsulfonic acid (CSA), that gave poorer results, failing to afford a single product. On the other hand, lactone 5 could also be

• ), 1.70 (td, J = 0.5, 3.2 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3, DEPT) δ 204.8 (C), 174.0 (C), 101.6 (C), 77.0 (CH2), 71.5 (CH), 60.5 (CH2), 30.4 (CH2), 30.0 (CH2), 14.5 (CH3), 14.2 (CH3) ppm; HRMS–ESI (Q-TOF, m/z): [M + H]+ calcd for C10H17O3, 185.1178; found, 185.1158. A lactone

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

• species to the α-ketoester 15 (Scheme 3) [6]. The ketoester 15 was synthesized by a chiral pool approach starting from (+)-3-carene derived cycloheptenone 13 [7][8] and aldehyde 12 (accessible from (R)-Roche ester [9]) via the γ-lactone 14. The ketoester moiety was established by an enolate hydroxylation

• , Scheme 6) [15]. Through a series of finely tuned CH oxidations, cedrol (31) was converted to the lactone 32. In a single step, using Riley oxidation conditions, the methyl ketone moiety was transferred to the α-ketoester 33. Reduction, lactonization, and elimination gave the ketoesters-derived enol 34

• reactivity in their synthesis of (+)-awajanomycin (92), a marine natural product with a γ-lactone-δ-lactam core structure (Scheme 15) [30][31]. Key step was an asymmetric allylboration of diethyl mesoxalate (90a) with boronate 89, which was easily accessible through a Matteson homologation of dichloromethyl

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

• responsible for the oxidation of deoxyhangtaimycin (3), a compound with antiviral activity, to 1 [8]. The thereby installed hemiaminal function is also the breaking point for 1 into a larger lactone-polyene peptide fragment and a smaller fragment HTM222 (2, named after its molecular mass of 222 Da) [2

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

• iron (Habanolide, (12E)-oxacyclohexadec-12-en-2-one) [3][4][9][46][47]. Although, all musks of natural origin are macrocyles, most synthetic musks are polycyclic musks (PCM), while the fourth synthetic generation of musks are linear molecules [3][4]. In 1999, juniper lactone (56) was isolated from the

• under acidic conditions to the corresponding triperoxides which form macrocyclic structures at high temperatures, e.g., juniper lactone (56) [49]. Despite the elegance of this access, the safety of this process is questionable complicating the large-scale production in batch. Very recently, Kirschning

• and co-workers developed a flow protocol to overcome these limitations and prepared various macrolactones from triperoxides by pyrolysis in an inductively heated flow reactor (Scheme 13) [50][51]. Due to the commercial relevance of juniper lactone (56), they designed a flow setup for a scalable and

Terpenoids from Glechoma hederacea var. longituba and their biological activities

• Dong Hyun Kim,
• Song Lim Ham,
• Zahra Khan,
• Sun Yeou Kim,
• Sang Un Choi,
• Chung Sub Kim and
• Kang Ro Lee

Beilstein J. Org. Chem. 2022, 18, 555–566, doi:10.3762/bjoc.18.58

• carbon signals, including four oxygenated carbons (δC 70.0, 61.4, 60.5, and 57.9), a lactone moiety (δC 172.6, 159.0, 131.2, and 109.2), and a glucopyranosyl moiety (δC 97.2, 78.7, 78.1, 74.5, 71.4, and 62.5) (Table 1). Comparison of these 1H and 13C NMR spectra of 1 with those of 1β,10α;4α,5β-diepoxy-8β

• 13C NMR spectrum of 2 showed 22 carbon signals including five oxygenated carbons (δC 76.6, 70.7, 65.7, 62.3, and 57.9), a lactone moiety (δC 171.9, 151.4, 136.9, and 110.9), a methoxy carbon (δC 51.3), and a glucopyranosyl unit (δC 103.1, 78.6, 78.4, 75.4, 71.9, and 63.3) (Table 1). These NMR spectra

Sesquiterpenes from the soil-derived fungus Trichoderma citrinoviride PSU-SPSF346

• Wiriya Yaosanit,
• Vatcharin Rukachaisirikul,
• Souwalak Phongpaichit,
• Sita Preedanon and
• Jariya Sakayaroj

Beilstein J. Org. Chem. 2022, 18, 479–485, doi:10.3762/bjoc.18.50

• , Nakhonsithammarat 80160, Thailand 10.3762/bjoc.18.50 Abstract Two new sesquiterpenes, trichocitrinovirenes A (1) and B (2), and five known compounds including four structurally related sesquiterpenes and one γ-lactone were isolated from the soil-derived fungus Trichoderma citrinoviride PSU-SPSF346. The structures

• . Compound 2 possesses a rare bicyclic sesquiterpene skeleton. The antimicrobial and cytotoxic activities of the isolated compounds were evaluated. Keywords: antimicrobial activity; cytotoxic activity; γ-lactone; soil-derived fungus; sesquiterpene; Trichoderma citrinoviride; Introduction The fungus

• chromatography techniques led to the isolation of two new sesquiterpenes, trichocitrinovirenes A (1) and B (2), four known structurally related sesquiterpenes including gliocladic acid (3), hydroheptelidic acid (4), and xylaric acids B (5) and D (6) [8], as well as one known γ-lactone, fusidilactone A (7) [9

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole

• Estelle Silm,
• Ivar Järving and
• Tõnis Kanger

Beilstein J. Org. Chem. 2022, 18, 167–173, doi:10.3762/bjoc.18.18

• using CPD as a precursor for high value-added fine chemicals such as a homocitric acid lactone was published by our group [19]. Since then we have developed synthetic pathways for lycoperdic acid [20] and nucleoside analogues [21] starting from CPD. The organocatalytic methods for the synthesis of

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• -oxabicyclo[5.2.1]decan-10-yl)carbamate was confirmed by X-ray diffraction. Keywords: aminocyclitol; azidolysis; bicyclic β-lactam; bicyclic lactone; cyclic β-amino acids; DFT; Introduction Cyclic β-amino acids have for the past few decades aroused widespread synthetic interest owing to their diverse

• expected product 9 failed. The product 8 was obtained as the major product in 80% yield, and the expected product 9 was formed as the minor product in 4% yield. We propose that diol isomer mixture 9 can be formed by solvolysis. The presence of the lactone ring in 8 was determined by 2D NMR spectroscopic

• H-7 and H-10 also showed weak correlation, which clearly supports the cis relation of the proton H-10. In this reaction, lactonization and hydrolysis of the Boc group to the corresponding amine were observed. The formation of lactone 8 as the major product can be explained by nucleophilic attack of

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones

• Yuki Yamamoto,
• Akihiro Tabuchi,
• Kazumi Hosono,
• Takanori Ochi,
• Kento Yamazaki,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 2906–2914, doi:10.3762/bjoc.17.198

• methyl ethyl ketone (MEK) was as effective. In addition, in situ-generated α-bromo-δ-valerolactone was directly converted into a sulfur-substituted functional lactone without difficulty by reacting it with a sulfur nucleophile in one pot without isolation. This new bromination system is expected to

• , and bromolactones are important synthetic intermediates for selectively, effectively, and practically introducing lactone units into organic molecules [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Among brominated lactones, the α-bromolactone, in which the bromine atom is located at

• polymerization (ATRP) reactions and functional polymer synthesis [29][30][31][32][33][34]. Although α-bromo-γ-butyrolactone, which is a five-membered lactone, is easily accessible from the five-membered lactone by some bromination methods [35][36], the bromination method for the six-membered lactone, δ

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

• at reflux temperature in toluene to synthesize the 1,3-oxathiolane lactone 6 via intermediate 5 after elimination of a water molecule. This was further reduced with diisobutylaluminum hydride (DIBAL) in toluene at −78 °C or by lithium tri-tert-butoxyaluminum hydride in THF at 0 °C to obtain lactol 7

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• alkynes [24][25]. Numerous synthetic routes have also been reported for the synthesis of anthraquinones [26][27][28][29]. On the other hand, preparative methods for dibenzo[a,h]anthracene derivatives are less common, mainly relying on the cyclization of the corresponding lactone derivative followed by

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• target lactone in 61% yield over two steps. The final steps involved a one-pot ozonolysis with quenching under Pinnick oxidation conditions to afford the carboxylic acid derivative in 83% yield, followed by White’s selective C–H oxidation (Scheme 26B). White’s selective C–H oxidation was also applied in

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• observations are noted: N-Fluoro-2,6-bis(methoxymethyl)pyridinium triflate (5-4l) fluorinated the trimethylsilyl ether of γ-butyrolactone and 1-cyclohexenyl acetate in much higher yields than the N-fluoro-2,4,6-trimethyl salt 5-4j [32]. Thus, as seen in Scheme 13, 5-4l converted the Corey lactone 5-7 via its

• silyl ether 5-8 to the fluorinated lactone 5-9 in a very satisfactory overall yield [32]. N-Fluoro-2,6-bis(CH2OAc)pyridinium triflate 5-4n [32], N-fluoro-2,6-bis(COOMe)pyridinium triflate 5-4y [30][32], and N-fluoro-2-cyano- and -2,6-dicyanopyridinium tetrafluoroborates [39] were useful reagents, too

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• employed, and an example of a seven-membered lactone was reported (Scheme 25A, 66). However, in the latter case, acid catalysis and reflux were needed to ensure cyclization. Still taking advantage of the enolate intermediate, the Cui group reported the use of olefins 68, containing tethered leaving groups

Analogs of the carotane antibiotic fulvoferruginin from submerged cultures of a Thai Marasmius sp.

• Birthe Sandargo,
• Leon Kaysan,
• Rémy B. Teponno,
• Christian Richter,
• Benjarong Thongbai,
• Frank Surup and
• Marc Stadler

Beilstein J. Org. Chem. 2021, 17, 1385–1391, doi:10.3762/bjoc.17.97

• Hz, H-1). The 13C NMR spectrum showed 15 signals including those of a lactone carbonyl at δC 177.6 (C-15); four olefinic carbons at δC 126.0 (C-4), 126.5 (C-2), 133.4 (C-3), and 144.0 (C-1); three methyl groups at δC 8.7 (C-14), 20.2 (C-13), and 28.0 (C-12) (Table 1). The remaining resonances were

• be attributed to an absence of the α-methylene lactone unit present in fulvoferruginin (1). Nevertheless, the cytotoxicity detected here for fulvoferruginin shows that re-evaluating the bioactivity of previously isolated basidiomycete metabolites in different bioassays can lead to unexpected results

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• ring size, unsaturated lactone, N-protected dihydropyridone and one example of a linear substrate. In all cases a decreased reactivity was observed, however, good to excellent enantioselectivity levels were maintained (81–99% ee; Table 8) [37]. To our best knowledge, at this time only one method for

• , the addition reaction to a 6,6,3-trimethylated substrate gave the product in only very low yield (9%), but with high enantioselectivity (90% ee; entry 3, Table 22) [48]. The application of the catalytic system in the addition reaction to an unsaturated lactone yielded the product with both low yield

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• ] cycloaddition reaction of an aldehyde and a ketene followed by their isomerization-free Stille coupling with (E)-5-(3-(tributylstannyl)allyl)oxazole (Schemes 8–10) [22]. In this synthesis, the enantiopure β-lactone (+)-79a was synthezised from (Z)-aldehyde 78 and propionyl chloride according to Nelson’s method

• [53][54][55] using quinidine TMS ether (TMSQD), LiClO4, and Hünig’s base. The aldehyde (Z)-78 was obtained from propargyl alcohol 14 via (Z)-iodo alcohol 15a. The β-lactone (+)-79a was converted to enantioenriched vinyl iodides (+)-84 and 85a separately. Thus, methanolysis of (+)-79a provided (–)-80a

• , and diisopropylethylamine in the presence of quinidine TMS ether (TMSQD) according to Nelson’s procedures [53][54][55] provided the enantioenriched β-lactone (−)-79b in 85% yield. The desired terminal acetylene (−)-82b was synthesized from β-lactone (−)-79b following a three-step sequence as shown in

The fluorescence of a mercury probe based on osthol

• Guangyan Luo,
• Zhishu Zeng,
• Lin Zhang,
• Zhu Tao and
• Qianjun Zhang

Beilstein J. Org. Chem. 2021, 17, 22–27, doi:10.3762/bjoc.17.3

• mode between OST and Hg2+ is suggested as shown in Figure 7. Hg2+ and the oxygen atoms of the lactone ring and the methoxy group formed a stable complex, resulting in the enhanced fluorescence. Isothermal titration calorimetry analysis A Hg2+ solution (2 × 10−3 mol∙L−1, 25 μL) was added to the 1 × 10−4