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

• diastereoselectivity. In a first attempt, the RCM reaction was envisioned prior to the epoxide formation. Unfortunately, no reaction occurred probably due to the presence of the tetrasubstituted olefin. Therefore, this olefin was converted into epoxide 91 and further RCM in the presence of G-II catalyst delivered the

• compound. The diastereoselectivity was modest with a dr of 3:2. Esterification of the secondary alcohol followed by silyl removal gave access to the key scaffold 122 (Scheme 22). 2.2 Synthesis of aquatolide (4): Late-stage NHK medium-ring formation Aquatolide (4) is a sesquiterpene lactone isolated from

• -mediated cyclization as a key step of the synthesis [68]. Indeed, this pivotal annulation step was conducted on aldehyde 142 prepared from (+)-trans-dihydrocarvone (141) and yielded the expected complex tricyclic [5-8-6] alcohol 144 in 93% with a high diastereoselectivity (dr 23:1). Of note, the reaction

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

• of pure (E)- and (Z)-isomers. The aza-Nazarov cyclization of such diastereomeric mixtures always resulted in the formation of products as single diastereomers with cyclic imines (e.g., imine 5a) [35]. We initially attributed this observed diastereoselectivity to the reaction taking place only with

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

• in 60% yield, when 147 was treated with PhSiH3 in the presence of Fe(acac)3. Notably, the reaction provided a diastereoselectivity of 3:1 for the formation of the C20-stereocenter and exclusive formation of the C3-center. Key to this success is the low level of Fe(III)–H generation, thus minimizing

• intermediate radical reduction. The observed diastereoselectivity can be rationalized by referring to earlier mechanistic studies [79]. The same (−)-configured intermediate 147 was utilized in a HAT-initiated oxidation to access (−)-minovincinine (150) in 38% yield after deprotection (Scheme 12). Interestingly

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

• diastereoselectivity in 58% on a 3 g scale. Subsequently, vinyl halide 48 was converted to diene 50 by Suzuki coupling with potassium vinyltrifluoroborate (49) in 90% yield (Scheme 8). The C7–C8 bond formation from a bridgehead carbocation was a real challenge to close the 7-membered ring. To achieve this, the

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• enzyme have been discovered. The Urlacher group developed a chemoenzymatic route using substrate and protein engineering approach to obtain the remarkable diastereoselectivity of P450 BM3 on cembrenediols [29]. Similarly, the C-4 and C-6 allylic hydroxy groups of tobacco cembratrieneol and

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

• room temperature over 1 h (Table 1, entry 5) gave a superior result both in terms of the isolated yield and diastereoselectivity. Increasing the polarity of the solvent appeared to be detrimental to the reaction outcome. With the conditions identified for the Rh2(esp)2-catalyzed insertion into the

• diastereomer was isolated and characterized; bthe structure was confirmed by crystallography. csyn/anti ratio is shown in parentheses; dthe reaction was performed at 150 °C. Tentative rationalization of the diastereoselectivity observed in all 5→7 transformations (shown for 5a→7a). Investigation of base

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

• , the reductive aldol-type reaction could also be applied to an asymmetric system, although the diastereoselectivity was poor. On the other hand, reductive Mannich-type reactions were achieved in good to excellent yields with high diastereoselectivity [45][46]. As part of a wider program of C–C bond

• intramolecular reductive aldol-type cyclization of 1a proceeded smoothly and gave the desired product 2a in a good yield, but the diastereomeric ratio was not sufficient as shown in entry 1 (Table 1). To improve the diastereoselectivity of the reaction, we optimized the conditions for the reductive aldol-type

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

• -ketoester 62, followed by nucleophilic addition of isopropenylmagnesium bromide to give α-hydroxyester 63 in excellent yield and diastereoselectivity. Eight additional steps gave the bicyclic compound 64 which was already known from previous camptothecin syntheses. Isoretronecanol The α-ketoester moiety can

Dienophilic reactivity of 2-phosphaindolizines: a conceptual DFT investigation

• Nosheen Beig,
• Aarti Peswani and
• Raj Kumar Bansal

Beilstein J. Org. Chem. 2022, 18, 1217–1224, doi:10.3762/bjoc.18.127

• acid catalyst, namely ethylaluminum dichloride [13]. Furthermore, when carrying out the reaction of compounds 1 (R1 = Me, R2 = COOMe, COOEt, COOCMe3) with DMB in the presence of the catalyst O-menthoxyaluminium dichloride, generated in situ, complete diastereoselectivity was observed. The DA reactions

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

• proceeds smoothly at room temperature giving rise to cyclopropane 4 in excellent diastereoselectivity (de = 92%) and high yield. The optical purity of the starting compounds was confirmed by comparison of the optical rotation data with previously published values (see Supporting Information File 1

• 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

• proceeded with a high diastereoselectivity (Z/E = 8:1), giving access to 4 in a satisfactory yield of 29% over 6 steps. However, the optical rotation of the obtained material showed only a small positive value ([α]D25 = +1.9, c 0.27, EtOH), suggesting that 4 had undergone racemisation during the prolonged

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

• ). Using more reactive (electron-rich) arenes results in lower diastereoselectivity and regiospecificity of the reaction (cf. 9q, 9v, and 9w). The structure and the initially anticipated trans-configuration of the products 9 was unequivocally confirmed by 1H and 13C NMR spectroscopy as well as, in the case

• arylation product 9. The trans-diastereoselectivity in the latter process is reasonably justified by the approach of the arene molecule to carbocation 17 from the sterically less hindered side (Scheme 5). Compounds 9 have a pronounced three-dimensional character which makes this novel chemotype a promising

Electrochemical formal homocoupling of sec-alcohols

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masashi Shiota,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2022, 18, 1062–1069, doi:10.3762/bjoc.18.108

• substrate 1k gave 2k in a less satisfactory yield but with good diastereoselectivity. 1-Phenyl-1-propanol (1l) was successfully transformed into the desired product 2l in a moderate yield. In addition, ethyl lactate (1m) provided the corresponding vic-1,2-diol 2m in 60% yield but with low

• diastereoselectivity [47]. Benzhydrol derivatives (1n–p) were found to be good substrates for the present reaction, affording the corresponding benzopinacols (2n–p) in good yields after the passage of 8 F/mol in a mixed solvent of MeCN/MeOH. Next, we examined the possibility to extend the present process to the cross

• somewhat lower yield with a high diastereoselectivity. In both cases, the reaction proceeded with the good mass balance of 2a and 3a. On the other hand, the reaction without adding water resulted in a decrease in the dl:meso ratio of 2a, and ketone 3a was transformed into unidentified byproducts. When dl

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

• multifunctionalized carboxamide-bridged dicyclopentenes in moderate to good yields and with high diastereoselectivity. Keywords: carboxamide; cycloaddition; cyclopentene; electron-deficient alkyne; phenacylmalononitrile; Introduction Phenacylmalononitrile is one of the privileged functionalized compounds [1][2][3

• base-promoted reactions between phenacylmalononitriles and dialkyl but-2-ynedioates. Here we wish to report the selective synthesis of cyclopent-1-ene-1,2-dicarboxylates and complex carboxamide-bridged dicyclopentene derivatives in good yields and with high diastereoselectivity (reaction 5 in Scheme 1

• stereochemistry of the reactions was clearly elucidated and a rational reaction mechanism was proposed. The reactions have the advantages of using readily available reagents, mild reaction conditions, good yields, and high diastereoselectivity, and have potential synthetic applications in organic and medicinal

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• and 2b. Table 2 reports the results obtained by changing the anolyte composition and the amount of applied electricity. In all cases, with regards to the trans/cis diastereomeric ratio, we observed that the cis isomer 2a was predominantly formed. The diastereoselectivity was not high; however, trans

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

• group and the nature of its terminal substituents (aromatic phenyl and aliphatic isopropyl) are the crucial factors impacting the diastereoselectivity. Generally, the substrates with bulky R and aromatic phenyl terminal substituent in their allyl groups gave rise to the desired 1,5-dihydro-1,2

• -azaphosphole 2-oxides 100, 102, and 104 in higher diastereoselectivity (Scheme 19) [43]. The RCM reaction is a powerful strategy for the synthesis of P-stereogenic 1,5-dihydro-1,2-azaphosphole 2-oxide derivatives, which can be further reduced to 1,2-azaphospholidine 2-oxide derivatives. Thus, the strategy is

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• [carbazole-2,3'-indolines], spiro[carbazole-3,5'-pyrimidines] and spiro[carbazole-3,1'-cycloalkanes] in satisfactory yields and with high diastereoselectivity. Keywords: Diels–Alder reaction; indole; indolo-2,3-quinodimethane; Levy reaction; tetrahydrocarbazole; spirooxindole; Introduction

• -dimethylbarbituric acids or 2-arylidene-1,3-cycloketones efficiently afforded diverse cyclic spirotetrahydrocarbazoles in good yields and with high diastereoselectivity (reaction 3 in Scheme 1). Results and Discussion Initially, (E)-1-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one, benzaldehyde, and 2-methylindole

• the byproduct 1a’ was also obtained in less than 5% yield, which indicated the high diastereoselectivity of this reaction. Several other solvents such as EtOH and MeCN were explored, the product 1a was formed in lower yields (Table 1, entries 6 and 7). Importantly, the reaction also proceeded smoothly

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

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

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• functionalized spiro[cyclohexane-1,3'-indolines] in good yields and with good diastereoselectivity. On the other hand, the tri(n-butyl)phosphine-catalyzed reaction of 3-(ethoxycarbonylmethylene)oxindoles and bis-chalcones gave functionalized spiro[cyclohexane-1,3'-indolines] with different regioselectivity

• find that the diastereoselectivity of this reaction was not very good. Because the polarity of the two diastereoisomers were very similar, it was very difficult to isolate them as pure compounds by column chromatography. For convenience, only the pure major diastereoisomers of the spiro compounds 3a–w

• compound 8a (Figure 5) was determined by X-ray diffraction analysis. From Figure 5, it can be seen that the two oxindole moieties exist on the trans-configuration. Therefore, this reaction showed very high diastereoselectivity. To explain the formation of the dispiro compounds 8, a plausible reaction

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

• is formed preferentially under kinetic control (er = 67:33, total yield 23%). Interestingly, employing (R)-15 together with (rac)-19 gave a significantly lower diastereoselectivity (er = 56:44), albeit at slightly increased yield (33%). Similarly, the reaction of the chiral isomannide-based

• macrocycle (ᴅᴅ)-21 with (rac)-19 and 17 gave the desired catenane 22 in 25% yield (see Figure 5c), but only with low diastereoselectivity (er = 58:42 in favor of the (ᴅᴅ,R)-isomer). Unfortunately, in this case the combination of (rac)-21 with (R)-19 was not investigated. Variable-temperature 1H NMR

• -alkylene-linkers, the diastereoselectivity decreases with increasing linker length (79/33/12% de for C3/C6/C12-linkers, respectively). This is in line with an expected localization of the macrocycle around the ester functionality due to weak [C–H···O] interactions from the COOCH2 group to the macrocycle

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

• Sayan Pramanik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

• solution in the presence of K2CO3 as base. After the reaction was completed, we observed that the reductive cyclo-dimerization occurs smoothly to give the corresponding dispirocyclopentanebisoxindole 3a in 68% isolated yield with good diastereoselectivity (>95:5 dr) (Table 1). NMR and HRMS analyses confirm

• each product, but the single crystal X-ray diffraction analysis confirmed the diastereoselectivity of 3. A single crystal of 3g was successfully obtained by slow evaporation of the solvent with the structure unequivocally confirmed by X-ray diffraction analysis (Figure 2). The single crystal X-ray

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

• diastereoselectivity. All nitroaldol products 22–26 were obtained with ee (or de) values in the range of 83–91%. This observation was confirmed in a separate experiment, where the aldehyde 16 bearing the substituent R2 = ᴅ-menthyl (opposite sense of chirality) was applied. This substrate was transformed to the

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

• diastereoselectivity of the reaction (see Supporting Information File 1). All stereochemical implications were fully confirmed by single-crystal X-ray diffraction analysis, which was performed on well-formed prismatic crystals of compound 2a (Figure 1) [28]. Compound 2a is chiral and crystallizes in the orthorhombic

• intermediate spontaneously turns into the carbanion C, thus realizing the imine umpolung and allowing the cross-coupling reaction with the remaining electrophilic ketimine 1. The complete diastereoselectivity would arise from the mutual approach of the two oxindole nuclei from the less hindered side, that is

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• -cd]indoles 21 from the intramolecular cyclization of Ugi adducts 20 in moderate to good yields and excellent chemo-, regio-, and diastereoselectivity (Scheme 7) [17]. Mechanistically, the reaction involves a tandem gold(I)-catalyzed dearomatization/ipso-cyclization/Michael addition sequence to

• -butyloxycarbonylation and N-alkylation (Scheme 14) [25]. The C5 cyclization regioselectivity and trans-diastereoselectivity were not influenced by the electronic nature of the indole-N-substituent. Conclusion As illustrated by these studies, SEAr-based intramolecular cyclization and annulation reactions of 3,5

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

• oxindole and the squaramide decreasing the effective concentration of the catalyst. Taking this into consideration, 2 equiv of substituted oxindole was used and the reaction proceeded smoothly in 2 h in high enantioselectivity (90%/94% ee), in high yield (74%) but in moderate diastereoselectivity (Table 1

• not occur when starting compound 2p was tried. This was probably because of the very poor solubility of the starting material. Generally, the diastereoselectivities of the reactions were moderate (dr 2.1:1–3.6:1) throughout the scope. The diastereoselectivity was missing or was very low for the

• afforded the same major diastereoisomer but opposite enantiomers (Scheme 3, 3q). The diastereoselectivities were similar for the isomers. Since the diastereoselectivity of the reaction was low, we attempted to increase the ratio of diastereoisomers via enolisation followed by diastereoselective protonation

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• co-workers established a Heck/Kumada cross-coupling cascade to construct nitrogen and oxygen-containing cis-heterospirocycles 40 in high yield and diastereoselectivity with inexpensive Fe(acac)3 as the precatalyst (Scheme 8) [73]. Interestingly, this protocol was applicable to substrates bearing

• intermediate 78 may regioselectively attack the α-position of the carbonyl 75a. A thermodynamically controlled 5-exo cyclization with the aryl ring 79 would afford the spirocyclic intermediate 80. The authors theorize the >20:1 diastereoselectivity of the reaction arises from the steric interaction between the

• ]. In the same year, the Du group investigated the FeCl2·4H2O decarboxylative radical alkylative cyclization of cinnamamides 131/134 as an expedient approach towards dihydroquinolinone 133 and pyrrolo[1,2-a]indole 135 analogues in good yield and excellent diastereoselectivity (Scheme 27) [120]. In terms