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

Selective sulfonylation and isonitrilation of para-quinone methides employing TosMIC as a source of sulfonyl group or isonitrile group

• Chuanhua Qu,
• Run Huang,
• Yong Li,
• Tong Liu,
• Yuan Chen and
• Guiting Song

Beilstein J. Org. Chem. 2021, 17, 2822–2831, doi:10.3762/bjoc.17.193

• 10). As depicted in Scheme 4, the substrate scope of p-QMs 1 was first examined. In general, the 1,6-conjugate reaction tolerated a wide range of p-QMs 1, furnishing a series of isonitrile diarylmethanes 4a–h in good to high yields (60–88%) with moderate diastereoselectivity. Substitution of the aryl

• providing, for example, the product 4h with a yield of 86% and excellent diastereoselectivity (dr > 19:1). To further underline the utility of this transformation, several experiments were carried out (Scheme 5). First, the model reaction is scalable. When 1b (3 mmol) and 2a (6 mmol) were mixed under the

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

• hydrogen peroxide catalyzed by phosphotungstic heteropoly acid. Each of the key reactions proceeded with an excellent diastereoselectivity (dr > 95:5). (±)-Codonopsinol B was prepared in 10 steps with overall 8.4% yield. The antiproliferative effect of (±)-codonopsinol B and its N-nor-methyl analogue was

• evaluated using several cell line models. Keywords: alkaloids; antiproliferative effect; codonopsinol B; diastereoselectivity; pyrrolidines; Introduction Codonopsinol B (1) is a polyhydroxylated pyrrolidine alkaloid isolated from the roots of the plant Codonopsis pilosula (Figure 1) [1]. This compound was

• the expected high syn diol diastereoselectivity (Scheme 1). The obtained anti,syn-(hydroxyamino)alkenol 4 will be then subjected to reductive cleavage of the N–O bond. Next, a key intermediate epoxide 5 with the desired syn (threo) configuration between the hydroxy group and the epoxide oxygen could

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• diastereoselectivity and 99% ee in the presence of the chiral phosphoric acid CPA 2. Subsequently, using the chiral phosphoric acid-catalyzed [3 + 2] formal cycloaddition and a moderate DDQ oxidation method over 34, enantiomerically enriched 2,3-diarylbenzoindoles 35 were successfully prepared by performing a central

• moderate yield with >90% enantioselectivity (Scheme 20c) and tolerable diastereoselectivity (4:1) [73]. The optically enriched benzimidazoles are N-heterocycles which are of great interest as drug-like molecules [75], and exhibit biological activities such as anticancer, antiviral, antifungal, and

• diastereoselectivity (10:1 to >20:1 dr). In addition, the enantioselective 1,8-conjugate addition of azlactones 112 to para-quinone methides generated in situ from propargyl alcohols 110 were carried out in the presence of 1 mol % chiral phosphoric acid CPA 7 and afforded the chiral allenes 114 in high yields (65–97

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

• -nitrostyrene (7a) catalyzed by (S,R)-C2 (Scheme 3). The reaction in CH2Cl2 at 5 °C with Et3N as a base gave 45% of adduct 8a with 86:14 dr and 24:76 er for both diastereomers. Slightly better yields (63%) were achieved in CHCl3 at room temperature with Et3N or NMP as a base, but both diastereoselectivity as

• without a base went much less efficiently (Table 1, entry 16), similarly to the reaction performed without acid additive and base (Table 1, entry 17). The product 10c by Michael addition of hexanal 6b to nitroalkene 9 was obtained with only 40% yield with comparable diastereoselectivity (Table 1, entry 18

• ). The aliphatic aldehydes propanal (6d) and hexanal (6b) provided medium yields and diastereoselectivity and enantioselectivity. The Michael addition of 3-phenylpropanal (6c) to (E)-3-(2-nitrovinyl)pyridine (11) required long reaction times (120 h) in solution, similar to those for the reaction with (E

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• afforded the corresponding adducts in good yields ranging from 72–99% with excellent diastereoselectivity (up to >99:1 dr) and enantioselectivity (>99% ee) (Table 6) [36]. In another report, Yang et al. accomplished a highly asymmetric cascade aza-Michael/Michael addition reaction for the synthesis of

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

• anti-addition of the sulfoxonium ylide to 52. Hou highlighted that the good diastereoselectivity control for the sulfoxonium ylide addition to acyclic α,β-unsaturated substrates such as 52 observed in their work represented the first example in literature. Hereupon, deprotonation of 53 over LiHMDS

• followed by addition of TBSOTf at low temperature successfully formed the (Z)-silyl enol ether 54. Application of the Sharpless asymmetric dihydroxylation, promoted by AD-mix-β, gave the expected β-(R)-hydroxy cyclopropyl product 55 in 84% yield with moderate diastereoselectivity (dr = 2). The formation of

• successfully attained in 97% yield with very high diastereoselectivity (dr 99:1). The free secondary alcohol group was re-protected as MOM ether 70 in 96% yield. After removal of the TBDPS group, the resulting free primary alcohol was oxidized under Dess–Martin conditions followed by Grignard reaction with

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

• isosteviol derivate furnished a useful and versatile oxathiazinane (46). The betulinic acid-derived sulfamate ester preferentially underwent amination at the γ primary C–H bond of the equatorial C23 methyl group with high site- and diastereoselectivity to furnish the oxathiazinane derivative in 76% yield

• observed at the Dha-3 part and, according to the substitution pattern from the coupling partner, a higher preference for the substitution at the Dha-1 (product A) over the Dha-2 (product B) site was also observed (Scheme 38B), characterizing an excellent and valuable regio- and diastereoselectivity. In the