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

• . Results and Discussion Initially, we focused on the synthesis of β-lactam 2, which was prepared by the cycloaddition of chlorosulfonyl isocyanate (CSI) to cis,cis-1,3-cyclooctadiene, as described in the literature [26]. β-Lactam 2 was transformed into cis-amino ester 3 by cleavage of the lactam ring with

The enzyme mechanism of patchoulol synthase

• Houchao Xu,
• Bernd Goldfuss,
• Gregor Schnakenburg and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 13–24, doi:10.3762/bjoc.18.2

• proceeded with full retainment of the labelling in both cases (Scheme 1B). Subsequent chemical degradation through acid catalysed conversion into 5, oxidative cleavage to the diketone 13, BF3∙OEt2 mediated ring closure by aldol reaction and catalytic hydrogenation gave 14. For both experiments a full

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• macrocyclisation product, which was confirmed by MALDI-ToF-MS of the crude reaction mixture after test cleavage (see Supporting Information File 1, Figure S1). However, deboronation and dehalogenation were observed as side reactions to some extent as well as oxidation, most likely of methionine (Met) [79]. The

• oxidation could be minimised by improved cleavage conditions under argon. Replacing sSPhos by tri(o-tolyl)phosphine (P(o-Tol)3), that had successfully been applied for peptide cyclisation by on-resin SMC [78][80], led to incomplete conversion. The cyclisation of the same peptide with the regioisomer 6

• stability of both peptides P5 and P6 was tested against proteinase K digestion. Whilst the linear analogue P6 is cleaved within a period of 120 min to give three fragments, the stapled peptide P5 allows access to only one of the three cleavage sites: i.e., proteolysis of the Leu–Asp bond within the

DABCO-promoted photocatalytic C–H functionalization of aldehydes

• Bruno Maia da Silva Santos,
• Mariana dos Santos Dupim,
• Cauê Paula de Souza,
• Thiago Messias Cardozo and
• Fernanda Gadini Finelli

Beilstein J. Org. Chem. 2021, 17, 2959–2967, doi:10.3762/bjoc.17.205

• a reactive species, often used in catalytic amounts, capable of promoting a highly selective homolytic cleavage of the C–H bond that results in a carbon-centered radical [5][6]. Nitrogenated structures are easily oxidized under mild conditions into their radical or radical cation forms [7], being

A photochemical C=C cleavage process: toward access to backbone N-formyl peptides

• Haopei Wang and
• Zachary T. Ball

Beilstein J. Org. Chem. 2021, 17, 2932–2938, doi:10.3762/bjoc.17.202

• are relatively common, access to photo-responsive modifications of backbone N–H bonds is quite limited. This letter describes a new photocleavage pathway, affording N-formyl amides from vinylogous nitroaryl precursors under physiologically relevant conditions via a formal oxidative C=C cleavage. The N

• -formyl amide products have unique properties and reactivity, but are difficult or impossible to access by traditional synthetic approaches. Keywords: formyl peptide; nitroaryl compound; nitroso compound; olefin cleavage; photocleavage; Findings The photochemistry of nitroaromatic functional groups has

• -nitroaryl compounds. Various 2-nitrobenzyl derivatives are used to photocage heteroatom functional groups, including alcohols, amines, carboxylic acids, and phosphates [11]. Typical photochemical pathways result in cleavage of a benzylic C–X bond following initial benzylic H-atom abstraction [11][13]. In

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• in DMF (20 mL) for 30 min and then filtered. The resin was washed with CH2Cl2 (20 mL × 5) and CH3OH (20 mL × 5). General procedures for cleavage the peptide from the resin: 0.5% TFA in DCM (20 mL) were added on the resin and the mixture was shaken for 2 h before filtered. The resin was washed with

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

• the 1,6-enyne 35 followed by reductive elimination of the carbon nucleophile 38. Interestingly, this reaction proceeds via the cleavage of heteroelements and activated C–C bonds prior to reductive elimination of the metallacyclic ate-complex, resulting in the net formation of two new C–C bonds

• products in appreciable yield. Alkenyl fluoride, chloride, and bromide substrates 51/52 were found to be amenable to the reaction although with varying degrees of success, likely due to the competing base-promoted 1,2-elimination. With the cyclopropylidene-functionalized substrates 50a, ring-cleavage led

• isotope studies revealed the cleavage of the C(sp3)–H bond may be involved in the rate-determining step of this transformation. Mechanistically, prototypical homolysis of the peroxide in the presence of the Fe(II) catalyst will generate the alkyl radical 78 formed via hydrogen abstraction. The

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

• standard conditions, the desired products 3b or 4b were obtained with yields of 92% and 88%, respectively. Second, the sulfonylated diarylmethane 3b obtained through the C–S bond-cleavage sulfonylation reaction is a versatile building block for preparing diarylmethane derivatives through a nucleophilic

• acids via a triphenylphosphine-mediated deoxygenation process, followed by reaction with sulfonylated diarylmethane 3b to obtain diarylmethane ketone derivatives 6 and 7 [53]. To gain mechanistic insight into this C–S-bond cleavage sulfonylation reaction, some control experiments were conducted (Scheme

• is exemplified in Scheme 6C. The sulfonylation reaction starts with ZnI2/base system mediated C–S-bond cleavage of TosMIC derivative 2c to yield Ts anion II, in which 2c acts as the sulfonyl source. Finally, the sulfonylated diarylmethane 3a is formed by a sequential addition/aromatization process

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

• 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

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

• accessible 3,6-substituted-4,6-dihydro-3H-pyrazolo[3,4-d][1,2,3]triazines as nitrogen-rich heterocycles. The target compounds were obtained in five steps, including an amidation and a cyclative cleavage reaction as key reaction steps. The introduction of two side chains allowed a variation of the pyrazolo

• transformations without decomposition [37][38][39]. In the herein presented study, we apply the cyclative cleavage reaction to pyrazolyltriazenes instead of aryltriazenes, which results in the synthesis of diverse pyrazolo[3,4-d][1,2,3]-3H-triazine derivatives 5. Results and Discussion According to the literature

• have a major influence on the outcome of the reaction: (1) the addition of side chains R1 to the core pyrazole ring system, which can occur in position N-6 or N-7, and (2) the cyclative cleavage of the triazene group of compounds 9 and 10 which should lead to the target compounds 5 and 6. To carry out

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

• ]. Organocatalytic aryl C–H activation via a nonradical process represents an enormous challenge in organic synthesis, although the nucleophilic aromatic substitution with cleavage of the electrophilic aryl C–H bond has only recently been developed by transition-metal-catalyzed aryl C–H activation [57]. In the

• presence of a chiral phosphoric acid, the azo group has recently been revealed to be a useful moiety that may efficiently activate an aromatic ring for formal nucleophilic aromatic substitution, resulting in the cleavage of the aryl C–H bond and direct arylation of the nucleophile [58]. In 2018, Tan and co

• chiral N-arylbenzimidazoles involving a carbon–carbon bond cleavage under optimal reaction conditions. In the presence of CPA 2, N1-(aryl)benzene-1,2-diamines 66 were used in the reaction with multicarbonyl compounds 67 and 68 and afforded the corresponding products, axially chiral N-arylbenzimidazoles

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• should lead to an N-methyl group and to reductive cleavage of the carbonate-protected phenol(s); route B is based on treatment with an alkyllithium compound [26], which should remove all ethoxycarbonyl groups and provide N-nor analogues of the products obtained in route A (Figure 3). The required

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

• -butyldiphenylsilyl chloride (TBDPSCl) for selective protection. The compound was further debenzoylated by ammonolysis, which gave compound 16. Compound 16 underwent oxidative cleavage using lead tetraacetate, and the intermediate aldehyde was oxidized to the carboxylic acid using sodium chlorite, which afforded acid

• ). Sodium periodate was used for oxidative cleavage of cis-diol 3d. The subsequent aldehyde was then converted to a vicinal diol by reduction with sodium borohydride. Further, it was protected by 2,2-dimethoxypropane to give the 1,3-oxathiolane derivative 21. The benzoylated compound 22 was obtained by

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

• intermediate 117. C–O bond cleavage produces an α-iminol intermediate 118, which proceeds to rearrange by ring expansion to ultimately yield 119 (Figure 21a). Using the benzoate ester of 118 (R = Ph; X = CH2) as the substrate and N-methylindole as the heteroarene, optimal reaction conditions (95% yield) were

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• during degradation of cryogels, the walls of the cryogel decrease in thickness and are in some cases broken. This analysis was made for enzyme-degraded cryogels, so it is unclear whether the process is likely to occur for cryogels degraded by other mechanisms such as disulphide cleavage [30][31] and

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• [28][50], Cu(dap)Cl2 acted as a potential precatalyst in this photoreaction. Upon irradiation, the CuII complex undergoes homolytic cleavage of a Cu–Cl bond forming CuI as the catalytically active species; thus, the CuII complex is the precatalyst and provides a more efficient transformation than CuI

• mechanistic study, CuII serves as the catalytically active species that undergoes homolytic cleavage to form a CuI species and an azide radical. The latter adds to the alkene to form an alkyl radical, which is then trapped by oxygen to form the desired product. The homolytic cleavage of the active species

• alkyne (Scheme 18). Under visible-light irradiation, disulfides are easy transformed to thiyl radicals via the homolytic cleavage of the S–S bond [79]. In 2020, Anandhan and co-workers [80] explored the C(sp)–S coupling of terminal alkynes with 2-aminothiophenol dimer 38 as a radical precursor. Under

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• exchange was observed at the ortho-position of 1a with 3.0 equivalents of CD3CO2D under standard conditions (Scheme 5a). Furthermore, a larger value of kinetic isotope effect (KIE = 2.4) was detected (Scheme 5b). These results indicated that the cleavage of C–H bond was most likely involved in the rate

Synthesis of phenanthridines via a novel photochemically-mediated cyclization and application to the synthesis of triphaeridine

• Songeziwe Ntsimango,
• Kennedy J. Ngwira,
• Moira L. Bode and
• Charles B. de Koning

Beilstein J. Org. Chem. 2021, 17, 2340–2347, doi:10.3762/bjoc.17.152

• hypothesized that oxime 7 undergoes a homolytic cleavage of the N–O bond giving the iminyl radical 11 [14] followed by an intramolecular cyclization with concomitant expulsion of the ortho-methoxy group, liberating phenanthridine 9. To the best of our knowledge, such a reaction in which the aromatic methoxy

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• -deazaguanine failed in our hands. The 6-chloro atom of compound 3 was substituted using sodium methoxide under concomitant cleavage of the pivaloyl group to yield the desired O6-methylated compound 1, m6preQ0 (Scheme 4). After dissolving this compound under strong silylating conditions in the presence of N,O

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

• -alkylated with bromo ester 13. The formed product (i.e., 14) was first amidated and then cyclised using benzylamine 11 to generate spirooxindole 15 in 54% yield and 94% ee. Chlorination with NCS, followed by tert-butyl ester cleavage in TFA/CH2Cl2 provided the final bioactive compound 6 in 93% ee

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

• participates in the ionization step by an anion abstraction-type process (Figure 2b). In the latter approach, the C–X bond cleavage can then either follow a SN1 or SN2 pathway. For enantioselective purposes, solvation of the ion pair is crucial for obtaining high stereoinduction. While more polar solvents give

• example utilizing this strategy was provided by Jacobsen and co-workers for the desymmetrization of meso-aziridines 29. In their work, the bifunctional phosphinothiourea catalyst 31 promoted the C–N bond cleavage by hydrochloric acid upon initial protonation (Scheme 7) [55]. Subsequently, the catalyst

• heterolytic cleavage of HCl as displayed in Scheme 7 [55]. Moreover, other catalysts with amine functional groups were found more efficient in the enantioselective α-alkylation of aldehydes (Scheme 10b) [48] or in the asymmetric Mannich synthesis of α-amino esters using Takemoto’s bifunctional catalyst 44 [67

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• similar reaction conditions with moderate to good yields. Based on their detailed mechanistic studies, the authors proposed a possible catalytic cycle involving a C–H cleavage via a HAT process between the triplet excited ketone photocatalyst 24 and the C(sp3)–H substrates (Figure 8) [66]. Thus, the

• yields were observed for carboxylic acid substrates 81 with different steric properties. Similarly, amine substrates 80 with diverse substitution patterns and functional groups were well tolerated to provide the desired products in optimal yields. The proposed mechanism involves the cleavage of the C(sp3

• high yields. Based on the detailed computational and experimental mechanistic studies, the authors proposed a catalytic cycle which involves the C–H cleavage prior to the oxidative addition of N-acylsuccinimide (Figure 19) [125]. The acylation of benzylic C‒H bonds with acid chlorides 45 by means of

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

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

• were found to be unreactive, probably due to steric hindrance. The one-pot difunctionalization of arenes involving a sequential C–O cleavage and C(sp2)–H activation mediated by chromium was recently reported by Luo and Zeng [124]. The reaction allows an ortho-directed diarylation of o

• action of Meerwein’s salt (Me3OBF4) and a mild base (proton sponge) to afford a methoxy cedrene derivative. Next, oxidative cleavage of the double bond using NaIO4/RuCl3·xH2O enabled a ring opening, followed by lactonization promoted by CuBr2 via an intramolecular acyloxylation. The 5,5-fused ring system

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• latter strategy can be divided into the conjugation of amine groups onto ONs still attached to the solid support, or onto ONs in solution after cleavage from the solid support. The C-5 position of the pyrimidine ring has in general been the most used attachment point since it is not involved in hydrogen

•  3A) [57]. The G-clamp modification was later observed to have antisense inhibition activity involving RNase H cleavage with a single incorporation into a PS-ON [58]. Afterwards, a guanidino-G-clamp (modification 24) was synthesized to increase the number of hydrogen bonds that could be established

• simultaneously with cleavage from the solid support [66]. It was found that the modified ON gave an improved duplex stability relative to the unmodified ON by 15 °C at 150 mM NaCl [66]. Later, improved syntheses of the phosphoramidite derivatives of guanine analogues have been developed [67]. Thus, many studies