High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine

• Eric Yu,
• Hari P. R. Mangunuru,
• Nakul S. Telang,
• Caleb J. Kong,
• Jenson Verghese,
• Stanley E. Gilliland III,
• Saeed Ahmad,
• Raymond N. Dominey and
• B. Frank Gupton

Beilstein J. Org. Chem. 2018, 14, 583–592, doi:10.3762/bjoc.14.45

• synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous

Addition of dithi(ol)anylium tetrafluoroborates to α,β-unsaturated ketones

• Yu-Chieh Huang,
• An Nguyen,
• Simone Gräßle,
• Sylvia Vanderheiden,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2018, 14, 515–522, doi:10.3762/bjoc.14.37

• dithiolane and dithiane protecting groups which are irreplaceable intermediates for the introduction of, e.g., fluorine via gem-difluorination [1][2]. They also allow the formation of valuable building blocks that can be used for diverse transformations in organic chemistry (e.g., Umpolung) [3]. Ketene 1,3

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• use of photolabile protecting groups [38] of allyloxycarbonyl groups deprotected by Pd(0) [39] and of fluoride-labile groups [40] in place of the standard acyl protection of nucleobases has made possible the acquisition of short sequences of heteropolymer pro-oligonucleotides. However, none of these

• to their rapid removal under mild conditions [57]. Heat-sensitive phosphate/thiophosphate-protecting groups have been incorporated into ONs via phosphoramidite chemistry using solid-support methodology. However, some required more drastic conditions (90 °C for a long period of time) to be cleaved

• potential immunotherapeutic prodrugs [58]. The first impressive result was obtained in vivo with a CpG ODN (CpG ODN fma1555) functionalized with the 2-(N-formyl-N-methyl)aminoethyl (fma) thiophosphate protecting groups, which were cleaved at 37 °C to yield the well-known immunomodulatory CpG ODN 1555

Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines

• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 416–429, doi:10.3762/bjoc.14.30

• sugars as substrates presents some limitations, as any remaining protecting groups must be removed in a subsequent step. Firstly, and most importantly, glycosyl oxazolines are extremely labile to acidic hydrolysis, and so this approach precludes the use of any OH-protecting groups that require acidic

• conditions for their cleavage. Secondly some glycosyl oxazolines are also prone to reductive cleavage by catalytic hydrogenation [41], presenting a significant further limitation as to which OH-protecting groups may be employed. Most of the reports in the literature have therefore used a protecting group

• of the 3-branched arm. Subsequent removal (or regioselective reductive ring-opening) of the 4,6-benzylidene protecting group allowed a second glycosylation at position 6. Conversion of all OH-protecting groups to acetate and the phthalamide to acetamide was followed by oxazoline formation using TMSBr

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• gene libraries stands out as facilitating fully controlled total or partial randomization at any predefined number and position of codons of a given gene. Trinucleotide synthons need to be chemically synthesized. Here, the challenge has been to find a suitable set of orthogonal protecting groups that

• ]. A key issue in all these methodologies is that the 5'- or the 3'-O-protecting group is selectively cleaved, whereas all other protecting groups (at the nucleobases, the phosphorous and the 5'- or alternatively 3'-OH group) remain intact. Basically, this aim has been achieved, although in particular

• in earlier reports a number of problems associated with insufficient stability of protecting groups under synthesis conditions, as well as restricted orthogonality have been described, which was mirrored in the sometimes severely limited quality of the trinucleotide synthons and accordingly of the

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides

• Lingjun Xu,
• Shuwen Han,
• Linjie Yan,
• Haifeng Wang,
• Haihui Peng and
• Fener Chen

Beilstein J. Org. Chem. 2018, 14, 309–317, doi:10.3762/bjoc.14.19

• . Different protecting groups for the nitrogen at the C-2 position and oxygen at C-3 are also investigated to yield the desired chiral catalysts using a simple procedure. With various bifunctional catalysts in hand, assessment of their catalytic behavior in enantioselective alcoholysis of meso-cyclic

• reactivity with this electron-poor 7i suggested that the pKa is crucial for this catalysis. Further modifications of the chloramphenicol skeleton with various protecting groups on the nitrogen at C-2 position and oxygen at C-3 did not improve the reaction but with lowered enantioselectivity (Table 1, entries

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• trifluoromethyl radical was generated from CF3SO2Na in the presence of TBHP at room temperature using a mixture of water and DCM as solvent. Arylboronic acids with electron-donating substituents proceeded smoothly to give the corresponding products in good yields. Common hydroxy protecting groups (Bn and TBS

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• or 2-aminophenol afforded compounds 5 and 6, respectively. Refluxing 5 with t-BuOK in EtOH generated 7 in 38% isolated yield. When 6 was treated with the same cyclization conditions as 5 only dehalogenation was observed. Compound 8 was obtained by first removing the acetyl protecting groups using

• , the oxo-analogue tCO, which Lin et al. initially prepared in 1995 [41], was re-synthesized in order to characterize its photophysical properties, using the same procedure except that p-toluoyl protecting groups rather than acetyl were used [31]. In 2009, we published the first base–base FRET system

• yields, was effectively obtained in 86% yield by using an excess of KF in ethanol and microwave heating at 140 °C. Conveniently, at the same time all the three acetyl protecting groups were cleaved and the free nucleobase was isolated via precipitation. A 5´-DMTr protection followed by 2´-TBDMS

Stereochemical outcomes of C–F activation reactions of benzyl fluoride

• Neil S. Keddie,
• Pier Alexandre Champagne,
• Justine Desroches,
• Jean-François Paquin and
• David O'Hagan

Beilstein J. Org. Chem. 2018, 14, 106–113, doi:10.3762/bjoc.14.6

• years, there has been an increasing interest in C–F bond activation [2], with a view to using organic bound fluoride as a leaving group in substitution reactions that typically require more activated leaving groups. Such an approach could circumvent the requirement for protecting groups in multistep

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• comprising lipid A and describes the synthesis and immunobiological properties of representative lipid A variants corresponding to different bacterial species. The main criteria for the choice of orthogonal protecting groups for hydroxyl and amino functions of synthetically assembled β(1→6)-linked

• fluoride required an excess of Lewis acid as promotor which was incompatible with the acid-labile protecting groups present in the key diglucosamine precursor. Therefore, a new N-phenyltrifluoroacetimidate Kdo donor 35 was developed (Scheme 4) [21]. The disaccharide acceptor 34 was prepared by

• regioselectively phosphorylated in a stereoselective manner by 1-O-lithiation with LHMDS, and subsequent treatment with tetrabenzyl pyrophosphate at −78 °C. Protecting groups were removed by hydrogenolysis on Pd-black to give H. pylori lipid A 39. For the synthesis of Kdo-lipid A 41 entailing a phosphoethanolamine

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• (rt, 24 h) and TBDMS protecting groups were removed with HCl (pH 2, rt, 12 h). (B) Large-scale production of RNAs with cap0 or cap1 by a combination of solid-phase synthesis and enzymatic methylation [111]. Deprotection conditions: DBU (1,8-diazadicyclo[5,4,0]undec-7-ene) in acetonitrile (rt, 3 min

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• free alcohol which was oxidized to provide the N-protected dipeptide isostere 9. Some limitations were observed towards the compatibility of the N-protecting groups and in particular, N-tert-butoxycarbonyl-protected amines were not compatible with this methodology. Xaa-ψ[CF=CH]-Gly To access Xaa-ψ[CF

A semisynthesis of 3'-O-ethyl-5,6-dihydrospinosyn J based on the spinosyn A aglycone

• Kai Zhang,
• Shenglan Liu,
• Anjun Liu,
• Hongxin Chai,
• Jiarong Li and
• Lamusi A

Beilstein J. Org. Chem. 2017, 13, 2603–2609, doi:10.3762/bjoc.13.257

• opportunities to synthesize spinosyn analogues and rhamnose derivatives. Keywords: 3-O-ethyl-2,4-di-O-methylrhamnose; protecting groups; semisynthesis; spinetoram; spinosyn A; Introduction Spinosyns, a large family of secondary metabolites produced by aerobic fermentation of Saccharopolyspora spinosa, are a

• ). Rhamnose contains several hydroxy groups with similar chemical activities, so regioselective protection and alkylation are challenges. Common protecting groups of the hydroxy group at 1-position of rhamnose include allyl [28], methoxyphenyl [29] and 1-thiorhamnoside [30]. Compared with the reaction

• conditions of the other two protecting groups, the conditions of selective allyl protection are mild, and no irritant gas is produced during the reaction, so selective allyl protection was chosen to afford 1. A survey of literature [31][32][33] shows that the combination of Bu2SnO and EtBr can selectively

Diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside: synthesis, derivatives and antimicrobial activity

• Henryk Myszka,
• Patrycja Sokołowska,
• Agnieszka Cieślińska,
• Andrzej Nowacki,
• Maciej Jaśkiewicz,
• Wojciech Kamysz and
• Beata Liberek

Beilstein J. Org. Chem. 2017, 13, 2310–2315, doi:10.3762/bjoc.13.227

• . This procedure removes the TCP and acetyl protecting groups in a one-pot reaction and yields diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside (4). Saponin 4 treated with the HCl in MeOH was converted into hydrochloride 5. To explore the influence of different modifications of the amino group in 4 on its

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

• Ophélie Maurin,
• Pascal Verdié,
• Gilles Subra,
• Frédéric Lamaty,
• Jean Martinez and
• Thomas-Xavier Métro

Beilstein J. Org. Chem. 2017, 13, 2087–2093, doi:10.3762/bjoc.13.206

• , thereby leading to a lower overall conversion [14]. The removal of the protecting groups was performed by treatment of the Boc-protected peptides with gaseous HCl in the absence of solvents, providing the amino esters as hydrochlorides in high yield and purity (Scheme 1). Alternatively, removal of the Boc

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• that affected the removal of the template and all benzyl protecting groups followed by acetylation of the resulting hydroxy groups. Peptide tether/template Short peptide chains have also been investigated as templates for glycosylation. The general underpinning idea is to streamline the oligosaccharide

• -selectivity. With the varying anomeric stereoselectivities and yields, it was hypothesized that the benzylic methylene group may be responsible for the increased rotational freedom between the triazoyl and benzyl moieties. Investigations with o-azidobenzyl protecting groups were used to reduce the degrees of

1,3-Dibromo-5,5-dimethylhydantoin as promoter for glycosylations using thioglycosides

• Fei-Fei Xu,
• Claney L. Pereira and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2017, 13, 1994–1998, doi:10.3762/bjoc.13.195

• of their aglycons (SEt or STol). This promoter is compatible with most commonly used protecting groups, except some electron-rich groups like 4-methoxybenzyl ethers that may be partly brominated under these conditions [40]. To probe the scope of DBDMH/TfOH-mediated 1,2-cis-glycosylation

• inexpensive reagent DBDMH has been demonstrated to be a powerful promoter for the activation of thioglycosides. This promoter is readily available, highly soluble, and shelf-stable. A variety of substrates containing diverse protecting groups have been investigated with promising results, while the

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• ], published in 2007, Kishi and co-workers increased the overall efficiency of the synthesis by reorganizing the assembly of the principal fragments and by optimizing the key C(sp2)–C(sp3) Negishi cross-coupling reactions as well as the choice of protecting groups. The 3rd generation approach [123], published

• secondary TES and the primary TBS ether protecting groups was followed by selective oxidation of the ensuing primary alcohol to deliver seco acid 27. The crucial macrolactonization was performed under Yamaguchi conditions [135] in 70% yield and subsequent cleavage of the secondary TBS ether under mildly

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

• Raja Ben Othman,
• Mickaël J. Fer,
• Laurent Le Corre,
• Sandrine Calvet-Vitale and
• Christine Gravier-Pelletier

Beilstein J. Org. Chem. 2017, 13, 1533–1541, doi:10.3762/bjoc.13.153

• -Paris), 45 rue des Saints Pères, 75270 Paris 06, France 10.3762/bjoc.13.153 Abstract The 5’-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2’,3’-di-O-protecting groups (R1): O-alkyl groups led to

• ; nucleoside; protecting groups; uridine; Introduction Nucleoside and nucleotide derivatives or analogues are biologically active compounds of major interest [1][2]. Their widespread applications span from therapeutic agents, such as antibacterial [3][4][5], antiviral [6] or antitumor [7][8] drugs, to

• organometallic reagents onto nucleoside aldehyde (Table 1), we decided to investigate the influence of the protecting groups of the uridine aldehyde on the stereochemical outcome of the nucleophilic addition of a Grignard reagent and we wish to report herein the results of our study. Results and Discussion We

A new member of the fusaricidin family – structure elucidation and synthesis of fusaricidin E

• Marcel Reimann,
• Louis P. Sandjo,
• Luis Antelo,
• Eckhard Thines,
• Isabella Siepe and
• Till Opatz

Beilstein J. Org. Chem. 2017, 13, 1430–1438, doi:10.3762/bjoc.13.140

• single signal set, so the fate of the assumed minor stereoisomer remains unclear and it was probably lost during HPLC purification. The analysis also revealed that the acylation with the GHPD side chain was selective for the amine and no O-acylated product was formed. Side chain protecting groups were

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• oligonucleotide. Since the phosphate protecting groups are normally base-labile and the repeatedly removable 5´-O protecting group is acid-labile, the 2´-O-protection should preferably be removable under orthogonal conditions. For this purpose, numerous protecting groups have been proposed [18][19], the fluoride

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• diastereoselectivity (3:97 dr). To further extend the reaction scope, we attempted to exchange the N-Boc group of the 3-substituted oxindoles with other protecting groups, such as Bn, CH3 or an acetyl group. The results demonstrated that only an acetyl protecting group proved to be well tolerated, providing for the

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• Abstract Glycosylation is an immensely important biological process and one that is highly controlled and very efficient in nature. However, in a chemical laboratory the process is much more challenging and usually requires the extensive use of protecting groups to squelch reactivity at undesired reactive

• review, we showcase the methods available for the selective activation of the anomeric center on the glycosyl donor and the mechanisms by which the glycosylation reactions take place to illustrate the power these techniques. Keywords: glycosides; glycosylation; oligosaccharides; protecting groups

• result, in synthetic chemistry, this process of glycosylation is very often cumbersome and can involve the use of highly toxic reagents [5][6][7][8]. The idealized scenario would be a glycosylation strategy that can occur in the complete absence of protecting groups under mild, neutral conditions. The

Synthesis of alkynyl-substituted camphor derivatives and their use in the preparation of paclitaxel-related compounds

• M. Fernanda N. N. Carvalho,
• Rudolf Herrmann and
• Gabriele Wagner

Beilstein J. Org. Chem. 2017, 13, 1230–1238, doi:10.3762/bjoc.13.122

• practical synthetic methods for the selective synthesis of precursor dialkynes bearing different substituents (alkyl, aryl) at the triple bonds, based on ketals or an imine as protecting groups. We show for isomeric dialkynes that the reaction cascade induced by Pt(II) includes ring annulation, sulphur

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks

• Sushil K. Maurya and
• Rohit Rana

Beilstein J. Org. Chem. 2017, 13, 1106–1118, doi:10.3762/bjoc.13.110

• and 2c) irrespective of the position of the propargyl group on the primary OH (1e) or secondary OH group (1d). Next we thought of exploring the effect of protecting groups on the feasibility of the reaction and the yields and various building blocks with free OH groups were selected. It is worth