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

• the mixture of 38 and 39 induced a second α-ketol rearrangement to 40 as a tautomeric mixture. The same research group later utilized the same [3 + 2] cycloaddition and α-ketol rearrangement approach to prepare the 2′′′-epimer of 35, which bears an inverted methyl acetal in the dioxane ring, but this

Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure

• Agnieszka Grajewska,
• Maria Chrzanowska and
• Wiktoria Adamska

Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168

• reaction (Scheme 2). Results and Discussion Our investigations commenced with the synthesis of N-benzylated aminoacetaldehyde acetals 3a–e, the amine components for the Petasis reaction. The condensation of aminoacetaldehyde diethyl acetal 1 and 2,3-dimethoxybenzaldehyde (2a) was carried out at rt in

• 5a–d carried out in DCM at rt for 24 h to afford amino acids 6a–g (Scheme 4). The condensation of N-(2,3-dimethoxybenzyl)aminoacetaldehyde acetal (3a) with glyoxylic acid hydrate (4) and 3,4-dimethoxyphenylboronic acid (5a) afforded the Petasis reaction product 6a in a high 94% yield. The double

• decarboxylated analogue of 6a, under the reaction conditions that led to products 7a or 8 starting from acid 6a. The substrate for the synthesis of compound 12 was aminoacetal 3f, obtained with moderate 49% yield through the condensation of aminoacetaldehyde diethyl acetal (1) and 3,4-dimethoxybenzaldehyde (2f

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

• (−)-DIPT affording ent-85 in 65% yield. A series of functional group transformations involving hydroxy group protection, reduction of the epoxide, protection of the resultant free alcohol as TBS ether, and removal of the acetal protection afforded the expected allylic alcohol 83. Accordingly, cross

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)

• Tania Xavier,
• Sylvie Condon,
• Christophe Pichon,
• Erwan Le Gall and
• Marc Presset

Beilstein J. Org. Chem. 2021, 17, 2085–2094, doi:10.3762/bjoc.17.135

• incompatible with either base-sensitive or acid-sensitive substituents, as the desired SMAHOs are isolated after acidification to pH ≤ 2. It was thus impossible to prepare reagents bearing a phthalimide, an ester or an acetal group. This limitation is overcome by the other possibilities afforded by this

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

• via an acid-catalyzed cyclization of O-protected ortho-acetal diarylmethanols 81a and 81b as a new type of reactants (Scheme 19) [52]. To carry out the cyclization step, this new methodology employed a diluted aqueous methanolic solution of HCl at room temperature. This step was based on a modified

• intramolecular Friedel–Crafts-type cyclization. This was the first report of the same molecule bearing an acid-sensitive acetal and dibenzyl alkoxy groups. The key steps described in the work were protection of the aldehyde group of 6-bromopiperonal (80) by using 1,2-ethanediol or 1,3-propanediol, followed by

• ortho-acetal diarylmethanols. Lewis acid-mediated regioselective cyclization of asymmetric diarylmethine dipivalates and diarylmethine diols. BF3·OEt2/CF3SO3H-mediated cyclodehydration reactions of 2-(arylmethyl)benzaldehydes and 2-(arylmethyl)benzoic acids. Synthesis of 2,3,6,7

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• , respectively, has proved to be the most effective for the promotion of the conjugate addition of 4-hydroxycoumarins 1 to 2-hydroxycinnamaldehydes 109, leading to chiral bridged bicyclic acetal products 110 with high ee (Scheme 35). The mechanistic study performed showed that possibly the phenolic hydroxy group

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• -hydroxypipecolic acid 145 was reported recently by Zhang and Sun. Compound 145 is an intermediate for the synthesis of β-lactamase inhibitors. A key step in this synthesis was the hydrocyanation of chiral sulfinyl imine 141, prepared from commercially available and inexpensive ʟ-glyceraldehyde acetal, with

• trimethylsilyl cyanide (TMSCN) in THF at −10 °C. The reaction product 142 was obtained in quantitative yield and good diastereomeric ratio. Further hydrolysis of the cyclic acetal, and subsequent epoxidation of the resulting diol under typical Mitsunobu conditions led to epoxide derivative 143. The piperidine

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• C2, can be accomplished by nucleophilic fluorination and azidolysis starting from dianhydro derivatives 1 and 2 as we described previously [26]. The resulting intermediates 3 can be transformed into 2-azidohexopyranosides 4 by cleavage of the internal acetal and protection of the anomeric position

• internal acetal with PhSTMS was accompanied by the formation of low quantities of side-products detectable by TLC and separable by careful chromatography except for the cleavage of 12 where the side products co-eluted with the fraction containing the β-anomer of the product. In the case of the cleavage of

• ). 4,6-O-Benzylidenation of diol 18 followed by regioselective opening of the benzylidene acetal produced compound 35. Subsequent DAST deoxyfluorination delivered the desired thioglycoside 36 (Scheme 3). For both compounds 18 and 35, deoxyfluorination of the C4 hydroxy group occurred with inversion of

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• with DTBP for the synthesis of polyketide SCH 351448 [43], as shown in Scheme 14. Hart and Bennett have also examined the trifluroacetic acid-catalyzed Prins cyclization of acetal 71 to afford 72 along with side-chain-exchanged product 73 (Scheme 15) [44]. This method was utilized for the synthesis of

• -unsaturated acetals 164 in the presence of electron-rich olefins using Ce(NO3)3 and SDS in water [74]. The mechanism of the reaction is shown in Scheme 39, which plausibly proceeded through trapping of oxocarbenium ion 166 in a chair-like transition state. The stability of the acetal under these reaction

• conditions reflected that the acid-sensitive functional groups are well tolerated in the cyclized product. Furthermore, a natural product, (+)-dactyloide, was synthesized by following the above strategy using an appropriate acetal (Scheme 40) [75]. The synthesis of enantiomerically enriched 172, cis-2,6-DHP

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

Manganese/bipyridine-catalyzed non-directed C(sp³)–H bromination using NBS and TMSN₃

• Kumar Sneh,
• Takeru Torigoe and
• Yoichiro Kuninobu

Beilstein J. Org. Chem. 2021, 17, 885–890, doi:10.3762/bjoc.17.74

• , without any loss of the halogen substituents. Although the C(sp3)–H bromination of isobutyl benzoate 1f did not proceed at 60 °C, the corresponding C(sp3)–H brominated compound 2f was produced at higher temperature (80 °C). The C(sp3)–H bond in acetal 1g was efficiently brominated to give 2g in 79% yield

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

• Carl Recsei and
• Yaniv Barda

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

• was available. We report a simple, new procedure which we applied to the synthesis of some of these unusual structures. Keywords: acetal; aryloxyfluoromethane; dihalocarbene; herbicide; organofluorine; Introduction Organofluorine molecules are widely used for medicinal, agrochemical and material

• )chloromethane via a published protocol for radical chlorination of an acetal due to the presence of vulnerable benzylic methyl groups proximate to the acetal [10]. We then synthesized carboxylic acid 9, from which we anticipated creating an aryloxylchlorofluoromethane (10, X = Cl, Scheme 4) via

• 5 h, with 85% hydrolysis observed after 20 hours. The relative stability of 11 to acidic hydrolysis and its presumably enhanced lipophilicity with respect to a des-fluoro acetal, might presage a role for compounds possessing the acyclic bis(aryloxy)fluoromethane moiety in medicinal or agrochemical

Helicene synthesis by Brønsted acid-catalyzed cycloaromatization in HFIP [(CF₃)₂CHOH]

• Takeshi Fujita,
• Noriaki Shoji,
• Nao Yoshikawa and
• Junji Ichikawa

Beilstein J. Org. Chem. 2021, 17, 396–403, doi:10.3762/bjoc.17.35

• fluorine, which helps to generate cations but does not affect cationic reactions [23][24][25][26][27]. Thus, HFIP greatly facilitates reactions via cationic intermediates [28]. In the presence of a catalytic amount of trifluoromethanesulfonic acid in HFIP, (biaryl-2-yl)acetoaldehydes or their acetal

• -shot construction of helicene frameworks. Based on ease of preparation, symmetrical cyclization precursors would be preferable, and thus they should possess either (i) one acetal moiety on each terminal aromatic ring (Ar2) of the teraryl core (Scheme 3, route a) or (ii) two acetal moieties on the

• ) in the teraryl structure, because the diborylated arenes were less available. Either (a) the coupling of boronic acid esters bearing one acetal moiety with dihalogenated arenes or (b) the coupling of dihalogenated arenes bearing two acetal moieties with arylboronic acids were conducted for the

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• group was found to be essential in this reaction as 2,4-pentanedione did not react with benzene under similar conditions. The use of acetal derivatives in place of ketones as precursors of oxygen-stabilized α-(trifluoromethyl)carbenium ions was also investigated. For instance, the readily available

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• -difluorocyclopropyl acetals 110 to form 2-aryl-3-fluorofurans 112 (Scheme 50) [99]. The reaction could proceed either via the intermediacy of the gem-difluorocyclopropyl ketone 111 (path a) or by the direct rearrangement of the protonated acetal (path b). Recently, the group of Amii has reported the conversion of 1

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

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

• . J. K. Taylor and co-workers reported the first total synthesis of inthomycin B ((+)-2) using a Stille coupling of a stannyl-diene with an oxazole vinyl iodide unit followed by a Kiyooka ketene acetal/amino acid-derived oxazaborolidinone procedure as its cornerstones (Scheme 4) [43]. In the beginning

• (Z,E)-52 with silyl ketene acetal 53 in the presence of oxazaborolidinone derived from N-tosyl-ʟ-valine and BH3·THF generated the desired alcohol (Z,E)-(+)-54 in 74% yield and 64% ee. Next, a wide range of catalysts/conditions were screened for the crucial Stille coupling between iodide 48 and (Z,E

• )-diene 66 (E/Z = 19:1, separable) using the standard (E)-selective Horner–Wadsworth–Emmons (HWE) reaction. DIBAL-H reduction of ester 66 followed by MnO2 oxidation produced aldehyde (E,E)-67 stereoselectively. Unfortunately, attempted enantioselective aldol reactions of (E,E)-67 with silylketene acetal

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• dipolar cycloaddition to produce tricyclic isoxazolidines [40]. The synthesis started from 5-hexyn-1-ol (4, Scheme 2). The alcohol was treated with dihydropyran followed by alkylation using butyllithium and then, acetal deprotection, providing the alcohol 5 as a key starting compound for the (±)-adaline

• , activated by lithium ion in a tricyclic N,O-acetal (−)-46, and an olefin metathesis (RCM) of a dialkenylpiperidine (−)-50 for the construction of an azabicyclononane system [48]. The synthetic sequence described by the authors is shown in Scheme 6. The lactam present in 43 was opened by treatment with

• LiH2NBH3 in THF at 40 °C to provide amino alcohol (−)-44 in 88% yield. This amino alcohol underwent cyclization through a one-pot process in the presence of TPAP-NMO, which involved oxidation in generated aldehyde 45, followed by dehydrocondensation leading to N,O-tricyclic acetal (−)-46 in 80% yield

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• adduct 105 in 93% yield with 99% ee. The freshly prepared enantioenriched adduct 105 was subjected to ozonolysis [47] followed by decarboxylation to give bisoxindole 106 in 68% yield over two steps. Conversion of 106 to the corresponding acetal and subsequent allylation afforded 108 in 86% yield over two

• on 160 to the enone and produces 161. The newly formed 161 was subjected to 5-exo radical addition to the allyl sulfane and subsequent loss of a thiyl radical produces 162. A successive hydrolysis/decarboxylation upon heating and cleavage of acetal on 162 afforded aldehyde 163 in 90% yield. Coupling

Ultrasound-assisted Strecker synthesis of novel 2-(hetero)aryl-2-(arylamino)acetonitrile derivatives

• Emese Gal,
• Luiza Gaina,
• Hermina Petkes,
• Alexandra Pop,
• Castelia Cristea,
• Gabriel Barta,
• Dan Cristian Vodnar and
• Luminiţa Silaghi-Dumitrescu

Beilstein J. Org. Chem. 2020, 16, 2929–2936, doi:10.3762/bjoc.16.242

• ] appeared improved under ultrasound-assisted conditions, which also enhanced the yields of the final α-aminonitrile derivatives. The Strecker reaction of cyclopropanone acetal substrates with sodium cyanide and several amines was also facilitated by sonication conditions which afforded cleaner N-alkylated α

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• -bromoacetaldehyde acetal by using aluminum(III) chloride as a Lewis acid catalyst through [1 + 2 + 2] annulation. This new versatile methodology provides a wide scope for the synthesis of different functional N-(hetero)aryl-4,5-unsubstituted pyrrole scaffolds, which can be further derived to access multisubstituted

• expensive and nonrecyclable homogeneous metal catalysts. To alleviate all these problems, herein, we used easily available α-bromoacetaldehyde acetal (2a) and a simple 1,3-dicarbonyl compound as a reagent couple to react with (hetero)arylamines. The established [1 + 2 + 2] annulation reaction provided a

• straightforward approach for accessing various N-(hetero)aryl-4,5-unsubstituted pyrroles, and some of the pyrrole products are not accessible with the methods reported hitherto. Results and Discussion Initially, a mixture of aniline (1a), α-bromoacetaldehyde acetal (2a), and ethyl acetoacetate (3a) was treated

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• glycol to afford monocyclic acetal 53 with less hindered keto-group in respectable yield. Since the introduction of powerful electron-withdrawing groups such as fluorine atom(s) in any material changes its behavior significantly, in this regard, Sakurai’s group installed six fluorine atoms at the

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• with a poor stereoselectivity, however, a similar reduction of the diethyl acetal of 38, followed by an acetal hydrolysis gave the aldehyde 39 with a good stereocontrol (>10:1). It is not possible to make a direct comparison of the efficiency of these three routes as they do not lead to an identical

• iodine-catalyzed Mukiyama–Michael addition of the ketene silyl acetal 104 to 103 afforded the trans-1,5-disubstituted tetrahydropyranone 105. After the generation of the C-3-exocyclic olefin and functional group manipulation, the Takai olefination [40] of the aldehyde 106 gave the trans-vinyl iodide 107

• generation of the mixed acetal 113 (Scheme 18) [33]. A ring-closing metathesis gave an inseparable mixture of the dihydropyranyl ethers 114a and 14b, which could be equilibrated under acidic conditions (114b/114a > 20:1). A standard functional group manipulation afforded the vinyldihydropyran-2-one (−)-115

Synthesis of monophosphorylated lipid A precursors using 2-naphthylmethyl ether as a protecting group

• Jundi Xue,
• Ziyi Han,
• Gen Li,
• Khalisha A. Emmanuel,
• Cynthia L. McManus,
• Qiang Sui,
• Dongmian Ge,
• Qi Gao and
• Li Cai

Beilstein J. Org. Chem. 2020, 16, 1955–1962, doi:10.3762/bjoc.16.162

• compound 13. Then, (2-naphthyl)methylene acetal [21] was used to protect the C-4,6-hydroxy groups using 2-naphthaldehyde dimethyl acetal and 0.2 equiv of camphorsulfonic acid (CSA). These protecting group manipulations resulted in the exposure of the C-3 hydroxy group in compound 14 for further acylation

• FmocCl in the presence of diisopropylethylamine (DIPEA) to give the fully protected compound 17. The regioselective opening of the arylidene acetal at O6 with Et3SiH and PhBCl2 in the presence of molecular sieves at −78 °C [22] gave compound 18 in good yield (80%) having a free C-6 hydroxy group

• phosphorylated using tetrabenzyl diphosphate in the presence of lithium bis(trimethyl)silylamide (LHMDS) in THF at −78 °C [23] to afford the anomeric phosphate 23 exclusively as the α-anomer. Finally, global deprotection of 23 (benzyl phosphate, Nap ethers, and naphthylidene acetal) were accomplished by

Synthesis of the tetrasaccharide repeating unit of the O-specific polysaccharide of Azospirillum doebereinerae type strain GSF71^T using linear and one-pot iterative glycosylations

• Arin Gucchait,
• Pradip Shit and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2020, 16, 1700–1705, doi:10.3762/bjoc.16.141

• led to the formation of disaccharide acceptor 5 in 73% yield. The quantity of HClO4-SiO2 present in the reaction mixture was very low, which allowed the selective deprotection of the highly acid labile PMB group without affecting the benzylidene acetal in the molecule in dichloromethane as the solvent

• without the isolation and purification of the intermediate glycosylation products. Finally, compound 7 was subjected to a set of reactions involving (a) transformation of the azido group to an acetamido group by the treatment with thioacetic acid [33]; (b) removal of the benzylidene acetal by the

One-pot synthesis of 1,3,5-triazine-2,4-dithione derivatives via three-component reactions

• Gui-Feng Kang and
• Gang Zhang

Beilstein J. Org. Chem. 2020, 16, 1447–1455, doi:10.3762/bjoc.16.120

• the reaction of trialkyl orthoformate 3 with thiourea (2) to produce imidate intermediate 9, which is nucleophilically attacked by intermediate 10 and transfers the alkyl group R2 to deliver the alkylated intermediate 11. Meanwhile, N,N-dimethylformamide dialkyl acetal might also play a role in this