Bi(III) Catalysed O-acylative cleavage of 2,5-dimethyltetrahydrofuran: a substrate dependent borderline mechanism

The Bi(III) catalysed O-acylative cleavage of cis- and trans-2,5-dimethyltetrahydrofuran 4 with AcCl, BzCl or i-PrCOCl is stereochemically consistent with the operation of a concerted process (A_ND_N), which proceeds via a stabilised carbocation or ‘loose’ S_N2 transition state. However, the O-acylative cleavage of cis-2,5-dimethyltetrahydrofuran 4 with sterically demanding electrophiles such as t-BuCOCl, appears to be stereochemically consistent with the alternative S_N1 (D_N+A_N) pathway. The apparent merging of mechanistic pathways is rationalised by the participation of a strained acyloxy cation.     

Base-promoted O-deprotonation/alkylation reaction of P(O)–OH compounds with alkyl halides

A novel base-promoted O-deprotonation/alkylation reaction of P(O)–OH compounds with alkyl halides has been developed. The protocol is practical, representing a simple way to produce a broad spectrum of functionalized phosphinates, phosphonates, and phosphates from basic starting materials with good to excellent yields. A plausible mechanism was proposed for this reaction.     

Synthesis of 4-O-[3-(aryl)prop-2-ynyl]-Neu5Ac2en and its 4-epi-analogs modified at C-4 by Sonogashira coupling reaction

To explore new inhibitors of the sialidase of human parainfluenza virus type 1 (hPIV-1), a series of novel Neu5Ac2en derivatives were synthesized. Thus, 8,9-O-isopropylidene-4-O-2-propynyl-Neu5Ac2en methyl ester 8 was subjected to a Sonogashira coupling reaction with a variety of heteroaryl halides to produce a series of 4-O-(3-heteroaryl-2-propynyl) compound 9. Treatment of 9 with 80% acetic acid followed by alkaline hydrolysis afforded deprotected Neu5Ac2en compounds. The 4-epi-analogs of this type of Neu5Ac2en were synthesized in a similar manner. Compound 5d showed the most potent inhibitory activity (IC₅₀ 1.2 μM) against hPIV-1 sialidase.     

C-N bond formation followed by N-Cl bond breaking. One more and unexpected case of the formation of a hydroxamic group via heterolytic bond cleavage

An unexpected and previously unknown reaction sequence in the interactions of the acyl halides with nitrosobenzenes, which involves carbon-nitrogen bond formation followed by heterolytic nitrogen-chlorine bond cleavage giving the corresponding unsubstituted N-phenylalkylhydroxamic acids (or N-phenylarylhydroxamic acids) and chlorine as the products has been observed. The kinetic and other evidence obtained suggest that the carbon-nitrogen bond formation is the consequence of a nucleophilic interaction of an N-phenylchlorohydroxylamine intermediate, formed in the first reaction step, with the acyl halide in the second step of the complex sequence, which leads to an N-acyl-N-chlorophenylhydroxylamine cation intermediate. The key reaction step involves the interaction of an N-acyl-N-chlorophenylhydroxylamine cation intermediate with chloride ion, which leads to the N-Cl heterolytic bond cleavage and the final formation of the hydroxamic group and a molecule of chlorine.     

Ring-opening reaction of methylenecyclopropanes with LiCl, LiBr or NaI in acetic acid

The methylenecyclopropanes 1 react with LiCl, LiBr or NaI at 80 °C to give the corresponding gem-disubstituted homoallylic halides 2 in good to excellent yields in acetic acid. In some cases, the ring-opening reaction can be completed within 5 min to give the corresponding gem-disubstituted homoallylic halides in high yields.     

Palladium(0)-catalyzed cascade one-pot synthesis of isoxazolidines

A highly diastereoselective cascade reaction protocol has been developed for the synthesis of isoxazolidine derivatives utilizing aryl halides, O-homoallyl hydroxylamine and palladium(0) in a one-pot reaction.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

Reactivity of TEMPO anion as a nucleophile and its applications for selective transformations of haloalkanes or acyl halides to aldehydes

Sodium 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO⁻Na⁺), generated by reduction of TEMPO· with sodium naphthalenide in THF, reacted with alkyl halides or acyl halides to produce O-alkylated or acylated TEMPOs, which were in turn oxidized with mCPBA or reduced with DIBAL-H to afford the corresponding aldehydes, thus accomplishing a new protocol for the halides-carbonyls conversion.     

N-(Diethoxyphosphoryl)-O-benzylhydroxylamine—a convenient substrate for the synthesis of N-substituted O-benzylhydroxylamines

Easily available N-(diethoxyphosphoryl)-O-benzylhydroxylamine was shown to be convenient, orthogonally protected substrate for regioselective N-alkylation by means of diverse halides under basic conditions (sodium hydride/tetrabutylammonium bromide). An efficient procedure for dephosphorylation of N-substituted N-(diethoxyphosphoryl)-O-benzylhydroxylamine to provide N-substituted O-benzylhydroxylamines was also established.     

Substituted tubaic acids, new oxidative rotenoid metabolites from Lonchocarpus nicou

A lipophile extract of Lonchocarpus nicou roots afforded two likely O-substituted isomers of the known tubaic acids. Spectroscopic analysis assigned to the former, named (−)-rotoic acid, the new 4-(2,3-dihydro-6,7-dimethoxychromon-3-oxy) tubaic acid structure which differs from (−)-deguoic acid, the latter, by the β-tubaic acid part. Biogenetically, the two compounds could be considered as resulting from the parent rotenone and deguelin, respectively, by oxidative ring-C cleavage.     

2-Ethoxy-3-pyridylboronic acid: a versatile reagent for the synthesis of highly-functionalised 3-aryl/heteroaryl-pyridines via Suzuki cross-coupling reactions

This paper describes the commercially-viable synthesis and isolation of 2-ethoxy-3-pyridylboronic acid on a ca. 70 g scale via a directed ortho-metalation reaction on readily-available 2-ethoxypyridine. A range of efficient cross-coupling reactions of 2-ethoxy-3-pyridylboronic acid with selected aryl/heteroaryl halides under palladium-catalysed Suzuki-Miyaura conditions yield novel 2-ethoxy-3-aryl/heteroaryl-pyridines in high yield (heteroaryl=pyridyl, pyrimidyl, pyrazyl). The X-ray crystal structure of 2-ethoxy-3-pyridylboronic acid reveals that the boronic acid group takes part in an intramolecular O-H?O bond with the adjacent ethoxy substituent, and an intermolecular O-H?N bond.     

Reaction of an Introverted Carboxylic Acid with Carbodiimide

The reaction of carboxylic acids with carbodiimides is reviewed, and an ‘introverted’ carboxylic acid is proposed as a means of trapping reactive intermediates along the reaction pathway. The introverted acid is a cavitand with the carboxylic function directed toward the floor of the cavity. Its reaction with diisopropyl carbodiimide gives a covalent adduct that is either the elusive O-acylisourea or the commonly encountered N-acylurea.     

Synthesis of novel photolabile glycosides from methyl 4,6-O-(o-nitro)benzylidene-α-d-glycopyranosides

Novel photolabile sugar derivatives bearing a 4- or 6-O-(o-nitro)benzyl group have been prepared from the corresponding methyl 4,6-O-(o-nitro)benzylidene α-d-glycopyranosides. Regioselective cleavage with BF₃·Et₂O/Et₃SiH led to the methyl 6-O-(o-nitro)benzyl gluco- and manno-α-d-glycopyranosides 3 and 6. Inversion of configuration at 4-OH position of gluco and manno derivatives offered the otherwise inaccessible methyl 6-O-(o-nitro)benzyl galacto- and talo-α-d-glycopyranosides 4, 5, and 7. Careful reaction with PhBCl₂/Et₃SiH (3 equiv of reagents, 10 min at −78 °C) led to the desired methyl 4-O-(o-nitro)benzyl gluco- and manno-α-d-glycopyranosides 8 and 9 in very good yield. However, prolonged reaction with 6 equiv of PhBCl₂/Et₃SiH transformed the methyl 4,6-O-(o-nitro)benzylidene α-d-glucopyranoside 11 into the reduced d-glucitol derivative 15. Oxidative cleavage of 5,6-diol function of 15 gave the corresponding photolabile l-xylose 17. The photolabile glucosides 3 and 8 have been further transformed into the photolabile α-C-allyl d-glucopyranosides 20 and 22.     

Bis-β-sulfanylethylester and cyclic disulfide-S-oxides as precursors of bifunctionalized anionic derivatives with two oxidized sulfurs

The cyclic disulfide and the bis-β-sulfanyl ethyl ester derived from dithiol, N,N′-1,2-phenylenebis(3-methyl-3-sulfanylbutanamide) were used as precursors to prepare upon oxidation the cyclic disulfide-S-oxides and the thioether sulfur oxidized species including thioether/sulfoxide, bis-sulfoxide, sulfoxide/sulfone, and bis-sulfone. Ring cleavage with KOH/EtOH of the cyclic disulfide-S-monooxide followed by reaction of the opened intermediate with ethyl acrylate afforded the sulfinate/β-sulfanyl ethyl ester derivative. Selective oxidation with 1 and 2 equiv of (3S)-3-tert-butyl-3-methyl-2-(phenylsulfonyl)oxaziridine or with 3 equiv of DMD led to the isolation of a series of compounds containing a sulfonate and a β-sulfanyl, a β-sulfinyl, and a β-sulfonyl ethyl ester. Retro-Michaël reaction applied to the β-sulfonyl/β-sulfinyl and bis-β-sulfonyl derivatives enabled to produce compounds containing a sulfinate and a β-sulfinyl or a β-sulfonyl ethyl ester as well as the bis-sulfinate dianion. DMD oxidation of the latter afforded the bis-sulfonate dianion. All these anionic species were characterized by ¹H NMR, mass spectrometry, HRMS or elemental analysis. Sulfenates in such pseudopeptidic structures could not be isolated from the ring cleavage of the cyclic disulfide-S-dioxide or from a retro-Michaël reaction applied to the β-sulfinyl ethyl ester. A cyclization reaction leading to an isothiazolidin-3-one is likely to occur as observed from the ring cleavage of the cyclic disulfide-S-dioxide. Finally, Ni(II) and Co(III) have been inserted into the disulfinate dianion leading to the corresponding diamidato/disulfinato complexes S-bonded to Ni(II) or Co(III) centers.     

Efficient asymmetric synthesis of α-alkylated benzylic methyl sulfonates

The first highly efficient auxiliary-controlled synthesis of various α-substituted sulfonic acid derivatives is described. Alkyl or aryl halides were reacted with lithiated benzylic sulfonic esters bearing 1,2:5,6-di-O-isopropylidene-α-d-allofuranose as a removable enantiopure alcohol auxiliary to give the alkylated products in excellent diastereomeric excesses. The racemization-free cleavage conditions provided highly enantioenriched sulfonic acid derivatives (ee≥98%).     

Efficient synthesis of 5′-O(N)-carbamyl and -polycarbamyl nucleosides

A simple and efficient method for the preparation of 5′-O(N)-carbamyl and 5′-O(N)-polycarbamyl nucleoside derivatives is reported. The method consisted of treatment of 2′,3′-O-protected purine (Ado, Ino) or pyrimidine nucleosides (Thd, Urd) with trichloroacetylisocyanate, followed by cleavage of the trichloroacetyl moiety by silica-gel promoted methanolysis during column chromatography. Iterative application of this method gave mono, di, and tricarbamyl derivatives in good to excellent yields (ave = 80%).     

Synthesis of aza-aromatic hydroxylamine-O-sulfonates and their application to tandem nucleophilic addition-electrophilic 5-endo-trig cyclization

Hydroxylamine-O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine-O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition-electrophilic 5-endo-trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G^∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine-O-sulfonates and N-(5-methoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2H-[1,2,4]thiadiazolo[3,2-a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC₅₀ in the range 1.47-2.97 μM).     

Convenient high yield and stereoselective synthesis of O-glycopeptides using N-α-Fmoc-Tyr/Ser[β-d-Glc(OAc)4]OPfp generated in solution

Fmoc-AA-OPfp (AA=Tyr or Ser) (1 equiv) was reacted with β-d-Glc(OAc)₅ (6 equiv) in the presence of BF₃.Et₂O (6 equiv) in CH₂Cl₂ at room temperature for 2 h, and the glycosylation reaction mixture was used directly to couple to the amino group of the peptide resin without isolation and purification of the Fmoc-AA[β-d-Glc(OAc)₄]-OPfp. Moreover, the -OAc protecting groups of glucose was removed just prior to releasing the peptide from the resin using 6 mM NaOMe in 85% DMF-MeOH. The crude product obtained by TFA cleavage contained >90% of the target O-glycopeptide, and the 500 MHz ¹H NMR analysis revealed that the glycosylation reaction was nearly stereoselective (>97% β-anomer). This method is rapid and stereoselective, and can now be exploited for the routine synthesis of O-glycopeptides.     

An efficient and simple ligand from phthalandione for palladium-catalyzed Suzuki reaction in aqueous media

An efficient and simple ligand derived from phthalandione was used for palladium catalyzed Suzuki coupling reaction in water/ethanol (V/V = 2/1) under aerobic conditions. The reaction exhibited a high catalytic efficiency even with lower Pd loading (0.002 mol %). In this work, the catalyst could be successfully used in coupling reaction between various aryl halides with phenylboronic acid in excellent yields with high turnover number (TON) (the maximal TON was up to 49,000 for the reaction of bromobenzene with phenylboronic acid). Moreover, this new ligand had been elucidated by ¹H NMR, ¹³C NMR and X-ray crystal diffraction.     

DNA binding and cleavage behaviors of copper(II) complexes with amidino-O-methylurea and N-methylphenyl-amidino-O-methylurea,and their antibacterial activities

The two designed copper(II) complexes, [Cu(L^1m)₂]Cl₂ (1) (L^1m = amidino-O-methylurea) and [Cu(L^2m)₂]Cl₂ (2) (L^2m = N-methylphenyl-amidino-O-methylurea), have been investigated for their interaction with calf thymus DNA by utilizing the absorption titration method, viscometric studies and thermal denaturation. The cleavage reaction on pBR322 DNA has been monitored by agarose gel electrophoresis. The results suggest that the two complexes can bind to DNA by non-intercalative modes and exhibit nuclease activities in which supercoiled plasmid DNA is converted to the linear form. Complex 2, with an intrinsic binding constant (K_b) of 1.16 × 10⁵ M⁻¹, shows a higher binding efficiency and a better nuclease activity than complex 1, with a K_b value of 5.67 × 10⁴ M⁻¹. Their DNA cleavage potential can be significantly enhanced by hydrogen peroxide, indicating an oxidative cleavage process. Further examination of the antibacterial activities against Campylobacter has revealed inhibition zones of 9.0 (for 1) and 14.5 mm (for 2), which are in agreement with their minimum inhibitory concentration (MIC) values of 1.56 and 0.78 mg mL⁻¹, respectively. The substantially better reactivity of 2 results from the aromatic moieties on the side chain of the L^2m ligand which act as an additional binding site.