Acyloxy Group Research Articles

Structure–activity relationship studies on acremomannolipin A, the potent calcium signal modulator with a novel glycolipid structure 4: Role of acyl side chains on d-mannose

As part of an ongoing study on the structure–activity relationship of acremomannolipin A (1)—the novel glycolipid isolated from Acremonium strictum possessing potent calcium signal-modulating activity—the role of acyl substituents on the d-mannose moiety was examined. Three partially deacylated homologs (2a–2c) and 20 homologs (2d–2w) bearing different acyloxy side chains were synthesized via the stereoselective β-mannosylation of appropriately protected mannosyl sulfoxides (3) with d-mannitol derivatives (4), and their calcium signal-modulating activities were examined. The activities of 2a–2c were completely lost. Homologs bearing relatively short acyloxy groups at C-3, C-4, and C-6 positions (2t–2v) exhibited less activity than 1, whereas a heptanoyl homolog (2w: C7) maintained activity nearly equal to that of 1. When the acyl groups at these three positions were substituted by an octanoyl group (2i: C8), the activity was completely lost. On the other hand, of the 10 homologs in which the octanoyl at C-2 was substituted by other acyloxy moieties (2j–2s), three (2m: C7, 2n: C9, 2o: C10) maintained potent activity. These results suggested that peracylated mannose structure is critical for calcium signal-modulating activity, and this activity is precisely dependent on the length of four acyl side chains on d-mannose.

Rhodium-Catalyzed Intramolecular [5+2] Cycloaddition of Inverted 3-Acyloxy-1,4-enyne and Alkyne: Experimental and Theoretical Studies.

By switching the position of the alkene and alkyne, a new type of 3-acyloxy-1,4-enyne (ACE) five-carbon building block was developed for Rh-catalyzed intramolecular [5+2] cycloaddition. An electron-withdrawing acyl group on the alkyne termini of the ACE was essential for a regioselective 1,2-acyloxy migration. This new method provided bicyclic [5.3.0]decatrienes that are different from previous methods because of the positions of the alkenes and the acyloxy group. Multiple mechanistic pathways become possible for this new [5+2] cycloaddition and they are investigated by computational studies.

Candida antarctica lipase B-catalyzed regioselective deacylation of dihydroxybenzenes acylated at both phenolic hydroxy groups

Candida antarctica lipase B proved to be highly active in the deacylation of substituted hydroquinones and resorcinols acylated at both phenolic hydroxy groups. The deacylation reactions were much faster than the corresponding direct acylations of these dihydroxybenzenes catalyzed by the same lipase. More importantly, they took place generally in a markedly regioselective manner: the acyloxy group remote from the substituent was preferentially cleaved. The main or exclusive products obtained were the regioisomers of those produced through the direct acylation of the dihydroxybenzenes. In the case of alkyl-substituted hydroquinone derivatives, the regioselectivity increased with an increase in the bulk of the substituent. In the case of 4-substituted diacylated resorcinols, the 3-O-monoacyl derivatives were obtained generally as the sole products. Quite interestingly, some secondary alcohols proved to act as better acyl acceptors than the corresponding primary alcohols in these enzymatic deacylations.

ChemInform Abstract: Functionalization of a Pyridine Framework Through Intramolecular Reissert—Henze Reaction of N‐(Carbamoyloxy)pyridinium Salts and Unexpected Insertion of Ethereal Solvents.

Abstract2‐Pyridyl carbamates are synthesized involving a new intramolecular transformation of an acyloxy group from N‐carbamoyloxypyridinium salts as key step.

Mass spectrometric profiling of valepotriates possessing various acyloxy groups from Valeriana jatamansi.

Valepotriates, plant secondary metabolites of the family Valerianaceae, contain various acyloxy group linkages to the valepotriate nucleus and exhibit significant biological activities. Identification of valepotriates is important to uncover potential lead compounds for the development of new sedative and antitumor drugs. However, making their structure elucidation by nuclear magnetic resonance (NMR) experiments is too difficult to be realized because of the overlapped carbonyl carbon signals of acyloxy groups substituted at different positions. Thus, the mass spectrometric profiling of these compounds in positive ion mode was developed to unveil the exact linkage of acyloxy group and the core of valepotriate. In this study, electrospray ionization tandem multistage mass spectrometry (ESI-MS/MS(n)) in ion trap and collision-induced dissociation tandem MS were used to investigate the fragmentation pathways of four types of valepotriates in Valeriana jatamansi, including 5-hydroxy-5,6-dihydrovaltrate hydrin (5-hydroxy-5,6-dihydrovaltrate chlorohydrin), 5,6-dihydrovaltrate hydrin (5,6-dihydrovaltrate chlorohydrin), 5-hydroxy-5,6-dihydrovaltrate and valtrate hydrin (valtrate chlorohydrin). The high-resolution mass spectrum (HRMS) data of all the investigated valepotriates from quadrupole time-of-flight MS/MS were used as a supportive of the fragmentation rules we hypothesized from ion-trap stepwise MS(n). As a result, the loss sequence of acyloxy groups and the abundance of key product ions, in combination with the characteristic product ions corresponding to the valepotriate nucleus, could readily differentiate the four different types of valepotriates. The summarized fragmentation rules were also successfully exploited for the structural characterization of three new trace valepotriates from V. jatamansi. The results indicated that the developed analytical method could be employed as a rapid, effective technique for structural characterization of valepotriates, especially for the trace compounds that could not be identified by NMR techniques. This study may also arouse interest for further structural analysis of other valepotriate-containing type herbal medicines.

Functionalization of a Pyridine Framework through Intramolecular Reissert–Henze Reaction of N‐(Carbamoyloxy)pyridinium Salts and Unexpected Insertion of Ethereal Solvents

AbstractA new strategy for synthesis of the 2‐pyridyl carbamates is reported. This strategy exploits a new intramolecular transformation of an acyloxy group from N‐carbamoyloxypyridinium salts (Reissert–Henze‐type reaction) as the key step. Addition of a silver salt effectively accelerates the intramolecular attack of the carbonyl oxygen at the 2‐position of the pyridine ring. Additionally, a new rearrangement of the acyloxy group, combined with insertion of an ethereal solvent to give pyridine derivatives having a coordinating tether, is reported.

Synthesis of α-hydroxyalkyl peroxide esters and ethers as initiators of radical processes

α-Hydroxyalkyl peroxide esters and ethers containing, along with the peroxy bond, also acyloxy and alkoxy groups, are effective initiators of radical processes. The initiation efficiency is due to the capability of these molecules to generate simultaneously oxygen- and carbon-centered radicals capable of hydrogen abstraction from the substrate and of addition to 〉C=C〈 bonds. The selectivity of the synthesis of α-hydroxyalkyl peroxide esters and ethers is mainly determined by the steps of the synthesis and isolation of the intermediate α-chloroalkyl peroxides, because of their high reactivity. Experimental conditions allowing control of the synthesis of α-hydroxyalkyl peroxide esters and ethers were found.

ChemInform Abstract: Gold(I)‐Promoted Heterocyclization of Internal Alkynes: A Comparative Study of Direct Metallate 5‐endo‐dig Cyclization versus a Stepwise Cyclization.

AbstractThe title reaction affords five‐ and six‐membered ring nitrogen heterocycles.

A new mechanism of enantioselectivity toward chiral primary alcohol by lipase from Pseudomonas cepacia

The stereo-recognition of chiral primary alcohols by lipase from Pseudomonas cepacia was found to deviate from earlier observations. Enantioselectivity toward 14 pairs of chiral primary alcohol esters by this lipase was dependent on the existence of an Onon-α (oxygen at non-α-position of the acyloxy group) in the alcohol moiety, and decreased as the size of the acyl moiety increased. Chemical modification on the lipase and molecular dynamics simulations indicated that Tyr29 located within the catalytic cavity forms a hydrogen bond with the Onon-α of the preferred enantiomer of the primary alcohol ester. However, a larger acyl moiety suffered stronger hindrance from the catalytic cavity wall of the lipase, pushing the Onon-α away from Tyr29, and thus weakening the stereo-recognition.

An evidence of contact ion pair in β-(acyloxy)alkyl radical heterolysis during copper(I)-mediated synthesis of trisubstituted alkenes

The first evidence for a unified mechanism of heterolysis in β-(acyloxy)alkyl radical involving contact ion pair (CIP) is presented for both fragmentation and rearrangement of the acyloxy group in the reaction of 1-alkoxy-2,2,2-trichloroethyl acetate with 2molequiv each of CuCl and bpy in refluxing DCE under a N2 atmosphere and availed this reaction for the synthesis of Z-stereoselective trisubstituted alkenes. The stereochemistry of the trisubstituted alkenes was assigned by the uniform pattern of the chemical shift values of some relevant signals in 1H and 13C NMR spectra. This assignment was further supported by the X-ray diffraction spectroscopy of Z-1-chloro-2-(4-nitrobenzyloxy)vinyl acetates.

Gold(I)-promoted heterocyclization of internal alkynes: a comparative study of direct metallate 5-endo-dig cyclization versus a stepwise cyclization.

With cationic gold catalysts, internal alkynes bearing both propargylic acyloxy groups and tosylamide pronucleophiles were found to cyclize to give either five- or six-membered ring nitrogen heterocycles. A wide variety of gold catalysts, counterions, and solvents were examined to elucidate their effect on product distribution. In most cases, the direct 5-endo-dig cyclization was found to be the major pathway leading to good yields of dehydropyrrolidine products. Alkyne substrates bearing additional normal alkyl substituents at the propargylic position gave dehydropiperidines as the major product. This pathway is thought to proceed by way of a 1,2- Rautenstrauch rearrangement to produce a vinyl gold(I) carbene, which undergoes conjugate addition by the nitrogen pronucleophile. Structural and electronic factors were studied in the nitrogen pronucleophile and in the migrating acyloxy group. Each was found to have a minor effect on the product ratio.

Synthesis, structural and conformational study of some esters derived from 3-methyl-3-azabicyclo[3.2.1]octan-8(α and β)-ols

A series of α and β-esters bearing a 3-methyl-3-azabicyclo[3.2.1]octane moiety as well as methyl and aryl substituents were synthesized and studied by 1H and 13C NMR spectroscopies. In CDCl3 solution, at room temperature, a chair-envelope conformation for the bicycle moiety with the N-CH3 group in equatorial position with respect to the chair ring is proposed for both, α and β-esters. The chair conformation of the piperidine ring is puckered at C8 in the α-epimers and it is flattened at N3, in the β-epimers. Free rotation of the acyloxy group around the C8O bond has also been deduced. Analgesic activity of four of these substances was studied. 8β-Benzoyloxy-3-methyl-3-azabicyclo[3.2.1]octane demonstrated significant analgesic activity in the hot plate test compared to morphine. By measuring the rectal temperature in mice, results also showed a significant antipyretic activity of this compound.

ChemInform Abstract: Copper(I)‐Catalyzed Diastereoselective Hydroxytrifluoromethylation of Dienes Accelerated by Phosphine Ligands.

AbstractThe combination of CuCN with the bulky ligand P(tBu)3 effectively promotes the transfer of both the CF3 and acyloxy group from Togni′s reagent (II) to dienes, affording the corresponding E‐olefins or the trans configured allylic alcohol derivative (IX) after hydrolysis.

Synthesis of Functionalized Oxazoles via Silver-Catalyzed Cyclization of Propargylamides and Allenylamides

Silver(I)-catalyzed [3,3] rearrangement of N-sulfonyl propargylamides affords functionalized oxazoles with highly regioselective migration of the sulfonyl group by the introduction of acyloxy groups. The allenylamides, generated from the corresponding propargylamides, can also undergo the silver-catalyzed cyclization to give various 5-vinyloxazoles.

ChemInform Abstract: Oxy Effects on the Platinum‐Catalyzed Carbo‐ and Oxacyclizations of 2‐Oxiranyl‐1‐(1‐oxyalk‐2‐ynyl)benzenes.

AbstractEpoxides, bearing an acyloxy group, undergo a PtCl2‐catalyzed cyclization via an initial 1,3‐acyloxy‐shift, nucleophilic attack on an allenyl acetate and 1,2‐alkyl shift to afford 2‐naphthyl ketones.

17O-Dynamic NMR and DFT Investigation of Bis(acyloxy)iodoarenes

Bis(acetoxy)iodobenzene and related acyloxy derivatives of hypervalent I(III) were studied by variable temperature solution-state 17O-NMR and DFT calculations. The 17O-NMR spectra reveal a dynamic process that interchanges the oxygen atoms of the acyloxy groups. For the first time, coalescence events could be detected for such compounds, allowing the determination of activation free energy data which are found to range between 44 and 47 kJ/mol. The analysis of the 17O linewidth measured for bis(acetoxy)iodobenzene indicates that the activation entropy is negligible. DFT calculations show that the oxygen atom exchange arises as a consequence of the [1,3]-sigmatropic shift of iodine. The calculated activation barriers are in excellent agreement with the experimental results. Both the 17O-NMR and DFT studies show that the solvent and chemical alterations, such as modification of the acyl groups or para- substitution of the benzene ring, hardly affect the energetics of the dynamic process. The low I-O Wiberg bond index (0.41–0.42) indicates a possible explanation of the invariance of both the energy barrier and the 17O chemical shift with para-substitution.

14-Alkoxy- and 14-Acyloxypyridomorphinans: μ Agonist/δ Antagonist Opioid Analgesics with Diminished Tolerance and Dependence Side Effects

In the search for opioid ligands with mixed functional activity, a series of 5'-(4-chlorophenyl)-4,5α-epoxypyridomorphinans possessing alkoxy or acyloxy groups at C-14 was synthesized and evaluated. In this series, the affinity and functional activity of the ligands were found to be influenced by the nature of the substituent at C-14 as well as by the substituent at N-17. Whereas the incorporation of a 3-phenylpropoxy group at C-14 on N-methylpyridomorhinan gave a dual MOR agonist/DOR agonist 17h, its incorporation on N-cyclopropylmethylpyridomorphinan gave a MOR agonist/DOR antagonist 17d. Interestingly, 17d, in contrast to 17h, did not produce tolerance or dependence effects upon prolonged treatment in cells expressing MOR and DOR. Moreover, 17d displayed greatly diminished analgesic tolerance as compared to morphine upon repeated administration, thus supporting the hypothesis that ligands with MOR agonist/DOR antagonist functional activity could emerge as novel analgesics devoid of tolerance, dependence, and related side effects.

Oxy Effects on the Platinum‐Catalyzed Carbo‐ and Oxacyclizations of 2‐Oxiranyl‐1‐(1‐oxyalk‐2‐ynyl)benzenes

AbstractWe report new platinum‐catalyzed protocols for the synthesis of carbocycles and oxacycles from 2‐oxiranyl‐1‐(1‐oxyalk‐2‐ynyl)benzenes. For 1,2,2‐trisubstituted epoxides bearing an acyloxy group, their platinum‐catalyzed cyclizations proceed through an initial 1,3‐acyloxy shift, followed by an intramolecular attack of an allenyl acetate at the carbonyl group, ultimately giving 2‐naphthyl ketones through a selective 1,2‐alkyl shift. 1,1‐Disubstituted epoxides bearing a siloxy group undergo an oxacyclization to give bicyclic ketals with high diastereoselectivity.

Rhodium-catalyzed carbonylation of cyclopropyl substituted propargyl esters: a tandem 1,3-acyloxy migration [5 + 1] cycloaddition.

We have developed two different types of tandem reactions for the synthesis of highly functionalized cyclohexenones from cyclopropyl substituted propargyl esters. Both reactions were initiated by rhodium-catalyzed Saucy-Marbet 1,3-acyloxy migration. The resulting cyclopropyl substituted allenes derived from acyloxy migration then underwent [5 + 1] cycloaddition with CO. The acyloxy group not only eased the access to allene intermediates but also provided a handle for further selective functionalizations.

Synthesis of Phenanthroindolizidine Alkaloids with an Acyloxy Group at the C3 Position and their Antitumor Activities and Toxicities

We previously reported that the phenanthroindolizidine alkaloid 3 and its derivatives had markedly potent in vitro cytotoxicity. However, they had low in vivo antitumor activities and high in vivo toxicities, which was a serious problem for further development. Based on the finding that antitumor activity and toxicity could be improved by acetylation of 3, we synthesized new derivatives of 3, which possessed various acyl groups, and evaluated their antitumor activities and toxicities. We found that derivatives with sterically less bulky acyl groups had improved antitumor activities.