Abnormal Michael Reaction: Condition-Dependent Product Distributions in the Michael Reaction of Monoalkyl-Substituted Malonates.

The abnormal Michael reaction reported by Thorpe and Michael in 1900, which involves the transfer of an activating group from a nucleophilic species to an α-carbon of the Michael acceptor in reaction with monosubstituted malonates, was revisited using prototypical substrates for both intramolecular and intermolecular reactions. In both reactions, condition-dependent product distributions were observed. Thus, under the conditions using NaHMDS or NaH in THF or Et2O, no formation of the abnormal Michael product was observed, and the major product was an apparent retrograde Michael reaction in the abnormal Michael product resulting from an elimination of a malonate anion with the migrated acyl group as a part of it. The use of a base capable of generating a proton source such as NaOEt resulted in formation of the abnormal Michael product in the intermolecular reaction, although the retrograde Michael product was still a major product. On the other hand, in the intramolecular reaction, the abnormal product was not detected under any conditions used. A plausible reaction mechanism in which the lower kinetic acidity of the malonate proton compared to the thermodynamic acidity plays a significant role has been proposed.

Tophaceous pseudogout of the temporomandibular joint extending into the cranium: a case report with literature review.

Pseudogout is a disease characterized by calcium pyrophosphate crystal deposition. Involvement of the temporomandibular joint (TMJ) is rare. We herein report a case of tophaceous pseudogout of the TMJ with cranial extension. An 83-year-old woman was referred to our institution for treatment of right TMJ pain. The patient's medical and family histories were unremarkable. Magnetic resonance imaging showed a mass of about 35 mm in diameter compressing the bottom of the right temporal lobe of the brain. Based on a clinical diagnosis of a right TMJ tumour, biopsy was performed under general anaesthesia. The histopathological diagnosis was pseudogout. Considering the risk of surgically induced brain damage, the patient's advanced age and her relatively good quality of life, the treatment plan simply involved the observation of the lesion. Fourteen months after biopsy, the patient's activities of daily living remained unchanged and she had no TMJ pain.

Cranial Reconstruction Using Antibiotic-Impregnated Calcium Phosphate Bone Cement With a Titanium Mesh Sheet.

BACKGROUND: The authors treated skin ulcer accompanied by cranial osteomyelitis using a combination of antibiotic-impregnated calcium phosphate bone cement (Biopex; Pentax, Tokyo, Japan) and a titanium mesh sheet (3D Mesh Plate; Bear Medic, Tokyo, Japan). METHOD: A 71-year-old male was treated with superficial temporal artery-middle cerebral artery bypass surgery for diffuse cerebral infarction and obstruction of the left internal carotid artery by a previous doctor. Skin necrosis and epidural abscess developed in the sutured region after surgery, and ulcer accompanied by temporal bone exposure remained. Thus, the patient transferred to our department. A bone defect formed by debridement and sequestrectomy was measured at 4.5 × 8 cm (30 cm). Methicillin-resistant Staphylococcus aureus was detected on wound culture test. Cranioplasty with a combination of calcium phosphate bone cement impregnated with teicoplanin, to which the causative bacteria showed high sensitivity, and a titanium mesh sheet and scalp reconstruction with a free rectus abdominis musculocutaneous flap were performed. RESULTS: As of 6 months after surgery, no infection has relapsed and no complication, such as resorption of the calcium phosphate bone cement and breakage of the titanium mesh sheet, was noted on postoperative computed tomography. CONCLUSION: The authors performed cranial reconstruction with a combination of teicoplanin-impregnated calcium phosphate bone cement and a titanium mesh sheet in a patient with Methicillin-resistant Staphylococcus aureus infection-induced skin ulcer accompanied by cranial osteomyelitis and achieved subsidence of infection. Drug-impregnated calcium phosphate bone cement has a problem with strength, but combination with a titanium mesh sheet as an auxiliary support material enables application to relatively extensive cranial full-thickness defects and it may be a useful treatment method.

Carbanion-Induced [3 + 2] Annulation of Donor-Acceptor Cyclopropanes.

The [3 + 2] annulation of donor-acceptor cyclopropanes and ylidenemalonates, in which an α-p-tosyl carbanion functions as a donor substituent, is described. A notable feature of the annulation is that the auxiliary p-tosylmethyl group can be removed via a cycloreversion during the tandem annulation sequence.

Spontaneous Oxygenation of Siloxy-N-silylketenimines to α-Ketoamides.

Siloxy-N-silylketenimines generated in situ from O-silyl cyanohydrins were converted to α-ketoamides by brief exposure to air or oxygen. Oxidation under extremely mild conditions can be explained by assuming the intermediacy of a 3-imino-1,2-dioxetane derivative generated via triplet-singlet intersystem crossing after the reaction of siloxy-N-silylketenimines with triplet oxygen.

Inhibitory effects of antibiofilm compound 1 against Staphylococcus aureus biofilms.

A novel benzimidazole molecule that was identified in a small-molecule screen and is known as antibiofilm compound 1 (ABC-1) has been found to prevent bacterial biofilm formation by multiple bacterial pathogens, including Staphylococcus aureus, without affecting bacterial growth. Here, the biofilm inhibiting ability of 156 µM ABC-1 was tested in various biofilm-forming strains of S. aureus. It was demonstrated that ABC-1 inhibits biofilm formation by these strains at micromolar concentrations regardless of the strains' dependence on Polysaccharide Intercellular Adhesin (PIA), cell wall-associated protein dependent or cell wall- associated extracellular DNA (eDNA). Of note, ABC-1 treatment primarily inhibited Protein A (SpA) expression in all strains tested. spa gene disruption showed decreased biofilm formation; however, the mutants still produced more biofilm than ABC-1 treated strains, implying that ABC-1 affects not only SpA but also other factors. Indeed, ABC-1 also attenuated the accumulation of PIA and eDNA on cell surface. Our results suggest that ABC-1 has pleotropic effects on several biofilm components and thus inhibits biofilm formation by S. aureus.

Stereochemical Course of Deprotonation-Acylation of N-Boc- and N-Carbamoyl-2-cyano-6-methylpiperidines.

The stereochemical course of electrophilic substitution of α-nitrile metallocarbanions generated by deprotonation from N-Boc- and N-carbamoyl-2-cyano-6-methylpiperidines was investigated. Deprotonation in the presence of an electrophile taking advantage of the high acidity of α-nitrile protons allowed examination of the effects of a chelating group on the nitrogen atom, a countercation, and the reactivity of an electrophile on the steric course. Analyses of reactions using aroyl chlorides and methyl iodide revealed the following: (1) the substitution reactions basically proceed with retention of configuration, (2) the extent of an inversion product increases with decreasing chelating ability of the N-substituent and with increasing leaving ability (ionic character) of a countercation (Li, Na, K) of the anionic species, and (3) the use of a more reactive electrophile results in an increase of the retention product.

Transnitrosation of non-mutagenic N-nitrosoproline forms mutagenic N-nitroso-N-methylurea.

N-Nitroso-N-methylurea (NMU) is a potent carcinogen and suspected as a cause of human cancer. In this study, mutagenic NMU was detected by HPLC after the transnitrosation of non-mutagenic N-nitrosoproline (NP) to N-methylurea in the presence of thiourea (TU) under acidic conditions. The structure of NMU was confirmed by comparing (1)H NMR and IR spectra with that of authentic NMU after fractionation by column chromatography. Furthermore, a fraction containing NMU formed by transnitrosation was mutagenic in Salmonella typhimurium TA1535. NMU was formed in the reaction of NP and N-methylurea in the presence of 1,1,3,3-tetramethylthiourea (TTU) or 1,3-dimethylthiourea in place of TU as an accelerator. The reaction rate constants (k) for NMU formation were correlated with their nucleophilicity of sulfur atom in thioureas. The N-methylurea concentration did not affect the NMU formation, whereas the rate of NMU formation correlated linearly with concentrations of NP, TTU and oxonium ion. The observed kinetics suggests a mechanism by which the nitroso group was transferred directly from the protonated NP to the thiourea then to N-methylurea to form NMU. The rate-determining step was the formation of the complex with the protonated NP and thiourea.

Enantioselective synthesis of allenylenol silyl ethers via chiral lithium amide mediated reduction of ynenoyl silanes and their Diels-Alder reactions.

An enantioselective Meerwein-Ponndorf-Verley-type reduction of ynenoylsilanes by a chiral lithium amide followed by a Brook rearrangement and anti-mode protonation across conjugated 1,3-enynes provides allene derivatives bearing a 2-siloxyvinyl moiety in high enantioselectivity. The E/Z geometry of enol silyl ethers is controlled by the geometry of the starting enyne moiety. Thus, (E)- and (Z)-enol silyl ethers are obtained from (Z)- and (E)-ynenoylsilans, respectively. The 2-siloxyvinylallene products can participate in Diels-Alder reactions with reactive dienophiles such as PTAD, which can be achieved in a one-pot operation from ynenoylsilanes.

Formation of 2-Cyano-2-siloxyvinylallenes via Cyanide-Induced Brook Rearrangement in γ-Bromo-α,ß,γ,δ-unsaturated Acylsilanes.

Reactions of γ-bromo-α,ß,γ,δ-unsaturated acylsilanes with KCN under phase-transfer catalyst conditions using n-Bu4NBr afforded 2-cyano-2-siloxyvinylallenes via a tandem process that involves a nucleophilic attack of a cyanide ion and a Brook rearrangement induced conjugate vinylic 1,4-elimination. Use of a chiral cyanide ion source, derived from KCN and quaternary ammonium bromide derived from cinchona alkaloids, provided nonracemic allene derivatives. Based on this result and the reaction using a chiral hydride ion source, we propose a reaction pathway in which a Brook rearrangement mediated vinylic conjugate 1,4-elimination occurs in a syn alignment between the C-Br bond and C-Si bond in the silicate intermediate.

Enantioselective synthesis of α-silylamines by Meerwein-Ponndorf-Verley-type reduction of α-silylimines by a chiral lithium amide.

Meerwein-Ponndorf-Verley-type reduction of N-tosylsilylimines with chiral lithium amide 2 affords α-silylamines in high enantioselectivity. Since the enantioselectivity observed was inconsistent with our previously proposed chairlike six-membered transition structure, we performed density functional theory (DFT) calculations on transition states leading to (S)- and (R)-7a and (S)- and (R)-7e using an N-phenylsulfonyl derivatives 12 and 13 as model systems. Results of the calculations showed that the structures are considerably deformed from the chairlike form with steric repulsions between the 1'-methylene group and the imine-carbon substituents playing an important role in the control of the enantioselectivity.

Enantiodivergent deprotonation/acylation of α-amino nitriles.

Back to 'base'ics: The title reaction of enantioenriched α-ureidonitriles was found to proceed in a highly enantiodivergent manner despite the intermediacy of stereolabile α-nitrile metallocarbanions. Enantiodivergence is dependent upon the base used. For the less basic hexamethyldisilazides (HMDS), deprotonation in which a metal (M) cation is precomplexed with an electrophile is proposed. LDA=lithium diisopropylamide.

Antisense morpholino targeting just upstream from a poly(A) tail junction of maternal mRNA removes the tail and inhibits translation.

Gene downregulation by antisense morpholino oligonucleotides (MOs) is achieved by either hybridization around the translation initiation codon or by targeting the splice donor site. In the present study, an antisense MO method is introduced that uses a 25-mer MO against a region at least 40-nt upstream from a poly(A) tail junction in the 3'-untranslated region (UTR) of maternal mRNA. The MO removed the poly(A) tail and blocked zebrafish cdk9 (zcdk9) mRNA translation, showing functional mimicry between miRNA and MO. A PCR-based assay revealed MO-mediated specific poly(A) tail removal of zebrafish mRNAs, including those for cyclin B1, cyclin B2 and tbp. The MO activity targeting cyclins A and B mRNAs was validated in unfertilized starfish oocytes and eggs. The MO removed the elongated poly(A) tail from maternal matured mRNA. This antisense method introduces a new application for the targeted downregulation of maternal mRNAs in animal oocytes, eggs and early embryos.

Enantioselective trapping of an α-chiral carbanion of acyclic nitrile by a carbon electrophile.

An α-chiral nitrile carbanion generated by deprotonation of enantioenriched O-carbamoyl cyanohydrin was trapped in situ with ethyl cyanoformate to give the corresponding ester derivative in 92% yield and 90 : 10 er, providing the first example of trapping of an α-chiral acyclic nitrile carbanion that has been considered to be very configurationally labile.

One-pot approach to 2,3-disubstituted-2,3-dihydro-4-quinolones from 2-alkynylbenzamides.

Concise and efficient syntheses of various trans-2,3-disubstituted-2,3-dihydro-4-quinolones have been achieved via tandem Hofmann-type rearrangement of 2-alkynylbenzamides, nucleophilic addition of alcohols to the isocyanate intermediates, intermolecular [2+2]-cycloaddition with carbon-carbon triple bonds and aldehydes, and intramolecular aminocyclization of nitrogen of carbamates to the α,ß-unsaturated ketones.

Regio- and stereoselective multisubstituted enol ester synthesis.

Regio- and stereoselective cohalogenation of alkynes with NXS (X = Br, I) was achieved, and the stereoselectivity of the resulting alkenes was dependent on the substituent on the alkyne. Cohalogenation and successive cross-coupling gave multisubstituted enol esters in a one-pot process.

A novel hydrazide type organocatalyst for enantioselective Diels-Alder reactions.

The development of a new class of hydrazide type organocatalyst, (4R,5R)-1,3-bis(isopropylamino)-4,5-dihenylimidazolidin-2-one 2a, for enantioselective Diels-Alder reactions between cyclopentadiene and α,ß-unsaturated aldehydes are presented. The new organocatalyst 2a promoted the reaction, affording Diels-Alder adducts in good yields with good levels of enantioselectivity.

Platinum-catalyzed, one-pot tandem synthesis of indoles and isoquinolines via sequential rearrangement of amides and aminocyclization.

By using platinum(II) chloride as a Lewis acid catalyst, concise and efficient syntheses of indole carbamates, 1,2-dihydroisoquinoline carbamates, macrocyclic indole carbamates, indole ureas, and indole phosphoranes have been achieved via tandem Hofmann-type rearrangement of 2-alkynylbenzamides and 2-alkynylbenzylamides, nucleophilic addition of alcohols and amines to the isocyanate intermediates, and intramolecular aminocyclization of the thus-formed carbamates and ureas to 2-alkynyl functions. A variety of nucleophiles such as alcohols, amines, and stable Wittig reagents could be introduced to the highly electrophilic carbon of the isocyanate intermediates derived from amides. We observed enhancement of the reaction rates when the reactions were run under microwave irradiation.

Formal total syntheses of (+)-prelaureatin and (+)-laurallene by diastereoselective brook rearrangement-mediated [3 + 4] annulation.

The formal syntheses of (+)-prelaureatin (1) and (+)-laurallene (2), halogenated eight-membered-ring ethers, are described. The key step of our strategy relies on diastereoselective construction of a trans-alpha,alpha'-disubstituted oxocene structure through a Brook rearrangement-mediated [3 + 4] annulation with acryloylsilane 9 and 6-oxa-2-cycloheptenone derivative 22'.