Gold(III)-Catalyzed Propargylic Substitution Reaction Followed by Cycloisomerization for Synthesis of Poly-Substituted Furans from N-Tosylpropargyl Amines with 1,3-Dicarbonyl Compounds.

The treatment of N-tosylpropargyl amines 1 with 1,3-dicarbonyl compounds 2 in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) afforded poly-substituted furans 3 in good-to-high yields via the gold-catalyzed cleavage of the sp3 carbon-nitrogen bond.

Intermolecular 1,3-Dipolar Cycloaddition Reaction of N-Carbamoyl Nitrones Generated by N-Selective Carbamoylation of Oximes with Isocyanates.

N-Selective carbamoylation reaction of oximes with isocyanates generates nitrones, which undergo 1,3-dipolar cycloaddition with various dipolarophiles to afford diverse isoxazolidines. Notably, combinations of highly electron-rich oxime and highly electron-deficient dipolarophile exhibited high reactivity, with product yields of up to 94 %. The substituent on the isoxazolidine-nitrogen atom could be successfully removed without loss of the cyclic structure. Computational studies have also elucidated the mechanism of the reaction and origin of stereoselectivity.

Directing-Group-Free Palladium-Catalyzed C-H Arylation of Aldoxime Using Oxime's Umpolung Properties.

Alkyl aldoximes without a directing group undergo palladium-catalyzed C-H arylation with aryl bromides to afford alkyl aryl ketoximes in moderate to high yields. The reaction of electron-rich aryl bromides and linear oximes proceeded to afford the coupling products in up to 98% yield. This reaction has broad scope and excellent functional group tolerance. Although reactions using hydroxyl oximes as nucleophiles have generally proceeded on the oxygen atom, this reaction selectively proceeds on oxime carbons by taking advantage of the oxime's umpolung properties and Pd reactivity.

Cationic palladium(ii)-catalyzed synthesis of substituted pyridines from α,ß-unsaturated oxime ethers.

An efficient method for the synthesis of multi-substituted pyridines from ß-aryl-substituted α,ß-unsaturated oxime ethers and alkenes via Pd-catalyzed C-H activation has been developed. The method, using Pd(OAc)2 and a sterically hindered pyridine ligand, provides access to various multi-substituted pyridines with complete regioselectivity. Mechanistic studies suggest that the pyridine products are formed by Pd-catalyzed electrophilic C-H alkenylation of α,ß-unsaturated oxime followed by aza-6π-electrocyclization. The utility of this method is showcased by the synthesis of 4-aryl-substituted pyridine derivatives, which are difficult to synthesize efficiently using previously reported Rh-catalyzed strategies with alkenes.

Electrophilic Epoxidation of α,ß-Unsaturated Oximes with Dioxiranes and Ring Opening of the Epoxides.

α,ß-Unsaturated oximes underwent electrophilic epoxidation with in-situ-generated dimethyldioxirane to give the corresponding epoxides in good yields. This reaction is an example of "carbonyl umpolung" by transformation of α,ß-unsaturated ketones to their oximes. Nucleophilic ring-opening reactions of the epoxides afforded α-substituted products. Shi asymmetric epoxidation of the oximes proceeded with moderate enantioselectivity.

Palladium(II)-Catalyzed Substituted Pyridine Synthesis from α,ß-Unsaturated Oxime Ethers via a C-H Alkenylation/Aza-6π-Electrocyclization Approach.

An efficient synthetic method for multisubstituted pyridines from ß-aryl-substituted α,ß-unsaturated oxime ethers and alkenes via Pd-catalyzed C-H activation has been developed. Systematic optimization of catalyst ligands revealed that sterically hindered pyridines increased the reactivity. Mechanistic studies suggested that the products are formed by Pd-catalyzed ß-alkenylation of α,ß-unsaturated oxime followed by aza-6π-electrocyclization. Various oximes and alkenes could be utilized to afford multisubstituted pyridines with complete regioselectivity. The usefulness of this methodology was showcased by the synthesis of 4-aryl-substituted pyridine derivatives, which are difficult to access with previously reported Rh-catalyzed approaches with alkenes.

Synthesis and Formation Mechanism of a Compound with an Unprecedented Skeleton: Dodecahydro-4,10:5,9-diepoxydipyrrolo[3,4-b:3',4'-f][1,5]diazocine.

The reaction of N-(2-{[(tert-butyldimethylsilyl)oxy]imino}ethyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (6b) with BF3·OEt2 afforded a compound with an unprecedented dodecahydro-4,10 : 5,9-diepoxydipyrrolo[3,4-b:3',4'-f][1,5]diazocine skeleton (7) after aqueous work-up. The formation mechanism of meso-7 appears to involve dimerization of the hydrated forms (6aS)-C and (6aR)-C of the initial racemic product 9 via cation B generated by facile protonation at the C3a position of 9. Extensive computational studies revealed that the driving force of the facile hydration of 9 is probably release of the ring strain of 9, which arises in part from the bent sp2-hybridized C3a carbon.

Thioether Ligand-Enabled Cationic Palladium(II)-Catalyzed Electrophilic C-H Arylation of α,ß-Unsaturated Oxime Ethers.

The use of the cationic palladium(II) catalyst realized electrophilic C-H arylation of α,ß-unsaturated O-SEM oximes with arylboronic acids. This Pd-catalyzed electrophilic C-H arylation is facilitated by employing alkyl aryl thioether ligands, and optimization of the ligand structure greatly improves the yield. The resulting α,ß-unsaturated oximes would provide access to multisubstituted heterocyclic compounds.

Inverse-Electron-Demand oxa-Diels-Alder Reactions of α-Keto-ß,γ-unsaturated Esters and α,ß-Unsaturated Hydrazones.

A concise synthetic method for dihydropyrans has been developed by inverse-electron-demand oxa-Diels-Alder reaction of α-keto-ß,γ-unsaturated esters with α,ß-unsaturated hydrazones as electron-rich olefins. This reaction is catalyzed by Eu(hfc)3 and proceeds in an endo-selective manner. This umpolung cycloaddition affords a variety of substituted dihydropyrans stereoselectively in high yields. In addition, indirect synthesis of formyl-substituted dihydropyran was achieved by dehydrazonation of the cycloadduct. This method is expected to be useful for the synthesis of dihydropyrans and tetrahydropyrans with unusual substitution patterns.

Inverse-electron-demand Diels-Alder reactions of α,ß-unsaturated hydrazones with 3-methoxycarbonyl α-pyrones.

Inverse-electron-demand Diels-Alder reactions of 3-electron-withdrawing group substituted α-pyrones with α,ß-unsaturated hydrazones as electron-rich counterparts are catalyzed by Eu(hfc)3 to afford bicyclic lactone cycloadducts. This is an example of umpolung cycloaddition based on functional transformation of carbonyls to hydrazones. A subsequent dehydrazonation reaction enables indirect synthesis of carbonyl group-containing bicyclic lactones, which cannot be easily obtained by the cycloaddition of α-pyrones and enals.

Total Synthesis of Neodysiherbaine A via 1,3-Dipolar Cycloaddition of a Chiral Nitrone Template.

The total synthesis of neodysiherbaine A was achieved via 1,3-dipolar cycloaddition of a chiral nitrone template with a sugar-derived allyl alcohol in the presence of MgBr2·OEt2. This cycloaddition constructed the C2 and C4 asymmetric centers in a single step. Then reductive cleavage, intramolecular SN2 reaction of the tertiary alcohol, and oxidation of the primary alcohol afforded neodysiherbaine A.

Thiyl radical-mediated cyclization of ω-alkynyl O-tert-butyldiphenylsilyloximes.

ω-Alkynyl O-tert-butyldiphenylsilyloximes, upon treatment with odorless 4-tert-butylbenzenethiol in the presence of azobisisobutyronitrile (AIBN) in refluxing benzene, underwent addition of a thiyl radical to the alkynyl group followed by radical cyclization of the corresponding vinyl radical onto the O-silyloxime moiety to give cyclic O-silylhydroxylamines in good yields. The reactivity of O-silyloximes in radical cyclization was similar to or even higher than that of O-benzyloximes. Facile removal of the silyl group of the cyclization products leading to hydroxylamines and nitrone formation of the hydroxylamines were also demonstrated.

Utilization of electron-donating α,ß-unsaturated oximes: regioselective inverse 1,3-dipolar cycloaddition of nitrones.

The cycloaddition of nitrones with α,ß-unsaturated carbonyl compounds (enones) afforded predominantly 4-acylisoxazolidines, whereas the cycloaddition of the corresponding oximes afforded 5-iminoisoxazolidines. This inverse regioselection is due to HOMO activation by the oxime functionality.

Gold(I)/(III)-Catalyzed Synthesis of Cyclic Ethers; Valency-Controlled Cyclization Modes.

Strategic use of oxophilic (hard) gold(III) and π-philic (soft) gold(I) catalysts provides access to two types of cyclic ethers from propargylic alcohols. Thus, heating propargylic alcohols with an oxophilic gold(III) catalyst (AuBr3) results in cyclization to afford cyclic ethers bearing an acetylenic moiety, due to coordination of gold(III) to the oxygen of the propargylic hydroxyl group. On the other hand, propargylic alcohols with a π-philic gold(I) catalyst (Ph3PAuNTf2) induces Meyer-Schuster rearrangement to afford α,ß-unsaturated ketones, which undergo gold(III)-catalyzed intramolecular oxa-Michael addition to afford cyclic ethers bearing a carbonyl group, due to coordination of gold(III) to the oxygen of the carbonyl group.

BF3-Mediated cis-Selective Cycloaddition of O-Silyloxime with Alkenes.

A C-amide-substituted O-silylated oxime, (E)-(tert-butyldimethylsiloxyimino)acetic acid N,N-dimethylamide (8b), on treatment with 2.2 equiv of BF3·OEt2, in situ generated boracyclic nitrone-type intermediate BF3·14, which underwent cycloaddition with alkenes to give 3,5-cis-isoxazolidines as the major products. The mechanism was strongly supported by isolation of the reaction intermediate 14 that was characterized by X-ray diffraction and its further reaction. This cycloaddition was successfully applied to the synthesis of syn-HPA-12 known as an inhibitor of CERT that mediates the transport of ceramide.

Prevalence of mental illness, intellectual disability, and developmental disability among homeless people in Nagoya, Japan: A case series study.

AIM: While it has been reported that the prevalence of mental illness is higher in homeless people than in the national population, few studies have investigated the prevalence of intellectual and developmental disability among the homeless. In this study, we conducted a survey to comprehensively assess these mental problems among homeless people in Nagoya, Japan. METHODS: The subjects were 18 homeless men. Mental illness was diagnosed with semi-structured interviews conducted by psychiatrists. We used the Wechsler Adult Intelligence Scale III to diagnose intellectual disability. Discrepancies between Wechsler Adult Intelligence Scale III subtest scores were used as criteria for developmental disability. RESULTS: Eleven of the 18 participants were diagnosed with mental illness: six with mood disorder, two with psychotic disorder, and six with alcohol problems. The mean IQ of all subjects was 83.4 ± 27.4. The 95% confidence interval (CI) was 96.2-69.1. Seven participants were found to have intellectual disability. Three men showed discrepancies of more than 10 between subtest scores, and all of them were diagnosed with a mental illness. We divided the participants into four groups: those with mental illness only; those with intellectual disability only; those with both problems; and those without diagnosis. The men with intellectual disability only were significantly younger and had been homeless since a younger age than the other groups. Participants diagnosed with a mental illness had been homeless for longer than those without mental health problems. CONCLUSION: Although the sample size was limited, this study revealed the high prevalence of mental illness and intellectual disability, 61% (95%CI, 35-83%) and 39% (95%CI, 17-64%), respectively, in homeless people in Nagoya, Japan.

Establishment of relative and absolute configurations of phaeosphaeride A: total synthesis of ent-phaeosphaeride A.

The relative and absolute configurations of phaeosphaeride A have been established via the first total synthesis of ent-phaeosphaeride A. The three contiguous stereogenic centers were installed by Sharpless asymmetric dihydroxylation and a stereoselective intramolecular vinyl anion aldol reaction. This synthesis has altered the originally proposed structure of natural phaeosphaeride A.

Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with N-gulosyl nitrones.

Stereoselective vinylogous Mannich reaction of 2-trimethylsilyloxyfuran with L-gulose-derived chiral nitrones in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate was investigated. The selectivity was strongly influenced by the bulkiness of the C-substituent of the nitrone: for example, C-benzyloxymethyl nitrone afforded four stereoisomers, whereas bulky C-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]nitrone gave a single stereoisomer. The latter product was elaborated to afford key synthetic intermediates for polyoxin C and dysiherbaine.

Synthesis of the proposed structure of phaeosphaeride A.

The first total synthesis of the proposed structure of phaeosphaeride A has been achieved via six-membered-ring formation by means of an intramolecular vinyl-anion aldol reaction as the key step. This synthesis suggests a revised configurational assignment for phaeosphaeride A.

Synthesis and biological evaluation of tubulysin D analogs related to stereoisomers of tubuvaline.

The synthesis and biological evaluation of stereoisomers in tubulysin D are described. The stereoselective synthesis of all possible stereoisomers of C-11 and C-13 positions in tubulysin D was achieved by employing 1'-epi-Tuv-Me, 3'-epi-Tuv-Me, and ent-Tuv-Me and their biological properties were evaluated. It is clear that the stereochemistries of the C-11 and C-13 positions in tubulysin D have no practical impact on the inhibition of tubulin polymerization but play a role in the potent antiproliferative activities.