Gold-Catalyzed Propargylic Substitution Followed by Cycloisomerization in Ionic Liquid: Environmentally Friendly Synthesis of Polysubstituted Furans from Propargylic Alcohols and 1,3-Dicarbonyl Compounds.

Gold-catalyzed propargylic substitution of propargylic alcohols with 1,3-dicarbonyl compounds followed by cycloisomerization in ionic liquid enables the environmentally friendly synthesis of polysubstituted furans in good-to-high yields. The reaction proceeds via the hydrated propargylic substitution product . The gold catalyst can be recycled at least three times.

Hetero Cope-Type Hydroamination of Hetero-Allenes with Oximes Having Olefin Moieties Leading to Nitrones, Causing Intramolecular Cycloaddition.

Hetero-allenes such as isocyanates, isothiocyanates, and carbodiimides reacted with oxime having olefin moieties in the manner of hetero Cope-type hydroamination to generate -modified nitrones, which underwent intramolecular cycloaddition to give intramolecular cycloadducts. Among them, the reaction of isocyanates with oximes proceeded at room temperature to provide the corresponding cycloadducts in very high yields. The efficiencies of these sequential cycloadditions were directly compared by competitive reactions.

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

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

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.

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

An efficient method for the synthesis of multi-substituted pyridines from β-aryl-substituted α,β-unsaturated oxime ethers and alkenes Pd-catalyzed C-H activation has been developed. The method, using Pd(OAc) 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,β-unsaturated oxime followed by aza-6π-electrocyclization.

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

α,β-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,β-unsaturated ketones to their oximes. Nucleophilic ring-opening reactions of the epoxides afforded α-substituted products.

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

An efficient synthetic method for multisubstituted pyridines from β-aryl-substituted α,β-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 β-alkenylation of α,β-unsaturated oxime followed by aza-6π-electrocyclization.

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 BF·OEt 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 sp-hybridized C3a carbon.

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

The use of the cationic palladium(II) catalyst realized electrophilic C-H arylation of α,β-unsaturated -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,β-unsaturated oximes would provide access to multisubstituted heterocyclic compounds.

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

A concise synthetic method for dihydropyrans has been developed by inverse-electron-demand oxa-Diels-Alder reaction of α-keto-β,γ-unsaturated esters with α,β-unsaturated hydrazones as electron-rich olefins. This reaction is catalyzed by Eu(hfc) and proceeds in an endo-selective manner. This umpolung cycloaddition affords a variety of substituted dihydropyrans stereoselectively in high yields.

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

Inverse-electron-demand Diels-Alder reactions of 3-electron-withdrawing group substituted α-pyrones with α,β-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 MgBr·OEt. This cycloaddition constructed the C2 and C4 asymmetric centers in a single step. Then reductive cleavage, intramolecular S2 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,β-unsaturated oximes: regioselective inverse 1,3-dipolar cycloaddition of nitrones.

The cycloaddition of nitrones with α,β-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,β-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.

[A case of trastuzumab-resistant breast cancer responding to lapatinib/capecitabine therapy].

Here we report a case of a 56-year-old woman who presented at our hospital with a chief complaint of a red lump in her right breast. Breast cancer(Rt C, T4bN0M0; ER[-], PgR[-], HER2: 3[+]; stage IIIb)was diagnosed, and subsequent preoperative chemotherapy, mastectomy and axillary lymph node dissection were performed. Five months after surgery, bone metastasis in the thoracolumbar vertebrae developed and trastuzumab/zoledronic acid hydrate therapy was initiated.

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.

Total syntheses of tubulysins.

The total syntheses of tetrapeptides tubulysins D (1 b), U (1 c), and V (1 d), which are potent tubulin polymerization inhibitors, are described. The synthesis of Tuv (2), an unusual amino acid constituent of tubulysins, includes an 1,3-dipolar cycloaddition reaction of chiral nitrone D-6 derived from D-gulose with N-acryloyl camphor sultam (-)-9 employing the double asymmetric induction, whereas the synthesis of Tup (20), another unusual amino acid, involves a stereoselective Evans aldol reaction of (Z)-boron enolate generated from (S)-4-isopropyl-3-propionyl-2-oxazolidinone with N-protected phenylalaninal and a subsequent Barton deoxygenation protocol. We accomplished the total syntheses of tubulysins U (1 c) and V (1 d) by using these methodologies, in which the isoxazolidine ring was used as the effective protective group for γ-amido alcohol functionality.

Synthesis and evaluation of opioid receptor-binding affinity of elaeocarpenine and its analogs.

Both enantiomers of elaeocarpenine (1) and its analogs, 21, 22, 25, and 27, were synthesized from bicyclic aldehydes 8-10 via a flexible route previously established for total synthesis of grandisines, and their binding affinities for mu-, kappa- and delta-opioid receptor subtypes were evaluated. We found that (9R)-1 exhibited higher affinity than (9S)-1 for all the subtypes, but the enantiomers showed little subtype selectivity. Analogs 21 having a pyrrolizidine skeleton and 27 having a stemona-type skeleton in place of the indolizidine unit of (9S)-1 showed mu-selective and mu-, kappa-selective binding, respectively.

A flexible approach to grandisine alkaloids: total synthesis of grandisines B, D, and F.

This article describes in detail the first total synthesis of grandisine alkaloids, grandisines B, D, and F, which show affinity for the human delta-opioid receptor. The key steps in this synthesis are construction of the isoquinuclidinone moiety of 2 by intramolecular imine formation and the tetracyclic ring system of 4 by stereoselective ring closure of the enolate of amine 8 generated by 1,4-addition of ammonia to 9. Synthesis of key intermediate 9 featured a highly stereoselective Brønsted acid mediated Morita-Baylis-Hillman (MBH) reaction via the N-acyl iminium ion.

Total synthesis of grandisine D.

Total synthesis of grandisine D (5) was achieved by a Brønsted acid mediated Morita-Baylis-Hillman (MBH) ring-closure reaction and stereoselective aldol condensation with (S)-5-methylcyclohexenone (9) as key steps. The MBH approach was also applicable for the construction of the aza-fused bicyclic systems of pyrrolizidine and stemona alkaloids.