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.

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 N-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. As a result, the order of reactivity to oxime 1a is isocyanate 2a, isothiocyanate 3a, and carbodiimide 6a. Theoretical studies were also conducted.

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.

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.

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.

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.

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.

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.

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.

[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. Four months after the therapy, tumor marker levels increased and docetaxel was added to the treatment regimen. Although the patient's condition temporarily improved, tumor marker levels increased again after 6 months, and the treatment regimen was switched to trastuzumab/nab-paclitaxel therapy. However, such regimen was discontinued owing to the development of liver metastasis, and lapatinib/capecitabine therapy was initiated. Two months after lapatinib/capecitabine therapy, tumor marker levels normalized and the liver metastasis markedly reduced. Side effects included paronychia(grade 3), which improved with dose reduction. The patient's therapy is being continued.

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.

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.

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.

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.

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.

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. Furthermore, to understand the structure-activity relationship of tubulysins, we synthesized tubulysin D (1 b) and cyclo-tubulysin D (1 e) from 2-Me and 20, and ent-tubulysin D (ent-1 d) from ent-2-Me and ent-20, respectively. The preliminary results regarding their biological activities are also reported.

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.

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.