Photochemical planar-to-planar chirality transfer was effected by using (R)-[10] paracyclophane-12-carboxylates as a planar-chiral sensitizer and (Z)-cyclooctene and (Z,Z)-1,5-cyclooctadiene as prochiral substrates to give a planar-chiral (E)and (E,Z)-isomer in up to 44% and 87% enantiomeric excess, respectively, the latter of which being the highest ever reported for a sensitized photochirogenic reaction.

Novel planar-chiral pyridinium ylides were designed, and generated in situ from the corresponding pyridinium salts with triethylamine. Ylides with a common parapyridinophane skeleton reacted efficiently with electron-deficient dicyanoalkenes, or malononitriles, to produce optically active cyclopropane derivatives with high enantioselectivity (up to 99% ee). Remote steric effects were observed on the enantioselectivities, where the R(2) groups of the pyridinophane core resulted in higher ee values of the products. Density function theory (DFT) calculations are in good agreement with our experimental results: the energetically favored transition state leads to the major stereoisomer, namely the trans-cyclopropane products.

We have accomplished efficient synthesis of planar-chiral bridged 2,2'-bipyridine (S)-6, C(2)-symmetric bipyridinophane (S,S)-7, bridged 2,2':6',2 ''-terpyridines (S)-11, and C(2)-symmetric terpyridine (S,S)-12 by metal-mediated biaryl cross-coupling or homo-coupling reactions of the corresponding 6-halo[10](2,5)pyridinophanes. Stille-type and Negishi cross-coupling reactions are particularly useful for the syntheses of 6, 11, and 12. On the other hand, nickel-mediated homo-coupling reaction worked best for achieving the synthesis of structurally unique bipyridinophane 7. (C) 2009 Elsevier Ltd. All rights reserved.

Synchronized stereocontrol of two planar-chiral units was accomplished by using crystallization-induced asymmetric transformation (CIAT) of cyclophane-type bridged bisnicotinate derivatives 5b and 7. After screening Various linkers, (S)-2-amino-1-butanol and (S)-tert-leucinol were found to be the most effective for CIAT of the corresponding bridged bisnicotinate 5b and 7, respectively, whose diastereomeric ratio finally reached 97% and 88%. respectively. (c) 2008 Elsevier Ltd. All rights reserved.

Synthesis of various bridged nicotinates 6 having [n](2,5)pyridinophane skeletons (n=8-14) was accomplished by the unique pyridine-fori-nation reaction of methyl propiolate with a series of formyl-substituted (vinylimino)phosphoranes 5, which were prepared from the corresponding cycloalkanones 1 via Vilsmeier-Haack formylation giving chloro-substituted cycloalkenals 2, their thermal and photochemical transformation to formyl azirines 4, and the following ring-opening reactions with triphenylphosphine. The HPLC analysis of [11](2,5)pyridinophane derivatives, (S-p,S)-14 and (R-p,S)-14, showed that these diastereomers rapidly epimerize themselves at room temperature and that their planar-chirality was thermodynamically less stable as compared to the corresponding [11](2,5)cyclophane systems. (c) 2006 Elsevier Ltd. All rights reserved.

A series of [n]paracyclophanediols (n = 8-12) was synthesized by samarium-catalyzed pinacol coupling for their ansa-bridge formation. Enantiomerically pure [n]paracyclophane esters were derived from the diols in a several steps via chiral resolution (for n = 10) or via crystallization-induced asymmetric transformation (for n = 11) by using amino alcohol auxiliaries and their selective cleavages.

Nitrogen aromatics always remain updated synthetic targets as functional or bioconjugate molecules from the aspects of unique reactivity of their nitrogen atom incorporated. We have been studying structurally unique nitrogen aromatics prepared by the reaction of (vinylimino)phosphoranes and demonstrated their synthetic application to coenzyme analogs reacting in highly enantioselective and regioselective manner in some biomimetic systems and stereoselective transformation of their planar-chiral molecules. In this article, we review our research works including the latest results regarding design, syntheses and biomimetic asymmetric reactions of bridged NADH analogs and their stereocontrol of planar chirality via crystallization-induced asymmetric rope-skipping transformation, namely stereocontrol of molecular jump-rope.

A facile and practical removal of 2-oxazolidinone and 2-hydroxyethylamine auxiliaries was accomplished by treating the corresponding N-acyl-2-oxazolidin one and N-(2-hydroxyethyl)amide derivatives in simple methoxide-carbonate systems. The presence of excess DMC (dimethyl carbonate) accelerates the N-acyl bond cleavage for those substrates under mild reaction conditions, and the present method was found to be useful especially for the synthesis of planar-chiral nicotinate. (C) 2003 Elsevier Science Ltd. All rights reserved.

Coenzyme NAD+/NADH, a major cofactor of dehydrogenases, functions as an autorecycling redox agent in biological systems, which is exemplified by enantioselective reduction of pyruvate to L-lactate and oxidation of glyceraldehyde-3-phosphate to 1, 3-bisphosphoglycerate as is observed in anaerobic glycolysis. This article reviews biomimetic asymmetric reduction and oxidation in NAD+/NADH model systems. The first part outlines highly enantioselective reduction of benzoylformate, a lactate analog, with representative NADH model compounds mimicking biological reduction in lactate dehydrogenase. In this section, the well-developed model reactions are grouped based on the types of NADH models ; one having a chiral center at the C-4 position of its 1, 4-dihydronicotinoyl ring and the other good for recycling use. The latter half describes the detailed history on the less developed biomimetic oxidation with NAD+ model compounds. This section classifies the model reactions based on the types of model substrates to summarize the oxidation of alcohols, aldehydes, and formates into aldehydes (or ketones), carboxylates, and carbon dioxide, respectively, with regioselective formation of the corresponding NADH model compounds as analogous reactions in alcohol-, glyceraldehyde-3-phosphate-, and formate dehydrogenases

Preparation of 2-(phosphoranylideneamino)acrylaldehydes, novel formyl-substituted (vinylimino)phosphoranes, was accomplished by the reaction of formyl-2H-azirines with triphenylphosphine. Their novel pyridine-formation reactions with acetylenic esters achieved the preferential formation of 2-mono- and 2,5-disubstituted nicotinate derivatives.

Nitro groups on alternate corners of cubane enhance the acidity of cubyl hydrogen (pK(a) similar to 21) and provide sufficient activation for ready anion formation. The sodium salt of 1,3,5,7-tetranitrocubane reacts easily with electrophiles and leads thereby to yet more highly substituted cubanes, like carbomethoxy- and (trimethylsilyl)tetranitrocubane. Anions from these species are also easily formed and are useful for further substitution on the cubane nucleus. Dinitrogen tetraoxide reacts with the anion of tetranitrocubane to give 1,2,3,5,7-pentanitrocubane, the first cubane to contain vicinal nitro groups. The reaction probably involves oxidation of the anion to the corresponding radical. Similarly, the anion of pentanitrocubane is used to prepare 1,2,3,4,5,7-hexanitrocubane, the most highly nitrated cubane made to date. Single-crystal X-ray structural information is given for both penta- and hexanitrocubane.

Polychloroazines (1-6) are susceptible to homolytic chlorine substitution by alkyl radicals. In general, the chlorine at the ortho-position to the ring nitrogen is readily replaced by an alkyl radical like adamantyl and tert-butyl. However, the chlorine at the C2-position of pyrimidine did not show any sign of the radical substitution. The reactivity decreases in the order of adamantyl, tert-butyl, and isopropyl radicals.

Structural modification of NAD(P) model compounds, N,N,N',N'‐tetramethylpyridine‐3,5‐dicarboxamide (1), pyridine‐3,5‐dicarbonitrile (2), and 4‐methylpyridine‐3,5‐dicarbonitrile (3), have been explored by the reaction with alkyl radicals such as the 1‐adamantyl, tert‐butyl, and isopropyl radicals. The alkyl substitutions of compounds 1, 2, and 3 with the 1‐adamantyl and the tert‐butyl radical gave both 2‐mono and 2,6‐disubstitution products, whereas the reaction of compound 2 with the isopropyl radical gave 2‐mono 6c, 2,4‐di 7c, 2,6‐di 8c, and 2,4,6‐trisubstitution 9c products. Copyright © 1992 Journal of Heterocyclic Chemistry

The title compound was synthesized by thermal reaction of 3-phosphoranyldeneamino-1,6-methano[10]annulene with 2-cholortropone in a single step. The examination of 1H NMR spectrum revealed that there is little contribution of peripheral 18-π electron conjugation, but it is rather composed of 1-azaaxulene and methano[10]annulene moieties.

Novel 1-aza-6,11- and 1-aza-4,9-methnocyclopentacycloundecene ring systems were synthesized by the reaction of 3,8-methano[11]annulenone with N-(1-phenylvinylimino)triphenylphosphorane followed by dehydrogenation. These compounds are diatropic as 14pielectron vinylogues of 1-azaazulene.

A short new synthesis of the [n](2,4)pyridinophane ring system (n= 9–6) consists of allowing N-vinyl- and N-(1-phenylvinyl)iminophosphoranes to react with cyclic α,β-unsaturated ketones. Structural studies of the compounds prepared were based on spectroscopic measurements and MNDO calculations. The 1H and 13C NMR spectra at various temperatures showed dynamic behaviour for the oligomethylene chains of [7]- and [6]-(2,4)pyridinophane derivatives (8c,d). The energy barriers ΔGc‡ of the bridge flipping are 12–13 kcal mol–1(Tc, 20 °C) for (8c) and 21–22 kcal mol–1 kcal mol–1(Tc, 150° C) for (8d). The lower-energy process of the oligomethylene chain in (8d) is the pseudorotation with Ea= 10.3 ± 0.2 kcal mol–1, ΔH‡= 9.8 ± 0.2 kcal mol–1, and ΔS‡=–4.8 cal mol–1 deg–1. Two stable conformations of the hexamethylene bridge of (8d) were unambiguously determined by low-temperature NMR. The strain of the [n](2,4)pyridinophane ring system was found to increase as the chain length becomes shorter. Remarkable deformation of the pyridine rings of (8c,d) was suggested by the geometrical optimization by MNDO calculation and the red shift of the UV spectrum.

The reaction of N-(1-phenylvinyl)iminotriphenylphosphorane and of N-(1,3,5-cycloheptatrienyl)iminotributylphosphorane with 2,4,6-cyclooctatrienone gave an intermediacy of 8-azabicyclo[5.3.1]undeca-2,4,7,9-tetraene derivatives, which underwent an intramolecular Diels–Alder reaction to construct a tetracyclic ring system.

The facile synthesis of [n](2,4)pyridinophane ring system (n = 9–6) was accomplished by the reaction of N-(1-phenylvinyl)iminophosphorane with cyclic α, β-unsaturated ketones. The chain flipping was studied by 1H NMR spectra at various temperatures.

The facile synthesis of [n](2,4)pyridinophane ring system (n = 9-6) was accomplished by the reaction of N-(1- phenylvinyl)iminophosphorane with cyclic α,β-unsaturated ketones.

The 1,3-Dipolar cycloaddition of phenyl azide with 1,3,5-trimethyl-6-methylenetricyclo[3.2.1.02,7]oct-3-en-8-one occurred onto the endocyclic double bond to give the exo- and endo-adducts (7 and 8) in a similar ratio. Upon photoirradiation, 7 and 8 eliminated a nitrogen molecule to give 3,5-exo- and 3,5-endo-1,3,6-trimethyl-7-methylene-4-azatetracyclo[4.2.1.0.2,803,5]nona-9-ones (9 and 10) in good yields. The 1,3-Dipolar cycloaddition of 2,4,6-trimethylbenzonitrile oxide with 9 and 10 occurred onto the exocyclic double bond to give two stereoisomers in each case. The stereoselectivity of the reactions is discussed on the basis of the stereoelectronic factor of the aziridine ring. The thermal reaction of 9 and 10 as well as photoirradiation of 9 caused a simple C–N bond cleavage of the aziridine ring. However, photoirradiation of 10 or its dimethyl analogue caused an unusual skeletal rearrangement resulting in the formation of 9-methylene-6-phenyl-6-azatricyclo[3.3.1.02,8]nona-3-en-7-one ring system. Mechanistic pathways of the rearrangement were postulated.

Novel norcaradiene-cycloheptatriene systems fused with arylisoxazoles were synthesized and their temperature dependent 1H nmr spectra were studied. while the fusion of isoxazole ring much shifted the norcaradiene-cycloheptatriene equilibrium to the side of norcaradiene form, the rapid isomerizations of the norcaradienes with their enantiomers were observed and their δG‡c values were obtained.

3-Arylcyclohepta[d]isoxazolylium tetrafluoroborates were synthesized by the cycloaddition of tricarbonyl(2-5-η-2,4,6-cycloheptatrienone)iron with aromatic nitrile oxides followed by several reactions. The pKR+ values of these ions are less than +1.0 showing that the stability of the tropylium ions is much decreased by the fusion of the isoxazole ring.

The total synthesis of racemic azaspirene was accomplished over 12 steps in a 17% overall yield via a convergent strategy featuring the coupling of isocyanate and 3(2H)-furanone and an intramolecular aldol reaction to construct the spiro core. Later, a complete conversion was achieved via the crystallization-induced diastereomer transformation of the kinetically favored epimer—produced primarily via spirocyclic construction—to the thermodynamically stable and desirable epimer. Finally, a stereoselective hydration produced the target azaspirene.

Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.

Total synthesis of the proposed structure 2 for phomopsin B was achieved by using an intramolecular olefin metathesis as a key step. The spectral data, however, did not match with those of the natural product reported. Re-examination of the reported NMR data led to the structural revision of phomopsin B to known dothiorelone A 18. The R configuration of dothiorelone A was determined by total synthesis through a cross-metathesis with a chiral olefin 19.

The formal total synthesis of aspergillide A 1 is described. The cross-metathesis of enone 6 with 6-hepten-2-ol derivative 5 provided E-olefin 15 corresponding to the C4–C14 backbone of 1. The CBS asymmetric reduction of 15 gave allyl alcohol 16, which was transformed into β-alkoxyacrylate 4 which had a formyl group. SmI2-induced reductive cyclization of 4 gave a 2,6-syn-2,3-trans THP derivative 3 in good yield. After methoxymethylation of 3, the resulting compound 19 was submitted to desilylation and hydrolysis, to afford Fuwa’s key intermediate 2 for the total synthesis of 1.

The purpose of the present study was to develop a new method of chemoembolization to improve the therapeutic effectiveness and safety profile of cancer treatment. A chemoembolization approach was designed for human solid tumors using resorbable calcium-phosphate ceramic microspheres loaded with an agent anti-angiogenic to tumor vasculature in vivo. The human uterine sarcoma cell line FU-MMT-3 was used in this study because this tumor is aggressive and also exhibits a poor response to radiotherapy or any chemotherapy currently used. The calcium-phosphate ceramic microspheres loaded with TNP-470, an antiangiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment using TNP-470-loaded microspheres suppressed tumor growth, compared to treatment with TNP-470 alone, microspheres alone, and the control. The mean tumor weight after treatment using TNP-470-loaded microspheres was significantly lower than that after treatment with microspheres alone. These ceramic microspheres were remarkably embolized in tumor microvessels as well as in the feeding arteries and a significant reduction of intratumoral vascularity was also demonstrated following treatment with TNP-470-loaded microspheres. Severe loss of body weight was not observed in any mice treated with the TNP-470-loaded microspheres, compared to treatment with TNP-470 alone. These results suggest that targeting tumor vasculature in human uterine sarcoma using calcium-phosphate microspheres might be more effective and safer than the treatment that employs anti-angiogenic agent alone. This new chemoembolization method incorporating an anti-angiogenic agent may contribute to the effective treatment of locally advanced or recurrent solid tumors. (Cancer Sci 2010; 101: 984-990)

We have successfully synthesized hollow biphasic calcium -phosphate microspheres consisting of the P-tricalcium phosphate (beta-Ca-3(PO4)(2); beta-TCP) and calcium-deficient hydroxyapatite (DAp) using an ultrasonic spray-pyrolysis technique. The resulting hollow biphasic microspheres have been applied as a carrier of a drug delivery system (DDS) for medical treatment of cancers. An anti-angiogenic agent, TNP-470 (Takeda), was used as one of drug models. We have performed biological evaluations in vitro and in vivo using the biodegradable calcium-phosphate microsphere loaded with TNP-470. The results of in vitro and in vivo testing indicate that the microspheres loaded with TNP-470 inhibit i) the proliferation of FU-MMT-3 cells as a tumor model and ii) the enlargement of tumor sizes as a model of nude mice injected with FU-MMT-3 cells. The biological evaluations demonstrate that the present microspheres loaded with TNP-470 have an excellent anti-tumorigenesis effect.

Structural modification of NAD(P) model compounds, N,N,N′,N′ tetramethylpyridine-3,5-dicarboxamide (1), pyridine-3,5-dicarbonitrile (2), and 4-methylpyridine-3,5-dicarbonitrile (3), have been explored by the reaction with alkyl radicals such as the 1-adamantyl, tert-butyi, and isopropyl radicals. The alkyl substitutions of compounds 1, 2, and 3 with the 1-adamantyl and the fert-butyl radical gave both 2-mono and 2,6-disubsti-tution products, whereas the reaction of compound 2 with the isopropyl radical gave 2-mono 6c, 2,4-di 7c, 2,6-di 8c, and 2,4,6-trisubstitution 9c products.

Dynamic 1H‐NMR spectra between room temperature and −90 °C for the title compounds indicate that the flipping of the nonamethylene bridge is slowed down on cooling (ΔGc‡ = 9.8 kcal/mol for the 2/8 methylene groups in the pyridinophane with coalescence temperature Tc = −58 °C) but the pseudorotation persists even at −90 °C. The bridge flipping is somewhat easier in the N‐methylpyridinium (ΔGc‡ = 9.7 kcal/mol, Tc = −63 °C) and in the pyrylophanium perchlorates (ΔGc‡ = 8.9 kcal/mol, Tc = −78 °C).