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Reversible deactivation radical polymerization (RDRP) of biomass-based acrylates, (S)- and (R)-2-isopropyl-5-methylene-1,3-dioxolan-4-ones (S-MiPDO and R-MiPDO), was successfully performed to produce a well-defined polymer with simultaneously controlled tacticity and molecular weight, and low dispersity (Đ

Radical polymerization of lactic acid-based chiral and achiral methylene dioxolanones, a model for conformationally s-cis locked acrylate, was carried out with AIBN to demonstrate an isospecific free radical polymerization controlled by chirality and conformation of monomer. Polymerization of the dioxolanones proceeded smoothly without ring opening to give a polymer with moderate molecular weight and 100% of maximum isotacticity. ESR spectrum indicated a twisted conformation of the growing poly(methylene dioxolanone) radical in contrast to an acyclic analogous radical, suggesting a restriction of the free rotation around main chain CαCβ bond of the growing radical center. Chirality as well as the polarity and bulkiness of monomer affected the polymer tacticity, and chiral alkyl substituent would afford a high isotactic polymer, in which higher the enantiomeric excess of the monomer was, higher the isotacticity of the polymer was. While, achiral or polar substituents including dibenzyl and trichloromethyl groups would afford an atactic polymer. In addition, glass transition temperature (Tg) of the resulting polymers was significantly high, ranging from 172.2 to 229.8 °C, and even for an isotactic polymer Tg was as high as 206.8 °C. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2007–2016

To investigate the relationships between the ability of mastication and physical fitness, and between the ability of mastication and dietary behaviour in children, I examined these parameters using the data of sugar elution rate, physical fitness and athletic ability survey and self-administered questionnaire on dietary behaviour on 171 sixth grade children (88 boys and 83 girls). The sugar elution rate was the index of the ability of mastication and was evaluated by the chewing gum method. The results of self-administered questionnaire on dietary behaviour were used as an index of dietary behaviour. Physical fitness was evaluated by the physical fitness and athletic ability survey of the Ministry of Education, Culture, Sports, Science and Technology, Japan. Regression analysis revealed that the sugar elution rate had significantly positive correlations with the mean grip strength, sit-up, sit-and-reach, repetition side steps and ball throw. The results of self-administered questionnaire on dietary behaviour revealed that the sugar elution rate was significantly higher in children, who had high expectation of food intake and high frequency of vegetable intake, than those with lower parameters. These results suggest that the ability of mastication correlates with physical fitness and dietary behaviour in children.

The purpose of this study is to elucidate the interaction between the cell and the surface of poly(L-lactide) (PLLA) samples, which were modified using a low-temperature plasma treatment apparatus at atmospheric pressure. The plasma treatments were carried out in the atmospheres of air, carbon dioxide (CO2), and perfluoro propane (C3F8) gas. The PLLA samples before and after the plasma treatment were analyzed by XPS and their contact angles with water. Furthermore, the cell adhesion capability and cell mass culturing tests on the PLLA samples were carried out using MC3T3-E1 cells. The results showed that the contact angle of the samples, which was plasma treated in air or in CO2 gas, decreased compared with that of the untreated samples. On the other hand, the contact angle of the samples, which was plasma treated in the C3F8 gas, increased compared with the untreated plasma samples. The cell response on the PLLA samples plasma treated in air or in the CO2 gas were significantly superior to that of the PLLA samples, which was plasma treated in the C3F8 gas. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2006

Background: Valproic acid (2-propyl-N-pentanoic acid, VPA) causes severe hepatic dysfunction, similar to Reye’s syndrome, in a small number of patients. An enhanced excretion of dicarboxylic acids by patients indicates an interference with mitochondrial β-oxidation. We investigated the expression of various acyl-coenzyme A (acyl-CoA) dehydrogenases (ACD), which catalyze the first step of β-oxidation in VPA-treated rats. Methods: The control group received normal saline and the experimental group received VPA (500 mg/kg per day) by intraperitoneal injections for 7 days. Various clinical chemistry parameters in rat blood and free and total carnitine levels in plasma and tissue were determined. Mitochondria were isolated from rat liver and heart and the relative amount of each ACD protein was determined by immunoblot analysis. Total RNA was prepared from various tissues and the mRNA levels for various ACD were measured by slot-blot hybridization analysis using respective cDNA probes. Results: Administration of VPA to rats caused various metabolic effects including hypoglycemia, hyperammonemia and decreased β-hydroxybutyrate concentration. Free carnitine levels in plasma and heart were also decreased. Enzyme activities of various acyl-CoA dehydrogenases, which are involved in fatty acid oxidation, decreased moderately in heart (57–79%), and slightly in liver (78–95%). The most prominent effects were observed in mRNA levels involved in fatty acid oxidation (short-, medium- and long-chain acyl-CoA dehydrogenase). Each mRNA increased in the liver, kidney, skeletal muscle and heart to varying degrees when rats were fed ad libitum. The increase of short- and medium- chain acyl-CoA dehydrogenase mRNA in the heart were particularly large. However, 3 day starvation strongly inhibited expression of ACD in VPA-treated rats. There was an apparent decrease in the amount of ACD mRNA and proteins in VPA-treated liver. Conclusions: Valproic acid causes enhanced expression of fatty ACD mRNA, especially in the heart, by a feedback mechanism related to inhibition of β-oxidation in rats fed ad libitum. However, it impairs the expression of ACD in the liver when there is a drastic change in nutritional state.

An efficient method for the stereoselective synthesis of tetracyclic spirolactams is presented.

An alternative enantioselective total synthesis of (+)-monomorine I has been achieved, based on asymmetric nitrone cycloaddition using a chiral allyl ether.

Chiral synthesis of (−)-nupharamine and (+)-3-epinupharamine, based on elaboration of the intramolecular asymmetric Diels-Alder reaction of N-acylnitroso compounds and the introduction of the furyl group in a fully stereocontrolled manner, is described.

An enantioselective total synthesis of (+)-monomorine I ( 1 ) is described. The key feature of the synthesis is the asymmetric 1,3-dipolar cycloaddition of the prochiral nitrone 9 with the chiral ( S )-allylic ether 8 as a dipolarophile, which provides stereoselectively the C-3,C-5- trans -isoxazolidine 10 with the correct relative and absolute stereochemistry suitable for the synthesis of (+)-monomorine I.

Several methods for the preparation of (2R,5R)- and (2S,5S)-1,2,5,6-diepoxyhexane (2) from 3,4-dideoxy-D-threo-hexitol [(2S, 5S)-1,2,5,6-hexanetetrol (1)] as a single common chiral synthon are described. Among these methods, the methods via (2S,5S)-1,6-bis(pivaloyloxy)-2,5-hexanediol and (2S,5S)-2,5-bis(benzoyloxy)-1,6-dibromohexane, both derived from 1, provide the best results in terms of the selectivity, yield, and optical purity for the preparation of (R,R)-2 and (S,S)-2, respectively

Facile routes for the preparation of an optically active allylic ether bearing the tert-butyl group at an allylic chiral center, i. e. 2-(benzyloxy)-3,3-dimethyl-1-pentene, in both (R)- and (S)-enantiomeric forms, which are expected to be promising, efficient dipolarophiles in highly stereoselective asymmetric nitrone cycloaddition, have been developed, utilizing commercially available L-tert-leucine and (R)-pantolactone, respectively, as chiral precursors

A new noncarbohydrate-based enantioselective approach to (-)-swainsoni- ne (1) is described, in which the aqueous intramolecular Diels-Alder reaction of a chiral acylnitroso diene has been employed as a key reac- tion. The intramolecular cycloaddition of the chiral hydroxamic acid (9), available from D-malic acid in (10) steps, with Pr 4 NIO 4 was con- ducted under the conventional nonaqueous conditions using CHCl 3 as a solvent, where upon intermediacy acylnitroso compound (10) cyclized spontaneously to give the trans- and cis-1,2-oxazinolactams (11) and (12) with a low diastereoselction of 1.3:1 in 76% combined yield. When the corresponding reaction was performed in water, it led to signifi- cant enhancements of trans selectivity of 4.1:1 as well as combined yield (89%). The trans adduct (11) was subjected to reductive N-O bond cleavage followed by diastereoselective hydroxylation with OsO 4 to provide the 1,2-glycol (21), which was then converted to the amino alcohol (25). Intramolecular cyclodehydration of (25) with CBr 4 /PPh 3 - /Et 3 N and subsequent deprotection furnished (-)swainsonine

Remarkably high regio- and stereoselective approaches for the syntheses of dendrobatid alkaloids (+)-allopumiliotoxin 267A and 339A have been developed. As a model study for the syntheses of these alkaloids, we initially undertook intramolecular chromium(II)-mediated cyclization of the racemic N-(iodoalkenyl)piperidine 8, which smoothly proceeded by treatment with CrCl 2 (5 equiv) and catalytic NiCl 2 (2.5 mol%) in DMF to form a 1.3:1 epimeric mixture of 2-hydroxy-3(E)-alkylidene-trans-quinolizidines 33a and 33b. When the alternative chiral N-(iodoalkenyl)piperidine 9 was subjected to the identical cyclization conditions, the 3(E)-alkylidene-trans-quinolizidine 35a with the axially oriented 2-hydroxy group was formed as a single isomer. Based on these model studies, we then undertook the enantioselectivie total synthesis of (+)-allopumiliotoxin 267A (1). For the synthesis of (1), coupling of the two segments, (E)-vinyl iodide 45, obtained via stereospecific palladium-catalyzed hydrostannation, and the pyrrolidine derivative 54, gave the N-(iodoalkenyl)pyrrolidine 56, which underwent intramolecular chromium-(II)-mediated cyclization, exclusively providing 58 with complete retention of the required (E)-alkenyl geometry. Subsequent cleavage of the benzyl group furnished 1. Synthesis of allopumiliotoxin 339A (2) was next investigated bu employing the strategy developed for 1. The side-chain segment, (E)-vinyl iodide 74, was prepared via high-degree stereo- and regioselective reactions involving Evans alkylation and palladium-catalyzed hydrostannation. Intramolecular nickel (II)/chromium(II)-mediated cyclization of the N-(iodoalkenyl)pyrrolidine 82, available via coupling 74 with pyrrolidine derivative 79, led to exclusive formation of 83, which was deprotected to afford 2

A remarkably high regio- and stetreoselective approach for the syntheses of (+)-allopumiliotoxin alkaloids 267A and 339A based on intramolecular nickel(II)/chromium( 11)-mediated ring closure has been developed. South American poison-dart frogs of the family Dendrobatidae have been a rich source of various structurally unique alkaloids. Virtually all of these alkaloids possess high pharmacological activity on nerve and muscle. After the early discovery of four classes of dendrobatid alkaloids that are of the pumiliotoxin C class, the histrionicotoxins, gephyrotoxins, and batrachotoxins, new members of the pumiliotoxin A class and their allo series were isolated and structurally defined.* The latter subclass of alkaloids, the allopumiliotoxins, is a group of hydroxy congeners of the pumiliotoxin A class and they are the most complex members of the pumiliotoxin A alkaloid group.3 For several years, research efforts in our laboratory have been directed toward the development of chiral methods for the total syntheses of dendrobatid alkaloids.4 This article is concerned with the highly regio- and stereocontrolled approach to (+)-allopumiliotoxins 267A (1) and 339A (2).

Addition of carbon nucleophiles to cyclic N -acyliminium salts chirally modified by various optically active pyrrolidines leads to highly enantioselective synthesis of 2-substituted pyrrolidines and piperidines.

Macrodiolide (−)-vermiculine has been synthesized via intramolecular Mitsunobu reaction utilizing a C2 symmetrical diepoxide chiral synthon.

The first chiral synthesis of (–)-oncinotine 1 in natural form has been achieved starting from the protected (S)-N-benzyloxycarbonyl-2-piperidylacetaldehyde 3 based on a new route involving 17-membered ring formation via iminium cyclization, which establishes the 17R absolute configuration of natural 1.

An enantioselective synthesis of naturally occurring ( R )-(−)-cryptopleurine based on highly efficient asymmetric amidoalkylation using a cyclic N -acyliminium intermediate is described.

Nucleophilic addition of carbon nucleophiles and metal hydride reagents to hydrazonium salts modified by optically active 2-substituted pyrrolidine auxiliaries leads to highly enantioselective synthesis of 1-substituted tetrahydroisoquinolines. This methodology was applied to asymmetric synthesis of the title isoquinoline alkaloids.

In this review our own work on the development of chiral approaches to nitrogenous natural products based on a methodology involving conformational control in the transition states under nonchelation conditions has been presented. On 1, 2-asymmetric induction in the reaction of achiral reagents at the diastereotopic faces of a prochiral C=X (X=C, N, O etc.) group adjacent to an asymmetric carbon atom, the increased π-facial selectivity is brought about by conformational fixation of the single bond between the asymmetric center and the prochiral reaction center. Apart from cyclic chelation control, the useful ways to achieve this is to utilize the conformational restraints imposed by Cram-Felkin-Anh mode of nucleophilic addition, inside alkoxy effect, and allylic 1, 3-strain. Employing these nonchelation methodologies for controlling the stereochemistry of acyclic systems, we have succeeded in the enantiopure preparation of nitrogenous natural products including alkaloids, azasugars, and antibiotics.

The natural Z isomer of (+)-streptazolin (1), isolated from cultures of Streptomyces viridochromogenes, was synthesized in an optically pure form for the first time on the basis of a palladium-catalyzed enyne bicyclization approach in 12 steps and 4.3% overall yield from (3R,4R)-3,4-bis(benzyloxy)succinimide (5). The requisite enyne 13 for palladium-catalyzed bicyclization was prepared from 5 via N-acyliminium ion cyclization of the acetoxy lactam 9, partial reduction of 10 with DIBALH−BuLi, and conversion to the dibromo olefin 12. The best result in the palladium-catalyzed bicyclization was obtained when treated with 30 mol % Pd(OAc)2 and N,N ‘-bis(benzylidene)ethylenediamine (BBEDA) as the ligand in benzene at reflux, thus affording a 93:7 mixture of the 1,2,4a,7a,6,7-hexahydro-5H-1-pyrindine (Z)-14 along with its isomerized product (Z)-15 in 84% total yield. The isomerization of the 1,4-diene in (Z)-14 to the 1,3-diene was achieved by treatment with triiron dodecacarbonyl to generate the stable tricarb...

A chiral approach to (–)-pumiliotoxin C based on an aqueous intramolecular acylnitroso Diels–Alder reaction is described. Upon treatment of the (S)-1,3-diene hydroxamic acid 19, available from L-malic acid, with Pr4NIO4 under the aqueous conditions, the in situ generated acylnitroso compound 19 was subjected to intramolecular [4 + 2] cycloaddition to yield the trans-1,2-oxazino lactam 21 with significantly increased diastereoselectivity in comparison with the same cycloaddition conducted in a chloroform solution. Subsequent addition of the propyl side chain was achieved by means of a tandem Grignard reaction–NaBH3CN reduction in a completely stereocontrolled manner. The bicyclic 1,2-oxazine 26 thus obtained was converted into the all-cis-decahydroquinoline 34 by sequential reductive N–O bond cleavage, aldol condensation of the diketone 31 and hydrogenation of the octahydroquinolone 33. Clemmensen reduction of 34, followed by LiAlH4 reduction, provided a ca. 2 : 1 epimeric mixture of α-methyl and β-methyl isomers 36 and 37, and subsequent debenzylation converted the major isomer 36 into 5-epi-pumiliotoxin C 2. On the other hand, 34 underwent LiAlH4 reduction followed by Swern oxidation to afford a 1.2 : 1 epimeric mixture of the decahydroquinolones 39 and 41. Equilibrium control of this epimeric mixture by prolonged heating with Zn(OTf)2 followed by treatment with ethane-1,2-dithiol resulted in the exclusive formation of the thermodynamically more stable β-methyl epimer 43 as a single isomer, which was converted into (–)-pumiliotoxin C 1 by desulfurization and debenzylation.

Lewis acid-promoted conjugate addition reaction of an allylsilane to a series of the chiral 8-arylmenthol-derived N -acyl-2,3-dihydro-4-pyridones leads to the 2-allyl-4-piperidones with moderate to high levels of asymmetric induction, indicating π-stacking contribution to chirality control. This methodology was applied to the asymmetric synthesis of (−)- N -methylconiine.

Hydroxyl-promoted reductive cyclization of enyne compounds catalyzed by Pd(OAc) 2 -BBEDA was explored and found to effect constructing the pyrindine framework with the alkylidene appendage. This methodology was applied to the stereoselective synthesis of (−)-4a,5-dihydrostreptazolin.

Upon treatment with catalytic Pd2(dba)3•CHCl3 in the presence of AcOH, the enyne compounds were subjected to hydropalladation followed by cyclic carbopalladation to form the homoallylpalladium complexes, which subsequently underwent in situ Stille type cross coupling with various vinyltin reagents to give the cyclized products bearing allyl appendages. © 1997 Elsevier Science Ltd.

Et 2 AlCl-mediated nucleophilic alkylation with Grignard reagents on chiral perhydropyrido[2,1- b ]pyrrolo[1,2- d ][1,3,4]oxadiazine has proved to proceed via an S N 2 mechanism at low temperatures (below −80 °C) with high to excellent inversive stereoselection, while, at an elevated temperature, hydrazonium ions are formed preferentially leading to retentive stereoselection. This methodology provides useful access to enantioselective preparation of 2-substituted piperidines and is used for asymmetric synthesis of (+)-coniine.

A new practical route for the first total synthesis of (+)-homopumiliotoxin 223G is described, in which the palladium-catalyzed carbonylation of the vinyl iodide, leading to efficient construction of the quinolizidine nucleus incorporating the (Z)-alkylidene side chain, is the key strategic element. Another key feature of this synthesis involves the Lewis acid-induced chelation-controlled propargylation using the allenylsilane with complete diastereoselectivity.

Publisher Summary This chapter documents the synthetic development in the field of dendrobatid alkaloids accumulated during 1990s under six sub-divisions: 2,5-Disubstituted decahydroquinoline alkaloids, histrionicotoxins, indolizidine alkaloids, pumiliotoxin A class alkaloids, epibatidine, and miscellaneous. The unusual chemical and neuromuscular characteristics have prompted chemists to develop numerous approaches to non-chiral and chiral syntheses of the 2,5-disubstituted decahydroquinoline alkaloids mainly pumiliotoxin C. 5-Substituted 8-methylindolizidines occur in a wide range of dendrobatid species and represent one of the many classes of dendrobatid alkaloids. The absolute configuration of the natural epibatidine is determined by the comparison of synthetic material with authentic material by using chiral High Performance Liquid Chromatography (HPLC) and by using X-ray crystallography by the Merck group.