Das Carotinoidspektrum der Hagebutten von Rosa pomifera: Nachweis von (5Z)-Neurosporin; Synthese von (3R, 15Z)-Rubixanthin

Carotenoids from Hips of Rosa pomifera: Discovery of (5Z)-Neurosporene; Synthesis of (3R, 15Z)-Rubixanthin Extensive chromatographic separations of the mixture of carotenoids from ripe hips of R. pomifera have led to the identification of 43 individual compounds, namely (Scheme 2): (15 Z)-phytoene (1) , (15 Z)-phytofluene (2) , all-(E)-phytofluene (2a) , ξ-carotene (3) , two mono-(Z)-ξ-carotenes ( 3a and 3b ), (6 R)-?, ψ-carotene (4) , a mono-(Z)-?, ψ-carotene (4a) , β, ψ-carotene (5) , a mono-(Z)-β, ψ-carotene (5a) , neurosporene (6) , (5 Z)-neurosporene (6a) , a mono-(Z)-neurosporene (6b) , lycopene (7) , five (Z)-lycopenes (7a–7e) , β, β-carotene (8) , two mono-(Z)-β, β-carotenes (probably (9 Z)-β, β-carotene (8a) and (13 Z)-β, β-carotene (8b) ), β-cryptoxanthin (9) , three (Z)-β-cryptoxanthins (9a–9c) , rubixanthin (10) , (5′ Z)-rubixanthin (=gazaniaxanthin; 10a ), (9′ Z)-rubixanthin (10b) , (13′ Z)- and (13 Z)-rubixanthin (10c and 10d , resp.), (5′ Z, 13′ Z)- or (5′ Z, 13 Z)-rubixanthin (10e) , lutein (11) , zeaxanthin (12) , (13 Z)-zeaxanthin (12b) , a mono-(Z)-zeaxanthin (probably (9 Z)-zeaxanthin (12a) ), (8 R)-mutatoxanthin (13) , (8 S)-mutatoxanthin (14) , neoxanthin (15) , (8′ R)-neochrome (16) , (8′ S)-neochrome (17) , a tetrahydroxycarotenoid (18?) , a tetrahydroxy-epoxy-carotenoid (19?) , and a trihydroxycarotenoid of unknown structure. Rubixanthin (10) and (5′ Z)-rubixanthin (10a) can easily be distinguished by HPLC. separation and CD. spectra at low temperature. The synthesis of (3 R, 15 Z)-rubixanthin (29) is described. The isolation of (5 Z)-neurosporene (6a) supports the hypothesis that the ?-end group arises by enzymatic cyclization of precursors having a (5 Z)- or (5′ Z)-configuration.     

Synthesis and characterization of double hydrophilic block copolymers containing semi-rigid and flexible segments

3-Methyl-(E)-stilbene (3MSti) and 4-(diethylamino)-(E)-stilbene (DEASti) monomers are synthesized and polymerized separately with maleic anhydride (MAn) in a strictly alternating fashion using reversible addition-fragmentation chain transfer (RAFT) polymerization techniques. The optimal RAFT chain transfer agents (CTAs) for each copolymerization affect the reaction kinetics and CTA compatibilities. Psuedo-first order polymerization kinetics are demonstrated for the synthesis of poly((3-methyl-(E)-stilbene)-alt-maleic anhydride) (3MSti-alt-MAn) with a thiocarbonylthio CTA (methyl 2-(dodecylthiocarbonothioylthio)−2-methylpropionate, TTCMe). In contrast, a dithioester CTA (cumyl dithiobenzoate, CDB) controls the synthesis of poly((4-(diethylamino)-(E)-stilbene)-alt-maleic anhydride) (DEASti-alt-MAn) with pseudo-first order polymerization kinetics. DEASti-alt-MAn is chain extended with 4-acryloylmorpholine (ACMO) to synthesize diblock copolymers and subsequently converted to a double hydrophilic polyampholyte block copolymers (poly((4-(diethylamino)-(E)-stilbene)-alt-maleic acid))-b-acryloylmorpholine) (DEASti-alt-MA)-b-ACMO) via acid hydrolysis. The isoelectric point and dissociation behavior of these maleic acid-containing copolymers are determined using ζ-potential and acid–base titrations, respectively. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 219–227     

Terpenoids from the Roots of Ligularia muliensis

Three new eremophilane‐type sesquiterpenes, (6β,8α)‐6‐(acetyloxy)‐8‐hydroxyeremophil‐7(11)‐en‐12,8‐olide ( 1 ), (6α,8α)‐6‐hydroxyeremophil‐7(11)‐en‐12,8‐olide ( 2 ), and (6α,8α)‐6‐(acetyloxy)eremophil‐7(11)‐en‐12,8‐olide ( 3 ) ((8α)‐eremophil‐7(11)‐en‐12,8‐olide = (4aR,5S,8aR,9aS)‐4a,5,6,7,8,8a,9,9a‐octahydro‐3,4a,5‐trimethylnaphtho[2,3‐b]furan‐2(4H)‐one), besides the recently elucidated eremoligularin ( 4 ) and bieremoligularolide ( 5 ), as well as a new highly oxygenated monoterpene, rel‐(1R,2R,3R,4S,5S)‐p‐menthane‐1,2,3,5‐tetrol ( 12 ), together with six known constituents, i.e., the sesquiterpenes 6 and 7 , the norsesquiterpenes 8 – 10 , and the monoterpene 13 , were isolated from the roots of Ligularia muliensis. In addition, an attempt to dimerize 1 to a bieremophilenolide (Scheme) resulted in the generation of the new derivative (6β,8β)‐6‐(acetyloxy)‐8‐chloroeremophil‐7(11)‐en‐12,8‐olide ( 11 ). The new structures were established by means of detailed spectroscopic analysis (IR, FAB‐, EI‐, or HR‐ESI‐MS as well as 1D‐ and 2D‐NMR experiments). Compounds 4 and 5 were evaluated for their antitumor effects in vitro (Table 3).     

Secondary Interactions or Ligand Scrambling? Subtle Steric Effects Govern the Iridium(I) Coordination Chemistry of Phosphoramidite Ligands

The like and unlike isomers of phosphoramidite (P*) ligands are found to react differently with iridium(I), which is a key to explaining the apparently inconsistent results obtained by us and other research groups in a variety of catalytic reactions. Thus, the unlike diastereoisomer (aR,S,S)‐[IrCl(cod)( 1 a )] ( 2 a ; cod=1,5‐cyclooctadiene, 1 a =(aR,S,S)‐(1,1′‐binaphthalene)‐2,2′‐diyl bis(1‐phenylethyl)phosphoramidite) forms, upon chloride abstraction, the monosubstituted complex (aR,S,S)‐[Ir(cod)(1,2‐η‐ 1 a ,κP)]⁺ ( 3 a ), which contains a chelating P* ligand that features an η² interaction between a dangling phenyl group and iridium. Under analogous conditions, the like analogue (aR,R,R)‐ 1 a′ gives the disubstituted species (aR,R,R)‐[Ir(cod)( 1 a′ ,κP)₂]⁺ ( 4 a′ ) with monodentate P* ligands. The structure of 3 a was assessed by a combination of X‐ray and NMR spectroscopic studies, which indicate that it is the configuration of the binaphthol moiety (and not that of the dangling benzyl N groups) that determines the configuration of the complex. The effect of the relative configuration of the P* ligand on its iridium(I) coordination chemistry is discussed in the context of our preliminary catalytic results and of apparently random results obtained by other groups in the iridium(I)‐catalyzed asymmetric allylic alkylation of allylic acetates and in rhodium(I)‐catalyzed asymmetric cycloaddition reactions. Further studies with the unlike ligand (aS,R,R)‐(1,1′‐binaphthalene)‐2,2′‐diyl bis{[1‐(1‐naphthalene‐1‐yl)ethyl]phosphoramidite} ( 1 b ) showed a yet different coordination mode, that is, the η⁴‐arene–metal interaction in (aS,R,R)‐[Ir(cod)(1,2,3,4‐η‐ 1 b ,κP)]⁺ ( 3 b ).     

On the behavior of α-brominated dimethyl o-benzenediacetate toward nitrogen nucleophiles . Part I. Reaction of dimethyl α,α'-dibromo o-benzenediacetate with hydrazines

Meso- ( 1a ) and racemic dimethyl α,α'-dibromo o-benzenediacetate ( 1b ) when condensed with hydrazine and methylhydrazine furnished respectively 1,3-dicarbomethoxyisoindole ( 5a ) and its N-methyl derivative ( 5b ). Reaction of phenylhydrazine with 1a led to the N-phenylisoindole ( 5c ) and to the N-anilino isoindoline ( 6 ) as the cis isomer; conversely, 1b was transformed into a mixture of the 2-phenyl-1,2,3,4-tetrahydrophthalazine ( 7 ), the trans isomer of ( 6 ), the N-anilinoisoindole ( 5d ) and dimethyl α-(N'-phenylhydrazino)-o-benzenediacetate ( 8 ). Compounds 1a and 1b were also condensed with acetylhydrazine to give a mixture of the N-acetylaminoisoindoline ( 12 ) and of the 2-acetyl-1,2,3,4-tetrahydrophthalazine ( 13 ).     

Bimanes (1,5-diazabicyclo[3.3.0]octadienediones): Laser activity in syn-bimanes

The conversion of 3-methyl-4-benzyl-4-chloro-2-pyrazolin-5-one 10b was catalyzed by a mixture of potassium fluoride and alumina to give syn-(methyl, benzyl)bimane 6 (62%) without detectable formation of the anti isomer, A6 [a 1 : 1 mixture (87%) of the isomers 6 and A6 was obtained when the catalyst was potassium carbonate]. In a similar reaction syn-(methyl,carboethoxymethyl)bimane 7 (15%) with the anti isomer A7 (36%) was obtained from 3-methyl-4-carboethoxymethyl-4-chloro-2-pyrazolin-5-one 10c . syn-(Methyl, β-acetoxyethyl)bimane 8 (70%) was obtained from 3-methyl-4-β-acetoxyethyl-4-chloro-2-pyrazolin-5-one 10d (potassium carbonate catalysis) and was converted by hydrolysis to syn-(methyl, β-hydroxyethyl)bimane 9 (40%). Acetyl nitrate (nitric acid in acetic anhydride) converted anti-(amino,hydrogen)bimane 11 to anti-(amino,nitro)bimane 15 (91%), anti-(methyl,hydrogen)bimane 13 to anti-(methyl,nitro)(methyl,hydrogen)bimane 16 (57%), and degraded syn-(methyl,hydrogen)bimane 12 to an intractable mixture. Treatment with trimethyl phosphite converted syn-(bromomethyl,methyl)bimane 17 to syn-(dimethoxyphosphinylmethyl,methyl)bimane 18 (78%) that was further converted to syn-(styryl,methyl)bimane 19 (29%) in a condensation reaction with benzaldehyde. Treatment with acryloyl chloride converted syn-(hydroxymethyl,methyl)bimane 20 to its acrylate ester 21 (22%). Stoichiometric bromination of syn-(methyl,methyl)bimane 1 gave a monobromo derivative that was converted in situ by treatment with potassium acetate to syn-(acetoxymethyl,methyl)(methyl,methyl)bimane 47 . N-Amino-μ-amino-syn-(methylene,methyl)bimane 24 (68%) was obtained from a reaction between the dibromide 17 and hydrazine. Derivatives of the hydrazine 24 included a perchlorate salt and a hydrazone 25 derived from acetone. Dehydrogenation of syn-(tetramethylene)bimane 26 by treatment with dichlorodicyanobenzoquinone (DDQ) gave syn-(benzo,tetramethylene)bimane 27 (58%) and syn-(benzo)bimane 28 (29%). Bromination of the bimane 26 gave a dibromide 29 (92%) that was also converted by treatment with DDQ to syn-(benzo)bimane 28 . Treatment with palladium (10%) on charcoal dehydrogenated 5, 6, 10, 11-tetrahydro-7H,9H-benz [6, 7] indazol [1, 2a]benz[g]indazol-7,9-dione 35 to syn-(α-naphtho)bimane 36 (71%). The bimane 35 was prepared from 1,2,3,4-tetrahydro-1-oxo-2-naphthoate 37 by stepwise treatment with hydrazine to give 1,2,4,5-tetrahydro-3H-benz[g]indazol-3-one 38 , followed by chlorine to give 3a-chloro-2,3a,4,5-tetrahydro-3H-benz[g]indazol-3-one 39 , and base. Dehydrogenation over palladium converted the indazolone 34 to 1H-benz[g] indazol-3-ol 36 . Helicity for the hexacyclic syn-(α-naphtho)bimane 36 was confirmed by an analysis based on molecular modeling. The relative efficiencies (RE) for laser activity in the spectral region 500–530 nm were obtained for 37 syn-bimanes by reference to coumarin 30 (RE 100): RE > 80 for syn-bimanes 3, 5, 18 , and μ-(dicarbomethoxy)methylene-syn-(methylene,methyl)bimane 22 : RE 20–80: for syn-bimanes 1,2,4,20,24,26 , and μ-thia-syn-(methylene,methyl)bimane 50 : and RE 0-20 for 26 syn-bimanes. The bimane dyes tended to be more photostable and more water-soluble than coumarin 30. The diphosphonate 18 in dioxane showed laser activity at 438 nm and in water at 514 nm. Presumably helicity, that was demonstrated by molecular modeling, brought about a low fluorescence intensity for syn-(α-naphtho)bimane 36 , Φ0.1, considerably lower than obtained for syn-(benzo)bimane 28 , Φ0.9.     

The molecular structure and chemical reactivities of the condensation products of o-substituted benzylidenacetylacetone with hydrazine dihydrochloride

Reaction of o-nitrobenzylideneacetylacetone ( 1a ) with hydrazine dihydrochloride in methanol gave 4-(α-methoxy-o-nitrobenzyl)-3,5-dimethylpyrazole hydrochloride ( 4a ), whose structure was unambigously confirmed by an X-ray crystallographic analysis, via 4-(o-nitrobenzylidene)-3,5-dimethylisopyrazole ( 2a ). Compound 2a was synthesized by condensation of 1a with hydrazine dihydrochloride in acetonitrile. Analogously the corresponding o-chloro derivatives ( 2b, 4b ) were obtained. These were converted to N-methyl ( 6b ) and N-acetyl ( 7a,b ) derivatives and the behaviors on bromination and pyrolysis were investigated.     

Synthesis and transformations of (±)-trans-4aβ(H), saα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one

Hydrogenation of 4,7-dimethylcoumarin ( 1 ) in alkaline medium has been shown to furnish a mixture of (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7β-dimethyl-2H-1-benzopyran-2-one ( 2 ), (±)-trans-4aβ(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 3 ) and (±)-cis-4aα(H),8aα(H)-octahydro-4α,7α-dimethyl-2H-1-benzopyran-2-one ( 4 ) in 40:25:35:ratio, respectively. The stereochemistry of the major hydrogenation product 2 , has been established by transforming it to p-menthane derivatives e.g. (±)-2 (R)-[2′(R)hydroxy-4′(R) methylcyclohex-(1′S)-yl]propan-1-ol ( 20 ) and (±)-trans-3α,6β-dimethyl-3aβ(H),7aα(H)-octahydrobenzofuran ( 12 ). Starting from a mixture of lactones 2, 3 and 4 , lactone 3 has been obtained in pure state employing a sequence of reactions.     

Cadinene Derivatives from Eupatorium adenophorum

A new norsesquiterpene named eupatorone (= (4S,4aR,6R)‐1‐acetyl‐6‐(acetyloxy)‐4,4a,5,6‐tetrahydro‐4,7‐dimethylnaphthalen‐2(3H)‐one; 1 ) and a new sesquiterpene derivative named 2‐deoxo‐2‐(acetyloxy)‐9‐oxoageraphorone (= (1R,4S,4aR,6R,8aS)‐6‐(acetyloxy)‐3,4,4a,5,6,8a‐hexahydro‐4,7‐dimethyl‐1‐(1‐methylethyl)naphthalen‐2(1H)‐one; 2 ), together with the five known cadinene derivatives 3 – 7 were isolated from the flower of Eupatorium adenophorum (Spreng. ). Their structures were established by extensive NMR experiments, including 1D and 2D NMR.     

Synthesis of the Bretonins,Polyolefinic Esterified Glyceryl Ethers of an Unidentified Sponge from the North-Brittany Sea: Absolute Configuration and Novel Structure Assignment

The absolute configurations of acetylated bretonin A (= (+}-( R )-1-[(acetoxy)methyl]-2-{[(4E,6E,8E)-dodeca-4,6,8-trienyl]oxy}ethyl 4-acetoxybenzoate; (?)- 1b ) and isobretonin A (= (+)-(S)-3-{[(4E,6E,8E)-do-deca-4,6,8-trienyl]oxy}-2-hydroxypropyl 4-hydroxybenzoate; (+)-2), previously isolated from an undetermined sponge of the North Brittany sea, were established by comparison with synthetic (+)- lb and (+)- 2 , obtained from the condensation of commerical (?)-(R)-2,2-dimethyl-1,3-dioxolan-4-yl p-toluenesuifonate ((?)-(R)- 15 ) with a mixture of (4E,6E,8E)- ( 14e ) and (4E,6Z,8E)-dodeca-4,6,8-trien-1-ol ( 14z ). This also allowed confirming the structure and configuration of bretonin B (= (S)-2-{[(4E,6Z,8E)-dodeca-4,6,8-trienyl]oxy}-1-(hydroxy-methyl)ethyl 4-hydroxybenzoate; 3 ) which was also isolated from the same sponge, albeit in a too small amount for a complete study. As concerns the glyceryl ethers precursors of the bretonins, co-occurrence of the usual (S)-con-figuration (from 1a ) with the unusual (R)-configuration (from (+)- 2 )) poses intriguing biogenetic problems.     

Partialsynthese der Grandidone A, 7-Epi-A,B, 7-Epi-B,C, D und 7-Epi-D aus 14-Hydroxytaxodion

Partial Synthesis of Grandidones A, 7-Epi-A, B, 7-Epi-B, C, D and 7-Epi-D, from 14-Hydroxytaxodione Oxydative addition of coleon U ( 6 ) to 14-hydroxytaxodione ( 5 ) in the presence of Fétizon's reagent mainly leads to grandidone A ( 1a ) and 7-epigrandidone A ( 1b ) (ca. 15:1), whereas coleon V ( 7 ) and 5 under the same conditions yield grandidone B ( 2a ) and 7-epigrandidone B ( 2b ) (ca. 3:1). Dimerization of 14-hydroxytaxodione ( 5 ) gives grandidone C ( 3 ; ca. 40%), grandidone D ( 4a ; ca. 50%) and 7-epigrandidone D ( 4b ; ca. 10%). All these compounds obtained by partial synthesis are in every respect identical with the natural products, thus establishing their absolute configurations. The thermal transformation of grandidone C ( 3 ) to grandidone D ( 4a )/7-epigrandidone D ( 4b ) and interconversions of 4a and 4b were achieved. Oxydative addition of coleon U ( 6 ) to 14-hydroxytaxodione ( 5 ) in the presence of Fétizon's reagent mainly leads to grandidone A ( 1a ) and 7-epigrandidone A ( 1b ) (ca. 15:1), whereas coleon V ( 7 ) and 5 under the same conditions yield grandidone B ( 2a ) and 7-epigrandidone B ( 2b ) (ca. 3:1). Dimerization of 14-hydroxytaxodione ( 5 ) gives grandidone C ( 3 ; ca. 40%), grandidone D ( 4a ; ca. 50%) and 7-epigrandidone D ( 4b ; ca. 10%). All these compounds obtained by partial synthesis are in every respect identical with the natural products, thus establishing their absolute configurations. The thermal transformation of grandidone C ( 3 ) to grandidone D ( 4a )/7-epigrandidone D ( 4b ) and interconversions of 4a and 4b were achieved. Oxydative addition of coleon U ( 6 ) to 14-hydroxytaxodione ( 5 ) in the presence of Fétizon's reagent mainly leads to grandidone A ( 1a ) and 7-epigrandidone A ( 1b ) (ca. 15:1), whereas coleon V ( 7 ) and 5 under the same conditions yield grandidone B ( 2a ) and 7-epigrandidone B ( 2b ) (ca. 3:1). Dimerization of 14-hydroxytaxodione ( 5 ) gives grandidone C ( 3 ; ca. 40%), grandidone D ( 4a ; ca. 50%) and 7-epigrandidone D ( 4b ; ca. 10%). All these compounds obtained by partial synthesis are in every respect identical with the natural products, thus establishing their absolute configurations. The thermal transformation of grandidone C ( 3 ) to grandidone D ( 4a )/7-epigrandidone D ( 4b ) and interconversions of 4a and 4b were achieved. Oxydative addition of coleon U ( 6 ) to 14-hydroxytaxodione ( 5 ) in the presence of Fétizon's reagent mainly leads to grandidone A ( 1a ) and 7-epigrandidone A ( 1b ) (ca. 15:1), whereas coleon V ( 7 ) and 5 under the same conditions yield grandidone B ( 2a ) and 7-epigrandidone B ( 2b ) (ca. 3:1). Dimerization of 14-hydroxytaxodione ( 5 ) gives grandidone C ( 3 ; ca. 40%), grandidone D ( 4a ; ca. 50%) and 7-epigrandidone D ( 4b ; ca. 10%). All these compounds obtained by partial synthesis are in every respect identical with the natural products, thus establishing their absolute configurations. The thermal transformation of grandidone C ( 3 ) to grandidone D ( 4a )/7-epigrandidone D ( 4b ) and interconversions of 4a and 4b were achieved.     

Formation of 1,1,2,3,3-pentakis(arylthio)-1-propenes from tris(arylthio)cyclopropenyl cations and their conversion into 1,1,2,5,6,6-hexakis(arylthio)-(3E)-1,3,5-hexatriene

The reaction of tetrachlorocyclopropene (1) with arenethiols (2a–e), followed by treatmentwith perchloric acid, gave tris(arylthio)cyclopropenylium perchlorates (3a–c and e), 1,1,2,3,3-pentakis(arylthio)-1-propenes (4a–d), and 2,3,3-tris(arylthio)propenals (5a–d). The structures of tris(phenylthio)cyclopropenylium perchlorate (3a), 1,1,2,3,3-pentakis(phenylthio)-1-propene (4a), and 2,3,3-tris(o-tolylthio)propenal (5b) were analyzed by single-crystal X-ray diffraction studies. The yields depended significantly on the electron-withdrawing property of the substituents of the arenethiols and the molar ratio of 2 to 1. The reaction with 2,6-dimethylbenzenethiol (2e) gave only tris(2,6-dimethylphenylthio)cyclopropenylium perchlorate (3e) without the formation of 4e and 5e. Compounds 5a–d were produced by acid hydrolysis of 4a–d. Pyrolysis of 4a–d gave (3R,4S)-1,1,2,3,4,5,6,6-octakis(arylthio)-1,5-hexadienes (9a–d) and 1,1,2,5,6,6-hexakis(arylthio)-(3E)-1,3,5-hexatrienes (10a–d) together with diaryl disulfides (11a–d). Compound 10a was also produced by photolysis. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:387–397, 1998     

The Total Synthesis and Biological Assessment of trans‐Epothilone A

The total synthesis of (12S,13S)‐trans‐epothilone A ( 1a ) was achieved based on two different convergent strategies. In a first‐generation approach, construction of the C(11) C(12) bond by Pd⁰‐catalyzed Negishi‐type coupling between the C(12)‐to‐C(15) trans‐vinyl iodide 5 and the C(7)‐to‐C(11) alkyl iodide 4 preceded the (nonselective) formation of the C(6) C(7) bond by aldol reaction between the C(7)‐to‐C(15) aldehyde 25 and the dianion derived from the C(1)‐to‐C(6) acid 3 . The lack of selectivity in the aldol step was addressed in a second‐generation approach, which involved construction of the C(6) C(7) bond in a highly diastereoselective fashion through reaction between the acetonide‐protected C(1)‐to‐C(6) diol 31 (‘Schinzer's ketone') and the C(7)‐to‐C(11) aldehyde 30 . As part of this strategy, the C(11) C(12) bond was established subsequent to the critical aldol step and was based on B‐alkyl Suzuki coupling between the C(1)‐to‐C(11) fragment 40 and C(12)‐to‐C(15) trans‐vinyl iodide 5 . Both approaches converged at the stage of the 3‐O, 7‐O‐bis‐TBS‐protected seco acid 27 , which was converted to trans‐deoxyepothilone A ( 2 ) via Yamaguchi macrolactonization and subsequent deprotection. Stereoselective epoxidation of the trans C(12) C(13) bond could be achieved by epoxidation with Oxone ^® in the presence of the catalyst 1,2 : 4,5‐di‐O‐isopropylidene‐L ‐erythro‐2,3‐hexodiuro‐2,6‐pyranose ( 42a ), which provided a 8 : 1 mixture of 1a and its (12R,13R)‐epoxide isomer 1b in 27% yield (54% based on recovered starting material). The absolute configuration of 1a was established by X‐ray crystallography. Compound 1a is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 1b is at least two orders of magnitude lower than that of epothilone A or 1a .     

Synthesen und Untersuchungen von [Oxazolo[2,3-a]isoindol-9b(2H)-yl]phosphonaten und -phosphinaten: Eine neue Klasse von Heterocyclen

Syntheses and Investigations of [Oxazolo[2,3-a]isoindol-9b(2H)-yl]phosphonates and -phosphinates: a New Class of Heterocycles We attempted to synthesize diethyl (1-methyl-2-phthalimidoethyl)phosphonate ( 14a ) in a Michaelis-Becker reaction using diethyl sodiophosphonate ( 13 ) and the tosylate 12a of (2-hydroxypropyl)phthalimide as starting materials. Instead of TsO substitution in 12a by the nucleophile 13 , the carbonyl C-atom of the phthalimido moiety was attacked by 13 , followed by an intramolecular nucleophilic substitution at C(2) of the side chain leading to the (oxazolo[2,3-a]isoindolyl)phosphonate 15a (Scheme 1). Similarly, 12a and N-(2-bromoethyl)phthalimide ( 12b ) reacted with butyl (benzene)sodiophosphinate ( 18 ) to the (oxazolo[2,3-a]isoindolyl)(phenyl)phosphinates 20a and 20b , respectively (Scheme 2). The attempt to synthesize enantiomerically pure 2-substituted (2-phthalimidoethyl)phosphonates 27 starting from L -α-amino-acids failed, too (Scheme 3): the main products of the reaction of the N,N-phthaloyl-O¹-tosyl-L -aminoalcohols 25a–d with 13 were the 3-substituted (oxazolo[2,3-a]isoindolyl)-phosphonates 26a–d , the desired 27b and 27c being observed as by-products in the ³¹P-NMR spectrum.     

1,2,4-benzothiadiazine 1,1-dioxides 3. Reactions of 2-aminobenzenesulfonamide with chloroalkyl isocyanates

Reactions of 2-aminobenzenesulfonamide ( 1 ) with allyl, methyl, 2-chloroethyl aor 3-chloropropyl isocyanates gave 2-(methylureido)-, 2-(allylureido)-, 2-(2′-chloroethylureido)- and 2-(3′-chloropropylureido)-benzene sulfonamides 3a,b and 7a,b in excellent yields. Treatment of 3a,b at refluxing temperature of DMF afforded 2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide ( 4 ) in good yield. However, when compounds 7a,b were refluxed in 2-propanol, 3-(2′-aminoethoxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide ( 11a ) and 3-(3′-aminopropoxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide ( 11b ) were obtained in a form of the hydrochloride salts 10a,b in 87% and 78% yields respectively. Heating 11b in ethanol gave a dimeric form of 2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide and 3-(3′-aminopropoxy)-2H-1,2,4-benzothiadiazine 1,1-dioxide ( 12 ) in 55% yield. Treating of 7a,b or 11a,b with triethylamine at the refluxing temperature of 2-propanol afforded 3-(2′-hydroxyethylamino)-2H-1,2,4-benzothiadiazine 1,1-dioxide ( 2a ) and 3-(3′-hydroxypropylamine)-2H-1,2,4-benzothiadiazine 1,1-dioxide ( 2b ) via a Smiles rearrangement.     

Crystal and Molecular Structures of Mononuclear Coordinated Copper(I) Complexes with Thio-triazole and Thio-triazine based Schiff base Ligands

Reaction of 4-amino-5-methyl-1,2,4-triazol-3(2H)-thione (AMTT) and 4-amino-6-methyl-3-thio-3,4-dihydro-1,2,4-triazin-5(2H)-one (AMTTO) with 2-hydroxybenzaldehyde led to the synthesis of corresponding Schiff base ligands [(Z)-4-((2-hydroxybenzylidene)amino)-3-methyl-1H-1,2,4-triazole-5(4H)-thione ( L1 ) and (Z)-4-((2-hydroxybenzylidene)amino)-6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one ( L2 )]. Treatment of synthesized Schiff base ligands with CuCl provided the complexes [Cu(L1)₃Cl] ( 1 ) and [Cu(L2)₂Cl] ( 2 ). Synthesized complexes were characterized by elemental analyses, IR spectroscopy and X-ray diffraction studies. Complex 1 consists of a metal ion coordinated with one chloride ion and three Schiff base ligands via sulfur atoms in a distorted tetrahedral environment, whereas 2 consists of a metal ion coordinated with one chloride ion and two sulfur atoms from two different Schiff base ligands in a trigonal planar arrangement. Crystal data for 1 at –153 °C revealed an orthorhombic space group Fdd2, a = 34.8088(7), b = 33.8156(8), c = 11.6142(2) Å, Z = 16, R₁ = 0.0357; for 2 at –178 °C the symmetry was triclinic, space group P1 , a = 7.27520(10), b = 15.4620(2), c = 23.7985(4) Å, α = 72.1964(13), β = 86.5208(12), γ = 89.8597(11)°, Z = 4, R₁ = 0.0359.     

Synthesis of Heterotelechelic Poly(ethylene glycol)-block-poly(succinimide) Possessing Both Acetal and Tert-Butoxycarbonyl-amino Terminals with Narrow Molecular Weight Distribution

A novel heterotelechelic linear block copolymer of poly(ethylene glycol) (PEG) and poly(succinimide) (PSI) possessing both acetal and tert-butoxycarbonyl-amino (Boc-NH) terminals (Acetal-PEG-b-PSI-NH-Boc) with a narrow molecular weight distribution (MWD) was successfully prepared by the nucleophilic attack of triethylamine (TEA) to the poly(β-benzyl L-aspartate) (PBLA) segment of Acetal-PEG-b-PBLA-NH-Boc. Acetal-PEG-b-PBLA-NH-Boc with MWD of 1.07 was prepared by living anionic ring-opening polymerization of β-benzyl L-aspartate N-carboxy-anhydride with α-acetal-ω-amino PEG as a macroinitiator, followed by Boc protection. The subsequent conversion of PBLA segment to PSI was successfully carried out by reacting with the catalytic amount of TEA. The characterization by ¹H NMR, GPC and IR demonstrates that the formation of poly(succinimide) proceeded completely without any remarkable side reactions. Acetal-PEG-b-PSI-NH-Boc thus obtained may have a potential utility as a targetable drug carrier in the field of drug delivery system.     

Catalytic Asymmetric Mannich‐Type Reaction Enabled by Efficient Dienolization of α,β‐Unsaturated Pyrazoleamides†

(E)‐α,β‐Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)‐(1Z,3Z)‐dienolates as the major in the presence of a copper(I)‐(R)‐DTBM‐SEGPHOS catalyst and Et₃N, which react with aldimines to afford syn‐vinylogous products as the major diastereoisomers in high regio‐ and enantioselectivities. In some cases, the diastereoselectivity is low, possibly due to the low ratio of copper(I)‐(1Z,3Z)‐dienolates to copper(I)‐(1Z,3E)‐dienolates. (Z)‐Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)‐(1Z,3Z)‐dienolates. Interestingly, the present methodology is a nice complement to our previous report, in which (E)‐β,γ‐unsaturated pyrazoleamides were employed as the prenucleophiles in the copper(I)‐catalyzed asymmetric vinylogous Mannich‐Type reaction and anti‐vinylogous products were obtained. In the previous reaction, copper(I)‐ (1Z,3E)‐dienolates were generated through α‐deprotonation, which might form an equilibrium with (E)‐allylcopper(I) species. Therefore, it is realized in the presence of a copper(I) catalyst that (E)‐α,β‐unsaturated pyrazoleamides lead to syn‐products and (E)‐β,γ‐unsaturated pyrazoleamides lead to anti‐products. Finally, by use of (E)‐β,γ‐unsaturated pyrazoleamide, (E)‐α,β‐unsaturated pyrazoleamide, (R)‐DTBM‐SEGPHOS, and (S)‐DTBM‐SEGPHOS, the stereodivergent synthesis of all four stereoisomers is successfully carried out. Then by following a three‐step reaction sequence, all four stereoisomers of N‐Boc‐2‐Ph‐3‐Me‐piperidine are synthesized in good yields, which potentially serve as common structure units in pharmaceutically active compounds.     

1,4-Cyeloaddition reactions. IV. preparation of Cyclopenta[g]furo[3,2-c]quinolines,Cyclopenta- [f]furo[3,2-c]quinolines,Benzo[H]furo[3,2-c]quinolines,and Furo- [3,2-c]indeno[1,7-gh] quinolines from 2,3-Dihydro-5-methylfuran and schiff bases

The boron trifluoride catalyzed 1,4-addition of 2,3-dihydro-5-methylfuran to N-(p-methoxybenzylidene)-5-indanamine (VI) gave 2 pairs of epimers, dl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-methoxyphenyl)-10b-methyl-2H-cyclopenta[g]furo[3,2-c]quinoline (VIIa and b) and dl-3,3a, 4,-5,8,9,10,10c-octahydro-4-(p-methoxyphenyl)-10c-methyl-2H-cyclopenta[f]furo[3,2-c]quinoline (VIIIa and b). When 4-(benzylideneamino)-1-naphthol (IXa) was condensed with 2,3-dihydro-5-methylfuran in an analogous manner, a mixture of two isomers of dl-1,2,2a,3,4,5a-hexahydro-5a-methyl-2-phenylbenzo[h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? H)] was obtained. Likewise, 4-[(p-hydroxybenzylidene)amino]-1-naphthol (IXb) and 4-(p-methoxybenzylidene)amino]-1-naphthol (IXc) gave a mixture of two isomers of dl-1,2,2a,3,4,5a-hexahydro-2-(p-hydroxyphenyl)-5a-methylbenzo[h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? OH)] and dl-1,2,2a,3,4,5a-hexahydro-2-(p-methoxyphenyl)-5a-methylbenzo [h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? OCH₃)], respectively. The condensation of N-(p-methoxybenzylidene)-5-acenaphthenamine (XI) with 2,3-dihydro-5-methylfuran afforded a mixture of two isomers of dl-2,3,3a,4,5,9,10,-11b-octahydro-4-(p-methoxyphenyl)-11b-methylfuro[3,2-c]indeno[1,7-gh]quinoline (XIIa and b). Structural assignments for all of the products were made from NMR spectra. None of these compounds possessed appreciable biological activity.     

Application of FTIR Microscopy in Combinatorial Experimentation on Polymer Blends

Summary: A novel combinatorial, high-throughput experimentation (HTE) setup has been developed, which allows for rapid mapping of the phase behavior of blends of homopolymers and block copolymers. The principle is based on the preparation of composition (ϕ)-temperature (T) gradient films. Linear ϕ gradients were obtained over a large composition range, as shown by FTIR microscopy. The applicability of this combinatorial approach was demonstrated by studying the phase behavior of a poly(styrene-co-acrylonitrile) (SAN)/poly(methyl methacrylate-co-ethyl acrylate) (PMMA-EA) blend with varying EA content and a poly(styrene-b-butadiene-b-methyl methacrylate) (SBM) triblock copolymer.