Comparative study of diastereoisomer interconversion in chiral BINOL-ate and diamine platinum complexes of conformationally flexible NUPHOS diphosphines

A thorough and detailed study of diastereointerconversion in the chiral platinum complexes [(NUPHOS)Pt{(S)-BINOL}] (3a-e) has been undertaken and compared with the results of a similar study with [(BIPHEP)Pt{(S)-BINOL}]. Rate data revealed that this process obeys first-order relaxation kinetics, and rate constants for conversion of the minor to the major diastereoisomer have been obtained. Eyring analysis of the data gave DeltaH(double dagger) and DeltaS(double dagger) values of 22-25 kcal mol(-1) and -1 to -16 eu, respectively. In combination with computational analysis, these studies indicate that atropinversion most likely occurs via an on-metal pathway involving a planar seven-membered transition state. Substitution of (S)-BINOL for (S,S)-DPEN results in a marked reduction in the barrier to atropinversion; a DeltaH(double dagger) value of 17 kcal mol(-1) has been determined for the conversion of delta-[(Ph-4-NUPHOS)Pt{(S,S)-DPEN}]Cl-2 to lambda-[(Ph-4-NUPHOS)Pt{(S,S)-DPEN}]Cl-2, which could indicate that an alternative mechanism operates.

Total Synthesis of the GRP78-Downregulatory Macrolide (+)-Prunustatin A, the Immunosuppressant (+)-SW-163A, and a JBIR- 04 Diastereoisomer That Confirms JBIR-04 Has Nonidentical Stereochemistry to (+)-Prunustatin A

A unified total synthesis of the GRP78-downregulator(+)-prunustatin A and the immunosuppressant(+)-SW-163A based upon [1 + 1 + 1 + 1]-fragment condensationand macrolactonization between O(4) and C(5) is hereindescribed. Sharpless asymmetric dihydroxylation was used toset the C(2) stereocenter present in both targets. In like fashion,coupling of the (+)-prunustatin A macrolide amine with benzoicacid furnished a JBIR-04 diastereoisomer whose NMR spectradid not match those of JBIR-04, thus confirming that it hasdifferent stereochemistry than (+)-prunustatin A.

Bioaccumulative characteristics of hexabromocyclododecanes in freshwater species from an electronic waste recycling area in China

Hexabromocyclododecanes (HBCDs) are now emerging ubiquitous contaminants due to their wide usage, persistence and toxicities. To investigate the bioaccumulative characteristics of HBCDs, sediments, Winkle (Littorina littorea), crucian carp (Carassius carassius) and loach (Misgurnus anguillicaudatus) were collected from two streams near an E-waste dismantling site in China. and HBCD exposure test was then conducted on Chinese rare minnow. The concentration of HBCDs was 14 ng g(-1) dry weight in sediments, 186. 377 and 1791 ng g(-1) lipid weight in winkle, crucian carp and loach, respectively. gamma-HBCD was found to be the dominant diastereoisomer in the sediments (63% of total HBCDs). However, alpha-HBCD was selectively accumulated in the biotic samples and contributed to 77%, 63% and 63% of total HBCDs in winkle, crucian carp and loach, respectively. Moreover, an enrichment of (-)-enantiomers of alpha- and gamma-HBCD were found in the winkle. The reverse results were observed in the crucian carp and loach. Similar observations of diastereoisomeric and enantiomeric composition were obtained in Chinese rare minnow with those found in the crucian carp and loach. These results indicate that the freshwater species from the streams are contaminated by HBCDs. alpha-HBCD can be selectively accumulated in organisms and the accumulative characteristics are enantioselective among species. (C) 2009 Elsevier Ltd. All rights reserved.

Chiral Salan Aluminium Ethyl Complexes and Their Application in Lactide Polymerization

Synthetic routes to aluminium ethyl complexes supported by chiral tetradentate phenoxyamine (salan-type) ligands [Al(OC6H2(R-6-R-4)CH2)(2){CH3N(C6H10)NCH3}-C2H5] 7: R = H ; 5, 8: R = Cl; 6, 9: R = CH3) are reported. Enantiornerically pure salan ligands 1-3 with (R,R) configurations at their cyclohexane rings afforded the complexes 4, 5, and 6 as mixtures of two diastereoisomers (a and b). Each diastereoisomer a was, as determined by X-ray analysis, monomeric with a five-coordinated aluminium central core in the solid state, adopting a cis-(O,O) and cis-(Me,Me) ligand geometry. From the results of variable-temperature (VT) H-1 NMR in the temperature range of 220-335 K, H-1-H-1 NOESY at 220 K, and diffusion-ordered spectroscopy (DOSY), it is concluded that each diastereoisomer b is also monomeric with a five-coordinated aluminium central core.

Quantification of urinary excretion of ethosuximide enantiomers and their major metabolites in the rat.

A chiral gas chromatographic assay has been developed for quantitative analysis of ethosuximide and its major metabolites in rat urine. The extraction procedure was found to be precise and reproducible. Recovery was in the range of 94-98%, intraday CV(%) was 0.92% for (S)-ethosuximide (50 mug/ml) and 0.51% for (R)-ethosuximide (50 mug/ml). Interday CV(%) was 1.12% for (S)-ethosuximide and 0.72% for (R)-ethosuximide. The limit of detection was determined to be around 0.01 mug/ml for each enantiomer. Following administration of rac-ethosuximide by i.v., i.p. and oral routes, unchanged ethosuximide was detected in urine up to 72h after drug administration. The appearance of all detected metabolites occurred Within 24h of drug administration. Significantly more (S)-ethosuximide was excreted unchanged than (R)-ethosuximide with all three routes studied. A substantial amount of the drug was eliminated as the 2-(1-hydroxyethyl)-2-methylsuccinimide (2 pairs of diastereoisomers). Much less drug was eliminated as the 2-ethyl-3-hydroxy-2-methylsuccinimide with only one diastereoisomer observed. Examination of the one pair of diastereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide that was resolved showed preferential excretion of one isomer. Comparison of both pairs of diastereoisomers showed that one pair was formed in preference to the other with a ratio of approximately 0.8:1. It is concluded that stereoselective metabolism of ethosuximide occurs. Copyright (C) 2001 John Wiley & Sons, Ltd. Author Keywords: chiral pharmacokinetics; ethosuximide enantiomers; metabolism; rat; urinary excretion; gas chromatography

Self-assembled triple helicates with preferential helicity

The enantiomerically pure ligands LRR and LSS (N,N'-bis(-2,2'-bipyridyl-5-yl)carbonyl-(1S/R,2S/R)-(+/-)-1,2-diaminocyclohexane) have been synthesised by linking two 2,2'-bipyridine units by (R,R)- and (S,S)-1,2-diaminocyclohexane respectively. The crystal structure confirmed that the ligand had a twisted orientation between the two chelating units. The reaction of LRR and LSS with Fe(II), Co(III), Cd(II) and Zn(II) afforded dinuclear complexes confirmed by ES mass spectroscopy. CD spectroscopy indicated that the chiral diaminocyclohexane conferred helicity to the metal centre giving a dominant triple helicate diastereoisomer, with the LRR ligand giving a delta-configuration of each metal centre (P helicate) and the LSS ligand a lambda configuration (M helicate). 1H NMR spectroscopy confirmed a dominant major diastereoisomer with cadmium. The Zn(II) and Cd(II) complexes however were observed to undergo rapid ligand dissociation in solution.

Chemoenzymatic synthesis of trans-dihydrodiol derivatives of monosubstituted benzenes from the corresponding cis-dihydrodiol isomers

Enantiopure trans-dihydrodiols have been obtained by a chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites, obtained by dioxygenase-catalysed arene cis-dihydroxylation at the 2,3-bond of monosubstituted benzene substrates. This generally applicable, seven-step synthetic route to trans-dihydrodiols involves a regioselective hydrogenation and a Mitsunobu inversion of configuration at C-2, followed by benzylic bromination and dehydrobromination steps. The method has also been extended to the synthesis of both enantiomers of the trans-dihydrodiol derivatives of toluene, through substitution of a vinyl bromine atom of the corresponding trans-dihydrodiol enantiomers derived from bromobenzene. Through incorporation of hydrogenolysis and diMTPA ester diastereoisomer resolution steps into the synthetic route, both trans-dihydrodiol enantiomers of monohalobenzenes were obtained from the cis-dihydrodiols of 4-haloiodobenzenes.

The stereoselective coordination chemistry of the helicating ligand N,N '-bis(-2,2 '-dipyridyl-5-yl)carbonyl-(S/R,S/R)-1,2-diphenylethylenediamine

Enantiomerically pure N,N'-bis(-2,2'-dipyridyl-5-yl)carbonyl-(S/R,S/R)-1,2-diphenylethylenediamine has been synthesised by linking two 2,2'-bipyridine units by (R,R)- and (S,S)-1,2-diphenylethylenediamine. The ligands possess a hindered rotation between the bipyridine chromophores, which are held together by intramolecular hydrogen bonds. ES mass spectroscopy confirmed that reaction with Fe(II), Co(III) and Cd(II) afforded dinuclear complexes. CD spectroscopy implied that enantiopure ligands conferred helicity to the metals centre giving a dominant triple helicate diastereoisomer (with the RR isomer giving a P helicate). H-1 NMR spectroscopy of the cadmium complex confirmed the presence of a single diastereoisomer. (C) 2003 Elsevier B.V. All rights reserved.

Multi component coupling reactions of N-acetyl-2-azetine

N-Acetyl-2-azetine undergoes Lewis acid catalysed formal [4+2]-cycloaddition with imines derived from aromatic amines to initially give an approximately 1: 1 mixture of exo-endo-diastereoisomeric 1-(2a,3,4,8b-tetrahydro-2H-1,4-diaza-cyclobuta[a]naphthalen-1-yl)-ethanone cycloadducts which were detected by proton NMR spectroscopy. These products, which were too unstable to isolate, and characterise, reacted further with aromatic amines to give 2,3,4-trisubstituted tetrahydroquinolines in good to excellent yield, predominantly as a single diastereoisomer, with the minor diastereoisomer converting to the major diastereoisomer on silica. The cycloaddition was irreversible and a mechanism is presented for the formation of the major diastereoisomer from the mixture of diastereoisomeric intermediates. A range of conditions is described for converting the 2,3,4-trisubsitituted tetrahydroquinolines into 2,3-disubstituted quinolines.

Three component coupling reactions of N-acetyl-2-azetine-rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines

N-Acetyl-2-azetine undergoes Lewis acid catalysed [4 + 2]-cycloaddition with imines derived from aromatic amines and gave a 1:1 mixture of exo-endo diastereoisomeric azetidine cycloadducts which reacted further with aromatic amine, to give 2,3,4-trisubsitituted tetrahydroquinolines in good to excellent yield, predominantly as one diastereoisomer.

Expedient synthesis of (+)-trans-5-allylhexahydroindolizidin-3-one

Treatment of the bicyclic iminium ion derived from 5-methoxyhexahydroindolizidin-3-one with allyltrimethylsilane gave exclusively the diastereoisomer in which the allyl group was axial. This substrate is a useful precursor to 5-propyl-3-alkylindolizidine alkaloids. (C) 1999 Elsevier Science Ltd. All rights reserved.

Influence of alpha-helicity, amphipathicity and D-amino acid incorporation on the peptide-induced mast cell activation

Mast cell activation by polycationic substances is believed to result from a direct activation of G protein alpha subunits and it was suggested that the adaption of amphipathic, alpha-helical conformations would allow the peptide to reach the cytosolic compartment to interact with G proteins (Mousli et al., 1994, Immunopharmacology 27, 1, for review). We investigated the histamine-releasing activity of model peptides as well as analogues of magainin 2 amide and neuropeptide Y with different amphipathicities and alpha-helix content on rat peritoneal mast cells. Amphipathic helicity is not a prerequisite for mast cell activation. Moreover, non-helical magainin peptides with high histamine-releasing activity were less active in the liberation of carboxyfluoresceine from negatively charged liposomes, indicating that peptide-induced mast cell activation and peptide-induced membrane perturbation do not correlate. In contrast to the negligible influence of the secondary structure, amino acid configuration may exert a striking influence on peptide-induced mast cell activation. Thus histamine-release by substance P was markedly impaired when the L-amino acids in the positively charged N-terminal region were replaced by D-amino acids, with [D-Arg(1)]substance P being the most inactive substance P diastereoisomer.

Convergence of products from Povarov and von Miller reactions: approaches to helquinoline

Yttrium triflate or triflic acid catalysed Povarov reaction of methyl anthranilate with ethyl vinyl ether, both as aldehyde surrogate and as alkene, gave the desired 2-methyl-4-ethoxytetrahydroquinoline diastereoisomers as the major products along with four component coupling von Miller adducts. A proton NMR-study, using yttrium triflate as catalyst, revealed that the cis-diastereoisomers were the initial major products in both the Povarov and von Miller reactions but that these isomerised to the trans-diastereoisomers under the reaction conditions. Two distinct pathways for forming von Miller adducts were uncovered with the initial Povarov products being converted to von Miller adducts under the reaction conditions. Replacement of the 4-ethoxy with a 4-methoxy group under acidic conditions gave predominantly the trans-diastereoisomer, which was subsequently converted to a cis/trans mixture of the tetrahydroquinoline antibiotic helquinoline. It was also possible to convert the von Miller products to Povarov products under acidic conditions

On the halogenation of N(1),N(2)-di-t-Boc-5-hydroxy-piperazic acid esters and the conformational preferences of their 5-halo-piperazic acid products. The importance of A1,3 rotameric-strain in determining N(2)-acyl piperazic acid ring conformation

In this Letter, an unambiguous synthetic strategy is reported for the preparation of enantiomerically purecis-5-halo-piperazic acid derivatives in single diastereoisomer form. Contrary to the recent report by Shin and co-workers (Chem. Lett. 2001, 1172), in which it is claimed that the Ph₃P and N-chlorosuccinimide (NCS)-mediated chlorination of (3R,5S)-trans-N(1),N(2)-di-t-Boc-5-hydroxy-piperazic acid derivative 1proceeds with retention of configuration at C(5) to give 2, we now show that this and related Ph₃P-mediated halogenations all occur with S_N2 inversion at the alcohol center, as is customary for such reactions. Specifically, we demonstrate that the (3R,5S)-trans-5-Cl-piperazic acid derivative 2 claimed by Shin and co-workers (Chem. Lett. 2001, 1172) is in actual fact the chlorinated (3S,5R)-enantiomer 6, which must have been prepared from the cis-(3S,5S)-alcohol 3, a molecule whose synthesis is not formally described in the Shin paper. We further show here that the cis-(3R,5R)-5-Cl-Piz 13 claimed by Shin and co-workers inChem. Lett. 2001, 1172, is also (3S,5R)-trans-5-Cl-Piz 6. Authentic 13 has now been synthesized by us, for the very first time, here. Since Lindsley and Kennedy have recently utilized the now invalid Shin and co-workers’ retentive Ph₃P/NCS chlorination procedure on 1 in their synthetic approach to piperazimycin A (Tetrahedron Lett. 2010, 51, 2493), it follows that their claimed 5-Cl-Piz-containing dipeptide 25 probably has the alternate structure 26, where the 5-Cl-Piz residue has a 3,5-cis-configuration. The aforementioned stereochemical misassignments appear to have come from a mix-up of starting materials by Shin and co-workers (Chem. Lett. 2001, 1172), and an under-appreciation of the various steric and conformational effects that operate in N(2)-acylated piperazic acid systems, most especially rotameric A^1,3-strain. The latter has now been unambiguously delineated and defined here under the banner of the A^1,3-rotamer effect.

Synthèse stéréosélective de motifs polypropionates via la chimie des radicaux : application à l'élaboration de l'hémisphère ouest de la narasine

Cet ouvrage traite principalement de la synthèse de motifs polypropionates de type stéréopentade ainsi qu’une application à la synthèse d’une molécule naturelle possèdant des propriétés biologiques. La stratégie envisagée pour l’élaboration de ces motifs récurrents dans plusieurs structures d’origine naturelle fait appel à la chimie des radicaux. Cette thèse se divise en différents chapitres dans lesquels la versatilité de la méthodologie développée sera démontrée. En premier lieu, il sera question de présenter l’importance de la synthèse de motifs polypropionates. Le domaine couvert par la chimie de ces molécules complexes hautement fonctionnalisées a contribué énormément à l’avancement de nos connaissances en synthèse organique, particulièrement dans le contexte des réactions impliquant des molécules acyliques. Une brève description des méthodes connues est présentée afin de saisir l’étendue des défis restants pour construire efficacement tous les isomères possibles des polypropionates de type stéréopentade. La stratégie proposée est basée sur une approche contrôlée entièrement par le substrat. Ce contrôle s’appuie sur le choix judicieux de l’acide de Lewis activant les deux réactions impliquées, soit la réaction de Mukaiyama et le transfert d’hydrogène. La seconde section de cette thèse concerne principalement le développement d’une réaction de Mukaiyama impliquant un éther d’énol silylé portant un lien pouvant être homolytiquement brisé dans la réaction suivante et un aldéhyde de type propionate. Le contrôle de l’aldolisation provient de la nature de l’acide de Lewis. Une espèce monodentate (BF3·OEt2) génère une relation 3,4-syn selon le modèle dit Felkin-Anh tandis que les acides de Lewis bidentates mènent à la relation 3,4-anti via un état de transition définit comme Cram-chélate. Une optimisation des conditions réactionnelles en variant l’acidité et la stoechiométrie de l’acide de Lewis de titane a permis de construire diastéréosélectivement le produit de Mukaiyama ayant une relation 3,4-anti. En outre, la nature des complexes impliqués dans ces réactions a été élucidée par des études RMN 13C à basse température. Une fois les précurseurs radicalaires synthétisés, notre méthodologie de réduction par transfert d’hydrogène contrôlée également par les acides de Lewis s’avère très efficace. Les acides de Lewis dérivés d’aluminium mènent sélectivement à la relation 2,3-syn selon un contrôle endocyclique tandis que les acides de Lewis de bore permettent la création des relations 2,3-anti en se basant sur une stabilisation par les divers facteurs de contrôle de molécules acycliques. Cette stratégie novatrice nous a ainsi permis de construire efficacement les 16 diastéréoisomères possibles. Le chapitre suivant concerne l’application de cette méthodologie à la synthèse de l’hémisphère ouest de la salinomycine et de la narasine. Plusieurs défis synthétiques ont été relevés à cette occasion par la présence de nombreux centres stéréogènes contigus. Nous avons réalisé que la relation stéréochimique 2,3-anti de la salinomycine n’est pas accessible sélectivement par la chimie des radicaux via l’effet exocyclique. Des études ont été entreprises afin de comprendre cette perte de sélectivité. Les conclusions suggèrent que les substituants sur le cycle imposent un biais conformationnel conduisant à des faibles sélectivités. Une alternative utilisant un réactif de crotylsilane chiral a été développée pour arriver à la molécule cible. Cette situation est différente dans le cas de la narasine où la présence du méthyle sur le carbone en position β du radical bloque efficacement l’approche d’une des faces d’attaque par l’hydrure. Des sélectivités impressionnantes nous ont permis de construire le fragment C1-C9 de la narasine de manière expéditive et efficace. Finalement, l’élongation sélective utilisant à nouveau la séquence d’aldolisation de Mukaiyama/réduction radicalaire suivie d’un couplage de type aldol stéréosélectif conduit au fragment C1-C17 de la narasine (hémisphère ouest)en 19 étapes avec un rendement global de l’ordre de 7 %. En dernier lieu, nous nous sommes penchés sur la réactivité des α-bromo-β- alkoxycétones lors de transfert d’hydrogène. Nous avons découvert que la chimie de ces derniers pourrait s’avérer utile dans le contexte de la synthèse de motifs complexes polypropionates. La présence d’un centre stéréogène de l’autre coté de la cétone semble avoir un impact sur la sélectivité.